Annual Report 2010 - Istituto di Ricerche Farmacologiche Mario Negri

Transcription

IRFMN
PREFACE
ANNUAL REPORT
MARIO NEGRI INSTITUTE, MILAN
www.marionegri.it
DEPARTMENTS
Department of Oncology ………………….………………………….………………………
Department of Environmental Health Sciences ……….………….……….………………
Department of Neuroscience ………………….………………………….…………………
Department of Cardiovascular Research ………………….…………………….…………
Department of Molecular Biochemistry and Pharmacology .…….………….…………
Department of Epidemiology……………………………..…….………….………………..
Department of Public Health.............................................................................
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159
185
235
LABORATORIES AND CENTERS
Laboratory of Regulatory Policies ……….………………………..……….………….………
Centre of Computer Science Engineering………………………………………….…………
Italian Cochrane Center …….….………………………………………………………………
The Catullo and Daniela Borgomainerio Center……………………………………………
Library ……….….…………………………………………………………….………….…………
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269
273
281
283
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73
NEGRI BERGAMO LABORATORIES
DEPARTMENTS
Department of Molecular Medicine ……….……………………………………….………… 289
Department of Biomedical Engineering……….……………………………………………… 309
Laboratory of Biology and Therapy of Metastasis…………………………………….. 327
ALDO and CELE DACCO’ CENTER
DEPARTMENT
Department of Renal Medicine…………….…………………………………………………… 331
LABORATORIES AND CENTERS
Rare Diseases Documentation and Research..................................................…..… 359
International Relations Office of rare Diseases........................................................ 371
T he Transplant Research Center…………….………………………………………………… 377
EDUCATIONAL ACTIVITIES
379
STAFF
383
All the staff of the Institute is listed on its website www.marionegri.it
PUBLICATIONS
A comprehensive list of the Institute’s publications is available on the www.marionegri.it
website – Section Publications
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Edited by Isabella Bordogna
printed May 2011
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PREFACE
This booklet provides a brief description of the research and training work done at the Mario
Negri Institutes in Milan and Bergamo. It is divided by departments, and in some cases by
single laboratories. Details of the results are provided in the text itself, so here we shall just
draw a few general remarks.
This is our first year in the new Milan Headquarters: during this time we devoted most of our
efforts improving the new available technologies. Particularly, we have carried out translational
research following the “mouse clinic” patterns. Nuclear magnetic resonance, micro cat scanner,
ultrasound, Doppler, photon microscope are some of the methodologies used to do research on
human diseases in mice, following the techniques utilized in medical clinic.
This will allow to transfer data in more effective ways, to study more in depth and to use a lower
number of animals in experimental research. Imaging will play an important role, thanks to the
installation of electronic microscopy, of contrast, time- lapse microscopy and atomic force
microscopy. New important technologies will also allow us to develop our proteomics research.
The tendency nowadays is towards widespread use of molecular biology techniques, especially
for studying the mechanism of action of drugs.
In vitro studies are an essential basis for thorough investigations although a significant number
of in vivo experiments are still needed as this is the only mean we have of validating in vitro
findings and establishing models that resemble human diseases as closely as possible. This
has led to a substantial increase in the use of transgenic animals.
The Institute is still concentrating on its traditional research lines: oncology, neurosciences,
cardiovascular and renal diseases, organ transplants, rare diseases – with strong cell biology
and molecular biochemistry connotations. Significant work has been carried out on the
environment and health as a whole. Experimental, clinical and epidemiological research on rare
diseases and orphan drugs is growing all the time.
The Mario Negri Institute strives to develop a multifaceted approach to all these research
themes, ranging from basic research, to pharmacokinetics, pharmacology, controlled clinical
trials, epidemiological analysis and – whenever possible – the epidemiology of services.
So far we have published more than 11.000 articles on peer reviewed scientific journals.
If research is to continue young scientists must be continually trained. Working in the laboratory
not only gives them an outlet for their ideas, but enables them to obtain worthwhile
qualifications by taking part in the Institute’s training schemes, which are recognised by the
Lombardy Region in Italy, or by working for a Ph.D. awarded by the Open University, UK .
Training courses are also available on biomedical statistics, for general practitioners, family
pediatricians, and clinical trial nurses.
A vital part of the Institute’s work involves providing information, at all levels. This is done, in
particular, through the Rare Diseases Information Center, the Center for Information on
Medicinal Drugs and the Website (www.marionegri.it). We also provide information to medical
doctors, nurses, patients’ associations and lay people, through the media and through a
recently developed website: www.partecipasalute.it.
Because research is going through a very difficult time it is vital to be supported by the
Government, by private and public bodies as well as by foundations and private citizens.
Silvio Garattini
Director
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Mario Negri
INSTITUTE FOR
PHARMACOLOGICAL RESEARCH
Milan
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departments and laboratories
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DEPARTMENT OF ONCOLOGY
STAFF
Chief
Maurizio D’INCALCI, M.D.
Oncological Studies Office and Documentation
Scientific Documentalist
Stefania FILIPPESCHI, Chemist
Laboratory of Cancer Pharmacology
Head
Maurizio D’INCALCI, M.D.
Biophysics Unit
Head
Paolo UBEZIO, Phys.D.
Flow Citometry Unit
Head
Eugenio ERBA, Biochem.D
Cancer Clinical Pharmacology Unit
Head
Massimo ZUCCHETTI, Chem.Pharm.D.
Laboratory of Molecular Pharmacology
Head
Massimo BROGGINI, Ph.D.
DNA Repair Unit
Head
Giovanna DAMIA, M.D.
Laboratory of Biology and Treatment of Metastases
Head
Raffaella GIAVAZZI, Biol.Sci.D., Ph.D.
Tumor Angiogenesis Unit
Head
Unit located in Bergamo
Giulia TARABOLETTI, Biol.Sci.D.
Molecular Cancer Therapeutics Unit
Head
Maria Rosa BANI, Biol.Sci.D., Ph.D.
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Laboratory for the development of new pharmacological strategies
Head
Valter TORRI, M.D.
Laboratory of Clinical Trials
Head
Irene FLORIANI, Dr.Sci.Biol., Dr.Stat., Ph.D.
Clinical Trials Informatics and Management Unit
Head
Davide POLI, Phys.D.
Laboratory of Translational and Outcome Research in Oncology
Head
Giovanni APOLONE, M.D.
Gynecology Oncology Unit
Head
Roldano FOSSATI, M.D.
CERP: Center for the Evaluation and Research on Pain
Head
Giovanni APOLONE, M.D.
Oscar CORLI, M.D.
Laboratory of Medical Research and Consumer Involvement
Head
Paola MOSCONI, Biol.Sci.D.
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CURRICULA
Maurizio D'Incalci obtained his Medical Degree cum Laude from the University of Milan in 1977. After
specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of
Genoa, he worked in the Laboratory of Molecular Pharmacology of the National Cancer Institute in
Bethesda, MD, USA. Since 1986 he has been chief of the Laboratory of Cancer Chemotherapy at the
Mario Negri Institute and since 1996 he has become chief of the Department of Oncology at the Mario
Negri Institute.
He has been President of the Pharmacology and Molecular Mechanisms Group of the European
Organization for Research and Treatment of Cancer (EORTC). From 1994 to 1997 he was Chairman of
the New Drug Development Coordinating Committee and from 1997 to 2000 he was chairman of the
Research Division of the EORTC. He has been member of the Board of the EORTC from April 2000 to
2003.
Since 1995 he is member of the Board of Directors of the Nerina and Mario Mattioli Onlus Foundation. From 1997 he is the Preclinical Coordinator of the Southern Europe New Drug Organization (SENDO)
and since 2005 the Chairman of the New Agents Committee (NAC).
From 2006 he is president of the Scientific Committee of the Mario Negri Gynecologic Oncology group
(MaNGO).
From 2007 he is member of the Scientific Committee of the Italian Association for Cancer Research
(AIRC).
From 2009 he is member of the Board of Directors of the Italian Cancer Society (SIC).
From 2010 he is member of the Scientific Committees of the ABO (Application of Biotechnologies in
Oncology) Foundation, a national foundation for cancer research, and of the Buzzi Unicem Onlus
Foundation for the research, diagnosis and cure of malignant mesothelioma.
FHe is on the editorial board of many international cancer-related scientific journals and from September
2000 to December 2010 he is Editor for Experimental Oncology of the European Journal of Cancer. Dr
D'Incalci is author of more than 440 papers on cancer chemotherapy published in peer reviewed
international journals, and of several chapters in books on cancer chemotherapy.
Selected publications
•
Frapolli R., Tamborini E., Virdis E., Bello E., Tarantino E., Marchini S., Grosso F., Sanfilippo R., Gronchi A., Tercero
J.C., Peloso G., Casali P., Pilotti S., D’Incalci M. Novel models of myxoid liposarcoma xenografts mimicking the
biological and pharmacological features of human tumors. Clinical Cancer Res., 16(20): 4958-4967 (2010).
•
Germano G., Frapolli R., Simone M., Tavecchio M., Erba E., Pesce S., Pasqualini F., Grosso F., Sanfilippo R., Casali P.,
Gronchi A., Virdis E., Tarantino E., Pilotti S., Greco A., Nebuloni M., Galmarini C.M., Tercero J.C., Mantovani A.,
D’Incalci M., Allavena P. Anti-tumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells.
Cancer Res., 70(6): 2235-2244 (2010).
•
Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C,
Carminati P, D'Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patient
variability is related to α(1)-acid glycoprotein plasma levels. Eur. J. Cancer, 46: 505-516 (2010)
•
Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P,
D'Incalci M, Pilotti S, Mantovani R. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol
Cancer Ther, 8 : 449-457 (2009).
•
Marchini S, Mariani P, Chiorino G, Marrazzo E, Bonomi R, Fruscio R, Clivio L, Garbi A, Torri V, Cinquini M,
Dell'Anna T, Apolone G, Broggini M, D'Incalci M. Analysis of gene expression in early-stage ovarian cancer
Clin Cancer Res, 14 : 7850-7860 (2008).
•
Grosso F., Jones R.L. Demetri G.D., Judson I.R., Blay J.Y., Le Cesne A., Sanfilippo R., Casieri P., Collini P., Dileo P.,
Spreafico C., Stacchiotti S., Tamborini E., Tercero J.C., Jimeno J., D’Incalci M., Gronchi A., Fletcher J.A., Pilotti S.,
Casali P.G. Efficacy of Trabectedin (ET-743) in advanced pre-treated myxoid liposarcomas. Lancet Oncology, 2007;
8:595-602.
Giovanni Apolone, got his Medical degree in 1982 (Pavia, Italy) and his post-doctoral specializations in
Internal Medicine in 1987 (Pavia, Italy) and Pharmacological Research (1992). He is Head of the
Laboratory of Translational and Outcome Research. He is also Vice-President of the Ethics Committee
of the European Institute of Oncology in Milan (Italy). His main fields of interest are:
• Methodological, ethical and regulatory aspects of clinical research, with special emphasis on oncology
and the cancer pain.
• Health care evaluation with special emphasis on oncology;
• Development and validation of case-mix and patient-reported outcome measures;
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• Education and health promotion research and programs.
He is author or co-author of more than 270 publications, most in International peer-reviewed Journals.
Mean Impact Factor, computed on peer-reviewed papers: 3.2. H-index (from ISI-Web of knowledge,
March 2010): 30. Number of citations: 4111. Average citation per item: 32.37. Number of papers with
>50 citations: 19.
•
Greco M T, Corli O, Montanari M, Deandrea S, Zagonel V, Apolone G, CPOR SG Investigators. Epidemiology and
pattern of care of Breakthrough cancer Pain (BTcP) in a longitudinal sample of cancer patients. Results from the CPORSG. Clin J Pain 2010, e-pub.
•
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Mannucci E, Petroni M L, Villanova N, Rotella C M, Apolone G, Marchesini G, QUOVADIS Study Group. Clinical and
psychological correlates of health-related quality of life in obese patients. Health Qual Life Outcomes 2010 8 : 90.
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Knudsen K A, Brunelli C, Kaasa S, Apolone G, Corli O, Montanari M, Fainsinger R, Aass N, Fayers P, Caraceni A,
Klepstad P, European Palliative Care Research Collaborative (EPCRC), European Pharmacogenetic Study
(EPOS).Which variables are associated with pain intensity and treatment response in advanced cancer patients?
Implications for a future classification system for cancer pain. Eur J Pain 2010, e-pub.
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Gacci M, Corona G, Apolone G, Lanciotti M, Tosi N, Giancane S, Masieri L, Serni S, Maggi M, Carini M. Influence of
serum testosterone on urinary continence and sexual activity in patients undergoing radical prostatectomy for clinically
localized prostate cancer. Prostate Cancer Prostatic Dis 2010 13 : 168-172.
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Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone M V, Detoma P, Giacomin A,
Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta M G, Riva E. Prevalence, incidence and types of mild
anemia in the elderly: the " Health and Anemia" population-based study. Haematologica 2010 95 : 18491856.
Massimo Broggini followed the faculty of Science of the University of Milan, got the specialization in
Biochemistry at Mario Negri Institute, and the PhD degree at the Open University, London,UK.
He worked in the laboratory of Molecular Pharmacology of the National Cancer Institute of Bethesda,
Md, in 1986. From 1991 he is the head of the Molecular Pharmacology Unit of the Mario Negri Institute
and from 1999 he his the head of the Laboratory of Molecular Pharmacology of the same Institute.
His main fields of interest are the study of the mechanism of action of new anticancer agents, the search
of altered proteins and genes in human cancer and the study of oncosuppressor genes. He is member of
the "Pharmacology and Molecular Mechanisms Group" of the European Organisation for the Research
and Treatment of Cancer (EORTC) and of the American Association for Cancer Research. He is in the
Editorial board of the European Journal of Cancer.
He is author of more than 100 articles published in international journals.
•
Floriani I, Garassino MC, Broggini M, Veronese S, Marsoni S, Marabese M, Farina G, Scanni A. Role of cetuximab in
the treatment of patients with NSCLC: are we throwing out the baby with the bath water? J Clin Oncol. 2010 ;28:467.
•
Mazzoletti M, Broggini M. PI3K/AKT/mTOR inhibitors in ovarian cancer. Curr Med Chem. 2010;17(36):4433-47.
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Sala G, Dituri F, Raimondi C, Previdi S, Maffucci T, Mazzoletti M, Rossi C, Iezzi M, Lattanzio R, Piantelli M, Iacobelli
S, Broggini M, Falasca M. Phospholipase Cgamma1 is required for metastasis development and progression. Cancer
Res. 2008 Dec 15;68(24):10187-96.
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Marrazzo E, Marchini S, Tavecchio M, Alberio T, Previdi S, Erba E, Rotter V, Broggini M. The expression of the
DeltaNp73beta isoform of p73 leads to tetraploidy. Eur J Cancer. 2009 Feb;45(3):443-53. Epub 2008 Nov 12.
•
Falasca M, Chiozzotto D, Godage HY, Mazzoletti M, Riley AM, Previdi S, Potter BV, Broggini M, Maffucci T. A novel
inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate. Br J Cancer. 2010 Jan
5;102(1):104-14. PubMed PMID: 20051961;
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Ganzinelli M, Carrassa L, Crippa F, Tavecchio M, Broggini M, Damia G. Checkpoint kinase 1 down-regulation by an
inducible small interfering RNA expression system sensitized in vivo tumors to treatment with 5-fluorouracil. Clin
Cancer Res. 2008 Aug 15;14(16):5131-41.
Irene Floriani got her degree in Biological Sciences at the University of Milan in 1988, her degree in
Biostatistics and Experimental Statistics at the University of Milan in 2003 and her phD in Life Sciences
at Open University of London (UK) in 2005. After ten-year experience in pharmaceutical industry, in
2002 she became Head of the Biometry and Data Management Unit of the Laboratory of Clinical
Research in Oncology and since 2006 she is Head of Laboratory of Clinical Trials. She is President of the
Ethics Committee of the Ospedale Sant’Anna of Como, Vice-President of that of the Fondazione IRCCS
Istituto Neurologico ‘Carlo Besta’ of Milan, and member of further two Ethics Committees. Her main
fields of interest are: statistical aspects of methodology of clinical research with focus on Controlled
Clinical Trials in Oncology; Systematic Overview of the medical literature and Methodological aspects of
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diagnostic test evaluation.
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Floriani I, Garattini S, Torri V. Looking for efficiency rather than efficacy in randomized controlled trials in oncology.
Ann Oncol. 2010 Jul; 21(7):1391–1393.
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Luciani A, Ascione G, Bertuzzi C, Marussi D, Codecà C, Di Maria G, Caldiera SE, Floriani I, Zonato S, Ferrari D, Foa
P. Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and
vulnerable elders survey-13. J Clin Oncol. 2010 Apr 20;28(12):2046-50.
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Floriani I, Torri V, Rulli E, Garavaglia D, Compagnoni A, Salvolini L, Giovagnoni A. Performance of imaging
modalities in diagnosis of liver metastases from colorectal cancer: a systematic cancer: a systematic review and metaanalysis. J Magn Reson Imaging. 2010 Jan;31(1):19-31.
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Floriani I, Garassino MC, Broggini M, Veronese S, Marsoni S, Marabese M, Farina G, Scanni A. Role of Cetuximab in
the Treatment of Patients With NSCLC: Are We Throwing out the Baby With the Bath Water? J Clin Oncol. 2010 Jun
28.
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Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I,
Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAS
codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type
metastatic colorectal cancer. Br J Cancer 2009 101 : 715-721
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Floriani I, Santini D, Torri V, Cremolini C, Falcone A, Loupakis F. Do we need biopsies of metastases for colorectal
cancer patients? Br J Cancer 2009 101 : 374-375
Raffaella Giavazzi got her Biological Sciences degree (1979) at the University of Milan, and her PhD
in Pharmacology at the Mario Negri Institute of Milan (1984), followed by a specialization in
pharmacology (1994) at the University of Milan. From 1981 to 1983 she was a Fellow in the Cancer
Metastasis and Treatment Laboratory, NCI-FCRDC, Frederick, MD, and from 1983 to 1985 Assistant
Professor at the Department of Cell Biology of M.D. Anderson Hospital and Tumour Institute,
University of Texas System Cancer Centre in Houston, TX.
Raffaella Giavazzi’s research interests are in the field of tumour biology and pharmacology. Specifically,
she is studying aspects related to the metastatic process and angiogenesis. She is involved in the preclinical evaluation of new therapeutic strategies against cancer focusing on the angiogenesis inhibitors
and combination therapies.
From 1986 to 1993 she was Head of the Cancer Metastasis Treatment Unit and since 1993 she has been
the Head of the Laboratory of Biology and Treatment of Metastasis at Mario Negri Institute for
Pharmacological Research.
She is also adjutant Professor in Oncology, Medical School-University of Brescia, member of the
Teaching Committee for the PhD course in Physiology-Pharmacology-Molecular and Cellular
Toxicology-University of Siena, member of the Executive Committee at SENDO (Southern Europe New
Drug Development Organization) and member of the Executive Committee of the European Association
for Cancer Research (EACR).
She was consulting scientist for the NCI-Drug Therapeutics Program, USA (1996-2006);
She is a member of the American Association for Cancer Research (AACR), International Metastases
Research Society, EORTC-Screening and Pharmacology Group, European Association for Cancer
Research (EACR), Italian Cancer Society (SIC) of which she was President (2006-2007).
She is on the Editorial Board of international scientific journals such as the European Journal of Cancer,
Journal of Clinical & Experimental Metastasis, and The International Journal of Biological Markers.
She has published approximately 200 articles on “peer reviewed” scientific journals.
•
Borgia B., Rösli C., Fugmann T., Schliemann C., Cesca M., Neri D., Giavazzi R. A proteomic approach for the
identification of vascular markers of liver metastasis. Cancer Research, 70(1):309-18, 2010.
• Rösli C., Borgia B., Schliemann C., Gunther M., Wunderli-Allenspach H., Giavazzi R., Neri D. Comparative analysis of
the membrane protome of closely related metastatic and non-metastatic tumor cells. Cancer Research, 69(13):5406-14,
2009.
• Cesca M., Frapolli R., Berndt A., Scarlato V., Richter P., Kosmehl H., D’Inclaci M., Ryan A.J., Giavazzi R. The effects
of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma.
Neoplasia, 11(11):1155-64, 2009.
• Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through
gene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008.
• Giavazzi R., Bani M.R.,Taraboletti G.: Tumor–host interaction in the optimization of paclitaxel-based combination
therapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481–88, 2007
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Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccardi E., Scanziani E., Eccles S.A., Bani M.R.,
Giavazzi R. The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor,
causing apoptosis of endothelial cells and inhibition of angiogenesis. Clin. Cancer Research 12(6):1839-49, 2006.
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Rybak J.N., Ettore A., Kaissling B., Giavazzi R., Neri D., Elia G. In vivo protein biotinylation for identification of
organ-specific antigens accessible from the vasculature. Nature Methods 2(4):291-98, 2005.
Paola Mosconi got her Biological Science degree (Milan 1982) and the specialisation in Pharmacological
Research (Milan 1984). Paola Mosconi is involved in several national projects on issues pertaining the
patient involvement in care aspects and outcome research. She published more than 300 articles in
leading national and international journals (111), as well as books on issues related to her main areas of
interest.
Significant experiences has been coordinated:
• development of research projects and strategies to involve patients or consumer
associations in health debate, and clinical research, consensus conferences
• training for consumers on quality of information, and methodological aspects of clinical
research;
• studies for estimate the type of information on diseases and treatments received by patients,
mainly in cancer patients; set-up of websites targeted on consumers/patients
www.partecipasalute.it, www.paincare.it, www.fondazionemattioli.it;
• projects on the assessment of Quality of Life in randomised clinical trials or in
epidemiological survey; translation and cultural adaptation of questionnaires for Quality of
Life;
• evaluation of the consumers’ satisfaction with the health services and the care received.
Paola Mosconi has participated as teacher, or coordinator, to the realization of training course
on “Methodological aspects of clinical research” or “Evaluation of quality of life” for health
care professionals and representatives of voluntary associations.
Major present functions
- President of the Ethical Committees of the AUSL Bologna
- Elected member of Associazione per la Ricerca sulla Efficacia della Assistenza Sanitaria - Italian
Cochrane Centre
- Founding member of Europa Donna Italia, the European breast cancer coalition
•
Mosconi P, Colombo C
Fostering a strategic alliance between patients’ associations and health care professionals
J Ambul Care Manage 2010, 33 (3): 223-30.
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Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone MV, Detoma P, Giacomin A,
Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta MG, Riva E
Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia" population-based study
Haematologica 2010; 95(11): 1849-1856
•
Mosconi P, Donati S, Colombo C, Mele A, Liberati A, Satolli R. The Consensus Conference WorkingGroup. Informing
women about hormone replacement therapy: the Consensus conference statement. BMC Woman Health Journal 2009; 9:14
doi:10.11886/1472-6874-9-14
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Mosconi P, Colombo C, Satolli R, Liberati A. PartecipaSalute, an Italian project to involve lay people, patients’ associations
and scientific-medical representatives on the health debate. Health Expectations 10: 194-204, 2007.
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Mosconi P, Poli P, Giolo A, Apolone G. How health consumers feel about clinical research: a questionnaire survey. European
Journal of Public Health 15: 372-379, 2005.
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Mosconi P, Buchanan M, Kyriakides S, Fernandez-Marcos A, Horvatin J, O'Connell D, Zernik N, on behalf of EUROPA
DONNA. EUROPA DONNA: has strength in its heterogeneity. European J Cancer 40: 1145-1149, 2004.
Valter Torri got his Medical degree in 1985 and the specialization in medical Oncology in 1989 at the
University of Milano.
Education: 1985: MD Degree with full honors cum Laude, University of Milano; 1988 Post-Doctoral
Degree in Pharmacological Research, Mario Negri Institute, Milano; 1989 Post-Doctoral Degree in
Medical Oncology, University of Milano; 1989-1991 Research Fellow at the Biometric Research Branch
of Cancer Treatment Evaluation Program, NCI, Bethesda, MD (USA)
Areas of Interest: Statistical aspects of clinical research methodology with focus on Controlled Clinical
Trials in Oncology; Systematic Overview of the medical literature; Methodological aspects of diagnostic
test evaluation.
Present Position: Head of Laboratory of Clinical Research In Oncology, Oncology Department, Mario
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Negri Institute, Milano.
Chronology of Professional Appointments: 1983-1985: Clinical research Fellow in Internal Medicine at
the University Hospital, University of Milan; 1985-1989: Research assistant at the Clinical Trial Unit of
the Laboratory of Clinical Epidemiology, Mario Negri Institute for Pharmacological Research, Milano;
1989-1991: Research fellow at the Biometric Research Branch of Cancer Treatment Evaluation Program,
NCI, Bethesda, MD (USA); 1994: Head of Biometric Unit of the Laboratory of Cancer Clinical
Epidemiology, Oncology Department, Mario Negri Institute for Pharmacological Research, Milano, Italy;
1995 Vice Director of the Italian “Cochrane” Center; 2001: Head of Laboratory of Clinical Research In
Oncology, Oncology Department, Mario Negri Institute, Milano. 2006: Head of Laboratory for the
development of new pharmacological strategies , Oncology Department, Mario Negri Institute, Milano.
Member of Consiglio Direttivo Nazionale dell’Associazione Italiana di Oncologia Medica
Member of Independent data monitoring committee of International Randomised Clinical trials in
NSCLC and ovarian carcinoma
Co-author of more than 160paper published on peer reviewed journals and of 5 chapters of scientific
books relative to clinical research methodology for therapeutic and diagnostic studies.
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Rossi A, Garassino MC, Cinquini M, Sburlati P, Di Maio M, Farina G, Gridelli C, Torri V. Maintenance or consolidation
therapy in small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer. 201;70(2):119-28.
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Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, Ribic
C, Grothey A, Moore M, Zaniboni A, Seitz JF, Sinicrope F, Gallinger S. Defective mismatch repair as a predictive marker for
lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010 Jul 10;28(20):3219-26. Epub 2010
May 24. Erratum in: J Clin Oncol. 2010 ; 28(30):4664. 3.
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Floriani I, Garattini S, Torri V. Looking for efficiency rather than efficacy in randomized controlled trials in oncology. Ann
Oncol. 2010 21(7):1391-3. Epub 2010 May 25. PubMed PMID: 20501504.
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Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A,
Roncalli M, Malesci A. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of postsurgical metastasis: a longitudinal study. Lancet Oncol. 2009; 10 (9): 877-84.
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Garassino MC, Borgonovo K, Rossi A, Mancuso A, Martelli O, Tinazzi A, Di Cosimo S, La Verde N, Sburlati P, Bianchi C,
Farina G, Torri V. Biological and clinical features in predicting efficacy of epidermal growth factor receptor tyrosine kinase
inhibitors: a systematic review and meta-analysis. Anticancer Res. 2009; 29 (7): 2691-701.
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Torri V: Clinical trials and data management In: Oxford textbook of oncology, 2nd. ed. Vol. 1. Oxford Univ. Press, Oxford;
2002 : 1123-1134
Maria Rosa Bani got her Biological Sciences degree at the University of Milan in 1998 attaining the
Italian Government Qualification to practice as Biologist in 1990. She obtained the specialization in
Pharmacological Research from the Department of Education of the Regional Government of
Lombardia in 1991 and the specialization in Biomedical Research from the Department of Education of
the Regional Government of Abruzzo in 1993.
In 2005 she was awarded the degree of Doctor of Philosophy (PhD), Discipline of Life Sciences of the
Open University Research School (UK).
From 1991 to 1995 she was a Post Doctoral Fellow at the Cancer Research Division, Sunnybrook Health
Science Centre, University of Toronto (Canada); from 2000 to 2001 she was Guest Scientist at the
Advance Technology Centre, National Cancer Institute, National Institute of Health (USA).
From 1996, she was a Fellow Research Scientist at the Mario Negri Institute for Pharmacological
Research, Laboratory of Biology and Treatment of Metastasis and she became a staff research scientist
in 2003. Since 2004 she was appointed Head of the Molecular Cancer Therapeutics Unit in the same
laboratory.
She has been the Scientific Manager of STROMA (since 2004) and ADAMANT (since2008), two
Integrated Projects funded in the 6th and 7th Framework Programs of the European Commission.
She is a member of the American Association for Cancer Research (AACR), the European Association
for Cancer Research (EACR) and the Italian Cancer Society (SIC).
Maria Rosa Bani research interests are in the field of cancer biology and therapeutics, with a focus on
molecular studies of the malignant progression and on the preclinical efficacy of therapeutics modalities.
She is co-author of 36 peer reviewed publications, 2 book chapters and 67 abstracts of which 15 selected
for oral presentations at international meetings.
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Silini A., Ghilardi C., Ardinghi C., Bernasconi S., Carraro F., Naldini A., Bani M.R., Giavazzi R. Protease-activated
receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype. Clinical
Experimental Metastasis, 27 (1) : 43-53, 2010
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Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through
gene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008.
Giavazzi R., Bani M.R.,Taraboletti G.: Tumor–host interaction in the optimization of paclitaxel-based combination
therapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481–88, 2007.
Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccardi E., Scanziani E., Eccles S.A., Bani M.R. &
Giavazzi R. The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor,
causing apoptosis of endothelial cells and inhibition of angiogenesis. Clinical Cancer Research 12: 1839-1849, 2006.
Bani M.R., Nicoletti M.I., Alkharouf N.W., Ghilardi C., Petersen D., Erba E., Sausville E.A., Liu E.T. and Giavazzi R.
Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Molecular Cancer Therapeutics
3: 111-121, 2004.
Taraboletti G., Sonzogni L., Vergani V., Hosseini G., Ceruti R., Ghilardi C., Bastone A., Toschi E., Borsotti P.,
Scanziani E., Giavazzi R., Pepper M.S., Stetler-Stevenson W.G., Bani M.R. Post-transcriptional stimulation of
endothelial cell matrix metalloproteinases 2 and 1 by endothelioma cells. Experimental Cell Research 258 : 384-394,
2000.
Giovanna Damia obtained her Medical Degree cum Laude from the University of Milan in 1985. After
specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of
Milan, she worked as a post-doctoral fellow in the Laboratory of Experimental Immunology of the
National Cancer Institute, Frederick, USA. She worked as a research fellow in the Laboratory of Cancer
Chemotherapy at the Mario Negri Institute and since April 2003 she has become chief of the DNA Repair
Unit at the Mario Negri Institute. From 1992 to1995 she has been consultant of the General Secretariat of
the Progetto Finalizzato CNR "Applicazioni Cliniche della Ricerca Oncologica". Since September 2005
she is Deputy Editor for Experimental Oncology of the European Journal of Cancer.
Her main fields of interest are: mechanism of action of anticancer drugs, cell cycle checkpoints
and natural compounds.
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Damia G, D'Incalci M. Genetic instability influences drug response in cancer cells. Curr Drug Targets. 2010
Oct;11(10):1317-24.
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Carrassa L, Montelatici E, Lazzari L, Zangrossi S, Simone M, Broggini M, Damia. G. Role of Chk1 in the differentiation
program of hematopoietic stem cells. Cell Mol Life Sci. 2010 May;67(10):1713-22.
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Carrassa L, Sanchez Y, Erba E, Damia G. U2OS cells lacking Chk1 undergo aberrant mitosis and fail to activate the
spindle checkpoint. J Cell Mol Med. 2009 Aug;13(8A):1565-76.
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Ganzinelli M, Carrassa L, Crippa F, Tavecchio M, Broggini M, Damia G. Checkpoint kinase 1 down-regulation by an
inducible small interfering RNA expression system sensitized in vivo tumors to treatment with 5-fluorouracil. Clin
Cancer Res. 2008 Aug 15;14(16):5131-41.
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Tavecchio M, Simone M, Erba E, Chiolo I, Liberi G, Foiani M, D'Incalci M, Damia G. Role of homologous
recombination in trabectedin-induced DNA damage. Eur J Cancer. 2008 Mar;44(4):609-18. Epub 2008 Feb 19.
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Damia G, D'Incalci M. Targeting DNA repair as a promising approach in cancer therapy. Eur J Cancer. 2007
Aug;43(12):1791-801.
Eugenio Erba has obtained his Biological and Biochemistry Analysis Degree at the University of
Urbino. He worked as a research fellow in the Laboratory of Cancer Chemotherapy at the Mario Negri
Institute and since 1984 he is head of the Flow Cytometry Unit in the Department of Oncology at the
Mario Negri Institute of Milan. He has worked as a visiting fellow in the Department of Istochemistry
and Cytochemistry of the University of Leiden, The Netherlands in 1983. Since 1997 he is Teacher of
Post-Graduate Studies in Cytometry at the University of Milan and Co-ordinator and Teacher of PostGraduate Studies in Cytometry for the Italian Cytometry Group. He has been President of the Italian
Cytometry Group from 1999 to 2001. Since 2001 he is member of the Executive Board of the Italian
Cytometry Group.
Scientific areas of interest: studies on the mechanism of action of different compounds with provided
antitumoral activity evaluating the mechanism of cell death and cell cycle phase perturbations induced
on different human cancer cell lines by using flow cytometry. Co-ordinator of working-group in a
quality control study on flow cytometric DNA content analysis in human tumors.
• Urru S.A.M., Veglianese P., De Luigi A., Fumagalli E., Erba E., Gonella Diaza R., Carrà A., Davoli E., Borsello T.,
Forloni G., Pengo N., Monzani E., Cascio P., Cenci S., Sitia R., Salmona M. A new fluorogenic peptide determines
proteasome activity in single cells. J.Med.Chem., 53: 7452-7460 (2010).
• Germano G., Frapolli R., Simone M., Tavecchio M., Erba E., Pesce S., Pasqualini F., Grosso F., Sanfilippo R., Casali P.,
Gronchi A., Virdis E., Tarantino E., Pilotti S., Greco A., Nebuloni M., Galmarini C.M., Tercero J.C., Mantovani A.,
D’Incalci M., Allavena P. Anti-tumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma
cells. Cancer Res., 70(6): 2235-2244 (2010).
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• C. Forni, M Minuzzo, E. Virdis, E. Tamburini, M. Simone, M. Tavecchio, E. Erba, F. Grosso, A. Gronchi, P.Aman, P.
Casali, M. D’Incalci, S. Pilotti , R. Mantovani. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma
tumors. Mol. Ca. Ther. 8(2), 449-57, 2009
• E. Marrazzo, S. Marchini, M. Tavecchio, T. Alberio, S. Previdi, E. Erba, V. Rotter, M. Broggini
The expression of the ΔNp73β isoform of p73 leads to tetraploidy. Eur J Ca 45, 443-53, 2009
• M.Tavecchio, M. Simone, E.Erba, I. Chiolo, G. Liberi, M. Foiani, M. D’Incalci, G. Damia. Role of homologous
recombination in trabectedin-induced DNA damage. Eur. J. Ca 44:609-618 (2008)
• Paulis M., Bensi M., Orioli D., Mondello C., Mazzini G., D’Incalci M., Falcioni C., Radaelli E., Erba E.,
Raimondi E., De Carli L. Transfer of a Human Chromosomal Vector from a Hamster Cell Line to a Mouse
Embryonic Stem Cell Line. Stem Cell , 25:2543-2550 (2007)
Roldano Fossati got his Medical Degree cum Laude from the University of Milan in 1980, his PostDoctoral Degree in Endocrinolgy cum Laude from the University of Verona in 1983 and his PostDoctoral Degree in Medical Statistics from the University of Milan in 1992. He has been consultant at
the Mario Negri Institute since 1983 and, at present, he is head of the Gynecology and Oncology Unit of
the Laboratory of Translational and Outcome Research.
Areas of Interest: Statistical and methodologic aspects of clinical research with focus on Controlled
Clinical Trials in Oncology; Systematic Overview of the medical literature.
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Hogberg T, Signorelli M, de Oliveira CF, Fossati R, Lissoni AA, Sorbe B, Andersson H, Grenman S, Lundgren C,
Rosenberg P, Boman K, Tholander B, Scambia G, Reed N, Cormio G, Tognon G, Clarke J, Sawicki T, Zola P, Kristensen
G. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Eur J
Cancer. 2010 Sep;46(13):2422-31. Epub 2010 Jul 7.
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Signorelli M, Lissoni AA, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R,
Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, Fossati R. Modified Radical Hysterectomy Versus
Extrafascial Hysterectomy in the Treatment of Stage I Endometrial Cancer: Results From the ILIADE Randomized Study.
Ann Surg Oncol. 2009 Oct 16
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Andrea Alberto Lissoni, Nicoletta Colombo, Antonio Pellegrino, Gabriella Parma, Paolo Zola, Dionyssios Katsaros,
Stefania Chiari, Alessandro Buda, Fabio Landoni, Michele Peiretti, Tiziana Dell’Anna, Robert Fruscio, Mauro Signorelli,
Roberto Grassi, Irene Floriani, Roldano Fossati , Valter Torri, Eliana Rulli. A phase II, randomized trial of neoadjuvant
chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide and cisplatin (TIP) versus paclitaxel and
cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap02 Italian Collaborative Study. Annals of Oncology, 20:660-665;2009
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Fruscio R, Colombo N, Lissoni AA, Garbi A, Fossati R, Ieda' N, Torri V, Mangioni C.A phase II randomised clinical trial
comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced
epithelial ovarian cancer: long-term survival analysis. Br J Cancer. 2008 Feb 5;
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Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, Colombo A, Fossati R. Adjuvant chemotherapy vs
radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006 Aug 7;95(3):266-71
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Maggioni A, Benedetti Panici P, Dell'anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E,
Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C.Randomised
study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br
J Cancer. 2006 Sep 18;95(6):699-704.
Davide Poli got his degree in Physics at the University of Milan in 2007 and his specialization in
“Biochemical Research Technician" at the Mario Negri Institute for Pharmacological Research in 2004.
Since 2010 he is Head of Clinical Trials Informatics and Management Unit of the Clinical Trials
Laboratory.
His areas of interest are: design of eCRF in Clinical Trials, new electronic aspects of Clinical Research
especially towards technologies of Web-based Electronic Data Capture, methodology and data
management aspects in Clinical Research.
Selected Publications
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Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group (EGPS), Poli D
“The accuracy and clinical application of predictive models for primary open-angle glaucoma in ocular hypertensive
individuals”
Ophthalmology, Volume 115, Number 11 pp. 2030-2036, November 2008
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Porcu L, Poli D, Torri V, Rulli E, Cropalato di Tullio M, Cinquini M, Bajetta E, Labianca R, Di Costanzo F, Nitti D,
Floriani I
“Impact of recent legislative bills regarding clinical research on Italian ethics committee activity”
Journal of Medical Ethics 2008, Volume 34, pp. 747-750
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Gordon MO, Torri V. Miglior S, Beiser JA, Floriani I, Miller JP, Gao F, Adamsons I, Poli D, D'Agostino RB, Kass MA.
“A validated prediction model for the development of primary open-angle glaucoma in individuals with ocular
hypertension”.
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Ophthalmology, Volume 114, Number 1, pp. 10-19, January 2007
The European Glaucoma Prevention Study (EGPS) Group, Poli D
“Results of the European Glaucoma Prevention Study”.
Ophthalmology, Volume 112, Number 3, pp. 366-375, March 2005
Icon, Torri V, Floriani I, Poli D, Santillo M, Buda A
“Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with
relapsed ovarian cancer: The ICON4/AGO-OVAR-2.2 Trial”.
Lancet 2003; 361: 2099-2106
Giulia Taraboletti got her degree cum laude in Biological Sciences at the University of Pavia
(Pavia, Italy) in 1983, and the specialization in Pharmacological Research at the Mario Negri
Institute, Milano, Italy in 1986. From 1986 to 1988 she was a post-doctoral fellow at the
Laboratory of Pathology, NCI, NIH, Bethesda, MD, and from 1988-1995 research scientist at
Mario Negri Institute in Bergamo, Italy. Since 1995 she is Head of the Unit of Tumor
Angiogenesis, at Mario Negri Institute, in Bergamo. Research interests include tumor
angiogenesis, endogenous inhibitors of angiogenesis (thrombospondin-1) and preclinical studies
of antiangiogenic and vascular disrupting compounds, including tubulin-targeting agents. She is
member of Metatasis Research Society (MRS), American Association for Cancer Research
(AACR), European Association for Cancer Research (EACR), and the Italian Society of
Oncology (SIC). She is on the editorial board of European Journal of Cancer and Current Cancer
Therapy Reviews.
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Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis DS, Stravalaci M, Tomaselli S, Giavazzi R, Rusnati
M, Presta M, Zetta L, Mosher DF, Ribatti D, Gobbi M, Taraboletti G. Non-peptidic thrombospondin-1-mimics as
fibroblast growth factor-2 inhibitors: an integrated strategy for the development of new antiangiogenic compounds. J
Biol Chem, 285: 8733-8742, 2010.
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Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular disrupting activity of tubulin-binding
1,5-diaryl-1H-imidazoles. J Med Chem 52, 7906–7910, 2009.
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Margosio B, Rusnati M, Bonezzi K, Cordes B-lA, Annis DS, Urbinati C, Giavazzi R, Presta M, Ribatti D, Mosher DF,
and Taraboletti G. Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic
domain. Int J Biochem Cell Biol 40: 700-709, 2008.
Giavazzi R., Bani M.R.,Taraboletti G. Tumor–host interaction in the optimization of paclitaxel-based
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combination therapies with vascular targeting compounds. Cancer Metastasis Rev, 26:481–88, 2007.
Martinelli M., Bonezzi K., Riccardi E., Kuhn E., Frapolli R., Zucchetti M., Ryan A.J., Taraboletti G., Giavazzi R.
Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel. Br J
Cancer 97:888-94, 2007.
Margosio B., Marchetti D., Vergani V., Giavazzi R., Rusnati M., Presta M., and Taraboletti G. Thrombospondin-1 as a
scavenger for matrix-associated fibroblast growth factor-2. Blood 102: 4399-4406, 2003.
Paolo Ubezio got his B.Sc. degree in Physics at the University of Milan, in 1982, and the specialisation
in Pharmacological Research Specialist" at the Mario Negri Institute for Pharmacological Research in
1986.
Main activities are: i) Computer simulation of tumor proliferation during/after treatments using models
based on the cell cycle; ii) Development of new methods and data analysis tools in flow cytometry and in
time-lapse imaging of living cells; iii) Optimization of anticancer drug scheduling.
Since 1991 is Head of the Unit of Biophysics at the Mario Negri Institute
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Ubezio, P.; Lupi, M., Branduardi, D.; Cappella, P., Cavallini, E., Colombo, V., Matera, G., Natoli, C., Tomasoni, D.,
D’Incalci, M. (2009) Quantitative assessment of the complex dynamics of G1, S and G2M checkpoint activities. Cancer
Res. 69: 5234-5240
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Valentini, G., D’Andrea, C., Ferrari, R., Pifferi, A., Cubeddu, R., Martinelli, M., Natoli, C., Ubezio, P. and Giavazzi R.
(2008) In-vivo measurement of vascular modulation in experimental tumors using a fluorescent contrast agent.
Photochem. Photobiol. 84:1249-1256.
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Ubezio, P. and Cameron, D. (2008) Cell killing and resistance in pre-operative breast cancer chemotherapy. BMC Cancer
8:201.
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Basse, B., Ubezio, P. (2007) A generalised age and phase structured model of human tumour cell populations both
umperturbed and exposed to a range of cancer therapies. Bull. Math. Biol. 69:1673-90.
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Lupi, M., Matera, G., Natoli, C., Colombo, V., Ubezio, P. (2007) The Contribution of p53 in the Dynamics of Cell Cycle
Response to DNA Damage Interpreted by a Mathematical Model. Cell Cycle 6:943-950.
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Lupi, M., Matera, G., Branduardi, D., D'Incalci M. and Ubezio, P. (2004) Cytostatic and cytotoxic effects of topotecan
decoded by a novel mathematical simulation approach. Cancer Res. 64: 2825-2832.
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Massimo Zucchetti obtained his Chem. Pharm. Degree from the University of Milan in 1982. After
specializing in Pharmacology at the Mario Negri Institute of Milan (1988), he worked in the Laboratory
of Clinical Pharmacology of Department of Oncology at San Giovanni Hospital, Bellinzona, Switzerland
(1988-1990). Since 1996 he has been chief of the Cancer Clinical Pharmacology Unit at the Mario Negri
Institute. He is member of the Pharmacology and Molecular Mechanisms Group of the European
Organization for Research and Treatment of Cancer (EORTC) from 1988 up to date. His main field of
interest are:
- Clinical pharmacology, phase I and Phase II studies
- Analysis of drugs, development of new analytical method, pharmacokinetic and
pharmacodynamic studies in humans in GCP and GLP conditions
- Pharmacokinetic, toxicokinetic and metabolic studies in animals
- Pharmacokinetic drug interaction
Dr Zucchetti is author of more than 90 papers on pre-clinical and clinical cancer chemotherapy published
in peer reviewed international journals.
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Sala F., Marangon E., Bagnati R., Livi V., Cereda R., D’Incalci M., Zucchetti M. Development and validation of a
HPLC-MS/MS method for the determination of the novel proteasome inhibitor CEP-18770 in human plasma and its
application in a clinical pharmacokinetic study. J Mass Spectrom. 2010; 45: 1309-15.
Frapolli R., Zucchetti M., Sessa C., Marsoni SA., Viganò L., Locatelli A., Rulli E., Compagnoni A., Bello E., Pisano C.,
Carminati P., D’Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the intra-patients
variability is related to α1-acid glycoprotein plasma levels. Eur J Cancer 2010, 66:635-41
Sala F., Zucchetti M., Bagnati R., D’Incalci M., Pace S., Capocasa F., Marangon E. Development and validation of a
HPLC-MS/MS m,ethod for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in
human plasma of patients partecipatig in a phase I study. J Chromatogr B: Anal. Tecnol. Biomed. Life Sci. 2009; 31: 1826.
Gambacorti-Passerini CB, Tornaghi L, Marangon E, Franceschino A, Pogliani EM, D'Incalci M, Zucchetti M.. Imatinib
concentrations in human milk Blood. 2007 Feb 15;109(4):1790.
Marangon E, Sala F, Caffo O, Galligioni E, D'Incalci M, Zucchetti M. Simultaneous determination of gemcitabine and
its main metabolite, dFdU, in plasma of patients with advanced non-small-cell lung cancer by high-performance liquid
chromatography-tandem mass spectrometry. J Mass Spectrom. 2008 Feb;43(2):216-23.
Frapolli R., Marangon E., Zaffaroni M., Colombo T., Falcioni C., Bagnati R., Simone M., D’Incalci M., Manzotti C.,
Fontana G., Morazzoni P., Zucchetti M. Pharmacokinetics and metabolism in mice of IDN 5390 (13-(N-Boc-3-ibutylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III), a new oral C-seco-taxane derivative with antiangiogenic property
effective on paclitaxel-resistant tumors. Drug Metabolism and Disposition, 34(12):2028-2035 (2006).
ACTIVITIES
The Oncology Department comprises three preclinical experimental laboratories (Laboratory of
Cancer Pharmacology, Laboratory of Molecular Pharmacology and Laboratory of Biology and
Treatment of Metastases) and four laboratories dealing with clinical research and clinical trials
(Laboratory for the Development of New Pharmacological Strategies, Laboratory of Clinical
Trials, Laboratory of Translational and Outcome Research in Oncology and Laboratory for
Medical Research and Consumer Involvement). The Oncology department hosts the
coordination center of two networks of hospitals that carry on clinical research in gynecologic
cancer (MaNGO: Mario Negri Gynecologic Oncology) and in cancer pain (CPOR-SG: Cancer
Pain Outcome Research Study Group) and a center for cancer pain assessment and research
(CERP:Center for the Evaluation and Research on Pain). In some cases research projects are
carried out by single laboratories or research units, in other cases by collaborations between
different laboratories of the Oncology Department or other departments, or other groups outside
the Institute (see National and International Collaborations).
Preclinical laboratories focus on the discovery and development of new antitumor and
antimetastatic drugs and their new combinations; on tumor biology, not only to acquire new
scientific knowledge, but particularly as a base for more selective therapeutic approaches and to
identify and evaluate experimental models for discovering and studying new drugs or
treatments.
Clinical new drug development involves close participation in the activity of SENDO (Southern
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Europe New Drug Organization) and studies driven by the Laboratory of Cancer Pharmacology,
the Laboratory of Molecular Pharmacology and the Laboratory of Biology and Treatment of
Metastases. The Laboratory for the Development of New Pharmacological Strategies, the
Laboratory of Clinical Trials, the Laboratory of Translational and Outcome Research in
Oncology and the Laboratory for Medical Research and Consumer Involvement are involved in
the evaluation of the effects of new therapeutic modalities in phase I/II and in phase III
comparative and effectiveness outcome studies.
Outcome Research implies organizing trials to clarify the results of certain health care practices
and interventions in clinical practice. Observational (surveys) and outcome research
(effectiveness) studies are carried out, in collaboration with regional and national health
authorities and other scientific associations.
At the preclinical and clinical level there are studies of various human tumors, with particular
emphasis on ovarian tumors and more recently on soft tissue sarcomas.
MAIN FINDINGS
At nanomolar concentrations, Trabectedin affects the regulatory mechanisms of the
transcription. Cells that are deficient in Homologous Recombination DNA Repair -e.g. with
mutations of BRCA1 or BRCA2 genes- are hypersensitive to the drug Nucleotide excision
repair deficient cells that are hypersensitive to UV rays and to other DNA damaging drugs are
resistant to Trabectedin.
The selective activity of Trabectedin against human myxoid liposarcoma appears related to the
drug ability to modulate the transcription of genes involved in adipocytic differentiation.
Trabectedin modulates the transcription of genes involved in pro-inflammatory mechanisms that
are potentially relevant for tumor growth and progression and inhibits the production of
cytokines and chemokines by macrophages that are tumor associated.
New sarcoma experimental models have been obtained. They will be useful to investigate new
drugs for these diseases.
Use of mathematical models of tumor growth and anticancer treatment to interpret experimental
data and to manage the complexity of underlying biological phenomena.
A new method enabling to perform dynamical measures of cell cycle checkpoint activities in
response to anticancer treatments.
Gene profiling analysis shows specific molecular signatures according to the histotype and
prognosis of stage I ovarian carcinoma.
The expression of a truncated form of p63 (DNp63) increases with the increased malignancy of
ovarian cancer. Patients expressing high levels of DNp63 have a worst prognosis. DNp63
represents therefore a new potential target for selective therapies in this malignancy.
CHK1 downregulation by specific inhibitors or siRNA, increases the antitumor activity of 5fluorouracil in vivo. This effect is particularly evident in p53 deficient tumors indicating that
this combination increases the selectivity of this anticancer agent.
An anthracycline derivative, Nemorubicin, has a peculiar mechanism of action and is active
against tumors resistant to drugs such as cisplatin. A mechanism of resistance against this drug
has been identified, which involves the abrogation of the expression of a nucleotide excision
repair gene.
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The use of combinations of PI3K/akt/mTOR inhibitors acting at different sites of the same
target, induces a pronounced antitumor effect. Mechanistically there is a selective inhibition of
the translation of proteins involved in the cellular growth.
Mutations in the K-RAS gene have a different impact on the response to treatment that is
dependent from the type of aminoacid substitution present at codon 12.
The growth of breast cancer cells in the bones is slowed down by selective c-met inhibitors.
Human umbilical cord-derived stem cells express checkpoints proteins only in specific
differentiation stages. It is likely that this is related to the different susceptibility of the cells.
Identification of genes differentially expressed by tumor isolated endothelial cells, in respect of
healthy tissue endothelial cells. For some of them we demonstrated their expression in human
tumors, in which the protein was associated to vasculature and stromal component..
The vascular endothelial growth factor (VEGF) released by cancer modifies the gene expression
of tumoral microenvironment and response to treatment: in this condition a number of
differentially expressed genes has been identified. We are currently studying, their role in tumor
progression and in affecting the response to therapy.
Soluble VEGFC levels (the main mediator in lymphoangiogenesis) in plasma and ascites
correlate with progression and invasion of ovarian cancer. Preclinical studies are in progress to
assess the antitumor and antimetastatic properties of selective inhibitors of the VEGF/VEGFRs
pathway.
A new antiangiogenic domain of thrombospondin (a physiological inhibitor of angiogenesis)
that binds the angiogenic factor FGF-2 has been identified and characterized. Non peptidic
small molecules, mimetic of this domain, have been identified and are studied as potential
inhibitors of angiogenesis.
A series of proteins preferentially expressed in liver metastases has been identified in vivo
tissue perfusions through mass spectrometric analysis. These proteins could be a potential target
for selective therapies.
Preclinical pharmacokinetic and pharmacodynamic studies have been used to support the
biological and pharmacological rationale for the treatment regimens, which combine
chemotherapeutics and inhibitors of angiogenesis.
The website of the project PartecipaSalute (www.partecipasalute.it) has a very innovative
character in comparison with the other health Italian sites because it introduces and develops
information in a very active way with specific instruments.
A randomized phase III trial has shown that pelvic systematic lymphadenectomy in early
endometrial cancer does not improve overall survival. As pelvic systematic lymphadenectomy
is not devoid of side effects, this trial will spare patients with early endometrial cancer
important early and late surgical morbidities. A twin trial in ovarian carcinoma, published in
2005, came to similar conclusions.
Results from a systematic review of literature and from a prospective epidemiologic study
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IRFMN
suggest that an important proportion of patients with cancer pain (up to 43%) receive an
analgesic treatments that is not appropriate with the intensity of pain
Results from a survey carried out on a national level on a sample of 1801 patients with cancer
pain confirm that in Italy a relevant part of cancer patients does not receive an appropriate
information about their prognosis: physicians reported that according to their knowledge only
31% received information about their prognosis. An independent survey carried out in a
Northern Italian Region confirmed this finding: among 550 patients treated at home for cancer
pain with palliative care , only 58% were classified to be fully aware of their prognosis.
An observational longitudinal study carried out in 110 Italian centers and involving about 1800
patients with metastatic cancer and pain have documented that that in terms of analgesics
effectiveness, that each drugs prescribed by investigators (morphine, fentanyl, buprenorphine
and oxycodone) were able to reduce the intensity of pain of about 2 points on a 11-eleven point
numerical rating scale (p<0.001). The application of specific pe-planned algorithm identified
about 30% cases who were classified as non-responders. Preliminary analyses documented
some differences between drugs in terms of size of the analgesic effect, dosages required and
side effects reported.
A randomized phase III trial has shown that a modified radical (Piver-Rutledge class II)
hysterectomy does not improve survival and locoregional control compared to the standard
extrafascial (Piver-Rutledge class I) hysterectomy in patients with stage I endometrial cancer .
This trial has enrolled 520 patients who have been followed-up for over 5 years
The training and information activity organized with the associations of citizens & patients in
the framework of the PartecipaSalute project has been finalized to the organization of the Parita
task “Participate to the research project with the associations”. Parita is organised to discuss
with the scientific community the grey areas of the medical assistance and clinical research
identified from the patients and their associations, and to develop specific protocols for future
research programs.
NATIONAL COLLABORATIONS
Agenzia Sanitaria Regionale (ASR), Bologna
Agenzia Italiana del Farmaco (AIFA), Roma
Alleanza Contro il Tumore Ovarico (ACTO)
Azienda Sanitaria Locale, Rimini
Azienda Sanitaria Locale, Vercelli
Assessorato Sanità, Regione Emilia Romagna
Associazione Italiana di Oncologia Medica (AIOM)
Azienda Sanitaria Unica Regionale, Regione Marche
Azienda Ospedaliera di Reggio Emilia Arcispedale S. Maria Nuova
Azienda Ospedaliera San Gerardo, Università Milano-Bicocca, Monza
Casa Sollievo della Sofferenza, San Giovanni Rotondo (IRCCS)
CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, Milano
CNR IGBE, Pavia
CNR, Istituto di Chimica del Riconoscimento Molecolare, Milano
Cochrane Collaboration
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ENEA Centro Ricerche, Unità di Tossicologia e Scienze Biomediche, Roma
Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milano
Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milano
Fondazione LUVI, Milano
Fondazione Nerina e Mario Mattioli Onlus, Milano
Fondazione Salvatore Maugeri, Pavia
Fondazione SmithKline (FSK), Milano
Fondo Edo Tempia, Laboratorio di Farmacogenomica, Biella
I.A.S.I., Roma
Istituti Ospitalieri di Cremona
Istituto Clinico Humanitas, Rozzano MI
Istituto Dermopatico dell'Immacolata, Roma
Istituto Ortopedico Galeazzi, Milano
Istituti Ortopedici Rizzoli, Bologna
Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS), CNR, Napoli Istituto
Europeo di Oncologia (IEO), Milano
Istituto di Fisica, Politecnico di Milano
Istituto di Genetica Molecolare CNR, Sezione di Istochimica e Citometria, Pavia
Istituto Nazionale per la Ricerca sul Cancro (IST), Genova
Istituto Nazionale Tumori Fondazione G. Pascale, Napoli
Istituto Neurologico Carlo Besta, Milano
Istituto Regina Elena, Roma
Istituto Superiore di Sanità, Roma
Laboratorio Cell factory, Policlinico di Milano
Ospedale Fatebenefratelli e Oftalmico, Milano
Ospedale San Matteo, Pavia
Ospedale Santa Chiara, Trento
Regione Toscana
Rete Oncologica Lombarda (ROL), Milano
Spedali Civili di Brescia
Università Cattolica del Sacro Cuore, Roma
Università di Bari
Università di Brescia
Università di Catania
Università di Chieti
Università di Milano
Università di Modena e Reggio Emilia
Università di Monza
Università di Padova
Università di Siena
Università di Torino
Università “La Sapienza”, Roma
Zadig, Agenzia di Giornalismo scientifico
INTERNATIONAL COLLABORATIONS
ADAMANT Consortium, IP 7th FP, EC
ARCAGY (Association de Recherche sur les Cancers Gynécologiques), France
Breakthrough Breast Cancer Center, Instutite of Cancer Reasearch, London, U.K.
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Cancer Biomarkers and Prevention Group, University of Leicester, U.K.
Cancer Research UK, London, U.K.
EORTC, Brussels, Belgium
EUROPA DONNA
European Agency for the Evaluation of Medicinal Products (EMEA), London, U.K.
European Association for Palliative Care (EAPC)
European Network of Gynaecological Oncology Trials groups (ENGOT)Eusoma – (European
Society of Breast Cancer Specialist) Florence, Italy
Executive Board of GCIG (Gynecologic Cancer Intergroup)
Frontier science & technology Research Foundation Southern Europe (FSE), Switzerland
Genome Institute of Singapore (GIS), Singapore
German Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Heidelberg,
Germany
Goteborg University, Lundberg Laboratory for Cancer Research, Goteborg, Sweden
Gynecologic Cancer Intergroup (GCIG)
Helios Klinikum Erfurt GmbH, Institute of Pathology, Germany
Institute of Pathology, Friedrich Schiller University, Jena, Germany
Istituto Oncologico della Svizzera Italiana
Johns Hopkins University, USA
Ludwig Institute for Cancer Research, London, U.K.
National Cancer Center, Singapore
Stony Brook University, NY, USA
Massachusetts General Hospital and Harvard Medical School, USA
MD Anderson Cancer Center, Houston, Texas, USA
MRC, London, U.K.
National Cancer Institute (NCI), Bethesda and Frederick, MD, USA
Ospedale San Giovanni, Bellinzona, Switzerland
Paterson Institute for Cancer Research, Manchester, U.K.
Southern Europe New Drug Organization (SENDO), Milan, Italy
Swiss Federal Institute of Technology, Zurich, Switzerland
The Sackler Institute, University College London, U.K.
Tumor Biology and Metastasis Institute of Cancer Research, Sutton, U.K.
University College, London Medical School, London, U.K.
University of Birmingham, U.K.
University of Cincinnati, USA
University of Crete Medical School, Greece
University of Newcastle, U.K.
University of Pau, France
University of Wisconsin, Madison, WI, USA
Kyoto University, Japan
Weizmann Institute of Science, Israel
EDITORIAL BOARD MEMBERSHIP
American Journal of Cancer Research (Maurizio D’Incalci)
Attualità in Senologia (Paola Mosconi)
British Journal of Cancer (Maurizio D’Incalci)
Chemotherapy (Maurizio D’Incalci)
Clinical Experimental Metastasis (Raffaella Giavazzi)
Current Opinion in Oncologic, Endocrine and Metabolic Drugs (Maurizio D’Incalci)
ANNUAL REPORT
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IRFMN
Current Cancer Therapy Reviews (Raffaella Giavazzi, Giulia Taraboletti)
European Journal of Cancer (Maurizio D’Incalci, Giovanna Damia, Raffaella Giavazzi,
Massimo Broggini e Giulia Taraboletti)
Frontiers in Pharmacology (Maurizio D’Incalci)
Health and Quality of Life Outcomes (Giovanni Apolone, Paola Mosconi)
International Journal of Biological Markers (Raffaella Giavazzi)
International Journal for Quality in Health Care (Giovanni Apolone)
Journal of Ambulatory Care and Management (Giovanni Apolone)
Journal of B.U.ON. (Maurizio D’Incalci)
Journal of Cancer Microenvironment (Raffaella Giavazzi)
Journal of Chemotherapy (Raffaella Giavazzi)
Journal of Medicine and the Person (Giovanni Apolone)
Journal of Preventive Medicine anf Hygiene (Giovanni Apolone)
Molecular Cancer Therapeutics (Maurizio D’Incalci)
Oncology Research (Maurizio D’Incalci)
Tumori (Maurizio D’Incalci, Raffaella Giavazzi)
www.PartecipaSalute.it (Paola Mosconi)
PEER REVIEW ACTIVITIES
Acta Orthopaedica, American Journal of Pathology, Annals of Hematology, Annals of
Oncology, Anti-cancer Drugs, Biochemical Pharmacology, BioMed Central Editorial, British
Journal of Cancer, British Journal of Pharmacology, British Medical Journal, Cancer
Chemotherapy and Pharmacology, Cancer Detection and Prevention, Cancer Letters, Cancer
Research, Carcinogenesis, Chemico-Biological Interactions, Clinical & Experimental
Metastasis, Clinical Cancer Research, Cytometry, European Journal of Cancer, European
Journal of Immunology, Faseb Journal, Gynecologic Oncology, Health and Quality of Life
Outcomes, Health Expectations, European Journal of Neurology, Intensive Care Medicine,
International Journal of Biological Markers, International Journal of Cancer, International
Journal of Gynecological Cancer, International Journal for Quality in Health Care, Journal of
Ambulatory Care and Management, Journal of Biological Chemistry, Journal of Biological
Markers, Journal of Cell Biochemistry, Journal of Cellular and Molecular Medicine, Journal of
Chemotherapy, Journal of Clinical Oncology, Journal of Experimental Therapeutics and
Oncology, Journal of Medicinal Chemistry, Journal of Medicine and the Person, Journal of the
National Cancer Institute, Journal of Neurology, Journal of Nucleic Acids, Journal of Preventive
Medicine and Hygiene, Journal of the National Cancer Institute, Leukemia, Molecular Cancer
Therapeutics, Molecular Medicine, Nature Biotechnology, Nature Reviews, Oncology
Research, PharmacoEconomics, PLoS ONE, Psycho-Oncology, Quality of Life Research,
Science, The Patient: patient-centered outcomes research, Tumori, ZEG Centre for
Epidemiology & Health Research.
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
Ethical Committee, Centro di Riferimento Oncologico, Aviano PN, Italy
Ethical Committee, Ente Ospedaliero San Paolo, Milan, Italy
Comitato Etico Fondazione CNAO - Centro Nazionale di Adroterapia Oncologica, Pavia
Comitato Etico Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milano
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IRFMN
Comitato Etico Istituto Clinico Humanitas, Rozzano, MI
Ethical Committee, Istituto Europeo di Oncologia, Milan, Italy
Ethical Committee, Istituto Neurologico Carlo Besta, Milan, Italy
Ethical Committee, Istituto Scientifico Eugenio Medea, Bosisio Parini, Lecco, Italy
Ethical Committee, Ospedale San Gerardo, Monza, Milan, Italy
Ethical Committee, Ospedale Sant’Anna, Como, Italy
Ethical Committee, Ospedale della Valtellina e Valchiavenna, Sondrio, Italy
Ethical Committee, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
Ethical Committee, Azienda USL di Bologna, Italy
Executive Board of GCIG (Gynecologic Cancer Intergroup)
Comitato Scientifico, Fondazione Buzzi Unicem Onlus
Comitato Strategico e di Studio per la Leucemia Linfoblastica Acuta (CSS - LLA)
Comitato Tecnico-Scientifico, Alleanza Contro il Tumore Ovarico (ACTO), Milano
Scientific Committee, Associazione Italiana Ematologia e Oncologia Pediatrica, Monza, Milan,
Italy
Scientific Committee, Pezcoller Foundation, Trento, Italy
Technical-Scientific Commitee, Associazione Italiana per la Ricerca sul Cancro, Milan, Italy
Board of Directors, Fondazione Nerina e Mario Mattioli Onlus, Milan, Italy
Board of Directors, Società Italiana di Cancerologia (SIC)
Board of Directors, Società Italiana di Citometria (GIC)
Directional Council Areas- Centro Cochrane Italiano (CCI), Milan
National Advisory Board 8th World Congress of Psycho-Oncology
Developmental Therapeutics Program, National Cancer Institute (NCI)
Decision Network and Executive Committee, South Europe New Drug Organization (SENDO)
Executive Board, Europa Donna
Executive Committee, European Association for Cancer Research (EACR)
Fondazione Attilia Pofferi, Pistoia, Italy
NHS R&D National Coordinating Centre for Health Technology Assessment, UK
Pezcoller Foundation-ECCO Award
University Medical School of Siena, Italy
EVENT ORGANIZATION
Investigators’ meeting: Studio clinico randomizzato e controllato, in aperto, per comparare
l’efficacia analgesica di percorsi terapeutici effettuati con ossicodone, fentanyl e buprenorfina
verso morfina, in pazienti con dolore associato a cancro di intensità moderata-severa, a partire
dal momento in cui iniziano il trattamento con 3° scalino della scala analgesica del WHO.
STUDIO CERP, Milan, April 13, 2010.
Conference: International Clinical Trials’ Day 2010. Quale ricerca per quale salute? La
centralità di cittadini & pazienti nel dibattito sulla dimensione sociale della salute. Milan, May
19, 2010.
Meeting: “Nuovi farmaci in ginecologia oncologica” e 7° Assemblea Gruppo MaNGO, Milan,
June 18-19, 2010.
Meeting: V edizione percorso di formazione PartecipaSalute - “Orientarsi in salute e sanità”.
Rimini, October-September 2010.
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IRFMN
Conference: XXVIII Conferenza Nazionale di Citometria - Scuola Nazionale di Citometria,
Corsi residenziali di formazione e aggiornamento. Urbino, September 29 –October 2 2010.
Conference: IV edizione percorso di formazione PartecipaSalute - “L’Accademia del
Cittadino”. Milan - Montecatini Terme, October 2009-March 2010.
Conference: Informarsi, conoscere e partecipare per migliorare la qualità della vita - Il caso di
asma, diabete di tipo 2 e cancro al seno. Milan, November 24, 2010.
Conference: Tumore Ovarico – Primo incontro pazienti, ricercatori e clinici. Alleanza Contro il
Tumore Ovarico (ACTO). Milan, December 3, 2010.
CONFERENCE AND WORKSHOP CONTRIBUTIONS
Conference: International Conference in memory of Judah Folkman - Update on angiogenesis:
translational research. Rome (Italy), January 15-16, 2010.
“Inhibitors of angiogenesis in preclinical models”.
Conference: La chemioterapia metronomica: quale razionale e quali evidenze. Brescia (Italy),
February 26, 2010.
“Inibitori dell’angiogenesi in combinazione con chemioterapici: nuove strategie terapeutiche”.
Conference: CONTACI. Biella (Italy), March 20, 2010.
“Raccontaci: i percorsi di diagnosi e cura, l’esperienza di… Ascoltaci: esperienze di pazienti,
noi contiamo su di voi”.
Meeting: XIV Riunione Scientifica Annuale Italian Sarcoma Group. Pordenone (Italy), March
18-19, 2010.
“Ricerca traslazionale e sviluppo di farmaci per i sarcomi”.
Conference: Stress ossidativo e infiammazione nel malato oncologico. Milan (Italy), March 27,
2010.
“Chemioterapici antineoplastici di origine naturale vegetale nell’era delle terapie mirate”.
Meeting: 4° Meeting Internazionale: Imaging Metabolico PET per una moderna Radioterapia.
Reggio Emilia (Italy), April 16-17, 2010.
“Health Technology Assessment: modelli, strutture ed esperienze”.
“Ipotesi, opportunità e limiti di: Ricerca di Base”.
Course: 9° Corso di formazione avanzata – Cellule staminali tumorali: il vero bersaglio nella
cura dei tumori. Pavia (Italy), April 19-23, 2010.
“Come il paradigma di cellula staminale tumorale (e sua nicchia) indirizza la strategia
terapeutica nella cura dei tumori”.
Conference: 5th International Conference on Thrombosis and Hemostasis Issues in Cancer.
Stresa (Italy), April 23-25, 2010.
“Biology of blood coagulation”.
Simposyum: First EFIC Symposium – Societal Impact Pain (SIP). Brussels (Belgium), May 4-5,
2010.
“Pain undertreatment in oncological patients”.
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IRFMN
Workshop: SIICA - Angiogenesi: basi molecolari ed implicazioni terapeutiche III. Pontignano,
Siena (Italy), May 10-12, 2010.
“F8-IL2 immunocytokine in combination with chemotherapy on melanoma xenograft”.
“Identifying rational combination therapies with inhibitors of angiogenesis and chemotherapy in
cancer treatment”.
“PRSS3/Trypsinogen IV, a potential marker of tumor endothelium and its role in angiogenesis”.
“Tubulin acetylation as a possible mechanism of the antiangiogenic activity of paclitaxel:
implications for combination therapies with HDAC inhibitors”.
“Design of antiangiogenic agents based on the endogenous inhibitor thrombospondin-1”
Congress: V Giornata Novarese di Studio: Malattie dell’apparato uro-genitale maschile e
femminile. Santa Margherita Ligure (Italy), May 15, 2010.
“Dalla diagnosi alla terapia: ruolo e valore dell'HTA (Health Tecnology Assessment)”.
Course: 3rd Course of in vivo Preclinical Assays in Cancer Therapy. Paris (France), May 17-19,
2010.
“Testing anti-angiogenesis drugs in vivo”.
Congress: 10° Congresso Nazionale Associazione Italiana di Miologia. Milan (Italy), June 3-5,
2010.
“La scala SF-36: Perché altri questionari?”.
Meeting: Annual Meeting ASCO. Chicago (USA), June 4-8, 2010.
“Effect of tumor-specific KRAS mutational status on impact of anti-EGFR therapy in non-small
cell lung cancer (NSCLC)”
Conference: Gordon Research Conference: Molecular Mechanisms in Lymphatic Function and
Disease. Lucca (Italy), June 13-18, 2010.
“VEGFC and VEGFR3 in ovarian tumor progression”.
Meeting: MaNGO - Nuovi farmaci in ginecologia oncologica. Milan (Italy), June 18-19, 2010.
“Angiogenesi e anti-angiogenesi”.
Meeting: 21st Meeting of the European Association for Cancer Research. Oslo (Norway), June
26-29, 2010.
“Inflammation and cancer”.
“The FGF-2 binding domain of thrombospondin-1: functional characterization and exploitation
to design
antiangiogenic compounds”.
“Differences in the stroma of human ovarian carcinoma xenografts endowed with different
angiogenic phenotypes”.
Conference: Thrombospondins and matricellular proteins in tissue organization and
homeostasis. FASEB summer research conferences. Snowmass Village (USA), July 18-23,
2010.
“Rational design of antiangiogenic agents based on thrombospondin-1”.
Conference: 9th Global Conference - Making Sense of: Health, Illness and Disease, Oxford
(UK), September 11, 2010.
“Self-rated health: the impact of symptoms in a gender perspective”.
Conference: MRS-AACR Joint Conference on Metastasis and the Tumor Microenvironment.
Philadelphia (USA), September 12-15, 2010.
“Molecular profile of the stroma from human ovarian carcinoma xenografts equipped with
different angiogenic phenotypes”.
ANNUAL REPORT
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IRFMN
Conference: XXVIII Conferenza Nazionale di Citometria - Scuola Nazionale di Citometria,
Corsi residenziali di formazione e aggiornamento. Urbino (Italy), September 29 –October 2,
2010.
“Proliferazione cellulare e apoptosi”.
Meeting: 52nd Meeting della Società Italiana di Cancerologia (SIC). Rome (Italy), October 4-7,
2010.
“Cancer modeling”.
“Combinations of chemotherapy and Bevacizumab in a xenograft model of human ovarian
carcinoma”.
Congress: ESMO. Milan (Italy), October 8, 2010.
“Metabolic approach to the enhancement of antitumor effect of chemotherapy: a key role for
carnitine system” (Simposio Sigma-Tau “Cancer: the bioenergetic challenge”)
“Sorafenib activity in NSCLC cell lines seems related to a different type of K-RAS mutations”
“KRAS mutations differing for aminoacid substitution confer different drug sensitivity and
resistance in NSCLC”.
Congress: 2010 Joint Colloquium of the Cochrane and Campell Collaborations. Keystone
(Colorado, USA), October 18-22, 2010.
“Integrating and deriving evidence, experiences and preferences (IN-DEEP): developing
research-based health information applicable to decision making and self-management by
people with multiple sclerosis”.
“Training for patients and citizens representatives: evaluating the PartecipaSalute courses”.
Meeting: I Cantieri ravennati “Eticità e laicità nella ricerca biomedica”. Ravenna (Italy),
October 23, 2010.
“La ricerca biomedica indipendente”.
Congress: The International Event & Conference on Biotechnologies - Biotech’s promises for
the future: turning challenges into opportunities. Milan (Italy), October 26-28, 2010.
“Angiogenesis inhibitors: from preclinical studies to clinical development”.
Meeting: EORTC-NCI-ASCO Annual Meeting on Molecular Markers in Cancer. Brussels
(Belgium), October 27-29, 2010.
“Role of different types of K-Ras mutations in determining drug sensitivity and tumor behavior
in non-small cell lung cancer”.
Congress: Le biblioteche per pazienti in Italia, esperienze a confronto. Reggio Emilia (Italy),
October 29-30, 2010.
“Fare informazione attraverso la partecipazione: l’esempio del progetto PartecipaSalute”.
Course: Introductory PhD course in translational medicine. Milan (Italy), November 8-12, 2010.
“How to develop an anti-tumor drug, a few examples of success”.
Congress: 3rd European Public Health Conference Integrated Public Health. Amsterdam (The
Netherlands), November 10–13, 2010.
“A community health program to promote women’s knowledge of menopause and hormone
therapy”.
Simposyum: 22nd EORTC-NCI-AACR Symposium. Berlin (Germany), November 16-19, 2010.
“Myxoid liposarcoma tumors with different chimera subtypes xenografted in nude mice are
characterized by different response to trabectedin and gene expression profile”.
“Paclitaxel enhances therapeutic efficacy of F8-antibody mediated delivery of Interleukin-2 to
xenografted melanoma cancer”.
ANNUAL REPORT
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2010
IRFMN
“E-3810, an inhibitor of the VEGF and FGF family receptors, inhibits the FGF-dependent
growth of tumor cells”
“Changes in the transcription regulation mediated by FUS-CHOP gene in a myxoid liposarcoma
cell line resistant to trabectedin”
“Pharmacokinetics (Pk) and pharmacodynamics (Pd) of the novel proteasome inhibitor Cep18770 during a phase I trial in patients with solid tumor, non-hodgkin lymphoma or multiple
myeloma”.
Congress: 27° Congresso Nazionale SIMG. Florence (Italy), November 25-27, 2010.
“Il Progetto SIMG sulla valutazione e gestione del dolore cronico nella Medicina Generale.
Studio di un intervento randomizzato”.
Course: Highlight in oncologia ginecologica. Santa Margherita Ligure (Italy), November 25-27,
2010.
“Molecular Box I”
“Molecular Box II”
Congress: Tumore Ovarico – Primo incontro pazienti, ricercatori e clinici. Alleanza Contro il
Tumore Ovarico (ACTO). Milan, December 3, 2010.
“Cellule tumorali staminali dell’ovaio”.
“Un nuovo progetto di ricerca in collaborazione Ieo/Ifom e Istituto Mario Negri per
l’identificazione dei fattori alla base della sensibilità o resistenza ai farmaci”.
GRANTS AND CONTRACTS
ABO Project SpA
Arcispedale Santa Maria Nuova di Reggio-Emilia
Associazione Italiana Otorinolaringologi Ospedalieri (AOOI)
Associazione Volontarimini - Associazione per lo Sviluppo del Volontariato della Provincia di
Rimini
Azienda Sanitaria Locale, Reggio Emilia
Agenzia Italiana del Farmaco (AIFA)
Amgem SpA, Milano
AIRC Associazione Italiana per la Ricerca sul Cancro
ArQule USA
Astra Zeneca UK
AVAPO (Associazione Volontari Assistenza Pazienti Oncologici)
Azienda Ospedaliera Fatebenefratelli e Oftalmico- Milano
Boehringer
CIPOMO (Collegio Italiano dei Primari Oncologi Medici Ospedalieri)
CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, Milano
Compagnia di San Paolo
Elsevier Science Ltd
EOS SpA
European Commission - 7th Framework Programme (ADAMANT)
European Union (EPOC)
FIRB-MIUR Fondo per gli Investimenti della Ricerca di Base-Ministero Istruzione Università e
Ricerca
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FIRC Fondazione Italiana per la Ricerca sul Cancro
Fondazione Cassa di Risparmio delle Province Lombarde
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Fondazione Lilly
Fondazione Nerina e Mario Mattioli Onlus
Fondazione SmithKline, Roma
FSE Frontier Southern Europe
GISCAD (Gruppo Italiano Studi di Carcinomi Apparato Digerente)
GlaxoSmithKline, Verona
Grunenthal Italia, Milano
Indena SpA
Istituto Europeo di Oncologia
(IOSI) Istituto Oncologico Svizzera Italiana
Istituto Superiore di Sanità
Italfarmaco SpA
Merck Sharp & Dome
Ministero della Salute
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
Oncoethix
OTD - Oncology Therapeutic Development s.a.r.l.
Pfizer Italia
Pharma Mar, SA
Regione Emilia Romagna
Regione Lombardia
Regione Toscana – Formas
Sanofi-Aventis Pharma
SENDO-Tech Srl
Sia-ssb SpA
Sigma-Tau SpA
SIMG Firenze
Università Federico II – Napoli (Dipartimento di Endocrinologia ed Oncologia molecolare e
clinica)
SCIENTIFIC PUBLICATIONS (2010)
Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C,
Carminati P, D'Incalci M
Clinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patient variability is related to α(1)-acid
glycoprotein plasma levels
Eur J Cancer 2010 46 : 505-516
Mosconi P, Taricco M, Bergamini M, Bosisio Fazzi L, Colombo Cinzia, Patrucco V, Corti M, Giobbe D, Guerreschi
M, Magnarella M R, Sallemi G
Family burden of severe brain injury: The Italian experience with families and volunteer associations
Patient 2010 E-pub
Silini Antonietta, Ghilardi A, Ardinghi C, Bernasconi S, Naldini A, Bani M R, Giavazzi R
Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their
metastatic phenotype
Clin Exp Metastasis 2010 27 : 43-53
Borgia B, Roesli C, Fugmann T, Schliemann C, Cesca M, Neri D, Giavazzi R
A proteomic approach for the identification of vascular markers of liver metastasis
Cancer Res 2010 70 : 309-318
ANNUAL REPORT
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IRFMN
Andreis F, Rizzi A, Mosconi P, Braun C, Rota L, Meriggi F, Mazzocchi M, Zaniboni A
Quality of life in colon cancer patients with skin side effects: preliminary results from a monocentric cross sectional
study
Health Qual Life Outcomes 2010 8 : 40
Azzariti A, Porcelli L, Simone G M, Quatrale A E, Colabufo N A, Berardi F, Perrone R, Zucchetti M, D'Incalci M,
Xu J M, Paradiso A
Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences
Cancer Chemother Pharmacol 2010 65 : 335-346
Greco M T, Corli O, Montanari M, Deandrea S, Zagonel V, Apolone G, CPOR SG Investigators
Epidemiology and pattern of care of Breakthrough cancer Pain (BTcP) in a longitudinal sample of cancer patients.
Results from the CPOR-SG
Clin J Pain 2010 E-pub
De Pangher V, Recchia L, Cafferata M, Porta C, Siena S, Giannetta L, Morelli F, Oniga F, Bearz A, Torri V,
Cinquini M
Malignant peritoneal mesothelioma: a multicenter study on 81 cases
Ann Oncol 2010 21 : 348-353
Previdi S, Maroni P, Matteucci E, Broggini M, Bendinelli P, Desiderio M A
Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth
factor/Met and beta-catenin/Wnt pathways
Eur J Cancer 2010 46 : 1679-1691
Zucchetti M, Meco D, Di Francesco A M, Servirei T, Patriarca V, Cusano G, D'Incalci M, Forestieri D, Pisano C,
Riccardi R
Antitumor activity and pharmacokinetics of oral gimatecan on pediatric cancer xenografts
Sabatino M A, Marabese M, Ganzinelli M, Caiola E, Geroni C, Broggini M
Down-regulation of the nucleotide excision repair gene XPG as a new mechanism of drug resistance in human and
murine cancer cells
Mol Cancer 2010 9 : 259
Falasca M, Chiozzotto D, Godage H Y, Mazzoletti M, Riley A M, Previdi S, Potter B V L, Broggini M, Maffucci T
A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate
Br J Cancer 2010 102 : 104-114
Berndt A, Kollner R, Richter P, Franz M, Voigt A, Berndt Angela, Borsi L, Giavazzi R, Neri D, Kosmehl H
A comparative analysis of oncofetal fibronectin and tenascin-C incorporation in tumour vessels using human
recombinant SIP format antibodies
Histochem Cell Biol 2010 133 : 467-475
Floriani I, Torri V, Rulli E, Garavaglia D, Compagnoni A, Salvolini L, Giovagnoni A
Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and
meta-analysis
J Magn Reson Imaging 2010 31 : 19-31
Urru S A M, Veglianese P, De Luigi A, Fumagalli E, Erba E, Gonella Diaza R, Carrà A, Davoli E, Borsello T,
Forloni G, Pengo N, Monzani E, Cascio P, Cenci S, Sitia R, Salmona M
A new fluorogenic peptide determines proteasome activity in single cells
J Med Chem 2010 53 : 7452-7460
Cazzola M, Floriani I, Page C P
The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual
patient data
Pulm Pharmacol Ther 2010 23 : 135-144
Pezzola S, Antonini G, Geroni C, Beria I, Colombo M, Broggini M, Mongelli N, Leboffe L, MacArthur R, Mozzi A
F, Federici G, Caccuri A M
Role of glutathione transferases in the mechanism of brostallicin activation
Biochemistry 2010 49 : 226-235
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Carrassa L, Montelatici E, Lazzari L, Zangrossi S, Simone M, Broggini M, Damia G
Role of Chk1 in the differentiation program of hematopoietic stem cells
Cell Mol Life Sci 2010 67 : 1713-1722
Howells L M, Britton R G, Mazzoletti M, Greaves P, Broggini M, Brown K, Steward W P, Gescher A J, Sale S
Preclinical colorectal cancer chemopreventive efficacy and p53-modulating activity of 3',4',5'-trimethoxyflavonol, a
quercetin analogue
Cancer Prev Res (Phila Pa) 2010 E-pub
Previdi S, Malek A, Albertini V, Riva C, Capella C, Broggini M, Carbone G M, Rohr J, Catapano C V
Inhibition of Sp1-dependent transcription and antitumor activity of the new aureolic acid analogues mithramycin
SDK and SK in human ovarian cancer xenografts
Gynecol Oncol 2010 118 : 182-188
Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis D S, Stravalaci M, Tomaselli S, Giavazzi R,
Rusnati M, Presta M, Zetta L, Mosher D F, Ribatti D, Gobbi M, Taraboletti G
Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for the
development of new antiangiogenic compounds
J Biol Chem 2010 285 : 8733-8742
Sansone V A, Panzeri M, Montanari M, Apolone G, Gandossini S, Rose M R, Politano L, Solimene C, Siciliano G,
Volpi L, Angelini C, Palmieri A, Toscano A, Musumeci O, Mongini T, Vercelli L, Massa R, Panico M B, Grandi M,
Meola G
Italian validation of INQoL, a quality of life questionnaire for adults with muscle diseases
Eur J Neurol 2010 E-pub
Mannucci E, Petroni M L, Villanova N, Rotella C M, Apolone G, Marchesini G, QUOVADIS Study Group
Clinical and psychological correlates of health-related quality of life in obese patients
Health Qual Life Outcomes 2010 8 : 90
Brunelli D, Tavecchio M, Falcioni C, Frapolli R, Erba E, Iori R, Rollin P, Barillari J, Manzotti C, Morazzoni P,
D'Incalci M
The isothiocyanate produced from glucomoringin inhibits NF-kB and reduces myeloma growth in nude mice in vivo
Biochem Pharmacol 2010 79 : 1141-1148
Naldini A, Filippi I, Moschetta M, Giavazzi R, Carraro F
Interleukin-1β regulates the migratory potential of MDAMB231 breast cancer cells through the hypoxia-inducible
factor-1α
Eur J Cancer 2010 46 : 3400-3408
Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S, Pasqualini F, Grosso F, Sanfilippo R, Casali P,
Gronchi A, Virdis E, Tarantino E, Pilotti S, Greco A, Nebuloni M, Galmarini C M, Tercero J C, Mantovani A,
D'Incalci M, Allavena P
Antitumor and anti-inflammatory effects of trabectedin on human mixoid liposarcoma cells
Cancer Res 2010 70 : 2235-2244
Miserocchi E, Modorati G, Mosconi P, Colucci A, Bandello F
Quality of life in patients with uveitis on chronic systemic immunosuppressive treatment
Ocul Immunol Inflamm 2010 18 : 247-254
Frey K, Schliemann C, Schwager K, Giavazzi R, Johannsen M, Neri D
The immunocytokine F8-IL2 improves the therapeutic performance of sunitinib in a mouse model of renal cell
carcinoma
J Urol 2010 184 : 2540-2548
D'Incalci M, Galmarini C M
A review of trabectedin (ET-743): A unique mechanism of action
Mol Cancer Ther 2010 E-pub
Floriani I, Garassino M C, Broggini M, Veronese S, Marsoni S, Marabese M, Farina G, Scanni A
Role of cetuximab in the treatment of patients with NSCLC: are we throwing out the baby with the bath water?
J Clin Oncol 2010 28 : e467
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Cremolini C, Loupakis F, Ruzzo A, Perrone G, Rulli E, Vincenzi B, Tonini G, Graziano F, Onetti Muda A, Falcone
A
Predictors of benefit in colorectal cancer treated with cetuximab: are we getting "Lost in TranslationAL"?
J Clin Oncol 2010 28 : e173-e174
Luciani A, Ascione G, Bertuzzi C, Marussi D, Codecà C, Di Maria G, Caldiera S, Floriani I, Zonato S, Ferrari D,
Foa P
Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and
Vulnerable Elders Survey-13
J Clin Invest 2010 28 : 2046-2050
Rossi A, Garassino M C, Cinquini M, Sburlati P, Di Maio M, Farina G, Gridelli C, Torri V
Maintenance or consolidation therapy in small-cell lung cancer: A systematic review and meta-analysis
Lung Cancer 2010 70 : 119-128
Caffo O, Fallani S, Marangon E, Nobili S, Cassetta M I, Murgia V, Sala F, Novelli A, Mini E, Zucchetti M,
Galligioni E
Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin
in patients with advanced non-small-cell lung cancer
Mosconi P, Colombo Cinzia
Fostering a strategic alliance between patients' associations and health care professionals
J Ambul Care Manage 2010 33 : 223-230
Wale J, Colombo Cinzia, Belizan M, Nadel J
International health consumers in the cochrane collaboration: fifteen years on
J Ambul Care Manage 2010 33 : 182-189
Knudsen K A, Brunelli C, Kaasa S, Apolone G, Corli O, Montanari M, Fainsinger R, Aass N, Fayers P, Caraceni A,
Klepstad P, European Palliative Care Research Collaborative (EPCRC), European Pharmacogenetic Study (EPOS)
Which variables are associated with pain intensity and treatment response in advanced cancer patients? Implications
for a future classification system for cancer pain
Eur J Pain 2010 E-pub
Bertuzzi F, Suzani M, Tagliabue E, Cavaletti G, Angeli R, Balgera R, Rulli E, Ferrarese C, Miglior S
Diagnostic validity of optic disc and retinal nerve fiber layer evaluations in detecting structural changes after optic
neuritis
Ophthalmology 2010 117 : 1256-1264
Sargent D J, Marsoni S, Monges G, Thibodeau S N, Labianca R, Hamilton S R, French A J, Kabat B, Foster N R,
Torri V, Ribic C, Grothey A, Moore M, Zaniboni A, Seitz J - F, Sinicrope F, Gallinger S
Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon
cancer
J Clin Oncol 2010 28 : 3219-3226
Pisano C, Vesci L, Milazzo F M, Guglielmi M B, Foderà R, Barbarino M, D'Incalci M, Zucchetti M, Petrangolini G,
Tortoreto M, Perego P, Zuco V, Orlandi A, Passeri D, Carminati P, Cavazza C, Zunino F
Metabolic approach to the enhancement of antitumor effect of chemotherapy: a key role of acetyl-L-carnitine
Clin Cancer Res 2010 16 : 3944-3953
Gacci M, Corona G, Apolone G, Lanciotti M, Tosi N, Giancane S, Masieri L, Serni S, Maggi M, Carini M
Influence of serum testosterone on urinary continence and sexual activity in patients undergoing radical
prostatectomy for clinically localized prostate cancer
Prostate Cancer Prostatic Dis 2010 13 : 168-172
Corli O, Maltoni M
Pain and bone metastases
In :Osteo-oncology textbook Poletto Editore, Vermezzo (MI), 2010; 277-294
Damia G, D'Incalci M
Genetic instability influences drug response in cancer cells
Curr Drug Targets 2010 11 : 1317-1324
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NSCLC Meta-Analyses Collaborative Group, Torri V
Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two
meta-analyses of individual patient data
Lancet 2010 375 : 1267-1277
Sala F, Marangon E, Bagnati R, Livi V, Cereda R, D'Incalci M, Zucchetti M
Development and validation of a high-performance liquid chromatography–tandem mass spectrometry method for the
determination of the novel proteasome inhibitor CEP-18770 in human plasma and its application in a clinical
pharmacokinetic study
J Mass Spectrom 2010 45 : 1299-1305
Mosconi P, Donati S, Colombo Cinzia, Senatore S
Role of hormone therapy in the management of menopause
Obstet Gynecol 2010 116 : 442
Mazzoletti M, Broggini M
PI3K/AKT/mTOR inhibitors in ovarian cancer
Current Medicinal Chemistry - Anti-Cancer Agents 2010 E-pub
Colombo C, Satolli R, Liberati A, Mosconi P, Giurie dei cittadini Working Group
Citizens' juries in health care
BMJ 2010 341 : c5141
Casciani E, Masselli G, Di Nardo G, Polettini E, Bertini L, Oliva S, Floriani I, Cucchiara S, Gualdi G
MR enterography versus capsule endoscopy in paediatric patients with suspected Crohn's disease
Eur Radiol 2010 E-pub
Catalano M, Scandale G, Minola M, Carzaniga G, Carotta M, Perilli A, Dimitrov G, Cortellazzo A, Cinquini M
Elastic properties and structure of the radial artery in patients with type 2 diabetes
Diab Vasc Dis Res 2010 6 : 244-248
Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone M V, Detoma P, Giacomin
A, Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta M G, Riva E
Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia" population-based
study
Haematologica 2010 95 : 1849-1856
Hogberg T, Signorelli M, Freire de Oliveira C, Fossati R, Lissoni A A, Sorbe B, Andersson H, Grenman S, Lundgren
C, Rosenberg P, Boman K, Tholander B, Scambia G, Reed N, Cormio G, Tognon G, Clarke J, Sawicki T, Zola P,
Kristensen G
Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer - Results from two randomised studies
Eur J Cancer 2010 46 : 2422-2431
Sessa C, D'Incalci M
Trabectedin in ovarian cancer:could we expect more?
Ann Oncol 2010 E-pub
Taraboletti G, Rusnati M, Ragona L, Colombo G
Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of
endogenous inhibitors
Oncotarget 2010 E-pub
Rusnati M, Urbinati C, Bonifacio S, Presta M, Taraboletti G
Thrombospondin-1 as a paradigm for the development of antiangiogenic agents endowed with multiple mechanisms
of action
Pharmaceuticals 2010 3 : 1241-1278
Floriani I, Garattini S, Torri V
Looking for efficiency rather than efficacy in randomized controlled trials in oncology
Ann Oncol 2010 21 : 1391-1393
Colombo C, Mosconi P, Buratti M G, Liberati A, Donati S, Mele A, Satolli R
Press coverage of hormone replacement therapy and menopause
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Eur J Obstet Gynecol Reprod Biol 2010 153 : 56-61
Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, Aglietta M, Lonardi S, Corsi D, Turci D, Beretta G D,
Fornarini G, Dapretto E, Floriani I, Zaniboni A, GISCAD
Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial
Ann Oncol 2010 E-pub
LAY PRESS SELECTION (2010)
Villani W, Mosconi P
Il nuovo MisuraAssociazioni
http://www.partecipasalute.it/cms_2/node/1574 , 21/10/2010
Mosconi P
Un progetto-ricerca di crescita e sviluppo centrato sul paziente: PartecipaSalute
In: Quale salute per chi, a cura di Fede Ruggeri, Franco Angeli/Sanità Editore Ottobre 2010: 127-141
Carra L, Colombo C.
L’informazione in medicina: come destreggiarsi
In: Quale salute per chi, a cura di Fede Ruggeri, Franco Angeli/Sanità Editore Ottobre 2010: 81-105.
Mosconi P, Carra L
‘A salute nun s’accatta ma s’abbusca
Mosconi P
L’anno del girasole pallido
Colombo C
Prima dell’ipertensione, ma già a rischio
Braun C, Mosconi P
Farmaci: la lunga strada per l’autorizzazione all’immissione in commercio
http://www.partecipasalute.it/cms_2/node/1542, 31/8/2010
Mosconi P, Colombo C, Liberati A, Satolli R
Fare empowerment con le associazioni di cittadini e pazienti. L’esperienza di PartecipaSalute.
I Quaderni di Monitor 2010, 25 (Suppl 6): 124-130
Mosconi P, Marsico G, Satolli R, Casali P
Attività formative e progetti collaborativi destinati ai componenti laici dei comitati etici
Mosconi P
Cittadini, pazienti e partecipazione
Bollettino SIFO Volume 56 N° 3 (marzo-aprile 2010): 86-87
Mosconi P
A proposito di farmaci equivalenti
Mia Farmacia Online, marzo 2010: 26-27
Greco M T, Montanari M, Deandrea S, Corli O, Zagonel V, Caraceni A, Apolone G, CPOR SG Investigators
Il dolore nel paziente con cancro: sintesi dei risultati di un progetto quinquennale
Ricerca & Pratica 2010 n.153 : 95-105
Gallus S, Apolone G, Padula A, Casadei G, Motterlini N, Garattini L
"Quaderni di farmacoeconomia" risponde ai lettori
Quaderni Farmacoeconomia 2010 12 : 24-31
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Mercadante S, Amadori D, Apolone G, Arcuri E, Barbato A, Caraceni A, Maltoni M, Marchetti P, Mattia C, Varrassi
G, Zagonel V, Zucco F
Raccomandazioni per la gestione del Breakthrough cancer Pain (BTcP)
Rivista Italiana di Cure Palliative 2010 1 : 17-23
Torri V
Valutazione della risposta clinica
In :Oncologia medica pratica, 3a Ed. Società Editrice Universo, Roma, 2010; 921-930
RESEARCH ACTIVITIES
Laboratory of Cancer Pharmacology
Mode of action of Ecteinascidins
A project ongoing since several years is about the characterization of marine natural products
possessing antitumor activity. In particular we carried on the studies on the effects of ET-743 in
cells defective for some DNA repair mechanisms. Cells deficient for Homologous
Recombination (HR) are very sensitive to the drug, while cells deficient for Non Homologous
End-Joining (NHEJ) are only slightly more sensitive, but surpraisingly cell lines defective for
Nucleotide Excision Repair (NER) are less sensitive to ET-743. Flow cytometric analysis
coupled to a software of computer simulation, developed in our laboratory, has demonstrated
that NER defective cells showed, after ET-743 treatment, cell cycle perturbations different than
those occurring in NER proficient cells, probably for the activation of different and more
efficient repair mechanisms.
We study also a functional evaluation of the DNA repair mechanisms by the cell capacity to
recognize and repair double helix breaks with a recently introduced test that is very sensitive to
detect the phosphorylation of histone H2AX. An in vitro study is ongoing with flow cytometry
and immunofluorescence techniques to evaluate in different tumor cell lines the phosphorylation
level of histone H2AX in relation to the distribution of the cells in the different phases of the
cell cycle and the cytotoxic effect induced after treatment with ET-743.
Studies are in progress on the mechanism of action of new ET-743 derivates compounds that
have shown antitumoral activity on cell lines with different DNA repair mechanisms.
A new project is the study of the selective action of ET-743 on mixoid lyposarcoma, a
pathology representing 10% of all soft tissue sarcomas, trying to understand if the significative
antitumor effect is due to a selective action of the compound on pathogenetic alterations
characteristic of this pathology. In particular we are trying to evaluate how ET-743 interact with
the transcriptional modifications of specific genes due to the translocation FUS-CHOP that
characterizes mixoid sarcomas or those caused by the interaction host-tumor, modifying
inflammatory and angiogenetic processes. Studies are in progress to obtain cell lines and
xenografts of mixoid lyposarcomas exhibiting the same molecular features of the patients’
tumors.
Combinations of natural products of marine origin with other anticancer
drugs
We have observed additive or synergistic activity of ET-743 combined with other anticancer
drugs such as cisplatin, doxorubicin, campthotecin,inhibitors of telomerase, bleomicin and
varinostat.
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Analysis of cell cycle data and interactions of different drugs
The Biophysics Unit is engaged in theoretical and methodological studies aimed at a critical
evaluation of current techniques of investigation of drug effects on heterogeneous cell
populations. Several computing tools have been produced to simulate the cell proliferation at
different levels (from molecular interactions to in vivo growth of solid tumours) and the process
of measure.
Collaborations are ongoing with other research groups for design and data analysis of drug
combination studies in vitro. In this field, a number of computer programs have been developed,
allowing comparative data analysis with the most common models of drug interaction.
Evaluation of the complexity of the response of cell populations to
treatment with anticancer drugs
This project of the Biophysics Unit addresses the issue of establishing a connection between the
intracellular drug interactions and the resulting cell cycle perturbations. It starts from the singlecell level of investigation to reach the cell-population level where the relevant end points of
treatment efficacy are evaluated by flow cytometry and growth inhibition/cytotoxicity assays.
The model adopted for data analysis and interpretation is the result of the merging of two
mathematical models. One model describes the cell cycle, exploiting the results of the theory of
age-structured cell population dynamics. The second model describes the response to the drug's
challenge, using distinct parameters ("effect descriptors") measuring either the strength of cell
cycle arrest, damage repair or cell death in every phase (G1, S and G2M). In this way, it is
possible to reach a quantitative interpretation of the experimental results, overcoming the
current qualitative and partial approaches to this problem, which are unable to resolve the
overlapping of cytostatic and cytotoxic effects, and to establish a connection with phase-related
events.
Cell cycle dYsregulation in erlotinib-based treatments decoded by flow
cytometry and mathematical modeling
Epidermal growth factor receptor (EGFR) inhibitors represent one of the most promising class
of anticancer compounds, some of them, like erlotinib, are already used for clinical therapy.
Nevertheless, so far, the research has focused on molecular interaction of these compounds,
somewhat neglecting the study of the dynamics of cell cycle perturbations and underscoring the
importance of this issue for the optimization of both single and multidrug therapies.
In order to fill this gap, the Biophysics Unit is currently studying in detail the time- and dosedependence of the cell cycleperturbations induced by different treatment schedules of erlotinib
and gemcitabine. The results are expected to disclose the origin of the interactions between the
two drugs and advance towards optimization of the combined treatment.
Anticancer Drug Effects Decoded by Time-Lapse Imaging, Flow Cytometry
and Modeling in silico
We use flow cytometric (cell-population based analysis) and time-lapse imaging (single cell
lineage based analysis) techniques to generate data that will be used to predict drug responses in
term of the major components of cytostatic/cytotoxic actions of anticancer drugs: specific cell
cycle perturbations (detecting accumulation or depletion of cells in G1, S and G2M phases) and
the commitment to cell death (apoptosis).
Time lapse data are currently integrated with those from single and multiparametric flow
cytometric experiments, and univocally interpreted with a common computer program that
renders in silico the proliferation process through the cell cycle and in the cell generations that
follow one another during and after treatment. This kind of dynamic rendering establishes a
connection between the available “macroscopic” data (time-lapse and flow cytometric) and the
activity of molecular pathways which are in charge to the several functions that concur in the
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pharmacological response – with individual timing and dose-dependence-, and which are not
otherwisemeasurable. Final aim is to achieve a quantitative level of understanding of the
dynamics of response to anticancer treatment, enabling a full appreciation of the role and
relative importance of the main cellular functions contributing to the overall response. Methods
and computing tools with intuitive interface developed for these tasks will be shared with the
scientific community.
Clinical pharmacokinetics of E-3810 (a novel inhibitor of angiogenesis)
The phase I clinical trial started in October. In the months before we developed a new method to
measure the drug in human plasma by HPLC-mass-spectrometry in order to study the drug
pharmacokinetic profile in the enrolled patients. The trial showed that this compound, which is
administered orally for 28 consecutive days, provides high plasma exposure reaching drug
concentrations at steady state potentially pharmacologically active after one week of therapy.
Clinical pharmacology of CEP-18770 (a new proteasome inhibitor)
The study in collaboration with SENDO, that was performed in 40 patients, has defined the
pharmacokinetic and the pharmacodynamic profiles of the new proteasoma inhibitor, CEP18770, in patients enrolld in the phase I clinical study. This study evidencied for this compound
a very long plasma half-life assuring a prolonged drug esposition. Pharmacodynamic studies
showed that in patients treated at the recommended dose CEP-18770 caused a significant
inhibition (50%) of the proteasome activity.
Quality assurance program
During the year 2010 we improved the quality assurance program aims to bring the
pharmacokinetic unit, inside the laboratory of Cancer Pharmacology, in compliance with Good
Laboratory Practice (GLP). The first phase has been completed and also the writing of the
operating procedures has been finalized. We hope in this year to end the process of development
and to request GLP certification for the laboratory.
Antitumoral activity and pharmacokinetic properties of new drugs and
combinations
The antitumor activity, pharmacokinetic properties and toxicity of novel anticancer drugs with
specific targets (e.g. different kinase inhibitors), conventional anticancer drugs (taxanes and
camptothecins) and combinations is being investigated using rodent tumors and human tumor
xenografts.
Development of a software framework for a rationalized process of
Microarrays analysis
It is currently active in the Institute a multidisciplinary group involved in the rationalization of
the various microarray analysis aspects, with many external collaborations.
The different possible analysis procedures have been discussed, compared and formalized in
order to obtain a common work flow to be accepted from the scientific community.
Thanks to this activity it is now possible to automate some aspects of the analysis making them
faster end better reproducible for people managing the analysis itself.
This activity has involved the development of the necessary software for data analysis and the
implementation of a Beowulf computer cluster, using the old computers dismissed by the
desktop users in order to obtain a sufficient power.
External collaborations:
Fondo Edo Tempia (ref.: Giovanna Chiorino)
Istituto Toscano Tumori (ref: Duccio Cavalieri)
Aberdeen University (ref. Tony Travis)
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Microarray data analysis for the Oncology Department
The data analysis activities concern the biology of sensible versus resistant to therapy human
ovarian carcinoma and the study of the trabectedin working mechanism in human sarcoma,
sensible and resistant.
Ospedale S.Gerardo, Monza
Development of the new database handling software for the ovarian
tumors bio-bank, compliant with the new privacy related laws for data
handling for clinical trials and with a new reporting engine for a better
data extration
External collaborations;
Ospedale S.Gerardo, Monza
Development of a validated distributed database for clinical trials
This activity involves the continuous development of a validated distributed database engine for
clinical trials. The system architecture is a decentralized platform (push based peer-to-peer) for
data sharing for virtual organizations.
Istituto Toscano Tumori (ref: Duccio Cavalieri)
Aberdeen University (ref. Tony Travis)
Laboratory of Molecular Pharmacology
G2 checkpoint and cell cycle
In the last years our laboratory has clarified the role of the Chk1 protein in the G2, S and M
blocks induced by different chemotherapeutic drugs. More recently the role of chk1 in
unperturbed cell cycle progression has been highlighted in some tumor cell lines. Treatment
of small inhibitors of the catalytic activity of chk1 or small interference RNA (siRNA)
against chk1 has been shown to cause cell death. In fact, chk1 inhibitors have been though
to be used in combination with DNA damaging agents as they would interfere with the
activation of the chk1 induced cell cycle checkpioint and would increase the cytotoxic
activity of the anticancer agents. The new data on the activity of chk1 inhibitors in some
tumor cell lines would suggest a possible use of the inhibitors as single agents. In order to
better understand the mechanism at the basis of the observed cytotoxic activity of the
inhibitors, we set up a high-through put screening through which we will hopefully find
those proteins, whose inactivation is in synthetic lethality with chk1. We will use a siRNA
library against 700 human protein kinases, described to have a key role in tumor cells. The
results of this screening will allow us the identification of those proteins whose inactivation
render tumor cells particularly sensitive to chk1 inhibition and could help in selection the
patients that would potentially benefit from a chk1 inhibitor mono-therapy.
Characterization of new potential oncosuppressor genes
DRAGO gene, identified and cloned in our laboratory is one of the most interesting projects of
the group. The characterization of the response of KO mice for DRAGO to ionising radiation is
similar to normal mice.
Mice KO for DRAGO have been crossed with with p53 KO mice to evaluate the potential
oncosuppressive function of DRAGO. The double mutants are viable and the genotypes arising
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from the crossing are at the normal Mendelian ratio, indicating that no specific genotypes
(p53;DRAGO) are favoured.
In a p53KO background, removal of DRAGO gene accelerates tumor development suggesting a
cooperative role of the two genes in the prevention of tumnor formation. We are currently
evaluating the spectra of tumor formation to determine whether the lack of DRAGO gene
preferentially increases the number of some specific histologycal type of tumor. We are
characterising the function of the gene both in in vitro and in in vivo systems.
Molecular characterization of ovarian carcinoma
Micro RNAs are small non coding RNAs playing an important role in the regulation of mRNA
transcription. They have been found deregulated in several human cancers. We have started a
study aimed at evaluating the expression of approximately 600 microRNAs in ovarian cancer
from patients with a very high response to treatment (surviving more than 10 years from
diagnosis) compared to patients not responding at first line therapy. The analysis of the tumors
so far characterised indicates that microRNAs are differentially expressed in the two subgroups
. If confirmed in a larger sample size, that could represent a potential therapeutic target.
In parallel we have characterised retrospectively, polymorphisms in genes participating in the
response to damage such as mdm2, ERCC1 and XPG as possible predictors of response to
treatment in patients with ovarian cancer. 420 patients have been genotyped and the allelic
frequency found is the expected one for a Caucasian population. The data generated will be
analysed together with the clinical parameters and with the follow-up data available for all the
samples analysed.
Expression of gene involved in DNA repair in human ovarian cancer
By Real Time PCR, the expression of genes involved in DNA repair has been evaluated in 77
stage I, 81 stage III and 13 borderline samples of ovarian cancer. The genes analysed include
those belonging to the nucleotide excision repair, in the fanconi anemia repair, in the base
excision repair. In addition, genes important for the cellular response to damage, such as chk1
and claspin have been studied.
Two were the aims of the study: 1) to understand whether there are genes differentially
expressed in the three categories analysed that could help us in understanding the biology of
ovarian cancer; 2) to correlate mRNA levels of the different genes with the response to
treatment with the idea of finding new possible response markers.
Data analysis showed that genes involved in the Fanconi Anemia pathway and some of the
genes involved in checkpoints are more expressed in stage I carcinoma than stage I borderline
tumors. These data might suggest that the malignant phenotype is associated with an upregulation of these genes that would endow tumor ovarian cell with higher growth and
metastatic potentials. In Stage III ovarian patients a number of correlation between the
expression of the repair genes and the response to therapy have been performed; however no
clear cut statistically significant correlation could be found. The data, even if negative, have
been obtained in a quite large sample size and we think pose some doubts on role of the
expression of single gene as predictive of response, as suggested by other studies.
Inhibition of the signal mediated by PI3K/akt
Pi3K/akt axis represents one of the major altered pathway in human cancers and therefore is a
good target for the development of new drugs. The laboratory has been involved in the
pharmacological characterisation of new molecules able to inhibit the pathway.
We have characterised the molecular mechanism at the basis of the interaction between two
molecules able to inhibit mTOR (the kinase downstresam PI3K/akt) at two different portion of
the protein. In vitro and in vivo data indicate that the strategy to inhibit the same target acting at
different level could be an intersting strategy to shut down a transduction signal. The
combination of the molecules, in fact, is able to inhibit tumor growth more than the single
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drugs, even when these are used at doubled doses. The mechanism of activity of the
combination is the ability to selectively inhibit one of the downstream effectors of mTOR
leading to a selective inhibiton of translation. The study combines cellular, molecular and
proteomic analysis.
Role of phospholipase C γ1 in the development of metastasis
The already performed studies on the role of phospholipase C γ1 in favouring the metastatic
process, have been extended in a human breast cancer model with a strong ability to metastatize
to the bones. In this model we have reproduced the systes previously utilized to inhibit
phospholipase C γ1 and new clones with inducible expression of phospholipase C γ1 have been
consequently generated. These models will be extremely useful for better understanding the
role of this protein in the metastatic process. In particular we are currently evaluating whether
phospholipase C γ1 has a role in bone metastasis formation or if its role is confined to specific
tissue districts.
Oncosuppressors p53, p63 and p73
The p63 protein, belonging together with p73 to the p53 family, can be expressed in cells in
different isoforms. Among these the DN isoform , which originates from an alternative internal
promoter, seems to have a role in the development and progression of cancer.
In the previous year, our laboratory the expression of p63 members in human ovarian cancer,
both at early and advanced stage, has been evaluated. We have shown that the advanced stage
expresses much higher levels of DNp63 than early stage tumors. Following these results, we
have generated cellular clones in vitro which express a differential, inducible expression of
DNp63. These clones which have been characterised for their protein expression, will allow us
to define the role of this protein in the growth and response to treatment of cancer cells. In
parallel we are evaluating the molecular mechanism responsible for the modulation of DNp63
levels in human ovarian cancers. To date we have been able to exclude an involvement of a
chromosomal rearrangement in the area where the p63 gene is present. In this chromosomal
area, in fact, we did not find duplication, amplification of genetic material both in early and
advanced ovarian cancer.
Mechanisms of action of new antitumor drugs
In collaboration with the laboratory of Biology and Therapy of Metastasis, we have
characterised the mechanism of action and the antitumor activity of a new antiangiogenic drug,
E3810. This drug is a small molecule able to inhibit receptors playing important roles in the
tumor angiogenesis processes (VEGFR, FGFR). Our studies allowed us to define that the drug
has a potent antiangiogenic activity, with a broad spectrum of activity in different human tumors
transplanted in immunodeficient mice. We are currently investigating combinations of E3810
with other anticancer agents to better define in which context the new drug might be included in
the polychemoterapy treatments of human tumors.
Generation of new cellular systems for in vivo imaging
We have generated new cell clones derived from human cancer cells growing in vitro, which
stably express fluorescent or luminescent probes which can allow us to follow in vivo the
growth of primary tumors and metastasis in mice. These systems generated in human ovarian,
breast and prostate cancer cell lines, can be implanted in nude mice and the growth and response
to therapy followed by either optical and luminescent imaging or microTAC analysis.
We have in particular set up models derived from human breast cancer, which are able to
metastasis to the bone which can be evidentiated by optical imaging and microTC techniques in
laboratory animals. Utilising different reporter genes, we have generated fluorescent and
luminiscent human cancer cell lines which can be transplanted in immunodeficient mice. These
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cells can then be visualised in organs such as peritoneum and lungs were these cells were
previously be observed only after sacrifice of the animal. The cells generated to be fluorescent
or bioluminiscent will also have specific gene defects which will be useful for understanding the
mechanism of action of new molecules. These systems will be particularly useful to study the
antimetastatic potential of new drugs.
Studies on the bone metastatic processes
Using a model of human breast cancer cells metastatizing to the bones, we have characterised
some molecular pathways involved in the colonisation and metastatic growth. In particular, we
have evaluated the role of cMet receptor and of its activation both in vitro and in vivo.
The in vivo model utilized develops bone metastasis following intraventricular injection of
cancer cells. The bone metastasis can be visualized by optical imaging already after 10 days
from cancer cell inoculum. By microTC analysis, bone osteolytic lesions can be evidentiated
after 3-4 weeks from tumor cells injection.
With this model we have shown that c-met plays an important role in the process and we have
been able to demonstrate a cross-talk in vivo between human cancer cells and host cells. In
particular we have found that inside cancer cells growing in the bone, there is HGF, the ligand
of c-met, both produced by the cancer cells themselves and by the murine host cells. HGF
present in the bone can therefore be activated by human cancer cells there have colonized in the
bones, thus activating an autoregulatory loop able to stimulate tumor growth. The data obtained
with selective c-met inhibitors or with shRNA directed against c-met, indicate that the inhibition
of the HGF/c-met axis is effective in inhibiting bone metastatic growth, particularly when the
two treatment modalities are combined.
Identification of cancer stem cells from ovarian cancer
This project is aimed at isolating and characterizing a possible cancer stem cell from ovarian
cancers. There are increasing evidences supporting the idea that few important multipotent
cancer cells, termed cancer stem cells, are among the most relevant cells to be killed in a tumor.
Normally present as quiescent cells inside the tumors, they are able to rapidly generate dividing
and growing cancer cells. The current hypothesis is that normally dividing cancer cells can be
preferentially killed by chemotherapy while the cancer stem cells would be more difficult to kill
and would be responsible for the relapse following treatment. The possibility to identify and
characterize the cancer stem cell would theoretically open the way to the selection of new
generation molecules able to preferentially kill these cells.
Several studies have been conducted in ovarian fresh tumor samples, obtained from the
Gynecological Department of Ospedale San Gerardo di Monza, directed by Prof Mangioni, that
lead to the identification of a cell bearing the characteristic of a tumor initiating cells. We have
almost completed the molecular and pharmacologycal characterisation of ovarina cancer stem
cell. The results of this characterisation will possibly lead to the identification of specific genes
that could be targeted in the ovarian tumor initiating cells with the final aim to improve the
therapy of this tumor.
Determination of the impact of EGFR mutations in the activity of tyrosine
kinase inhibitors in patients with NSCLC
The study on the characterisation of the response of patients with NSCLC to therapy with or
without EGFR inhibitors is ongoing. The data available so far show that among the patients
enrolled in the study, the percentage with mutations in the EGFR gene is 8-9%, in line with
what previously reported for this tumor in the Caucasian population.
The study aims also to evaluate the role of mutations in another gene, K.RAS , in determining
the response to treatments. This gene is mutated in a significantly higher proportion of patients
than EGFR. The mutational spectrum found in this tumor is different from that reported in other
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types of tumor, such as the colrectal cancer. These differences could be responsible for a
different effect on tumor growth and response to treatment and this hypothesis will be tested by
generating new cellular models harbouring different mutations of the K-RAS gene in NSCLC
cell lines.
Determination of the impact of K-RAS mutations on the activity of
anticancer agents.
The K-RAS gene results mutated in significantly higher percentage of NSCLC patients than
EGFR. The spectrum of mutation found in NSCLC is different from that observed in other
tumor types such as colorectal cancer. The different mutations could explain the different
impact of K_RAS on the selction of patients for therapies. In fact in colon cancer mutation in
the K_RAS gene is an exclusion criteria for treatment with anti EGFR drugs such as cetuximab.
In NSCLC the role fo K-RAS is more controversial. From the available clinical data we went
back to the laboratory generating isogenic cellular systems differning for the type of K-RAS
mutation. In particular we have generated in NSCLC cell lines clones overexpressing the wt KRAS or mutants in which the glycine at codon 12 is substituted with aspartic acid, cysteine or
valine. These mutants have indeed a different impact on the response to treatment of these cells
with drugs such as cisplatin, sorafenib or taxol. Our data suggest that for the stratification of
patients it is necessary to consider not only the presence of K-RAS mutation, but also the kind
of mutation present which could modify the selection f the best therapeutic options.
Laboratory of Biology and Treatment of Metastases
Physiologic regulation of angiogenesis
Angiogenesis - the neoformation of blood vessels from existing ones - has a critical role in
tumor progression. A delicate balance between pro- and antiangiogenic factors finely tunes this
process. We have long studied endogenous angiogenesis-regulatory factors, as a basis to
develop new inhibitors. In particular, our studies focus on thrombospondin-1 (TSP-1), an
endogenous angiogenesis inhibitor. The ability to directly bind to angiogenic factors, in
particular FGF-2 (Fibroblast Growth Factor-2), reducing its bioavailability and activity is one of
the manifold functions of this molecule. In a structure/function relationship analysis of different
active domains of TSP-1, we have identified its binding site to FGF-2. This active sequence of
TSP-1 is being used as a model to design new antiangiogenic and antineoplastic compounds.
Lymphangiogenesis in ovarian carcinoma
Lymphatic spread in ovarian cancer is an important predictor of outcome both in early and
advanced stages of this cancer. To clarify the molecular mechanisms involved in the lymphatic
spread of ovarian cancer we have developed animal tumor models derived from human ovarian
cancer transplanted under the bursa (orthotopic xenograft), expressing luciferase and
disseminating in the peritoneal cavities of immunodeficient mice.
Preliminary results show that the levels of soluble VEGFC – the main factor stimulating the
formation of lymphatic vessels – as measured in plasma and ascites of mice bearing ovarian
cancer, correlates with the tumor growth – as measured through optical fluorescence – as well as
the lymphatic invasion. Studies are in progress to assess the antitumor and antimetastatic
activities of selective inhibitors of the VEGF/VEGFR pathway.
How the tumor microenvironment affects endothelial cell gene expression
Blood vessels play a major role in the tumor development, malignant progress and generation of
metastasis.
The understanding of qualitative and functional differences between endothelial cells (EC)
lining the tumor vasculature and EC of normal blood vessels should allow the identification of
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selective markers/targets and lead to novel pharmacological interventions. We have identified
gene expression difference in the tumor derived EC with respect to normal EC, through
"microarray" analysis followed by validation with RealTime PCR, and in situ hybridization
analysis of normal and tumor tissue. Notably the expression of some of these genes is modified
by conditions simulating , in vitro, the “angiogenic/tumoral” microenvironment. We are
studying the relevance of these gene transcripts, which are abundant in the tumor EC and whose
proteins are expressed in the tumor endothelium/stroma.
The vascular Endothelial Growth Factor (VEGF) modifies the tumoral
microenvironment
We have observed that the production of VEGF from the tumoral cells and its release in the
tumoral microenvironment is accompanied with an altered response to chemotherapy (e.g.
paclitaxel). Bevacizumab (Avastatin®) – an antibody directed to VEGF – restores the
therapeutic efficacy of paclitaxel, suggesting that the tumoral environment might play a role in
modulating the sensitivity to therapy. To determine the molecular mechanism/s of tumor-VEGF
modified microenvironment, we are studying the transcriptional activity of the stromal
component (microdissected from the tumoral tissue), using the hybridization of micromatrix of
DNA. The results of the analysis with GeneChip® Mouse Genome 430 2.0 Array (Affymetrix)
indicate that the stroma (microenvironment) of highly producing VEGF tumors preferentially
expresses 294 genic transcripts. For some of them the expression of the protein preferentially
localizing in the stromal component and/or associated to the vasculature of VEFG-rich tumors
has been demonstrated. Their relevance in the tumor progression and response to treatments is
under investigation.
Preclinical evaluation of inhibitors of angiogenesis and combination
therapies
Antineoplastic therapies directed against the tumor vascular system may be developed
accordingly to two
different strategies. Antiangiogenic therapy (inhibitors of angiogenesis) prevents the formation
of new vessels, while vascular disrupting agents (VDA) aim to selectively destroy the already
formed tumor vessels. For the last decade we have investigated the antiangiogenic/antivascular
activity of novel antitumor molecules of interest for the clinical development, in particular: a)
peptides and non-peptidic small molecules, which mimic endogenous inhibitors of
angiogenesis, including compounds similar to thrombospondin-1; b) small molecules inhibiting
tyrosin kinase receptors, in particular VEGFRs, FGFR and PDGR, which mediate the signal
with the angiogeneic growth factors; c) vascular disrupting compounds, in particular tubuline
binding molecules (colchicines and combrestatins analogues) which, causing a depolimerization
of microtubules, selectively deteriorate the tumor blood vessels. The study of the combination
of angiogenesis inhibitors or VDA with conventional chemotherapy is one of the main interests
in our laboratory. In particular, studies have been conducted and are in progress to optimize the
modalities of administration of the combinations (i.e. choice of the drugs accordingly to the
characteristic of the tumor, dose and treatment schedules accordingly to their mechanism of
action), which are connected to the pharmacokinetic and pharmacodynamic profiles associated
to the treatment efficacy.
Laboratory for the development of new pharmacological
strategies
The laboratory was born out of the consideration that the advent of oncological drugs endowed
with mechanisms of action different from those of traditional chemiotherapics, introduces new
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treatment opportunities. At the same time, new problems arise concerning the choice of the
most appropriate and effective design for research into the clinical activity profile of these new
treatments.
The traditional paradigm where the choice of dose is based on the maximal tolerated toxicity,
and the screening of therapeutic activity focus on tumor mass reduction, may not necessarily be
suitable for the evaluation of new agents whose targets may include the extracellular
compartment or specific molecular targets.
The clinical development of ‘non toxic’ anti tumor molecules requires a critical review of the
existing models as well as of all the aspects relative to the conduction of clinical trials
including: dose selection criteria, methods for determination and confirmation of
pharmacological activity, and the validation of new technologies and laboratory methods.
This is where the need for a profound integration of the ‘clinical screening’ and the preclinical
research lies. It is a prerequisite for the construction of the pharmacological rationale for the
identification of the most interesting molecules, the choice of dose, the hypotheses of
combination with other drugs, and of the most appropriate indicators of clinical activity.
The acquisition of know how and the development and application of new designs for clinical
activity studies, including the use of randomization, the introduction of groups of patients
treated with placebo, and new discontinuation designs, proceed in parallel to the above.
Another fundamental issue in laboratory research is the recognition that the genomic
characterization of any single tumor may now play a more relevant role in drug development
and treatment identification.
This notwithstanding, numerous uncertainties remain regarding the role of biomarkers in drug
development and in the implementation of genomic technologies in clinical trials. It is therefore
necessary to improve the methodology and more biomarkers evaluation already in the early
stages of research, thus shifting translational research from a simple process of correlation
search to one producing knowledge regarding the predictive role of the clinical activity of the
investigational treatments.
Therefore, the primary focus of the laboratory is the optimization of the methods for evaluating
the activity of cytotoxic drugs, but mostly for those therapies aimed at specific molecular
targets, as well as the identification of factors predictive of therapeutic response. In 2010, phase
II studies on activity of Panitumumab in breast cancer patients, and of ET743 in pancreatic
cancer and mesothelioma patients have been initiated.
Laboratory of Clinical Trials
The Laboratory of Clinical Trials is involved in the planning, coordination and analysis of
randomized clinical trials in oncology, conducted in cooperation with a network of medical
oncologists. Main covered research areas are gastric, colo-rectal, breast and lung cancer.
Moreover the laboratory works on a second line study in patients with pediatric glaucoma in
collaboration with Azienda Ospedaliera “Spedali Civili Di Brescia” and supported by AIFA.
Gastric cancer
ITACAS ”Intergruppo Nazionale Adiuvante Gastrico” study is a randomised, open-label,
multicenter, trial aimed at assessing the role of adjuvant chemotherapy in the treatment of
gastric cancer. It compares the efficacy and safety of a sequential treatment (campto plus
flurouracil/leucovorin, followed by taxotere and cisplatin) versus flurouracil/leucovorin
regimen, used as standard reference in patients with radically resected adenocarcinoma of the
stomach or gastroesophageal junction. The study, sponsored by Mario Negri Institute, involves
11 oncological collaborative groups and is being conducted in more than 110 Italian
experimental centers. From February 2005 to August 2009, 1107 patients have been enrolled.
The follow-up ends for all patients after the achievement of the target number of events. First
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results about feasibility and tollerability will be published after the mid-2011. The expertise of
ITACA-S will be followed by another study “ ITACA-S2” conducted in patients with
adenocarcinoma of the stomach. This randomized, multicentre, 2x2 factorial study, supported
by a grant of AIFA, evaluates the efficacy of a peri-operative versus a post-operative
chemotherapy treatment and the efficacy of a post-surgical chemo-radiotherapy treatment
versus no other treatment , irrespectively of the timing of chemotherapy. The study is in
progress and the first patient is expected to be enrolled on the mid-2010.
Lung cancer
On September 2007 the accrual of a multicentre, randomized, Italian study started. The aim of
this project (TAILORAIFA trial) is the optimization of second line therapy in patients with
advanced NSCLC.
The development of target-therapy suggested evaluating the treatment efficacy according to
molecular featuresof the tumoral cell. In particular the epidermal growth factor (EGFR) is a
promising target for anticancer therapy. A "tailored therapy" based on individual molecular
features may result in better responses and optimization of sources and costs. The predictive
value of EGFR protein expression, EGFR gene amplification and KRAS mutations in
determining the effect of erlotinib as compared to chemotherapy will be assessed .
TAILORAIFA trial sponsored by Azienda Ospedaliera Fatebenefratelli e Oftalmico of Milan
and supported by the Agenzia Italiana del Farmaco (AIFA), has already registered more than
500 patients.
Another multicentre, randomized, double-blind, randomized, placebo-controlled, phase III study
conducted in patients with advanced or metastatic NSCLC is starting recruitment. It is aimed at
assessing whether acetilcarnitine prolongs toxicity free survival, and reduce neurotoxicity due to
platinum compounds.
In fact, in patients receiving chemotherapy administered with legitimate “curative intent”, many
toxicities can be justified to accomplish this goal in patients with metastatic cancer for whom
the goal is to “palliate symptoms” and optimise the quality of life this is less acceptable and
justified. The target number of patients is 650, randomized in approximately 30 Italian
experimental centres.
Colon cancer
On June 2007 started the accrual of a randomised, phase III clinical trial aimed at identifying the
best therapeutic adjuvant strategy in radically resected colon cancer patients is starting. The
study, sponsored by Fondazione Giscad per la Cura dei Tumori and supported by the Agenzia
Italiana del Farmaco (AIFA), will assess the following two questions:
1)
Optimal duration of FOLFOX-4 regimen (3 vs 6 months)
2)
Efficacy of the addition of Bevacizumab to FOLFOX-4 regimen (only in high risk stage
III patients)
For both questions, primary efficacy endpoint will be recurrence free survival.
Another phase III clinical trial has started. This study aimed at comparing the efficacy in terms
of PFS of the addition of cetuximab to FOLFIRI vs. FOLFIRI alone given as first line therapy
in patients with advanced CRC KRAS wild-type. In particular, the predictive value of PTEN
mutation will be assessed in determining the effect of cetuximab+FOLFIRI as compared to
chemotherapy alone.
The patient accrual period is planned for approximately 30 months. To assess PFS, all patients
will be followed for up to 24 months after the last patient is randomized. The maximum
estimated study duration is approximately 54 months.
This study, sponsored by Regione Lombardia, forsees the involvement of 30 centers and the
enrollment of 290 KRAS negative patients.
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At last a phase III clinical trial has been activated. This study (COMETS), sponsored by
Fondazione Giscad per la Cura dei Tumori and supported by AIFA, aimed at identifying the
best sequence of treatment (Irinoteca/Cetuximab followed by FOLFOX-4 vs FOLFOX-4
followed by Irinotecan/Cetuximab) in KRAS negative patients with advanced colorectal cancer
after a first line chemotherapy with FOLFIRI/Bevacizumab.
Primary efficacy endpoint will be overall survival. The maximum estimated study duration is
approximately 52 months and about 350 patients will be enroll.
Head and neck
On March 2008 started the accrual of a randomized multicenter open label phase 3 factorial trial
evaluating the overall survival in patients with locally advanced squamous cell carcinoma of
head and neck treated with locoregional treatment (radiotherapy plus concomitant chemotherapy
or cetuximab) with or without neoadjuvant chemotherapy. Patients will be randomized to
receive 3 cycles of neoadjuvant chemotherapy (TPF) followed by radiotherapy plus concomitant
chemo or cetuximab, or radiotherapy plus concomitant chemo or cetuximab alone. The primary
objectives of the study are to compare the overall survival between neoadjuvant and no
neoadjuvant arm and to compare the toxicity between concomitant chemoradiotherapy and
radiotherapy plus Cetuximab. The study will be conducted by a multidisciplinary team,
composed by oncologists, radiotherapists and othorinolaryngologists and will enroll
approximately 350 patients in Italian centers.
Laboratory of Translational and Outcome Research in Oncology
The Laboratory is mainly aimed at documenting, by using either Systematic Literature Review,
Randomized or Outcome Research studies, the value of new diagnostic and therapeutic
interventions in oncology, paying particular attention to two critical steps: the passage from
early to late clinical research (from the activity to efficacy evaluation) and from phase III to
clinical practice (from efficacy to effectiveness). The principal lines of research are three:
cancer pain evaluation, clinical research on gynecologic cancers and evalution of the
effectiveness of complex clinical programs in oncology care. In order to facilitate the research
activities and optimize the outputs, the Laboratory hosts the Coordination Centers of two multidisciplinary Groups (MANGO: Mario Negri Gynecologic Oncology and the CP-OR: Cancer
Pain Outcome Research Study Groups). As from 2007 on, all the activities of research and
training in the field of chronic pain has been coordinated by a dedicated center (CERP:Center
for the Evaluation and Research on Pain).
The Center for Evaluation and Research on Pain (CERP)
CERP is active since early 2008. It coordinates several studies and other activities regarding
chronic pain, particularly of oncologic nature. CERP is aimed at advancing the scientific
knowledge in this field and at improving the quality of palliative care and pain treatment. CERP
activities mainly focus on clinical research, but pre-clinical research (in vivo), information and
educational activities are also considered.
Main activities of CERP in 2010 were primarily focused to plan and launch the new randomized
clinical trial:”Studio clinico randomizzato e controllato, in aperto, per comparare l’efficacia
analgesica di percorsi terapeutici effettuati con ossicodone, fentanyl e buprenorfina verso
morfina, in pazienti con dolore associato a cancro di intensità moderata-severa, a partire dal
momento in cui iniziano il trattamento con 3° scalino della scala analgesica del WHO” (an
open, controlled, randomized clinical trial to compare the analgesic effectiveness of therapies
with oxycodone, fentanyl, buprenorphine versus morphine, in patients with moderate-severe
cancer pain at the start of the 3rd-step-WHO analgesic ladder therapy). This study also includes
an ancillary pharmaco-genomic project: “Valutazione, in parallelo, dell’assetto genico dei
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pazienti e delle possibili correlazioni con gli effetti clinici osservati” (Evaluation, in parallel to
the main project, of the genetic profiles of patients and their potential correlations to observed
clinical effects).
- In May 2010 CERP completed the writing of the study protocol and the CRF.
- In July 2010 the single option was received by the Ethic Committee of IRCCS
Fondazione INT, Milan.
- From September 2010 until the end of the year, the entire documentation was sent to all
Centers that will participate in the study (85 Centers in total, divided into oncology
wards and palliative care centers).
- Along this project, CERP concluded the planning and performed the launch of the study
“Progetto di ricerca per la validazione di un algoritmo e di una scheda elettronica per
la gestione del paziente con Dolore Cronico Non Oncologico in Medicina Generale”
(A research project for the validation of algorithm and electronic form for the
management of patients with non-oncological chronic pain in General Medicine), in
collaboration with S.I.M.G. (Italian Society of General Medicine).
Regarding the educational/formative activities of CERP, in March 2010, module clinical
module of the 9th “Master in Cure Palliative al termine della vita” (Master in Palliative Care at
the End of Life) was done, in collaboration with the Università degli Studi di Milano.
The website http://crc.marionegri.it/cancerpain dedicated to all activities of CERP was
completely renewed and updated.
The collaborative group in clinical gynecologic oncology named MaNGO
The Mario Negri Gynecologic Oncology group (MaNGO) is a new name for a collaborative
group that has been active in clinical gynecologic oncology for several years. Infact, this group
consolidated its network and logistics while running the ICONs studies which were conducted
in very close partnership with researchers at the Medical Research Council, Clinical Trial Unit,
UK. MaNGO was formally set up in May 2006 and is mainly representative of the northern part
of Italy, although there are important sites in the central and southern part of the country too.
Participating centers are either general public and private hospitals or university clinics. One of
MaNGO’s main statutory objectives was to foster an active collaboration with the Gynecologic
Cancer Intergroup (GCIG), and the European Network of Gynaecological Oncology Trials
groups (ENGOT) that represent two International Forum circulating the scientific proposals
from many national collaborative groups. MaNGO group is actively involved in many
international phase III trials.
MaNGO has been coordinating the Italian participation to the PORTEC 3 study: this is an
academic randomized phase III trial in endometrial cancer promoted by the Dutch collaborative
group. MaNGO received government funds from the Italian Agency for Drugs (AIFA)
supporting its national coordinating role. In 2010 the MaNGO network has been the third group
in terms of number of patients enrolled into the trial. In 2010 the randomized clinical trial in
ovarian cancer with a new antiangiogenic drugs (pazopanib) and internationally coordinated by
the German onco-gynecologic group named AGO reached the target sample size. This protocol
was emended in 2010 to prolong the maintenance therapy with pazopanib from one to two
years. Another international randomized clinical trial centrally managed by AGO was launched
in 2010. This trial will compare a maintainance treatment with vargatef (an angiogenesis paninhibitor) with placebo. The MaNGO group is the promoter of an ancillary study for the
vargatef trial aimed at clarifying the role of angiogenic markers such as VEGFC, VEGFB,
VEGFA and their receptors VEGFR3, VEGFR2) This translational study will be receiving
specific funds. In 2009 MaNGO launched the TAUL study, a randomized phase II trial aimed to
evaluate the efficacy of trabectedina in the treatment of patients with uterine leiomyosarcoma
and, during 2010, 26 Italian sites have been activated and 9 patients randomized. During 2010
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the MaNGO group developed and implemented the INOVATYON protocol. This is an
academic, international, phase III, randomized clinical trial aimed at comparing the combination
of pegylated liposomal doxorubicin+carboplatin with the combination of pegylated liposomal
doxorubicin and trabectedin in partially platinum sensitive ovarian carcinoma relapses.This
protocol was approved in October by the Ethics Committee of the European Institute of
Oncology in Milan and will be run under the aupsices of the international intergroups GCIG and
ENGOT.
During 2010, MaNGO’s Technical-Scientific Committee met quarterly while MaNGO affiliates
were conveyed at the 7° General Assembly that was held in June.
As to the third lineof activities (development and evaluation of complex
health carevinterventions) two activites are at the moment ongoing on
colo-rectal and breast cancer patients
Colo-rectal cancer
The assessment of efficacy of screening for relapses of colorectal carcinoma has been debated
for a long time, with controversial results. GILDA is an open label, international, randomised
study comparing two different strategies of post surgical surveillance in colorectal cancer
(Dukes B2-C stage): minimalist versus intensive. Primary endpoints of this trial are disease free
survival (which is used to assess diagnostic anticipation of metastases), overall survival, health
related quality of life, direct and indirect costs evaluation. At present, GILDA trial is the largest
randomised study evaluating the efficacy of two follow-ups in colorectal carcinoma. The trial
was closed to patient entry in September 2006 when a total of 1200 patients had been enrolled.
At the end of 2008 a manuscript for an Italian journal has been prepared to present the progress
of the trial, in 2009 a preliminary analysis on data available has been carried out to test the data
maturity and the final analyses is planned for the first half of 2011.
Breast cancer
In the context of a multi-regional project sponsored by the Italian Ministery of Health (6°
Progetto Integrato Oncologia) LaTOR is coordinating a project in which 5 different regional
groups are involeved: so far, 2 multi-center RCTs testing the efficacy of different follw-up
regimens in breast and uterus cancers, after diagnosis and first curative therapy , are ongoing
and a third prospective study to test the predictive value of bio-markers in the prognosis of
brest cancer is going to be launched.
Other research activities
LaTOR has continued on 2010 the collaboration with other laboratories of the Mario Negri
Institute. The most important collaboration are those epertaining the evaluation of incidence and
impact of mild anemia in elderly patients and on the attitude of smokers in the utilization of
pharmacological interventions to quit smoking. Resulst of these collaboration have been
extensively published on international peer-reviewed journals. Another collaboration is ongoing
with a regional network of General Practitioner to evaluate the frequency and effect of
determinants related to social vulnerability on indicators of care accessibility and continuity
Laboratory of Medical Research and Consumer Involvement
The Laboratory promotes various research activities aimed at developing the participation of
citizens & patients and their representatives to the choices and decisions regarding health. The
laboratory organize training courses and information discussion that would enable consumers to
deal effectively with physicians and researchers. Also carried out by the laboratory research
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projects to evaluate the type of information provided on illness and treatment, development of
internet website and information on health issues (www.partecipasalute.it); projects involving
groups of patients for publication of information material; projects to assess quality of life and
health.
PartecipaSalute (“Participate in Health Care”) - fostering a strategic
alliance between consumers’ associations and medical community
The project, started in 2003, is coordinated by Mario Negri Institute, with the collaboration of
the Italian Cochrane Centre and Zadig, an editorial and publishing company. The project
develops initiatives dedicated both to patients, citizens and their organizations, and to clinicians,
researchers and medical societies.
The main aims of the project are to boost patients’ participation to health care debate and
decision making processes - also through their organizations - and to increase medical societies’
attention to patients demands related to clinical research and dissemination of medical
information. Different stakeholders are involved: patients and consumers’ associations, medical
societies, researchers, medical journalists, experts in medical communication.
The main 2010 activities are:
- a five modules training course for consumers’ and patients’ representatives - called
“Accademia del
cittadino” - organized together with the Centro Gestione Rischio
Clinico e Sicurezza dei Pazienti ed il Settore Equità e Accesso della Direzione Generale
Diritto alla Salute della Toscana;
- a two modules training course organized together with the Centro del Volontariato in Rimini;
- the
development
of
PartecipaSalute
website
2.0
http://www.partecipasalute.it/cms_2/drigg_home where users can post comments, articles
and share documents. Every article published on the website can be commented and rated by
users. Areas restricted to participants of the training course have been created, where online
forms with exercises are available. A tool to evaluate patients’ associations’ credibility and
quality – called Misurassociazioni - has been developed together with the advisory of
training courses’ participants;
- the development of a project called Citizens juries, a method of deliberative democracy to
directly involve the citizens in healthcare decisions. It is based on the idea that many issues
are best decided by a group of lay people who have no vested interests and who apply their
common sense and experience, having been presented with the best possible evidence. One
of the matter at issue is the availability of prostate cancer screening;
- a survey on the correspondence between clinical research and patients needs addressed to
123 pediatric volunteers’ associations. The survey has been developed with the Mother and
Child care Laboratory and dealt with unanswered needs of patients, volunteers associations’
knowledge of ongoing studies, their involvement in research activities, their funding, their
support to research projects. Results are in press;
- a survey on the transparency of patients associations’ and drug companies’ websites. The
websites of 17 drug companies and 157 patients’ and citizens’ associations have been
evaluated trough two forms dealing with the disclosure of sponsorships respectively
delivered and received. Several issues have been considered. Supported patients associations
-declared by drug companies- who have no websites have been contacted by mail.
Project “ConMe Conoscere la menopausa”
The Partecipasalute project together with the National Guidelines System (SNLG) based at the
Istituto Superiore di Sanità organized in 2008 the Consensus conference (CC) “Informing
women on hormone replacement therapy” in order to assess the current status of the quality of
information on hormone replacement therapy (HRT) and re-visit recent research findings on its
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risks/benefits. The final recommendations concern menopause, HRT and information to convey
to women (http://www.partecipasalute.it/cms/files/Documento-definitivo-consenso.pdf).
The Laboratory of Medical Research and Consumer Involvement, Zadig
- editorial and publishing company, and the Istituto Superiore di Sanità developed the project
CONoscere la MEnopausa to evaluate the impact of training and information initiatives targeted
to women and healthcare operators, focused on the CC recommendations. The project is funded
by the Agenzia Italiana del Farmaco. Four regions participate in the project: Lombardia,
Toscana, Lazio, Sicilia. The training and information interventions are carried out in four local
healthcare agencies: ASL di Bergamo, ASL 7 di Siena, ASL RMH, ASL di Enna.
Education programs on this issue are organized trough residential sessions and online modules
dedicated to medical practitioners, gynecologists, pharmacists, obstetricians. A booklet for
women and information material for healthcare operators are also provided.
Three main outcomes will be considered: HRT prescriptions, healthcare operators’ and women
knowledge about menopause and HRT, quality of information conveyed to women through the
press.
In 2010 the booklets addressed to women and information material addressed to healthcare
operators have been developed, printed and sent to the healthcare agencies involved. The survey
on knowledge, attitude and practice of physicians and gynecologists has been concluded. The
survey on the press dealing with HRT is ongoing.
SNAP project - Smoke, Nutrition, Alcohol and Physical Activity
SNAP - Smoke, Nutrition, Alcohol and Physical Activity - is a campaign for the health with
particular attention to young people between 11 and 20 years. This project, commissioned by
FSE - Frontier Science & Technology Research Foundation, Southern Europe, a foundation to
support independent research - in collaboration with the Mario Negri Institute, has been
launched with the aim of increasing knowledge and changing opinions, attitudes and behaviors
of young people on the four issues examined, with an active process of information through the
distribution of written material, a website built ad hoc and a public event.
Between 2008 and 2009, a prototype phase was carried out in a company furnishing, to assess
the effectiveness of training-information. A questionnaire on the 4 themes SNAP, on
knowledge, opinions and attitudes has been distributed to more than 500 employees before a
formation-information public event and then 3 months and one year after the event. Data from
the first and second survey have been analyzed and data were presented to employees through a
brochure. Data from the third questionnaire will be analyzed and compared with those of the
first two.
Programma 1, WP5 -Alleanza contro il cancro – Servizio nazionale di
accoglienza e informazione sul cancro. Gruppo per l'Informazione ACCP1
WP5
The project is coordinated by the Istituto superiore di sanità. Other partners are the Centro di
Riferimento Oncologico - Aviano, AIMaC Associazione italiana malati di cancro, Istituto
Nazionale dei Tumori, Istituto Europeo di Oncologia. The Laboratory of Medical Research and
Consumer Involvement refers to the working group focusing on information, composed by
members of Istituto Superiore Sanità, ospedale S. Giovanni Rotondo, S. Raffaele, Fondazione
Pascale di Napoli, Università di Genova - MEDINFO, AIMaC, INT di Milano, CRO di Aviano,
Oncologico di Bari, Az. ospedaliera S. Andrea di Roma.
The Laboratory evaluated the quality of websites dealing with breast cancer, colon rectal cancer,
cervical cancer. An ad hoc evaluation form was created, considering the quality of the website
and some issues related to the contents. Each website was independently evaluated by two
reviewers, using the defined form. Data collected were analyzed and discussed by the
Laboratory.
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Each evaluation form was included in Cignoweb, a website that publishes a database collecting
websites and information materials about cancer.
In 2010 the results of the project have been presented in a meeting dealing with the national
cancer program and publications have been planned.
Project: inform, learn and participate in improving the quality of life. The
case of asthma, type 2 diabetes and breast cancer
This project on the quality of information provided to citizens and patients, sponsored by the
Smith Kline Foundation, was established with the objective of evaluating the quality of the
pamphlets produced and distributed by the associations of patients of the three diseases and to
produce a core of information from which associations can draw evidence-based information to
produce their own brochures.
During the project were contacted associations in Lombardy, Veneto, Tuscany, Emilia
Romagna, Puglia and Sardinia were evaluated ad hoc board with all the pamphlets, produced or
distributed by the associations contacted. In the course of 2010 a document called "core
information", with the information-base needed to provide an evidence-based information, has
been organised. The "core information" was discussed during a public meeting.
Follow-up in oncology setting
Two studies on follow-up have been designed and carried out in collaboration with the
Laboratory of Giovanni Apolone.
The first in collaboration with the Network Oncologica Piemontese regards the follow-up of
patients with endometrial cancer organization for which the evidence available is not sufficient
to draw a path of sure effectiveness. TOTEM study that has the characteristics of an open
randomized multicenter study comparing two different modulations of visits and examinations.
The second study that takes place in the context of the 6th Integrated Project Oncology (Health
Ministry) provides for the comparative assessment of two follow-up for women at moderatelow risk with a diagnosis of breast cancer and lead to a randomization minimalist follow-up
coordinated by the oncologist or by general practitioner. The study starts the randomization in
September 2010.
Quality of life projects
No specific research projects have been carried out on quality of the life evaluation. However
we have been supporting and coordinating other groups using the instruments of quality of life
translated and validated by our research group, SF-36, SF-12, PGWBI. During the year the
website http://crc.marionegri.it/qol has been periodically updated.
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DEPARTMENT OF ENVIRONMENTAL
HEALTH SCIENCES
STAFF
Head
Roberto FANELLI, Biol.Sci.D.
Laboratory of Analytical Biochemistry
Head
Chiara CHIABRANDO, Biol.Sci.D.
Laboratory of Environmental Chemistry and Toxicology
Head
Emilio BENFENATI, Chem.D.
Industrial and Environmental Health Unit
Head
Marco LODI, Chemist
Laboratory of Food Toxicology
Head
Ettore ZUCCATO, M.D.
Laboratory of Mass Spectrometry
Head
Enrico DAVOLI, Anim.Sci.D.
Laboratory of Molecular Toxicology
Head
Luisa AIROLDI, Pharm.D.
Protein and Gene Biomarkers Unit
Head
Roberta PASTORELLI, Biol.Sci.D
Department’s Units
Environmental Pollutants Risk Assessment Unit
Head
Elena FATTORE, Biol.Sci.D
Analytical Instrumentation Unit
Head
Renzo BAGNATI, Chem.D.
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CURRICULA
Roberto Fanelli, Head of the Environmental Health Sciences Department since 1997, Laboratory Head
1978-97, Researcher 1975-78, Research fellow 1969-74 at the Mario Negri Institute.
Doctoral Degree in Biological Sciences (University of Milan, 1973), Assistant Professor in Biochemistry
at Baylor College of Medicine (Houston, Texas). Member of the Commissione Consultiva Prodotti
Fitosanitari (Ministero Salute), Member of the Scientific Panel on Contaminants in the Food Chain
(European Food Safety Authority, 2003-2006), Certified Italian Toxicologist. Member of the Comitato
Scientifico Ente Risi.
Research areas: Sources, diffusion, toxicology, human exposure and risk assessment of persistent
environmental pollutants. Environmental risk of plant protection products. Development of analytical
methods for identification and measurement of biomarkers in toxicology. Mechanisms of toxic action by
proteomic techniques.
Selected publications:
1.
Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E, Noris M, Buelli S, Zoja C, Corna D, Mele C, Fanelli
R, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am Soc
Nephrol 2009 ; 20 : 123-130.
2.
Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometric analysis of illicit drugs in wastewater and
surface water. Mass Spectrom Rev 2008 ; 27 : 378-394
3.
Zuccato E, Chiabrando C, Castiglioni S, Bagnati R, Fanelli R. Estimating community drug abuse by wastewater analysis.
Environ Health Perspect 2008 ; 116 : 1027-1032
4.
Hodgson S, Thomas Laura, Fattore E, Lind P M, Alfven T, Hellstrom L, Hakansson H, Carubelli G, Fanelli R, Jarup L. Bone
mineral density changes in relation to environmental PCB exposure. Environ Health Perspect 2008 ; 116 : 1162-1166
5.
Pastorelli R, Carpi D, Campagna R, Airoldi L, Pohjanvirta R, Viluksela M, Hakansson H, Boutros P C, Moffat I D, Okey A B,
Fanelli R. Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance: correlation with
genomic and transcriptomic analyses. Mol Cell Proteomics 2006; 5: 882-894
6.
Zuccato E, Chiabrando C, Castiglioni S, Calamari D, Bagnati R, Schiarea S, Fanelli R. Cocaine in surface waters: a new
evidence-based tool to monitor community drug abuse. Environ Health 2005; 4: 14
(http://www.ehjournal.net/content/4/1/14 2005)
Luisa Airoldi, Head of the Molecular Toxicology Laboratory since 1994, Unit Head 1987-94, Researcher
1978-87, Technician 1967-75 at the Mario Negri Institute.
Doctoral Degree in Pharmacy (University of Milan, 1975), Postdoctoral fellow at the Massachusetts
Institute of Technology (Cambridge, MA, 1976) and at the Northwestern University Medical School
(Chicago, Il, 1977), Researcher at the Yale University Medical School (New Haven, CT, 1980-81).
Research areas: Proteomics in toxicology with particular interest on the study of proteome changes in
tissues and biological fluids from animals and humans after exposure to toxic compounds; clinical
proteomics aimed at the identification of protein biomarkers as diagnostic tools; molecular epidemiology
focused on the identification and measurement of biomarkers of exposure to environmental carcinogens
and disease susceptibility.
1.
Gallo V, Neasham D, Airoldi L, Ferrari P, Jenab M, Boffetta P, Overvad K, Tjonneland A, Clavel-Chapelon F, Boeing H, Pala
V, Palli D, Panico S, Tumino R, Arriola L, Lund E, Bueno-De-Mesquita H B, Peeters P H, Melander O, Hallmans G, Riboli E,
Saracci R, Vineis P. Second-hand smoke, cotinine levels, and risk of circulatory mortality in a large cohort study of neversmokers. Epidemiology 2010 ; 21 : 207-214.
2.
Airoldi L, Magagnotti C, Iannuzzi AR, Marelli C, Bagnati R, Pastorelli R, Colombi A, Santaguida S, Chiabrando C, Schiarea
S, Fanelli R. Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun. 2009 381: 397402.
3.
Carpi D, Korkalainen M, Airoldi L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R. Dioxinsensitive proteins in differentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci. 2009 108: 330-43.
4.
Peluso M, Airoldi L, Colombi A, Munnia A, Veglia F, Autrup H, Dunning A, Garte S, Gormally E, Malaveille C, Matullo G,
Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Linseisen J, Boeing H, Trichopoulou A, Palli D, Krogh V, Tumino R,
Panico S, Bueno-De-Mesquita H B, Peeters P H, Kumle M, Gonzalez C A, Martinez C, Dorronsoro M, Barricarte A, Tormo M
J, Quiros J R, Berglund G, Janzon L, Jarvholm B, Day N E, Key T J, Saracci R, Kaaks R, Riboli E, Bingham S, Vineis P.
Bulky DNA adducts, 4-aminobiphenyl hemoglobin adducts, diet and air pollution in a healthy European population. Br J Nutr
2008 100: 489-495.
5.
Veglia F, Loft S, Matullo G, Peluso M, Munnia A, Perera F, Phillips D H, Tang D, Autrup H, Raaschou-Nielsen O,
Tjonneland A, Vineis P, Genair-EPIC Investigators. DNA adducts and cancer risk in prospective studies: a pooled analysis and
a meta-analysis. Carcinogenesis 2008 ; 29 : 932-936.
6.
Pastorelli R, Saletta F, Campagna R, Carpi D, Dell'Osta C, Schiarea S, Vineis P, Airoldi L, Matullo G Proteome
characterization of a human urothelial cell line resistant to the bladder carcinogen 4-aminobiphenyl Proteome Sci 2007 5: 6
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Emilio Benfenati, Head of the Laboratory of Environmental Chemistry and Toxicology since 1997, Unit
Head 1987-97, Researcher 1986-87, Research fellow 1981-86 at the Mario Negri Institute. Researcher at
Istituto Biochimico Italiano 1979-1981.
Doctoral Degree in Chemistry (University of Milan, 1979).
Member of Commissione Consultiva Prodotti Fitosanitari (Ministero Salute 1997-99), Certified Italian
Chemist.
Research areas: Computer-based models for chemistry and toxicology; Molecular descriptors; QSAR;
Toxicity prediction; Metabolism studies; Characterization and assessment of wastes, industrial effluents,
emissions from landfill and incinerator; Integration of chemical analysis and eco-toxicological data;
Chemical analysis of organic compounds by mass spectrometry.
1.
Boriani E, Mariani A, Baderna D, Moretti C, Benfenati E, ERICA: a multiparametric toxicological risk index for the
assessment of environmental healthiness, Environmental International, 2010 36 : 665–674
2.
Toropov A A, Toropova A P, Benfenati E, Leszczynska D, Leszczynksi J, InChI-based optimal descriptors: QSAR analysis
of fullerene[C60]-based HIV-1 PR inhibitors by correlation balance, Eur J Med Chem 2010 45 : 1387-1394
3.
Benfenati E, Benigni R, DeMarini D M, Helma C, Kirkland D, Martin T M, Mazzatorta P, Ouédraogo-Arras G, Richard A,
Schilter B, Schoonen W G E J, Snyder R D, Yang C. Predictive models for carcinogenicity and mutagenicity: frameworks,
state-of-the-art, and perspectives. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2009 ; 27 : 57-90.
4.
Colombo A, Benfenati E, Mariani G, Lodi M, Marras R, Rotella G, Senese V, Fattore E, Fanelli R. PCDD/Fs in ambient air in
north/east Italy: The role of a MSWI inside an industrial area. Chemosphere 2009; 77: 1224-1229
5.
Zhao C, Boriani E, Chana A, Roncaglioni A, Benfenati E, A new hybrid QSAR model for the prediction of
bioconcentration factors (BCF), Chemosphere 2008 73 : 1701-1707
6.
Roncaglioni A, Benfenati E, In silico-aided prediction of biological properties of chemicals: oestrogen receptor-mediated
effects, Chem Soc Rev 2008 37: 441-450
Chiara Chiabrando, Head of the Analytical Biochemistry Laboratory since 1997, Unit Head 1987-97,
Researcher 1978-87, Research fellow 1975-78 at the Mario Negri Institute.
Doctoral degree in Biological Sciences (University of Milan, 1974), Postdoctoral fellow at the Baylor
College of Medicine (Houston, Texas, 1974-75). Postgraduate degree in Pharmacological Research,
Mario Negri Institute (1977).
Research areas: Development and application of bio-analytical methods based on mass spectrometry in
the fields of biochemistry, metabolism, clinical chemistry and pharmacology. Identification and
characterization of proteins and peptides of biomedical interest by proteomic approaches and mass
spectrometry. Structural characterization of proteins by mass spectrometry. Proteomics in oncology.
Comparative characterization of cancer cell lines secretomes by a global proteomic approach and systems
biology tools.
1.
Schiarea S, Solinas G, Allavena P, Scigliuolo GM, Bagnati R, Fanelli R, Chiabrando C. Secretome analysis of multiple
pancreatic cancer cell lines reveals perturbations of key functional networks. J Proteome Res. 2010;9:4376-92.
2.
Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C, Mantovani A,
Allavena P. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization,
influencing tumor cell motility. J Immunol. 2010;185:642-52.
3.
S, Fanelli R. Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun. 2009; 381:397402.
4.
Nephrol 2009 ; 20 : 123-130.
5.
Environ Health Perspect 2008; 116: 1027-1032.
6.
Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometric analysis of illicit drugs in wastewater and
surface water. Mass Spectrom Rev 2008; 27: 378-394.
Enrico Davoli, Head of the Mass Spectrometry Laboratory since 1997, Unit Head 1994-97, Researcher
1989-94, Research Fellow 1985-87 at the Mario Negri Institute. Fellow at USDA, Beltville, MD 1977-78.
Doctoral Degree in Animal Sciences (University of Milan, 1983), Postdoctoral fellow at the University of
Nebraska (Lincoln, NE, 1987) and at the University of Colorado Health Sciences Center (Denver, CO,
1988). Postgraduate degree in Pharmacological Research, Mario Negri Institute (1988). Member of the
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American Association for Mass Spectrometry (ASMS) of the Environment and Safety Commission of
IGQ and of the ETS (Emission Trading System) commission. Member of the National Biomass Research
Center Scientific Committee. Environmental Applications Interest Group Coordinator (ASMS).
Research areas: Development of methodology, instrumentation and software for environmental research.
Studies of urban air pollution and characterization of environmental odor annoyance.
1.
Adani F, Tambone F, Davoli E, Scaglia B. Surfactant properties and tetrachloroethene (PCE) solubilisation ability of humic
acid-like substances extracted from maize plant and from organic wastes: A comparative study. Chemosphere 2010 78 : 10171022.
2.
Orzi V, Cadena E, D'Imporzano G, Artola A, Davoli E, Crivelli, M, Adani F. Potential odour emission measurement in
organic fraction of municipal solid waste during anaerobic digestion: relationship with process and biological stability
parameters. Bioresour Technol 2010 101 : 7330-7337.
3.
Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Fanelli R, Rossi A N, Il Grande M. Waste management health risk
assessment: A case study of a solid waste landfill in South Italy. Waste Manag 2009, DOI 10.1016/j.wasman.2009.10.013.
4.
Davoli E, Bianchi G. Odour emission rates from a waste treatment plant: results from a multi year follow-up study. Chemical
Engineering Transactions 2008; 15 : 95-102.
5.
Zuccato E, Grassi P, Davoli E, Valdicelli L, Wood D, Reitano G, Fanelli R. PCB concentrations in some food from European
countries. Food Chem Toxicol 2008, 46: 1062-1067.
6.
Bagnati R, Bianchi G, Marangon E, Zuccato E, Fanelli R, Davoli E. Direct analysis of isopropylthioxanthone (ITX) in milk by
high-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007 ; 21 : 1998-2002
Ettore Zuccato, Head of the Food Toxicology Laboratory since 2005, Unit Head 1997-2005, Researcher
1986-97, Technician 1975-86 at the Mario Negri Institute.
Doctoral degree in Medicine (University of Milan, 1986), Postdoctoral degree in Human Nutrition
(1999), Postdoctoral fellow at the King’s College School of Medicine (London, UK, 1988-89).
Member of the ANSISA, EMEA expert, member of the Commissione Consultiva per i Prodotti
Fitosanitari, and expert for the evaluation of plant protection products for registration within the EU.
Research areas: Food safety, including the study of dietary chemical contaminants, safety assessment of
GMO in human nutrition, food allergens and toxicants, emerging issues in food toxicology, risk
perception and risk communication to the consumers, and evaluation of plant protection products for
registration within the European Union. Environmental pollution by pharmaceuticals, and monitoring of
illicit drugs in surface waters to estimate community drug abuse.
1.
Zuccato E, Castiglioni S, Bagnati R, Melis M, Fanelli R. Source, occurrence and fate of antibiotics in the Italian aquatic
environment. J Hazard Mater 2010 ; 179 : 1042-1048
2.
Grassi P, Fattore E, Generoso C, Fanelli R, Arvati M, Zuccato E. Polychlorobiphenyls (PCBs), polychlorinated dibenzo-pdioxins (PCDDs) and dibenzofurans (PCDFs) in fruit and vegetables from an industrial area in northern Italy. Chemosphere
2010 ; 79 : 292-298
3.
Illicit drugs in the environment: Emerging contaminants and indicators of drug abuse. Castiglioni S, Zuccato E. Integrated
Environmental Assessment and Management 2010 ; 6 : 186-187
4.
Zuccato E, Castiglioni S. Illicit drugs in the environment. Philos Transact A Math Phys Eng Sci 2009 ; 367 : 3965-3978.
5.
Environ Health Perspect 2008, 116: 1027-1032.
6.
Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometry analysis of illicit drugs in wastewater and
surface water. Mass Spectrom Rev, 2008, 27: 378-394.
Renzo Bagnati, Head of the Analytical Instrumentation Unit since 2005, Researcher 1992-2005,
Research fellow 1986-92 at the Mario Negri Institute.
Doctoral degree in Chemistry (University of Turin, 1985), Postgraduate degree in Pharmacological
Research, Mario Negri Institute (1989).
Research areas: Mass spectrometry applied to the analysis of biological and environmental relevant
substances (proteins, peptides, hormones, pharmaceuticals, drugs of abuse, pesticides).
1.
Schiarea S, Solinas G, Allavena P, Scigliuolo G, Bagnati R, Fanelli R, Chiabrando C. Secretome analysis of multiple
pancreatic cancer cell lines reveals perturbations of key functional networks. J Proteome Res 2010; 9: 4376-4392.
2.
Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giudice C, Scanziani E, Mancuso A, Tiveron C,
Garattini E. Role of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoic acid: generation and
characterization of a knockout mouse. Mol Cell Biol 2009 ; 29 : 357-377.
3.
Zuccato E, Castiglioni S, Bagnati R, Chiabrando C, Grassi P, Fanelli R. Illicit drugs, a novel group of environmental
contaminants. Water Res 2008 ; 42 : 961-968.
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4.
5.
6.
Bagnati R, Bianchi G, Marangon E, Zuccato E, Fanelli R, Davoli E. Direct analysis of isopropylthioxanthone (ITX) in milk by
high-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007 ; 21 : 1998-2002.
Castiglioni S, Zuccato E, Crisci E, Chiabrando C, Fanelli R, Bagnati R. Identification and measurement of illicit drugs and
their metabolites in urban wastewater by liquid chromatography-tandem mass spectrometry. Anal Chem 2006; 78: 8421-8429.
Zuccato E, Chiabrando C, Castiglioni S, Calamari D, Bagnati R, Schiarea S, Fanelli R. Cocaine in surface waters: a new
evidence-based tool to monitor community drug abuse. http://www.ehjournal.net/content/4/1/14 2005.
Elena Fattore, Head of the Environmental Pollutants Risk Assessment Unit since 2005, Researcher
2001-2004, Research fellow 1991-1997 at the Mario Negri Institute.
Doctoral Degree in Biological Sciences (University of Milan, 1991), Postgraduate degree in
Pharmacological Research, Mario Negri Institute (1994), Postdoctoral fellow at the National Institute of
Environmental Medicine, Karolinska Institutet, Stockholm (1998-2000). Member of the Working Group
of External Scientific Experts to externally review the quality of the scientific outputs of the European
Food Safety Authority (EFSA) in the area of activity of chemical risk assessment and connected fields.
Research areas: Environmental chemistry, toxicology, assessment of human exposure and risk from
environmental pollutants with emphasis on dioxins and dioxin-like compounds.
1.
Grassi P, Fattore E, Generoso C, Fanelli R, Arvati M, Zuccato E. Polychlorobiphenyls (PCBs), polychlorinated dibenzo-pdioxins (PCDDs) and dibenzofurans (PCDFs) in fruit and vegetables from an industrial area in northern Italy. Chemosphere
2010; 79: 292-298
2.
Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Rossi A N, Il Grande M, Fanelli R. Waste management health risk
assessment: A case study of a solid waste landfill in South Italy. Waste Manag 2010; 30: 1608-1613.
3.
Oberg M, Westerholm E, Fattore E, Stern N, Hanberg A, Haglund P, Wiberg K, Bergendorff A, Hakansson H. Toxicity of
Bromkal 70-5DE, a technical mixture of polybrominated diphenyl ethers, following 28 d of oral exposure in rats and impact of
analysed impurities. Chemosphere 2010; 80, 137-143.
4.
Fattore E, Fanelli R, Dellatte E, Turrini A, Di Domenico A. Assessment of the dietary exposure to non-dioxin-like PCBs of the
Italian general population. Chemosphere 2008, 73: S278-S283.
5.
Hodgson S, Thomas L, Fattore E, Lind P M, Alfven T, Hellstrom L, Hakansson H, Carubelli G, Fanelli R, Jarup L Bone
mineral density changes in relation to environmental PCB exposure. Environmental Health Perspective 2008, 116: 1162-1166.
6.
Carubelli G, Fanelli R, Mariani G, Nichetti S, Crosa G, Calamari D, Fattore E. PCB contamination in farmed and wild sea bass
(Dicentrarchus labrax L.) from a coastal wetland area in central Italy. Chemosphere 2007 ; 68 : 1630-1635.
Marco Lodi, Head of the Industrial and Environmental Unit since 2002, Consultant 1997-2002 at the
Mario Negri Institute.
General Certificate of Education in Industrial Chemistry (Milan, 1974).
Member of AIDII (Italian Industrial Hygiene Association), certified by ACGIH (American Conference of
Governmental Industrial Hygienist).
Research areas: Emission sources, environmental diffusion, toxicology, human exposure and risk
assessment of persistent environmental pollutants. Environmental risk of chemical pollution products.
Development of sampling methods for environmental toxic compounds.
1.
Colombo A, Benfenati E, Mariani G, Lodi M, Marras R, Rotella G, Senese V, Fattore E, Fanelli R. PCDD/Fs in ambient air in
north/east Italy: The role of a MSWI inside an industrial area. Chemosphere 2009 ; 77 : 1224-1229.
2.
Benfenati E, Azimonti G, Auteri D, Lodi M Environmental and ecological toxicology: computational risk assessment.
Computational toxicology. Risk assessment for pharmaceutical and environmental chemicals John Wiley, Hoboken, NJ, 2007;
625-650
3.
Grosso M, Cernuschi S, Palini E, Lodi M, Mariani G. PCDD/Fs release during normal and transient operation of a full scale
MSWI plant. Organohalogen Compounds 2004; 66: 1243-1249
4.
Benfenati E, Mariani G, Lodi M, Reitano G, Fanelli R. Is bioexsiccation releasing dioxins? Organohalogen Compounds
2004; 66: 955-961
5.
Fattore E, Mariani G, Guzzi A, Di Guardo A, Benfenati E, Lodi M, Fanelli R. Air dioxin concentrations in Seveso area. In:
Halogenated Environmental Organic Pollutants, 18th. Symp., Stockholm, Sweden, august 17-21, 1998. 1998 : 237-240
6.
Benfenati E, Mariani G, Schiavon G, Lodi M, Fanelli R. Diurnal, weekly and seasonal air concentrations of PCDD and PCDF
in an industrial area. Fresenius Journal Analytical Chemistry 1994; 348: 141-143
Roberta Pastorelli, Head of Protein and Gene Biomarkers Unit since 2004, Researcher 1992-2003,
Research fellow 1983-92 at the Mario Negri Institute.
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Doctoral Degree in Biological Sciences (University of Milan, 1982), Postgraduate degree in
Pharmacological Research, Mario Negri Institute (1986), Postdoctoral fellow at the Massachusetts
Institute of Technology, Cambridge, MA (1987-89 and 1991).
Research areas: Toxicoproteomic investigation of global protein expression profiles and their modulation
evoked by environmental compounds in different biological compartments. Critical targets and pathways
in toxicology. Pharmacogenetics: effects of genetic polymorphisms in the human population on the
individual susceptibility to environmental xenobiotic and carcinogen effects.
1.
S, Fanelli R. Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun. 2009 381: 397402.
2.
Carpi D, Korkalainen M, Airoldi L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R. Dioxinsensitive proteins in differentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci. 2009 108: 330-43.
3.
Pastorelli R, Saletta F, Campagna R, Carpi D, Dell’Osta C, Schiarea S, Vineis P, Airoldi L, Matullo G. Proteome
characterization of a human urothelial cell line resistant to the bladder carcinogen 4-aminobiphenyl. Proteome Science 2007.
4.
Moretti M, Dell'omo M, Villarini M, Pastorelli R, Muzi G, Airoldi L, Pasquini R. Primary DNA damage and genetic
polymorphisms for CYP1A1, EPHX and GSTM1 in workers at a graphite electrode manufacturing plant. BMC Public Health.
2007 7: 270
5.
Pastorelli R, Carpi D, Campagna R, Airoldi L, Pohjanvirta R, Viluksela M, Hakansson H, Boutros P C, Moffat I D, Okey A B,
Fanelli R. Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance: correlation with
genomic and transcriptomic analyses. Mol Cell Proteomics 2006; 5: 882-894
6.
Pastorelli R, Carpi D, Airoldi L, Chiabrando C, Bagnati R, Fanelli R, Moverare S, Ohlsson C.Proteome analysis for the
identification of in vivo estrogen-regulated proteins in bone. Proteomics 2005; 5: 4936-4945
ACTIVITIES
The Department works to investigate environmental factors and their effects on human health.
The main research lines focus on the survey of environmental contaminants, the assessment of
human exposure with related health risks, and toxicity mechanisms of pollutants.
The assessment of environmental contamination is carried out not only for well-known and
widespread compounds, like dioxins and PCBs, but also for new classes of "unconventional"
pollutants, e.g., endocrine disruptors, potentially toxic "natural" compounds, and drugs entering
the environment after human or veterinary use. The identification –for the first time– of illicit
drugs in urban waste and river waters, led to a new original tool for the evidence-based
monitoring of community drug abuse. For all these survey activities sophisticated analytical
methods based on advanced mass spectrometric techniques are developed.
The Department is active in the assessment of human exposure to toxic compounds in the
atmosphere and the diet, which is the main source of priority pollutants (PCBs, dioxins and
other endocrine disruptors). Assessment of the risk associated to contamination in real-life
scenarios has recently gained much importance. In order to respond to the growing demand for
information, the Department is more and more involved in toxicological and ecotoxicological
risk analysis, based on studies in field and predictive models of toxicity. The toxic effects of
environmental contaminants on the central nervous system are also investigated, using in vivo
and in vitro animal models.
Molecular epidemiology studies are used to identify genetic and/or environmental factors
posing risks to human health. By this approach, we search for new useful “biological markers"
to identify susceptible subjects, in view of finding appropriate preventive strategies.
The Department has implemented an advanced technological proteomic platform, in order to
identify proteins differentially expressed in biological compartments in various experimental
and clinical conditions. This approach is particularly relevant in toxicology, since it can
contribute to find new biomarkers of toxicity or pathology, and to identify molecular targets and
toxic effect mechanisms of pollutants and drugs. To integrate our proteomic studies, we have
now introduced among our activities metabolomics, i.e., the study of small molecules, such as
amino acids, carbohydrates, lipids, hormones etc., the final products of protein expression and
activity which contribute to define the biochemical phenotype of a biological system.
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Mass spectrometry (MS) is a central analytical technique at the Department, where a complete
set of state-of-the-art instrumentation is available, from GC-MS and LC-MS to MALDI-TOFMS. These instruments are provided with modern solutions for sample introduction (chip-based
nanoLC), sample ionization (ESI, DESI and MALDI), tandem MS (MSn) by triple quadrupole
and TOF-TOF instruments, high mass resolution analysis (hybrid ion trap/orbitrap).
FINDINGS/MAIN RESULTS
Evidence of new molecular players in the effects of TCDD on bone development provided by
proteomics coupled to networks analysis.
Resistance to the bladder carcinogen 4-aminobiphenyl in human urothelial cells is mediated by
deregulation of apoptosis and membrane trafficking proteins.
Bone protein profile in a murine model of osteoporosis.
Identification of novel protein targets responsive to the effects of estrogens in bone.
TCDD's effect on the liver proteome profile of exposed rats. Determination of a subset of rat
hepatic proteins indicative of differences in dioxin susceptibility.
The presence of 4-aminobiphenyl-hemoglobin adducts may help identify nonsmokers at high
risk of cancers related to environmental tobacco smoke exposure.
Reference values of allele and genotype frequency of several metabolic genes in 15,000 control
subjects.
CYP1A1 polymorphism affects lung tumor risk.
Identification of CYP2C9 genetic polymorphism as a determinant of severe adverse reactions to
phenytoin.
On-line in silico models to predict ecotoxicity of pesticides for regulatory purposes.
New in silico models, freely available on-line, to predict toxicity and ecotoxicity of chemicals
for the REACH European legislation.
A tool to assess if a chemical is bioaccumualive, with a high rate of accuracy, avoiding the use
of the experimental fish model.
A new model for identification of endocrine disruptors using molecular docking.
A new index integrating risk assessment for human and ecotoxicity endpoints.
A method aimed at characterizing environmental odors to identify odor sources in complex
environments.
Proteomic/bioinformatic workflow for comparative secretome analysis in cancer cell lines.
Global proteomic profiles of pancreatic carcinoma cell lines secretomes with identification of
perturbed functional networks.
Albumin can become a source of potentially antigenic peptides in proteinuric nephropaties.
Moderate-to-high fish consumption can result in exceeding the daily intake safety levels of
PCBs and dioxin-like compounds established by the European Commission.
The same food type may contain significantly different concentrations of PCBs and dioxin-like
compounds, depending on the geographic origin (this may help lower the risk for the consumers
by understanding and controlling the causes of the differences).
The environmental levels of several drugs exceed the “safety limits” established for them.
Environmental pollution from pharmaceuticals is a general phenomenon that can be described
by controllable variables (environmental load and mass balance).
Illicit drug residues and their metabolites were found in urban waste and river waters.
Environmental levels can be used as a new tool to estimate illicit drugs consumption in the
population.
The distribution of dietary intake values of dioxins, dioxin-like PCBs and non dioxin-like PCBs
was characterized for the general Italian population.
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The higher intake of PCBs due to consumption of farmed fish vs. wild fish is mainly due to the
higher fat content in farmed fish.
Development of novel mass spectrometric methods for the selective measurement of therapeutic
and illicit drugs in environmental samples.
Activation of Toll-like receptor 4 (TLR4) by endotoxin/lipopolysaccharide (LPS) induces
neuroinflammatory responses and motor neuron degeneration in spinal cord primary cultures;
protective role of a cyanobacteria-derived TLR4 antagonist (VB3323).
ARPA Emilia Romagna
ARPA Veneto
ASL di Bergamo
ASL di Brescia
ASL di Como
ASL di Cagliari
ASL di Napoli
Centro Reach Srl
CLIR Spa Lomellina
CNR – IRSA
Comune di Peschiera del Garda (BS)
Comune di Rosignano Marittimo (LI)
Comune di Sant’Urbano (PD)
CSRA-Asti
Dipartimento delle Politiche Antidroga, Presidenza del Consiglio dei Ministri
Federchimica
Fondazione 'S. Maugeri'
Fondazione ISI, Torino
Gruppo Collaborativo sulla Suscettibilità Genetica ai Cancerogeni Ambientali (GSEC), Milano,
Italia
INRAN-Istituto Nazionale di Ricerca sugli Alimenti e la Nutrizione
ISPO, Firenze
Istituto Clinico Humanitas, Milano
I.Z.S.L.T - Istituto Zooprofilattico Sperimentale del Lazio e Toscana
Metropolitana Milanese
Mineracqua
Ministero dell'Ambiente
Ministero dello Sviluppo Economico
Politecnico di Milano
Politecnico di Torino
Provincia di Vercelli
Provincia Pordenone
Rotary Club Sirmione (BS)
Stazione Sperimentale dei Combustibili, Milano
Università degli Studi del Piemonte Orientale
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Università degli Studi di Cagliari
Università degli Studi di Genova
Università degli Studi di Milano
Università degli Studi di Napoli "Federico II"
Università degli Studi di Palermo
Università degli Studi di Pavia
Università degli Studi di Perugia
Università degli Studi di Roma "La Sapienza"
Università degli Studi di Siena
Università degli Studi di Torino
Università dell’Insubria, Varese
Università degli Studi di Verona
BASF Agricultural Centre, Limburgerhof, Germany
Centre for Environmental Policy, Imperial College, London, UK
Danish Institute of Agricultural Sciences, Research Centre Foulum, Tjele, Denmark
Department of Analytical and Pharmaceutical Chemistry, The Royal Danish School of
Pharmacy, Denmark
Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland
Department of Computer Science and Engineering, University of Galati, Romania
Department of Electrical and Computer Engineering, University of Patras, Greece
Department of Environmental Health, National Public Health Institute, Kuopio, Finland
Department of Epidemiology & Public Health, Imperial College, London, UK
Department of Inland Fisheries, Institute of Freshwater Ecology and Inland Fisheries, Berlin,
Germany
Department of Molecular Biology, University of Bergen, Bergen, Norway
Department of Organic Chemistry, Universidad de Cadiz, Cadiz, Spain
Division of Endocrinology, Department of Internal Medicine, Sahlgrenska University Hospital,
Gothenburg, Sweden
Environmental Chemistry, IIQAB-CSIC, Barcelona, Spain
Environmental Hygiene and Chemistry Department, Institute of Environmental Medicine and
Hospital Epidemiology, University of Freiburg, Germany
Environmental Protection Agency, US EPA - National Risk Management Research Laboratory
(NRMRL), Cincinnati OH, USA
European Chemicals Agency, ECHA, Helsinki, Finland
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal
Faculté de Médicine et de Pharmacie, Université de Mons-Hainaut, Mons, Belgium
Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
Food and Environment Research Agency, York, UK
Forschungzentrum Jülich Gmbh, Jülich, Germany
Helmholtz-Zentrum für Umweltforschung UFZ, Leipzig, Germany
Institute of Environmental Medicine. Karolinska Institute, Stockholm, Sweden
Institute of Pharmaceutical Chemistry, University of Pécs, Pecs, Hungary
Institute of Phytomedicine, Biological Control, Horticulture and Nematology, Vienna, Austria
Institute of Soil Science and Plant Cultivation, Pulawy, Poland
Interuniversitaeres Forchunginstitut fuer Agrarbiotechnologie, Tulln, Austria
Istituto di Chimica di São Carlos, Università di São Paulo, Brazil
KnowledgeMiner Software, Berlin, Germany
In Vitro Testing Industrial Platform, Tres Cantos (Madrid), Spain
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Laboratory of Chemometrics & Bioinformatics, University of Orléans, Orléans, France
Laboratory of Neurobiology, Centro de Investigation Principe Felipe, Valencia, Spain
Lithuanian Institute of Agricultrure, Vilnius, Lithuania
Liverpool John Moores University, Liverpool, UK
National Institute of Chemistry, Kemijski Institut Ljubljana, Ljubliana, Slovenia
Natural Resources Research Institute, University of Minnesota, Duluth, USA
National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
Pesticide Safety Directorate, York, UK
Plant Protection Institute, Hungarian Academy of Sciences, Budapest, Hungary
PublicSpace Ltd, Ulverstone, UK
School of Biomedical Sciences, University of Ulster, Coleraine, UK
SETAC Europe, Brussels, Belgium
Symlog, Paris, France
Syngenta Crop Protection AG, Basel, Switzerland
Technische Universitaet Dresden, Dresden, Germany
TNO, Delft, Netherlands
Unit of Environmental Risk and Health, Flemish Institute for Technological Research,
Boeretang, Belgium.
Universitat Politècnica de Catalunya, Barcelona, Spain
Universitat Rovira i Virgili, Tarragona, Spain
University of Tartu, Tartu, Estonia
Journal of Environmental Science and Health, Part B (Emilio Benfenati), Journal of
Environmental Science and Health, Part C (Emilio Benfenati), International Journal of
Computational Intelligence (Emilio Benfenati), International Journal of Information Technology
(Emilio Benfenati), International Journal of Signal Processing (Emilio Benfenati), Chemistry
Central Journal (Emilio Benfenati), Current Computer Aided Drug Design (Emilio Benfenati),
Advances in Chemoinformatics and Computational Methods (Emilio Benfenati), The Open
Biomarkers Journal (Luisa Airoldi).
Addiction, Analytical Chemistry, Analytical and Bioanalytical Chemistry, Chemical Biology &
Drug Design, Chemical Research Toxicology, Chemometrics and Intelligent Laboratory
Systems, CHEMOLAB, Chemosphere, Clinical Biochemistry, Drug and Alcohol Dependence,
Environment International, Environmental Pollution, Environmental Modelling & Software,
Environmental Science & Technology, International Journal of Molecular Sciences, Journal of
Cellular Biochemistry, Journal of Chemical Information and Modeling, International Journal of
Molecular Science, Journal Computer-Aided Molecular Design, Journal of Hazardous
Materials, Molecular Cellular Proteomics, Molecular Diversity, Proteome Science, Royal
Society's Philosophical Transactions, Stroke, Toxicology Letters, Waste Management, Water
Research, International Journal of Environmental Analytical Chemistry, Molecular Nutrition
and Food Research, Journal of Chromatography A, The Open Biomarkers Journal,
Toxicological Sciences, External review of the quality of the scientific outputs of the European
Food Safety Authority (EFSA).
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NATIONAL AND INTERNATIONAL
COMMITTEE MEMBERSHIP
CCPF - Commissione Consultiva Prodotti Fitosanitari (Ministero della Salute, Ministero
dell'Ambiente)
ECCO - European Commission Coordination
EFSA - European Food Safety Authority
IGQ - Commissione Ambiente e Sicurezza
EVENT ORGANIZATION
58th American Society for Mass Spectrometry Conference “Finding unknowns in the
environment: high resolution and MS/MS approach”, Salt Lake City, UT, USA, June 1-5, 2010.
OSIRIS Training Course on Integrated Testing Strategies (ITS), Istituto di Ricerche
Farmacologìche Mario Negri, Milano, Italy, November 3-5, 2010.
Participation, as leader of the Local Organizing Committee (Emilio Benfenati), to the
organization of the 21st SETAC Europe Annual Congress, Milano, Italy, May 15-19 2011.
Workshop “Risk Assessment: valutazione dei rischi da inquinamento ambientale ed effetti sulla
salute umana”, GSISR-CNR, Milano, Italia, March 2, 2010.
7th Federation of European Neurosciences (FENS) Forum, Amsterdam, Paesi Bassi, July 3-7,
2010.
1st RISKCYCLE Workshop “Risk-based management of chemicals and products in a circular
economy at a global scale”, Hanoi, Vietnam, May 4-5, 2010.
SETAC Europe 20th Annual Meeting, Seville, Spain, May 23-27, 2010.
14th International Workshop on Quantitative Structure‐Activity Relationships
in Environmental and Health Sciences, QSAR 2010, Montreal, Canada, May 24-28, 2010.
58th American Society for Mass Spectrometry Conference, Salt Lake City, UT, USA, June 1-5,
2010.
Workshop “Ecopharmacovigilance wich future?”, Academie Nationale de Pharmacie, Paris,
France, September 21, 2010.
NOSE 2010. International Conference on Environmental Odour Control and Monitoring.
Florence, Italy. September 22-24, 2010
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NATO SfP 982590 project workshop “Characterization of hazardous chemical contamination From environmental chemistry and toxicology to risk assessment ”, Dubrovnik, Croatia,
September 23 - 26, 2010.
OSIRIS Training Course on Integrated Testing Strategies (ITS), Istituto di Ricerche
Farmacologìche Mario Negri, Milano, Italy, November 3-5, 2010.
2nd RISKCYCLE Workshop “Risk of chimical additives and recycled materials: State of the
art, new challenges and future trends”, Shenyang, China PR, November 15-19, 2010.
A2A Brescia
ACEGAS S.p.A, Trieste
AIIPA (Associazione Italiana Industrie Prodotti Alimentari)
AMA, Roma
ASL Cagliari
ASL Como
ASL Mantova
ASL Napoli 2
ASSOFOODTEC/UCIMAC (Costruttori Italiani Macchine per Caffè Espresso ed Attrezzature
per Bar)
Bergamo Pulita S.r.l.
Bluegreen Biotech
Bracco Imaging Spa
Cambrex, Paullo (MI)
Catanzaro Costruzioni S.r.l.
CLIR S.p.A.
COGEIDE S.p.A.
COOP Italia
CSRA
Comune di Lomello (PV)
Comune di Mazzano e Rezzato (BS)
Comune di Rosignano Marittimo (LI)
Comune di Sant’Urbano (PD)
Consorzio Quadrifoglio S.p.A.
Dipartimento delle Politiche Antidroga, Presidenza del Consiglio dei Ministri
ECODECO S.r.l.
EnergyGreen S.r.l.
European Commission (ANTARES, ORCHESTRA, OSIRIS, RISKCYCLE)
Federchimica, Milano
FIAT Auto S.p.A.
Fondazione CARIPLO, Milano
Fondazione Italo Monzino, Milano
Gruppo CSA, S.p.a. Rimini (RN)
HERA S.p.A. (Holding Energia Risorse Ambiente)
INDENA S.p.A.
I.Z.S.L.T - Istituto Zooprofilattico Sperimentale del Lazio e Toscana
Lachifarma, Zollino (LE)
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Ministero dell'Ambiente, Italia
Ministero della Salute, Italia
Nufarm S.A.S., Francia
Oxon Italia S.p.A., Pero (MI)
Politecnico di Milano
Provincia di Pordenone
Provincia di Vercelli
Regione Lombardia
SO.GE.NU.S. S.p.A
Tenacta Group
TM.E. S.p.A.
Università degli Studi di Milano
Veolia Servizi Ambientali S.p.A.
Gallo V, Neasham D, Airoldi L, Ferrari P, Jenab M, Boffetta P, Overvad K, Tjonneland A, Clavel-Chapelon F,
Boeing H, Pala V, Palli D, Panico S, Tumino R, Arriola L, Lund E, Bueno-De-Mesquita H B, Peeters P H, Melander
O, Hallmans G, Riboli E, Saracci R, Vineis P. Second-hand smoke, cotinine levels, and risk of circulatory mortality
in a large cohort study of never-smokers. Epidemiology 2010 21 : 207-214.
Schiarea S, Solinas G, Allavena P, Scigliuolo G, Bagnati R, Fanelli R, Chiabrando C. Secretome analysis of multiple
pancreatic cancer cell lines reveals perturbations of key functional networks. J Proteome Res 2010 9 : 4376-4392.
Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C,
Mantovani A, Allavena P. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for
m2-polarization, influencing tumor cell motility. J Immunol 2010 185 : 642-652.
Diana V, Botti F, Fumagalli E, Calcagno E, De Paola M, Cagnotto A, Invernici G, Parati E, Curti D, Mennini T.
Neural precursor-derived astrocytes of wobbler mice induce apoptotic death of motor neurons through reduced
glutamate uptake. Exp Neurol 2010 225 : 163-172.
Toropov A A, Toropova A P, Benfenati E. QSPR modelling of normal boiling points and octanol/water partition
coefficient for acyclic and cyclic hydrocarbons using SMILES-based optimal descriptors. Central European Journal
Chemistry 2010 8 : 1047-1062.
Benfenati E, Gini G, Hoffmann S, Luttik R. Comparing in vivo, in vitro and in silico methods and integrated
strategies for chemical assessment: problems and prospects. Altern Lab Anim 2010 38 : 153-166.
Toropov A A, Toropova A P, Benfenati E, Leszczynska D, Leszczynksy J. SMILES-based optimal descriptors:
QSAR analysis of fullerene-based HIV-1 PR inhibitors by means of balance of correlations. J Comput Chem 2010 31
: 381-392.
Senese V, Boriani E, Baderna D, Mariani Alessandro, Lodi M, Finizio A, Testa S, Benfenati E. Assessing the
environmental risks associated with contaminated sites: Definition of an Ecotoxicological Classification index for
landfill areas (ECRIS). Chemosphere 2010 80 : 60-66.
Toropov A A, Toropova A P, Benfenati E, Leszczynska D, Leszczynksy J. QSAR analysis of 1,4-dihydro-4-oxo-1(2-thiazolyl)-1,8-naphthyridines exhibiting anticancer activity by optimal SMILES-based descriptors. J Math Chem
2010 47 : 647-666.
Lombardo A, Gonella Diaza R, Roncaglioni A, Benfenati E. CAESAR’s approach for alternative in silico methods
for REACH. ALTEX 2010 27 : 109-116.
Benfenati E. The CAESAR project for in silico models for the REACH legislation. Chem Cent J 2010 4 (Suppl 1) :
I1.
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Lombardo A, Roncaglioni A, Boriani E, Milan C, Benfenati E. Assessment and validation of the CAESAR predictive
model for bioconcentration factor (BCF) in fish. Chem Cent J 2010 4 (Suppl 1) : S1.
Chaudhry Q, Piclin N, Cotterill J, Pintore M, Price N, Chretien J R, Roncaglioni A. Global QSAR models of skin
sensitisers for regulatory purposes. Chem Cent J 2010 4 (Suppl 1) : S5.
Fjodorova N, Vrachko M, Novich M, Roncaglioni A, Benfenati E. New public QSAR model for carcinogenicity.
Chem Cent J 2010 4 (Suppl 1) : S3.
Cassano Antonio, Manganaro A, Martin T M, Young Douglas, Piclin N, Pintore M, Bigoni D, Benfenati E. CAESAR
models for developmental toxicity. Chem Cent J 2010 4 (Suppl 1) : S4.
Toropov A A, Toropova A P, Benfenati E, Manganaro A. QSAR modelling of the toxicity to Tetrahymena pyriformis
by balance of correlations. Mol Divers 2010 14 : 821-827.
Toropov A A, Toropova A P, Benfenati E. QSAR-modeling of toxicity of organometallic compounds by means of
the balance of correlations for InChI-based optimal descriptors. Mol Divers 2010 14 : 183-192.
Toropov A A, Toropova A P, Benfenati E, Leszczynska D, Leszczynksy J. Use of the international chemical
identifier for constructing QSPR-model of normal boiling points of acyclic carbonyl substances. J Math Chem 2010
47 : 355-369.
Boriani E, Mariani A., Baderna D, Moretti C, Lodi M, Benfenati E. ERICA: A multiparametric toxicological risk
index for the assessment of environmental healthiness. Environ Int 2010 36 : 665-674.
Toropov A A, Toropova A P, Raska I, Benfenati E. QSPR modeling of octanol/water partition coefficient of
antineoplastic agents by balance of correlations. Eur J Med Chem 2010 45 : 1639-1647.
Toropov A A, Toropova A P, Benfenati E, Leszczynska D, Leszczynksy J. InChI-based optimal descriptors: QSAR
analysis of fullerene[C60]-based HIV-1 PR inhibitors by correlation balance. Eur J Med Chem 2010 45 : 1387-1394.
Toropova A P, Toropov A A, Lombardo A, Roncaglioni A, Benfenati E, Gini G. A new bioconcentration factor
model based on SMILES and indices of presence of atoms. Eur J Med Chem 2010 45 : 4399-4402.
Piir G, Sild S, Roncaglioni A, Benfenati E, Maran U. QSAR model for the prediction of bio-concentration factor
using aqueous solubility and descriptors considering various electronic effects. SAR QSAR Environ Res 2010 21 :
711-729.
Toropov A A, Toropova A P, Benfenati E. SMILES-based optimal descriptors: QSAR modeling of carcinogenicity
by balance of correlations with ideal slopes. Eur J Med Chem 2010 45 : 3581-3587.
Toropova A P, Toropov A A, Benfenati E, Leszczynska D, Leszczynksy J. QSAR modeling of measured binding
affinity for fullerene-based HIV-1 PR inhibitors by CORAL. J Math Chem 2010 48 : 959-987.
Viganò L, Benfenati E, Bottero S, Cevasco A, Monteverde M, Mandich A. Endocrine modulation, inhibition of
ovarian development and hepatic alterations in rainbow trout exposed to polluted river water. Environ Pollut 2010
158 : 3675-3683.
Adani F, Tambone F, Davoli E, Scaglia B. Surfactant properties and tetrachloroethene (PCE) solubilisation ability of
humic acid-like substances extracted from maize plant and from organic wastes: A comparative study. Chemosphere
2010 78 : 1017-1022.
Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Rossi A N, Il Grande M, Fanelli R. Waste management
health risk assessment: a case study of a solid waste landfill in South Italy. Waste Manag 2010 30 : 1608-1613.
Forloni G, Pengo N, Monzani E, Cascio P, Cenci S, Sitia R, Salmona M. A new fluorogenic peptide determines
proteasome activity in single cells. J Med Chem 2010 53 : 7452-7460.
Orzi V, Cadena E, D'Imporzano G, Artola A, Davoli E, Crivelli M, Adani F. Potential odour emission measurement
in organic fraction of municipal solid waste during anaerobic digestion: relationship with process and biological
stability parameters. Bioresour Technol 2010 101 : 7330-7337.
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Bianchi G, Celeste G, Palmiotto M, Davoli E. Source identification of odours and VOCs from a composting plant by
multivariate analysis of trace volatile organic compounds. Chemical Engineering Transactions 2010 23 : 279-284.
Zuccato E, Castiglioni S, Bagnati R, Melis M, Fanelli R. Source, occurrence and fate of antibiotics in the Italian
aquatic environment.
J Hazard Mater 2010 179 : 1042-1048.
Castiglioni S, Zuccato E. Illicit drugs in the environment: Emerging contaminants and indicators of drug abuse.
Integrated Environmental Assessment and Management 2010 6 : 186-187.
Grassi P, Fattore E, Generoso C, Fanelli R, Arvati M, Zuccato E. Polychlorobiphenyls (PCBs), polychlorinated
dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in fruit and vegetables from an industrial area in northern
Italy. Chemosphere 2010 79 : 292-298.
Heath E, Kosjek T, Farre' M, De Alencastro F, Castiglioni S, Gans O, Langford K, Loos R, Radjenovic J, Mainero
Rocca L, Budzinski H, Tsipi D, Petrovic M, Barcelo D. Second interlaboratory exercise on non-steroidal antiinflammatory drug analysis in environmental aqueous samples. Talanta 2010 81 : 1189-1196.
Öberg M, Westerholm E, Fattore E, Stern N, Hanberg A, Haglund P, Wiberg K, Bergendorff A, Hakansson H.
Toxicity of Bromkal 70-5DE, a technical mixture of polybrominated diphenyl ethers, following 28 d of oral exposure
in rats and impact of analysed impurities. Chemosphere 2010 E-pub : 10.1016/j.chemosphere.2010.04.006.
Sala F, Marangon E, Bagnati R, Livi V, Cereda R, D'Incalci M, Zucchetti M. Development and validation of a highperformance liquid chromatography–tandem mass spectrometry method for the determination of the novel
proteasome inhibitor CEP-18770 in human plasma and its application in a clinical pharmacokinetic study. J Mass
Spectrom 2010 45 : 1299-1305.
Fattore E, Davoli E, Bonati M. Il Fantasma della discarica. Il Sole 24 ore Sanità. 30 nov. 6 dic. 2010
Fattore E. ADHD ed esposizione a pesticidi organofosforici. Ricerca & Pratica 2010, 155: 204-205
Fattore E. Neurotossicità dei composti chimici sullo sviluppo. Ricerca & Pratica 2010, 155: 205-207
Fattore E. Esposizione prenatale agli IPA e QI nei bambini. Ricerca & Pratica 2010, 156: 257-260
Zuccato E, Olandese R, Antinozzi R, Castiglioni S. Stima dei consumi di sostanze stupefacenti mediante analisi delle
acque reflue: confronto anni 2008 e 2009. Il “case-study” della città di Como.
RESEARCH ACTIVITIES
Laboratory of Molecular Toxicology
Proteome Analysis
Proteome analysis includes protein separation by one- and two-dimensional gel electrophoresis,
protein excision from the gel, their digestion with proteolytic enzymes and their identification
by mass spectrometry (MALDI-TOF-MS, LC-ESI-MS/MS) coupled to the use of existing
databases. Alternatively, peptides resulting from the digestion of protein mixtures with specific
proteases are separated by two-dimensional liquid chromatography.
Toxicoproteomics
Studies are ongoing on the characterization of changes in the proteome profile induced by
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environmental toxic compounds, with the aim of obtaining protein biomarkers with the ability
to differentiate two or more biological states. Proteome changes in tissues and target organs of
animals, and cells treated with endocrine disruptors, estrogens, or environmental carcinogens,
are related to functional changes during toxicological processes.
Clinical Proteomics
Qualitative and quantitative proteome changes resulting from the exposure to environmental
toxic compounds or in pathological conditions are monitored in human biological plasma and
urine. Ongoing studies aim at the characterization of protein biomarkers for early diagnosis of
diseases and for the identification of therapeutic targets.
Pathways analysis
An integrated data-mining platform such as MetaCore (GeneGo Inc., USA) is used in order to
map the differentially expressed proteins into biological networks and for functional
interpretation of the protein data.
Metabolomics
Metabolites are the biological endpoints of gene expression and enzyme activity and include
small molecules such as amino acids, carbohydrates, fatty acids, hormones, etc., that provide the
metabolic phenotype of individuals. Metabolomic research focuses on the quantitative analysis
of metabolites in biological fluids to link human metabolic profile variations to endogenous or
exogenous pathophysiological stimuli and to genetic modifications.
Selected metabolites are extracted from plasma or urine by solid phase extraction and analyzed
by HPLC coupled to high-resolution mass spectrometry.
The integration of proteomic and metabolomic studies will provide information that can help to
better understand disease development and to identify preventive interventions.
Molecular Epidemiology
The laboratory works mainly on the measurement of biological markers used to assess human
exposure to environmental toxic compounds. Our studies include DNA- and blood proteinadduct formation by several environmental carcinogens. In addition, we study whether the
polymorphism of genes coding for enzymes involved in the activation and detoxification of
carcinogens are determinants of adduct formation. Genotypes are detected by restriction
fragment length polymorphism analysis, after the amplification by polymerase chain reaction of
specific nucleotide sequences of the genes under study.
The laboratory participates in an international cooperation study aimed at the collection of
reference values on allele and genotype frequency of the most common metabolic enzyme
polymorphisms in control populations.
Laboratory of Analytical Biochemistry
Identification and characterization of proteins by mass spectrometry
Our laboratory is developing different analytical and instrumental techniques –based on mass
spectrometry– for the identification and characterization of proteins and peptides in biological
samples. This activity is mainly aimed at 1) global proteomic characterization and comparison
of secretomes from human cancer cell lines; 2) profiling proteins in biological fluids for
discovery and identification of biomarkers of physiopathological and toxicological relevance, 3)
identifying and characterizing endogenous degradation products of proteins, 4) identifying
proteins produced by cells in vitro in response to given stimuli, 5) identifying and characterizing
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biologically relevant proteins isolated from biological samples by immunoaffinity-based
techniques.
Proteomics in oncology
This activity is mainly aimed at discovering –among the proteins we find abnormally secreted
by human cancer cell lines– new molecules of oncological interest, and in particular novel
candidate therapeutic targets or diagnostic/prognostic biomarkers. Ongoing projects include the
characterization of the secretomes of cancer cell lines in vitro to identify the most relevant
abnormalities. The complex alterations observed in the cancer secretomes are then rationalized
and interpreted by using “systems biology” tools that are able to highlight the functional
networks most significantly perturbed.
Inflammation and neurodegeneration induced by environmental agents
We are studying the neurotoxic effects of endotoxin (LPS) and other environmental proinflammatory agents on neuronal cell primary cultures. The mechanisms leading to the
activation of the inflammatory reaction are studied by biochemical and immunochemical
methods, and proteomic approaches. Novel anti-inflammatory drugs of natural origin are being
tested in this model, with the aim of evaluating their neuroprotective effects.
Laboratory of Environmental Chemistry and Toxicology
Development and use of analytical methods to evaluate contamination in
water bodies, soil, biota, human samples in exposed population
Analytical methods are developed to study environmental pollutants in water ecosystems,
landfills, contaminated sites. Qualitative and quantitative analyses of organic pollutants are done
by mass spectrometry (GC-MS, LC-MS, LC-MS/MS). Typical analyses include PCDD/F, PCB,
PAH, polybrominated diphenylethers, pesticides, endocrine disruptor chemicals, and industrial
pollutants.
Studies on environmental, toxicological and ecotoxicological properties
of chemicals
Research is carried out on pollutant properties, searching literature data, comparing and
evaluating different sources, and mainly developing predictive models to cope with the lack of
experimental data. Thus, we develop models starting merely from the chemical structure. The
research addresses the different kinds of chemical descriptors and chemical fragments, obtained
with different software. Then, we develop models using algorithms such as neural network,
fuzzy logic, genetic algorithms, classifiers, multivariate analysis, etc. Different methods are
compared and integrated within a structured ensemble. Standardized methods for pesticides
were developed and validated according to OECD guidelines.
Risk assessment of pollutants
Studies are aimed at assessing the risk of pollutants for human population and environment. For
this we model transport and diffusion of pollutants, to obtain a predicted concentration on given
space and time scales. Such an activity is integrated with those above described on chemical
analyses and toxicity prediction, to achieve a continuous transfer of data and research.
Research on pollutants emitted in the atmosphere (Unit of Industrial and
Environmental Hygiene)
Studies address different aspects of atmospheric pollution. Research deals with: sampling areas
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around the pollution source, chemical analyses, transport modeling depending on
meteorological conditions and orography, risk assessment for population and environment.
Qualitative and quantitative analyses are done by gas chromatography-mass spectrometry using
high resolution for PCDDs/PCDFs, and negative ion-chemical ionization for PCBs.
Laboratory of Mass Spectrometry
Particulate air pollution
Epidemiological studies consistently show an association between an increasing number of
pathologies, both acute and chronic, and particulate air pollution. This has been shown not only
in respiratory, but in cardiovascular diseases as well. Airborne particulate sampling and analysis
strategies are developed to characterize both adsorbed compounds and exposition in different
activities.
Method development in environmental sciences
Methods, analytical methodologies, instrumentation and software for data acquisition and
reduction, are developed for environmental studies. High-sensitivity instrumentation, mainly
based on mass spectrometry, is developed for trace and ultra-trace analysis. Also, transportable
instrumentation is developed for field studies or continuous monitoring.
Characterization of environmental odor annoyance
Characterization of odors poses several analytical problems because they result from a complex
mixture of compounds (odorants) stimulating receptors in the nasal cavity. Most odorants are
volatile organic compounds (VOC) generated by bacterial degradation of organic matter. They
are often present at trace levels, while numerous sources can contribute to the total odor. Using
sampling techniques specifically developed for olfactometry, solid phase microextraction and
GC/MS analysis, we can detect traces (low ppb to high ppt) of a wide polarity/volatility range of
airborne VOC odorant compounds. With a chemometric approach, we can characterize the
sources of emissions, assess odor control methods, and identify emissions that contribute to
odors in ambient air.
Laboratory of Food Toxicology
Chemical contaminants in food
We are studying human exposure to dietary PCBs and dioxins in Italy. In particular,
contaminants were measured in samples of human milk collected from mothers living in highly
contaminated areas i Further studies were aimed at measuring PCBs and dioxins in samples of
fish caught in Italy and in food items from an Italian area at high risk of contamination. .
Therapeutic and illicit drugs in the environment
Pharmaceuticals are a class of emerging environmental pollutants. We have organized a
campaign to detect the presence of pharmaceuticals and their metabolites in Italian rivers and
sewage treatment plants and in samples of drinking water, with the aim of characterizing the
contamination and assessing related risks.
Further ongoing studies are aimed at investigating a possible relationship between antibiotic
occurrence and resistance in environmental bacteria.
The possible presence of illicit drugs in water samples from sewage treatment plants and rivers
was investigated, starting with cocaine and its metabolites. Their levels, used to estimate drug
abuse in the local population, revealed that cocaine consumption greatly exceeds official
estimates. This approach has been subsequently extended to include other common drugs of
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abuse such as cannabis, opiates (heroin, morphine), and amphetamines (amphetamine,
methamphetamine, ecstasy). Our evidence-based method allows monitoring of patterns and
trends of drug abuse in local communities, and is able to detect qualitative and quantitative
consumption changes in real time. This tool can therefore complement survey methods in more
realistically describing the drug abuse phenomenon. Ongoing studies are focussed to assess
consumptions at national scale, in collaboration with the National Agency for Drug Policy, at
regional scale in collaboration with Regione Lombardia, and locally, in collaboration with
Metropolitana Milanese.
Unit of Environmental Pollutants Risk Assessment
Toxicological risk assessment
Starting from real cases of contamination, the unit aims to develop methods for the exposure
assessment also employing probabilistic approaches, and more refined statistical models. The
activities focus on risk assessment related to specific environmental conditions, or human
activities, which pose a risk for human health. These studies include risk assessments related to
contamination of water or soil, emissions of toxics pollutants from waste management
processes, including transfer of these compounds into the food chain. During 2010, studies
focused on health effects due to waste disposal into landfills, and on soil treatment with sludge
and the potential transfer of persistent organic pollutants across the food chain.
Exposure to environmental pollutants
Research activities also include measurement of contaminants in environmental samples, and
assessment of human exposure. Specific research projects focused on the analysis of
polychlorinated and polybrominated dioxins and furans (PCDD, PBDD, PCDF and PBDF),
polychlorinated biphenyls (PCBs), perfluorooctanoic acid (PFOA), and perfluorooctane
sulphonate (PFOS), in aquatic organisms at different levels of the food chain, and farmed fish
coming from different areas of the Mediterranean sea. The purpose wass to estimate, for the
general Italian population, the exposure to these pollutants trough fish consumption.
Evaluation of toxicological data
Toxicological data, resulting from in vivo sub-chronic studies in rats exposed to individual
dioxin-like and non dioxin-like PCBs are evaluated in detail, in order to investigate the doseresponse relationship and the applicability of the “benchmark dose” approach.
Unit of Analytical Instrumentation
Development and application of analytical methods for compounds of
biological and environmental interest.
Biological fluids and environmental samples are analysed mainly using solid phase extraction
(SPE) and liquid chromatography - mass spectrometry (LC-ESI-MS/MS). Proteins and peptides
are also analysed by laser desorption ionization techniques. Tissue samples are directly analyzed
by using MALDI or PALDI Imaging (Matrix or nanoParticle Laser Desorption Ionization).
Available instruments include liquid chromatographs and mass spectrometers equipped with
different analyzers: time of flight (TOF), triple quadrupoles, ion traps and high resolution LTQOrbitrap, with conventional and nanoElectroSpray sources.
Substances of interest include proteins, peptides, hormones, pharmaceuticals, drugs of abuse,
and other environmental contaminants (pesticides, perfluorinated compounds).
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DEPARTMENT OF NEUROSCIENCE
STAFF
Head
Gianluigi FORLONI, Biol.Sci.D.
Laboratory of Biology of Neurodegenerative Disorders
Head
Gianluigi FORLONI, Biol.Sci.D.
Laboratory of Cell Death and Neuroprotection
Head
Tiziana Borselllo, Biol.Sci.D.
Laboratory of Experimental Neurology
Head
Annamaria VEZZANI, Biol.Sci.D.
Neuro-glia communications Unit
Head
Teresa Ravizza, Biol.Sci.D.
Laboratory of Experimental Psychopharmacology
Head
Luigi CERVO, Ph.D.
Laboratory of Geriatric Neuropsychiatry
Head
Ugo LUCCA, MSc
Epidemiology and Social Psychiatry Unit
Head
Barbara D’AVANZO, Philos.D.
Geriatric Epidemiology Unit
Head
Mauro TETTAMANTI, Biol.Sci.D.
Geriatric Pharmacology Unit
Head
Emma RIVA, M.D.
Laboratory of Inflammation and Nervous System Diseases
Head
Maria Grazia DE SIMONI, Biol.Sci.D.
Pharmacology of septic shock
Head
Pia VILLA, Biol. Sci. D
Laboratory of Molecular Neurobiology
Head
Caterina BENDOTTI, Farm.D.
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Laboratory of Neurobiology of Prions
Head
Roberto CHIESA, Biol. Sci. D
Laboratory of Neurochemistry and Behavior
Head
Roberto William INVERNIZZI, Biol. Sci D
Pharmacology of Cognitive Behavior Unit
Head
Mirjana CARLI, Ph.D.
Laboratory of Neurological Disorders
Head
Ettore BEGHI, M.D.
Laboratory of Quality Assessment of Geriatric Services Unit
Head
Alessandro NOBILI, M.D.
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CURRICULA
Gianluigi Forloni, obtained the Degree of Biological Science at the University of Milan in 1985. After
two years of post doc at the Department of Neuroscience and Psychiatry at Johns Hopkins University in
Baltimore, USA, he came back to the Mario Negri Institute and between 1992 and 1996 he was the head
of the Neurobiology of Alzheimer's disease Unit; since 1996 he is the Head of the Biology of
Neurodegenerative Diseases Lab and since 2002 also the Head of the Neuroscience Department. His
scientific interest is focused on the biological and genetic bases of aging-related disorders in particular
Alzheimer’s disease, Prion-related encephalopathies and Parkinson’s disease. He has been member of
several European committees for the examination of projects in the neuroscience field. He is now
member of the coordination group of the European IMI Consortium PharmaCog. He is President of the
Italian Association on Brain Aging Research (AIRIC) and member of the European Academy of
Sciences. He is the author of more than 190 peer-reviewed scientific articles and about 30 reviews or
book chapters.
•
Forloni G., Angeretti N., Chiesa R., Monzani E., Salmona M., Bugiani O.,Tagliavini F. Neurotoxicity of a prion protein
fragment. Nature 362: 543-546 (1993)
•
Forloni, G., Tagliavini, F.,Bugiani, O. and Salmona, M. Amyloid in Alzheimer’s disease and prion-related
encephalopathies: Studies with synthetic peptides. Progr. Neurobiol. 49: 287- 315 (1996)
•
Forloni G. Iussich, S. Awan T. Colombo L. Angeretti, N. Girola, L. Bertani, I. Poli, G. Caramelli, M. Bruzzone,
MG.Farina, L. Limido, L. Rossi, G. Giaccone G. Ironside, JW. Bugiani, O.Salmona M. and Tagliavini, F. Tetracyclines
affect prion infectivity Proc. Natl. Acad. Sci . New York 99: 10849-10854 (2002)
•
Fioriti, L. Angeretti, N.. Colombo, L., De Luigi A., Manzoni, C., Colombo A., Morbin, M., Tagliavini, F., Salmona, M.
Chiesa, R. Forloni, G. Neurotoxic and gliotrophic activity of a synthetic peptide homologous to Gerstmann-SträusslerScheinker disease amyloid protein. J. Neurosci. 27: 576-83 (2007)
•
Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, Restelli E, Balducci C, Fiordaliso F, Salio M,
Bianchi S, Fioriti L, Morbin M, Pincherle A, Marcon G, Villani F, Carli M, Tagliavini F, Forloni G, Chiesa R. Mutant
prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model.
Neuron. 60: 598-609 (2008)
•
Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro
A, Forloni G. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused
by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem. 110:1445-56 (2009).
•
Balducci, C., Beeg, M., Stravalaci, M., Bastone, A.,, Sclip, A., Biasini, E., Tapelll., Colombo, L. Canzoni, C., Borsello,
T., Chiesa, R., Gobbi, M., Salmona M. Forloni, G., A Synthetic β oligomers impair memory independently of cellular
prion potein
Proc. Natl. Acad. Sci USA, 107: 2295-2300 (2010)
Ettore Beghi graduated in Medicine in 1972 and received his specialty in neurology in 1976 at the
University of Milan. He trained in epidemiology with a fellowship at the Department of statistics and
Epidemiology of the Mayo Clinic in Rochester, MN (USA). He is Head of the Laboratory of
Neurological Disorders at the Mario Negri Institute, Director of the Neurophysiology/Epilepsy Unit and
Professor of Neuroepidemiology at the University of Milano-Bicocca, Monza. He is member of the
editorial board of the journals Epilepsia, Neuroepidemiology, Inpharma, Drugs in R & D, Clinical Drug
Investigation, Neurological Sciences and is a referee of several national and international medical
journals. The main areas of interest and research include studies on the descriptive, analytic, and
experimental epidemiology in the field of epilepsy, peripheral neuropathies, headache, and amyotrophic
lateral sclerosis.
•
E. Beghi, G. Logroscino, A. Chiò, O. Hardiman, A. Millul, D. Mitchell, R. Swingler, B.J. Traynor. Amyotrophic lateral
sclerosis, physical exercise, trauma and sports: results of a population-based pilot case-control study. Amyotrophic
Lateral Sclerosis 2010; 11: 289-292.
•
E. Beghi, A. Carpio, L. Forsgren, D.C. Hesdorffer, K. Malmgren, J.W. Sander, T. Tomson, W.A. Hauser.
Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010; 51: 671-675.
•
A. Del Felice, E. Beghi, G. Boero, A. La Neve, G. Bogliun, A. De Palo, L.M. Specchio. Early versus late remission in a
cohort of patients with newly diagnosed epilepsy. Epilepsia 2010; 51: 37-42.
•
G. Logroscino, B.J. Traynor, O. Hardiman, A. Chiò, D. Mitchell, R.J. Swingler, A. Millul, E. Benn, E. Beghi. Incidence
of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 2010; 81: 385-390.
•
Leone MA, Solari A, Beghi E, for the FIRST Group. Treatment of the first tonic-clonic seizure does not affect long-term
remission of epilepsy. Neurology 2006; 67: 2227-2229
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•
Van den Broek M, Beghi E, for the RESt-1 Group. Accidents in patients with epilepsy: type and complications. A
European Cohort Study. Epilepsia 2004; 45: 667-672.
Caterina Bendotti, got her degree in Pharmacy at the University of Milano in 1984; In 1986 -1988 she was
postdoc at the Genetic Developmental Lab, Dept. of Physiology of the Johns Hopkins University, Baltimore,
USA. In 1988 -1992 she was research fellow in the laboratory of Neuropharmacology and in the 1992, she
became head of the Molecular Neurobiology Unit in Institute, since 1998 she is head of laboratory. The
major research interest is the study of pathogenetic mechanisms of familial Amyotrophic Lateral Sclerosis..
Since 2002 she is a member of the editorial board of Journal of Neurochemistry. In 2002-2003 has been
Member of Scientific Committees of the International Symposia on ALS held in Milano, 17-19
Novembre,2003. In 2003-2007 has been member of the Italian Ministry of Health Committees for the
diagnosis, cure, care and assistance of patients with ALS. Since 2005-2009 she has been member of the
Executive Council of the Italian Society of Neuroscience. Since 2006 is member of the Research Advisory
Panel of the MND Association, UK. Scientific reviewer of 11 international scientific journals. In 2007 she
has co-organised the first international meeting on” Mutant SOD1 and familial ALS: from the molecule to
man” held in Milano (13-16 September). She is author and co-author of 110 articles 100 of which with
peer-review. Rapporteur of many communications in national and international meetings.
•
Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S, Bendotti
C, De Biasi S, Poletti A. The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins
involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet. 19(17):3440-56, 2010
•
Peviani M, Caron I, Pizzasegola C, Gensano F, Tortarolo M, Bendotti C. Unraveling the complexity of amyotrophic
lateral sclerosis: Recent advances from the transgenic mutant SOD1 mice. CNS Neurol Disord Drug Targets. 9(4):491503, 2010
Ludolph AC, Bendotti C, Blaugrund E, Chio A, Greensmith L, Loeffler JP, Mead R, Niessen HG, Petri S, Pradat PF,
•
Robberecht W, Ruegg M, Schwalenstöcker B, Stiller D, van den Berg L, Vieira F, von Horsten S. Guidelines for
preclinical animal research in ALS/MND: A consensus meeting. Amyotroph Lateral Scler.11(1-2):38-45, 2010
•
Basso M, Samengo G, Nardo G, Massignan T, D'Alessandro G, Tartari S, Cantoni L, Marino M, Cheroni C, De Biasi S,
Giordana MT, Strong MJ, Estevez AG, Salmona M, Bendotti C, Bonetto V. Characterization of detergent-insoluble
proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis.PLoS One. 4(12):e8130.
2009
•
Bendotti C, Carrì MT. Amyotrophic lateral sclerosis: mechanisms and countermeasures. Antioxid Redox Signal.
11(7):1519-22, 2009
•
Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, Carrì MT, Bendotti C.Treatment with lithium carbonate does not
improve disease progression in two different strains of SOD1 mutant mice. Amyotroph Lateral Scler. 10(4):221-8, 2009
•
Nardo G, Pozzi S, Mantovani S, Garbelli S, Marinou K, Basso M, Mora G, Bendotti C, Bonetto V.Nitroproteomics of
peripheral blood mononuclear cells from patients and a rat model of ALS. Antioxid Redox Signal. 11(7):1559-67, 2009
•
Cheroni C, Marino M, Tortarolo M, Veglianese P, De Biasi S, Fontana E, Zuccarello LV, Maynard CJ, Dantuma NP,
Bendotti C.Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial
amyotrophic lateral sclerosis. Hum Mol Genet. 18(1):82-96, 2009
Tiziana Borsello got her Degree in Biological Science at the University of Torino in 1990 and she then
obtained a PhD in Neuroscience at the University of Turin Medical School. She won 1 year fellow of the
European Science Foundation scholarship for work at the Netherlands Research Institute of Amsterdam. From
1997 to 1999 she was a Researcher at the Institute of Neurobiology, CNR, Rome Italy. In the period 1999-2003
she was Premier Assistant, Département de Biologie Cellulaire et de Morphologie, Université de Lausanne,
Switzerland, and then became Maitre Assistant and group leader in the same institute. In 2004 joined the Biol.
Neurodeg. Disorders Lab at the "Mario Negri” Institute. In 2005 won the Prize of the Pfizer Foundation,
Neuroscience and Diseases Nervous System. Since 2006 she is the Head of the Unit: Neuronal Death and
Neuroprotection. Her main scientific interest is understanding the role of signaling pathways in neuronal death
after different stress-stimuli and the neuroprotection. In particular, the present research is focused on the study
of the mechanisms of excitotocic stress, ischemia, Traumatic Brain Injury and the cell death pathways in
neurodegenerative diseases as Alzheimer, with the challenge to define the neuronal death pathways to design
more specific methods of neuroprotection.
Selected pubblications
•
Antoniou X, Falconi M, Di Marino D, Borsello T. JNK3 as a therapeutic target for Neurodegenerative disease. J
Alzheimers Dis. 2010 Feb 24.
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Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa
R, Gobbi M, Salmona M, Forloni G. Synthetic Amyloid-Beta Oligomers Impair Long-Term Memory Independently Of
Cellular Prion Protein. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300
•
Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, Borsello T. JNK Regulates App Cleavage And
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Degradation In A Model Of Alzheimer's Disease Neurobiology Of Disease, 2009 Mar;33(3):518-25
Borsello T Ed “Neuroprotection: Methods In Molecular Biology” Published By Humana Press, Usa HYPERLINK
"http://www.humanapress.com/"Humana Press, USA, Methods in Molecular Biology, June 2007
Colombo A, Repici M, Pesaresi M, Santambrogio S, Forloni G, Borsello T. The Tat-Jnk Inhibitor Peptide Interferes With
Beta Amyloid Protein Stability Cell Death Differ. 2007, 14:1845-8.
Borsello T and Forloni G. JNK signalling: a possible target to prevent neurodegeneration. Current Pharmaceutical
Design 2007, 13, 1875-1886
Centeno C., Repici M., Chatton J. Y., Riederer B. M., Bonny C., Nicod P., Price M., Clarke P. G., Papa S., Franzoso G.
and Borsello T. Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. Cell Death Differ ,
2007, 14: 240-253.
Borsello T. and Bonny C.Use of cell-permeable peptides to prevent neuronal degeneration. Trend in Mol. Med. 2004, 10:
239-44
Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C. A peptide inhibitor of
c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nature Med. 2003, 9: 1180-6
Luigi Cervo was awarded the degree of Doctor of Philosophy (Ph.D.) from the Open University, Milton
Keynes, U. K. in 2005. Since 2006 he has been the head of the Experimental Psychopharmacology
Laboratory. From 1978 to 2001 he has been a research fellow and then Chief of the Behavioural
Pharmacology Unit in the laboratory of Neuropharmacology and in 1981 he was awarded the degree in
Biochemical Research from the “M. Negri” Institute. Between 1981 and 1983 he spent two years as a
research fellow in the Department of Psychiatry at the Chicago University, Illinois, U.S.A. His main
research interests concern Neuropsychopharmacology and the mechanism of action of psychotropic
drugs. In particular the role of receptors subtypes for serotonin, dopamine, noradrenaline and glutamate
in drug dependence and drug craving, depression, anxiety. Author and co-author of several peer-review
articles, author of communications in international meetings, he is scientific reviewer of several
international scientific journals. Member of Society for Neuroscience, European Behavioural
Pharmacological Society, Italian Society for Neuroscience and Italian Society of
Neuropsychopharmacology.
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Cervo L, Carnovali, F, Stark JA, Mennini T. Cocaine-seeking behavior in response to drug-associated stimuli in rats:
involvement of D3 and D2 dopamine receptors. Neuropsychopharmacology 2003; 28: 1150-1159
Grignaschi G, Burbassi S, Zennaro E, Bendotti C, Cervo L. A single high dose of cocaine induces behavioural
sensitization and modifies mRNA encoding GluR1 and GAP-43 in rats. Eur J Neurosci 2004; 20:2833-2837
Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, Invernizzi R.
Deficits of serotonin synthesis cause resistance to antidepressants, J Neuroscience 2005; 25: 8165-8172
Cervo L, Cocco A, Petrella C, Heidbreder CA. Selective antagonism at dopamine D3 receptors attenuates cocaineseeking behaviour in the rat. Int J Neuropsychopharmacol. 2007; 10: 167-181.
Burbassi S, Cervo L. Stimulation of serotonin(2C) receptors influences cocaine-seeking behavior in response to drugassociated stimuli in rats. Psychopharmacology (Berl). 2008; 196: 15-27.
Burattini C, Burbassi S, Aicardi G, Cervo L. Effects of naltrexone on cocaine- and sucrose-seeking behaviour in
response to associated stimuli in rats. Int J Neuropsychopharmacol. 2008; 11, 103-109.
Marchesi F, Piemonti L, Fedele G, Destro A, Roncalli M, Albarello L, Doglioni C, Anselmo A, Doni A, Bianchi P,
Laghi L, Malesci A, Cervo L, Malosio M, Reni M, Zerbi A, Di Carlo V, Mantovani A, Allavena P. The chemokine
receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer
Res. 2008; 68, 9060-9069.
Fumagalli F, Franchi C, Caffino L, Racagni G, Riva MA, Cervo L. Single session of cocaine intravenous selfadministration shapes goal-oriented behaviours and up-regulates Arc mRNA levels in rat medial prefrontal cortex Int J
Neuropsychopharmacol. 2009; 12:423-9.
Calcagno E, Guzzetti S, Canetta A, Fracasso C, Caccia S, Cervo L, Invernizzi RW. Enhancement of cortical extracellular
5-HT by 5-HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-responder
mice. Int J Neuropsychopharmacol. 2009 12: 793-803.
Watson J, Guzzetti S, Franchi C, Di Clemente A, Burbassi S, Emri Z, Leresche N, Parri HR, Crunelli V, Cervo L.
Gamma-hydroxybutyrate does not maintain self-administration but induces conditioned place preference when injected
in the ventral tegmental area. Int J Neuropsychopharmacol. 2010, 13:143-53.
Roberto Chiesa graduated in Biological Sciences with major in Genetics at the University of Pavia in
1991, and obtained a Ph.D. in Pharmacology at the Mario Negri Institute for Pharmacological Research of
Milan in 1994. From 1996 through 2000 he was Research Associate at the Department of Cell Biology
and Physiology of Washington University in St. Louis, MO, USA. In 2001 Dr. Chiesa moved back to the
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Mario Negri Institute where he is currently head of the Prion Neurobiology lab in the Department of
Neuroscience. He also holds an Associate Telethon Scientist position (Dulbecco Telethon Institute,
Telethon Foundation).
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Chiesa R, Piccardo P, Ghetti B, Harris DA Neurological illness in transgenic mice expressing a prion protein with an
insertional mutation. Neuron. 21:1339-51 (1998)
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Fioriti L, Dossena S, Stewart LR, Stewart RS, Harris DA, Forloni G, Chiesa R. Cytosolic prion protein (PrP) is not toxic in
N2a cells and primary neurons expressing pathogenic PrP mutations. J Biol Chem. 280:11320-8 (2005)
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Biasini E, Massignan T, Fioriti L, Rossi V, Dossena S, Salmona M, Forloni G, Bonetto V, Chiesa R Analysis of the cerebellar
proteome in a transgenic mouse model of inherited prion disease reveals preclinical alteration of calcineurin activity.
Proteomics. 6:2823-34 (2006)
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Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, Restelli E, Balducci C, Fiordaliso F, Salio M, Bianchi S,
Fioriti L, Morbin M, Pincherle A, Marcon G, Villani F, Carli M, Tagliavini F, Forloni G, Chiesa R. Mutant prion protein
expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model. Neuron. 2008,
60:598-609 (2008).
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Biasini E., Tapella L., Mantovani S., Stravalaci M., Gobbi M., Harris D.A. and Chiesa R. (2009) Immunopurification of
pathological prion protein aggregates. PloS ONE, 4(11): e7816
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Massignan T. Stewart R.S., Biasini E. Solomon I.H., Bonetto V., Chiesa R. and Harris D.A. (2010) A novel, drug-based,
cellular assay for the activity of neurotoxic mutants of the prion protein. J. Biol. Chem. 285: 7752-7765
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Balducci C., Beeg M., Stravalaci M., Bastone A., Sclip A., Biasini E., Tapella L., Colombo L., Manzoni C., Borsello T.,
Chiesa R., Gobbi M., Salmona M., Forloni G. (2010) Ab oligomers impair memory independently of cellular prion protein.
Proc. Natl. Acad. Sci. 107: 2295-2300
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Massignan T., Biasini E., Lauranzano E., Veglianese P., Pignataro M., Fioriti L., Harris D.A., Salmona M., Chiesa R., and
Bonetto V. (2010) Mutant prion protein expression is associated with an alteration of the Rab GDP dissociation inhibitor alpha
(GDI)/Rab11 pathway. Mol Cell Proteomics 9: 611-22
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Biasini E., Tapella L., Restelli E., Pozzoli M., Massignan T., and Chiesa R. (2010) The hydrophobic core region governs
mutant prion protein aggregation and intracellular retention. Biochemical Journal 430: 477-86
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Restelli E., Fioriti L., Mantovani S., Airaghi S., Forloni G., and Chiesa R. (2010) Cell type-spcific neuroprotective activity of
untranslocated prion protein. PloS ONE, 5(10): e13725
Maria Grazia De Simoni, Doctoral Degree in Biological Sciences in 1977, University of Milano, Italy,
110/110 summa cum laude. 1981: PhD in Neuropharmacology. 1981-1982: European Community
fellowship for "Advanced Professional Training", INSERM U 171, Universitè Claude Bernard, Lyon,
France. Presently: Head of the Laboratory of Inflammation and Nervous System Diseases, Mario Negri
Institute Milan, Italy. She developed a long lasting expertise in experimental models of CNS diseases.
The main scientific interests presently include the pathogenesis of cerebral ischemia/reperfusion and of
traumatic brain injury; the inflammatory response as target of therapeutic strategies; peripheral
inflammatory markers in CNS diseases; the protective mechanisms of stem cells. Member of the
Scientific Board of Associazione Italiana per la Ricerca sull’Invecchiamento Cerebrale (AIRIC) and of
the Editorial Board of Stroke, a Journal of Cerebral Circulation. Author of more than 100 scientific
papers on peer-reviewed international journals.
- Gesuete R, Orsini F, Zanier ER, Deli MA, Albani D, Bazzoni G, De Simoni MG. Glial cells drive preconditioning-induced
blood-brain-barrier protection. Stroke, 2011 (in press).
- Zanier ER, Brandi G, Peri G, Longhi L, Zoerle T, Tettamanti M, Garlanda C, Sicurtà A, Valaperta S, Mantovani A, De
Simoni MG, Stocchetti N. Cerebrospinal fluid pentraxin-3 early after subarachnoid hemorrhage is associated with
vasospasm. Intensive Care Medicine 2011, in press.
- Ortolano F, Maffia P, Dever G, Rodolico G, Millington OR, De Simoni MG, Brewer JM, Bushell T, Garside P, Carswell
HV. Advances in imaging of new targets for pharmacological intervention in stroke: real-time tracking of T-cells in the
ischemic brain. Br J Pharmacol 2010; 159: 808-811.
- Ortolano F, Colombo A, Zanier ER, Sclip A, Longhi L, Perego C, Stocchetti N, Borsello T, De Simoni MG. c-Jun Nterminal kinase pathway activation in human and experimental cerebral contusion. J Neuropathol Exp Neurol 2009; 68:
964-971.
- Gesuete R, Storini C, Fantin A, Stravalaci M, Zanier ER, Orsini F, Vietsch H, Mannesse MLM, Ziere B, Gobbi M, De
Simoni MG. Recombinant C1-inhibitor in Brain Ischemic Injury. Annals of Neurology 2009; 66: 332-342.
- Longhi L, Perego C, Ortolano F, Zanier E R, Bianchi P, Stocchetti N, McIntosh T and De Simoni MG .C1-Inhibitor
attenuates neurobehavioral deficits and reduces contusion volume following controlled cortical impact brain injury in
mice. Critical Care Medicine 2009; 37: 659-665.
- Capone C, Frigerio S, Fumagalli S, Gelati M, Principato M C, Storini C, Montinaro M, Kraftsik R, De Curtis M, Parati E,
De Simoni MG. Neurosphere - derived cells exert a neuroprotective action by changing the ischemic microenvironment.
PLoS ONE 2007; 2(4): e373.
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- Balosso S, Ravizza T, Perego C, Peschon J, Campbell IL, De Simoni MG, Vezzani A. Tumor necrosis factor-α inhibits
seizures in mice via p75 receptors. Annals Neurol 2005; 57: 804-812.
- Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, De Luigi A, Vergani C, De Simoni MG.
Peripheral treatment with enoxaparin, a low-molecular weight heparin, reduces plaques and β-amyloid accumulation in a
mouse model of Alzheimer’s disease. J. Neurosci 2004; 24: 4181-4186.
Roberto W. Invernizzi started his career in the laboratory of Neuropharmacology of the “Istituto di
Ricerche Farmacologiche “Mario Negri” in 1976, where, at present, he heads the Laboratory of
Neurochemistry and Behavior. In 1986 he got his degree in Biological Sciences at the Università Statale di
Milano and in 1996 he was nominated head of the Intracerebral Microdialysis Unit. Of particular interest
to Invernizzi’s research team is the study of the neurochemical mechanisms and neuronal circuitries
involved in the pathology of the main psychiatric diseases, such as depression and schizophrenia and in
the mechanism of action of psychotropic drugs. Since 1987 he applied the intracerebral microdialysis
technique to study the in vivo release of monoamines. Using this technique, Invernizzi’s team first
contributed to clarifying the role of serotonergic and adrenergic autoreceptors in the effect of
antidepressant drugs suggesting new hypotheses on their mechanism of action. Currently, Invernizzi’s
laboratory is involved in two main collaborative projects aimed at clarifying the neurochemical
mechanisms involved in the “resistance” to antidepressant drugs and the role of glutamatergic and
serotonergic mechanisms in attentional processes. Reviewer for various international journals in the field
of pharmacology and neurochemistry. Author and co-author of more than 60 peer-reviewed articles.
Member of the Italian Society of Neuroscience and the Italian Society of Pharmacology.
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Calcagno E, Invernizzi RW Strain-dependent serotonin neuron feedback control: role of serotonin receptors. J Neurochem 2010; 114:
1701-1710
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Calcagno E, Guzzetti S, Canetta A, Fracasso C, Caccia S, Cervo L, Invernizzi RW. Enhancement of cortical extracellular 5-HT by 5HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-responder mice. Int J
Neuropsychopharmacol 2009 12: 793-803
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Calcagno E, Carli M, Baviera M, Invernizzi RW. Endogenous serotonin and serotonin2C receptors are involved in the ability of
M100907 to suppress cortical glutamate release induced by NMDA receptor blockade. J Neurochem 2009 108 : 521-532
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Balosso S, Ravizza T, Pierucci M, Calcagno E, Invernizzi RW, Di Giovanni G, Esposito E, Vezzani A. Molecular and functional
interactions between tumor necrosis factor-alpha receptors and the glutamatergic system in the mouse hippocampus: Implications for
seizure susceptibility. Neuroscience 2009 161 : 293-300
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Baviera M, Invernizzi RW, Carli M. Haloperidol and clozapine have dissociable effects in a model of attentional
performance deficits induced by blockade of NMDA receptors in the mPFC. Psychopharmacology 2008; 196: 269-280.
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Guzzetti S, Calcagno E, Canetta A, Sacchetti G, Fracasso C, Caccia S, Cervo L, Invernizzi RW
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Strain differences in paroxetine-induced reduction of immobility time in the forced swimming test in mice: Role of
serotonin. Eur. J. Pharmacol. 2008; 594: 117-124
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Calcagno E, Canetta A, Guzzetti S, Cervo L, Invernizzi RW. Strain differences in basal and post-citalopram extracellular
5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan with tryptophan
hydroxylase-2 activity. J Neurochem 2007; 103 : 1111-1120
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Invernizzi RW, Pierucci M, Calcagno E, Di Giovanni G, Di Matteo V, Benigno A, Esposito E. Selective activation of
5HT2C receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: a combined in vivo
electrophysiological and neurochemical study. Neuroscience 2007 144 : 1523-1535
Ugo Lucca got his Master of Science, University of Aberdeen - UK, 1999. At the Mario Negri Institute
he was investigator from 1986- 1995, head of the "Clinical Evaluation of Antidementia Drugs Unit"
(1995-1996) and, since 1996, head of the "Laboratory of Geriatric Neuropsychiatry". The main areas of
interests include epidemiology and clinic features of dementia; natural history of dementia;
neuropsychiatric disorders of the elderly; instruments for the screening diagnosis and clinical course
assessment of dementia; clinical evaluation of anti dementia treatments and CNS active drugs (phase I,
II, III, IV and observational studies).
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Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, et al. Long-term acetyl-L-carnitine
treatment in Alzheimer's disease. Neurology 1991; 41:1726-1732
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Lucca U, Comelli M, Tettamanti M, Tiraboschi P, Spagnoli A. Rate of progression and prognostic factors in Alzheimer’s
disease: a prospective study. J Am Geriats Society 1993; 41: 45-49.
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Lucca U, Tettamanti M, Forloni G, Spagnoli A. Nonsteroidal anti-inflammatory drug use in Alzheimer’s disease.
Biological Psychiatry 1994; 36: 854-856.
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Imbimbo BP, Martelli P, Troetel WM, Lucchelli F, Lucca U, Thal LJ, and the Eptastigmine Study Group. Efficacy and
safety of eptastigmine for the treatment of patients with Alzheimer’s disease. Neurology 1999; 52: 700-708.
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Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer’s disease and Vascular Dementia. Am J Clinical Nutr 2004; 80: 114-122.
Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. New England Journal of
Medicine 2006; 355: 1390.
Lucca U, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M,
Tempia P, Guala A, Fasolo G, Riva E.Association of mild anemia with cognitive, functional, mood and quality of life
outcomes in the elderly: the "Health and Anemia" study. PLoS ONE. 3(4):e1920 (2008)
Alessandro Nobili got his degree in Medicine (Milan, 1990). Master in Biotechonological Research,
Regione Lombardia, Milan 1988. International School of Pharmacology, 31° Course on: Drug
Epidemiology and Post-marketing Surveillance, Erice, September 1990. Course on: Methods in
Epidemiological Research, Milan, October 1990. Course: Long Term Clinical Trials, Cogne January
1991.
Main areas of interest Methodology of Randomized Clinical Trials; Pharmacoepidemiology and postmarketing surveillance research; Drug utilization studies; Quality assessment of geriatric services;
Qualitative studies on caregiver role in the care of patients with dementia; Methodological evaluation of
the Special Care Unit for Alzheimer Disease patients; Methodology of drug information. Employment
and research experience Chief of the Unit of Quality Assessment of Geriatric Services Chief of the Drug
Information Services for the Elderly, Laboratory of Geriatric Neuropsychiatry, Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan. Editorial Board of the MICROMEDEX Inc., Englewood,
Colorado 80111-4740 USA. National Expert accredited by Italian Ministry of Health for The Italian
(AIFA) and European Agency for the Evaluation of Medicinal Products (EMEA). Head of the
Laboratory of the Quality Assessment of Geriatric Services at the Mario
Negri Institute since 2007.
Nobili A, Riva E, Tettamanti M, et al. The effect of a structured intervention on cergivers of patients with dementia and
problem behaviour: a randomized controlled pilot study. Alzheimer Dis Assoc Disord 2004; 18: 75-82.
Nobili A, Piana I, Balossi L, Pasina L, Matucci M, Tarantola M, Trevisan S, Riva E, Lucca U, Tettamanti M. Alzheimer
special care units compared with traditional nursing home for dementia care: are there differences at admission and in
clinical outcomes? Alzheimer Dis Assoc Disord. 2008; ;22:352-61.
Nobili, L. Pasina, M. Tettamanti, U. Lucca, E. Riva, I. Marzona, L. Monesi, R. Cucchiani, A. Bortolotti, I. Fortino, L.
Merlino, G. Walter Locatelli, G. Giuliani. Potentially severe drug interactions in elderly outpatients: results of an
observational study of an administrative prescription database. Journal of Clinical Pharmacology and Therapeutics 2009;
34: 377-386.
Alessandro Nobili, Luca Pasina, Silvia Trevisan, Emma Riva, Ugo Lucca, Mauro Tettamanti, Marina Matucci, Massimo
Tarantola. Use and misuse of antipsychotic drugs in patients with dementia in Alzheimer special care units. Int Clin
Psychopharmacol 2009; 24:97-104.
Marengoni A, Bonometti F, Nobili A, Tettamanti M, Salerno F, Corrao S, Iorio A, Marcucci M, Mannucci PM; Italian
Society of Internal Medicine (SIMI) Investigators. In-hospital death and adverse clinical events in elderly patients
according to disease clustering: the REPOSI study. Rejuvenation Res. 2010;13:469-77.
Marcucci M, Iorio A, Nobili A, Tettamanti M, Pasina L, Marengoni A, Salerno F, Corrao S, Mannucci PM; REPOSI
Investigators. Factors affecting adherence to guidelines for antithrombotic therapy in elderly patients with atrial
fibrillation admitted to internal medicine wards. Eur J Intern Med. 2010; 21:516-23.
Annamaria Vezzani got her Degree in Biological Science at the University of Milan in 1978 and she
specialized in Neuropharmacology at the Mario Negri Institute in 1982. She spent her post-doctoral
period in Baltimore at the University of Maryland in 1983-1984 working on the mechanisms of
epileptogenesis in experimental models of epilepsy. She spent additional post-doctoral periods at the
University of Stockholm and at the Karolinska Institute between 1985 and 1999. She was on
sabbatical at the Albert Einstein College of Medicine in 2002 in the laboratory of Developmental
Epilepsy. She is involved in studies on the biochemical and molecular mechanisms involved in the
etiopathogenesis of seizures disorders using experimental models of epilepsy. The present research is
focused on the functional role of neuroactive peptides and inflammatory mediators in the modulation
of neuronal excitability and seizure-related neurodegeneration. Focus of the research is also on the
mechanisms of pharmacoresistance. Since 1997 she is the Head of the Laboratory of Experimental
Neurology at the Mario Negri Institute. She is member of the Editorial Board of Epilepsy Currents
and Neuroscience and Associate Editor for Exp Models of Epilepsia. She is appointed of the Chair of
the Commission on Neurobiology of International League Against Epilepsy which is promoting
initiatives for improving translational research in epilepsy.
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Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoni MG. Interleukin-1beta
immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence
for enhancement of electrographic seizures.(1999) J Neurosci.19:5054-65.
Vezzani A., Moneta D., Conti M., Richichi C., Ravizza T., De Luigi A., De Simoni M.G., Sperk, Andell-Jonsson S.,
Lundkvist J., Iverfeldt K. and Bartfai T. Powerful anticonvulsant action of IL-1 receptor antagonist upon intracerebral
injection and astrocytic overexpression in mice (2000) Proc Natl Acad Sci USA, 97: 11534
Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, Aliprandi M, Bagnati R, Fanelli R, D'Incalci M, Samanin
R, Vezzani A. Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance
(2002) J Neurosci, 22: 5833
Balosso S, Ravizza T, Perego C, Peschon J, Campbell I, De Simoni MG, Vezzani A. TNF-alpha inhibits kainic acidinduced seizures in mice via p75 receptors (2005) Ann Neurol, 57: 804-12
Ravizza T, Gagliardi B, Noè F, Boer K, Aronica E and Vezzani A. Innate and adaptive immunity during epiletogenesis
and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy (2008) Neurobiol Dis,
29: 142
Noè F, Pool AH, Nissinen J, Gobbi M, Bland R, Rizzi M, Balducci C, Ferraguti F, Sperk G, During MJ, Pitkänen A,
Vezzani A. Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe
epilepsy (2008) Brain, 131:1506
Balosso S, Maroso M, Sanchez-Alavez M, Ravizza T, Frasca A, Bartfai T, Vezzani A. A novel non-transcriptional
pathway mediates the proconvulsive effects of interleukin-1beta. (2008) Brain, 131:3256
Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer A, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA,
Bianchi ME and Vezzani A. Toll-Like Receptor 4 (TLR4) and High Mobility Group Box 1 (HMGB1)are involved in
ictogenesis and can be targeted to reduce seizures (2010) Nature Medicine, 16:413-9.
Mirjana Carli started his scientific career in the laboratory of Neuropharmacology of the “Istituto di
Ricerche Farmacologiche Mario Negri” Milan in 1977, where, at present, she is head of the
Pharmacology of Cognitive Behaviour Unit. She spent a few years in the laboratory of Cognitive
Neuroscience, Dept. of Experimental Psychology, University of Cambridge (UK) directed by Prof.
Trevor W. Robbins. Here she took interest in the role of brain monoamines in attention, and for this
purpose developed several behavioral tests for rats. In 1986 she returned to the laboratory of
Neuropharmacology of the “Istituto di Ricerche Farmacologiche Mario Negri”. Here she devoted her
efforts to the study of the role played by neuronal mechanisms in cognitive processes such as memory,
attention and executive functions. Her work has improved the knowledge of the role played by some
serotonin receptors in cognitive processes.
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Carli M, Baviera M, Invernizzi R, Balducci C Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial
prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rat
Neuropsychopharmacology 2006; 31: 757-767
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Greco B, Carli M Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: Relation to anxiolyticlike phenotype Behav Brain Res 2006; 169: 325-334
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Carli M, Baviera M, Invernizzi R, Balducci C The serotonin 5-HT2A receptors antagonist MI00907 prevents impairment
in attentional performance by NMDA receptor blockade in the rat prefrontal cortex Neuropsychopharmacology 2004;
29: 1637-1647
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Balducci C, Nurra M, Pietropoli A, Samanin R, Carli M Reversal of visual attention dysfunction after AMPA lesions of
the nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT(1A) receptor
antagonist WAY 100635 Psychopharmacology (Berl) 2003; 167: 28-36
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Carli M, Balducci C, Samanin R. Stimulation of 5-HT1A receptors in the dorsal raphe ameliorates the impairment of
spatial learning caused by intrahippocampal 7-chloro-kynurenic acid in naive and pretrained rats Psychopharmacology
(Berl) 2000; 158: 39-47
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Carli M, Samanin R The 5-HT1A receptor agonist 8-OH-DPAT reduces rats' accuracy of attentional performance and
enhances impulsive responding in a five-choice serial reaction time task: Role of presynaptic 5-HT1A receptors
Psychopharmacology (Berl) 2000; 149: 259-268
Barbara D’Avanzo obtained her master in Philosophy in 1989 at the University of Milan. Her main field
of interest is epidemiologic research in mental health. She was involved in the analysis of the
implementation of the psychiatric reform in Italy and quality evaluation of services and their recent
modifications with specific attention to the role of psychiatric residential facilities in the community
service networks; evaluation of effectiveness of the most common psychosocial interventions; suicide
trend monitoring and study of suicide prevention programs and initiatives. More recently, she is working
on issues like recovery-oriented services, consumers’ empowerment, and methods of participation of
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consumers to evaluation of services, and acknowledgment of the value of the consumers’ point of view
about psychiatric treatments and services.
She worked as researcher in the Laboratory of General Epidemiology between 1991 and 1996, and she is
Chief of the Unit of Epidemiology and Social Psychiatry since 2002. Member of the Scientific National
Board of WAPR Italy and of the World Head Office of the WAPR.
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Barbato A, Parabiaghi A, Panicali F, Battino N, D'Avanzo B, De Girolamo G, Rucci P, Santone G, PROGRES-Acute
Group. Do patients improve after short psychiatric admission? A cohort study in Italy Nord J Psychiatry 2010; E-pub
Campi R, Barbato A, D'Avanzo B, Guaiana G, Bonati M Suicide in Italian children and adolescents J Affect Disord
2009; 113:291-295
Barbato A, D'Avanzo B. Efficacy of couple therapy as a treatment for depression: a meta-analysis. Psychiatr Q 2008;
79:121-132
D'Avanzo B, Aliprandini E, Beghi M, Cornaggia C M, Erlicher A, Frova M, Mascarini A, Miragoli P, Righi A. Strutture
residenziali e semiresidenziali nei servizi di salute mentale. Dove sta la differenza? Epidemiologia e Psichiatria Sociale
2008; 17:57-64
Barbato A, D'Avanzo B. Marital therapy for depression. Cochrane Database Systematic Reviews 2006; Issue 2.
Parabiaghi A, Barbato A, D'Avanzo B, Erlicher A, Lora A. Assessing reliable and clinically significant change on Health
of the Nation Outcome Scales: method for displaying longitudinal data. Aust N Z J Psychiatry 2005; 39: 719-725.
Barbato A, D'Avanzo B. Involuntary placement in Italy. Br J Psychiatry 2005; 186: 542-543.
Guaiana G, Andretta M, Corbari L, Mirandola M, Sorio A, D'Avanzo B, Barbui C. Antidepressant drug consumption and
public health indicators in Italy, 1955-2000. J Clinical Psychiatry 2005; 66: 750-755.
D'Avanzo B, Battino R N, Gallus S, Barbato A. Factors predicting discharge of patients from community residential
facilities: A longitudinal study from Italy. Aust N Z J Psychiatry 2004; 38: 619-628.
D'Avanzo B, Barbato A, Barbui C, Battino N, Civenti G, Frattura L. Discharges of patients from public psychiatric
hospitals in Italy between 1994 and 2000. Int J Social Psychiatry 2003; 49: 27-3
Emma Riva, Medical Doctor degree in 1984 University of Milan, PhD in 1990 in Cardiovascular
Pathophysiology at the University of London (UK) Training: Research Assistant, Department of
Pharmacology, Medical School, University of Ottawa, Canada; Internship in Internal Medicine, Ospedale
Luigi Sacco, Milan; Cardiac Fellow, St Thomas' Hospital, London, UK. Field of interest: Prevalence and
effects of anemia on cognitive, functional and clinical variables in the elderly; Problem behaviors in
dementia; Burden for care-givers of Alzheimer Disease patients; End of life care. Present and past roles
in Institute Head of the Geriatric Pharmacology Unit, Istituto "Mario Negri", Milan; Scientific Director
of the hospice “Via di Natale Franco Gallini”, Aviano, Italy; Consultant Istituto Geriatrico “Pio Albergo
Trivulzio”, Milan: Project member of PREDICT (Policy Review and Evaluation of Dementia and
Institutional Care Trends): a Transnational Comparison.
Riva E, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M,
Tempia P, Guala A, Fasolo G, Lucca U. Association of mild anemia with hospitalization and mortality in the Elderly:
The Health and Anaemia Population-based Study. Haematologica 2009; 94:22-28
Nobil i A, Franchi C, Pasina L, Tettamanti M, Baviera M, Monesi L, Roncaglioni C, Riva E, Lucca U, Bortolotti A,
Fortino, I Merlino L. Drug utilization and polypharmacy in an Italian elderly population: the EPIFARM-Elderly Project.
Pharmacoepidemiology and Drug Safety, 2011 DOI: 10.1002/pds.2108
Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone MV, Detoma P, Giacomin A,
Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta MG, Riva E. Prevalence, incidence and types of mild
anemia in the elderly: the "Health and Anemia" population-based study. Haematologica. 2010;95(11):1849-1956
Pasina L, Nobili A, M. Tettamanti M, Riva E, Lucca U, Piccinelli R, Defendi L, Perego L, Lucifora S, Bulla C. Coprescription of gastroprotective agents in patients taking non-selective NSAIDs or COX-2 selective inhibitors: analysis
of prescriptions. Int J Clini Pharmacol and Ther 2010;48:735-743
Avanzini F, Marelli G, Donzelli W, Sorbara L, Palazzo E, Bellato L, Colombo EL, Roncaglioni MC, Riva E, De Martini.
Hyperglycemia during acute coronary syndrome: a nurse-managed insulin infusion protocol for stricter and safer control.
Eur J Cardiovasc Nursig 2009;8:182-189
Nobili A, Pasina L, Tettamanti M, Lucca U, Riva E, Marzoni I, Monesi L, Cucchiani R, Bortolotti A, Fortino I, Merlino
L, Locatelli W. Giuliani G. Potentially severe drug interactions in elderly outpatients: results of an observational study of
an administrative prescription database. J Clin Pharm Ther 2009;34:1-10
Lucca U, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M,
Tempia P, Guala A, Fasolo G, Riva E. Association of Mild Anemia with Cognitive, Functional, Mood and Quality of
Life Outcomes in the Elderly: The “Health and Anemia” Study. Plos ONE 2008;3(4):e1920
Tettamanti M, Garrì MT, Nobili A, Riva E, Lucca U. Low folate and risk of cognitive and functional deficits in the very
old: The Monzino 80-plus study. J Am Coll Nutr 2006;25:502-508
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Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch Neurol
2006;63:154-155
Mauro Tettamanti got his Biology Degree at the Università degli Studi di Milano in 1986, and the
specialisation in Epidemiology and Medical Statistics in 1993, at the Università degli Studi di Pavia.
Teaching experience Introduction course to statistics, Master in Ergonomy, Politecnico di Milano, years
2001-2004 Areas of interest: Planning, conduction and analysis of clinical trials and epidemiologic
researches in the geriatric field: Phase I, II, III and observational studies on the efficacy of drugs on
neurologic disorders, with special emphasis on dementia; Effects of multi-disciplinary interventions on
geriatric/dementia patients; Epidemiology and risk factors of dementia; Care of patients with terminal
illness; Association of anemia with prevalence of diseases and cognitive problems Scholarship between
1989 and 1998, Senior Researcher since 1999 and Head of the Unit of Geriatric Epidemiology at the
Mario Negri Institute since 2001.
•
Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, et al. Long-term acetyl-L-carnitine
treatment in Alzheimer's disease. Neurology 1991; 41:1726-1732.
•
Lucca U, Comelli M, Tettamanti M, Tiraboschi P, Spagnoli A. Rate of progression and prognostic factors in Alzheimer's
disease: A prospective study. J Am Geriatr Soc 1993; 41:45-49
•
Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004; 80: 114-122
•
Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch Neurol
2006; 63:154-155
•
•
Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. N Engl J Med 2006; 355:1390
•
Tettamanti M, Garri' M T, Nobili A, Riva E, Lucca U. Low folate and the risk of cognitive and functional deficits in the
very old: The Monzino 80-plus study. J Am Coll Nutr 2006; 25: 502-508
Nobili A, Piana I, Balossi L, Pasina L, Matucci M, Tarantola M, Trevisan S, Riva E, Lucca U, Tettamanti M.Alzheimer
special care units compared with traditional nursing home for dementia care: are there differences at admission and in
clinical outcomes? Alzheimer Dis Assoc Disord. 22:352-6 (2008).
ACTIVITIES
The Department of Neuroscience is formed by ten Laboratories; the activities of research are
devoted to the study of neurological and psychiatric diseases, evaluated by the biological point
of view, clinical and epidemiological aspects and the quality of care. Together with these
activities, in the Department other more general expertise are present. Drug information service
and preparation of protocols for clinical trial and epidemiological studies are activities in charge
of the Neuroscience Department. Traditionally part of the Department was devoted to the
creation of experimental models for the pharmacological, neurochemical and pathogenetic
studies in Alzheimer or prion's diseases, epilepsy, depression and cognitive impairment. More
recently, consolidated expertise were created in the pathogenesis of amyotrophic lateral
sclerosis (ALS), cerebral stroke and drug abuse. Some of these disorders, like epilepsy, ALS
and Alzheimer's disease are investigated from the clinical and epidemiological points of view
for the evaluation of drug and care efficacy. The activities of the Department are aimed to an
integration of the different expertise to develop multidisciplinary approaches. The purpose is to
address at different levels, knowledge, therapy and clinical practice to the numerous questions,
largely unresolved, proposed by the disorders of nervoussystem.
MAIN FINDINGS
The intracerebral application of synthetic β amyloid 1-40 e 1-42 in oligomeric form is
associated with a cognitive damage that does not occur when the pepetides are applied in
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monomeric form of fibrils species. In contrast with other evidence, the effect of oligomers is
reversible and idependent from the presence of cellular prion protein.
Analysis by Magntic Resonance Image (MRI) of Alzheimer’s disease (AD) experimental
models showed structural alterations aging associated reminiscent of the brain structural
changes reported in AD patients.
The exposure of cultured hippocampal cells to β amyloid 1-42 in oligomeric form induces an
alteration of dendritic spines. This effect was evident also when the oligomers did not induce
cell death.
A chronic treatment with doxycycline, a tetracycline that pass the blood brain barrier, with antiamyloidogenic activity, reduces the aggregates of β amyloid and antagonize the dysfunction
indeuced by β oligomers
By performing the first in vivo chronic-treatment with the specific cell-penetrating JNK
inhibitor peptide D-JNKI-1 we demonstrated that JNK is regulating the main pathogenic
mechanisms of AD and might hold promise as an innovative and therapeutic target against it.
We obtained a complete rescue in AD mouse model of both long-term potentiation and longterm recognition memory impairments in D-JKNI1 treated mice. The functional recovery shows
a strong relationship with the JNK signaling pathway and reduction of Ab oligomers, derived by
APP cleavage.
The overexpression of SUMO-1 neuroblastoma cells lines reduces phosphorylation of JNKs and
c-Jun in H2O2 stress conditions and decreases JNKs expression level. SUMO-1 has a possible
dual role in modulating JNKs stress response: contrasting JNKs phosphorylation results in
inhibition of cell death and controlling JNKs degradation.
Design and synthesis of the new cell permeable inhibitor peptides MKK7 inhibitor: The in vitro
inhibitory tests showed no toxicity of these peptides and a high neuroprotective effect against
excitotoxicity
The resveratrol, a well-known antioxidant induces its neuroprotective effect through the
activation of SIRT.1
In the transgenic mice overexpressing a mutated form of human prion protein associated with
CJD generated in the Institute has been found a significant alteration of endoplasmic reticulum
associated with the presence of mutated prion protein.
It has been developed a cellular assay to evaluate the neurotoxicity of mutated prion proteins in
immoratilized cell lines. The assay can be used to understand the molecular basis of PrP
neurotoxicity and to evaluate potential therapeutic approaches.
Proteomic analysis in cellular model of fatal familial insomnia it has been show that alterations
of intracellular protein transport might play a role in the pathogenesis of grnetic prion’s
diseases
Polymorphisms in gene encoded for serotonin transporter protein influenced the risk to develop
Parkinson’s disease
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In a prospective population-based study in the very old (Monzino 80-plus Study), the the risk
associated with a family history of deementia was significantly high also among the oldes old,
but, at variance with the prevalence of dementia, it decreases with age and is not significant
after 90.
The same prospective population-based study (Monzino 80-plus Study) failed to demonstrate a
significant association between diabetes or glucose concentration and dementia in the very old.
Though increasing with age, apathy is pervasive among dementia sufferers and its prevalence
and severity increases along the disease course. Together with depression and possibly alone,
apathy could be a prodromic manifestation of dementia ( Monzino 80-plus Study).
In a prospective ambulatory population of cognitively normal or mildly cognitively impaired
elderly, dissecting mild cognitive impairment into severity levels was found to increase the
accuracy of progression predictions to dementia.
More than one out of 10 elderly persons (65 years or older) were anemic and most of the cases
had a mild grade anemia. Hemoglobin concentrations decreased and prevalence of (mild)
anemia increased with increasing age.
After controlling for many potential confounders, mild anemia was found to be associated with
poorer health conditions and with increased risk of clinically relevant outcome such as
hospitalization and mortality (Health and Anemia Study).
In Trentino, where the Form for Hospital Assessment of Self-Harm and Suicide Attempts has
been in use since June 2009, was found a rate of 37/100,000 cases of self-harm and suicide
attempts seen in the Emergency Departments of the province, with women showing higher
rates.
The quality assessment of the network of mental health services indicated that a few areas
needed to be improved: pharmacotherapy, self-help, facilities of the psychiatric ward,
information on illness and the drugs, possibility to choose the profesional to be cared by, wait
time for the appointments and at the phone.
According to the GiSAS survey questionnaire, the majority of psychiatrists (63%) trusted in the
superiority of second-generation antipsychotics. Those who indicated pharmaceutical
representatives as their main source of knowledge of antipsychotics (n=103) all preferred the
other SGAs over clozapine (OR 2.1, CI 1.1–3.9; p=0.01). The influence of industry-mediated
information might have affected opinions on SGAs and the lack of uncertainty about
antipsychotics attitudes may have hindered trial participation.
In years 2000-2006 the prescriptions of fluoxetine, paroxetine and mirtazapine increased. On the
contrary, the use of reboxetine progressively declined and was associated with higher
discontinuation rates. These findings are consistent with recent experimental evidence.
Both treated incidence and prevalence of mental disorders in Lombardy increased between 1999
and 2009. Incidence of schizophrenic and personality disorders decreased and that of affective
and neurotic disorders increased, while increasing prevalence concerned all diagnostic groups.
The majority of patients, even those with schizophrenia, were cared at outpatient level through
clinical and community packages.
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Patients with dementia resident in Alzheimer’s special care units (ASCU) had a lower rate of
hospitalisation and use of physical restraints than those in traditional nursing homes.
In ASCU 60% of patients with dementia were taking at least one antipsychotic, 49% typical and
51% atypical. More than 50% of patients exposed to antipsychotics at baseline, were still taking
the drug after 18 months of follow-up. The use of antipsychotic agents was strongly related to
the presence of agitation, irritability, delusions, anxiety, night-time behaviour and aberrant
motor behaviour.
In the Lecco Local Health Authority 16% of elderly patients were exposed to potential severe
drug-drug interactions; age and number of chronic drugs were associated with an increasing risk
of DDIs. Since physicians still have some difficulty in managing this topic, it is essential to
provide them with adequate information on which factors raise the risk of DDIs.
Age, local health unit (LHU) of residence, number of drugs and co-prescribed PIDs were
predictors of hospitalization for hemorrhage.
During 2005 in Lombardy Region, 76% of the elderly aged 65 years ore more (76% women and
75% men) received at least one chronic drug, 46% were exposed to polypharmacy (46% women
and 45% men) and 20% to chronic polypharmacy (18% women and 22% men). Elderly in the
age groups of 75-79, 80-84 and 85-89 years had the highest risk to be exposed to chronic
polypharmacy (OR 2.25; 95%CI: 2.23-2.27, OR 2.68; 95%CI: 2.65-2.71, and OR 2.84; 95%CI:
2.79-2.89 respectively).
During 2005, 34 % of the population living in Lombardy Region received at least one antibiotic
drug prescription. The highest prescription prevalence was observed in the 0-17 and 80 or more
year age ranges (41.6% and 41.9%, respectively). Patients aged <18 years (OR= 1.73; 95% CI
1.73, 1.74), aged 65 or older (OR= 1.64; 95% CI 1.63, 1.65), and those that live in Brescia (OR
1.66, 95% CI 1.65, 1.66) had a statistically significant higher risk of antibiotic drug exposure.
In a large population sample of subject living in Lomabrdy Region, the use of paroxetine and
fluoxetine peaked in 2002 and then decreased. The prescripition rates of mirtazapine gradually
increased all through the study period: from 0.07% in 2000 to 0.13% in 2006. On the contrary,
the prescription rates of reboxetine showed a different trend and progressively decreased from
0.20 in 2000 to 0.04 in 2006.
In a sample of 38 internal medicine and geriatric wards, at hospital admission 52% of 1332
elderly patients aged 65 years or older taken five or more different drugs (polypharmacy) and
were in the ward for a mean of 11 days. At hospital discharge there was an increase in the rate
of patient with polypharamacy (+13%) and with multiple disease (+16%).
Among elderly patients admitted with a diagnosis of AFF to internal medicine wards, an
appropriate antithrombotic prophylaxis was taken by less than 50%, with an underuse of VKAs
prescription independently of the level of cardio-embolic risk. Hospitalization did not improve
the adherence to guidelines.
After multiadjustment, the diagnosis of dementia was associated with in-hospital death (OR =
2.1; 95% CI = 1.0 - 4.5). Having dementia and at least one adverse clinical event during
hospitalization showed an additive effect on in-hospital mortality (OR = 20.7 ;95% CI = 6.9 –
61.9).
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There is a direct correlation between ALS and mechanical trauma as a result of the following
observations: The risk of ALS increases with the number of traumatic events and the severity of
injuries. There is an inverse correlation between ALS and coffee intake.
The treatment of the first unprovoked seizure does not affect short and long-term mortality in
patients with epilepsy.
The prevalence of some neurological disorders in Albania differs from that of other European
countries. Differences can be explained by the study methodology and by the diverse
distribution of genetic and environmental risk factors.
The incidence of acute symptomatic seizures in patients with a firstly diagnosed stroke followed
prospectively is fairly low. Cerebral hemorrhage and cortical lesions are the only independent
predictors of acute symptomatic seizures while hypercholesterolemia reduces the risk of
hemorrhagic stroke
Patients with epilepsy-headache comorbidity differ from patients with epilepsy or headache
alone in terms of family history and severity of the clinical picture.
About one-fourth of patients with epilepsy starting or changing an antiepileptic drug are
unsatisfied with treatment. Poor satisfaction with treatment is most frequent in patients with
long-lasting disease, adverse drug reactions, and with parents/caregivers declaring poor quality
of life.
We have demonstrated the crucial involvement of some pro- and anti-inflammatory cytokines in
seizures using experimental models of epilepsy in rodents, thus describing a new
etiopathological mechanism which may be relevant for human epilepsy.
We have demonstrated that membrane-bound drug transport proteins are functionally activated
by seizures and have a significant role in decreasing the brain concentrations of antiepileptic
drugs in experimental models. Pharmacological intervention to block the activity of these
proteins may contribute to reverse multidrug resistance in epilepsy.
Gene therapy studies highlight the possibility to significantly reduced spontaneous seizure that
are refractory to anticonvulsant drugs opening the perspective of using gene therapy in
pharmacoresistant forms of epilepsy.
Mannose-binding lectin (MBL), a key protein in the complement lectin pathway, is a novel
target for stroke treatment
Microglia can favour protective actions in the ischemic environment
Stem cells from umbilical cord blood decrease post-traumatic brain functional deficts and lesion
in injuried mice
In some motor neurons of mice with mutant SOD1 is evident an early induction of the protein,
HspB8, which promotes the transport of the altered proteins to the autophagy system of the cell
for being destroyed and thus preventing their accumulation.
The increase of HspB8 is also evident in the motor neurons that survive in the terminal stages of
disease suggesting a neuroprotective role of this protein. This discovery opens the way for a
possible therapeutic strategy, based on the identification and application of substances that
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promote the activation of HspB8 in the entire population of motor neurons in order to protect
them from the accumulation of protein aggregates and from death
Differences in feedback control of serotonergic transmission influence the efficacy of SSRIs
Co-treatment with 5-HT2C receptor antagonists enhance the effects of SSRI on serotonergic
transmission and restore their antidepressant-like effect in “non-responder” mice
The blockade of NMDA receptors of the rat prefrontal cortex induces an increase of glutamate
release, activates the transcription factor CREB in the dorsal striatum and is deleterious for
prefrontal cortex-dependent cognitive functions
5-HT2A receptor antagonists and 5-HT1A and 5-HT2C receptor agonists prevent the increase of
glutamate release and attentional deficits caused by NMDA receptors blockade suggesting that
some serotonin receptor subtypes might constitute a molecular target for the development of
drugs for the treatment of cognitive deficits of schizophrenia
We show that in a glutamate NMDA model of cognitive deficit of schizophrenia antipsychotics
may be differentiated by a selective effect of typical antipsychotics on compulsive
perseveration, and atypical antipsychotics on impulsivity.
A single session of cocaine self-administration is sufficient to shape rat behavior towards goaldirected behaviors and selectively up-regulate Arc expression in mPFC. This is the first
evidence that the mPFC's function is already profoundly influenced by the first voluntary
cocaine exposure.
Gamma-hydroxybutyric acid (GHB) does not maintain self-administration but induces
conditioned place preference when injected in the ventral tegmental area.
Environmental stimuli associated to drug self-administration induce drug seeking behavior
when present to rodents after a long period of abstinence.
Bifeprunox, a partial agonist at dopamine D2 and serotonin1A receptors, influences nicotineseeking behaviour in response to drug associated stimuli in rats
Genetic differences in serotonin synthesis may contribute to the efficacy of SSRIs in a murine
model predictive of the antidepressant activity.
In non-responder mice, 5-HT1A and 5-HT2C receptor antagonists restore the antidepressant-like
to the SSRI.
Associazione Familiari Insonnia Familiare Fatale malattie da prioni, Treviso
Associazione Italiana GIST A.I.G.
Associazione per la Ricerca Neurogenetica, Lamezia Terme (CS) e ASL 6, Regione Calabria
Agenzia di Sanità Pubblica del Lazio, Regione Lazio
Assessorato alla Salute, Comune di Milano
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Azienda Ospedaliera Ospedali Riuniti di Bergamo
Azienda Sanitaria Locale di Bergamo
Azienda ULS TO2, Torino
CEND, Centro Eccellenza per le Malattie Neurodegenerative, Università di Milano
Centro di Terapie per l’Adolescenza, Milano
Centro Fatebenefratelli San Giovanni di Dio, Cernusco sul Naviglio
Centro di Neurofarmacologia, Dipartimento di Scienze Farmacologiche, Università di Milano
Centro Studi in Psichiatra, ASL 2, Torino
Centro Parkinson-Istituti Clinici di Perfezionamento
Clinica IRCSS S. Maria Nascente, Milano
Clinica Neurologica III Università di Milano, Azienda Ospedaliera S. Paolo, Milano
Clinica Psichiatrica, Università Milano Bicocca
Consorzio Ricerche Luigi Amaducci, CRIC, Arcugnano (Vc)
Consorzio MIA, Milano
DIBIT, San Raffaele Scientific Insitute, Milano.
Dipartimento di Chimica Biologica, Università di Padova
Dipartimento di Chimica, Università egli Studi di Firenze
Dipartimento di Chirurgia "P. Valdoni" - Lab., Ricerca Center for Research in Neurobiology
"Daniel Bovet" (CRiN), "Sapienza" Università di Roma
Dipartimento Endicronologia, Università di Milano
Dipartimento Farmaco Chimico Tecnologico, Università di Siena
Dipartimento di Farmacologia Medica, Università di Milano
Dipartimento di Fisiologia Umana, Facoltà di Medicina, Università di Milano
Dipartimento di Medicina e Sanità Pubblica, Sezione di Psichiatria e Psicologia Clinica,
Università di Verona
Dip. di Morfofisiologia, Scuola di medicina Veterinaria, Università di Torino, Grugliasco (TO).
Dip. Neurologia, IRCCS Fondazione Maugeri, Pavia
Dipartimento Neurologia, Ospedale Molinette, Torino
Dipartimento di Neurologia Università di Milano, Ospedale Luigi Sacco.
Dipartimento di Neuroscienze, Università di Parma, Parma
Dipartimento di Salute Mentale di Niguarda, Milano
Dipartimento di Salute Mentale ASL 3 ”Genovese”, Genova
Dipartimento di Salute Mentale San Carlo, Milano
Dipartimento di Salute Mentale della Ulss 5 Ovest Vicentino
Dip. di Scienze Biomolecolari e Biotecnologie, Università di Milano
Dipartimento di Scienze Fisiologiche Università di Pavia, Pavia
Dipartimento Scienze Neurologiche, Università di Genova, Genova
Dipartimento Scienze Neurologiche, Ospedale Maggiore Policlinico di Milano
Direzione Generale Famiglia e Solidarietà Sociale, Regione Lombardia, Milano
Direzione Generale Sanità, Regione Lombardia, Milano
Direzione Regionale Sanità e Servizi Sociali, Regione Umbria
Divisione di Ematologia, Università di Pavia e Fondazione IRCCS Policlinico S. Matteo, Pavia
Divisione Neurologica, Università di Bologna
EPAPSY, Scientific Association for Regional Development and Mental Health, Athens, Greece
Evidentia Medica, Grottaferrata, Roma
Federazione Alzheimer Italia, Milano
Franco Calori Cell Factory, Centro Trasfusionale e di Immunologia dei Trapianti, IRCCS
Ospedale Maggiore, Milano
Fondazione Clelio Angelino
Fondazione Cecchini Pace, Milano
Fondo Edo Tempia
Hospice “Franco Gallini”, Aviano (PN)
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IRCSS "Casa Sollievo della Sofferenza", San Giovanni Rotondo
IRCCS Istituto Auxologico Italiano, Milano
Istituto di Ricovero e Cura a Carattere Scientifico IRCCS (I.N.R.C.A.), Ancona
IRCSS Fatebenefratelli di Brescia
IRCSS "San Raffaele", Milano
Istituto Europeo di Oncologia, IRCCS, Milano
Istituto di Farmacologia e Farmacognosia, Università di Urbino
Istituto di Farmacologia, Università di Milano
Istituto di Fisiologia Umana II Università degli Studi di Milano, Milano
Istituto “G. Ronzoni”, Milano
Istituto Nazionale Neurologico “Carlo Besta”, Milano
Istituto Scientifico Humanitas
Istituto di Scienze e Tecnologie della Cognizione, CNR, Roma
Istituto "Stella Maris", IRCCS, Calambrone (PI)
Istituto Zooprofilattico Piemonte Liguria Val D'Aosta,Torino
Laboratorio di Immunopatologia Renale, Ospedale San Carlo, Milano
Laboratorio di Neuroscienze, Centro Dino Ferrari, Università di Milano
Lega Italiana per la Lotta contro i Tumori
Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova
Ospedale del Bambin Gesu’, Roma
Ospedale Regionale Ca Fondello, Treviso
Ospedale "Molinette", Torino
Polo Oncologico, ASL 12, Biella
Polo Tecnologico, IRCCS S. Maria Nascente, Fondazione Don Carlo Gnocchi Onlus, Milano
Provincia Lombardo-Veneta Ordine Ospedaliero San Giovanni di Dio, Fatebenefratelli di
Cernusco sul Naviglio
Progetto Itaca, associazione Volontari per la Salute Mentale – ONLUS, Milano
Scuola di Specializzazione in Psicoterapia IRIS-Insegnamento e Ricerca Individuo e Sistemi,
Milano
Scuola di Terapia Cognitiva “Studi Cognitivi”, Milano
Società Italiana Medicina Interna, Roma
Unione Nazionale delle Associazioni per la Salute Mentale (UNASAM), Milano
Unità di Geriatria, Ospedale Maggiore IRCCS, Università di Milano
Unità Operativa di Psichiatria, Azienda Ospedaliera Luigi Sacco di Milano, Milano
Unità Operativa di Psichiatria, Azienda Ospedaliera San Gerardo di Monza, Monza, Unità
Operativa di Psichiatria di Garbagnate, Azienda Ospedaliere Salvini di Garbagnate, Garbagnate
Milanese
Unità Operativa di Psichiatria, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli
e Regina Elena di Milano, Milano
Università degli Studi di Foggia
Università Cattolica del Sacro Cuore di Roma
Università dell’Insubria, Varese
Università del Piemonte Orientale, Novara
Università di Milano, IRCCS Ospedale Maggiore, Milano
Università Milano-Bicocca, Monza
Università La Sapienza, Roma
U.O. Neurologia, Clinica S. Maria, IRCCS, Castellanza (VA).
UNASAM, Unione Nazionale delle Associazioni per la Salute Mentale
Unità Operativa di Psichiatria, Azienda Ospedaliera Luigi Sacco di Milano, Milano
Web Medica, Grottaferrata, Roma
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Albert Einstein College of Medicine, Bronx, NY, USA
Atomic Energy Commission, Service de Neurovirologie, Fontenay-aux-Roses, France
Beaumont Hospital, Dublin, Ireland
Brain Repair Centre, University of Cambridge, Cambridge, UK
Cambridge Centre for Brain Repair, University of Cambridge, UK
Centre for Neuroscience Research and Division of Biomolecular Sciences, GKT School, King’s
College, London, UK
Centre National de la Recherche Scientifique, Paris. France
Chorley & South Ribble General Hospital, Chorley,
Cochrane Schizophrenia Group, Università di Nottingham, Nottingham, UK
Columbia Univ, Haverstraw, NY, USA
Department of Anatomy and Physiology, Laval University, Quebec
Department of Biochemistry, Boston University, Boston USA
Department of Cell Biology, Washington University, St Louis, USA
Department of Chemistry, The Australian National University, Canberra City, Australia
Department of Experimental Psychology, University of Cambridge, UK
Department of Neuroscience, Physiology & Pharmacology University College London, , UK
Department of Pathology and Infectious Diseases Royal Veterinary College, Herts, UK
Department of Psychiatry, Medical Center University of Mississippi, Jackson, USA Directorate
General for the Health and Consumer Protection, European Commission, Luxembourg
Division of Medical Genetics, CHUV Lausanne, Switzerland
Divisione di Geriatria, Ospedali Regionali di Lugano e Mendrisio, Svizzera
EPAPSY, Scientific Association for Regional Development and Mental Health, Athens, Greece
European Union of Family Associations of People with Mental Illness (EUFAMI)
Geriatric Division and Department of Metabolic Diseases, Ospedali Regionali of Lugano and
Mendrisio, Switzerland
HSPH Harvard University, Boston, USA
IBCM, University of Lausanne, Lausanne, Switzerland
INSERM U 751, Marseille, France
Institut de Génétique Humaine du CNRS, Montpellier, France
Jefferson Med Coll, Philadelphia, USA
Karolinska Institutet, Stockholm, Sweden
King’s College Hospital, London, UK
Lancaster University, Lancaster, UK.
Lexicon Pharmaceuticals Texas, USA
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
MPRC, Univ Baltimore, Baltimore, MD, USA
National Insitute on Aging, NIH, Baltimore, USA
Neuroprion, Network of Excellence, WP VI, EC
Neurological Department of the University of Tirana, Albania
Neurology, GlaxoSmithKline, New Frontiers Science Park North, Harlow UK
Ninewells Hospital and Medical School, Dundee, Scotland UK
Northern Illinois University, DeKalb, IL, USA
Novartis Pharma, Basel, Switzerland
NYU, NY, USA
Observatoire National Santé mentale et Précarité, Région Rhône-Alpes, Lione, France
Ohio State Univ, Columbus, Ohio, USA
Robarts Research Institute, London, Ontario, Canada
Royal Manchester Children's Hospital, Manchester, UK
ANNUAL REPORT
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Royal Preston Hospital, Preston, UK
Sergievsky Center, Columbia University, New York, NY, USA
Servizio di Geriatria, Ospedale della Beata Vergine, Mendrisio, Switzerland
The Scripps Research Institute, Jupiter, Florida, USA
Technology Park of Bizkaia, Bizkaia, Spain
Toxicology Unit MRC, Leicester, UK
University of Alberta, Canada
University of Bristol, Frenchay Hospital, Frenchay, Bristol, UK.
University of Bristol, School of Medical Sciences, UK
Univ of California at Irvine, Irvine, CA, USA
University of Cardiff, United Kingdom
University of Chicago, Chicago, IL , USA.
Univ of Colorado, Denver, USA
University Hospital, London, ON, Canada
Univ of Innsbruck, Innsbruck, Austria
University of Lausanne, Lausanne Switzerland
Univ of Maryland, Baltimore, USA
University of Maastricht, the Netherlands
University of Rijeka Medical School, Rijeka, Croatia
University of Szeged, Hungary
Université de la Méditerranée -Hôpital de la Timone Marseille, France
Université Victor Segalen, Bordeaux, France
Unit of Molecular Genetics, CHUV Lausanne, Switzerland
Virtanen Institute for Molecular Sciences, University of Kuopio, Finland
Vrije Universiteit Medical Center, Amsterdam, The Netherlands
Walton Hospital, Liverpool, UK
WAPR (World Association for Psychosocial Rehabilitation)
Washington University, St Louis, MI,USA
Weill Cornell Medical College, New York, USA
World Mental Health, Department of Mental Health and Substance Abuse, Geneva,
Switzerland
World Association for Psychosocial Rehabilitation
World Health Organization, Disability and Rehabilitation Team
Annals Pharmacotherapy (Nobili)
Biochemical Journal (Chiesa)
Brain Aging (Forloni)
Clinical Drug Investigation (Beghi)
Clinical Neurology and Neurosurgery (Beghi)
Cochrane Collaboration, Epilessia (Beghi)
Dialogo sui Farmaci (Nobili)
Drugs in the R&D (Beghi)
Early Intervention in Psychiatry (Barbato)
Epidemiologia e Prevenzione (Lucca)
Epilepsia (Beghi, Vezzani, assistant editor)
Epilepsy Current (Vezzani)
Epilepsy Research (Vezzani)
Inpharma (Beghi)
International Journal of Mental Health (Barbato)
ANNUAL REPORT
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International Journal of Molecular Epidemiology and Genetics (Forloni, senior, Albani
associate)
Journal of Alzhiemer’s disease (Albani, Forloni)
Journal of Neurochemistry (Bendotti)
Journal of Neuroscience Online (Forloni)
Neurological Sciences (Beghi)
Neuroepidemiology (Beghi)
Neuroscience (Vezzani)
Open Aging Journal (Forloni)
Open Geriatric Medicine Journal (Forloni)
Psichiatria di Comunità (Barbato)
Quality of Life Research (Barbato)
Ricerca & Pratica (Nobili)
Stroke (De Simoni, Associate editor)
Acta Neurologica Scandinavica
Acta Psychiatrica Scandinava
Alzheimer's & Dementia
Alzheimer Disease and Associated Disorders
American Journal of Clinical Nutrition
American Journal of Hematology
American Journal of Human Genetics
American Journal of Pathology
American Journal of Physiology
Annals of Neurology
Annals of Pharmacotherapy
Archives of Internal Medicine
Arthritis Research & Therapy
Behavioural Brain Research
Behavioural Neuroscience
Biochimica et Biophysica Acta
Biochemical Journal
Biochemistry
BioMed Central Neurology
Biological Psychiatry
BMC Psychiatry
BMC Public Health
Brain Research
Brain Research Bulletin
Brain Research Review
Clinical Drug Investigation
Clinical Neurology and Neurosurgery
Clinical Pharmacokinetics
Clin Pharm Therapy
CNS Drugs
Dialogo sui farmaci
Drugs
ANNUAL REPORT
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2010
IRFMN
Epidemiologia e Psichiatria Sociale
Epilepsia
Epilepsy & Behavior
European Journal of Immunology
European Journal of Neuroscience
European Journal of Pharmacology
European Journal of Public Health
Experimental Neurology
European Neuropsychopharmacology
Expert Opinion on Pharmacotherapy
FASEB Journal
FEBS letters
Fundamental Clinical Psychopharmacology
Future Drugs
Giornale di Neuropsichiatria dell’Età Evolutiva
Glia
International Journal of Neuropsychopharmacology
Journal of Alzhiemer’s disease
JAMA
Journal of the American Board of Family Practice
Journal of Biological Chemistry
Journal of Cell. Biology
Journal of Cell Physiology
Journal of Cerebral Blood Flow and Metabolism
Journal of Chemical Neuroanatomy
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Science
Journal of Gerontology
Journal of Headache and Pain
Journal of Histochemistry and Cytochemistry
Journal of Immunology
Journal of Internal Medicine
Journal of Neurochemistry
Journal of Neuroimmunology
Journal of Neurology, Neurosurgery and Psychiatry
Journal of Neuroscience
Journal of Pharmacology and Experimental Therapeutics
Journal of Pharmacy and Pharmacology
Journal of Psychopharmacology
Journal of Psychosomatic Research
Journal of Structural Biology
Journal of Virology
Life Sciences
Lancet
Lancet Neurology
Molecular Brain Research
Molecular and Cellular Neuroscience
Molecular Therapy
Nature Neuroscience
Neuroepidemiology
Neurology
Neurological Sciences
ANNUAL REPORT
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2010
IRFMN
Neurobiology of Learning and Memory
Nerobiology of Aging
Neurobiology of Diseases
Neuropharmacology
Neuropsychopharmacology
Neuroscience
Neuroscience Letters
N.S. Archives Pharmacology
Parkinsonism & Related Disorders
Pharmacological Research
Pharmacoepidemiology and Drug Safety
Pharmacology Biochemistry & Behavior
PlosONE
Proc Natl Acad Sci, USA
Progress in Neuro-Psychopharmacology & Biological Research
Psychopharmacology
Schizophrenia Research
Social Psychiatry and Psychiatric Epidemiology
Synapse
Trends Molecular Medicine
Vaccine
Agenzia Europea di Valutazione dei Medicinali (EMEA)
Agenzia Italiana per il Farmaco (AIFA)
Associazione Italiana per la Ricerca sull’Invecchiamento Cerebrale (AIRIC, Presidenza)
Board of "Master in Advanced Technologies for the Study of Neurodegenerative Diseases",
Milan University
Comitato di coordinamento internazionale del progetto europeo”Quelles professionnalités en
santé mentale. Perspectives croisées, usagers, élus professionnels”.
Commissione sulla Health Care Policy della Lega Internazionale contro l’Epilessia (ILAE)
Comitato Ordinatore del Master in "Tecnologie Avanzate Applicate alle Patologie
Neurodegenerative", Università di Milano
Committee for Proprietary Medicinal Products (CPMP) presso L’EMEA
Consiglio Direttivo AIRIC
Coordination Group IMI-PharmaCog project
Direttivo della Lega Italiana contro l’Epilessia (LICE)
Editorial Committee, Guidelines of community based rehabilitation, World Health
Organization.
Esperto Nazionale, accreditato dall’AIFA (Agenzia Italiana del Farmaco), per l’EMEA (Esperto
per il Medical Research Council (MRC), UK
Gruppo di Approfondimento Tecnico per lo sviluppo dell’area ‘Promozione della salute
mentale’, Regione Lombardia
Gruppo di lavoro sull'epilessia dell'Organizzazione Mondiale della Sanità
Gruppo di Studio sull’Epilessia della Società Italiana di Neurologia (SIN)
Gruppo di Studio sulla Qualità della Vita della Società Italiana di Neurologia (SIN)
Gruppo di Studio sulla Sclerosi Laterale Amiotrofica della Società Italiana di Neurologia (SIN)
Medical Research Council Strategic Grant Application, UK
Mental Health Working Party, gruppo di lavoro nominato dal Direttorato Generale per la
ANNUAL REPORT
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2010
IRFMN
Protezione del Consumatore della Commissione Europea (DG-SANCO), Bruxelles.
Gruppo di coordinamento Neuroprion NoE, EU
International Committee su “Epilepsy and the Law”
International Organizing Committee e coordinator della segreteria al Global Forum for
Community Mental Health, istituito dal Department of Mental Health della World Health
Organization.
International Subcommittee della American Academy of Neurology
International Steering Committee dell’European Network on mental health promotion and
mental disorder prevention (EMHPA).
International Subcommittee dell’American Academy of Neurology
National Institutes of Health of the USA and World Health Organization supported project on
The Future of Psychiatric Diagnosis: Refining the Research Agenda.
Neurobiology Commission of the International League Against Epilepsy
Neuroepidemiology Section of the American Academy of Neurology (Chair uscente)
Research Advisory Panel, MND Association, UK
Task Force sull’epidemiologia dell’epilessia della ILAE
Scientific Advisory Board of Sheffield Institute Foundation for MND
Scientific Advisory Board del Thierry Latran Foundation, Francia
Working Group on Epilepsy della World Health Organization (WHO)
EVENT ORGANIZATION
8a Giornata di studio sulla malattia di Alzheimer
Polipatologie e politerapie nel paziente con demenza
Stili di vita e insorgenza di demenza
13 March 2010, Ateneo Veneto, Venezia
Third GiSAS Investigators’ Meeting
Salerno 28 January 2010
Fourth GiSAS Investigators’ Meeting
Milano 9 November 2010
Abbott GmbH & Co. KG
Agenzia di Sanità Pubblica del Lazio
Amgen, Milano
ASL 2 Piemonte.
ASL TO1 Torino
Assessorato alla Salute, Comune di Milano
Association pour la recherché sur la SLA, France
Azienda USL 3 Pistoia e Valdinievole
Bristol-Myers Squibb
Boehringer Ingelheim
Centro Studi in Psichiatria ASL TO2, Torino
CURE
EISAI
Epilepsy
ANNUAL REPORT
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2010
IRFMN
Dana Foundation
Dipartimento di Salute Mentale, Azienda Ospedaliera Niguarda Ca’ Granda, Milano
Dipartimento di Salute Mentale di Pistoia e Valdinievole Evidentia Medica, Grottaferrata
(Roma)
Fondazione Cariplo, Milano
Fondazione Golgi-Cenci, Abbiategrasso
Fondazione Mariani, Milano
Fondazione Italo Monzino, Milano
Fondazione Vialli e Mauro per la Ricerca
FP6, European Union
Glaxo-SmithKline, Italy
Hospice "via di Natale Franco Gallini", Aviano (PN)
Human Frontiers Scientific Programme
IMI-PharmaCog
IMPHA II, DG-SANCO, Public Health and Consumers' Protection (Directorate General
Istituto Comprensivo Statale "G.D. Romagnosi", Carate Brianza (MI)
Istituto Regionale Lombardo di Formazione per l’Amministrazione Pubblica – IREF
I.R.I.S
Janssen-Cilag
H. Lundbeck A/S, Danimark
Hoffmann-La Roche AG, Svizzera
Ministero della Ricerca Scientifica
MND Association, UK
Newron
Ospedale “Casa Sollievo” di San Giovanni Rotondo
Pharming
Provincia Autonoma di Trento
Progetto Itaca, Milano
Regione Lombardia, Assessorato alla Famiglia e Solidarietà Sociale e Assessorato alla Sanità,
Milano
Rimoldi e Bergamini
Rotary Clubs Gruppo 1, Milano
Rotary Clubs Milano Naviglio Grande San Carlo, Milano Scala, Inner Wheel Milano San Carlo
Sanofi-Aventis
SELECTA MEDICA, Pavia
Servier Laboratories, Parigi
Sigma-Tau
Telethon
Unione Nazionale Associazioni per la Salute Mentale – UNASAM
Vertex
WebMedica, Grottaferrata (Roma).
World Health Organisation
Aguglia U, Beghi E, Labate A, Condino F, Cianci V, Mumoli L, Gasparini S, Quattrone A,
Gambardella A.Age at onset predicts good seizure outcome in sporadic non-lesional and mesial
ANNUAL REPORT
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temporal sclerosis based temporal lobe epilepsy. J Neurol Neurosurg Psychiatry. 2010 Oct 22.
[Epub ahead of print]
Albani D, Polito L, Signorini A, Forloni G. Neuroprotective properties of resveratrol in different
neurodegenerative disorders. Biofactors. 2010; 36:370-6
Albani D, Polito L, Forloni G. Sirtuins as novel targets for Alzheimer's disease and other
neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis. 2010;
19:11-26..
Antoniou X and Borsello T., Cell permeable peptides: A promising tool to deliver
neuroprotective agents in the brain Pharmaceuticals 2010; 3: 379-392
Antoniou X, Falconi M, Di Marino D, Borsello T.,JNK3 as a Therapeutic Target for
Neurodegenerative Diseases. J Alzheimers Dis. 2010 Feb 24. [Epub ahead of print]
Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L,
Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G.Synthetic amyloid-beta
oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci
U S A. 2010; 107: 2295-300
Balducci C, Tonini R, Zianni E, Nazzaro C, Fiordaliso F, Salio M, Vismara L, Gardoni F, Di
Luca M, Carli M, Forloni G. Cognitive Deficits Associated with Alteration of Synaptic
Metaplasticity Precede Plaque Deposition in AbetaPP23 Transgenic Mice. J Alzheimers Dis.
2010 21:1367-1381
Barbato A, Parabiaghi A, Panicali F, Battino N, D'Avanzo B, De Girolamo G, Rucci P, Santone
G PROGRES-Acute Group. Do patients improve after short psychiatric admission? A cohort
study in Italy. Nord J Psychiatry 2010 E-pub.
Beghi E.Treating epilepsy across its different stages. Ther Adv Neurol Disord. 2010; 3:85-92
Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, Tomson T, Hauser
WA. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010; 51:671-5.
Beghi E, Bussone G, D'Amico D, Cortelli P, Cevoli S, Manzoni GC, Torelli P, Tonini MC,
Allais G, De Simone R, D'Onofrio F, Genco S, Moschiano F, Beghi M, Salvi S. Headache,
anxiety and depressive disorders: the HADAS study. J Headache Pain. 2010; 11:141-50.
Beghi E, Logroscino G, Chiò A, Hardiman O, Millul A, Mitchell D, Swingler R, Traynor BJ.
Amyotrophic lateral sclerosis, physical exercise, trauma and sports: results of a populationbased pilot case-control study. Amyotroph Lateral Scler. 2010; 11:289-92.
Biasini E., Tapella L., Restelli E., Pozzoli M., Massignan T., and Chiesa R. The hydrophobic
core region governs mutant prion protein aggregation and intracellular retention. Biochemical
Journal 2010; 430: 477-86
Bruni AC, Bernardi L, Colao R, Rubino E, Smirne N, Frangipane F, Terni B, Curcio SA,
Mirabelli M, Clodomiro A, Di Lorenzo R, Maletta R, Anfossi M, Gallo M, Geracitano S,
ANNUAL REPORT
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Tomaino C, Muraca MG, Leotta A, Lio SG, Pinessi L, Rainero I, Sorbi S, Nee L, Milan G,
Pappatà S, Postiglione A, Abbamondi N, Forloni G, St George Hyslop P, Rogaeva E, Bugiani
O, Giaccone G, Foncin JF, Spillantini MG, Puccio G.Worldwide distribution of PSEN1
Met146Leu mutation: a large variability for a founder mutation. Neurology. 2010; 74:798-806.
Caccia S, Pasina L, Nobili A. New atypical antipsychotics for schizophrenia: iloperidone Drug
Des Devel Ther 2010; 4: 33-48
Calcagno E, Invernizzi RW. Strain-dependent serotonin neuron feedback control role of
serotonin 2C receptors. J Neurochem. 2010; 114:1701-10.
Carli M, Calcagno E, Mainolfi P, Mainini E, Invernizzi RW. Effects ofaripiprazole, olanzapine,
and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with
glutamate release in the medial prefrontal cortex. Psychopharmacology (Berl). 2010 Nov 4.
[Epub ahead of print]
Carli M, Calcagno E, Mainini E, Arnt J, Invernizzi RW. Sertindole restore attentional
performance and suppresses glutamate release induced by the NMDA receptor antagonist CPP.
Psychopharmacology (Berl). 2010 Nov 4. [Epub ahead of print]
Chiappedi M, Beghi E, Ferrari-Ginevra O, Ghezzo A, Maggioni E, Mattana F, Spelta P,
Stefanini MC, Biserni P, Tonali P.Response to rehabilitation of children and adolescents with
epilepsy.
Epilepsy Behav. 2011 20: 79-82.
Chiò A, Borghero G, Calvo A, Capasso M, Caponnetto C, Corbo M, Giannini F, Logroscino G,
Mandrioli J, Marcello N, Mazzini L, Moglia C, Monsurrò MR, Mora G, Patti F, Perini M,
Pietrini V, Pisano F, Pupillo E, Sabatelli M, Salvi F, Silani V, Simone IL, Sorarù G, Tola MR,
Volanti P, Beghi E; LITALS Study Group. Lithium carbonate in amyotrophic lateral sclerosis:
lack of efficacy in a dose-finding trial. Neurology. 2010; 75: 619-25
Congedo M, Causarano RI, Alberti F, Bonito V, Borghi L, Colombi L, Defanti CA, Marcello
N, Porteri C, Pucci E, Tarquini D, Tettamanti M, Tiezzi A, Tiraboschi P, Gasparini M;
Bioethics and Palliative Care in Neurology Study Group of Italian Society of Neurology.
Ethical issues in end of life treatments for patients with dementia. Eur J Neurol 2010; 17: 774779.
Crippa V, Carra S, Rusmini P, Sau D, Bolzoni E, Bendotti C, De Biasi S, Poletti A. A role of
small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins
responsible for neurodegenerative diseases. 2010; Autophagy. 6: 958-60,
Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E,
Marino M, Carra S, Bendotti C, De Biasi S, Poletti A.The small heat shock protein B8 (HspB8)
promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis
(ALS). Hum Mol Genet. 2010 19:3440-56,
Dubé CM, Ravizza T, Hamamura M, Zha Q, Keebaugh A, Fok K, Andres AL, Nalcioglu O,
Obenaus A, Vezzani A, Baram TZ. Epileptogenesis provoked by prolonged experimental febrile
seizures: mechanisms and biomarkers. J Neurosci. 2010; 30: 7484-94.
ANNUAL REPORT
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Epis R, Marcello E, Gardoni F, Vastagh C, Malinverno M, Balducci C, Colombo A, Borroni B,
Vara H, Dell'Agli M, Cattabeni F, Giustetto M, Borsello T, Forloni G, Padovani A, Di Luca M.
Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer's disease.
Brain. 2010; 133:3323-35
Fumagalli S, Coles JA, Ejlerskov P, Ortolano F, Bushell T, Brewer JM, De Simoni MG, Dever
G, Garside P, Maffia P, Carswell HV. In vivo real time multiphoton imaging of T lymphocytes
in mouse brain after experimental stroke. Stroke, 2010. E-pub
Gallucci M, Ongaro F, Meggiolaro S, Antuono P, Gustafson DR, Forloni GL, Albani D, Gajo
GB, Durante E, Caberlotto L, Zanardo A, Siculi M, Muffato G, Regini C. Factors related to
disability: Evidence from the "Treviso Longeva (TRELONG) Study" Arch Gerontol Geriatr.
2010 Jun 8. [Epub ahead of print]
Gesuete R, Orsini F, Zanier ER, Deli MA, Albani D, Bazzoni G, De Simoni MG. Glial cells
drive preconditioning-induced blood-brain-barrier protection. Stroke, 2010. E-pub.
Gironi M, Saresella M, Marventano I, Guerini FR, Gatti A, Antonini G, Ceresa L, Morino S,
Beghi E, Angelici A, Mariani E, Nemni R, Clerici M. Distinct cytokine patterns associated with
different forms of chronic dysimmune neuropathy. Muscle & Nerve. 2010; 42: 864-70
Lescai F, Pirazzini C, D'Agostino G, Santoro A, Ghidoni R, Benussi L, Galimberti D, Federica
E, Marchegiani F, Cardelli M, Olivieri F, Nacmias B, Sorbi S, Bagnoli S, Tagliavini F, Albani
D, Boneschi FM, Binetti G, Forloni G, Quadri P, Scarpini E, Franceschi C. Failure to replicate
an association of rs5984894 SNP in the PCDH11X gene in a collection of 1,222 Alzheimer's
disease affected patients.
J Alzheimers Dis. 2010; 21: 385-8.
Logroscino G, Traynor BJ, Hardiman O, Chiò A, Mitchell D, Swingler RJ, Millul A, Benn E,
Beghi E; EURALS. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg
Psychiatry. 2010; 81: 385-9
Ludolph AC, Bendotti C, Blaugrund E, Chio A, Greensmith L, Loeffler JP, Mead R, Niessen
HG, Petri S, Pradat PF, Robberecht W, Ruegg M, Schwalenstöcker B, Stiller D, van den Berg
L, Vieira F, von Horsten S. Guidelines for preclinical animal research in ALS/MND: A
consensus meeting. Amyotroph Lateral Scler. 2010; 11: 38-45,
Marcucci M, Iorio A, Nobili A, Tettamanti M, Pasina L, Marengoni A, Salerno F, Corrao S,
Mannucci PM; REPOSI Investigators. Factors affecting adherence to guidelines for
antithrombotic therapy in elderly patients with atrial fibrillation admitted to internal medicine
wards. Eur J Intern Med. 2010; 21:516-23.
Marengoni A, Bonometti F, Nobili A, Tettamanti M, Salerno F, Corrao S, Iorio A, Marcucci M,
Mannucci PM; Italian Society of Internal Medicine (SIMI) Investigators. In-hospital death and
adverse clinical events in elderly patients according to disease clustering: the REPOSI study.
Rejuvenation Res. 2010; 13:469-77.
Marengoni A, Corrao S, Nobili A, Tettamanti M, Pasina L, Salerno F, Iorio A, Marcucci M,
Bonometti F, Mannucci PM; on behalf of SIMI Investigators SIMI denotes the Italian Society of
Internal Medicine. The participating units and co authors are listed in the Appendix. In-hospital
death according to dementia diagnosis in acutely ill elderly patients: the REPOSI study. Int J
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Geriatr Psychiatry. 2010 Nov 9.
Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M,
Casalgrandi M, Manfredi AA, Bianchi ME and Vezzani A. Toll-Like Receptor 4 (TLR4) and
High Mobility Group Box 1 (HMGB1) are involved in ictogenesis and can be targeted to reduce
seizures Nature Medicine, 2010; 16: 413-9.
Massignan T., Biasini E., Lauranzano E., Veglianese P., Pignataro M., Fioriti L., Harris D.A.,
Salmona M., Chiesa R., and Bonetto V. Mutant prion protein expression is associated with an
alteration of the Rab GDP dissociation inhibitor alpha (GDI)/Rab11 pathway. Mol Cell
Proteomics 2010; 9: 611-22
Massignan T., Stewart R.S., Biasini E., Solomon I.H., Bonetto V., Chiesa R. and Harris D.A. A
novel, drug-based, cellular assay for the activity of neurotoxic mutants of the prion protein. J.
Biol. Chem. 2010: 285: 7752-7765
Mecarelli O, Capovilla G, Romeo A, Rubboli G, Tinuper P, Beghi E.Past and present public
knowledge and attitudes toward epilepsy in Italy. Epilepsy Behav. 2010; 18: 110-5
Noe F, Vaghi V, Balducci C, Fitzsimons H, Bland R, Zardoni D, Sperk G, Carli M, During MJ,
Vezzani A Anticonvulsant effects and behavioural outcomes of rAAV serotype 1 vectormediated neuropeptide Y overexpression in rat hippocampus. Gene Ther. 2010; 17: 643-52
Ortolano F, Maffia P, Dever G, Rodolico G, Millington OR, De Simoni MG, Brewer JM,
Bushell T, Garside P, Carswell HV. Advances in imaging of new targets for pharmacological
intervention in stroke: real-time tracking of T-cells in the ischemic brain. Br J Pharmacol 2010;
159: 808-811.
Pasina L, Nobili A, Tettamanti M, Riva E, Lucca U, Piccinelli R, Defendi L, Perego L, Lucifora
S, Bulla C. Co-prescription of gastroprotective agents in patients taking non-selective NSAIDs
or COX-2 selective inhibitors: analysis of prescriptions. Int J Clin Pharmacol Ther. 2010,
48:735-43
Peviani M, Caron I, Pizzasegola C, Gensano F, Tortarolo M, Bendotti C. Unraveling the
complexity of amyotrophic lateral sclerosis: Recent advances from the transgenic mutant SOD1
mice. CNS Neurol Disord Drug Targets. 2010, 9: 491-503,
Piccinelli P, Beghi E, Borgatti R, Ferri M, Giordano L, Romeo A, Termine C, Viri M, Zucca C,
Balottin U.Neuropsychological and behavioural aspects in children and adolescents with
idiopathic epilepsy at diagnosis and after 12 months of treatment. Seizure. 2010; 19:540-6.
Politis A, Olgiati P, Malitas P, Albani D, Signorini A, Polito L, De Mauro S, Zisaki A, Piperi C,
Stamouli E, Mailis A, Batelli S, Forloni G, De Ronchi D, Kalofoutis A, Liappas I, Serretti
A.Vitamin B12 levels in Alzheimer's disease: association with clinical features and cytokine
production.
J Alzheimers Dis. 2010; 19: 481-8.
Pous MF, Camporese M, Nobili A, Frau S, Del Zotti F, Conforti A, Zimol R, Giustetto G,
Zermiani G, Lombardo G, Mezzalira L. Quality assessment of information about medications in
primary care electronic patient record (EPR) systems. Inform Prim Care. 2010;18:109-16
ANNUAL REPORT
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Pozzi L, Greco B, Sacchetti G, Leoni G, Invernizzi RW, Carli M. Blockade o serotonin 2A
receptors prevents PCP-induced attentional performance deficit and CREB phosphorylation in
the dorsal striatum of DBA/2 mice. Psychopharmacology (Berl). 2010; 208: 387-99.
Repici M, Wehrlé R, Antoniou X, Borsello T, Dusart I c-Jun N-Terminal Kinase (JNK) and p38
Play Different Roles in Age-Related Purkinje Cell Death in Murine Organotypic Culture.
Cerebellum. 2010 Dec 30. [Epub ahead of print]
Restelli E, Fioriti L, Mantovani S, Airaghi S, Forloni G, Chiesa R Cell type-specific
neuroprotective activity of untranslocated prion protein. PLoS One. 2010; 5:e13725.
Rischio and Prevenzione. Investigators.Efficacy of n-3 polyunsaturated fatty acids and
feasibility of optimizing preventive strategies in patients at high cardiovascular risk: rationale,
design and baseline characteristics of the Rischio and Prevenzione study, a large randomised
trial in general practice.
Trials. 2010; 28;11:68.
Termine C, Ferri M, Livetti G, Beghi E, Salini S, Mongelli A, Blangiardo R, Luoni C, Lanzi G,
Balottin U. Migraine with aura with onset in childhood and adolescence: long-term natural
history and prognostic factors. Cephalalgia. 2010; 30: 674-8
Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone MV,
Detoma P, Giacomin A, Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta MG,
Riva E. Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia"
population-based study. Haematologica. 2010; 95:1849-56.
Urru SA, Veglianese P, De Luigi A, Fumagalli E, Erba E, Gonella Diaza R, Carrà A, Davoli E,
Borsello T, Forloni G, Pengo N, Monzani E, Cascio P, Cenci S, Sitia R, Salmona M. A new
fluorogenic peptide determines proteasome activity in single cells.
J Med Chem. 2010; 53:7452-60.
Valerio A, Bertolotti P, Delbarba A, Perego C, Dossena M, Ragni M, Spano PF, Carruba MO,
De Simoni MG, Nisoli E. Glycogen synthase kinase-3 inhibition reduces ischemic cerebral
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Neurochem, 2010. E-pub
Vezzani A, Balosso S, Maroso M, Zardoni D, Noé F, Ravizza T. ICE/caspase 1 inhibitors and
IL-1beta receptor antagonists as potential therapeutics in epilepsy. Curr Opin Investig Drugs.
2010; 11: 43-50
Watson J, Guzzetti S, Franchi C, Di Clemente A, Burbassi S, Emri Z, Leresche N, Parri HR,
Crunelli V, Cervo L.Gamma-hydroxybutyrate does not maintain self-administration but induces
conditioned place preference when injected in the ventral tegmental area. Int J
Neuropsychopharmacol. 2010; 13:143-53.
Zanier ER, Brandi G, Peri G, Longhi L, Zoerle T, Tettamanti M, Garlanda C, Sicurtà A,
Valaperta S, Mantovani A, De Simoni MG, Stocchetti N. Cerebrospinal fluid pentraxin-3 early
after subarachnoid hemorrhage is associated with vasospasm. Intensive Care Medicine, 2010. E-
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Zanier E R, Refai D, Zipfel G J, Zoerle T, Longhi L, Esparza T J, Spinner M L, Bateman R J,
Brody D L, Stocchetti N. Neurofilament light chain levels in ventricular cerebrospinal fluid
after acute aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2010, E-pub
Clavenna A, Bonati M, Sequi M, Nobili A, Franchi C, Tettamanti M, Bortolotti A, Merlino L,
Fortino I. La prescrizione di farmaci per i bambini e gli anziani in Regione Lombardia. Ricerca
& Pratica 2010; 26: 9-18.
Forloni G. Ricerca traslazionale o semplicemente razionale, la ricerca per la malattia di Alzheimer,
Ricerca & Pratica 2010; 26: 183-192
Franchi, C. Arosio, F, Salvini Porro, G., Colombo, A., Nobili,
Studio della qualità delle Unità di Valutazione Alzheimer in Lombardia
Giornale di Gerontologia, 2010 58:278-282
Nobili A. A proposito di anziani e farmaci. Ricerca & Pratica 2010; 26: 31-3.
Nobili A, Pasina L, Garattini S. Il caso del clopidogrel e degli inibitori di pompa protonica.
Aggiornamento Medico 2010; 34: 56-59.
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Medico 2010; 34: 84-88.
RESEARCH ACTIVITIES
Laboratory of Biology of Neurodegenerative Disorders
Alzheimer's disease: genetic studies and clinical investigations
In collaboration with different neurological centers and the laboratory of Geriatric
Neuropsychiatry it has been created a bank of blood samples for DNA of patients with
Alzheimer’s disease (AD), in familial (FAD) or sporadic form (SAD), and patients with
vascular dementia (VD). In all subjects the diagnosis of dementia is performed according to the
international guidelines. Since 2005 we also started the collection of blood samples from
subjects with front-temporal dementia. The genetic studies are aimed at identifying causal
factors in FAD and risk factors in SAD. Mutations on genes encoding proteins involved in the
physiopathology of AD were investigated. The pathogenic role of these mutations is under
investigation using fibroblasts obtained from skin biopsy. Furthermore, we continued the
screening of FAD samples for the genes encoding for presenilin 1 and 2 (PS-1 and PS-2) and
APP, missense mutations in these three genes were associated with AD.
Alzheimer's disease: preclinical studies
The formation of β amyloid (Aβ) deposits in brain parenchyma and on the wall of cerebral blood
vessels is an early event in AD and there are now numerous genetic, biochemical and
neuropathological studies pointing to a causal role of Aβ in the pathogenesis of AD. Thus,
prevention the formation of Aβ aggregates or their elimination once formed is a potential
therapeutic approach to the disease. This aim is strongly persecuted with different strategies
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including the regulation of enzymes responsible of the synthesis and degradation of Aβ and the
enzymes influencing the metabolism of amyloid precursor protein (APP). In the lab, we developed
the idea to interfere directly with the Aβ deposits formation using anti-amyloidogenic drugs. The
experimental studies have shown the potential therapeutic activity of these drugs in AD, and now
they will be tested in a clinical setting.
Alzheimer’s disease: Translational studies
In the frame of the international study IMI-PharmaCog several protocols have been set up for
the MRI analysis in various transgenic mice models of Alzheimer’s disease (AD). The
PharmaCog project focused on the optimization of the translational studies to facilitate the
therapeutic approaches considering in experimental models and in the clinical studies the same
parameters, behaviorally, biochemically and of imaging. In this contest it will be analyzed
longitudinally in single, carrying human amyloid precursor protein mutated (APP) associated to
AD, double carrying APP and mutated PS1 transgene, and triple transgenic mice carrying APP,
PS2 and mutated tau transgene. We planned to peform the MRI analysis in the same animals
at 4, 8, 12, 18 and 24 months, the analysis will be structural, functional and spettroscopical. The
strumental parameters (ROI, T2, DTI) have been harmonized with the partners developing
similar approaches in humans. The first results seem to confirm the presence of a hippocampal
atropy in double transgenic mice similar to that shown in AD.
The role of oligomers in the Alzheimer pathogenesis
Recent data have shown the essential role played by oligomers, small and soluble aggregates of
Aβ, in the Alzheimer pathogenesis and in particular in the cognitive decline associated to the
disease. In collaboration with the Department of Biochemistry and Molecular Pharamacology
we developed some in vivo models to analyze the neuronal dysfunction induced by Aβ 1−42 but
not in monomeric or fibrillar species. The intracerebral application of these different forms
confirmed that Aβ oligomers induced behavioral impairment while monomeric or fibrillar forms
of Aβ did not affect the cognitive behavior.
The intracellular signaling pathways, by which Aβ oligomers induce synaptic failure and
consequently neuronal degeneration are poorly understood. Nevertheless increasing evidence
indicate the involvement of kinases-dependent signaling pathways, and more specifically the
JNK signaling pathway in these early degenerative events. The JNK kinase phosphorylates APP
(amyloid precursor protein) and its relevance in both neuronal death and brain plasticity is well
established. We recently demonstrated, by using the specific cell penetrating JNK inhibitor
peptide (D-JNKI1) characterized by dr. Borsello, that JNK is responsible for APP
phosphorylation at Thr668, and that its specific inhibition reduced the βAPPs and Aβ fragments
production in primary cortical neurons. In addition, we could show that JNK inhibition leads to
a shift from the amyloidogenic to the non-amyloidogenic pathway, a result with potentially
important therapeutic implications.
Sirtuins and aging
The sirtuins are a family of conserved proteins with de-acetylation activity. In human beings the
sirtuins are coded by 7 different genes and are localized in the citosol, within the nuclei and in
the cellular mitochondria. SIRT-1, the better known sirtuin, is involved in the aging physiology
and energetic metabolism, its activation induced beneficial effects in Alzheimer and Parkinson
experimental models. We studied sirtuins from different points of view, genetic, cellular and
behaviorally. The genetic studies are devoted to identify alterations associated to AD in Italian
populations. During the screening of all sirtuin genes, we found several single nucleic
polymorphisms that now are investigated in a larger population (560 AD subjects). The cellular
studies are focused on the role of SIRT-1 and SIRT-2 in the cell death mechanisms and
oxidative stress in cellular models of AD. Since sirtuins have been involved in the energetic
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metabolism, and mental as well as physical exercise exert protective effect in AD, we are
evaluating in AD animal models if sirtuins are able to mediate the beneficial effects of physical
exercise and environmental stimulation.
Genetics of aging
In collaboration with the Geriatric Neuropsychiatry Lab for the Monzino 80-plus study and with
dr. Maurizio Gallucci from the ARGel Association in Treviso for Trelong study we collected a
large number of blood samples from subjects over seventy. In these samples we are performing
a genetic analysis to identify genetic profiles associated to the longevity and /or to the agingassociated pathologies with specific attention to the dementias. The aim is to cross the
genotype/phenotype profile with pathologies and environmental aspects including lifestyle, diet
and economical conditions to identify risks and protective factors. Initially the subjects were
genotypized for ApoE, whom allele E4 is a well-known risk factor for Alzheimer’s disease and
several other disorders and sirt-1 a gene codified for protein member of a enzymatic family of
sirtuins associated to the longevity in several experimental models. The results are interesting
but before drawing any conclusion we need to consider the numerous other parameters collected
in our database.
Sirtuins and aging
The sirtuins are a family of conserved proteins with de-acetylation activity. In human the
sirtuins are coded by 7 different genes and are localized in the citosol, within the nuclei and in
the cellular mitochondria. SIRT-1, the better known sirtuin, is involved in the aging physiology
and energetic metabolism, its activation induced beneficial effects in Alzheimer and Parkinson
experimental models. We studied sirtuins from different points of view, genetic, cellular and
behaviorally. The genetic studies are devoted to identify alterations associated to AD in Italian
populations. During the screening of all sirtuin genes, we found several single nucleic
polymorphisms that now are investigated in larger population (560 AD subjects). The cellular
studies are focused on the role of SIRT-1 and SIRT-2 in the cell death mechanisms and
oxidative stress in cellular models of AD. Since sirtuins have been involved in the energetic
metabolism, and mental as well as physical exercise exert protective effect in AD, we are
evaluating in AD animal models if sirtuins are able to mediate the beneficial effects of physical
exercise and environmental stimulation.
Genetics of aging
In collaboration with Geriatric Neuropsychiatry Lab for the Monzino 80-plus study and with dr.
Maurizio Gallucci from the ARGel Association in Treviso for Trelong study we collected a
large number of blood samples from subjects over seventy. In these samples we are performing
a genetic analysis to identify genetic profiles associate to the longevity and /or to the agingassociated pathologies with specific attention to the dementias. The aim is to cross the
genotype/phenotype profile with pathologies and environmental aspects including lifestyle, diet
and economical conditions to identify risks and protective factors. Initially the subjects were
genotypized for ApoE, whom allele E4 is a well-known risk factor for Alzheimer’s disease and
several other disorders and sirt-1 a gene codified for protein member of an enzymatic family of
sirtuins associated to the longevity in several experimental models. The results are interesting
but before drawing any conclusion we need to consider the numerous other parameters collected
in our database.
Parkinson’s Disease: genetic studies
Parkinson’s disease (PD) is the second more diffuse neurodegenerative disorder with an
unknown pathogenesis, however for PD several therapies are available and, although at the
symptomatic level, their efficacies is well-established. In the etiological studies on PD the
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genetic component has been traditionally considered with scarce interest whereas the
environmental causes were carefully evaluated. This orientation was based on the evidence that
the exposure to several toxins can mimic the PD pathology. However the genetic studies in the
last few years have completely changed the perspective with the identification of mutations on
two genes, encoding for alpha-synuclein and parkin, associated to the juvenile forms of the
disease. A mutation on alpha synuclein gene is an extremely rare event, only three mutations
identified until now, the parkin mutations are numerous either in puntiform or in deletion form.
The mutations on alpha-synuclein gene are dominant while the parkin mutations are associated
with PD in recessive form. We collected, in collaboration with several neurological centers,
blood samples from PD subjects and the screening of the samples involved genes like alphasynuclein, parkin, DJ-1 and other factors potentially involved in PD. Recently, an association
between polymorphisms occurring in gene for serotonin transporter and the appearance of
depression in PD subjects has been investigated. The results indicate no association between the
serotonin transporter gene polymorphisms and depression in PD, but a direct association
between these polymorphisms and PD itself. This indicates a more relevant involvement o
serotonergic system in PD pathogenesis compared to whom is generally considered.
Parkinson’s disease: studies in vitro
The identification of the mutations associated to Parkinson’s disease (PD) gave a substantial
contribute to understand the disease and allowed the development of cellular models to
investigate the pathogenesis of the disease. In the past we showed the potential neurotoxic
activity of alpha-sinuclein using the synthetic peptide homologous to the fibrillogenic fragment
61-95 (NAC) of the protein. Successively with the help of dr. Negro at the Department of
Biochemistry at the University of Padova we prepared cDNA vectors including the sequence of
wild type and mutated alpha-synuclein. Their transfection to the PC12 cells induced in specific
conditions a cellular damage. More recently alpha-synuclein was associated to a TAT sequence
capable to transport inside the cells the protein. With this method the intracellular concentration
of alpha-sinuclein was better controlled. In a micromolar range alpha-synuclein was toxic, but
in nanomolar range, it exerted neuroprotective effect against oxidative stress induced by
hydrogen peroxide. This double effect dose-dependent was confirmed in an “inducible” model.
More recently again in collaboration with Dr. Negro (Padua University), we obtained the
recombinant form of DJ-1 associated with TAT (TAT-DJ-1). This protein is similar to alphasynuclein, mutations of its sequence has been associated to PD. TAT-DJ-1 silencing by small
interference RNA (siRNAi) were used to study the interaction between DJ-1 and alpha
synuclein..
Synaptic Dysfunction
Nowadays it is assumed that AD is a synapse-related pathology leading to synaptic dysfunction
and loss, a phenomenon that precedes extensive amyloid deposition in the brain. At the same
time, soluble diffusible forms of Aβ can perturb in an early stage of the disease the synaptic
function causing a reduction of dendritic spines density in the cortex and hippocampus, an acute
inhibition of long term potentiation (LTP) and the loss of critical spine proteins (e.g. membrane
expression of NMDA receptors).
However, the relationship between Aβ and synapses loss remains unclear and more efforts are
necessary to better understand the mechanisms underlying Aβ synaptic toxicity. Our aim is to
study the effects of Aβ oligomers on MAPKs pathways and elucidate the link between
synaptopathies and the activation/inhibition of the JNK, p38 and ERK cascades. This study can
potentially be a breakthrough in the comprehension of AD pathogenesis: understanding the
cellular and molecular alterations that lead to AD will help in developing effective and
preventive therapeutic strategies in order to counteract or nullify the degenerative processes
activated by Aβ.
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MAPKs (ERK, p38 and JNK) are also implicated in the regulation of the immediate early
signaling events that modulate synaptic plasticity by controlling LTP, LTD and the recycling of
glutamate receptors (NMDAR and AMPAR) as well as their expression. Nevertheless, MAPKs
involvement in the regulation of synaptic function and dysfunction and the mechanisms by
which they trigger the synaptic loss induced by Aβ oligomers are largely unknown.
The cargo strategy as a key tool in neuroprotection
The possibility to target protein complexes and enzymes involved in intracellular signaling
pathways by means of cell permeable peptide (CPP) conjugates represents a novel, versatile and
extremely powerful way of blocking the propagation of intracellular signaling events or
intracellular processes, with an unprecedented specificity allowing for reduction of side effects.
D-JNKI1 is a cell-permeable, biologically-active peptide consisting of a carboxyl terminal
sequence derived from the JNK binding domain of the scaffold protein JIP-1/IB1 (JBD20), and
an amino terminal portion containing the HIV-TAT 48-57 transporter sequence. D-JNKI-1 has
been designed to block the interaction, mediated by JBD domain, between JNK and its targets.
D-JNKI1 afforded powerful protection against NMDA excitotoxicity in cortical neurons and
against cerebral ischemia in vivo, as well as in two other neurodegenerative models (hair-cell
loss in animal models of sudden deafness and retinal ganglion cell loss following optic nerve
crush in vivo. The peptide progressed in clinical trails for preventing brain ischemia/stroke (see
CHUV/Xigenpharma Lausanne web-link). Among the possible targets for neuroprotection there
is MKK7, that is activated, unlikely MKK4, during NMDA-stress,. To inactivate MKK7 we use
lentiviruses because of the particular capability of integrating genetic material into the genome
of non-dividing cells stably. Our lentiviral vector will carry a single si-RNA duplex of MKK7.
A second approach is to test in vitro the specific inhibitor: Gadd45, a molecule active on
MKK7. Gadd45β binds to MKK7 directly and blocks its catalytic activity, the binding between
Gadd45β/MKK7 being tighter than JIP1/MKK7. The endogenous Gadd45 interacts to MKK7
through direct, high-affinity contact but not with the other JNK upstream kinase, MKK4. For
this study we initially plan to use a viral system that will allow us to observe the role of this
pathway in excitotoxicity, with a final goal of producing a cell-permeable peptide with a more
specific effect in the prevention of neuronal death.
SUMOlization in acute and chronic diseases
Small ubiquitin-like modifier (SUMO) is a group of proteins responsible for post translational
modifications influencing protein function, localization and stability. Recently, protein
Sumoylation has attracted neuroscientists since it is implicated in the altered protein dynamics
that are associated with various aspects of neurodegenerative disease, including stroke and
Alzheimer's Disease (AD). Our hypothesis is that SUMOylation confers neuroprotection against
stressful stimuli through regulation of important stress signaling pathways. The aim of this
study is to investigate the role of SUMOylation in models of acute (ischemia) and chronic brain
diseases (AD). At present we are characterising the changes in expression and localisation of
SUMO1-2/3 in an in vitro model of ischemia (NMDA application) as well as in a model of AD
(oligomers application).
Laboratory of Neurological Disorders
Epidemiological studies on amyotrophic lateral sclerosis (ALS)
Included are studies on the incidence, risk factors and mortality of ALS. The data are obtained
from a regional registry of the disease activated in 1998 and including all patients with newly
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diagnosed ALS identified in the Lombardy region. Using similar study protocols, the same data
are collected in two additional regional registries (from Piemonte and Puglia) included in a
network with the Lombard registry. Information obtained from patients enrolled in the Lombard
registry and from cases examined by members of the Italian ALS Study Group has been used to
assess the validity and reliability of diagnostic criteria for ALS and selected disability scales.
Based on the data recorded, the annual incidence of ALS is comparable to that obtained in other
Western countries where ALS registries have been activated, and is among the highest ever
published (1.9 per 100,000). Mortality of ALS has been found to be comparable to that of
studies from similar populations studied with the same protocol. The study on the validation of
the current diagnostic criteria for ALS (the El Escorial criteria) showed that to be considered
valid and reliable, the criteria should be used after proper training of the investigators.
In October 2004, the Laboratory of Neurological Disorders has started a European collaborative
group for the ALS registries (EURALS) with the intent to create a common database
(completed in the year 2005) with the participation of the existing regional and national disease
registries. With the collaboration of the UK and Irish groups participating in the EURALS
collaboration, a scientific report has been published on a meta-analysis of the incidence of ALS,
performed by pooling data from the 1998-99 cohorts of patients enrolled in the populationbased registries. Two studies have been recently concluded: 1. A case-control study on trauma
and risk of ALS (in collaboration with the Italian registries); 2. A survey of the prevalence of
cognitive impairment and extrapyramidal signs in patients with newly diagnosed ALS (Italian
registries). Other studies are ongoing under the coordination of the Laboratory of Neurological
Disorders: 1. A case-control study on ALS, physical exercise and sport (in collaboration with
the EURALS Consortium). 2. A study of the mortality of ALS in the 1998-99 cohort of patients
from the European population-based registries (EURALS Consortium).
Treatment of the first epileptic seizure and short and long-term mortality
A cohort of 419 patients with a first unprovoked seizure, randomized to immediate treatment of
to treatment at the time of relapse, were followed for up to 20 years in search of short-term and
long-term mortality. The mortality in this cohort was compared to that of the Italian population
and measured with the Standardized Mortality Ratio (SMR). The SMR was not significant (1.2;
95% CI 0.9-1.7) and was not changed for patients in whom the treatment of the first seizure was
withhold.
Innovative therapeutic strategies in patients with epilepsy
A cohort of patients with a first unprovoked seizure, randomised since 1988 by several Italian
centers to immediate treatment or to treatment only at the time of a seizure relapse, was
followed to verify the impact of the two therapeutic strategies on the long-term prognosis of
epilepsy, measured by the chance of achieving 5-year remission.
To provide a pragmatic definition of drug resistance in childhood epilepsy, children refractory
to two antiepileptic drugs (in sequence or in combination) were randomised to the use of a third
drug or to the optimization of the existing treatment and followed for up to three years.
Therapeutic response was measured by the achievement of a six-month period of remission. The
study has been conducted in collaboration with the IRCCS “Stella Maris” of Calambrone (PI).
The study has been concluded prior to completing patient recruitment because the eligible
patients could not be easily traced. The available data have processed and analyzed and a
scientific manuscript is in preparation
Epidemiology of neurological disorders in Albania
With the collaboration of the Fondazione Mariani and the Neurological Department of the
University of Tirana, an epidemiological survey has been completed to assess the prevalence
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and incidence of several neurological conditions (stroke, epilepsy, headache, dementia,
peripheral neuropathy, multiple sclerosis) comparing an urban and a rural community (Tirana
and Saranda). In 2005, a study on the validation of the diagnostic criteria was conducted.
A total of 9869 persons (Tirana 4953; Saranda 4916) were screened. The prevalence rates of the
clinical conditions (expressed as number per 1000) are, in decreasing order, 258 (headache), 36
(polyneuropathy), 15 (epilepsy), 13 (stroke), 11 (dementia), 9 (parkinsonisms), 5 (cerebral
palsy), and 0.3 (multiple sclerosis).
Headache and comorbidity
Headache is frequently associated with other comorbid disorders. Epilepsy is one of the
commonest associated clinical conditions. On this background, an observational study has been
recently completed. The aim of the study was to show any differences between patients with
epilepsy-headache comorbidity and those with epilepsy or headache alone. A total of 1167
patients were examined (156 with epilepsy-headache comorbidity, 675 with headache alone,
and 336 with epilepsy alone). Differences between the three groups were found for family
history of epilepsy (prevailing in patients with epilepsy-headache comorbidity) or headache
(prevailing in patients with headache alone) and for clinical features (less severe in patients with
epilepsy-headache comorbidity).
Cerebrovascular disorders and risk of epilepsy
Epilepsy is a frequent complication of stroke. Acute symptomatic seizures (i.e. seizures
occurring in the seven days after stroke) can occur in up to two-thirds of cases and epilepsy (i.e.
repeated unprovoked seizures) in 2-4%. There are no consistent findings on the risk factors for
acute symptomatic seizures, unprovoked seizures and epilepsy in patients with stroke. For these
reasons, in 2007 a multicenter national prospective survey has been started to assess the risk of
seizures and epilepsy (and the main risk factors) in a cohort of patients with a first ischemic or
hemorrhagic stroke followed for a maximum period of 24 months. The study was also
implemented to assess the feasibility of a pragmatic therapeutic trial on the prophylaxis of
seizures and epilepsy in stroke. Based on the analysis of 714 patients, the incidence of acute
symptomatic seizures was 6.7%. Cerebral hemorrhage and a cortical lesion increased overall
seizure risk while hypercholesterolemia decreased the risk of hemorrhagic stroke .
Therapeutic trials in neurological disorders
During the year 2010 six therapeutic trials sponsored by the Italian Drug Agency (AIFA) and a
therapeutic trial sponsored by the Italian Ministry of Health were ongoing. Included are: 1. A
randomized double-blind parallel-group placebo-controlled trial on the efficacy and tolerability
of L-acetylcarnitine in ALS; 2. A randomized open-label parallel-group trial comparing
Erythropoietin to Methyl-prednisolone in patients with acute spinal cord injury; 3. A
randomized double-blind parallel-group placebo-controlled trial on the efficacy and safety of
valproate in medication-overuse headache; 4. A randomized open-label trial of the efficacy of a
comprehensive rehabilitation program for the prevention of falls in Parkinson’s disease; 5. A
randomized open-label trial on the efficacy of an active monitoring of the adverse effects of
antiepileptic drugs and of relevant drug interactions; 6. A randomized open-label trial on the
efficacy of an educational program for physicians working in nursing homes.. The first trial
aims at finding a potentially effective drug in a clinical condition for which there is only one
product (Riluzole) with at best modest efficacy on survival. L-acetylcarnitine has been found to
improve survival in experimental models of motor neuron disease. The second trial intends to
verify the efficacy of erythropoietin, a drug shown to mitigate the effects of traumatic spinal
shock and accelerate recovery in experimental animals. The drug chosen for comparison
(Methylprednisolone at high doses) has been selected for being the present gold standard in
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clinical practice. The third trial aims at verifying whether valproate (a drug commonly used for
the prophylaxis of migraine) abates symptoms occurring in drug-overuse headache, a common
and frequently invalidating variety of chronic idiopathic headache. The fourth trial aims at
assessing whether a comprehensive rehabilitation program compared to usual care is followed
by a reduction in the incidence of falls in patients with Parkinson’s disease at risk of falls. The
fifth trial aims at verifying the added value of an active monitoring of adverse drug interactions
compared to usual care in patients receiving antiepileptic drugs associated to other compounds.
The sixth trial aims to verify the added value of a web-based educational program in reducing
the number of inappropriate prescriptions compared to usual care.
The laboratory of neurological disorders is the coordinator of the first trial and a partner in the
other trials, where the main tasks include protocol and CRF preparation, statistical analysis, and
preparation of the final scientific report.
Satisfaction with antiepileptic treatment in children and adolescents with
epilepsy
Epilepsy is a disease requiring chronic use of drugs having adverse effects which may affect
satisfaction with treatment. Poor satisfaction, particularly in children and adolescents, may
affect compliance and quality of life of patients and their parents and caregivers. Two hundred
and 93 children and adolescents with epilepsy aged 3 through 17 years were included in a
nationwide prospective observational study at treatment onset or at time of treatment
modification and reassessed at one and three months. At the end of the first month,
dissatisfaction with treatment was manifested by 29.4% of cases. The percentage fell to 24.2%
at three months. Patients with newly diagnosed epilepsy were better satisfied than patients
diagnosed in the past. The variables associated with poor satisfaction with treatment included
adverse drug reactions, disease duration and poor quality of life of parents/caregivers.
Laboratory of Experimental Neurology
Role of inflammatory molecules in ictogenesis and epileptogenesis
We are studying the role of IL-1beta and HMGB1 systems in the genesis and propagation of
seizures and in the associated neurodegenerative phenomena. We have demonstrated that
epileptic activity induces the synthesis of these pro-inflammatory molecules, danger signals and
their specific receptors. In particular, IL-1beta and HMGB1 have proconvulsant actions while
their receptor antagonist (IL-1Ra, BOX-A, Toll-like receptors inhibitors) or IL-1beta synthesis
inhibitors, have anticonvulsant activities. We are actively studying the role of these molecules in
epilepsy models with the intent of promoting their clinical applications in drug-resistant epileptic
patients. This possibility is encouraged by the clinical use of some of these molecules (e.g.
anakinra, the IL-1R antagonist) in chronic inflammatory and autoimmune diseases in humans.
We are studying pharmacological approaches to block IL-1beta- and HMGB1-signaling
involved in the proconvulsant effects of these molecules
Epilepsy and postnatal development
Seizure susceptibility is higher in early infancy although the immature brain appears to be less
susceptible to epileptogenesis. Using experimental models of seizures induced during pos-tnatal
development in rodents, we are studying the mechanisms involved in age-dependent seizure
susceptibility and the associated neuronal injury. Our studies are primarily focused on
inflammatory pathways, angiogenic processes and blood-brain barrier damage.
Blood-brain barrier and epileptogenesis
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We are studying BBB permeability and microvasculature changes induced in the brain by
seizures or by neurotrauma or infection and how these modifications may affect the process of
epileptogenesis. Experimental models of symptomatic epilepsy are used.
New therapeutic approaches of In vivo gene transfer
This study concerns the use of adeno-associated viral vectors to introduce genes with
therapeutic potential in the brain, thus increasing the synthesis of specific proteins to produce
long-lasting anticonvulsant effects. We have demonstrated that adeno-associated viral vector
carrying the human neuropeptide Y gene, significantly increases the brain concentration of this
peptide after its intrahippocampal injection for a prolonged time (at least up to 5 months after a
single intracerebral injection). The rats overexpressing this peptide are less susceptible to
seizures. Future development of this study concerns the optimization of the transgene transfer
technology to envisage a possible clinical application
In vivo MRI/MRS to determine glia activation and blood-brain barrier
damage
This study is focused on in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS)
techniques to evaluate the role of glia activation and blood-brain barrier damage in the epileptic
process. Our intention is to explore whether these two phenomena can be used as biomarkes of
epileptogenesis. This information may provide a clinically applicable method for predicting the
development of spontaneous seizures in individual at risk, thus permitting to envisage
prevention strategies.
Laboratory of Geriatric Neuropsychiatry
Population study on the prevalence of dementias in the older-old
Parallel to the progressive increase of individuals aged 80 years or older within the elderly
population (65+), the number of demented patients of 80 years or older makes up an ever
increasing fraction of the total population affected by dementia. As very often happens, the
exclusion from studies of subjects in the oldest age classes tends to inevitably underestimate
the total number of individuals affected by dementia present in the population. To fill this gap,
a door-to-door population study on the prevalence, incidence, risk factors and evolution of
dementias and age-associated cognitive deficits has been set up in an elderly population aged
80 years or older living in eight small towns of Varese Province. The study is funded by a
grant from the Fondazione Italo Monzino, Milano.
Health and Anemia in the elderly population
A large survey in old residents of Biella (65 years or older) has been conducted in
collaboration with the Local Health Authority of Biella (ASL 12) to estimate the prevalence
and incidence of anemia (mild, moderate and severe) in the elderly population and to
investigate the association of mild anemia with hospitalization and mortality. In a large
subgroup of eldely subjects also the effects of mild grade anemia on cognitive, functional,
mood, and quality of life variables have been investigated.
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Evaluating risk profiles in hospitalised elderly subjects
In collaboration with the Geriatric Division of the Ospedali Regionali of Lugano and
Mendrisio, Switzerland, hospitalized and ambulatory patients are evaluated from a
neuropsychological, functional and mobility point of view to estimate the impact of these
factors on heath-related outcomes and disease progression (Canton Ticino Study).
Longitudinal follow-up of individuals with mild cognitive impairment
(MCI)
In collaboration with the Geriatric Unit of Ospedali Regionali of Lugano and Mendrisio,
Switzerland, the follow-up study of all Mild Cognitive Impairment or Questionable Dementia
(CDR 0.5) patients seen at the Memory Clinic of the Hospitals is continuing to estimate the
rate of conversion to dementia and to evaluate the possible risk factors associated with
conversion (Canton Ticino Study).
Quality of care of terminally ill oncological subjects
In 1999 we started a collaborative programme with the hospice “via di Natale Franco Gallini”
in Aviano (PN). The present aim of the collaborative research project is to assess the hospice
activities after its opening and the analysis of the data collected in the first decade of activity
(2000-2009).
Randomised controlled trial of the Italian Group for the Study of the
Second Generation Antipsychotics – GiSAS
The study aims at evaluating efficacy and safety of three antipsychotic drugs - aripiprazole,
olanzapine and haloperidol – by a pragmatic design involving a large sample of patients with
schizophrenia treated in community psychiatric services across Italy. This is the first large
multicentre trial on this subject ever realized in Italy. The target is to recruit 260 patients. Of the
over 50 centers involved, 43 are currently actively participating. These centers have recruited
243 patients, among whom 129 completed the one-year follow-up.
GiSAS survey
This study examined the opinions of psychiatrists from centers participating in the GiSAS trial,
a pragmatic RCT of antipsychotic drugs in schizophrenia in order to explain and possibly
improve the limited Patient recruitment in randomized clinical trials in general and in the
GiSAS study.
A survey of all clinicians working in the trial recruiting centers was performed exploring four
critical areas: reasons for trial participation, recruitment barriers, antipsychotic preferences and
sources of information about antipsychotics.
Monitoring of self-harm and suicide attempts
In the framework of a wider project financed by the Ministry of Health (Call 2006) and led by
the Public Health Agency of the Lazio Region, the Unit of Epidemiology and Social Psychiatry
has enlarged the network of services where the Form for Hospital Assessment of Self-Harm and
Suicide Attempts is used. Data collection has started in various centres, covering a total of more
than 1 million inhabitants in various areas of North Italy. In the Province of Trentino, services
for adolescents have adopted the schedule after the necessary modifications. The Unit is also
involved on a project financed by the Italian Centre for Disease Control, where the form is
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further introduced in areas with high incidence of suicide and family practitioners will be
trained about depression identification and suicide risk detection.
European Network of Bipolar Research Export Centres - ENBREC
ENBREC is designed to build an EU-wide network of expert centres specialised in research and
care on bipolar disorders, in order to integrate research efforts on the mechanism of disease, and
optimized diagnostic and treatment. Common tools and practice, training and information will
help structuring the European bipolar disorders research community and translate research
outcome into healthcare. Epidemiology and Social Psychiatry Unit reviewed research findings
on effective psychosocial interventions and planned, in collaboration with the Department of
Mental Health of San Carlo Hospital in Milan, an investigation on use of psychosocial
intverventions for bipolar disorders in routine clinical practice. A psychoeducation intervention,
integrated with self-help and expression of the direct experience of patients was designed and
proposed to the patients in charge. A total of 35 patients were included in three intervention
groups.
Quality Evaluation of a Department of Mental Health with the participation
of users
The study investigates the quality of assistance offered to patients with severe mental illnesses
and intensively cared by the mental health services, through an instrument developed with a
substantial contribution of users and distributed by them. Of the 290 patients identified to be
interviewed, 204 gave valid questionnaires.
HoNOS-5 Study: towards the development of a clinically oriented
informative system
The study was approved by the Italian Health Department (Call 2008) and adopted as outcome
measure the Health of the Nation Outcome Scale (HoNOS). Its aim is to evaluate the clinical
outcomes of a cohort of subjects referring to a group of 25 Italian mental health services and to
create a dataset containing all available information drawing on already operating informative
flows, thus developing a clinically oriented informative system. More than 6,500 patients were
recruited and evaluated through the HoNOS scale and subsequently followed-up and reassessed
in July and November. The last follow-up is scheduled for March 2011.
Michael’s game: a table game for group cognitive-behavioural therapy of
psychotic symptoms.
Cognitive therapies (CBT) of psychotic symptoms have shown to be effective in the treatment
of psychoses. Their spreading within naturalistic settings is, however, limited. “Michael’s
Game”, a training module for hypothetical reasoning, coming in the form of a game of cards, is
a treatment inspired by CBT approach. It was conceived as a tool to promote the spreading of
CBT in natural clinical settings. The Unit coordinates the participation of two centers in Italy to
a multi-center international non-profit clinical trial evaluating the effectiveness of “Michael’s
Game” program on adult patients who show residual psychotic symptoms. In the two center of
Brescia, 10 patients were followed up to nine months and the study was concluded. In the center
of Senigallia, 11 subjects were included and the experimental phase was concluded.
Use of the Regional Database on Drug Prescriptions
Although reboxetine has been prescribed for many years in Europe for the treatment of
depression, a recent meta-analysis concluded that it is ineffective and potentially harmful. We
performed a population-based prescription study comparing use of reboxetine, fluoxetine,
paroxetine and mirtazapine in a large sample of adults in Lombardy.
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Use of the Regional Psychiatric Information System to monitor access to
mental health services and patterns of care
Data on mental health services in Lombardy were collected through rhe regional information
system and analyzed in terms of treated prevalence, treated incidence, contnuity of care and
packages of care for the period 1999-2009 and involving 120.000 patients corresponding to a
rate of 146/10,000 population aged 15 and over.
Laboratory of Inflammation and Nervous System Diseases
The complement system in stroke and traumatic brain injury experimental
models
Previous studies of ours have indicated that complement and related inflammatory systems such
as contact/kinin and fibrinolytic systems may represent novel targets for reducing
ischemia/reperfusion injury. We have shown that C1-INH, a serine-protease inhibitor that acts
as a major regulator of both complement and kinin systems, remarkably improves the
functional and neuropathological consequences of focal transient as well as permanent ischemia
induced by middle cerebral artery occlusion in mice. In particular we have shown that plasmaderived(pd)C1-INH effectively and markedly reduces brain ischemia/reperfusion injury,
inducing a decrease of the 90% of the ischemic lesion and that its actions lead to inhibition of
cell recruitment, inflammation and apoptosis. In addition we could show that pdC1-INH
protective effects are present also in traumatic brain injury models. More recently we
demonstrated that the recently available recombinant human(rh) C1-INH is as effective as
pdC1-INH in reducing the ischemic lesion but it has a much wider therapeutic window, being
protective whan adiminstered up to 18 h after transient ischemia and up to 6 h after permanent
ischemia. We could show that a major target of rhC1-INH neuroprotection is mannose-binding
lectin (MBL), a key protein in the complement lectin pathway.
Thus C1-INH, which is presently used as replacement therapy in patients with C1-INH
deficiency, possesses potent, multi-faceted neuroprotective actions that may be beneficial in
acute brain injury. Ongoing studies are focussed on MBL as a novel target for stroke and
traumatic brain injury.). Stem cells as a therapeutic approach in stroke and traumatic brain injury
We have previously demontrated a beneficial effect of neural stem cells after transient brain
ischemia Ethical issues involved in stem cell research and the limited availability of most adult
stem cells outline the need to look for other cell populations. We are presently focussing on
stem cells obtained from human umbilical cord blood that are an easily available source of
progenitors with multilineage capacity and could represent an ideal candidate for cell-based
therapy after acute brain injury.
The aim of the research is to verify the conditions for the effectivenss of Human Umbilical Cord
Blood Mesenchymal Stem Cells (CB-MSC, provided by Cell Factory, Ospedale Maggiore
Policlinico di Milano) in reducing the ischemic and traumatic brain injury (TBI) and to
investigate the mechanisms triggered by their infusion in the injured brain. CB-MSC are infused
into the brain ventricle of injured mice. At different time points and up to 3 months, several
parameters are being evaluated: distribution and phenotype of injected cells, neurodegeneration,
behavioral deficits, cytokine and trophic factor gene expression, microglia activation. In our
TBI model the results obtained show that CB-MSC: 1) migrate towards the contused tissue and
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survive in the injured brain up to 5 weeks postinjury; 2) induce an early and persistent
attenuation of functional impairments related to sensory/motor activity and cognitive functions
up to 6 weeks post-TBI; 3) significantly reduce the contusion volume as assessed one month
after trauma; 4) modify the brain environment by modulating the inflammatory response and
stimulating the production of trofic factors. These data indicate that this type of stem cells may
represent a useful therapeutic tool in TBI patients. In our focal ischemia model the results
obtained up to now indicate a similar protective effect on sensorymotor functions. Ongoing
studies include: 1) definition of the long term effects on behavioural and anatomical damage
after ischemia; 2) evaluation of the trophic effects of CB-MSC and of the reciprocal interaction
between CB-MSC and injured environment with specific analysis of the protective/toxic role of
microglia; 2) definition of the mechanisms of homing of stem cells in the injured brain; 3)
evaluation of the ability of CB-MSC to differentiate into functional neural progeny 3 months
after transplantation.
Ischemic preconditioning and the blood-brain barrier
Recent studies indicate that cell death resulting from ischemic injury can be reduced when a
sublethal injurious stimulus or ischemic episode occurs hours or days before a severe ischemic
insult. This phenomenon is known as ischemic pre-conditioning (IPC). Elucidating the
mechanisms responsible of ischemic preconditioning provides an opportunity to identify the
putative candidates that can confer neuroprotection against acute brain injury. A major goal is to
identify underlying endogenous protective signals, with the long-term goal to allow therapeutic
augmentation of the endogenous protective mechanisms in cerebral ischemia.
Although most attention has been focused on the neuronal effects of IPC, recent studies have
shown that IPC reduces ischemia-induced cerebrovascular damage. We have specifically
investigated the role of BBB in cerebral ischemia and preconditioning. To this purpose we have
established a bidimensional BBB model by means of co-cultures of mouse brain endothelial
cells and glial cells. BBB has been exposed to oxygen-glucose deprivation (OGD) to mimic
ischemic injury. We have specifically: 1) elucidated BBB involvement in cerebral ischemia and
IPC in in vivo and in vitro mouse models; 2) identified mediators and cell types involved in
activation and maintenance of ischemic tolerance in the cerebrovascular unit. The results
obtained have shown that BBB can be directly preconditioned and that astrocytes are the driving
gear of this protective mechanism.
In vivo real time imaging in ischemic mouse brain by two-photon
microscopy
Ischemic stroke triggers vascular responses including blood flow rearrangements, blood brain
barrier disruption and expression of adhesion molecules that stimulate immune cell infiltration.
These mechanisms contribute to the progression of the ischemic damage after the acute event
and represent potential therapeutic targets. In vivo imaging of the brain at cellular resolution in
3D provides an ideal tool to get an insight in these dynamic events. We have recently
established an original approach by means of two-photon microscopy that allows the
visualisation and measurement of dynamic events taking place in the brain. Two-photon
microscope benefits from high-energy electronic transition in a fluorescent molecule due to the
cooperation of two low-energy photons, thus enabling imaging over long periods in living
animals.
On-going projects (carried on in collaboration with the Centre For Biophotonics at the
Strathclyde University of Glasgow) focus on the blood flow dynamics following focal brain
ischemia and on the tracking of lymphocytes infiltrated in the ischemic territory. We obtained
highly detailed imaging and quantification of vascular dynamics and moving lymphocytes in the
brain in vivo after stroke. In particular we: 1) measured the massive vascular rearrangement
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occurring during and after ischemia, such as blood flow speed variations and temporal dynamics
of extravasation appearance; 2) collected data as number of infiltrated lymphocytes, their track
velocity, displacement rate and meandering index thus providing a comprehensive description
of lymphocyte behaviour in the brain. The final aim of the project will be to elucidate dynamic
events associated with the evolution of ischemic damage over time thus providing the bases for
a rational manipulation of blood supply and immune responses for therapeutic intervention in
stroke.
Laboratory of Molecular Neurobiology
Study on pathogenic mechanisms of Amyotrophic Lateral Sclerosis
Role of protein aggregation
One of the pathological features of ALS is the accumulation of protein aggregates in cell bodies
and axons of motor neurons. Having shown that the alteration of the ubiquitin / proteasome
contributes to the progression rather than the pathogenesis of the disease (see activity report
2009) in SOD1G93A mice, a model of familial ALS, this year we focused on another protein
degradation system, the lysosome-autophagy. We observed that in the spinal cord of
SOD1G93A mice at the end stage of disease there is an increase in the levels of LC3II which is
a marker for the formation of autophagosomes. This indicates that the activation of autophagy
could be an alternative defense mechanism of the cell aimed to eliminate the abnormal protein
aggregates when the proteasome is partially inhibited as we demonstrated in the previous study.
Furthermore, in collaboration with the Department of Endocrinology, Applied Biology and
Pathophysiology of the University of Milan, we have shown that in motor neurons of
SOD1G93A mice there is an increased expression of a chaperone protein, HspB8, already at the
presymptomatic stage and this phenomenon persists in the motor neurons that survive at the
terminal stages of disease. In vitro studies on motor neuron cell lines have shown that HspB8 by
interacting with a complex of other proteins such as Bag3/Hsc70/CHIP, is able to reduce
aggregation and increase the solubility of SOD through the activation of the autophagic
degradation pathway. The results of this work were published in Human Molecular Genetics
and Autophagy.
Comparative analysis of gene expression and proteome profiling of two mouse
models of familial ALS with phenotypic differences of disease. (MNDA UK
Project, No. 6054 and EUROMOTOR FP7 program)
Recently, we observed that two genetically distinct strains of mice (C57 and 129Sv), but
carriers of the same number of copies of the transgene for human SOD1 with G93A mutation,
develop a different phenotype of ALS as regard the age of onset and illness duration. The
genetic variability is probably a reason for differences in age of onset and severity of disease in
patients with both familial and sporadic ALS. Hence our interest was focused on the study of
two strains of mice and patients C57/G93A and 129Sv/G93A the behavioral, biochemical and
histopathological order to understand the mechanisms responsible for the different development
of the disease.
The study funded by the Motor Neuron Disease Association is done in collaboration with the
group of Professor Pamela Shaw, University of Sheffield (UK). The laboratory of Sheffield
isolated the spinal motor neurons of the two strains of mice at different stages of the disease by
laser-disector and performed the comparative transcriptome analysis between the two models.
Numerous data have emerged showing a profile of gene expression with some similarities and
many differences between the two strains of mice. The data are now being analyzed by the Gene
Ontology Classification to identify specific pathways involved in the different phenotype. In
parallel we have demonstrated histopathological and biochemical differences between the two
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SOD1G93A mouse models especially regarding the accumulation of insoluble proteins and the
formation of protein inclusions. Mice with a more aggressive disease show a greater amount of
aggregates at the early stages of the disease which is associated with a reduced expression of the
proteasome. We also noted that mice with more severe disease have levels of alpha beta
crystallin, a chaperone involved in the correct folding of proteins, 10 times lower than those of
mice with slower disease suggesting a protective role of this protein. We are currently planning
to examine whether an increase in expression and function of this protein is able to protect
motor neurons and slow the progression of the disease.
In vitro studies on neuron-glia interaction
To investigate further the role of inflammatory mechanisms, we have set up in vitro co-coltures
of spinal neurons and astrocytes derived from SOD1G93A mice embryos. This cellular system
reproduces the selective motor neuron degeneration induced by the expression of mutant SOD1
and allows to investigate the role of TNFalpha and associated pathways. Our results firstly
demonstrated the protective effect of p38MAPK inhibitors in this model, confirming the
hypothesis derived by the in vivo studies, and the involvement of TNFalpha and its receptors
type 2 in the motor neuron death. These findings suggest a possible new toxic pathway that can
represent an innovative target for curative intervention. Further studies are in progress to
validate this hypothesis.
Altered axonuclear communication in motor neurons of a mouse model of
familial amyotrophic lateral sclerosis (European collaborative project FP6
program EU-NES AXON SUPPORT))
The objective of this study is to test the hypothesis that a defect in the communication
of specific signals between the axonal compartment and peripheral nuclei of motor
neurons is responsible for the death of motor neurons in models of familial ALS. In
particular, we focused our attention to the study of two proteins whose interaction
fosters a regenerative response following acute axonal injury: vimentin and importin
beta. We observed that in pure motor nerves (nerve quadriceps) but not in sensory
nerves (saphenous nerve) of SOD1G93A rats, there is an increase of importin beta
which is not associated with an increase in vimentin, at variance with what happens
during the axon regeneration after an acute nerve insult. Hence we hypothesize that the
non-regenerative response of axons in models of ALS is due to the lack of an increase
in vimentin. To verify this hypothesis, we developed SOD1G93A mice that express a
green fluorescent protein only in motor neurons (Hb9-SOD1G93A mice) and therefore
allows to distinguish specifically the sensory from the motor axons under the structural
and biochemical profile. The characterization of these mice is currently under study.
Understanding the role of vimentin in the disease progression is important to determine
whether this protein could be a therapeutic target for amyotrophic lateral sclerosis.
Therapeutical interventions in mouse model of ALS
Induction and mobilization of bone marrow hematopoietic stem cells (HSC) by GCSF (granulocyte colony stimulating factor) in SOD1G93A mice. (Project
supported by Thierry Latran Foundation)
We evaluated the effect of GCSF on the distribution and cellular differentiation of the HSC in
the nervous tissue of SOD1G93A transgenic mice and verified the effectiveness of this
treatment on the progression of the disease and on neuropathological changes. We have seen
that the cell proliferation assessed by incorporation of a fluorescent molecule (EDU) in DNA
was increased in the spinal cord of SOD1G93A mice but this effect was only partially increased
by treatment with GCSF. While the preliminary results showed a tendency to ameliorate the
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motor deficit of SOD1G93A mice after treatment with GCSF a subsequent study did not
confirm this result. We are now considering other experimental conditions of treatment with
GCSF and other compounds very active in the mobilization of bone marrow in order to find the
ideal conditions for producing a more efficient infiltration of stem cells in the CNS.
Studies on the effects of the long-chain omega-3 polyunsaturated fatty acids
eicosapentaenoic acid and docosahexaenoic acid in the G93A SOD1 mouse
This is part of a collaborative project with Dr. A. Michael-Titus of Queen Mary University of
London supported by the MND Association) This study is based on the observation by Dr.
Michael-Titus of a neuroprotective effect of a diet enriched with fatty acids eicosapentaenoic
acid (EPA), acid docosahexaenoico (DHA) on motor neurons in a rat model of spinal trauma.
After a preliminary study in which we observed a trend toward improvement in the course of
the disease in SOD1G93A mice treated with EPA but not with DHA or with the combination of
the two compounds, we evaluated the effect of three doses of EPA alone. Unfortunately, none of
the 3 doses improved the progression of the disease although there was a significant decrease in
the levels of nitrotyrosine, a marker of oxidative stress in the spinal cord of mice treated with
EPA.
Studies aimed at identifying biomarkers for the diagnosis and progression
of the disease in ALS patients
In collaboration with the Translational Proteomics Laboratory of the Department of
Biochemistry, directed by Dr. Valentina Bonetto we performed a proteomic investigation on
peripheral blood cells (PBMC) of ALS patients provided by the department of neurology of the
Fondazione Salvatore Maugeri, IRCCS, Milan and Centro Nemo from Niguarda Hospital in
Milan. We obtained a panel of protein markers that are closely associated with ALS and can
discriminate with high significance and specificity patients with the ALS from control patients
with other diseases that may show a phenotype similar to ALS at the disease onset(eg,
neuropathies , multiple sclerosis). In addition, some markers are able to discriminate between
two levels of disease severity. The results are collected in a manuscript that is being submitted
to the journal Annals of Neurology.
Study of disease progression by magnetic resonance imaging (MRI) in
animal models of ALS
The purpose of this project is to verify whether the analysis of magnetic resonance imaging may
be a useful tool for monitoring the progression of ALS in vivo in mice and rats bearing SOD1
G93A mutation, models of the disease. The results obtained so far show that this technique can
detect the degeneration of the major cranial motor nuclei, trigeminal nucleus and facial nucleus,
before the onset of disease symptoms. This is manifested by an increased signal in T2 at these
nuclei, probably related to the presence of vacuoles in damaged motor neurons. In parallel we
are conducting histopathological analysis at different times during the course of the disease in
order to correlate the degree of degeneration of motor neurons with the modification of the MRI
signal. With this study we will determine whether MRI can be a useful means of investigation to
check the efficacy of a potential therapy on motor neuron degeneration without sacrificing the
animal. Through the use of MRI, and in particular with the technique called Fiber Tracking we
were also able to analyze the axonal degeneration in the lumbar spinal cord in ex-vivo isolated
spinal cord of SOD1G93A mice. We are now trying to replicate these data in viable mice,
during the progression of the disease. This will allow us to assess more accurately and at
different levels (somatic and axonal) the degree of degeneration of motor neurons. The use of
the technique of 'MRI is very important because it can be directly translated to the clinic as a
marker of disease progression in patients.
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Laboratory of Prion Neurobiology
Development of a cellular assay for the activity of neurotoxic PrP mutants
Several mutated forms of PrP induce neurodegeneration when expressed in transgenic
mice; however, they are not toxic when expressed in cultured cells. We found that
some PrP mutants sensitize cultured cells to the toxic activity of two classes of
antibiotics. Based on this result, we developed a new assay allowing the screening of
the cytotoxic activity of mutant PrP in immortalized cell lines. This assay could be
useful for dissecting the molecular mechanisms of PrP toxicity, and to test the efficacy
of potential therapeutic agents.
Proteomic analysis of a cellular model of fatal familial insonnia
The PrP mutation D178N/M129 is linked to fatal familial insomnia, characterized by
severe sleep abnormalities and autonomic dysfunction. We showed by immuno-electron
microscopy that this mutant PrP accumulates abnormally in the endoplasmic reticulum
and Golgi of transfected neuroblastoma N2a cells. To investigate the impact of
intracellular PrP accumulation on cellular homeostasis, we did a differential proteomic
analysis in collaboration with the Translational Proteomics Lab of the Mario Negri
Institute. We found changes in proteins involved in energy metabolism, redox
regulation and vesicular transport. Rab GDP dissociation inhibitor alpha (GDI) was one
of the proteins that changed most. GDI regulates vesicular trafficking by acting on the
activity of several Rab proteins. We found a specific reduction in the level of functional
Rab11 in mutant PrP expressing cells, associated with impaired post-Golgi trafficking.
These data indicate that mutant PrP expression alters the cellular mechanisms governing
intracellular membrane traffic.
Role of PrP in mediating the neurotoxic activity of amyloid beta oligomers
There is evidence that the amyloid-β (Aβ) peptide plays a key role in the pathogenesis
of Alzheimer’s disease. In collaboration with the Laboratory of Biology of
Neurodegenerative Disorders and the Department of Biochemistry of Mario Negri
Institute, we found that acute intracerebroventricular injections of synthetic Aβ
oligomers impaired consolidation of the long-term recognition memory, whereas mature
Aβ fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was
reversible and was prevented by an anti-Aβ antibody. It has been suggested that PrP
mediates the impairment of synaptic plasticity induced by Aβ. We confirmed that Aβ
oligomers interact with PrP, with nanomolar affinity. However, PrP-expressing and PrP
knock-out mice were equally susceptible to this impairment. These data suggest that Aβ
oligomers are responsible for cognitive impairment in AD and that PrP is not required.
Role of the hydrophobic core of PrP in misfolding
It is not clear how PrP mutations cause disease, but structural changes of the mutant
protein and aggregation inside the cells may contribute to the brain damage. We
modified the central region of mutant PrP, and found that the modified molecules folded
properly and reached the cell surface, where non-mutated PrP normally resides, more
efficiently. These findings indicate that the central region of PrP plays a pivotal role in
governing the folding and cellular fate of the mutant molecules, and may help in
devising rational therapeutic approaches for inherited prion diseases.
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Neuroprotective activity of cytosolic PrP
A key pathogenic role in prion diseases was proposed for a cytosolic form of PrP.
However, it is not clear how cytosolic PrP localization influences neuronal viability,
with either cytotoxic or anti-apoptotic effects reported in different studies. The cellular
mechanism by which PrP is delivered to the cytosol of neurons is also debated, and
either retrograde transport from the endoplasmic reticulum or inefficient translocation
during biosynthesis has been proposed. We investigated cytosolic PrP biogenesis and
effect on cell viability in primary neuronal cultures. We found that an untraslocated
form of cytosolic PrP was produced in certain neurons but not in others, and that this
form boosted the resistance of cortical and hippocampal neurons to apoptosis. These
results indicate cell type-dependent differences in the efficiency of PrP translocation,
and argue that cytosolic PrP targeting might serve a physiological neuroprotective
function.
Laboratory of Experimental Psychopharmacology
Drug Abuse. Neural basis of drug self-administration
To separate the direct pharmacological effects of cocaine from those associated with active drug
self-administration we employed a yoked control-operant paradigm and investigated the
expression of well established markers of the rapid action of cocaine, i.e. the inducible early
genes and trophic factors, in rats after a single intravenous (i.v.) cocaine self-administration
session. Animals self-administering cocaine did more active lever-presses than yoked-cocaine
(YC) and yoked-vehicle (YV) animals. This goal-oriented behaviour was accompanied by a
selective increase in Arc mRNA levels in the medial prefrontal cortex (mPFC). These findings
demonstrate that a single session of cocaine i.v. self-administration is sufficient to shape rat
behaviour towards goal-directed behaviours and selectively up-regulate Arc expression in
mPFC (of SA animals), providing the first evidence that the mPFC's function is already
profoundly influenced by the first voluntary cocaine exposure. Ongoing studies are evaluating
whether this effect is peculiar to cocaine or common to other drugs of abuse.
GHB mechanism of action
Gamma-hydroxybutyric acid (GHB) is an endogenous brain substance that has diverse
neuropharmacological actions, including rewarding properties in different animal species and in
humans. As other drugs of abuse, GHB affects the firing of ventral tegmental neurons (VTA) in
anaesthetized animals and hyperpolarizes dopaminergic neurons in VTA slices. We investigated
the effects of various doses of intravenous GHB in maintaining self-administration and its
ability to induce conditioned place preference (CPP) in rats when given orally or injected
directly either in the VTA or NAc. Our results indicate that GHB did not maintained selfadministration, while given orally induced CPP. CPP was also observed when GHB was
injected in the VTA but not in the NAc. Together with recent in-vitro findings, these results
suggest that the rewarding properties of GHB mainly occur via disinhibition of VTA
dopaminergic neurons.
Neural basis of “drug craving” and “relapse” in the drug abuse
assumption
Drug craving, defined as “the desire to experience the effect(s) of a previously experienced
psychoactive substance” is a cardinal feature of drug addiction and is clinically significant
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because of its potential link to relapse. To provide useful indications to the development of
novel therapeutic approaches to prevent the use and abuse and the relapse of drug assumption
following the outcome of “craving”, we elaborated experimental models of self-administration
and “relapse” induced by cocaine, nicotine and alcohol-associated cues, after a period of
abstinence. Ongoing studies are evaluating the role of several neurochemical mechanisms
potentially involved in the drug-seeking behavior.
Search for pharmacological agents capable of modulating the craving and
relapse in the consumption of psychotropic substances of abuse
Environmental stimuli associated with the intake of psychotropic substances of abuse may take
the ability to induce craving that often preludes to relapse in formally detoxified patients.
Studying nicotine in an experimental model of extinction-reinstatement induced by the
presentation of environmental stimuli associated with self-administration of psychotropic
substance of abuse, it was found that bifeprunox, a high-affinity partial agonist of dopamine D2
receptors and serotonin1A receptors, preferentially reduced nicotine-seeking behaviour in
response to drug-associated stimuli in rats after a long period of abstinence.
Resistance to antidepressant drugs: experimental and clinical studies
This project arises from a collaboration between the laboratories of Neurochemistry and
Behavior (R.W. Invernizzi), Drug Metabolism (Silvio Caccia), Biology of Neurodegenerative
Disorders (GianLuigi Forloni) and focus on behavioural and biochemical characterization of an
experimental model of resistance to the antidepressant drugs.
Using an animal model which is predictive of the antidepressant activity, the effects of selective
serotonin reuptake blockers (SSRI) was evaluated in several mice strains. It was found that
DBA/2J and BALB/c do not respond to the antidepressant-like activity of the SSRI. The lack of
effect was attributed to genotype-dependent impairment of 5-HT synthesis since DBA/2J and
BALB/c carring a single nucleotide polymorphism (C1473G mice) in the gene for the brainspecific isoform of tryptophan hydroxylase-2, the rate-limiting enzyme in the synthesis of
serotonin are characterized by a decreased serotonin synthesis. This hypothesis seems to be
supported by the observation that DBA/2J and BALB/c mice had less dialysate 5-HT in the
medial prefrontal cortex and dorsal hippocampus than C57BL/6J mice. Moreover, in DBA/2J
and BALB/c the SSRI raised significantly less extracellular 5-HT when compared to C57BL/6J
mice. More recently it was found that 5-HT1A and 5-HT2C receptor antagonists restored the
SSRIs’ effect on either the antidepressant-like activity and the extracellular 5-HT.
Laboratory of Neuronal Death and Neuroprotection
The role of oligomers in the pathogenesis of Alzheimer’s disease
Recent data have shown the essential role played by oligomers, small and soluble aggregates of
Aβ, in the pathogenesis of Alzheimer and in particular in the cognitive decline associated to the
disease. In collaboration with the Department of Biochemistry and Molecular Pharamacology
we developed some in vivo models to analyze the neuronal dysfunction induced by Aβ 1−40
and 1−42 structured in oligomers but not in monomeric or fibrillar species. The intracellular
signalling pathways, by which Aβ oligomers induce synaptic failure and consequently neuronal
degeneration are poorly understood. Nevertheless increasing evidence indicates the involvement
of kinases-dependent signalling pathways, and more specifically the JNK signalling pathway in
these early degenerative events.
The JNK kinase phosphorylates APP (amyloid precursor protein) and its relevance in both
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neuronal death and brain plasticity is well established. We recently demonstrated, by using the
specific cell penetrating JNK inhibitor peptide (D-JNKI1) characterized by Dr. Borsello, that
JNK is responsible for APP phosphorylation at Thr668, and that its specific inhibition reduces
the βAPPs and Aβ fragments production in primary cortical neurons. We now demonstrated that
JNK inhibition by D-JNKI1 gave total functional recovery of both long-term potentiation and
long-term recognition memory impairments in TgCRND8 mouse model. The functional
recovery shows a strong relationship with a reduction of Ab oligomers, derived by APP
cleavage, in brain parenchyma. Our findings demonstrate that JNK is regulating the main
pathogenic mechanisms of AD and might hold promise as an innovative and therapeutic target
against it.
Synaptic Dysfunction
Nowadays it is assumed that AD is a synapse-related pathology leading to synaptic dysfunction
and loss, a phenomenon that precedes extensive amyloid deposition in the brain. At the same
time, soluble diffusible forms of Aβ can perturb in an early stage of the disease the synaptic
function causing a reduction of dendritic spines density in the cortex and hippocampus, an acute
inhibition of long term potentiation (LTP) and the loss of critical spine proteins (e.g. membrane
expression of NMDA receptors).
However, the relationship between Aβ and synapses loss remains unclear and more efforts are
necessary to better understand the mechanisms underlying Aβ synaptic toxicity. Our aim is to
study the effects of Aβ oligomers on MAPKs pathways and elucidate the link between
synaptopathies and the activation/inhibition of the JNK, p38 and ERK cascades. This study can
potentially be a breakthrough in the comprehension of AD pathogenesis: understanding the
cellular and molecular alterations that lead to AD will help in developing effective and
preventive therapeutic strategies in order to counteract or nullify the degenerative processes
activated by Aβ.
MAPKs (ERK, p38 and JNK) are also implicated in the regulation of the immediate early
signalling events that modulate synaptic plasticity by controlling LTP, LTD and the recycling of
glutamate receptors (NMDAR and AMPAR) as well as their expression. Nevertheless, MAPKs
involvement in the regulation of synaptic function and dysfunction and the mechanisms by
which they trigger the synaptic loss induced by Aβ oligomers are largely unknown.
The cargo strategy as a key tool in neuroprotection
The possibility to target protein complexes and enzymes involved in intracellular signalling
pathways by means of cell permeable peptide (CPP) conjugates represents a novel, versatile and
extremely powerful way of blocking the propagation of intracellular signalling events or
intracellular processes, with an unprecedented specificity allowing for reduction of side effects.
D-JNKI1 is a cell-permeable, biologically-active peptide consisting of a carboxyl terminal
sequence derived from the JNK binding domain of the scaffold protein JIP-1/IB1 (JBD20), and
an amino terminal portion containing the HIV-TAT 48-57 transporter sequence. D-JNKI-1 has
been designed to block the interaction, mediated by JBD domain, between JNK and its targets.
D-JNKI1 afforded powerful protection against NMDA excitotoxicity in cortical neurons and
against cerebral ischemia in vivo, as well as in two other neurodegenerative models (hair-cell
loss in animal models of sudden deafness and retinal ganglion cell loss following optic nerve
crush in vivo. The peptide progressed in clinical trails for preventing brain ischemia/stroke (see
CHUV/Xigenpharma Lausanne web-link).
Among the possible targets for neuroprotection there is MKK7, that, unlike MKK4, is activated
during NMDA-stress. To inactivate MKK7 we use lentiviruses because of the particular
capability of integrating genetic material into the genome of non-dividing cells stably. Our
lentiviral vector will carry a single si-RNA duplex of MKK7. A second approach is to test in
vitro the specific inhibitor: Gadd45, a molecule that acts on MKK7. Gadd45β binds to MKK7
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directly and blocks its catalytic activity, the binding between Gadd45β/MKK7 being tighter than
JIP1/MKK7. The endogenous Gadd45 interacts with MKK7 through direct, high-affinity
contact but not with the other JNK upstream kinase, MKK4. Using this knowledge we
synthesized the first 2 peptides: GADD45 (69-86) by XEGEN, containing the MKK7 binding
region only and GADD45 (60-86), by Dr. Mario Salmona (Mario Negri) that contains the
MKK7 docking region as well as a region that is essential for MKK7 inactivation. Application
of two peptides did not exert toxicity in our in vitro neuronal cultures (12 days in vitro) for
concentrations as high as 20uM and for the duration tested. Notably application of both peptides
30’ before NMDA application resulted in significant neuroprotection against NMDA toxicity
both at 5h and 12h. Our data show convincingly that application of GADD45 (69-86) at a
concentration of 20uM leads to complete abolishment of MKK7 phosphorylation, without
affecting MKK4 phosphorylation. In a similar way, Western Blot analysis confirmed that
application of GADD45 (69-86) completely inhibit MKK7 phosphorylation. Our preliminary
data indicate that the GADD45 peptides exert neuroprotective functions, through direct
regulation of the MKK7 signalling pathway.
Additionally we have performed viral infection experiments with fusion proteins of enhanced
green fluorescent protein (eGFP) and GADD45 and confirmed the role of GADD45 in
modulation of the MKK7. We are positive on the fact that we will soon be able to test the effect
of the GADD45 peptide in an in vivo ischemic model.
SUMOylation in acute and chronic diseases
Small ubiquitin-like modifier (SUMO) is a group of proteins responsible for post translational
modifications influencing protein function, localization and stability. Recently, protein
SUMOylation has attracted neuroscientists since it is implicated in the altered protein dynamics
that are associated with various aspects of neurodegenerative disease, including stroke and
Alzheimer's Disease (AD). Our hypothesis is that SUMOylation confers neuroprotection against
stressful stimuli through regulation of important stress signalling pathways. The aim of this
study is to investigate the role of SUMOylation in models of acute (ischemia) and chronic brain
diseases (AD).
Studies on neuron are starting using lentiviral technique for SUMO-1 over-expression to
confirm cell lines results. JNK activity inhibition regulates APP cleavage and degradation.
Since the observed modulation on JNKs activation we are testing if over-expression of SUMO-1
in H4-APPsw (cell line model of Alzheimer disease) can reduce b-amiloid fragments as cellautonomous mechanismSUMOylation of JNK3 has been successfully tested in bacterial assay,
cell lines (COS7 and SH-SY5Y) and we are testing in neurons, using SUMO-1 lentivirus with
promising results. Preliminary results showed that SUMO-1 regulates JNK3 expression and
phosphorylation. Other tests are currently on going on neuronal culture to confirm the results
obtained in cell line and bacterial. We think that SUMOylation could be a modulatory
mechanism of neuronal death and these findings could be bases for new therapeutical studies
against acute and chronic brain pathologies
Laboratory of Neurochemistry and Behavior
“Resistance” to antidepressant drugs
Biological mechanisms underlying the response to antidepressant drugs were studied in strains
of mice “responder” and “non-responder” to selective serotonin reuptake inhibitors (SSRI) in
the forced swimming test (FST), a behavioural procedure widely used to screen potential
antidepressant compounds. In 2010 we found that in “non-responder” mice serotonergic
autoregulatory feedback mechanisms are overactive because of an increase in the sensitivity of
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5-HT2C receptors controlling the release of GABA from inhibitory neurons in the midbrain
dorsal raphé nucleus. Blockade of 5-HT2C receptors with a selective antagonist restored the
effects of SSRI in the FST and abolished the excessive inhibitory GABAergic tone.
These results suggest that overactive feedback control suppresses the effects of SSRI and
identify pharmacological strategies that may enhance the response in treatment-resistant
depressed patients
Animal model of cognitive deficit of schizophrenia; typical and atypical
antipsychotics
The cognitive deficit is a core symptom of schizophrenia, which has been linked to functional
outcome and is relatively independent of psychotic symptoms. The antipsychotics, either typical
or atypical, are able to control positive symptoms such as delirium, hallucinations and paranoia.
However, the currently available atypical antipsychotics when compared to conventional
antipsychotics show somewhat superior efficacy for the management of cognitive deficits in
patients with schizophrenia.
The cognitive deficit of schizophrenia was modelled in rats and mice, by using a test of
attention such as the 5-choice serial reaction time task (5-CSRTT) and injections of glutamate
NMDA receptor antagonists into the medial prefrontal cortex (mPFC). This model makes clear
links with psychopathology as dysfunctional glutamate neurotransmission in the mPFC has been
implicated in cognitive deficits of schizophrenia and the 5-CSRTT is the rat analogue of the
continuous performance test used to assess attention and vigilance in schizophrenic patients.
Our studies compared the effects of conventional and atypical antipsychotics, including
haloperidol, olanzapine, clozapine, sertindole and aripiprazole in this model of cognitive deficit
of schizophrenia. The results show that antipsychotics may be differentiated by a preferential
effect of typical antipsychotics on compulsive perseveration, and atypical antipsychotics on
impulsivity. Biochemical studies show that attention deficits induced by NMDA receptor
antagonists are associated with excessive glutamate in the medial prefrontal cortex of the rat,
increased phosphorylation of the transcription factor CREB in the frontal cortex and decresed
phosphorylation of the same transcription factor in the dorsal striatum.
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DEPARTMENT OF CARDIOVASCULAR
RESEARCH
STAFF
Head
Maria Grazia FRANZOSI, Biol.Sci.D.
Laboratory of Cardiovascular Clinical Pharmacology
Head
Roberto LATINI, M.D.
Bio-imaging Unit
Head
Fabio FIORDALISO, Biol.Sci.D.
Cardiovascular Endocrine Unit
Head
Serge MASSON, Ph.D.
Tissue Culture Unit
Head
Giovanna BALCONI, BSc.
Laboratory of Clinical Drug Evaluation
Head
Maria Grazia FRANZOSI, Biol.Sci.D.
Bioinformatics Unit
Head
Enrico NICOLIS
Laboratory of General Practice Research
Head
Maria Carla RONCAGLIONI, Biol.Sci.D.
Laboratory of Medical Statistics
Head
Simona BARLERA, Dr.Sci.Pol., MSc.
Laboratory of Clinical Pharmacology
Head
Gianni TOGNONI, M.D.
Nursing Research Unit
Head
Paola DI GIULIO, R.N., MSc
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CURRICULA
Maria Grazia Franzosi got her Biological Science degree in 1972 at the University of Milan.
Education
1972
1978
Doctoral degree in Biological Sciences, University of Milan, Italy
Postdoctoral degree in Pharmacological Research, Istituto di Ricerche Farmacologiche "Mario
Negri” di Milano, Italy
Main fields of activity
Coordination of multicentric randomised clinical trials. Relationship between genetic and environmental risk
factors in coronary events. Pharmacogenetics. Cardiovascular genetic epidemiology. Pharmacoeconomics.
Drug Epidemiology and Post-Marketing Surveillance.
Position
from 2002
from 2005
from 2004
from 2001
from 1998
from 1997
from 1996
1994-1996
from 1993
from 2002
1989-2001
1985-1988
from 1984
1975-1984
Director of the Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
"Mario Negri", Milano, Italy
Member of the Coordinating Committee of Master course in Clinical Research – University of
Milano
Member of Steering Committee, Studio GISSI-AF Study, Milano, Italy
Member of Steering Committee, Studio GISSI-HF Study, Milano, Italy
Member of Steering Committee of the PROCARDIS Research Programme - A genome-wide
strategy to identify susceptibility loci in precocious coronary artery disease - University of
Oxford, UK
Member of “Antithrombotic Trialists’ Collaboration”, Oxford, UK
Member of the Steering Committee e National Coordinator for Italy of the Organization to
Assess Strategies for Ischemic Syndromes (OASIS-2, OASIS-4 CURE, Michelangelo
OASIS-5 e OASIS 6, , CURRENT OASIS-7, FUTURA OASIS-8), of the INTER-HEART
study and of the ACTIVE, RELY and AVERROES studies, Population Health Research
Institute, McMaster University, Hamilton, Canada
Director of European Coordinating Centre and Member of Steering Committee, Collaborative
Organization for RheothRx Evaluation (CORE), McMaster University, Hamilton, Canada
Member of Steering Committee, Studio GISSI-Prevenzione, Milano, Italy
Member of “Fibrinolytic Therapy Trialists’s Collaboration”, Oxford, UK e del “Collaborative
Group on Angiotensin Converting Enzyme Inhibitors Trials”, National Institutes of Health,
Bethesda, Washington, USA
Head of the Laboratory of Clinical Drug Evaluation, Istituto di Ricerche Farmacologiche "Mario
Negri"
Head of the Clinic Drug Evaluation Unit of the Laboratory of Clinical Pharmacology, Istituto di
Ricerche Farmacologiche "Mario Negri"
Member of the Scientific and Organising Secretariat, Gruppo Italiano per lo Studio della
Sopravvivenza nell'Infarto Miocardico (GISSI-1, GISSI-2, GISSI-3 studies) Milano, Italy
Researcher at the Laboratory of Clinical Pharmacology, Istituto di Ricerche Farmacologiche
"Mario Negri" and at the Regional Center for Drug Information of the Lombardy Region
•
Broadbent HM, Peden JF, Lorkowski S, Goel A, Ongen H, Green F, Clarke R, Collins R, Franzosi MG, Tognoni G,
Seedorf U, Rust S, Hamsten A, Farrall M, Watkins H, for the PROCARDIS Consortium. Susceptibility to coronary
artery disease and diabetes is encoded by distinct, tightly linked, SNPs in the ANRIL locus on chromosome 9p. Hum
Mol Genet 2008; 17: 806-814
•
GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,
Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of n-3 polyunsaturated fatty acids in patients with chronic heart
failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223-1230
•
Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF
trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231-1239
•
Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D,
Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R,
Watkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and
coronary disease. N Engl J Med 2009; 361: 2518-2528
•
GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni
AP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;
360: 1606-1617
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•
•
The FUTURA/OASIS-8 Trial Group. Low-Dose vs standard-dose unfractionated heparin for percutaneous coronary
intervention in acute coronary syndromes treated with fondaparinux: The FUTURA/OASIS-8 Randomized Trial. JAMA
2010; 304: 1339-1349
Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J,
Pogue J, Reilly PA, Yang S, Connolly SJ, on behalf of the RE-LY investigators. Efficacy and safety of dabigatran
compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial
fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975-983
Simona Barlera got her degree in Political Science, area Statistics at the “Università degli Studi di
Milano” in Milano in 1992, followed by a master in Medical Statistics at the London School of Hygiene
and Tropical Medicine, “University of London” in 1998.
Education and training
1987-1992
Degree in Political Science, course of studies Statistics, Università degli Studi di Milano,
Milano (Italy)
1993-1995
Post-degree Specialization in Pharmacological Research. School of Specialization in
Pharmacological Research Of Lombardia Region, Milan
1997-1998
Master of Science in Medical Statistics at the London School of Hygiene and Tropical
Medicine, University of London, London.
1998-1999
Visiting Scientist in the Department of Statistical Genetics, Wellcome Trust Centre for
Human Genetics, University of Oxford (UK).
Methodology of Clinical Trials in the cardiovascular field. Preparation and viewing of research protocols,
planning and conduct of statistical analyses and the reporting of findings on scientific journals.
Genetic epidemiology: genome-wide strategies (linkage analysis) to identify susceptibility genes in
coronary artery disease; case-control studies in order to identify candidate genes involved in the
cardiovascular pathology.
Position Held
from Oct 2006
1999 -2006
1992-1997
Head of the Laboratory of Medical Statistics, Department of Cardiovascular Research,
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Head of the Medical Statistics Unit, Department of Cardiovascular Research, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano, Italy
Researcher in the Unit of Applied Statistics and Information Technology, Istituto di
•
Barlera S, Specchia C, Farrall M, Chiodini BD, Franzosi MG, Rust S, Green F, Nicolis E, Peden J, Assmann G, Collins
R, Hamsten A, Tognoni G, PROCARDIS Consortium. Multiple QTL influence the serum Lp(a) concentration: a
genome-wide linkage screen in the PROCARDIS study. Eur J Hum Genet 2007; 15: 221-227
•
•
GISSI-HF Investigators (Writing Commitee:Tavazzi L, Maggioni A P, Marchioli R, Barlera S, Franzosi M G, Latini R,
Lucci D, Nicolosi G L, Porcu M, Tognoni G) Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF
trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008 372: 1231-1239
•
Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D,
Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R,
Watkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) Lipoprotein Level and
Coronary Disease. N Engl J Med 2009; 361: 2518-2528
•
AP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;
360: 1606-1617
•
Gori F, Specchia C, Pietri S, Crociati L, Barlera S, Franciosi M, Nicolucci A, Signorini S, Brambilla P, Franzosi MG,
for GISSI Prevenzione Investigators and SIBioC-GISSI Prevenzione Group. Common genetic variants chromosome
9p21are associated with myocardial infarction and type 2 diabetes in an Italian population. BMC Med Genet 2010; 11:
60
Roberto Latini got his Medical Doctor degree in 1978 at the University of Milan.
Education
1970-1978
University of Milan School of Medicine, degree in Medicine
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1981-1983
Merck Sharp & Dohme International Fellow in Clinical Pharmacology
Mechanisms of cardiac damage following ischemia, with focus on eurohumoral activation. Use of stem
cells for cardiac repair. Biohumoral investigations within large scale clinical trials in heart failure and
atrial fibrillation.
Positions
from 1990
Head of the Cardiovascular Clinical Pharmacology Laboratory (Cardiovascular Research
Department) Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
from 2001
Member of the GISSI-HF Steering Committee
from 2004
Member of the GISSI-AF Steering Committee
from 2005
Member of the CandHeart Steering Committee
1999-2009
Visiting Professor Dept of Medicine, New York Medical College, Valhalla, NY, USA
1981-1983
Cardiology Fellow (Dr. R. E. Kates, Laboratory) Stanford University Medical Center,
CA, USA
1976-1981
Member of the Sub-Group RMs for Drugs (Community Bureau of Reference,
Commission of the European Communities)
1973-1990
Fellow at the Laboratory of Clinical Pharmacology of the Istituto di Ricerche
Farmacologiche "Mario Negri", Milano, Italy
•
Galvez BG, Covarello D, Tolorenzi R, Brunelli S, Dellavalle A, Crippa S, Mohammed SAA, Scialla L, Cuccovillo I,
Molla F, Staszewsky L, Maisano F, Sampaolesi M, Latini R, Cossu G. Human cardiac mesoangioblasts isolated from
hypertrophic cardiomyopathies are greatly reduced in proliferation and differentiation potency. Cardiovasc Res 2009, 83:
707-716
•
AP, Lucci D, Di Pasquale G, Tognoni G), Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;
360: 1606-1617
•
Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, Caspani L, Raimondi F, Bordone G, Iapichino G,
Mancebo J, Guerin C, Ayzac L, Blanch L, Fumagalli R, Tognoni G, Gattinoni L, for the Prone-Supine II Study Group.
Prone positioning in patients with moderate and severe acute respiratory distress syndrome. A randomized controlled
trial. JAMA 2009; 302: 1977-1984
•
•
•
Masson S, Latini R, Anand IS. An update on cardiac troponins as circulating biomarkers in heart failure.
Curr Heart Fail Rep 2010; 7: 15-21
Masson S, Solomon S, Angelici L, Latini R, Anand IS, Prescott M, Maggioni AP, Tognoni G, Cohn JN, on behalf of the
Val-HeFT Investigators. Elevated plasma renin activity predicts adverse outcome in chronic heart failure, independently
of pharmacologic therapy: Data from the Valsartan Heart Failure trial (Val-HeFT). J Card Fail 2010; 16: 964-970
Røysland R, Masson S, Omland T, Milani V, Bjerre M, Flyvbjerg A, Di Tano G, Misuraca G, Maggioni AP, Tognoni G,
Tavazzi L, Latini R, on behalf of the GISSI-HF Investigators. Prognostic value of osteoprotegerin in chronic heart
failure: The GISSI-HF trial. Am Heart J 2010; 160: 286-293
Maria Carla Roncaglioni got her Biological Science degree in 1987 at the University of Milan.
Education
1987
1982-1983 “Research Fellow” at the Dept. of Biochemistry, Faculty of Medicine, Rijksuniversiteit of
Limburg, Maastricht , The Netherland (Prof. C.Hemker);
1998-1999 “Visiting Scientist” at the Cardiovascular Research Unit, Hammersmith Hospital, London,
UK (Prof. A. Maseri)
Coordination of multicenter clinical trials and observational studies in different cardiovascular areas
(neurological, angiological, cardiological). Coordination of a network of more than 1000 GPs actively
involved in epidemiological and experimental studies in the prevention of cardiovascular diseases.
Position
from 2001 Head of the Laboratory for General Practice Research, Istituto di Ricerche Farmacologiche
"Mario Negri", Milano, Italy
from 1989 Senior Researcher in the Clinical Pharmacology Laboratory, Istituto di Ricerche
from 1974 Researcher in the Laboratory for the Study of Haemostasis and Thrombosis, Istituto di
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•
Tognoni G, Avanzini F, Pangrazzi J, Roncaglioni M C, Bertele V, de Gaetano G, Caimi V, Tombesi M, Colombo Fabio,
Barlera S, PPP - Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: A
randomized trial in general practice. Lancet 2001; 357: 89-95
•
Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A, PPP - Primary Prevention Project.
Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients. Results of
the Primary Prevention Project (PPP) trial. Diabetes Care 2003; 26: 3264-3272
•
Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi J, Tognoni G, Brown DL. Aspirin for the primary prevention of
cardiovascular events in women and men: A sex-specific meta-analysis of randomized controlled trials. JAMA 2006;
295: 306-313
•
Montalvo G, Avanzini F, Anselmi M, Prandi R, Ibarra S, Marquez M, Armani D, Moreira J M, Caicedo C, Roncaglioni
MC, Colombo Fabio, Camisasca P, Milani V, Quimi' S, Gonzabay F, Tognoni G. Diagnostic evaluation of people with
hypertension in low income country: cohort study of "essential" method of risk stratification. BMJ 2008;
337: a1387
•
Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease:
collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860
•
Rischio and Prevenzione Investigators. Efficacy of n-3 polyunsaturated fatty acids and feasibility of optimizing
preventive strategies in patients at high cardiovascular risk: rationale, design and baseline characteristics of the Rischio
and Prevenzione study, a large randomised trial in general practice. Trials 2010; 11: 68
Gianni Tognoni got his Medical Doctor degree in 1970, University of Milan.
Main areas of methodology
Randomized clinical trials; outcomes studies; pharmacoepidemiology; pharmacoeconomics;
epidemiological monitoring and assessment of health care systems, drug policy; genetic epidemiology;
community epidemiology; transfer of technology; health and human rights.
Main clinical areas
Acute and chronic CV diseases; psychiatry; aging; intensive care; neurodegenerative disordes; hematooncology.
Position
from 2004 Member, Commission of Human Experimentation of the Italian Drug Agency (AIFA)
2001-2003 Member, Commissione Unica del Farmaco (CUF), Ministry of Health
from 2002 Director, Consorzio Mario Negri Sud, S. Maria Imbaro, Chieti.
1996-2002 Coordinator, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
"Mario Negri", Milano
from 1990 Co-Director, Scuola Superiore di Ricerca in Medicina Generale (CSeRMEG)
from 1976 Founding member of the International Society of Drug Bulletins (ISDB)
Coordinator, Commission of Human Experimentation, Regione Lombardia
from 1983 Founder and in the Editorial Board of the nursing research Journal Rivista
dell'Infermiere/Assistenza Infermieristica e Ricerca
from 1977 Consultant to WHO and other UN agencies for drug selection and policy; training in
methods of clinical and epidemiological research in developing countries mainly in Latin
America and Africa
1976-1999 Head, Laboratory of Clinical Pharmacology of the Istituto di Ricerche Farmacologiche
"Mario Negri", Milano
from 1975 Head, Regional Centre for Drug Information (CRIF), Regione Lombardia, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano
1969-1974 Research Assistant, Laboratory of Clinical Pharmacology, Istituto di Ricerche
Farmacologiche "Mario Negri", Milano
• GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,
• GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni
AP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009;
360: 1606-1617
• Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Tonelli M, Garg AX, Pellegrini F, Ravani P, Jardine M, Perkovic
V, Graziano G, McGee R, Nicolucci A, Tognoni G, Strippoli GF. Meta-analysis: erythropoiesis-stimulating agents in
patients with chronic kidney disease. Ann Intern Med 2010; 153: 23-33
• Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SRK, McMurray JJ, Freeman DJ, Jukema
JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM,
Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR,
Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of
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•
•
randomised statin trials. Lancet 2010; 375: 735-742
Sud S, Friedrich JO, Taccone P, Polli F, Adhikari NKJ, Latini R, Pesenti A, Guérin C, Mancebo J, Curley MAQ,
Fernandez R, Chan M-C, Beuret P, Voggenreiter G, Sud M, Tognoni G, Gattinoni L. Prone ventilation reduces mortality
in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med
2010; 36: 585-599
The NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J
Med 2010; 362: 1463-1476
Giovanna Balconi got her degree at the School for Technicians of Biomedical Institutes of the
University of Milan, with a specialisation in Histology in the Pathological Anatomy Laboratory of the
same University (1968).
Main fields of interest
Isolation, culture and characterization of peripheral blood circulating progenitor cells of patients with
heart failure. Isolation, culture and characterization of peripheral blood circulating progenitor cells in
rodents affected by diabetic cardiomyopathy. “In vitro” culture and characterization of stem cells for
repair of myocardial infarction in experimental animal models.
Positions
from July 2005
Head of Tissue Culture Unit, Cardiovascular Clinical Pharmacology Laboratory,
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Oct 1995 - June 2005 Head of Tissue Culture Unit, Vascular Biology Laboratory, Istituto di Ricerche
Dec 1983 - Oct 1995 Head of Tissue Culture Unit, Anticancer Chemotherapy Laboratory, Istituto di
Oct 1968 - Nov 1983 Researcher, Anticancer Chemotherapy Laboratory, Istituto di Ricerche
•
Cattelino A, Liebner S, Gallini R, Zanetti A, Balconi G, Corsi A, Bianco P, Wolburg H, Moore R, Oreda B, Kemler R,
Dejana E. The conditional inactivation of the beta-catenin gene in endothelial cells causes a defective vascular pattern
and increased vascular fragility. J Cell Biol 2003; 162: 1111-1122
•
Cusella De Angelis MG, Balconi G, Bernasconi S, Zanetta L, Boratto R, Galli D, Dejana E, Cossu G. Skeletal myogenic
progenitors in the endothelium of lung and yolk sac. Exp Cell Res 2003; 290: 207-216
•
Galli D, Innocenzi A, Staszewsky L, Zanetta L, Sampaolesi M, Bai A, Martinoli E, Carlo E, Balconi G, Fiordaliso F,
Chimenti S, Cusella G, Dejana E, Cossu G, Latini R. Mesoangioblasts, vessel-associated multipotent stem cells, repair
the infarcted heart by multiple cellular mechanisms. A comparison with bone marrow progenitors, fibroblasts, and
endothelial cells. Arterioscler Thromb Vasc Biol 2005; 25: 692-697
•
Sarto P, Balducci E, Balconi G, Fiordaliso F, Merlo L, Tuzzato G, Pappagallo GL, Frigato N, Zanocco A, Forestieri C,
Azzarello G, Mazzucco A, Valenti M T, Alborino F, Noventa D, Vinante O, Pascotto P, Sartore S, Dejana E, Latini R.
Effects of exercise training on endothelial progenitor cells in patients with chronic heart failure. J Card Fail 2007; 13:
701-708
•
Galvez BG, Sampaolesi M, Barbuti A, Crespi A, Covarello D, Brunelli S, Dellavalle A, Crippa S, Balconi G, Cuccovillo
I, Molla F, Staszewsky L, Latini R, DiFrancesco D, Cossu G. Cardiac mesoangioblasts are committed, self-renewable
progenitors, associated with small vessels of juvenile mouse ventricle. Cell Death Differ 2008; 15: 1417-1428
•
Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, Angelici L,
Masson S, Mohammed SAA, Dejana E, Gorini M, Zeiher AM, Latini R, GISSI-HF Investigators. Levels of circulating
pro-angiogenic cells predict cardiovascular outcomes in patients with chronic heart failure. J Cardiac Fail 2009; 15: 747755
Paola Di Giulio got her Nursing Diploma at the Nursing School of Istituto Nazionale dei Tumori in
Milano and her Master in Oncology Nursing at Guildford University (UK) in 1995.
Coordination of multicentre and observational studies in cardiology and palliative care. Coordination of
nursing networks.
Position
from March 2001 Associated professor at the Turin University.
from 1997
Responsible of the Nursing Research Unit
from 1995
Senior researcher of the Cardiovascular Research Department
from 1989
Consultant of the Clinical Phrmacology Laboratory
since 1998
Coordinator of the Editorial Board of Assistenza Infermieristica e Ricerca
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Saiani L, Di Giulio P, Gruppo PARI-FV (Percorsi Assistenziali e Ricerca Infermieristica-Farmaco Vigilanza).
Epidemiologia dei problemi assistenziali legati a farmaci e presidi in RSA e distretto. Assistenza Infermieristica e
Ricerca 2007; 26: 123-164
•
Lepore V, Cecchetto G, Di Giulio P, Saiani L, Samarelli V, Saugo M, Romero M, Scurti V, Tognoni G, Valerio M. Età
anziana-molto-anziana, e “aspettativa di vita”? Assistenza Infermieristica e Ricerca 2007; 26: 234-242
•
Di Giulio P, Toscani F, Villani D, Brunelli C, Gentile S, Spadin P. Dying with advanced dementia in long-term care
geriatric institutions: a retrospective study. J Palliat Med 2008; 11: 1023-1028
•
Amodeo R, De Ponti A, Sorbara L, Avanzini F, Di Giulio P, De Martini M. Come aumentare le conoscenze dei pazienti
con cardiopatia ischemica sulla loro malattia? Utilità di un incontro educazionale tenuto da infermieri. G Ital Cardiol
2009; 10: 249-255
•
Di Giulio P, Pera C, Scarano M, Ferri B, Lepore V, Miani D, Tognoni G. Rapporto finale dello studio QDF (Qualità di
vita, Depressione e Funzioni cognitive) nei pazienti con scompenso cardiaco. Assistenza Infermieristica e Ricerca 2009;
28: 5-38
•
Gouchon S, Gregori D, Picotto A, Patrucco G, Nangeroni M, Di Giulio P. Skin-to-Skin contact after cesarean delivery:
an experimental study. Nurs Res 2010; 59: 78-84
Fabio Fiordaliso got his Biological Science degree in 1995 at the University of Milan.
Education
1998
Postdoctoral degree in Pharmacological Research, Istituto di Ricerche Farmacologiche
“Mario Negri”, Milan, Italy
1995
Therapeutical potential of stem cell and antioxidant treatments in experimental model of diabetic
cardiomyopathy and in primary myocyte cultures exposed to hyperglycemia.
Morphological and structrural analysis of cells and tissue by optical, confocal and electron microscopy.
Positions
from 2007 Head of Bio-imaging Unit, Department of Cardiovascular Research, Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan
from 2006 Member of the Heart Failure Association (HFA) of the European Society of Cardiology
from 2005 Member of the Working group on myocardial function (WG 4) of the European Society of
Cardiology
from 2005 Member of the steering committee of the Consorzio of Microscopy and Image Analysis
(MIA)
from 2001 Senior Research Scientist, Laboratory of Cardiovascular Clinical Pharmacology
(Department of Cardiovascular Research), Istituto di Ricerche Farmacologiche “Mario
Negri”, Milan
1997-2001 Post-Doctoral Research Fellow at Cardiovascular Research Institute (Department of
Medicine), New York Medical College, Valhalla, New York
1994-1997 Research Fellow, Laboratory of Cardiovascular Clinical Pharmacology (Department of
Cardiovascular Research), Istituto di Ricerche Farmacologiche “Mario Negri”, Milan
1992-1994 Research training, Institute of General Pathology, University of Milan (Italy)
•
Fiordaliso F, Cuccovillo I, Bianchi R, Bai A, Doni M, Salio M, De Angelis N, Ghezzi P, Latini R, Masson S.
Cardiovascular oxidative stress is reduced by an ACE inhibitor in a rat model of streptozotocin-induced diabetes. Life Sci
2006; 79: 121-129
•
Fiordaliso F, De Angelis N, Cuccovillo I, Bai A, Salio M, Serra DM, Bianchi R, Razzetti R, Latini R, Masson S. Effect
of β-adrenergic and renin-angiotensin system blockade on myocyte apoptosis and oxidative stress in diabetic
hypertensive rats. Life Sci 2007; 81: 951-959
•
Latini R, Brines M, Fiordaliso F. Do non-hemopoietic effects of erythropoietin play a beneficial role in heart failure?
Heart Fail Rev 2008; 13: 415-423
•
Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, Angelici L,
Masson S, Mohammed SAA, Dejana E, Gorini M, Zeiher AM, Latini R, GISSI-HF Investigators. Levels of circulating
pro-angiogenic cells predict cardiovascular outcomes in patients with chronic heart failure. J Cardiac Fail 2009; 15: 747755
•
Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V, Crippa L, Avezza F,
Fiordaliso F, Salio M, Lauria G, Lombardi R, Cavaletti G. Regression of diabetic complications by islet transplantation
in the rat. Diabetologia 2009; 52: 2653-2661
•
Diomede L, Cassata G, Fiordaliso F, Salio M, Ami D, Natalello A, Doglia SM, De Luigi A, Salmona M. Tetracycline
and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting oligomers. Neurobiol Dis
2010; 40: 424-31
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Serge Masson obtained his doctorate (PhD) in Biochemistry and Cellular Biology in 1990 at the
University of Marseilles (France), followed by a postdoctoral stay at the Panum Institute in Copenhagen
(Denmark).
Education
1988-1990 Doctorate fellow, Faculty of Medicine, University of Aix-Marseilles, France
1990-1993 Post-doctoral Researcher, Panum Institute and Assistant Lecturer, University of
Copenhagen, Denmark
1993
Research Scientist, NMR Laboratory, Hospital “San Raffaele”, Milan, Italy
from 1994 Research Scientist, Department of Cardiovascular Research, Istituto di Ricerche
Physiopathology, diagnostic and prognostic role of the activation of neuroendocrine systems in
cardiovascular disease
Position
from 2002 Head of the Cardiovascular Endocrine Unit, responsible for Quality Assurance for the
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario
Negri", Milano, Italy
from 2002 Tutor of fellows of the School of Specialists in Pharmacological Research, Istituto di
from 2002 Fellows of the American Heart Association (Basic Council) and the Working Group on
Myocardial Function of the European Society of Cardiology
•
Latini R, Masson S, Anand I S, Missov E, Carlson M, Vago T, Angelici L, Barlera S, Parrinello G, Maggioni AP,
Tognoni G, Cohn J N, Val-HeFT Investigators. Prognostic value of very low plasma concentrations of troponin T in
patients with stable chronic heart failure. Circulation 2007; 116: 1242-1249
•
Masson S, Latini R, Anand IS, Barlera S, Angelici L, Vago T, Tognoni G, Cohn J N, for the Val-HeFT Investigators.
Prognostic value of changes in N-termianl pro-brain natriuretic peptide in the Val-HeFT (Valsartan Heart Failure Trial).
J Am Coll Cardiol 2008; 52: 997-1003
•
Boccanelli A, Mureddu GF, Cacciatore G, Clemenza F, Di Lenarda A, Gavazzi A, Porcu M, Latini R, Lucci D,
Maggioni AP, Masson S, Vanasia M, De Simone G, AREA IN-CHF Investigators. Anti-remodelling effect of canrenone
in patients with mild chronic heart failure (AREA IN-CHF study): final results. Eur J Heart Fail 2009; 11: 68-76
•
Masson S, Aleksova A, Favero C, Staszewsky L, Bernardinangeli M, Belvito C, Cioffi G, Sinagra G, Mazzone C ,
Bertocchi B, Vago T, Peri G, Cuccovillo I, Masuda N, Barlera S, Mantovani A, Maggioni AP, Franzosi MG, Disertori
M,Latini R, on behalf of the GISSI-AF investigators. Predicting atrial fibrillation recurrence with circulating
inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation
trial. Heart 2010; 96: 1909-1914
•
Masson S, Latini L, Milani V, Moretti L, Rossi M G, Carbonieri E, Frisinghelli A, Minneci C, Valisi M, Maggioni A P,
Marchioli R, Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators. Prevalence and prognostic value of
elevated urinary albumin excretion in patients with chronic HF. Data from the GISSI-Heart Failure (GISSI-HF) trial.
Circ Heart Fail 2010; 3: 65-72
•
Masson S, Latini R, Carbonieri E, Moretti L, Rossi MG, Ciricugno S, Milani V, Marchioli R, Struck J, Bergmann A,
Maggioni AP, Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators. The predictive value of stable precursor
fragments of vasoactive peptides in patients with chronic heart failure:data from the GISSI-heart failure (GISSI-HF) trial.
Eur J Heart Fail 2010; 12 : 338-347
Enrico Bjørn Nicolis has attended the courses in Computer Science at the University of Milan.
Education
1991-1999 “Research fellow”, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Data management and analysis of randomized clinical trials. Developing of database and tools for studies
of population genetics, particularly for linkage analysis.
Position
from 2001 Head of the Bioinformatics Unit, Istituto di Ricerche Farmacologiche "Mario Negri",
Milano, Italy
from 1999 Research fellow of the Laboratory of Clinical Drugs Evaluation
from 1997 System administrator at the EDP center, Istituto di Ricerche Farmacologiche "Mario Negri",
Milano, Italy
from 1991 Research fellow at the Medical Informatics and Applied Statistics Unit, Istituto di Ricerche
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Nobili A, Gebru F, Rossetti A, Schettino F, Zahn R W, Nicolis E, Macario G, Celani L, Acik V O, Farina ML, Naldi L.
Doctorline: A private toll-free telephone medical information service. Five years of activity: Old problems and new
perspectives. Ann Pharmacother 1998; 32: 120-125
•
Santoro E, Nicolis E, Franzosi MG.Telecommunication technology for the management of large scale clinical trials: The
GISSI experience. Comput Methods Programs Biomed 1999; 60: 215-223
•
Tognoni G, Franzosi MG, Nicolis E, Barlera S, Specchia C, Chiodini B, Crociati L, Ferrario L, PROCARDIS
Consortium. A trio family study showing association of the lymphotoxin-alfa N26 (804A) allele with coronary artery
disease. Eur J Hum Genet 2004; 12: 770-774
•
Barlera S, Specchia C, Farrall M, Chiodini BD, Franzosi MG, Rust S, Green F, Nicolis E, Peden J, Assmann G, Collins
R, Hamsten A, Tognoni G, PROCARDIS Consortium. Multiple QTL influence the serum Lp(a) concentration: a
genome-wide linkage screen in the PROCARDIS study. Eur J Hum Genet 2007; 15: 221-227
•
Specchia C, Barlera S, Chiodini BD, Nicolis EB, Farrall M, Peden J, Collins R, Watkins H, Tognoni G, Franzosi MG,
PROCARDIS Consortium. Quantitative trait genetic linkage analysis of body-mass index in familial coronary artery
disease. Hum Hered 2008; 66: 19-24
•
Disertori M, Latini R, Maggioni AP, Barlera S, Di Pasquale G, Franzosi MG, Lucci D, Staszewsky L, Masson S, Baviera
M, Nicolis E, Tognoni G, GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med
2009; 360: 1606-1617
ACTIVITIES
The areas of interest of the Department of Cardiovascular Research include the experimental,
clinical, genetic, epidemiological aspects of acute myocardial infarction, cardiac failure, cardiac
arrhythmias, as well as the clinical and epidemiological investigation of cardiovascular
prevention, hypertension and stroke. Following the successful experience of the GISSI-trials
(Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto), the activation of large
collaborative networks in the setting of the National Health Service hospitals and in general
practice has become a key characteristics of the Department, which can now rely on the
permanent collaboration of over 300 clinical groups and of several hundred general
practitioners. Over the years, firm links have also been established with international leading
research groups.
The experimental research activity concerns the physiopathology, the pharmacological
modulation and the prognostic role of the activation of the renin-angiotensin-aldosterone
system, as well as other neurohormonal systems, in myocardial infarction and heart failure, the
physiopathology, the pharmacological modulation and prognostic role of the activation of the
inflammatory processes in myocardial infarction and heart failure; a more recent research topic
is the cell therapy of experimental myocardial infarction. A model of cardiac arrest and
cardiopulmonary resuscitation in the rat has been recently set up and is being used for assessing
the role of inflammation in cardiac and brain injury after cardiac arrest.
The activity in clinical research includes the clinical assessment of therapeutic strategies and of
biomarkers of cardiovascular risk with large scale clinical trials in the field of acute coronary
syndromes, congestive heart failure and atrial fibrillation. A recently developing area is the
genetic epidemiology of myocardial infarction and heart failure. Several studies have been
conducted in the area of clinical epidemiology and risk factors assessment of myocardial
infarction. The collaboration with an european genetic network has allowed the participation to
large GWAS (genome wide association studies) on coronary disease and myocardial infarction.
The collaboration with a large network of General Practitioners in the area of cardiovascular
prevention allowed to test new hypotheses through large scale clinical trials and to evaluate the
actual transferability of evidence based interventions in the every day practice through
epidemiological or outcome research studies. Pharmacoepidemiological studies through the
analysis of a large sample of Local Health Units drug prescriptions were also performed. A
research network of nurses has been developed with the main focus on the assessment of healthrelated quality of life of patients and on the epidemiology of nursing interventions and their
implications for patients' well being and outcomes.
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MAIN FINDINGS
A subgroup analysis of patients enrolled in the GISSI-AF trial has shown that the risk of
incident atrial fibrillation is predicted by circulating cardiac markers (natriuretic peptides and
troponin T) and by left atrial function as assessed by echocardiography in patients in sinus
rhythm. Predictors of atrial fibrillation could help in treating this arrhythmia which has a
prevalence of 5-6% in the elderly and is associated with a 10-fold increase in risk of stroke.
The PROCARDIS study has identified two single nucleotide polymorphisms (SNPs) at the LPA
locus, strongly associated to coronary disease, with an odds ratio of 1.70 (95% CI 1.49-1.95) for
rs10455872,and with an odds ratio of 1.92 (95% CI 1.48-2.49) for rs3798220. Both variants
were strongly associated also with an increased level of lipoprotein(a), a reduced copy number
in LPA, and a small lipoprotein(a) size. These common variants explain over a third of the
variance in lipoprotein(a) levels in individuals of European descent. After adjustment for the
plasma lipoprotein(a) level, the association between these genotypes and coronary disease was
abolished, indicating a causal role of lipoprotein(a) in coronary disease.
The GISSI- Prevenzione Genetic study confirmed the results of the PROCARDIS concerning
the role of two SNPs located in the chromosome 9p21 region, that are independently associated
with CAD and with type 2 diabetes (T2D) respectively.
AMD (Associazione Medici Diabetologi) - Lombardia
ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri)
AREU - Azienda Regionale Emergenza Urgenza - Lombardia
Azienda Ospedaliera CTO/Maria Adelaide, Torino
Centro Cardiologico Monzino IRCCS, Milano
CINECA (Consorzio Interuniversitario per il Calcolo Automatico dell'Italia Nord-Orientale)
CSeRMEG (Centro Studi e Ricerche in Medicina Generale)
Dipartimento Cardio-Vascolare ed Endocrino-Metabolico, Ospedale Casa Sollievo della
Sofferenza IRCCS, San Giovanni Rotondo
Dipartimento Cardiologico “A. De Gasperis” - Struttura Complessa di Cardiologia 2 Insufficienza Cardiaca e Trapianto, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda,
Milano
Dipartimento di Cardiologia e UTIC, Istituto Clinico Humanitas IRCCS, Milano
Dipartimento di Immunologia, Istituto Clinico Humanitas IRCCS, Milano
Ematologia, Ospedale Sant’Anna, Torino
Fondazione Don Gnocchi IRCCS, Milano
Gruppi organizzati di MMG (FIMMG, CoS, Ass.Cu.M.I., AMISI)
IFOM-FIRC, Milano
IRC - Italian Resuscitation Council, Bologna
Istituto di Anestesiologia e Rianimazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli,
Regina Elena, Milano
Istituto di Anestesia e Rianimazione, Ospedale San Gerardo, Monza
Istituto di Ricerca in Cure palliative Lino Maestroni, Cremona
Istituto Ortopedico Galeazzi, Milano
Istituto Ortopedico Rizzoli, Bologna
Laboratorio di Endocrinologia, Ospedale Luigi Sacco, Milano
Regione Lombardia
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SIBioC (Società Italiana di Biochimica Clinica e Biologia Molecolare)
SIFO (Società Italiana di Farmacia Ospedaliera)
Stem Cell Research Institute, Ospedale San Raffaele, Milano
Unità Operativa Semplice di Neuroanestesia e Neurorianimazione, Dipartimento di Medicina
Perioperatoria e Terapie Intensive, Ospedale San Gerardo, Monza
Università degli Studi di Milano, Dipartimento di Medicina Interna
Università degli Studi di Milano Bicocca, Dipartimento di Biotecnologie e Bioscienze
Università degli Studi di Milano, Dipartimento di Scienze Farmacologiche
Università degli Studi di Torino, Dipartimento di Anatomia, Farmacologia e Medicina Forense
Università degli Studi di Torino, Dipartimento di Sanità Pubblica e Microbiologia
Università degli Studi di Verona, Dipartimento di Sanità Pubblica
Università degli Studi di Verona, Istituto di Anatomia Umana
Cecomet (Centro de Epidemiologia comunitaria y Medicina tropical, Esmeraldas) Ecuador
Cochrane Collaboration, Oxford, UK
Clinical Trial Research Unit, Auckland University, Nuova Zelanda
CNIC Centro Nacional de Investigaciones Cardiovasculares, Madrid , Spain
CTSU (Clinical Trial Service Unit) /ISIS (International Studies on Infarct Survival), Oxford,
UK
Department of Cardiology, Italian Hospital of Buenos Aires, Argentina
Department of Epidemiology, Harvard School of Public Health, Boston, USA
Division of Genetics and Development, Guy's, King's and St Thomas' School of Medicine,
King's College, London, UK
DSAN SUPSI (Scuola Universitaria Professioni Sanitarie), Lugano CH
ECLA (Estudios Cardiologicos de Latino-America)
Karolinska Institutet, Stockholm, Svezia
Laerdal Foundation for Acute Medicine, Stavanger, Norway
PHRI (Population Health Research Institute), McMaster University, Hamilton, Ontario, Canada
SIOP Europe (European Society for Paediatric Oncology)
University of Cambridge, UK
University of Minnesota, Minneapolis, USA
University of Oslo, Norvegia
University Medical Center, Groningen, Olanda
Wellcome Trust Centre for Human Genetics, University of Oxford, UK
WONCA (World Organization of Family Doctors)
Assistenza Infermieristica e Ricerca, European Journal of Cancer Care, European Journal of
Oncology Nursing (Paola Di Giulio)
European Heart Journal, International Journal of Health Services, Italian Journal of
Cardiology(Gianni Tognoni)
Italian Resuscitation Council Edizioni (Giuseppe Ristagno)
Journal of Cardiac Failure, Journal of Cardiovascular Medicine (Roberto Latini)
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IRFMN
American Heart Journal, American Journal of Cardiology, American Journal of Medicine,
Archives of Medical Research, Atherosclerosis Thrombosis and Vascular Biology, Biomarkers
in Medicine, Canadian Medical Association Journal, Cardiovascular Drugs and Therapy,
Cardiovascular Research, Circulation, Circulation Research, Clinical Pharmacology and
Therapeutics, Critical Care Medicine, European Heart Journal, European Journal of Cancer
Care, European Journal of Cardiovascular Nursing, European Journal of Oncology Nursing,
Free Radical Biology & Medicine, Health and Quality of Life, Heart, Heart Vessels,
International Journal of Cardiology, International Journal Diabetes in Developing Countries,
ISRN Nursing (International Scholarly Research Network), International Journal of Obesity,
Intensive Care Medicine, Italian Journal of Cardiology, Journal of American College of
Cardiology, Journal of Cardiac Failure, Journal of Clinical Laboratory Analysis, Journal of
Internal Medicine, Journal of Cardiovascular Medicine, The Lancet, Life Sciences, Metabolism,
PLoS Medicine, PharmacoEconomics, Pharmacological Research, Postgraduate Medical
Journal, Redox Report, Value in Health.
Comitato Etico ASL di Milano
Comitato Etico della Regione Lombardia
Comitato Etico della Provincia di Trento
Comitato Etico della Provincia di Verona
Comitato Etico Scientifico dell’A.O. Fatebenefratelli e Oftalmico di Milano
International Liaison Committee on Resuscitation, Task Force of the 2010 American Heart
Association Guidelines for Cardiopulmonary Resuscitation
EVENT ORGANIZATION
Investigator's Meeting – Riunione di avvio dello studio REGIA - Rischio Emorragico
GInocchio e Anca
Studio osservazionale prospettico di coorte sull’incidenza degli eventi emorragici nei pazienti
sottoposti ad interventi di sostituzione protesica di ginocchio ed anca
28/01/10, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Investigator's Meeting – Riunione per la presentazione dei risultati dello studio GLICINE
SPIDER – Gruppo Lombardo per lo studio dell’iperglicemia nelle sindromi coronariche acute Studio osservazionale prospettico sulla gestione dell’iperglicemia in corso di sindrome
coronarica acuta
08/09/10, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Investigator's Meeting – Riunione di avvio dello studio BeTACTIC - Best Therapy After
Cardiac Transplantation, the Italian Challenge
28/09/10, Centro Congressi Stella Polare – Porta Sud, Nuovo Polo della Fiera di Milano, PeroRho
Master di I° Livello in Ricerca Clinica dell’Università degli Studi di Milano, Facoltà di
Medicina e Chirurgia, Dipartimento di Medicina Interna (Anno Accademico 2010-2011).
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
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02/11/10
03/11/10
04/11/10
09/11/10
10/11/10
11/11/10
15/11/10
16/11/10
17/11/10
22/11/10
29/11/10
30/11/10
01/12/10
02/12/10
09/12/10
Introduzione al corso
La ricerca clinica oggi: profit e no-profit
Corso di introduzione alla statistica medica
La variabilità dei fenomeni biologici
Elementi di statistica descrittiva
Il disegno dello studio in epidemiologia
Farmacovigilanza
Misure di rischio in epidemiologia
Monitoraggio degli studi clinici no-profit
Il disegno degli studi clinici
Report delle reazioni avverse negli studi clinici no profit
Le interazioni tra farmaci
Analisi della sopravvivenza
Inferenza statistica
Legislazione sulla sperimentazione clinica e ruolo dei Comitati Etici
Esercitazione di inferenza statistica
Test diagnostici
Esercitazioni di statistica descrittiva
Ricerca clinica nel capo dell'epilessia. Ricerca clinica nell'ictus
Studi di fase 2: obiettivi, disegno e stima del campione in oncologia
Ricerca traslazionale. Outcome research
Dalla preclinica alla clinica: sviluppo di nuovi farmaci cardiovascolari
I bias negli studi clinici controllati
Revisioni sistematiche e metanalisi
La ricerca bibliografica oggi
Regolamentazione dei farmaci in Europa
Ricerca in medicina generale
Monitoraggio degli studi clinici profit
Report delle reazioni avverse
Internet e le nuove tecnologie per l'aggiornamento medico-scientifico
Associazione Internazionale dei Lions Clubs – Distretto 108 Ta 1 Italy. Il presente e il futuro
delle cellule staminali. Oltre l’orizzonte, 23/01/10, Verona, Italy
- Cellule per riparare un cuore malato: a che punto siamo?
American Heart Association – International Liaison Committee on Resuscitation. 2010
International Consensus on CPR & ECC Science with treatment and recommendations. 31/0106/02/10, Addison, Texas USA
- Automated vs manual defibrillation
European Society of Anaestesiology ESA. 6th EuroNeuro Congress, 04-06/02/10, Porto,
Portugal
- Evaluation of anesthesiological strategies in elective craniotomy: the Neuromorfeo trial
Amici dell’Istituto Mario Negri (Delegazione di Genova e Riviera di Levante) – Comune di
Lavagna. Le malattie cardio-cerebrovascolari: riconoscerle e prevenirle. 16/02/10, Auditorium
“G.B. Campodonico” Lavagna, Italy
- Il contributo della genetica alla prevenzione dell’infarto miocardico
ANNUAL REPORT
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2010
IRFMN
INTERcardio Onlus – UO Cardiologia Interventistica, Azienda Ospedaliera S. Camillo
Forlanini. INTERcardio 2010. L’espansione delle tecnologie, il ruolo della clinica, oggi. 2123/04/2010, SGM Conference Center Roma, Italy
- Atrial fibrillation: new approaches. New anticoagulant drugs
Regione Lombardia. Il profilo epidemiologico e il carico assistenziale del diabete nelle ASL
della Regione Lombardia. 17/05/10, I.ReF. Istituto Regionale lombardo di Formazione per
l’amministrazione pubblica, Milano, Italy
- Il profilo epidemiologico della popolazione con diabete in Regione Lombardia: analisi dei
database amministrativi
- Il carico assistenziale della popolazione con diabete in Regione Lombardia: analisi dei
ricoveri ospedalieri
- Profilo farmaco-epidemiologico della popolazione diabetica: il trattamento diabetico e i
farmaci cardiovascolari
ANMDO Associazione Nazionale dei Medici delle Direzioni Ospedaliere. 36° congresso
Nazionale ANMDO “Progettare e Costruire il Futuro”. 19-22/05/10, Royal Continental Hotel,
Napoli, Italy
- Terapia anticoagulante: novità organizzative in vista?
Associazione Nazionale Medici Cardiologi Ospedalieri. 41° Congresso Nazionale di
Cardiologia, 19-22/05/10, Fortezza da Basso, Firenze, Italy
- Infiammazione e scompenso cardiaco GISSI-HF & CORONA
- Qualità di vita Depressione Funzioni cognitive QDF - Rete Infermieri GISSI-HF
SMART-Organizing and Scientific Committee. 21° SMART – Simposio Mostra Anestesia,
Rianimazione e Terapia Intensiva, 26-28/05/10, MIC Convention Centre, Milano, Italy
- Research in emergency: where is it going?
- What’s new in defibrillation
- The adrenergic discharge in anesthesia: biohumoral markers
Italian Resuscitation Council. IRC 2010 Cardiac arrest, trauma and paediatric emergencies: a
multiprofessional health care approach. 04-05/06/10, Sheraton Hotel & Conference Center,
Catania, Italy
- Is epinephrine the best drug to protect cerebral perfusion during CPR?
Committee for European Education in Anaesthesiology - Università degli Studi di Catania.
Anestesia, medicina perioperatoria e terapia intensiva. Corso 2 – Ciclo 1, 18-20/06/10 Aula “G.
Pero” - Policlinico “G. Rodolico”, Catania, Italy
- Amplitude Spectrum Area (AMSA) quale indicatore del successo della defibrillazione
- Biomarkers del danno cardiaco
- Ruolo della capnometria negli stati di shock
European Society of Cardiology. Frontiers in Cardiovascular Biology, 16-18/07/10, Berlino,
Germany
- Effects of dipeptildyl peptidase-4 (DDP-4) inibition on angiogenesis and hypoxy injury in
type 2 diabetes
- Ex-vivo expanded bone marrow human CD34+ hematopoietic stem cells for repairing
myocardial ischemic injury in immunodeficient mice
European Society of Cardiology. ESC Congress 2010, 29/08-01/09/10, Stoccolma, Sweden
- Tubular damage and outcome in chronic heart failure
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IRFMN
- Prognostic value of osteoprotegerin in chronic heart failure: the GISSI-HF trial
- The long-chain pentraxin-3 (PTX3) predicts short-term functional recovery of rehabilitation
in patients with cardiac surgery
- The added value of depression to NYHA class: the results of the QDF (Quality of life,
Depression and Cognitive Function) Study
School of Medicine, University Hospital Policlinico di Catania. International symposium of
mediterranean school of intensive and critical care medicine, 13/09/10, Catania, Italy
- Clinical trials in cardiovascular care
- Survival and neurological outcome after nasopharyngeal cooling in experimental model
ISMETT Centre for transplantation. International symposium of mediterranean school of
intensive and critical care medicine, 14/09/10, Palermo, Italy
- Stem cell therapy in cardiac diseases
- Hypotherma improves ventricular myocyte contractility
European Society for Perioperative Care of the Obese Patients (ESPCOP). Multidisciplinary
approach to the obese patient. 2nd Annual Meeting, 18/09/10, Pordenone, Italy
- Cardiac arrest in an experimental model of obesity
European Society of Cardiology. Biomarkers and cardiovascular personalized medicine. Fifth
Annual Meeting: Transatlantic Heart Failure Biomarker Working Group, 16-17/10/10, Cannes,
France
- Update on novel CV biomarkers
- Findingh the high risk CVD patient – novel markers
Centro di Ricerche del Parco Tecnologico Padano. Genomics for research and molecular
diagnostics. European workshop - 5th edition, 21-22/10/10 Lodi (MI), Italy
- Common genetics variants on chromosome 9p21 are associated with myocardial infarction
and type 2 diabetes in an Italian population
European and Mediterranean School of Intensive and Critical Care. Anaesthesia Pharmacology
Intensive Care and Emergency. 23rd Annual Meeting, 05-07/11/10 Catania, Italy
- Nasopharyngeal cooling for neurological and myocardial outcome in an experimental model
- Amplitude spectrum area (AMSA) as predictor of successful defibrillation
- Advances in thoracic compression devices
- What’s new in defibrillation?
EATRIS European Advanced Translational Research Infrastructure in Medicine. Introductory
PhD Couse in Translational Medicine, 08-12/11/10 Milano, Italy
- Clinical trial in cardiology
- Mechanisms by which selective head cooling during cardio-pulmonary resuscitation (CPR)
decreases cerebral and myocardial ischemic injury
American Heart Association. AHA Scientific Session 2010, 13-17/11/10, Chicago, Illinois,
USA
- Enhanced cardioprotection by histone deacetylase inhibitor valproic acid-preconditioned
human cord blood (UCB)-derived CD34+ cells
- Evaluation of the efficacy of aminaftone in a rat model of monocrotaline-induced pulmonary
hypertension
- High dose of epinephrine administered during cardiopulmonary resuscitation leads to greater
oxidative stress following resuscitation from cardiac arrest
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- High sensitivity cardiac troponin T in patients with chronic heart failure: prognostic value of
changes over time and effects of randomized therapy
- How closely left atrial volume and circulating natriuretic peptides levels relate to the
duration of atrial fibrillation recurrences. The results of a GISSI-AF Trial substudy
- Worse hemodynamic and greater oxidative stress response in obese rats compared to normal
rats following resuscitation from cardiac arrest
- AMSA-based shock decision: a human retrospective analyses during pre-hospital CRP
intervention
- Cold saline infusion during CRP and continued following return of spontaneous circulation
does not impair resuscitation nor induce heart failure by volume overload after cardiac arrest
- Comparison of defibrillation efficacy between two pads placements in a pediatric pig model
of cardiac arrest
- Preserved heart rate variability during rapid head cooling correlated to better survival and
neurological outcomes in a pig model of cardiac arrest
- Selective head cooling initiated during CPR and continued following return of spontaneous
circulation improves coronary perfusion pressure and myocardial tissue perfusion after cardiac
arrest
- Association of plasma n-3polyunsaturated acids levels with metabolic and infiammatory
biomarkers in patients with chronic heart failure. Data from the GISSI-HF trial
European Resuscitation Council. Resuscitation – 10th Scientific Congress. The Guidelines
Congress, 02-04/12/10, Porto, Portugal
- AMSA for monitoring depth of chest compression during out-of-hospital cardiopulmonary
resuscitation
AIFA (Agenzia Italiana del Farmaco), Azienda Ospedaliera Ospedale Niguarda Ca’ Granda
Milano, Azienda Ospedaliera San Gerardo Monza, Chiesi Farmaceutici, Centro Cardiologico
Monzino IRCCS Milano, Comunità Europea, CONGENIA, Consorzio Mario Negri Sud Santa
Maria Imbaro, Fondazione CARIPLO, Fondazione Don Gnocchi Milano, Fondazione San
Raffaele Milano, Heart Care Foundation Firenze, Fondazione Humanitas per la Ricerca
Rozzano, Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid, International
Biomedical System SpA Trieste, IRC-Italian Resuscitation Council Bologna, Istituto
Dermopatico dell’Immacolata Roma, LACHIFARMA, MEDESTEA Research & Production
SpA, Laerdal Foundation for Acute Medicine Stavanger, Ministero della Salute, Novartis
Pharma, Ospedale Casa Sollievo della Sofferenza IRCCS San Giovanni Rotondo, Oxford
University, Population Health Research Institute-Mc Master University, Pfizer Italia, Regione
Lombardia, ROCHE Diagnostics, Sanofi-Aventis, Sigma Tau, SPA Società Prodotti Antibiotici
SpA, Takeda Italia SpA, Università degli Studi Milano Bicocca, Università degli Studi Torino,
University Medical Center di Groningen.
Balducci C, Tonini R, Zianni E, Nazzaro C, Fiordaliso F, Salio M, Vismara L, Gardoni F, Di Luca M, Carli M,
Forloni G.
Cognitive Deficits Associated with Alteration of Synaptic Metaplasticity Precede Plaque Deposition in AbetaPP23
Transgenic Mice.
J Alzheimers Dis 2010; 21: 1367-1381
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Burgess S, Thompson SG, CRP CHD Genetics Collaboration
Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables
Statist Med 2010; 29: 1298-1311
Chiodini BD, Specchia C, Gori F, Barlera S, D’Orazio A, Pietri S, Crociati L, Nicolucci A, Franciosi M, Signorini S,
Brambilla P, Franzosi MG, on behalf of GISSI-Prevenzione Investigators and SiBioC-GISSI Prevenzione Group
Adiponectin gene polymorphisms and their effect on the risk of myocardial infarction and type 2 diabetes: an
association study in an Italian population
Ther Adv Cardiovasc Dis 2010; 4: 223-230
Deban L, Castro Russo R, Sironi M, Moalli F, Scanziani M, Zambelli V, Cuccovillo I, Bastone A, Gobbi M,
Valentino S, Doni A, Garlanda C, Danese S, Salvatori G, Sassano M, Evangelista V, Rossi B, Zenaro E, Constantin
G, Laudanna C, Bottazzi B, Mantovani A
Regulation of leukocyte recruitment by the long pentraxin PTX3
Nat Immun 2010; 11 : 328-334
Diomede L, Cassata G, Fiordaliso F, Salio M, Ami D, Natalello A, Doglia SM, De Luigi A, Salmona M
Tetracycline and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting
oligomers
Neurobiol Dis 2010; 40: 424-431
Disertori M, Lombardi F, Barlera S, Latini R, Maggioni AP, Zeni P, Di Pasquale G, Cosmi F, Franzosi MG, on
behalf of the GISSI-AF Investigators
Clinical predictors of atrial fibrillation recurrence in the Gruppo Italiano per lo Studio della Sopravvivenza
nell'Infarto Miocardico–Atrial Fibrillation (GISSI-AF) trial
Am Heart J 2010; 159: 857-863
Dupuis J, Langenberg C, Prokopenko I, et al, on behalf of the MAGIC Investigators
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
Nat Genet 2010; 42: 105-116
Fosgerau K, Ristagno G, Jayatissa M, Axelsen M, Gotfredsen JW, Weber UJ, Kober L, Torp-Pedersen C, Videbaek C
Increased susceptibility to cardiovascular effects of dihydrocapcaicin in resuscitated rats. Cardiovascular effects of
dihydrocapsaicin
BMC Cardiovasc Disord 2010; 10: 39
Franzosi MG, Latini R
Beta-adrenoceptor antagonists and antianginal drugs In: Side effects of drugs. Annual 32.
Elsevier, Amsterdam, 2010; 363-369
Ghezzi P, Bernaudin M, Bianchi R, Blomgren K, Brines M, Campana W, Cavaletti G, Cerami A, Chopp M, Coleman
T, Digicaylioglu M, Ehrenreich H, Erbayraktar S, Erbayraktar Z, Gassmann M, Genc S, Gokmen N, Grasso G, Juul
S, Lipton SA, Hand CC, Latini R, Lauria G, Leist M, Newton SS, Petit E, Probert L, Sfacteria A, Siren AL, Talan M,
Thiemermann C, Westenbrink D, Yaqoob M, Zhu C.
Erythropoietin: not just about erythropoiesis
Lancet 2010; 375: 2142
Ghio S, Scelsi L, Latini R, Masson S, Eleuteri E, Palvarini M, Vriz O, Pasotti M, Gorini M, Marchioli R, Maggioni
AP, Tavazzi L, for the GISSI-HF Investigators
Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a
substudy of GISSI-HF trial
Eur J Heart Fail 2010; 12: 1345-1353
Gori F, Specchia C, Pietri S, Crociati L, Barlera S, Franciosi M, Nicolucci A, Signorini S, Brambilla P, Franzosi
MG, for GISSI Prevenzione Investigators and SIBioC-GISSI Prevenzione Group
Common genetic variants chromosome 9p21are associated with myocardial infarction and type 2 diabetes in an
Italian population
BMC Med Genet 2010; 11: 60
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Masson S, Aleksova A, Favero C, Staszewsky L, Bernardinangeli M, Belvito C, Cioffi G, Sinagra G, Mazzone C,
Bertocchi F, Vago T, Peri G, Cuccovillo I, Masuda N, Barlera S, Mantovani A, Maggioni AP, Franzosi MG, Disertori
M, Latini R, on behalf of the GISSI-AF Investigators
Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk
for atrial fibrillation: data from the GISSI atrial fibrillation trial
Heart 2010; 96: 1909-1914
Masson S, Latini L, Milani V, Moretti L, Rossi MG, Carbonieri E, Frisinghelli A, Minneci C, Valisi M, Maggioni
AP, Marchioli R, Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators
Prevalence and prognostic value of elevated urinary albumin excretion in patients with chronic HF. Data from the
GISSI-Heart Failure (GISSI-HF) trial
Circ Heart Fail 2010; 3: 65-72
Masson S, Latini R, Anand IS
An update on cardiac troponins as circulating biomarkers in heart failure
Curr Heart Fail Rep 2010; 7: 15-21
Masson S, Latini R, Carbonieri E, Moretti L, Rossi MG, Ciricugno S, Milani V, Marchioli R, Struck J, Bergmann A,
Maggioni AP, Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators
The predictive value of stable precursor fragments of vasoactive peptides in patients with chronic heart failure: data
from the GISSI-heart failure (GISSI-HF) trial
Eur J Heart Fail 2010; 12: 338-347
Masson S, Solomon S, Angelici L, Latini R, Anand IS, Prescott M, Maggioni AP, Tognoni G, Cohn JN, on behalf of
the Val-HeFT Investigators
Elevated plasma renin activity predicts adverse outcome in chronic heart failure, independently of pharmacologic
therapy: Data from the Valsartan Heart Failure trial (Val-HeFT)
J Card Fail 2010; 16: 964-970
Mauri T, Masson S, Pradella A, Bellani G, Coppadoro A, Bombino M, Valentino S, Patroniti N, Mantovani A,
Pesenti A, Latini R
Elevated plasma and alveolar levels of soluble receptor for advanced glycation endproducts are associated with
severity of lung dysfunction in ARDS patients
Tohoku J Exp Med 2010; 222: 105-112
Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, Faxon DP, Rupprecht HJ, Budaj A,
Avezum A, Widimsky P, Steg PG, Bassand JP, Montalescot G, Macaya C, Di Pasquale G, Niemela K, Ajani AE,
White HD, Chrolavicius S, Gao P, Fox KA, Yusuf S, on behalf of the CURRENT-OASIS 7 trial investigators
Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing
percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial
Lancet 2010; 376:1233-1243
Rischio and Prevenzione Investigators
Efficacy of n-3 polyunsaturated fatty acids and feasibility of optimizing preventive strategies in patients at high
cardiovascular risk: rationale, design and baseline characteristics of the Rischio and Prevenzione study, a large
randomised trial in general practice
Trials 2010; 11: 68
Røsjø H, Masson S, Latini R, Flyvbjerg A, Milani V, La Rovere MT, Revera M, Mezzani A, Tognoni G, Tavazzi L,
Omland T, on behalf of the GISSI-HF Investigators
Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial
Eur J Heart Fail 2010; 12: 549-556
Røysland R, Masson S, Omland T, Milani V, Bjerre M, Flyvbjerg A, Di Tano G, Misuraca G, Maggioni AP,
Tognoni G, Tavazzi L, Latini R, on behalf of the GISSI-HF Investigators
Prognostic value of osteoprotegerin in chronic heart failure: The GISSI-HF trial
Am Heart J 2010; 160: 286-293
Soranzo N, Sanna S, Wheeler E, et al
Common variants at 10 genomic loci influence hemoglobin A1C levels via glycemic and nonglycemic pathways
Diabetes 2010; 59: 3229-3239
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Shuster M, Lim SH, Deakin CD, Kleinman ME, Koster RW, Morrison LJ, Nolan JP, Sayre MR, on behalf of the CPR
Techniques and Devices Collaborators
Part 7: CPR techniques and devices: 2010 International Consensus on Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care Science With Treatment Recommendations
Circulation 2010; 122 Suppl 2: S338-S44
Sud S, Friedrich J O, Taccone P, Polli F, Adhikari NKJ, Latini R, Pesenti A, Guérin C, Mancebo J, Curley MAQ,
Fernandez R, Chang MC, Beuret P, Voggenreiter G, Sud M, Tognoni G, Gattinoni L
Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review
and meta-analysis
Intensive Care Med 2010; 36: 585-599
The CURRENT-OASIS 7 Investigators
Dose comparisons of clopidogrel and aspirin in acute coronary syndromes
N Engl J Med 2010; 363: 930-942
The FUTURA/OASIS-8 Trial Group
Low-Dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary
syndromes treated with fondaparinux: The FUTURA/OASIS-8 Randomized Trial.
JAMA 2010; 304: 1339-1349
Tonutti L, Manzi L, Tacconi MT, Bazzoni G
Eicosapentaenoic acid inhibits endothelial cell migration in vitro
J Angiogenes Res 2010; 2: 12
Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D'Isa R, Ungaro D, Stok M, Sanvito F, Mariani E,
Staszewsky L, Godi C, Russo I, Cecere F, Del Carro U, Rubinacci A, Brambilla R, Quattrini A, Di Natale P, Ponder
K, Naldini L, Biffi A
Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis
type I phenotype in the mouse model
Blood 2010; 116: 5130-5139
Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J,
Pogue J, Reilly PA, Yang S, Connolly SJ, on behalf of the RE-LY investigators
Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control
for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial
Lancet 2010; 376: 975-983
Aspromonte N, Di Tano G, Latini R, Masson S, Valle R, Emdin M
Ruolo dei biomarcatori per la stratificazione prognostica e la personalizzazione del follow-up nel paziente con
scompenso cardiaco
G Ital Cardiol 2010; 11: 17s-23s
De Berardis G, Sacco M, Evangelista V, Filippi A, Giorda C B, Valentini U, Tognoni G, Nicolucci A
Studio clinico randomizzato sull'efficacia dell'aspirina a basse dosi per la prevenzione degli eventi cardiovascolari nei
soggetti con diabete mellito trattati con statine (ACCEPT-D: studio di combinazione di aspririna e simvastatina per la
prevenzione di eventi cardiovascolari nel diabete)
Ricerca & Pratica 2010; n. 152: 63
Gori F
Prevenire l'infarto
Elisir di Salute 2010; n. 4 : 30-31
Maione A, Nicolucci A, Craig J C, Tognoni G, Palasciano G, Pugliese G, Procaccini D A, Gesualdo L, Pellegrini F,
Strippoli GFM, et al
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Effetti cardio-renali dell'inibizione del sistema renina-angiotensina in soggetti a rischio cardio-renale: studio di
confronto randomizzato tra ACE-inibitori, antagonisti recettoriali e terapia combinata con le due classi di farmaci in
soggetti con uno o più fattori di rischio cardiovascolare, positivi allo screening per albuminuria, diabetici e non
diabetici
Marchioli R, Filippi A, Maggioni AP, Cricelli C, Modena MG, Roncaglioni MC, Romero M, Tombesi M, Monte S,
Tognoni G, et al
Epidemiologia del rischio cardiovascolare in Italia: risultati preliminari dello Studio Rischio Cardiovascolare
Assoluto-Epidemiologia (RIACE)
Staszewsky L
Terapia farmacologica della fibrillazione atriale. Un crescente problema di salute pubblica
Informazioni sui Farmaci 2010; 34: 78-84
RESEARCH ACTIVITIES
Laboratory of Cardiovascular Clinical Pharmacology
The effects of mesoangioblasts and of different progenitor cells on injury
after experimental myocardial infarction in the mouse
Many studies have demonstrated that autologous and homologous cells of various origins can
repair myocardium damaged due to an acute ischemic insult. Mesangioblasts are potentially
interesting when compared with bone marrow precursors because (a) they are easily expanded
and (b) obtainable by a biopsy of skeletal muscle in man. Mesoangioblasts isolated from human
heart biopsies migrate and home in the heart of immunodeficient mice after coronary ligation,
and they survive for at least 4 weeks; however, there are no evidences of myocardial
regeneration, and improvement in cardiac function was modest. Experiments are being
conducted with mesoangioblasts transfected with lentivirus carrying genes for PlGF and/or
MMP-9. The same model of coronary ligation in immunodeficient mice is being used for testing
in vivo the angiogenic potential of other human progenitor cells such as CD34+ (collaboration
with F. Fagioli, Ospedale S. Anna, Torino), CD133+ (collaboration with M. Pesce and G.
Pompilio, Centro Cardiologico Monzino, Milano). Studies are ongoing using genetically
modified mesoangioblasts (transfected with lentivirus codifying for PlGF or MMP9) derived
from mice in the treatment of experimental myocardial infarction in immunocompentent mice.
These studies have been concluded end 2010.
Pulmonary injury by hydrochloric acid in the mouse: a model of
Aspiration pneumonitis to test protective interventions
Aspiration pneumonitis (AP) occurs when the acid content of the stomach makes his way
through the larynx in the lower respiratory tract. Patients with consciousness disturbance are at
risk for this event. Specifically, it has been shown that Pulmonary Aspiration can complicate
between 0.47-1.41% general anesthesia procedures.
The course of AP can be extremely variable, ranging from the “silent aspiration” characterized
by a modest desaturation to the dramatic sequelae of Acute Lung Injury (ALI) and Acute
Respiratory Distress Syndrome (ARDS), requiring prolonged mechanical ventilation and
potentially leading to death. In a murine model of monolateral acid instillation established in our
laboratory, we have shown the protective effect of exogenous pulmonary surfactant instillation.
We are currently working on a model of ventilation-induced lung injury (VILI) to assess the
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effect of exogenous surfactant. A study completed recently has shown that PTX3 modulates
inflammation in a murine model of ALI by interacting with P-selectin. The effects of a synthetic
surfactant have been compared with those of surfactanct of animal origin in the model of lung
acid injury: the two agents have been shown to be equivalent.
Roles of macrophages in cardiac ischemia/reperfusion injury and in
cardiac repair
Macrophages either resident or from blood-borne monocytes play several key roles in the
response of the heart to ischemic injury. They may be useful in particular during cardiac repair,
when collagen is deposited in the scar and neoangiogenesis occurs, stimulated by growth factors
produced by macrophages. The aim of the project is to assess the relevance of macrophages in
myocardial repair and scar formation after myocardial infarction, in the attempt to dissect the
role of inflammatory cells in myocardial injury vs repair.
Experiments of experimental infarction in transgenic mice expressing human Dyphtheria toxin
receptor (hDTR) in (CD11b-DTR) have shown (a) the halving of circulating monocytes, and
hence of cardiac macrophages, but at the same time (b) serious wasting of mice receiving
Dyphtheria toxin right after cardiac ischemia. The high mortality did not allow to continue the
experiments, and another model based on clodronate liposomes is now being tested. We are
now running experiments to evaluate the structural and functional consequences of the reduction
in circulating monocytes and in cardiac macrophages induced by clodronate. The animal treated
with clodronate showed an elevated mortality after myocardial infarction, due to higher
vulnerability. We also observed thrombi in the ventricles of mice treated with clodronate and
subjected to coronary artery ligation. We currently running adoptive transfer experiments with
mice lacking p50 protein, in collaboration with A. Sica (Istituto Humanitas, Rozzano, MI).
Effects of dipeptidyl peptidase-4 (DPP-4) inhibition on endothelial
progenitor cells and hypoxic injury in type 2 diabetes
The present study aimed at evaluating whether the administration to diabetic ob/ob mice of a
dipeptidyl peptidase-4 (DPP-4) inhibitor, an antihyperglycemic drug, with the ability to preserve
the active form of the SDF-1 (Stromal cell-Derived Factor-1), mediate progenitor cell
mobilization, increases EPC (Endothelial Progenitors Cell) circulating levels, which, in turn,
may contribute to the regeneration of blood vessels and reducing myocardial ischemic stress
induced by strenuous exercise. DPP-4 inhibitor improved glucose tolerance, increased level of
circulating EPCs and the production of new capillaries in ob/ob mice. DPP-4 inhibitor treatment
in ob/ob mice did not influence the level SDF-1 assessed in the blood by enzyme immunoassay
or in myocardium by western blot. In conclusion, the inhibitor of DPP-IV in ob/ob mice
improved glucose tolerance in response to an oral glucose challenge and re-established an
adequate capillary network in the myocardium of diabetic ob/ob mice by the
mobilization/homing of endogenous EPCs reducing the susceptibility to myocardial ischemic
injury induced by forced swimming in diabetic ob/ob mice. Nowadays we are trying to identify
other physiological substrates of DPP-IV, than SDF-1, involved in the phenomena previously
described.
Effects of propionyl-L-carnitine on vascular damage and cardiovascular
oxidative stress in type 2 diabetic mouse
The present study aimed at evaluating whether propionyl-L-carnitine treatments (PLC, 200
mg/kg and 1 g/kg) for 8 weeks in obese/diabetic ob/ob mice improved mobilization of
endothelial progenitor cells (EPCs) and diminished the vascular damage in myocardium and
aorta by reducing superoxide anion production at cellular levels in a model of swimming
exercise-induce oxidative stress. PLC did not improve the glucose tolerance in ob/ob mice and
did not attenuate the ischemic damage induced by forced swim but significantly reduced the
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production of superoxide anion and increased the number of capillaries in the myocardium of
ob/ob mice. Similarly, PLC diminished the reactive oxygen species and the expression of a
marker of endothelial damage (ICAM-1, intercellular adhesion molecule-1) in the thoracic aorta
of ob/ob mice. In conclusion, two different treatment regimens with PLC reduced oxidative
stress in myocardium and thoracic aorta of ob/ob diabetic mice, exerting an angiogenic activity
in the diabetic myocardium. Furthermore PLC significantly reduced the expression on
endothelial cell membrane of ICAM-1, an adhesion molecule involved in the migration of
inflammatory cells and in the detrimental process of atherosclerotic plaque formation.
Preclinical and clinical studies in cardiac arrest and cardiopulmonary
resuscitation
Cardiovascular disease remains the leading cause of death in the Western world with 350,000
Americans and 700,000 Europeans sustaining cardiac arrest each year. Instead of the initial
success of cardiopulmonary resuscitation, the majority victims die within 72 hours because of
severe heart contractile failure due to post-resuscitation myocardial dysfunction.
Furthermore, cardiac arrest and cardiopulmonary resuscitation represent a condition of systemic
ischemia-reperfusion injury causing multi-organ damage.
For this purpose we are currently studying a preclinical model of cardiac arrest and
cardiopulmonary resuscitation (CPR) in intact rats or in rats with metabolic syndrome (i.e.
obesity, diabetes) aiming to: (a) evaluate inflammatory response and organ dysfunction after
return of spontaneous circulation; (b) evaluate success of cardiopulmonary resuscitation
manoeuvres and survival after new pharmacological approaches ( i.e. n-3 PUFA, pentraxin
PTX3, carbon monoxide).
Moreover, the severity of post-resuscitation myocardial dysfunction has been recognized to be
related, partially, to the magnitude of the total electrical energy delivered with defibrillation.
Consequently, the development of a non-invasive and real-time monitoring that allow prediction
of outcome of the defibrillation attempt is therefore of great importance in decreasing the
defibrillation energy.
At present, we are evaluating a clinically applicable method based on electrocardiographic
analysis of ventricular fibrillation waveform aiming to asses a non-invasive approach in order to
guide the priority of interventions, namely chest compression or defibrillation (collaborating
institutions: Emergency Department, San Gerardo Hospital, Monza and Azienda Regionale
Emergenza Urgenza - Lombardia).
GISSI-HF: biohumoral substudy and urinary markers of renal injury
The GISSI-HF trial was designed to assess whether two treatments (a statin and n-3
polyunsaturated fatty acids or PUFA) can improve the prognosis of patients with heart failure of
any etiology, with preserved or compromised left ventricular ejection fraction. Main results
have been published (Lancet 2008; 372: 1223-1230 and Lancet 2008; 372: 1231-1239).
Microalbuminuria (defined as the ratio between urinary concentrations of albumin and
creatinine) is being measured in more than 2000 patients enrolled in the GISSI-HF trial as an
indicator of renal endothelial dysfunction. Microalbuminuria (albumin/creatinine = 30-299
mg/g) is present in 19% of the patients and is a robust marker of bad outcome. New and early
markers of renal tubular injury (KIM-1, N-GAL e NAG) have been assayed in the urine
samples. Preliminary analyses indicate that these markers are strongly associated with death,
independently of microalbuminuria or renal glomerular filtration rate. Results are being
submitted for publication.
PTX-3, a novel long pentraxin is a marker of severity of disease and of
outcome in cardiovascular diseases, independent of C-reactive protein
PTX-3 is a novel long pentraxin whose expression is induced by cytokines in endothelial and
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mononuclear cells, mostly in striated muscle and heart, while C-reactive protein (CRP) is
mainly synthesized in the liver. PTX3 was shown to peak in plasma around 7 h after onset of
symptoms of MI and to be an independent predictor of 3-month mortality. PTX3 has been
assayed with a more accurate method in 1200 patients with symptomatic heart failure (GISSIHF) and in 380 patients with atrial fibrillation (GISSI-AF) to explore its role in other
cardiovascular diseases. Inflammatory markers do not seem to predict recurrence of AF (Heart
2010; 96: 1909-14). First results indicate that PTX3 is associated with different clinical
characteristics in patients with heart failure, including advanced age, ventricular dysfunction,
functional class (NYHA class), and comorbidities such as atrial fibrillation and diabetes. PTX3
independently predicts mortality and morbidity in the patients with chronic heart failure. Plasma
concentrations of PTX3 have been measured, in collaboration with the laboratory headed by A.
Mantovani (Istituto Clinico Humanitas, Rozzano) in samples collected in the GISSI-HF trial,
but also in samples collected in another large-scale clinical study (CORONA), that enrolled
elderly patients with heart failure of ischemic origin, randomized to rosuvastatin or placebo.
Results from both trials will be examined together to evaluate the effect of a statin on PTX3
circulating levels and the prognostic value of this marker in a population of 2690 patients
(manuscript in preparation).
Echocardiographic and biohumoral substudy – GISSI-AF trial
The GISSI Atrial Fibrillation trial (GISSI-AF) tested the efficacy of valsartan, an angiotensin II
AT1-receptor blocker, in the prevention of atrial fibrillation recurrence in 1400 patients. A
substudy of the GISSI-AF has recently been concluded; it evaluated the potential role of
biohumoral factors and cardiac structural remodelling in the reoccurrence and severity of atrial
fibrillation. In approx. 400 patients three serial echocardiographic exams (at randomization, 6
months and 1 year) and contemporaneous blood collection were performed. Left ventricular and
atrial dimensions were determined by echocardiography, whereas plasma levels of natriuretic
peptides (BNP, NT-proBNP and MR-proANP), troponin T (high sensitive method), stable
vasopactive peptides (endothelin-1, Adrenomedullin and vasopressin), and inflammatory
markers (C-reactive protein, interleukin-6 and pentraxin-3) have been measured. Besides giving
clues on the pathophysiology of atrial fibrillation, the most common arrhythmia in elderly, this
substudy aims at providing mechanical insights of the potential benefits of the study drug. The
study was completed on January 31, 2008 and results being analyzed. Two papers, one on
cardiac markers and the other on inflammatory markers, are published, the first
echocardiographic paper is being submitted.
CandHeart: effects of candesartan on BNP and left ventricular function in
patients with symptomatic heart failure
Candesartan, an antagonist of angiotensin II type 1 receptors, significantly reduces mortality
and morbidity in heart failure, as shown by the CHARM trials. The principal objective of the
CandHeart trial is to assess the effects of Candesartan on circulating levels of brain natriuretic
peptide (BNP) in patients suffering from CHF with depressed or preserved left ventricular (LV)
systolic function. The study enrolled 514 patients in 70 clinical centers with a follow-up of 1year. Serial circulating blood samples and echocardiographic examinations have been
performed at baseline and after 3 and 12 months (end of study). Besides BNP, other prognostic
biomarkers such as aldosterone and microalbuminuria have been assayed. A paper is being
submitted showing a beneficial effect of candesartan on NYHA class, echocardiographic
variables and circulating aldosterone.
DyDa: left ventricular dysfunction in diabetes. Prevalence and incidence
of left ventricular dysfunction in diabetics patients without clinical cardiac
disease
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This is a prospective, multicentric, national and epidemiological trial aimed at evaluating the
prevalence of left ventricular dysfunction (systolic or diastolic) in 1000 patients with type 2
diabetes mellitus but no clinical cardiovascular disease at enrolment. The incidence of left
ventricular dysfunction is monitored during a 2-year follow-up using ECG and
echocardiography. The Biomarker Core Laboratory evaluated the biohumoral profile of these
patients at study entry, measuring the circulating levels of brain natriuretic peptide, C-reactive
protein, microalbuminuria and glycated hemoglobin. Enrolment started in July 2006 and ended
in March 2008 with 970 patients recruited. The assays of the biomarkers are concluded and first
data on the association between theses markers and baseline clinical characteristics are under
analysis. The follow-up phase of the study should be concluded in 2010 to get data on incident
left ventricular dysfunction. Two manuscripts on baseline data have been published.
Albumin Italian Outcome Sepsis Study. The ALBIOS Study (AIFA)
ALBIOS is a multicenter, controlled, randomized clinical trial that compares the efficacy of
human albumin and a crystalloid solution for volume replacement in patients with severe sepsis
or septic shock. The primary endpoint is survival at 28 and 90 days after enrolment. Secondary
endpoints include the number of organ dysfunctions, severity of organ dysfunction (SOFA
scale), and lengths of stay in (intensive care unit) ICU and in hospital. More than 150 ICU in
Italy are expected to participate to this large study, coordinated by the Ospedale Maggiore
Policlinico in Milan and the Consorzio Mario Negri Sud. A group of 48 ICUs participates to a
biomarkers substudy, coordinated by the laboratory of Clinical Cardiovascular Pharmacology,
with the aims of enrolling 800 patients. Serial blood samples are collected to measure the
possible effects of albumin on markers of inflammation, infection, cardiac function and
coagulation. 1350 patients have been randomized by the end of 2010, and blood samples
collected in at least 600 of them.
Evaluation of different anesthesiological strategies for supratentorial
neurosurgery. The NeuroMorfeo Study (AIFA)
The aim of the study was to evaluate whether an anesthesia with volatile anesthetics is
equivalent to endovenous anesthetics for elective supratentorial surgery. This was a multicenter,
randomized, controlled and opened study, based on a design of equivalence for comparison of
different anesthesiological strategies (see Laboratory of Clinical Drug Evaluation for details).
The biohumoral response to surgical stress was measured as an indicator of homeostasis and
neurovegetative status. The urinary excretion of catecholamines and cortisol and the plasma
concentration of cortisol were be measured in a central laboratory in collaboration with the
Laboratory of Pharmacokinetics and Clinical Chemistry from the Istituto Mario Negri at Ranica.
A manuscript is being submitted for publication.
Prevalence of asymptomatic cardiac dysfunction and heart failure in a
population of elderly subjects from Lazio. The PREDICTOR Study
This observational study aims at evaluating the prevalence of asymptomatic cardiac dysfunction
and heart failure in a random sample of elderly subjects from the Lazio area. The secondary
objective is to identify clinical, biohumoral (natriuretic peptides) and non-invasive instrumental
(echocardiography and ECG) markers of asymptomatic cardiac dysfunction and heart failure.
The population under observation is a randomly selected sample of elderly subjects (age ranging
from 65 and 84 years) resident in the area of 10 hospital cardiology centers. In a first phase,
1000 subjects have been recruited; a second phase has recently started with the objective of
enrolling another 2000 subjects. Blood samples are collected for each subject and stored in the
biobank in the Laboratory of Clinical Cardiovascular Pharmacology. Preliminary data obtained
in the first 1000 subjects show a good pathophysiological agreement between the circulating
levels of NT-proBNP and indexes of left or right asymptomatic cardiac dysfunction or the
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severity of heart failure. By the end of 2010, more than 2000 subjects have been enrolled, a
figure close to the final objective of this study. A paper is in preparation. Further assays are
being performed on new markers of cardiac dysfunction and of cardiovascular risk.
OPERA: Omega-3 Fatty Acids for Prevention of Post-Operative Atrial
Fibrillation
Peri-operative administration of n-3 polyunsaturated fatty acids (PUFA) may significantly
reduce the incidence of post-operative atrial fibrillation (AF) in patients undergoing cardiac
surgery (CAS). The aim is to determine, using a randomized, double-blind, placebo-controlled,
clinical trial, whether peri-operative administration of n-3 PUFA (8 g total pre-op and then 2 g/d
for 14 days or until hospital discharge) reduces the incidence of AF in 1,516 patients
undergoing CAS. It is a multinational, multicenter, double-blind, parallel design clinical trial
enrolling 1516 patients undergoing CAS in 40-50 major medical centers in the U.S., Argentina
and Italy. A core laboratory for Italy and Argentina is at Mario Negri. By the end of 2010, 137
pts have been enrolled, and their biologic samples have been collected.
GISSI-outliers: the CAPIRE study
Aim of the CAPIRE study is to analyze in patients undergoing coronary multislice tomography
the extreme populations: patients without risk factors for coronary disease, but with severe
coronary lesions, and patients with risk factors, but no major coronary lesions. A panel of
biomarkers and genetic polymorphisms will be assayed in the attempt to identify protective
factors/mechanisms.
Laboratory of Clinical Drug Evaluation
PROCARDIS: A genome-wide strategy to identify susceptibility loci in
precocious coronary artery disease
The PROCARDIS research programme, a genome-wide strategy to identify susceptibility loci
in precocious coronary artery disease (CAD) supported by the 5th Framework Programme of
the EC, was initiated as a collaboration between the Universities of Oxford and Munster, the
Karolinska Institute, and the Mario Negri Institute with the support of the GISSI group. The
objectives of the first stage of this programme were to collect a minimum of 2000 affected
sibling pairs (ASPs) and families with precocious CAD and to apply genome-wide linkage
mapping techniques, to identify chromosomal regions linked to the susceptibility to early-onset
CAD. The PROCARDIS collected 2036 CAD families from four European countries, in order
to maximise the power of detecting genes that confer modest risks. A genome-wide linkage scan
identified three promising regions for intensive study. Extensive clinical and biochemical
intermediate phenotype data have also been collected and assessed. The second stage of
PROCARDIS, supported by the EC 6th Framework Programme, is conducting a large GWAS
(genome wide association study), where the patients with myocardial infarction enrolled in the
first stage are compared with control subjects to identify novel candidate genes. The results are
replicated in different populations. The PROCARDIS study identified risk loci for coronary
disease by using a novel gene chip consisting of 48,742 SNPs for 2100 candidate genes that
were selected for their potential relevance to coronary artery disease. With this gene chip,
PROCARDIS confirmed the previous identification of three chromosomal regions that were
correlated with the risk of coronary disease: 6q26–27, 9p21, and 1p13. In the chromosome
9p21 region PROCARDIS has identified two SNPs, that are independently associated with
CAD and with type 2 diabetes (T2D) respectively. Recently, the PROCARDIS study has
identified two single nucleotide polymorphisms (SNPs) at the LPA locus, strongly associated to
coronary disease. Both variants were associated also with an increased level of lipoprotein(a), a
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reduced copy number in LPA, and a small lipoprotein(a) size. These common variants explain
over a third of the variance in lipoprotein(a) levels in individuals of European descent. After
adjustment for the plasma lipoprotein(a) level, the association between these genotypes and
coronary disease was abolished, indicating a causal role of lipoprotein(a) in coronary disease.
GISSI-HF Genetic Substudy
The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca) is a
collaborative group endorsed by ANMCO (Associazione Nazionale Medici Cardiologi
Ospedalieri) and by the Istituto Mario Negri, active from 20 years in the cardiovascular research
field. The GISSI-HF was the fifth large scale clinical trial conducted by the Group and was a
prospective, multicenter, randomized, double blind, placebo controlled study, with randomized
allocation of patients with a clinical diagnosis of heart failure to
n-3 PUFA and/or to rosuvastatin to assess the effects of long-term administration of n-3 PUFA
and/or rosuvastatin on all-cause mortality and cardiovascular hospitalizations.
The study randomized more than 7000 patients with the participation of 357 departments of
cardiology; in a follow-up time of four years, 27% of patients in the PUFA group died,
compared with 29% in the placebo group, meaning a relative risk reduction of 9% in the PUFA
group. A higher proportion of patients in the placebo group died or were admitted to hospital for
cardiovascular reasons than in the PUFA group. Statin treatment with rosuvastatin did not affect
clinical outcomes in patients with chronic heart failure.
Several substudies focus on possible mechanistic effects of the study treatments. Among them a
genetic
substudy conducted by nearly 100 Centres that have included 2500 patients, gives the
opportunity to improve knowledge on the role of genetic factors involved in heart failure,
through a collection of blood samples of a large population of patients, involving cases of heart
failure of different etiologies, i.e. non-ischaemic and ischaemic heart disease.
The role of genetic factors in causes, evolution, prognosis and treatment of heart failure is
largely unexplored, with the exception of heart failure originated by specific cardiomyopathies
(such as dilated, hypertrophic, arrhythmogenic right ventricular cardiomyopathies), for which
the role of heritable gene mutations is increasingly well understood. Heart failure (HF) is a
syndrome with different etiologies, and more than one half is caused by coronary heart disease
(CHD). The objective of the genetic substudy is 1) to assess the relationships between the
polymorphysms of various candidate genes and the clinical outcome in patients enrolled in
GISSI-HF study; 2) to assess whether these relationships are modified by the experimental
treatments.
GISSI-Prevenzione-Genetic Study
Myocardial infarction is a multifactorial disease. While the role of known risk factors on
coronary heart disease susceptibility is well defined, the impact of the genetic components and
its interaction with environmental factors need investigation. The GISSI-Prevenzione trial
investigated the effects of pharmacological treatments with n-3 PUFA and pravastatin on
morbidity and mortality after myocardial infarction. During the study more than 8000 samples
of a large population of patients affected by this disease have been collected and stored with the
collaboration of SIBioC (Societê Italiana di Biochimica Clinica e Biologia Molecolare). The
GISSI-Prevenzione-Genetic Study investigates the role of genetic factors in ischaemic heart
disease. The objectives of the project are 1) to assess the relationships between the
polymorphysms of various candidate genes and the clinical outcome in patients enrolled in the
large clinical trial GISSI-Prevenzione study; 2) to assess whether these relationships are
modified by the pharmacological treatments. According to these objectives, we investigated the
relationship between APOE, mortality and the response to treatment in 3300 myocardial
infarction survivors randomized to pravastatin or no treatment. We found that epsilon 4 allele is
a determinant of pravastatin response in terms of survival (Eur Heart J 2007; 28:1977-1983).
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Association studies in the same population on the adiponectin gene variants, the CRP (Creactive protein) gene variants, some genetic variants on Chromosome 9p21 have been
conducted. A genetic assessment of PTX3 protein, a novel long pentraxin whose expression is
induced by cytokines in endothelial and mononuclear cells, and involved in the atherogenesis
process, is ongoing in collaboration with the Istituto Clinico Humanitas and the IRCCS San
Giovanni Rotondo.
Evaluation of different anesthesiological strategies for supratentorial
neurosurgery. The NeuroMorfeo Study (AIFA)
NeuroMorfeo is a multicenter, randomized, controlled and open study, based on an equivalence
design, with the aim to assess whether an anesthesia with volatile anesthetics is equivalent to
endovenous anesthetics for elective supratentorial surgery. The study is financed by the AIFA
and is coordinated by the San Gerardo Hospital in Monza, with the support of the Department of
Cardiovascular Research of the Mario Negri Institute.
The study recruitment has been completed by 14 neurosurgical centers in Italy that have
randomized 411 patients admitted for elective intracranial surgery with supratentorial lesions
without signs of endocranial hypertension (range of age 18-75 years).
Statistical analyses and drafting of manuscripts are ongoing.
BeTACTIC Study: Best Therapy After Cardiac Transplantation, the Italian
Challenge
BeTactic is a multicenter, randomized, no-profit trial funded by the National Health Service.
The study compares efficacy and safety of Everolimus (Ev) and Mycophenolate (MMF) in
association with Cyclosporine (CyA) in pts with acute multiple/late rejection, cardiac allograft
vasculopathy (CAV), renal dysfunction after cardiac transplantation (HTx). Survival after HTx
has improved, while the attrition rate beyond the 1st year did not change substantially. CAV and
cancer are the leading causes of death late after HTx. Many factors as acute rejections and
citomegalovirus infections are involved in CAV pathogenesis. Cancer shows higher incidence
in immunosuppressed pts. Significant morbidity/mortality derive from renal insufficiency and
vascular complications.
Ev and MMF were adopted due to better efficacy vs Azathioprine in de novo HTx.
However, Ev and MMF have not been tested in a head to head comparison late after HTx.
The planned length of the BeTACTIC study is 5 yrs. Patients will be enrolled at least 1yr after
HTx. A total of 400 pts will be randomized in 11 Transplant Centers in Italy.
BeTACTIC is coordinated by the Cardiology Depatment, Trapianti e Insufficienza Cardiaca,
Ospedale Niguarda Ca' Granda di Milano, Milano, in collaboration with the Laboratory of
Clinical Drug Evaluation of the Istituto Mario Negri.
REGIA - Rischio Emorragico GInocchio e Anca
Assessment of the hemorrhagic risk of treatment with low molecular
weight heparins, oral anticoagulants, antiplatelet drugs in patients
undergoing total hip or knee replacement surgery.
Major orthopedic surgery is as a high-risk event for venous thromboembolism (VTE). The
anticoagulant prophylaxis reduces the risk of postoperative VTE by 50 to 70%. Major bleeding
is a possible complication of thromboprophylaxis with an estimated frequency of 1% to 3% in
randomized clinical trials (RCT). However, in clinical practice, the estimates may be argued
since: 1) bleeding rates are probably underestimated in RCT, due to frequent exclusion of the
high risk patients; 2) definition of bleeding is non-standardized and can vary from study to
study; 3) the
type of intervention, of anesthesia, of prophylactic agent and the timing of administration in
relation to surgery may influence bleeding rate. There is scarce information on the frequency of
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bleeding after hip or knee replacement in routine practice in Italy. The objectives of the study
are the incidence of major and minor bleedings in the first three months after surgery.
The REGIA study is funded by the National Health Service and will collect data on bleedings in
near 4000 patients admitted for hip or knee replacement in one year in the three participating
hospitals (Istituto Ortopedico Galeazzi, Milano; Istituto Rizzoli, Bologna; CTO Maria Adelaide,
Torino).
Collaboration with the Population Health Research Institute (PHRI)
The Population Health Research Institute (PHRI), McMaster University, Hamilton, Ontario, is
the coordinating center of a multinational network of cardiology clinics that collaborate to
multicenter large scale clinical trials (nearly 40 Countries and more than 600 cardiology clinics).
The Laboratory of Clinical Drug Evaluation is responsible for the scientific coordination in Italy
of some of these trials (INTER-HEART, CURE, ACTIVE, RE-LY, CURRENT, OASIS-8
FUTURA, AVERROES, RE-LY Registry, RIVAL). The state of advancement of the studies is
as follows:
RE-LY Study (Randomized Evaluation of Long term anticoagulant
therapY)
Non-valvular atrial fibrillation is implicated in nearly 15% of strokes. Dose-adjusted warfarin
decreases the risk of stroke by 62%. However, in practice, the risk of bleeding, the variability of
anticoagulation intensity and the need of frequent monitoring and dose adjustments limit the
treatment with warfarin, leaving patients outside the therapeutic range almost half the time.
Underuse of warfarin in patients with atrial fibrillation at high risk of bleeding calls for safer,
more reliable alternatives. For these reasons an international multicentre, randomized, active
controlled, parallel group, non-inferiority, clinical trial (RE-LY study) was designed to evaluate
the efficacy and safety of dabigatran etexilate, a direct thrombin inhibitor, compared with open
label adjusted warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The study recruited more than18000 patients. The median duration of
the follow-up period was 2.0 years. The results, published on New Engl J Med in 2009, showed
that dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic
embolism similar to those associated with warfarin, as well as lower rates of major hemorrhage.
Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with
lower rates of stroke and systemic embolism but similar rates of major hemorrhage. The direct
thrombin inhibitor dabigatran may offer fixed oral dosing without need for coagulation
monitoring, rapid onset and offset of action, stable pharmacokinetics with little potential for
drug interactions, and no known food interactions. Several secondary and subgroup analyses of
the RE-LY study are ongoing.
AVERROES Study (Apixaban VErsus ASA to Reduce the Rate Of Embolic
Stroke)
Although vitamin K antagonists (VKA) are effective for preventing stroke or systemic
embolism in patients with atrial fibrillation (AF), complexity of use and bleeding risk limit their
potential benefit. Many patients not treated with VKA receive aspirin.
There are two main groups of patients with AF who could benefit from a better antithrombotic
than ASA: (1) Those not expected to do well on VKA; and (2) Those with only a moderate risk
for stroke.
Aspirin is presently the only alternative to VKA to prevent stroke in patients with AF but is
relatively ineffective, reducing the risk of stroke or systemic embolism by about one-fifth
compared with a two-thirds reduction by VKA. New treatments that are more effective than
ASA but do not share the many limitations of VKA are required. AVERROES is the only study
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of a new anticoagulant that directly addresses this important unmet need. 5600 patients with AF
not suitable for VKA, have been randomized to receive a new oral anticoagulant, Apixaban, or
aspirin. Apixaban, an oral inhibitor of the Xa factor, is simple to use, convenient, does not
require laboratory monitoring, does not interact with foods, and has very few drug interactions.
AVERROES trial has been completed, showing that Apixaban is an effective alternative to
ASA for those unsuitable for oral anticoagulation and also for those at moderate risk.
CURRENT OASIS-7 Study
OASIS 7 is a randomized, multinational, 2X2 factorial design, parallel-group, double-blind
study, comparing a high loading dose regimen of clopidogrel versus standard dose and high
dose regimen of aspirin versus standard dose, in patients with acute coronary syndrome (ACS)
managed with an early invasive strategy. The study published on the New Engl J Med in 2010,
recruited more than 25000 patients in 800 clinical centers worldwide, 17232 of them undergone
planned angioplasty (PCI). The primary objective of the study was to determine whether a high
dose regimen of clopidogrel is superior to a standard dose of clopidogrel in preventing CV
death, myocardial infarction or stroke and to determine if high dose of aspirin is as safe as low
dose in terms of TIMI major bleeding rate.
In terms of efficacy, there was no significant difference in the primary outcome or its
components, although there was a numerical reduction with the higher dose of aspirin.
However, doubling the loading and maintenance doses of clopidogrel in ACS patients
undergoing planned PCI significantly reduced stent thrombosis and cardiovascular events,
largely driven by reductions in MI, without a significant increase in major bleeding.
FUTURA OASIS-8 Study
The FUTURA-OASIS-8 (FondaparinUx Trial with Unfractionated heparin (UHF) during
Revascularization in Acute coronary syndromes) study will expanded the safety experience in
UA/NSTEMI patients initially treated with fondaparinux and undergone PCI with adjunctive
UFH, while also addressing the question of the optimal dosing strategy with adjunctive UFH
during the procedure. The study design consisted of:
• An international, prospective cohort study of high risk patients presenting to hospital with
UA/NSTEMI who are treated with s.c. fondaparinux as initial medical therapy and referred
for early coronary angiography and potentially PCI.
• A double-blind, international, randomized, parallel-group study evaluating standard versus
low dose adjunctive i.v. UFH in those patients where a PCI procedure is indicated.
The main outcome measure was a composite of major bleeding, minor bleeding, or major
vascular access-site complications up to 48 hours after PCI. The results, published on JAMA in
September 2010, showed that low-dose compared with standard-dose unfractionated heparin
did not reduce major peri-PCI bleeding and vascular access-site complications. Therefore,
patients with acute coronary syndromes treated with fondaparinux and undergoing PCI, should
receive the guideline-recommended standard dose of unfractionated heparin.
RE-LY AF Registry: Risk Factors, Treatments and Outcomes for
Emergency Department Patients with Atrial Fibrillation in Multiple Regions
of the World
Due to variations in medical practice and access to care, there will be geographical variation in
presentation and management of patients with atrial fibrillation. They will have different
predisposing conditions, presenting symptoms, rates of adverse outcomes and will be managed
differently. The RE-LY AF Registry has the following objectives: 1. To determine variations in
the predisposing conditions for atrial fibrillation and atrial flutter (AF/flutter) between different
regions of the world and practice settings. 2. To document regional variations in the
management of AF/flutter and associated cardiovascular disease, including the frequency of
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anti-thrombotic and anti-hypertensive therapy and the degree of INR control. 3. To document
differences in the adverse cardiovascular outcomes of AF/flutter. The study will recruit 15000
patients with documented atrial fibrillation or atrial flutter at the time of an emergency
department visit for any reason, in approximately 300 participating clinical centres in multiple
regions of the world. Patients will be followed-up at one year after the enrolment in the study.
RIVAL: Radial vs. Femoral PCI Access Site Substudy
Major bleeding is the major common complication in patients with acute coronary syndrome
(ACS). Major bleeding is independently associated with an increased risk of ischemic events
(MI and stroke) and mortality. A significant proportion of major bleeding events can be related
to the femoral arterial puncture site for invasive procedures. Femoral access has been the
dominant method of access for coronary procedures for many years. Radial artery vascular
access has been developed as an alternative approach with potentially less major bleeding.
The RadIal Vs. femorAL (RIVAL) access site study was started as a randomized sub-study of
the OASIS 7-CURRENT and extended beyond its conclusion in order to reach the recruitment
goal of 6,000 patients randomized to to either radial or femoral approach for vascular access for
coronary angiography and PCI. The primary objective of RIVAL is to determine if radial
instead of femoral access for coronary angiography or intervention in patients with acute
coronary syndromes reduces the rate of death, MI, stroke or non-CABG related major bleeding.
The study has been completed with 7021 patients randomized and data analysis is ongoing.
Laboratory of General Practice Research
Risk and Prevention Study (R&P)
R&P is a study on the optimization of cardiovascular prevention of subjects at high risk
performed at national level by General Practitioners.
Study objective and design
- Controlled clinical trial, double-blind and randomised, of the efficacy of a n-3 PUFA treatment
in reducing the incidence of cardiovascular events, both fatal and non-fatal, in a population
defined as at high risk by participating GPs.
- Practicability and overall yield of the preventive interventions adopted (outcome study) The
epidemiological and care history of this population shall form the object of a specific evaluation
according to a plan of formal predefined analyses.
Study population
Inclusion criteria
Among the subjects deemed by GPs to be at high cardiovascular risk, patients are selected if
presenting:
- multiple risk factors (e.g. hypertension, hypercholesterolemia, diabetes, smoking, family
history of myocardial infarction, obesity, sex and old age)
- previous cardio-cerebrovascular events or clinical manifestations of atherosclerotic disease
(stroke, TIA, peripheral arteriopathy, previous arterial revascularisation procedures, angina
pectoris).
Exclusion criteria
- serious co morbidity with an unfavourable prognosis over the short term (e.g. cancer)
- expected non-compliance over a long period of time; contraindications (known allergies to n3PUFA)
- indications (previous MI) for treatment with n-3 PUFA.
Efficacy measures
The primary objective is to evaluate if a long-term administration of n-3 PUFA is more effective
than the corresponding placebo in reducing cardiovascular mortality and hospitalization for
cardiovascular causes (primary end-point).
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Randomisation is central, stratified by GP.
The experimental treatment consists of one capsule containing 1g of n-3 PUFA, or the
corresponding placebo, to be taken daily.
The duration of follow-up is 5 years.
In order to document with sufficient statistical reliability that the experimental treatment with n3 PUFA reduces of 15% the incidence of the events considered in the primary end-point, a total
of 12,000 patients is required.
Up-date of the study: From February 2004 to March 2007 12,521 patients have been enrolled
by a network of 860 GPs. The Local Health Authorities involved are 57 and in each one
investigator’s meeting has been organized. The characteristics of the population so far enrolled
are the following: mean age 65 years, males 62%, hypertension 79%, hypercholesterolaemia
62%, diabetes 56%, smokers 16%, obesity 35%, family history of premature myocardial
infarction 20%. Twenty five% of patients have a clinical manifestation of atherosclerotic
diseases, 50% have diabetes in association with another risk factor and 23% have multiple risk
factors.
The trial will continue until the minimum expected number of 1,383 events will occurred.
More information available on the website www.rischioeprevenzione.it.
Epidemiological and clinical profile of diabetic patients in Lombardy
Region using administrative databases.
The study is part of an ongoing pharmacoepidemiological project in collaboration with the
Health Department of the Lombardy Region. Its main objective is the definition of a model to
assess and control the use of health resources of diabetic patients by means of integrated
administrative database.
Specific aims of the study are:
• To describe prevalence, incidence, hospitalization and mortality of the diabetic population
each year, from 2000 to 2009.
• To assess the prescriptions of both anti-diabetic and cardiovascular drugs
Diabetic patients have been identified each year if they met one of the three following criteria: a prescription of an A10 drug: insulin and/or oral glucose lowering agent ; - the occurrence of at
least one hospitalization with Disease Related Group (DRG)=294 or DRG=295; presence of the
exemption code number 013.250 indicating diabetes. Data from prescription database, hospital
admission and outpatient clinic visits and examinations were also included in the analysis via
linkage to the personal identification number (national identifiers). Results are in the processing
phase.
“GLICINE-SPIDER” Study
“Glicine-Spider” is an observational study, carried out in the Coronary Care Unit (CCU) of
Lombardy. The protocol is a collaboration between the ANMCO (Italian Association of
Hospital Cardiologists) Lombardia , AMD (Association of Medical Diabetologists) Lombardia
and the Mario Negri Institute. The study is coordinated by the “General Practice Research
Laboratory” and the “Clinical Drug Evaluation Laboratory”.
Hyperglycemia at the onset of an acute coronary syndrome (ACS) constitutes a negative
prognostic factor in diabetic and non-diabetic patients and a poor control of blood glucose in the
early hours after hospital admission for ACS is an additional unfavourable prognostic factor.
Recent guidelines, although recognizing the importance of controlling blood glucose in ACS, do
not clearly define therapeutic strategies to apply and target range.
Patients with and without diabetes hospitalized in CCU for a confirmed ACS.
The aim of the study is to describe in a large sample of patients hospitalized in CCU for a ASC:
• the prevalence of diabetes and hyperglycemia
• the type of treatment and blood glucose control during the acute phase
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the incidence of mortality and cardiovascular complications occurred during the
hospitalization according to diagnosis and blood glucose level
From May 2009 to April 2010, 1,282 patients have been included from 31 CCUs. The data
analysis is in progress.
FOCUS
Study (Fixed Dose Combination Drug for Secondary
Cardiovascular Prevention. Improving Equitable Access and Adherence
to Secondary Prevention Therapy with a Fixed-Dose Combination Drug)
The study is supported by the 7th Framework Programme of the EC.
Several randomized controlled trials and metaanalyses have demonstrated that the long term
administration of aspirin, statins beta-blockers, and agiontensin converting enzyme inhibitors
(ACE inhibitor) improve prognosis in high risk patients, particularly those recovering from an
acute coronary event. However, wide variability in the pattern of prescription among physicians,
limited access to expensive drugs in emerging countries, and poor adherence to medications
limit the use of these drugs and the efficacy of cardiovascular prevention.
A Fixed Dose Combination (FDC) pill for cardiovascular prevention was first proposed by
Wald and Law in 2000 and supported by the WHO. During the last few years this concept,
particularly in the field of primary prevention has been questioned by some experts while the
potential role of a polypill for secondary cardiovascular prevention is receiving increasing
attention. However, a direct proof of the polypill effect on patients’ adherence is still lacking.
The global objective of the FOCUS consortium is to make FDC drugs for secondary
cardiovascular prevention available throughout the world at a low price, in order to improve
access to treatment in developing countries improving adherence to medication.
The Study is international, multicenter in two phases:
Phase 1 is a descriptive, non-interventional study. Its aim is to provide a comprehensive analysis
of factors precluding adequate secondary prevention, including health system characteristics,
drugs affordability and availability, as well as patients’ characteristics.
Phase 2 is an interventional, randomized, two-arm study. Patients will be randomized to receive
a FDC of ramipril, simvastatin and acetilsalycilic acid or the three medications separately. The
primary objectives is to compare the adherence to treatment in post myocardial infarction
patients receiving a FDC vs those with conventional treatment (3 drugs separately).
Secondary objectives are to evaluate the effect of a FDC on blood pressure control and lipid
profile and the safety and tolerability of FDC treatment.
Two countries in Europe (Spain and Italy) and three in South America (Argentina, Brazil e
Paraguay) are involved in the Study. A total number of 4,000 subjects will be included in
phase 1 and 1,340 in the phase 2. The study will start on March 2011.
The stratification of global cardiovascular risk in hypertensive patients of
the district of Borbon – Ecuador
The Laboratory is involved in a collaborative project with the Cecomet (Centro de
Epidemiologia comunitaria y Medicina tropical) in Esmeralda, Ecuador, on the prevalence and
treatment of hypertension in the district of Borbon, a rural zone of Ecuador in the northern part
of the country.
In this area, 36% of the adult population is affected by hypertension and more than half of
hypertensive patients present blood pressure levels > 160/110 mmHg.
From 2001, in the District is ongoing an intensive follow-up of the hypertensive population
with the following aims: to evaluate the global cardiovascular risk of the population, to better
control blood pressure levels increasing the number of subjects treated with hypertensive
therapy (in particular those at high cardiovascular risk) and monitoring of the clinical
complications. Preliminary data show that:
• Patients treated with hypertensive therapy are increased from 39% to 59%
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•
Antihypertensive drugs are mainly prescribed to subjects with high blood pressure levels
(80% of those with systolic blood pressure >180mmHg are actually under treatment) or at
high cardiovascular risk (82%)
• Blood pressure control is improved (patients with systolic blood pressure levels
> 180mmHg decreased from 33% to 24% and those with levels <160-179 increased from
26% to 34%)
• The fraction of patients at high or very high cardiovascular risk is decreased from 40% to
33%
However, the compliance to antihypertensive treatment is still unsatisfactory since only half of
the subjects are compliant with the prescribed therapy.
Laboratory of Medical Statistics
The Laboratory of Medical Statistics develops applied research in three main fields: controlled
clinical trials, observational studies and genetic epidemiology.
Controlled clinical trials
The laboratory deals with planning, management and statistical analysis of controlled clinical
trials, carried out in the different laboratories of the Cardiovascular Research Department, by
means of the GISSI trials sound experience.
At present, GISSI trials focus on GISSI-HF and GISSI-AF clinical trials, concerning heart
failure and atrial fibrillation and their respective subprojects aiming to assess the role of
biomarkers, of echocardiographic and electrocardiographic parameters on the patients’
prognosis. Recently, the superiority trial BeTACTIC that will randomize about 400 patients
undergone heart transplantation has been activated. A large trial concerning cardiovascular
prevention, Risk & Prevention study (Rischio & Prevenzione) which has included about 12000
patients is still ongoing. Statistical methodology applied to clinical studies has a leading and
developing role as far as methods are concerned (e.g.: missing data management; development
of prognostic risk scores, development of forecasting models for biomarkers based on
Reclassification techniques and on Discriminations Indices etc.).
Moreover, clinical trial management implies the setup of data planning and screening methods,
the ad interim analysis and the choice of the best study design (superiority, non-inferiority and
equivalence studies).
Observational studies
The activation of observational studies allows to characterize the epidemiological profile of
categories of patients followed in their natural clinical course. The prospective observational
study GLICINE-SPIDER has evaluated the risk profile of 1300 patients with hyperglycemia at
the onset of an acute coronary syndrome (ACS) in the hospitals of the Lombardia region. The
aim of the cohort study REGIA, presently ongoing, is the evaluation of the incidence of major
and minor hemorrhages and the characterization of the risk profile of about 4000 patients
undergoing hip and knee replacement surgery.
From a strictly epidemiologic point of view, the epidemiologic and health-care history of
diabetes mellitus in Regione Lombardia has been investigated by means of administrative
databases.
Genetic Epidemiology
The laboratory has recently developed specific skills on genetic epidemiology analysis. These
studies are carried out together with the laboratory of Clinical Drugs Evaluation. Statistical
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analysis techniques concerning cardiovascular genetics have been developed in the last five
years.
The study of the genetic component of multifactorial diseases, such as the cardiovascular
disease, has been dealt with in the PROCARDIS study, by means of the genome-wide
screening. This technique aims at identifying genes that can cause coronary disease.
PROCARDIS database gave the opportunity of studying some quantitative traits such as the
level of lipids or body max indexes.
During the second step of the PROCARDIS project, supported by the 6th Framework Program
of EEC, a screening on the whole genome has been carried out by means of the “genome-wide
association” technique. For this project about 1 million of polymorphisms (SNPs) have been
analyzed in order to identify a possible relationship with coronary disease.
Concerning the GISSI-Genetic Prevention study, the laboratory has developed statistics
genetics techniques to analyze case control studies in order to assess the association of genetic
variants linked to adiponectin, HsCRP, PTX3 with coronary disease. Besides, the association
between some polymorphisms of chromosome 9p area and coronary disease has been evaluated
in diabetic patients. With regard to the GISSI-HF genetic substudy that has included about
2500 patients to evaluate the role of genetic variants involved in heart failure, the association of
four polimorphisms of the adiponectin gene has been investigated by a case-control design.
Laboratory of Clinical Pharmacology
Quality of Life, Depression and Cognitive problems in heart failure
patients (QDF-GISSI-HF)
The QDF project is a sub-project of the GISSI-HF study. The aims of the study are 1) to
describe the evolution of depression, cognitive problems and the quality of life in a sample of
1500 heart failure patients; 2) to assess the use of common instruments that measure QDF
variables; 3) to compare the assessment of the instrument (Geriatric Depression scale, Mini
Mental State Examination, Kansas City Cardiomiopathy Questionnaire) with the clinical
perception of the nurses; 4) to describe if assessed or perceived patients' problems (low quality
of life, high depression or compromised cognitive function) lead to any caring intervention.
The baseline clinical characteristics of the 1564 patients included in the QDF study are closely
comparable with those of the GISSI-HF population. The study instruments could be validly
administered to the greatest majority of patients (KCQQ 97.2%, GDS 94.9%, MMSE 80.6% of
patients >70 years).
The nurses network nested in a major clinical trial, has produced one of the largest prospective
cohort of HF patients who are comprehensively assessed and prospectively monitored, to allow
an integrated evaluation of the relevance and implications of QDF measurements also on the
clinical outcomes of this population. Manuscripts with the study results are in preparation.
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DEPARTMENT OF MOLECULAR
BIOCHEMISTRY AND
PHARMACOLOGY
STAFF
Head
Mario SALMONA, Food Technology D, Ph.D.
Laboratory of Biochemistry and Protein Chemistry
Head
Ph.D.
Mario SALMONA, Food Technology D,
Laboratory of Molecular Biology
Head
Enrico GARATTINI, M.D.
Pharmacogenomics Unit
Head
Maddalena FRATELLI, Biol.Sci.D.
Gene Structure and Regulation Unit
Head
Mineko TERAO, Bioch.D., Ph.D.
Laboratory of Pharmacodynamics and Pharmacokinetics
Head
Marco GOBBI, Pharm.D.
Laboratory of Molecular Pathology
Head
Lavinia CANTONI, Biol.Sci.D.
Laboratory of Translational Proteomics
Head
Valentina BONETTO, Chem.Pharm.D.
Laboratory of Systems Biology
Head
Gianfranco BAZZONI, M.D.
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CURRICULA
Mario Salmona obtained his doctorate degree in Biochemistry and Food Technology at the University of
Milan in 1971. His background is in biochemistry, biophysics and pharmacology. His scientific interests
relate to problems of human and animal diseases originating from the aberrant folding of proteins. In this
context, a major portion of his studies was devoted to the etiopathogenesis and therapy of prion diseases.
He has published over 200 articles on peer reviewed scientific journals.
1971-1975 Ph.D in Pharmacology, Mario Negri Institute
1975 Visiting Fellow in the Department of Biology of the Weizmann Institute of Science, Rehovot, Israel
1976-1997 Head, Laboratory of Enzyme Research, Mario Negri Institute
1995 to date Dean of the School of Advanced Pharmacology, Mario Negri Institute
1997 to date Head, Department of Biochemistry and Molecular Pharmacology, Mario Negri Institute
2003 to date Member of the American Society of Biochemistry and Molecular Biology
Referee for international scientific journals.
•
Airoldi C, Colombo L, Manzoni C, Sironi E, Natalello A, Doglia S M, Forloni G, Tagliavini F, Del Favero E, Cantu' L,
Nicotra F, Salmona M
Tetracycline prevents Aβ oligomer toxicity through an atypical supramolecular interaction
Org Biomol Chem, 2010 9: 463-72
•
Urru S A M, Veglianese P, De Luigi A, Fumagalli E, Erba E, Gonella Diaza R, Carrà A, Davoli E, Borsello T, Forloni G,
Pengo N, Monzani E, Cascio P, Cenci S, Sitia R, Salmona M
J Med Chem 2010 53 : 7452-7460
•
Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T,
Chiesa R, Gobbi M, Salmona M, Forloni G
Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein
Proc Natl Acad Sci U S A. 2010 107 : 2295-2300
•
Di Fede G, Catania M, Morbin M, Rossi G, Suardi S, Mazzoleni G, Merlin M, Giovagnoli A R, Prioni S, Erbetta A,
Falcone C, Gobbi M, Colombo L, Bastone A, Beeg M, Manzoni Claudia, Francescucci B, Spagnoli A, Cantu' L, Del
Favero A, Levy E, Salmona M, Tagliavini F
A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis
Science 2009 323 : 1473-1477
•
Saracino GA, Villa A, Moro G, Cosentino U, Salmona M.
Spontaneous beta-helical fold in prion protein: The case of PrP(82-146).
Proteins. 2009 Jun;75(4):964-76
•
De Luigi A, Colombo L, Diomede L, Capobianco R, Mangieri M, Miccolo C, Limido L, Forloni G, Tagliavini F,
Salmona M.
The efficacy of tetracyclines in peripheral and intracerebral prion infection.
PLoS ONE. 2008;3(3):e1888
Gianfranco Bazzoni got his Medicine and Surgery degree in 1988 (at the University of Milan) and the
specialisation in Pharmacological Research in 1992 (at the Mario Negri Institute, Milan). His area of
expertise is cell biology, with focus on the processes of cell adhesion and migration.
1988-2000 Research Fellow, Mario Negri Institute
1993-1997 Post-doctoral Fellow, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA
2000-2002 Research Scientist, Mario Negri Institute
2003 Head, Unit of Cell Adhesion, Mario Negri Institute
2004 to date Head, Laboratory of Systems Biology, Mario Negri Institute
2004 Regular Member of The American Physiological Society, Bethesda, MD
Referee for international scientific journals
•
Paris L, Bazzoni G
The protein interaction network of the epithelial junctional complex: a system-level analysis Mol Biol Cell 19: 54095421, 2008
•
Paris L, Tonutti L, Vannini C, Bazzoni G
Structural organization of the tight junction. Biochim Biophys Acta 1778: 646-659, 2008
•
Huang H, Cruz F, Bazzoni G
Junctional adhesion molecule-A regulates cell migration and resistance to shear stress. J. Cell Physiol 209; 122-130,
2006
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•
•
Martinez-Estrada OM, Manzi L, Tonetti P, Dejana E, Bazzoni G
Opposite effects of Tumor Necrosis Factor and soluble fibronectin on Junctional Adhesion Molecule-A in endothelial
cells
Am J Physiol (Lung Cell Mol Physiol) 288: L1081-L1088, 2005
Bazzoni G, Tonetti P, Manzi L, Cera MR, Balconi G, Dejana E
Expression of Junction Adhesion Molecule-A prevents spontaneous and random motility. J Cell Sci 118: 623-632, 2005
Bazzoni G, Dejana E
Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84: 869-901,
2004
Valentina Bonetto has got the degree in Pharmaceutical Chemistry and Technology at the University of
Padua, Italy in 1993. She has got the Ph.D in Medical Biochemistry and Biophysics at Karolinska
Institutet, Stockholm, Sweden.
Her principal lines of research are: 1) Study of the pathogenetic mechanisms at the basis of amyotrophic
lateral sclerosis (ALS); 2) Identification of biomarkers of ALS; 3) Role of the oxidative modification in
neurological disorders. These issues are investigated by different experimental approaches, including
proteomics and mass spectrometry.
2000-2009 Research Scientist, Laboratory of Biochemistry and Protein Chemistry, Mario Negri Institute
2002-2009 also Assistant Telethon Scientist at Dulbecco Telethon Institute
2007-2009 Head, Unit of Medical Biochemistry, Laboratory of Biochemistry and Protein Chemistry,
Mario Negri Institute
From 2009 to date, Head Laboratory of Translational Proteomics and Associate Telethon Scientist.
She is author of 33 publications from 1994 to 2010, in peer-reviewed journals. She is reviewer for
scientific journals in the field of Proteomics and Neuroscience.
•
Massignan T, Biasini E, Lauranzano E, Veglianese P, Pignataro M, Fioriti L, Harris DA, Salmona M, Chiesa R, Bonetto
V
Mutant prion protein expression is associated with an alteration of the Rab GDP dissociation inhibitor alpha (GDI)/Rab11
pathway.
Mol Cell Proteomics, 9:611-622, 2010
•
Basso M, Samengo G, Nardo G, Massignan T, D’Alessandro G, Tartari S, Cantoni L, Marino M, Cheroni C, De Biasi S,
Giordana MT, Strong MJ, Estevez AG, Salmona M, Bendotti C, Bonetto V
Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in
pathogenesis
PLoS ONE 4:e8130, 2009
•
Nardo G, Pozzi S, Mantovani S, Garbelli S, Marinou K, Basso M, Mora G, Bendotti C, Bonetto V
Nitroproteomics of peripheral blood mononuclear cells from patients and a rat model of ALS
Antioxid. Redox Signal 11: 1559-1567, 2009
•
Massignan T, Casoni F, Basso M, Stefanazzi P, Biasini E, Tortarolo M, Salmona M, Gianazza E, Bendotti C, Bonetto V
Proteomic analysis of spinal cord of presymptomatic amyotrophic lateral sclerosis G93A SOD1 mouse
Biochem. Biophys. Res. Commun. 353: 719-25, 2007
•
Basso M, Massignan T, Samengo G, Cheroni C, De Biasi S, Salmona M, Bendotti C, Bonetto V
Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice
J. Biol. Chem. 281:33325-33335, 2006
•
Casoni F, Basso M, Massignan T, Gianazza E, Cheroni C, Salmona M, Bendotti C, Bonetto V
Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: Possible multifunctional role in the
pathogenesis. J. Biol. Chem., 280: 16295-16304, 2005
Lavinia Cantoni obtained her degree in Biological Sciences in 1973 at the University of Milan. Then
she specialized in pharmacological research at the Mario Negri Institute (1974-1977).
Research areas 1) biochemical-molecular mechanisms activated by oxidative stress 2) drug metabolism
3) porphyrias.
1977-1978 Post-doctoral Fellow, Medical Research Council, Toxicology Unit, Carshalton, UK
(Winner of a Welcome Trust Research Fellowship)
1979-1982 Research Scientist, Mario Negri Institute
1980-1990 Visiting Scientist, Toxicology Unit, Carshalton, UK, and Cornell Medical Center, New
York, NY (short periods)
1983-1997 Head, Unit of Heme and Hemoprotein Metabolism, Mario Negri Institute
1998 to date, Head, Laboratory of Molecular Pathology, Mario Negri Institute
1975 to date Member of the National Roll of Biologists
1983 to date Member of the Italian Toxicology Society
Referee for international scientific journals.
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Tartari S, D’Alessandro G, Babetto E, Rizzardini M, Conforti L, Cantoni L.
Adaptation to G93Asuperoxide dismutase 1 in a motor neuron cell line model of amyotrophic lateral sclerosis. The role
of glutathione
FEBS J. 276: 2861-2874, 2009
•
Raimondi A, Mangolini A, Rizzardini M, Tartari S, Massari S, Bendotti C, Francolini M, Borghese N, Cantoni L,
Pietrini G.
Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALS-linked
G93ASOD1
Eur. J. Neurosci. 24: 387-399, 2006
•
Babetto E, Mangolini A, Rizzardini M, Lupi M, Conforti L, Poletti A, Rusmini P, Cantoni L. Tetracycline-regulated gene
expression in the NSC-34-tTA cell line for investigation of motor neuron diseases
Mol. Brain Res. 140: 63-72, 2005
•
Cantoni L,Valaperta R, Ponsoda X, Castell JV, Barelli D, Rizzardini M, Mangolini A, Hauri L, Villa P.
Induction of hepatic heme oxygenase-1 by diclofenac in rodents: role of oxidative stress and cytochrome P-450 activity
J. Hepatology 38: 776-783, 2003
•
Cantoni L, Rozio M, Mangolini A, Hauri L, Caccia S.
Hyperforin contributes to the hepatic CYP3A-inducing effect of Hypericum perforatum extract in the mouse.
Toxicol.Sci. 75:25-30, 2003
•
Rizzardini M, Zappone M, Villa P, Gnocchi P, Sironi M, Diomede L, Meazza C, Monshouwer M, Cantoni L.
Kupffer cell depletion partially prevents hepatic heme oxygenase 1 messenger RNA accumulation in systemic
inflammation in mice: role of interleukin 1 beta
Hepatology 27: 703-710, 1998
Enrico Garattini obtained his degree in Medicine and Surgery with full marks (110/110) in 1982 at the
University of Milan. His scientific interests relate to problems of Cellular Biology and Molecular
Biology.
1982-1990 Research Fellow of the National Research Council, Mario Negri Institute
1983-1987 Postdoctoral Researcher at the Roche Institute of Molecular Biology, Department of
Neurosciences Nutley, New Jersey, US
1991-1997 Senior Researcher Regione Lombardia and Head of the Molecular Biology Unit, Mario Negri
Institute
1997 to date Head, Laboratory of Molecular Biology, Mario Negri Institute
From 2005 Dean, Advanced School of Pharmacology (Philosophy Doctor), Mario Negri Institute
Member of the Editorial Board of the European Journal of Cancer and of Current Cancer Therapy
Reviews
Member of the American Society of Biochemistry and Molecular Biology (ASBMB)
•
Gianni M, Boldetti A, Guarnaccia V, Rambaldi A, Parrella E, Raska I Jr, Rochette-Egly C, Del Sal G, Rustighi A, Terao
M, Garattini E
Inhibition of the peptidyl-propyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic
acid via stabilization of RARα and PML-RARα.
Cancer Res 69 : 1016-1026, 2009
•
Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giudice C, Scanziani E, Mancuso A, Tiveron C,
Garattini E
Role of the molybdo-flavoenzyme, aldehyde oxidase homolog 2, in the biosynthesis of retinoic acid: generation and
characterization of a knock-out mouse
Mol Cell Biol 29: 357-77, 2009
•
Gianni M, Parrella E, Raska I Jr, Gaillard E, Nigro EA, Gaudon C, Garattini E, Rochette-Egly C. P38MAPK-dependent
phosphorylation and degradation of SRC-3/AIB1 and RARalpha-mediated transcription
EMBO J. 25:739-51, 2006
•
Garattini E, Parrella E, Diomede L, Gianni M, Kalac Y, Merlini L, Simoni D, Zanier R, Ferrara F F, Chiarucci I,
Carminati P, Terao M, Pisano C
ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: Modulation of
intracellular calcium homeostasis
Blood 103: 194-207, 2004
•
Kurosaki M, Terao M, Barzago M M, Bastone A, Bernardinello D, Salmona M, Garattini E. The aldehyde oxidase gene
cluster in mice and rats: Aldehyde oxidase homologue 3, a novel member of the molybdo-flavoenzyme family with
selective expression in the olfactory mucosa
J Biol Chem 279: 50482-50498, 2004
•
Pisano C, Kollar P, Gianni M, Kalac Y, Giordano V, Ferrara F F, Tancredi R, Devoto A, Rinaldi A, Rambaldi A, Penco
S, Marzi M, Moretti G, Vesci L, Tinti O, Carminati P, Terao M, Garattini E
Bis-indols a novel class of molecules enhancing the cytodifferentianting properties of retinoids in myeloid leukemia
cells
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Blood 100: 3719-3730, 2002
Marco Gobbi got his degree in Pharmacy at the University of Milan, Italy, in 1989.
His main fields of interest are: i) neurodegenerative diseases associated to misfolding and aggregation of
peptides/proteins, such as beta-amyloid and prions; ii) alterations of synaptic transmission in the CNS,
either due to diseases or to the effects of drugs on receptors and transporters; iii) nanoparticles for
diagnostic and therapeutic purposes. These research fields are investigated by a close integration of
pharmacodynamics (e.g. biomolecular interactions, mainly using surface plasmon resonance) and
pharmacokinetics studies.
1981-1995 Researcher, Laboratory of Neuropharmacology and, from 1988, in the Laboratory of Receptor
Pharmacology, Mario Negri Institute
1995-2010 Head, Unit of Synaptic Transmission, Mario Negri Institute
From 2010, Head, Laboratory of Pharmacodynamics and Pharmacokinetics
Co-author in more than 100 scientific publications on peer-reviewed international journals. First or last
author in more than 50 of them.
Reviewer for international scientific journals operating in the
Neuroscience/Neuropharmacology/Biochemistry fields.
•
Gobbi M, Re F, Canovi M, Beeg M, Gregori M, Sesana S, Sonnino S, Brogioli D, Musicanti C, Gasco P, Salmona M and
Masserini ME. Lipid-based nanoparticles with high binding affinity for amyloid-beta1-42 peptide. Biomaterials 31:65196529 (2010).
•
Caccia S and Gobbi M St. John's Wort components and the brain: Uptake, concentrations reached and the mechanisms
underlying pharmacological effects. Curr Drug Metab 10(9):1055-1065 (2009).
•
Gesuete R, Storini C, Fantin A, Stravalaci M, Zanier ER, Orsini F, Vietsch H, Mannesse MLM, Ziere B, Gobbi M and
De Simoni MG Recombinant C1 inhibitor in brain ischemic injury. Ann Neurol 66(3):332-342 (2009).
•
Colleoni S, Jensen AA, Landucci E, Fumagalli E, Conti P, Pinto A, De Amici M, Pellegrini-Giampietro DE, De Micheli
C, Mennini T and Gobbi M. Neuroprotective effects of the novel glutamate transporter inhibitor (-)-3-hydroxy-4,5,6,6atetrahydro-3aH-pyrrolo[3,4-d]-isoxazole-4-carboxylic acid, which preferentially inhibits reverse transport (glutamate
release) compared with glutamate reuptake. J Pharmacol Exp Therap 326:646-656 (2008).
•
Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantù L, Kirschner DA, Manzoni
C, Beeg M, Ceci P, Ubezio P, Forloni G, Tagliavini F and Salmona M. Gerstmann-Sträussler-Scheinker disease amyloid
protein polymerizes according to the "dock-and-lock" model. J Biol Chem 281:843-849 (2006).
•
Crespi D, Mennini T, Gobbi M. Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine. Br J Pharmacol
121:1735-1743 (1997).
Maddalena Fratelli got her degree in Biological Sciences at the University of Pisa and at the Scuola
Normale Superiore di Pisa in 1983. Then the specialization in Pharmacological Research at the Mario
Negri Institute in 1986.
Her main fields of interest are: 1. High throughput genomic systems for the study of drug action and
pharmacoresistance. 2. Redox regulation of protein function and gene expression: glutathionylation and
gene expression profiling of glutathione dependent responses to oxidant challenge.
1988-1989 Postdoctoral Research Fellow in the Medical Research Council, Neurobiology Unit,
Cambridge, UK.
Since 1995, Head, Unit of Mediators of inflammation, Laboratory of Neuroimmunology, Mario Negri
Institute
Since 2005, Head, Unit of Pharmacogenomics, Laboratory of Molecular Biology, Mario Negri Institute
•
Garattini E, Fratelli M, Terao M.
The mammalian aldehyde oxidase gene family
Hum Genomics. 4: 119-30, 2009
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Fratelli M, Goodwin LO, Orom UA, Lombardi S, Tonelli R, Mengozzi M, Ghezzi P. Gene expression profiling reveals
a signaling role of glutathione in redox regulation.
Proc Natl Acad Sci U S A 102:13998-4003, 2005
•
Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E,
Diaz D, Gomez D, Hand C, Coleman T, Cerami A. Erythropoietin mediates tissue protection through an erythropoietin
and common beta-subunit heteroreceptor
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Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P,
Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S,
Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M.
Derivatives of erythropoietin that are tissue protective but not erythropoietic
Science 305:239-42, 2004
Fratelli M, Minto M, Crespi A, Erba E, Vandenabeele P, Del Soldato P, Ghezzi P. Inhibition of nuclear factor-kappaB
by a nitro-derivative of flurbiprofen: a possible mechanism for antiinflammatory and antiproliferative effect
Antioxid Redox Signal. 5:229-35, 2003
Fratelli M, Demol H, Puype M, Casagrande S, Eberini I, Salmona M, Bonetto V, Mengozzi M, Duffieux F, Miclet E,
Bachi A, Vandekerckhove J, Gianazza E, Ghezzi P.
Identification by redox proteomics of glutathionylated proteins in oxidatively stressed human T lymphocytes
Mineko Terao obtained her doctorate degree in Pharmaceutical Science from the Kobe Women’s
College of Pharmacy, Japan in 1978. Her scientific interests relate to problems of Cellular Biology and
Molecular Biology.
1983 Ph.D in Molecular Biology, Kyoto University, Japan
1982-1983 Research Fellow, Department of Medical Chemistry, Kyoto University Faculty of Medicine,
Japan
1983-1987 Postdoctoral Associate of the Institute for Cancer Research, Philadelphia, US
From 1987 Visiting Scientist of Mario Negri Institute
From 1998 Head of the Unit of Gene Structure and Regulation, Mario Negri Institute
•
Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giudice C, Scanziani E, Mancuso A,
Tiveron C, Garattini E
Role of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoic acid: generation and
characterization of a knockout mouse
Mol Cell Biol 29 : 357-377, 2009
•
Terao M, Kurosaki M, Barzago MM, Varasano E, Boldetti A, Bastone A, Fratelli M, Garattini E.
Avian and canine aldehyde oxidases. Novel insights into the biology and evolution of molybdo-flavoenzymes.
J Biol Chem. 281: 19748-61, 2006
•
Garattini E, Parrella E, Diomede L, Gianni M, Kalac Y, Merlini L, Simoni D, Zanier R, Ferrara F F, Chiarucci I,
Carminati P,Terao M, Pisano C.
ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: Modulation of
intracellular calcium homeostasis.
Blood 103: 194-207, 2004
•
Vila R, Kurosaki M, Barzago M M, Kolek M, Bastone A, Colombo L, Salmona M, Terao M, Garattini E.
Regulation and biochemistry of mouse molybdo-flavoenzymes. The DBA/2 mouse is selectively deficient in the
expression of aldehyde oxidase homologues 1 and 2 and represents a unique source for the purification and
characterization of aldehyde oxidase.
J Biol Chem 279: 8668-8683, 2004
•
Kurosaki M, Terao M, Barzago M M, Bastone A, Bernardinello D, Salmona M, Garattini E. The aldehyde oxidase gene
cluster in mice and rats: Aldehyde oxidase homologue 3, a novel member of the molybdo-flavoenzyme family with
selective expression in the olfactory mucosa
J Biol Chem 279: 50482-50498, 2004
•
Parrella E, Gianni’ M, Cecconi V, Nigro E, Barzago MM, Rambaldi A, Rochette-Egly C, Terao M and Garattini E.
Phosphodiesterase 4 inhibition by piclamilast potentiates the cyto-differentiating action of retinoids in myeloid leukemia
cells.
J Biol Chem 279: 42026-42040, 2004
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ACTIVITIES
The Department comprises six laboratories. Research is heterogeneous in terms of
scientific interests and aims, but it is unified by the structural and functional study of
specific, pharmacologically important gene products, using a common body of
techniques. Classical biochemistry and molecular biology methods are used to define
proteins that might be targets for the pharmacological activity of drugs. Potential direct
interactions between drugs and proteins are studied at the molecular level by a variety of
approaches ranging from animal studies to computer simulation.
MAIN FINDINGS
Identification of the molecular mechanisms responsible of oligomer formation of
amyloidogenic proteins.
Identification of tetracyclines as potential therapeutic agents for prion diseases.
Synthesis, biological and chemico-physical characterization of peptides deduced from
prion protein sequence.
Identification of a correlation between cholesterol synthesis and prion protein
production.
Protein identifications by mass spectrometry and data base searching using a
combination of techniques.
Characterization of the Pentraxin 3 role in the organization of the cumulus oophorus
extracellular matrix and in female fertility.
System-level analysis of protein interactions in the epithelial junctional complex.
Proteomic analysis of the aggregates isolated from spinal cord of a mouse model of
amyotrophic lateral sclerosis (ALS)
Identification of nitroprotein biomarkers in peripheral blood mononuclear cells of ALS
patients and a rat model of ALS
Proteomic analysis of a cellular model of fatal familial insomnia
Development of constitutive and conditional motor neuronal cell models to unravel the
toxicity of mutant G93A superoxide dismutase 1 responsible for some forms of familial
amyotrophic lateral sclerosis.
Drugs or exogenous compounds impairing the electron transport chain are a risk factor
to motor neurons of individuals carrying mutant forms of superoxide dismutase 1.
Mitochondrial damage due to mutant G93A superoxide dismutase 1 occurs selectively
in motor neurons.
Synthesis of glutathione, the main cellular antioxidant, is altered in motor neuronal cells
by human G93A mutant superoxide dismutase 1.
Identification and characterization of a novel class of retinoids endowed with strong and
selective apoptogenic activity on the neoplastic cell. Pre-clinical development of these
agents for the treatment of acute leukemia.
Identification and characterization of novel retinoid-based pharmacological
combinations for the treatment of acute myelogenous leukemia.
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Molecular cloning and characterization of the cDNAs and genes of four novel members
of the mammalian molybdo-flavoprotein family. Definition of a novel gene cluster on
human chromosome 2 and mouse chromosome 1.
Development of knok-out animals for molybdo-flavoproteins: AOX1, AOH1, AOH2,
AOH3.
Creation of integrated instruments for the rationalization of Microarray analysis
processes.
The treatment with a non haematopoietic derivate of Erythropoietin (CEPO) reduces
motor neuron loss and clinical progression in a mouse model of ALS related to
alterations in vesicle trafficking, the wobbler mouse.
Treatment with a soluble TNF receptor in the wobbler mouse, reduces motor neuron
degeneration and the phosphorylation of the two main stress kinases (p38 e JNK)
activated by TNF receptors.
Riluzole treatment reduces motor neuron loss and clinical progression of wobbler
mouse by increasing the endogenous BDNF expression .
Oxidative stress, glial activation and inflammation occur in the retinopathy as well as
in cerebral and spinal cord dysfunction in the mnd mouse, a model of progressive
epilepsy with mental retardation related to mutation in the CLN8 gene. These findings
provide further evidence for the implication of TNF death receptor signalling in the
pathology of Neuronal Ceroid Lipofuscinosis
Recombinant C1-inhibitor binds with high affinity with Mannose Binding Lectins, an
interaction possibly underlying its superior anti-ischemic properties in animal models.
Confirmation and characterization of the binding of β-amyloid oligomers to prion
protein.
Characterization of the binding properties of a new peptide inhibitor of β-amyloid
aggregation.
Development of new protocols to evaluate, by surface plasmon resonance, the
interaction between nanoparticles and their putative targets: application to nanoparticles
functionalized to bind β-amyloid.
Confirmation and characterization of the binding of pentraxin-3 to P-selectin, a new
mechanism involved in the leukocyte recruitment at sites of inflammation.
Determination of the binding properties of new FGF-2 ligands with antiangiogenic
activities.
Advanced Biology Center, Genoa
Centro Clinico Nemo, Ospedale Niguarda, Milan
Center of Excellence on Neurodegenerative Diseases, University of Milan, Segrate,
Milan
Dip. Anatomia, Farmacologia, Medicina Legale, University of Turin
Dip. Biochimica, University of Pavia
Dip. Biotecnologie, Università degli Studi, Milan
Dip. Chimica Biochimica e Biotecnologie per la Medicina, Università degli Studi,
Milan
Dip. Chimica Farmaceutica e Tossicologica, Università degli Studi, Milan
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Dip. Chimica Organica e Industriale Università degli Studi, Milan
Dip. Farmaco-Chimico, Università degli Studi, Messina
Dip. Farmaco-Chimico-Tecnologico, University of Siena
Dip. Farmacologia Medica, Università degli Studi, Milan
Dip. Medicina Sperimentale, Università Bicocca, Monza
Dip. Scienze Biochimiche, University of Florence
Dip. Scienze Farmaceutiche, University of Catania
Dip. Scienze Farmaceutiche, University of Genoa
Dip. Scienze Farmacologiche, Università degli Studi, Milan
Dip. Scienze Fisiologiche e Farmacologiche, University of Pavia
Dip. Scienze Molecolari, University of Milan
Dip. Studi pre-clinici, University of Milan
Facoltà di Biologia, Università degli Studi, Milan
Facoltà di Chimica, Università degli Studi, Milan
Facoltà di Chimica, University of Ferrara
Fondazione S. Maugeri, Milan
Fondo Edo Tempia, Biella
IFOM Fondazione Istituto FIRC di Oncologia Molecolare, Milan
IRCCS Fondazione "Istituto C. Mondino", Laboratorio di Neurobiologia Sperimentale,
Pavia
Istituto di Biologia Molecolare Buzzati Traverso, Naples
Istituto di Biomedicina e Immunologia Molecolare CNR, Palermo
Istituto di Chimica del Riconoscimento Molecolare CNR, Milan
Istituto di Endocrinologia, Centro di Eccellenza per le Malattie Neurodegenerative,
Università degli Studi, Milan
Istituto di Clinica Neurologica, Ospedale Maggiore Policlinico, Milan
Istituto Clinico Humanitas, Milan
Istituto di Neuroscienze C.N.R., Pisa
Istituto Nazionale dei Tumori, Milan
Istituto Nazionale dei Tumori, Naples
Istituto Nazionale Neurologico "C. Besta", Milan
Istituto Oncologico Europeo, Milan
Istituto Regina Elena, Rome
Istituto Toscano Tumori, Florence
Nanovector srl, Turin
Newron Pharmaceuticals, Milan
Ospedale Maggiore Policlinico, Milan
Ospedale Pediatrico Bambino Gesu', Rome
Ospedale Pediatrico "Gaslini", Genoa
Ospedale S. Gerardo, Monza, Milan
Ospedale San Matteo, Pavia
Sigma-Tau, Pomezia, Rome
Zambon, Milan
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The Babraham Institute, Cambridge, UK
Boston College, Boston, MA, USA
Burke Medical Research Institute, White Plains, new York, USA
Case Western Research University, Cleveland, OH, USA
Dept. de Quimica-Fisica de Macromoleculas Biologicas, CSIC, Madrid, Spain
Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster
University, Lancaster LA1 4YQ, UK
Faculdad de Ciencias Medicas, Universidad de Santiago de Chile, Chile
ETH, Zurig, Switzerland
FMP, Berlin, Germany
Giessen Polyclinic University, Giessen, Germany
Houston University, TX, USA
Keio University, Tokyo, Japan
IBSN CNRS, Marseille, France
Indiana University, Indianapolis, IN, USA
Institut de Genetique et Biologie Moleculaire et Cellulaire, Strasbourg, France
Institut Pasteur, Paris, France
John Innes Centre, Norwich, UK
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, , Univ Paris-Sud 11,
Chatenay-Malabry, France
Lundbeck, USA
Mayo Clinic College of Medicine, Jacksonville, FL, USA
National Institute of Health, Bethesda, MD, USA
Nippon University, Tokyo, Japan
Pepscan System BV, Lelystad, Holland
Polichem S.A., Lugano, Switzerland
Politecnico di Zurigo (ETH), Switzerland
Technical University Braunschweig, Germany
The Alexander Silberman Institute of Life Sciences, The Hebrew University of
Jerusalem, Jerusalem, Israel
Trinity College, Dublin, Ireland
Universidad de La Laguna, Tenerife, Spain
Universidad Nova, Lisbon, Portugal
Universitat des Saarlandes, Hamburg, Germany
Universitat Freiburg, Germany
Université Paris, France
Université Victor Segalen Bordeaux 2, Bordeaux, France
University of Aberdeen, UK
University of Amsterdam, The Netherlands
University of Birmingham, UK
University of Cardiff, UK
University of Glasgow, UK
University of Gottingen, Germany
University of Muenster, Germany
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University of Patrasso, Grece
University of Southampton, UK
University of Sussex, UK
University of Vienna, Austria
Waring-Webb Institute, University of Colorado, Denver CO, USA
Weizmann Institut, Rehovot, Israel
Westfaelische Wilhelms-Universitaet Muenster, Germany
Neurobiology of Lipids (L. Diomede)
European Journal of Cancer (E. Garattini)
American Journal Physiology, Antioxidants and Redox Signaling, BBA-Proteomics,
Biochemical Journal, Biochemical Pharmacology, Biochimica Biophysica Acta, BMCBiochemistry, Brain Research, Cancer Research, Cell Death and Differentiation, Cell
Research, Cellular and Molecular Life Sciences, Circulation, Drug Investigation,
European Journal of Cancer, European Journal of Immunology, European Journal of
Neuroscience, International
Journal of Cancer, Journal of Cell Biology, Journal of Hepatology, Journal of
Immunology,
Journal of Investigative Dermatology, Journal of Lipid Mediators, Journal of
Neurochemistry,
Journal of Neuroimmunology, Journal of Translational Medicine, Neuroscience,
Neuroscience
Letters, Pharmacological Research, Physiological Genomics, PLoS ONE, Proceedings
of the
National Academy of Sciences, Life Sciences, Proteomics, Proteome Science.
Meeting: “7th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical
Technology”, “Nanoparticles against ALZHEIMER'S disease: PEG-PACA
nanoparticles are able to link the Aβ-peptide and influence its aggregation kinetic”, 811 March, Malta, Valetta
Congress: “Microscale separation”, “Interaction between PEG-PACA nanoparticles and
amyloid peptide highlighted by Capillary Electrophoresis”. 21-25 May, Prague,
République Tchèque
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Workshop:
“Italian-Spanish Joint Workshop”, “NMR characterization of the
interaction between Aβ peptide and small ligands for the development of the new antiAlzheimer’s drugs”, 22 April, Milan, Italy
Conference: “3rd European Conference for Clinical Nanomedicine”, “Nanoparticles
against ALZHEIMER'S disease: PEG-PACA nanoparticles are able to link the Aβpeptide and influence its aggregation kinetic”, 10-12 May, Basel, Switzerland
Congress: “7th FENS Forum of European Neuroscience”, “Biophysical and biological
features of amyloid-beta 1-42 in its initial, oligomeric and fibrillar state, prepared by a
novel synthetic technique”, “In vitro characterization of nanoparticles functionalized for
targeting Amyloid-beta 1-42 peptide”. 3-7 July, Amsterdam, The Netherlands
Symposium: “EFMC-ISMC 2010 - XXIst International Symposium on Medicinal
Chemistry”, “Novel [1[benzothieno[3,2-d]pyrimidin-4(3H)-ones. Ligands for 5-HT7
receptor”, 5 September, Brussels, Belgium
Course: 2nd Training course “Pharmacokinetics of Nanoparticles and their passage
through the blood-brain barrier”, “Nanoparticles in biomedicine”, “NPs and stem cells
tracking”, “NPs and interaction to biological targets”, 22-24 September, Milan, Italy
Congress: “Nanotechitaly 2010”, “Synthesis and functionalization of polymeric
nanoparticles for clinical imaging application”, “Stability of novel polymer-based
nanoparticles designed for drug delivery and diagnostic purposes”
Nanotech Italy 2010, 20-22 October, Venice, Italy
Congress: “Neuroscience”, “[11C]PIB Shows Increased Binding in the Brain of the
Transgenic APP23 Mice Even With Modest Specific Radioactivity”, 13-15 November,
San Diego, USA
Agenzia Italiana del Farmaco, Rome, Italy
Associazione Italiana Ricerca sul Cancro (AIRC), Milan, Italy
Biotecnologie BT - Perugia, Italy
Comunità Europea (EU), Bruxelles, Belgium
Consiglio Nazionale delle Ricerche (CNR), Palermo, Italy
Fondazione Don Gnocchi, Milan, Italy
Fondazione Cariplo, Milan, Italy
Fondazione Mariani, Milan, Italy
Fondazione Monzino, Milan, Italy
Fondazione Weizmann-Pasteur-Negri, Paris, France
Istituto Auxologico Italiano, Milan, Italy
Istituto Nazionale Neurologico "C. Besta", Milan, Italy
Lundbeck A/S, Copenhagen, Denmark
Ministero della Salute, Roma, Italy
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Ministero dell'Istruzione, Università e Ricerca Scientifica (MIUR), Rome, Italy
North Shore University Hospital, NY, USA
Perfetti-Van Melle, Lainate, Milan, Italy
Sigma Tau, Pomezia, Rome, Italy
Telethon, Milan, Italy
Università di Firenze, Italy
Università di Milano-Bicocca, Italy
Università di Siena, Italy
Zambon Group, Bresso (Mi), Italy
Airoldi C, Colombo L, Manzoni C, Sironi E, Natalello A, Doglia S M, Forloni G, Tagliavini F, Del Favero E, Cantu'
L, Nicotra F, Salmona M
Tetracycline prevents Aβ oligomer toxicity through an atypical supramolecular interaction
Org Biomol Chem, 2010 9: 463-72
Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T,
Chiesa R, Gobbi M, Salmona M, Forloni G
Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein
PNAS 2010 107 : 2295-2300
Bate C, Tayebi M, Salmona M, Diomede L, Williams A
Polyunsaturated fatty acids protect against prion-mediated synapse damage in vitro
Neurotox Res 2010 17 : 203-214
Bazzoni G
Pathobiology of Junctional Adhesion Molecules
Antioxid Redox Signal, 2010 [Epub ahead of print]
Beeg M, Stravalaci M, Bastone A, Salmona M, Gobbi M
A modified protocol to prepare seed-free starting solutions of Aβ1-40/1-42 from the corresponding depsi-peptides
Anal Biochem, 2010 [Epub ahead of print]
Bigini P, Steffensen K R, Ferrario A, Diomede L, Ferrara G, Barbera S, Salzano S, Fumagalli E, Ghezzi P, Mennini
T, Gustafsson J - A
Neuropathologic and biochemical changes during disease progression in liver X receptor β-/- mice, a model of adult
neuron disease
J Neuropathol Exp Neurol 2010 69 : 593-605
Brambilla D, Verpillot R, Taverna M, De Kimpe L, Le Droumaguet B, Nicolas J, Canovi M, Gobbi M, Mantegazza
F, Salmona M, Nicolas V, Scheper W, Couvreur P, Andrieux K
New method based on capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) to monitor
interaction between nanoparticles and the amyloid-β peptide
Anal Chem 2010 82 : 10083-10089
Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis D S, Stravalaci M, Tomaselli S, Giavazzi R,
Rusnati M, Presta M, Zetta L, Mosher D F, Ribatti D, Gobbi M, Taraboletti G
Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for the
development of new antiangiogenic compounds
J Biol Chem 2010 285 : 8733-8742
Cooper I, Malina K C, Cagnotto A, Bazzoni G, Salmona M, Teichberg V I
Interactions of the prion peptide (PrP 106-126) with brain capillary endothelial cells: coordinated cell killing and
remodeling of intercellular junctions
J Neurochem 2010 [Epub ahead of print]
Corrado L, Gagliardi S, Carlomagno Y, Mennini T, Ticozzi N, Mazzini L, Silani V
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VPS54 genetic analysis in ALS Italian cohort
Eur J Neurol 2010 [Epub ahead of print]
Deban L, Castro Russo R, Sironi M, Moalli F, Scanziani M, Zambelli V, Cuccovillo I, Bastone A, Gobbi M,
Valentino S, Doni A, Garlanda C, Danese S, Salvatori G, Sassano M, Evangelista V, Rossi B, Zenaro E, Constantin
G, Laudanna C, Bottazzi B, Mantovani A
Regulation of leukocyte recruitment by the long pentraxin PTX3
Nat Immun 2010 11 : 328-334
De Paola M, Visconti L, Vianello E, Mattana F, Banfi G, Corsi M M, Beghi E, Mennini T
Circulating cytokines and growth factors in professional soccer players: correlation with in vitro-induced motor
neuron death
Eur J Neurol, 2010 [Epub ahead of print]
Diana V, Botti F, Fumagalli E, Calcagno E, De Paola M, Cagnotto A, Invernici G, Parati E, Curti D, Mennini T
Neural precursor-derived astrocytes of wobbler mice induce apoptotic death of motor neurons through reduced
glutamate uptake
Exp Neurol 2010 225 : 163-172
Diomede L, Cassata G, Fiordaliso F, Salio M, Ami D, Natalello A, Doglia S M, De Luigi A, Salmona M
Tetracycline and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting
oligomers
Neurobiol Dis 2010 40 : 424-431
Galizzi G, Russo Domenica, Deidda A, Cascio C, Passantino R, Guarneri R, Bigini P, Mennini T, Drago G, Guarneri
P
Different early ER-stress responses in the CLN8mnd mouse model of neuronal ceroid lipofuscinosis
Neurosci Lett 2010 [Epub ahead of print]
Giaccone G, Morbin M, Moda F, Botta M, Mazzoleni G, Uggetti A, Catania M, Moro M L, Redaelli V, Spagnoli A,
Rossi R S, Salmona M, Di Fede G, Tagliavini F
Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features
Acta Neuropathol 2010 120 : 803-812
Giorgetti S, Raimondi S, Pagano K, Relini A, Bucciantini M, Corazza A, Fogolari F, Codutti L, Salmona M,
Mangione P, Colombo Lino, De Luigi A, Porcari R, Gliozzi A, Stefani M, Esposito G, Bellotti V, Stoppini M
Effect of tetracyclines on the dynamics of formation and destructuration of β2-microglobulin amyloid fibrils
J Biol Chem 2010 [Epub ahead of print]
Gobbi M, Re F, Canovi M, Beeg M, Gregori M, Sesana S, Sonnino S, Brogioli D, Musicanti C, Gasco P, Salmona M,
Masserini M
Lipid-based nanoparticles with high binding affinity for amyloid-β1-42 peptide
Biomaterials 2010 31 : 6519-6529
Lacivita E, De Giorgio P, Lee I T, Rodeheaver S I, Weiss B, Fracasso C, Caccia S, Berardi F, Perrone R, Zhang M R, Maeda Y, Higuchi M, Suhara T, Schetz J A, Leopoldo M
Design, synthesis, radiolabeling and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin1-yl]ethyl]-3-methoxybenzamide, a potential Positron Emission Tomography tracer for the dopamine D4 receptors
J Med Chem 2010 53 : 7344-7355
Martinez de la Torre Y, Fabbri M, Jaillon S, Bastone A, Nebuloni M, Vecchi A, Mantovani A, Garlanda C
Evolution of the pentraxin family: the new entry PTX4
J Immunol 2010 184 : 5055-5064
Massignan T, Biasini E, Lauranzano E, Veglianese P, Pignataro M, Fioriti L, Harris D A, Salmona M, Chiesa R,
Bonetto V
Mutant prion protein expression is associated with an alteration of the Rab GDP dissociation inhibitor alpha
(GDI)/Rab11 pathway
Mol Cell Proteomics 2010 9 : 611-622
Massignan T, Stewart R S, Biasini E, Solomon I H, Bonetto V, Chiesa R, Harris D A
A novel, drug-based, cellular assay for the activity of neurotoxic mutants of the prion protein
J Biol Chem 2010 285 : 7752-7765
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Melo T, Bigini P, Sonnewald U, Balosso S, Cagnotto A, Barbera S, Uboldi S, Vezzani A, Mennini T
Neuronal hyperexcitability and seizures are associated with changes in glial-neuronal interactions in the hippocampus
of a mouse model of epilepsy with mental retardation
J Neurochem 2010, 115: 1445-1454
Mennini T, Testa R
Are descending control pathways of the lower urinary tract and pain overlapping systems?
Cent Nerv Syst Agents Med Chem 2010 10 : 113-147
Mourtas S, Canovi M, Zona C, Aurilia D, Niarakis A, La Ferla B, Salmona M, Nicotra F, Gobbi M, Antimisiaris S G
Curcumin-decorated nanoliposomes with very high affinity for amyloid-β1-42 peptide
Biomaterials 2010 [Epub ahead of print]
Oliva A, Sanchez Ashen D, Salmona M, Farina J B, Llabres M
Solid-state stability studies of cholecystokinin (CCK-4) peptide under nonisothermal conditions using thermal
analysis, chromatography and mass spectrometry
Eur J Pharm Sci 2010 39 : 263-271
Provenza G, Provenzano M, Visai L, Burke F M, Geoghegan J A, Stravalaci M, Gobbi M, Mazzini G, Arciola C R,
Foster T J, Speziale P
Functional analysis of a murine monoclonal antibody against the repetitive region of the fibronectin-binding adhesins
fibronectin-binding protein A and fibronectin-binding protein B from Staphylococcus aureus
FEBS J 2010 277 : 4490-4505
Stravalaci M, Beeg M, Salmona M, Gobbi M
Use of surface plasmon resonance to study the elongation kinetics and the binding properties of the highly
amyloidogenic Aβ(1-42) peptide, synthesized by depsi-peptide technique
Biosens Bioelectron 2010 [Epub ahead of print]
Taylor M, Moore S, Mayes J, Parkin E, Beeg M, Canovi M, Gobbi M, Mann D M A, Allsop D
Development of a proteolytically stable retro-inverso peptide inhibitor of beta-amyloid oligomerization as a potential
novel treatment for Alzheimer's disease
Biochemistry 2010 49 : 3261-3272
Terao M, Fratelli M, Kurosaki M, Zanetti A, Guarnaccia V, Paroni G, Tsykin A, Lupi M, Gianni' M, Goodall GJ,
Garattini E.
Induction of MIR-21 by retinoic acid in estrogen-receptor-positive breast carcinoma cells: biological correlates and
molecular targets.
J Biol Chem. 2010 [Epub ahead of print]
Tonutti L, Bononi E, Paris L, Breillout F, Corvaia N, Bailly C, Bazzoni G
Effect of microtubule-targeting drugs on cell-cell and cell-matrix junctions in tumor epithelial cells
Anticancer Drugs, in press 2010
Tonutti L, Manzi L, Tacconi M T, Bazzoni G
Eicosapentaenoic acid inhibits endothelial cell migration in vitro
J Angiogenes Res 2010 2 : 12-19
Forloni G, Pengo N, Monzani E, Cascio P, Cenci S, Sitia R, Salmona M
J Med Chem 2010 53 : 7452-7460
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RESEARCH ACTIVITIES
Laboratory of Biochemistry and Protein Chemistry
Development of new therapeutic strategies for the treatment of central
and peripheral amyloidosis
The development of an effective strategy for the prevention and cure of Alzheimer
disease and systemic amyloidosis is of great importance due to the absence of an
effective therapy. Their severity affects seriously the life of patients and their relatives.
The formation of amyloid fibrils and their deposition in specific tissues were for longtime considered the cause of the disease, however recent studies showed that soluble
oligomeric species are the actual culprits of the toxicity. The kinetics of protein
aggregation due to conformational modifications and the comprehension of genetic,
biochemical and structural determinants at the basis of this transformation are very
important for unveiling the pathogenic process and the development of therapeutic
strategies. Aiming at developing simple models that enable monitoring the
conformational changes that preceds fibril deposition, we have designed and developed
a variety of synthetic peptides as deduced from the primary sequence of human
amyloidogenic proteins in their wild-type or mutated forms.
In collaboration with the Istituto Neurologico “Carlo Besta” of Milan we have identified
a mutated form of beta-amyloid (A673V) that displays amazing biological features
since it binds to wild-type beta-amyloid and inhibits amyloid formation and the onset of
the disease. This observation opens new therapeutic perspectives both for genetic and
sporadic forms of Alzheimer disease based upon the use of protein fragments
containing this mutation or peptide-mimetic compounds. Moreover, we have
synthesized several Abeta peptides containing the same mutation and we have evaluated
its importance in the aggregation and amyloidogenic properties. Similar studies have
been carried out with prion protein and some amyloidogenic proteins responsible of
peripheral amyloidosis. The first approach for the development of candidate drugs
contemplates the development of molecules capable to interfere with oligomeric species
following direct interaction with protein molecules disrupting its beta-sheet
conformation or the fibrillary aggregates. This activity requires in vitro studies with cell
free models to determine the conformational features of amyloidogenic peptides, their
secondary structure, the hydrogen-deuterium exchange, the resistance to digestion by
proteases, the aggregation propensity and amyloidogenic characteristcs.
To understand the molecular and biochemical mechanisms of action underlying the
cause of the cytotoxic action, peptides are used for in vitro studies in variety of cellular
models trying to correlate their physical features and the biological effect. Moreover,
the subcellular distribution of peptides and their molecular targets are also investigated.
We have reported that tetracyclines are new candidates as anti-amyloidogenesis drugs,
in particular they disrupt amyloid tangles and increase the sensitivity of PrP to
proteinase K digestion. Tetracycline are able to inhibit neuronal cell death and astroglial
prolipheration induce by PrP peptides and, in animal model of disease, they prolong the
survival of animals inoculated with PrP.
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The nematode Caenorhabditis elegans as experimental model
to
investigate in vivo the molecular mechanisms underlying the aggregation
of amyloidogenic proteins
The description of the molecular events underlying the in vivo amyloidogenesis is
crucial for the design of effective therapeutic strategies. To this end, in our laboratory
we use Caenorhabditis elegans as experimental model since it offers the unique
opportunity to analyze the genetic and molecular functions of human disease-related
genes in vivo. This nematode offers also the major advantages of the easy generation of
transgenic strains expressing human genes, the production of distinct phenotypes offers
insight into the biology of the disease and help to elucidate fundamental cellular
processes related to it. In particular, it is possible to correlate the phenotype of the
transgene with the disease insurgence, the degeneration, the protein expression and its
aggregation into the oligomeric or fibrillar forms.
Different transgenic strains expressing various fragments of human β amyloid in
neurons or in muscles are available in our laboratory. We also developed new
transgenic strains expressing A-V or A-T mutated peptides in position 2 under a
neuronal promoter, to evaluate their in vivo effects.
The expression of these peptides results in the cytoplasmic amyloid β inclusion and in
the appearance of progressive phenotypes related to the disease. In these C. elegans
strains, amyloid aggregates were observed and they are similar to those observed in the
brain of patients with AD or in muscles of patients with sporadic forms of Inclusion
Body Myositis, the most common myopathy. These models were already used to study
the relationship between Aβ sequence, amyloid formation and toxicity. A transgenic C.
elegans strain producing only the oligomeric form of the β amyloid protein was also
available representing a good predictive model for the investigation of drugs
specifically interfering with oligomers. C. elegans is also applied to investigate the
molecular mechanisms underlying some systemic amyloidosis, like those caused by
tissue deposition of immunoglobulin light chain or β2 microglobuline. Using this
multidisciplinary genomic and molecular integrated approach, we will obtain important
informations for the development and validation of innovative therapeutic strategies and
for the comprehension of the in vivo molecular functions of genes related to human
amyloidosis.
Nanoparticles in pharmacology: new diagnosis and therapy systems
The clinical development of molecules with promising therapeutic activity for the
treatment of diseases with unfavorable prognosis, is sometimes limited by the
molecules’ scarse bioavailability, by a rapid clearance, or the difficulty to cross certain
biological barriers, and last but not least, by the onset of severe side effects. To
overcome those hurdles the usage of biocompatible and biodegradable nanoparticles
(NPs) has been suggested. These NPs “protect” the active compounds loaded in the NPs
and act as controlled release devices.
Various types of NPs, both lipidic and polymeric, have been used in our laboratories to
enhance the release kinetics of the loaded molecules. Modifying the NPs’ surfaces with
particular peptides, antibodies and ligands, it has been possible to change their
biodistribution with respect to healthy and tumoral tissues
Our laboratory has evaluated, within the European project “Nanoparticles for therapy
and diagnosis of Alzheimer Disease” (NAD), the ability of different NPs of lipidic and
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polymeric nature to cross the blood-brain-barrier in vivo, to deliver anti-amiloidogenic
drugs to the brain. Furthermore, in collaboration with Politecnico di Milano and the
Swiss Federal Institute of Technology (ETH), new polymeric NPs have been
synthesized and their stability has been evaluated in biological fluids. Utilizing non
degradable NPs loaded with fluorescent dyes and/or paramagnetic molecules,
biodistribution studies have been performed in vivo employing Optical Imaging
techniques, Magnetic Resonance Imaging, optical and fluorescence microscopy. These
results will represent the basis for the design of NPs for early diagnosis of specific
diseases and for monitoring the therapy’s efficacy.
A deeper analysis of the parameters influencing the in vitro and in vivo drug release
from NPs are currently in progress. All obtained data will be used for the development
of mathematical models able to describe the pharmacokinetics of the NPs and of the
released compounds.
Preclinical imaging to improve the translation of results from mice to
patients
One of the main goal of the modern pharmacological research is to translate the results
obtained form preclinical models (cells and animals) to the clinical practice. The use of
non invasive instruments of screening has been more and more taking place either for
the diagnosis or to follow the efficacy of therapy in different clinical fields. The recent
development of in vivo imaging instruments dedicated to small rodents may therefore
allow to perform the same strategy of investigation already at preclinical level.
The Department of Biochemistry and Molecular Pharmacology has been developing a
series of experimental procedures aimed at coupling the results obtained by different in
vivo analyses (Magnetic Resonance Imaging, micro Computerized Tomography,
Fluorescent Molecular Tomography, Ocular Coherence Tomography) to the data
obtained by ex vivo studies (histology and/or immunohistochemistry). The integration
of these two areas can be identified as “preclinical imaging”.
This approach has been recently exploited to better investigate the clinical progression
of an interesting of model of neuronal ceroid lipofuscinosis, the mnd mouse. Analyses
carried out by fluoro-angiography and ocular coherence tomography allowed us to
characterize the progressive ocular inflammation and retinal degeneration affecting mnd
mice by simply following the same group animals during the time. Histological
characterization, performed by sacrificing animals at different time points, confirmed
these data and highlighted that lipofuscin accumulation, apoptosis of retinal cells and
reactive gliosis, are the cellular bases for the alteration revealed by in vitro imaging
analyses. A series of experiments will be carried out, by three different degree of
resolution, to better characterize this peculiar accumulation of autofluorescent ceroid
and lipofuscin-like material in brain and in eyes of mnd mice. In collaboration with the
Department of Oncology, we investigated about the anatomical localization of
autofluorescent material by a non invasive approach (fluorescent molecular
tomography). Such strategy allowed us to follow the progressive deposition of
autofluorescent material in the same group of mice at different ages. A marked
fluorescence was first observed in the posterior area of forebrain and in the cerebellar
region. In older animals the fluorescent signal spread in the whole brain parenchyma
and in other peripheral organs.
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Histological analysis (by the observation of the autofluorescence in 20 µm thick
sections) confirmed the reliability of in vivo imaging and evidenced a selective
deposition of autofluorescent material in neurons. Finally, electron microscopy studies
(in collaboration with the Department of Cardiovascular Diseases) showed that
lipofuscin-like bodies were mainly segregated in swollen lysosomes and distributed in
the whole cytoplasm of neurons.
Contrast Enhanced (MnCl2) MRI experiments have demonstrated that in the
hippocampus of mnd micea marked process of hyperexcitability occurs before motor
symptom onset. Hippocampal hyperexcitabilty was further confirmed by EEG analysis
(in collaboration with the Laboratory of Experimental Neurology) and by c-fos
immunohistochemistry. The body of knowledge emerging from all these experiments
allow us to propose the mnd mouse as a reliable model of Epilepsy with mental
retardation, one of the most common form of neuronal ceroid lipofuscinosis and
associated with mutation(s) of the same gene (cln8) responsible for the phenotypic
changes found in mnd mice.
In collaboration with the Unit of Cancer Clinical Pharmacology we evaluated, by
Gadolinium enhanced MRI, the growth of an orthotopically implanted human
glioblastoma in the brain parenchyma of nude mice.
In addition, the internalization of paramagnetic and fluorescent probes in human foetal
stem cells has allowed to track the fate of these cells once transplanted in cerebral
ventricles of healthy and diseased mice (more specifically in a model of amyotrophic
lateral sclerosis: the wobbler mouse). Other studies with dual “paramagneticfluorescent” are now in progress to follow the route of human fetal stem cells by MRI
and fluorescent molecular tomography in the same group of animals at different times
after transplantation.
Laboratory of Molecular Biology
The family of molybdo-enzymes
Molybdo-enzymes are proteins requiring a molybdo-pterin cofactor (molybdenumcofactor, MoCo) for their catalytic activity. Until a few years ago, it was believed that
the family of molybdo-enzymes consisted only of three members: sulfite oxidase,
aldehyde oxidase and xanthine oxidoreductase. In the last few years of research, our
laboratory has determined the structure of the genes coding for different
molybdoenzymes in rodents and humans. In particular, we demonstrated that rodents
are endowed with four different aldehyde oxidase (AOX1, AOX3, AOX4 and
AOX3L1) characterized by remarkable structural and functional similarity. The
physiological substrate(s) and the physiological function(s) of this group of protein have
not yet been identified, although it is known that aldehyde oxidases can oxidize
aliphatic and aromatic aldehydes into the corresponding carboxylic acids and to
hydroxylate different types of n-heterocyclic aromatic rings. The four different
aldehyde oxidases of rats and mice are the product of an equivalent number of genes
located at the short distance one from the other on the same chromosome. These genes
originated through a number of a synchronous gene duplication events. Our studies
aimed at the determination of the evolutionary processes underlying the development of
the genes coding for aldehyde oxidases allowed us to establish that the natural history of
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this gene family is made of duplication and suppression events. These evolutionary
processes resulted in the presence of variable number of aldehyde oxidases in different
genomes. Man is characterized by the presence of a single active gene (AOX1) and two
inactive pseudo genes clustered on chromosome 2. In the last years we have focused on
the functional definition of the different mouse aldehyde oxidases and our long term
aim is to establish the reasons underlying the disparity in the number of these enzymes
between humans and rodents. To this purpose, we generated two knockout animals for
the AOX4 and AOX3L1 genes. The AOX4 knockout mouse was characterized
phenotypically demonstrating minimal alterations of the epidermis. Indeed, the AOX4
knockout animal shows epidermal hypertrophy, which is associated with a peculiar
fragility of the corneal layer. At the biochemical level, we observed a deficiency in the
synthesis of retinoic acid in the two organs where AOX4 is present in significant
amounts (skin and Harderian glands). This observation is in line with the idea that
AOX4 may have a role in the metabolism of retinaldehyde to retinoic acid, the active
metabolite of vitamine A. Recently we gathered novel data indicating a role for AOX4
in the control of the adipose tissue homeostasis. The observation is of particular
importance also in man as human AOX1 seems to exert a similar effect in the synthesis
and deposition of lipids. Currently we are performing similar studies in a knockout
mouse for AOX3L1.
Retinoids in the treatment and chemoprevention of myeloid leukemia and
mammary carcinoma
Our laboratory has a long standing interest in defining the therapeutic potential of
natural and synthetic derivatives of retinoic acid, the active metabolite of vitamin A.
These compounds, commonly defined as retinoids, are characterized by cytodifferentiating, anti-proliferative and apoptotic effects which are at the bases of their
therapeutic activity in the context of myeloid leukemia and mammary carcinoma.
Retinoids are very active therapeutic agents, although they are endowed with dose
limiting side effects, particularly chronic administration. A rational clinical use of
retinoids calls for a better knowledge of the mechanisms of action underlying the antineoplastic action exerted by these compounds. In-depth knowledge is of fundamental
value for the design of novel retinoid-based treatment strategies characterized by
increased therapeutic index. We have a long-standing interest in the definition of the
molecular mechanisms regulating the activity of retinoic acid nuclear receptors, as they
may lead to the identification of pharmacological targets to be modulated in a specific
manner. Indeed, we believe that knowledge in this field may lead to the development of
rational combinations between retinoids and other pharmacologically active agents to be
used in the treatment of different tumor types. Such an approach has led us to the recent
identification of the prolyl-isomerase, PIN1 as a negative regulator of the retinoic acid
receptor, RARα. Pharmacological inhibitors PIN1 proved to be particularly effective in
sensitizing the leukemic cell to the anti-neoplastic activity of retinoids. These results
open up the possibility to develop combinations based on PIN1 inhibitors and retinoids
for the treatment of acute myeloid leukemia. Following the same type of logic, we have
recently demonstrated that the inhibition of the microRNA, miR21 in mammary
carcinomas positive for estrogen receptor is of the utmost importance in potentiating the
anti-proliferative activity of retinoids in this particular type of tumor. Finally, we
observed that the peculiar subgroup of mammary cancer positive for HER2 may benefit
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from retinoid-based treatment or associations between retinoids and inhibitors of HER2
receptor tyrosine kinase activity.
Laboratory of of Pharmacodynamics and Pharmacokinetics
Misfolding proteins and related diseases
One of the laboratory’s main research fields regards the diseases associated with protein
“misfolding”, i.e. the formation of aberrant tertiary conformations of proteins or
peptides, as a consequence of mutations, stress or aging. Besides the loss of the
protein’s physiological properties, the misfolding often results in new biochemical
properties, particularly the propensity to aggregate and form amyloid-like deposits. We
are particularly interested in Alzheimer’s disease (AD), in which there is aggregation of
amyloid-β (Aβ) peptides (Aβ1-40 and Aβ1-42, detectable in the amyloid plaques typical of
AD brain), and in spongiform encephalopathies, due to misfolding and aggregation of
the prion protein (PrP). Recent studies suggest that misfolding and the consequent
propensity to form toxic aggregates is common to different proteins and results in
different diseases (e.g. alpha-synuclein for Parkinson disease, poly-Q expansions for
Huntington disease, superoxide dismutase in amiotrophic lateral sclerosis, transthyretin
in systemic amyloidosis). Better knowledge of the molecular and cellular mechanisms
involved in these events is needed for the development of useful therapeutic strategies.
We have investigated the kinetics and the mechanisms underlying protein aggregation
in different experimental conditions, using different biochemical and chemical-physical
techniques. In particular, we applied surface Plasmon resonance (SPR) to analyze the
polymerization kinetics of Aβ1-42 fibrils (Stravalaci et al., Biosens Bioelectron, 2011), to
investigate the effects of Aβ mutations (Di Fede et al., Science, 2009), and to test
molecules with potential anti-amyloidogenic activities (Di Fede et al., Science, 2009,
Taylor et al., Biochemistry, 2010). We have also optimized experimental protocols to
study the different aggregation states of amyloidogenic peptides, including the soluble
oligomers thought to be the most toxic species. This enabled us, for example, to
describe the interaction between PrP and Aβ1-42 oligomers (Balducci et al., PNAS,
2010).
Our laboratory is a partner in a European network (FP7), which plans to develop
nanoparticles for therapy and diagnosis of Alzheimer disease (NAD), focusing on Aβ as
the target. We have evaluated the affinities of functionalized nanoparticles for Aβ1-42
fibrils, immobilized on the SPR sensor surface (Gobbi et al., Biomaterials, 2010;
Mourtas et al., Biomaterials, 2011). We are also involved in examining the
pharmacokinetic properties of these nanoparticles, especially their blood-brain barrier
passage. By studying both pharmacodynamic and pharmacokinetic properties of
nanoparticles our laboratory adds value in this expanding field of research .
Q10 coenzyme in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease involving
brainstem and spinal cord motoneurons, leading to complete paralysis of skeletal
muscles and early death, usually from respiratory failure. Mutations in the copper-zinc
superoxide dismutase (SOD1) gene are responsible of some forms of familial ALS, and
on this basis transgenic rodents have been generated, contributing significantly to our
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understanding of the pathogenic mechanisms of the disease. For example, transgenic
mice carrying the mutant SOD1, and showing motoneuron degeneration, have increased
oxidative stress associated with mitochondrial damage. The Q10 coenzyme (CoQ10, or
ubiquinone) is a major component of the mitochondrial respiratory chain, and its
reduced form ubiquinol has antioxidant proprieties. We are therefore investigating
whether there is a correlation between CoQ10 levels (measured in plasma and CNS) and
the disease progression and survival in SOD1 transgenic mice. We shall also
investigate whether Q10 supplementation has positive effects on the disease
progression. These studies are carried out in collaboration with the Laboratory of
Molecular Neurobiology (headed by Dr. C. Bendotti), which is leading most of the
research on ALS carried out at the “Mario Negri” Institute.
Synaptopathies
A number of observations suggest that the neuronal degeneration in “misfolding
diseases” is preceded by more subtle cellular dysfunctions of synaptic transmission
(synaptopathies), in many cases thought to be caused by the toxic aggregates described
above. In collaboration with other laboratories of the Mario Negri Institute (e.g. the
“Neurobiology of Prions” laboratory , headed by Dr. R. Chiesa), we are characterizing
glutamatergic and GABAergic transmission in brains of transgenic animal models of
these diseases, using the biochemical methods available in our laboratory.
Glutamatergic and serotoninergic neuropharmacology
Our laboratory has long experience in neuropharmacological studies, particularly on the
glutamatergic and serotoninergic neurotransmission systems. Specific biochemical
techniques to analyze the main mechanisms of synaptic transmission (neurotransmitter
release, binding to receptors and reuptake by specific transporters) are used in
collaboration with chemico-pharmaceutical departments, for the characterization of new
molecules acting on these mechanisms.
Molecular interactions SPR, an advanced technique specifically developed for the study of molecular
interactions, enables us to make useful contributions to different projects in
collaboration with other laboratories of the Institute (Gesuete et al., Annals of
Neurology, 2009; Colombo et al., J Biol Chem, 2010; Deban et al., Nature Immunology,
2010; Provenza et al., FEBS J, 2010). In particular, one of these projects, carried out in collaboration with the Inflammation
and Nervous System Disease Laboratory headed by Dr. M.G. De Simoni, is
investigating the idea that MBL may play a role in ischemia-induced damage (Gesuete
et al., Annals of Neurology, 2009), where MBL inhibitors might have significant antiischemic effects. Studies include the synthesis of new potential MBL ligands
(Department of Organic and Industrial Chemistry, University of Milan, headed by Dr.
A. Bernardi), evaluation of their ability to interact with MBL in vitro (through SPR
studies in our laboratory) and their anti-ischemic effects in vivo (De Simoni’s
laboratory).
The laboratory is currently collaborating with the “Mario Negri ” Institute in Bergamo
(laboratories of Dr. M. Morigi and Dr. M. Noris) in research into new molecular
mechanisms involved in the haemolytic uremic syndrome (HUS) and thrombotic
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thrombocytopenic purpura (TTP). We are using SPR to investigate whether new
protein-protein interactions contribute to the link between thrombosis and complement
cascade activation.
Our laboratory is a partner in a multicentre triennial project sponsored by the Regione
Lombardia (Metadistretti) entitled “Miniaturized System for Molecular Diagnostic and
Proteomic of Sepsis Based on Integration of Surface Plasmon Resonance”, aiming at
identifying new biomarkers of sepsis and exploiting new SPR systems as low cost, rapid
diagnostic tools. Our laboratory will be responsible for biomarker identification and
validation, measuring them in plasma with our conventional SPR system.
Laboratory of Molecular Pathology
In vitro models for investigating motor neuron pathologies
Mutant forms of specific proteins play a key role in many neurodegenerative diseases.
Experimental models in vivo and in vitro are sorely needed to study the effects of these
toxic proteins. The motor neuronal cell line NSC-34, a widely used model to study
motor neuron degeneration, is available in the laboratory. We have applied the pTet-Off
system to control gene expression through the level of tetracyclines to the NSC-34 cell
line establishing a new cell line (NSC-34 tTA40) that stably expresses the
transactivating protein tTA. This cell line is suitable to study the pathogenic
mechanisms of motor neuron diseases after transient/stable transfection with genes of
interest for these pathologies.
The NSC-34 and the NSC-34 tTA40 cell lines were used to obtain in vitro models to
study the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). Mutant forms
of superoxide dismutase 1 are responsible for some of the familial forms of ALS. We
developed NSC-34-based cell lines expressing constitutively or conditionally human
G93A mutant superoxide dismutase 1 (G93ASOD1).
Novel intracellular targets in the selective degeneration of motor neurons
in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disease
characterized by loss of motor neurons. The management of this disease remains
essentially supportive and symptomatic. Understanding the mechanisms underlying the
disease is a way to favor more efficient therapeutic strategies. We utilized our cell
models to investigate the biochemical-molecular mechanisms underlying the alterations
of mitochondrial morphology observed in the early stages of the disease in the motor
nerve terminals of ALS patients and in the murine models of the disease. We showed
that motor neurons are selectively susceptible to mitochondrial damage induced by a
mutant form of human superoxide dismutase 1 (G93ASOD1) and that this damage was
modulated by the extent of expression of the mutant protein.
Furthermore the expression of G93ASOD1 protein increased the susceptibility of motor
neurons to inhibitors of the electron transport chain (ETC) and to oxidants. Exposure to
drugs or exogenous compounds impairing the ETC could thus be a risk factor to motor
neurons of individuals carrying mutant superoxide dismutase 1.
We have shown that in motor neuronal cells the activity of glutamate cysteine ligase,
the rate limiting enzyme for glutathione biosynthesis, was modulated by the level of
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G93ASOD1. As a consequence, the level of glutathione, the main cell antioxidant,
increased or decreased. A variation in the level of glutathione may influence the
formation of nitrated proteins, a pathogenic mechanism in ALS, which was investigated
in collaboration with the laboratory of Translational Proteomics.
Cytochrome P-450 superfamily
Cytochrome(s) P-450 have evolved into a large superfamily which plays a major role in
the metabolism of drugs and other chemicals. The majority of existing drugs depends on
the P-450 system for terminating their biological effects or for side effects or adverse
reaction. The laboratory has a long-standing interest in the induction/degradation
mechanisms of specific cytochrome P-450 families due to drug administration or to
disease states.
Activation of enzymes of the heme metabolic pathway (heme oxygenase
system, biliverdin reductase) as a protective response to stress
The enzymatic system of heme oxygenase (HO) is devoted to cellular degradation of
heme containing molecules, like cytochromes and hemoglobin, and to recycling of iron.
Products formed by the catalytic activity of HO - carbon monoxide and bile pigments are important regulating factors in the cell. An increase of HO activity (which is usually
sustained by activation of the inducible form HO-1) is now considered a protective
mechanism against untoward stimuli particularly when oxidative stress is involved. In
the past, the laboratory of Molecular Pathology identified cytokines as inducers of HO
activity and as transcriptional activators of the HO-1 gene. We are currently
investigating the functional significance of HO-1 activation in neurodegeneration.
Laboratory of Translational Proteomics
Nitrative stress and protein aggregation in amyotrophic lateral sclerosis: a
proteomic approach
The molecular mechanisms at the basis of neurodegenerative diseases including the
genetically linked ones, such as amyotrophic lateral sclerosis (ALS), are still unknown.
However, there is evidence that nitrative stress and protein aggregation play central
roles in the pathogenesis of such diseases. In collaboration with the Laboratory of
Molecular Neurobiology at the Mario Negri Institute in Milano we conducted proteome
analysis of an animal model of familial ALS (fALS). We focused the attention on the
analysis of protein expression changes and protein modifications, such as tyrosine
nitration (marker of nitrative stress), in a transgenic mouse, which over-express human
mutated (G93A) superoxide dismutase (SOD1). We analyzed, by proteomic tools,
spinal cord of presymptomatic G93A SOD1 mice, we identified nitrated proteins and
quantified the level of nitration for each protein in comparison with healthy controls.
We revealed that there was a substantial increase of the nitration level in at least five
proteins: actin, alpha and gamma enolase, ATP synthase and a chaperone protein,
HSC71. The alteration of the function of these proteins, due to the oxidative
modification, may have important consequences on the cellular metabolism/catabolism,
signaling pathways and phosphorylation cascades, therefore may be at the basis of the
molecular mechanisms leading to neurodegeneration. Regarding the aggregation
studies, we carried out a proteomic analysis of the protein composition of the insoluble
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fraction, as a model of protein aggregates, from the fALS mouse model at different
disease stages. We identified several proteins enriched in the detergent-insoluble
fraction already at a preclinical stage, including intermediate filaments, chaperones and
mitochondrial proteins. Aconitase, HSC70 and cyclophilin A were also significantly
enriched in the insoluble fraction of spinal cords of ALS patients. Moreover, we found
that the majority of proteins in mice and HSP90 in patients were tyrosine-nitrated. In
collaboration with the Laboratory of Molecular Pathology at the Mario Negri Institute
in Milan we therefore investigated the role of nitrative stress in aggregate formation in
fALS-like murine motor neuron-neuroblastoma (NSC-34) cell lines. By inhibiting nitric
oxide synthesis the amount of insoluble proteins, particularly aconitase, HSC70,
cyclophilin A and SOD1 can be substantially reduced. In conclusions, analysis of the
insoluble fractions from cellular/mouse models and human tissues revealed novel
aggregation-prone proteins and suggests that nitrative stress contribute to protein
aggregate formation in ALS.
Identification of biomarkers of ALS
In collaboration with the Laboratory of Molecular Neurobiology at the Mario Negri
Institute, “Fondazione Salvatore Maugeri”, IRCCS, Milano, and NEuroMuscular
Omnicentre (NEMO), Niguarda Ca’ Granda Hospital, Milano we are conducting a
series of studies with the aim to identify biomarkers of ALS useful in diagnosis and
prognosis and to unravel pathogenetic mechanisms, still unknown. Increased levels of
nitrotyrosine in the central nervous system have been found in patients and mouse
models of fALS, suggesting a possible use of nitrated proteins as biomarkers. We
analyzed peripheral blood mononuclear cells (PBMCs), easily accessible samples, from
sporadic ALS (sALS) patients and a rat model of fALS (a) to establish whether an
increased level of nitrated proteins was present in PBMCs, too, and (b) to identify
possible candidate biomarkers. With a proteomic approach, we identified for the first
time the major over-nitrated proteins in PBMCs from patients and rats at different
disease stages. In the rats, their increased levels were measured already at a
presymptomatic stage. Among them, actin, ATP synthase, and vinculin overlap between
sALS patients and the rat model. Both in patients and in rats the nitration level is at least
twice than the one in the controls. Interestingly, in a previous study, actin and ATPase
have been found over nitrated in the spinal cord of a mouse model of fALS before
disease onset, suggesting their possible involvement in motor neuron degeneration. In
conclusion, we observed that an increased level of nitrated proteins was not restricted to
the spinal cord but also was present in peripheral cells of patients and an animal model,
and that nitrated proteins are promising candidate biomarkers for early diagnosis of
ALS. We are now carrying out a global proteomic analysis of PBMC of sALS patients
to identify other protein alterations to be used as disease biomarkers.
Proteomic analysis of a cellular model of fatal familial insomnia
The prion protein (PrP) is a glycosyl-phosphatidyl-inositol (GPI)-anchored membrane
glycoprotein that plays a vital role in prion diseases, a class of fatal neurodegenerative
disorders of humans and animals. Approximately 20% of human prion diseases display
autosomal dominant inheritance and are linked to mutations in the PrP gene on
chromosome 20. PrP mutations are thought to favor the conformational conversion of
PrP into a misfolded isoform that causes disease by an unknown mechanism. The PrP
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mutation D178N/M129 is linked to fatal familial insomnia, which causes severe sleep
abnormalities and autonomic dysfunction. In collaboration with the Laboratory of
Neurobiology of Prions at the Mario Negri Institute in Milan we found that mutant PrP
accumulates abnormally in the endoplasmic reticulum and Golgi of transfected
neuroblastoma N2a cells. We then investigated the impact of intracellular PrP
accumulation on cellular homeostasis, we did a 2D gel-based differential proteomic
analysis. We used wide-range immobilized pH gradient strips, pH 4-7 and 6-11, to
analyze a large number of proteins. We found changes in proteins involved in energy
metabolism, redox regulation and vesicular transport. Rab GDP dissociation inhibitor
alpha (GDI) was one of the proteins that changed most. GDI regulates vesicular protein
trafficking by acting on the activity of several Rab proteins. We found a specific
reduction in the level of functional Rab11 in mutant PrP expressing cells, associated
with impaired post-Golgi trafficking. Our data are consistent with a model by which
mutant PrP induces over-expression of GDI activating a cytotoxic feedback loop which
leads to protein accumulation in the secretory pathway.
Laboratory for the Study of Biological Systems
System-level analysis of protein interactions in the epithelial junctional
complex
Inter-cellular junctions form the apical junctional complex and mediate adhesion
between adjacent cells, thus representing the cellular basis for tissue cohesion (for
instance, the epithelial lining of the intestine). In order to acquire system-level
understanding of the apical junctional complex, we have studied (using a
methodological approach of ‘network analysis’) all the protein interactions that have
been described at the junctions in epithelial cells of human origin. We also found that
proper ‘hubs’ (i.e., very rare proteins with an exceedingly high number of interactions
with other proteins) were absent from the junctional network. Nevertheless, we
observed that the most connected (albeit non-hub) proteins were also essential proteins.
In addition, we have detected modules within the junctional networks (i.e., densely
inter-connected groups of proteins). Analysis of the modules has highlighted general
organizing principles of the junctional complex, thus confirming the usefulness of
network analysis for studying the components and the interactions of the cell.
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DEPARTMENT OF EPIDEMIOLOGY
STAFF
Head
Carlo LA VECCHIA, M.D.
Laboratory of General Epidemiology
Head
Carlo LA VECCHIA, M.D.
Cancer Epidemiology Unit
Head
Cristina BOSETTI, Mat.Sci.D.
Lifestyle Habits and Prevention Unit
Head
Liliane CHATENOUD, Biol.Sci.D.
Epidemiology for Clinical Research Unit
Head
Silvano GALLUS, Comp.Sci.D.
Laboratory of Epidemiological Methods
Head
Eva NEGRI, Mat.Sci.D.
Laboratory of Epidemiology of Chronic Diseases
Head
Alessandra TAVANI, Biol.Sci.D.
Laboratory of Medical Informatics
Head
Eugenio SANTORO, Comp.Sci.D.
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CURRICULA
Carlo La Vecchia received his medical degree from the University of Milan and a master of science
degree in clinical epidemiology from Oxford University. He is recognized worldwide as a leading
authority in cancer etiology and epidemiology.
Work experiences: Presently, he is Chief of Epidemiology at the Mario Negri Institute in Milan, Italy and
on the faculty of Medicine at the University of Milan. Dr. La Vecchia serves as an editor for numerous
clinical and epidemiologic journals. He is among the most renowned and productive epidemiologists in
the field with over 1,560 peer-reviewed papers in the literature and is among the most highly cited
medical researchers in the world, according to ISIHighlyCited.comsm, the developer and publisher of the
Science Citation Index. Dr. La Vecchia is an Adjunct Professor of Medicine at Vanderbilt Medical Center
and the Vanderbilt-Ingram Cancer Center and of Epidemiology at the University of Lausanne, CH.
Dr. La Vecchia is a temporary advisor at the International Agency for Research on Cancer IARC/WHO
and at the World Health Organization in Geneva, and a registered journalist in Milan. He was Adjunct
Associate Professor of Epidemiology at Harvard School of Public Health between 1996 and 2001.
Areas of interest: Dr. La Vecchia’s main fields of interest include cancer epidemiology and the risk
related to diet, tobacco, oral contraceptive use and occupational or environmental exposure to toxic
substances; and analysis of temporal trends and geographical distribution of mortality from cancer,
cardiovascular diseases, perinatal and other selected conditions.
Eva Negri got a degree in Mathematics in 1985 at the University of Milan, School of Mathematics.
Work experiences: Since 2007: Laboratory Chief, Unit of Epidemiologic Methods, Department of
Epidemiology; 1992-2006: Unit Chief, Unit of Epidemiologic Methods, Laboratory Epidemiology; since
1990-1992: Researcher at the Laboratory of Epidemiology; 1984-1990: Collaborator of the Laboratory of
Epidemiology.
Areas of interest: Design, conduction and analysis of epidemiologic studies on chronic diseases (e.g.
cancer and myocardial infarction) and injuries, analysis of mortality of cohorts of workers, analysis of
temporal trends and geographic distribution of mortality from cancer, cardiovascular disease, injuries and
other selected conditions, analysis of national health surveys, application of linear modeling techniques to
the analysis of epidemiological data, collaborative re-analyses and meta-analyses of epidemiological
studies.
Awards: EEC scholarship for postgraduate training in Epidemiology (1988).
•
Negri E, La Vecchia C, Pelucchi C, Tavani A The risk of acute myocardial infarction after stopping drinking Prev Med
2005; 40: 725-728
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Negri E, Pelucchi C, Talamini R, Montella M, Gallus S, Bosetti C, Franceschi S, La Vecchia C Family history of cancer
and the risk of prostate cancer and benign prostatic hyperplasia Int J Cancer 2005; 114: 648-652
•
Negri E, Little D, Boiocchi M, La Vecchia C, Franceschi S. B-cell non-Hodgkin’s lymphoma and hepatitis C virus
infection: A systematic review Int J Cancer 2004; 111: 1-8
•
Negri E, Ron E, Franceschi S, La Vecchia C, Preston-Martin S, Kolonel L, et al. Risk factors for medullary thyroid
carcinoma: A pooled analysis Cancer Causes Control 2002; 13: 365-372
•
Levi F, La Vecchia C, Boyle P, Lucchini F, Negri E Western and eastern European trends in testicular cancer mortality
Lancet 2001; 357: 1853-1854
Alessandra Tavani - degree in Biological Sciences, University of Milan, Italy (July 1977);
Pharmacological Research Specialist, “Mario Negri” Institute for Pharmacological Research, Milan,
Italy (July 1979).
Work experiences: 1979-81: Researcher at the laboratory of Drug Metabolism, “Mario Negri” Institute
for Pharmacological Research. 1981: Researcher at the Unit for Research on Addictive Drugs (director
prof. H.W. Kosterlitz), University of Aberdeen, Scotland, U.K. 1982-1990: Head of the Unit of Opioid
Neuropharmacology, “Mario Negri” Institute for Pharmacological Research. 1990: Researcher at the
Unit of Clinical Perinatal Pharmacology, “Mario Negri” Institute for Pharmacological Research. From
1991-2006: Head of the Unit of Epidemiology of Chronic Diseases of the Laboratory of Epidemiology,
“Mario Negri” Institute for Pharmacological Research. 2007-: Head of the Laboratory of Epidemiology
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of Chronic Diseases of the Department of Epidemiology, “Mario Negri” Institute for Pharmacological
Research.
Areas of interest: Epidemiology of cancer and coronary heart disease. Organization of case-control
studies and cohort studies on cancer and coronary heart disease, including biological sample collection.
Analyses of risk factors related to genetic factors and lifestyles, particularly coffee, diet, physical activity.
Awards: "Rafaelsen Scholar Award" from the Collegium Internationale Neuro-Psychopharmacologicum
(CINP), 16th Meeting, Munich (F.R.G.), 1988.
•
•
•
•
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Bravi F, Scotti L, Bosetti C, Gallus S, Negri E, La Vecchia C, Tavani A. Coffee drinking and endometrial cancer risk: a
metaanalysis of observational studies. Am J Obstet Gynecol 2009; 200: 130-135
Herrero R, Castellsague X, Pawlita M, Lissowska J, Kee F, Balaram P, Rajkumar T, Sridhar H, Rose B, Pintos
J, Fernandez L, Idris A, Sanchez M J, Nieto A, Talamini R, Tavani A, et al. Human papillomavirus and oral cancer: The
International Agency for Research on Cancer Multicenter Study. J Natl Cancer Inst 2003; 95: 1772-1783
Galeone C, Tavani A, Pelucchi C, Turati F, Winn D M, Levi F, Yu G - P, Morgenstern H, Kelsey K, Dal Maso L, Purdue
M, McClean M, Talamini R, Hayes R B, Franceschi S, Schantz S, Zhang Z F, Ferro G, Chuang S - C, Boffetta P, La
Vecchia C, Hashibe M. Coffee and tea intake and risk of head and neck cancer: pooled analysis in the international head
and neck cancer epidemiology consortium. Cancer Epidemiol Biomarkers Prev 2010 ; 19: 1723-1736
Galeone C, Turati F, La Vecchia C, Tavani A. Coffee consumption and risk of colorectal cancer: a meta-analysis of casecontrol studies. Cancer Causes Control 2010 ; 21: 1949-1959
Galeone C, Turati F, La Vecchia C, Tavani A. Coffee consumption and risk of colorectal cancer: a meta-analysis of casecontrol studies. Cancer Causes Control 2010 ; 21: 1949-1959
Eugenio Santoro got his degree in Computer Science in 1990 at the Milan University. He started to
work at the “Mario Negri” Institute in 1985 as a research fellow. He was Head of the Applied Statistics
and Informatics Unit and of the Applied Statistics and Informatics laboratory, which was part of the
Department of Cardiovascular Research. Since 2001 he is Head of the Laboratory of Medical
Informatics that is currently part of the Department of Epidemiology. His main areas of interest have
been biostatistics and clinical informatics with the development of software for data management and
data analyses of large scale clinical trials in cardiology, such as the GISSI studies (Gruppo Italiano per
lo Studio della Sopravvivenza nell’Infarto miocardico). His main current area of interest is the Internet,
and more recently the web 2.0, the social media, and their application in the medical field, in clinical
research, and in medical education through the development of health related websites. He is author or
co-author of more than 200 scientific papers published in peer reviewed journals, and of more than 70
scientific abstracts submitted to the main international meetings in the cardiology and in the computer
science fields. He is also author of three books (available in Italian) about the use of the Internet in
medicine (“Web 2.0 and medicine”, “Guida alla medicina in rete” and “Internet in medicina. Guida
all’uso e applicazioni pratiche”, published by the Pensiero Scientifico Editore, Rome) and of one section
about Internet and medicine, included in one of the most important italian medical encyclopedia
(“Enciclopedia Medica Italiana”, UTET 2007). He also collaborates to the publication of the Italian
National Bioethics Committee’s guidelines about ethics, health, and the new information technologies.
•
Santoro E. "Web 2.0 e Medicine: how social networks, podcasts, wikis and blogs are transforming communication, care,
and education in health”. Il Pensiero Scientifco Editore, Roma 2009.
•
Santoro E., Tinazzi A.“Clinical Trials Data Management”. In “Clinical Trials Handbook” (Wiley 2009, Edited by Gad
S.C.).
•
Santoro E. Podcast, wiki e blog: il web 2.0 al servizio della formazione e dell’aggiornamento del medico. Recenti Prog
Med 2007;98:484-494.
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Santoro E, Rossi Valentina, Pandolfini C, Bonati M. DEC-NET: The development of the European register of clinical
trials on medicines for children. Clin Trials 2006; 3: 366-375
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Clivio L, Tinazzi A, Mangano S, Santoro E. The contribution of information technology: Towards a better clinical data
management. Drug Dev Res 2006; 67: 245-250
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Santoro E. Internet and information on breast cancer: an overview. Breast 2003; 12: 424-431
Cristina Bosetti got her degree in Mathematics in 1994 at the University of Milan, School of
Mathematics, and the Post-Graduate Diploma in Pharmacological Research in 1999 at the “Mario Negri”
Institute for Pharmacological Research in Milan.
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Work experiences: She is Head of the Unit of Cancer Epidemiology, Department of Epidemiology,
Istituto di Ricerche Farmacologiche “Mario Negri”, Milan since 2005. Previous work experiences
include: Visiting scientist at “Life style and cancer group” of the International Agency for Research on
Cancer (IARC), Lyon, France (Oct 2009); Collaboration with the “International Epidemiology Institute”,
Rockville, MD, USA (2002-2009); Visiting scientist at the Unit of “Field and intervention studies”,
IARC, Lyon, France (Sept. 2000/June 2001); Visiting scientist at the Department of Epidemiology,
Harvard School of Public Health, Boston, MA (Sept-Nov 1998); Researcher at the Laboratory of
Epidemiology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan (1998-2005); Researcher at the
Laboratory of Mother and Child Health, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan
(1996-1997).
Areas of interest: Epidemiology of cancer, cardiovascular diseases and other chronic conditions. In
particular case-control studies on cancers of the upper respiratory and digestive sites, thyroid, breast,
hormone-related cancers, and on ischemic heart disease; analysis of risk related to diet, alcohol, tobacco,
reproductive and hormonal factors, occupational and environmental exposure to toxic substances, through
the application of generalized linear models; meta-analysis and systematic reviews of the epidemiologic
evidence on cancer risk in relation to various (environmental) exposures .
She is author/coauthor of more than 230 publications on peer-reviewed scientific journals publications on
peer-reviewed scientific Journals cited in PubMed/MEDLINE. Mean I.F.: 3.8. H-index: 34 (on Google
Scholar or SCOPUS).
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Bosetti C, Scelo G, Chuang SC, Tonita JM, Tamaro S, Jonasson JG, Kliewer EV, Hemminki K, Weiderpass E, Pukkala
E, Tracey E, Olsen JH, Pompe-Kirn V, Brewster DH, Martos C, Chia KS, Brennan P, Hashibe M, Levi F, La Vecchia C,
Boffetta P. High constant incidence rates of second primary cancers of the head and neck: A pooled analysis of 13 cancer
registries. Int J Cancer. 2010 Sep 7. [Epub ahead of print]
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Bosetti C, Bertuccio P, Chatenoud L, Negri E, Levi F, La Vecchia C. Childhood cancer mortality in Europe, 1970-2007.
Eur J Cancer. 2010;46:384-94.
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Bosetti C, Gallus S, Peto R, Negri E, Talamini R, Tavani A, Franceschi S, La Vecchia C. Tobacco Smoking, Smoking
Cessation, and Cumulative Risk of Upper Aerodigestive Tract Cancers.Am J Epidemiol. 2007; 167:468-73.
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Bosetti C, Malvezzi M, Chatenoud L, Negri E, Levi F, La Vecchia C. Trends in cancer mortality in the Americas, 19702000. Ann Oncol 2005; 16: 489-511.
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Bosetti C, Spertini L, Parpinel M T, Gnagnarella P, Lagiou P, Negri E, et al. Flavonoids and breast cancer risk in Italy.
Cancer Epidemiol Biomarkers Prev 2005; 14: 805-808.
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Smith J S, Herrero R, Bosetti C, Munoz N, Bosch F X, Eluf-Neto J, et al. IARC Multicentric Cervical Cancer Study
Group Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl
Cancer Inst 2002; 94: 1604-1613.
Liliane Chatenoud Doctor in Science Biology, University of Milan (1987); Postgraduate Doctor in
Health Statistics University of Milan (1995).
Work experiences: Since Sept. 2005: Unit Head, “Lifestyle and Prevention”, Department of
Epidemiology. 1993-2005: Researcher at the Laboratory of Epidemiology; 1988-1990: Staff Statistician
Bracco S.p.A., Milan.
Areas of interest: Epidemiological studies on obstetric diseases. Dermato-epidemiology. Cancer
epidemiology (case-control studies on cancers of the breast, female genital tract). Analysis of temporal
trends and geographical distribution of perinatal, infant mortality, cancer and other selected conditions
(over 150 publications on these topics, 1993-2005).
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Chatenoud L, Malvezzi M, Pitrelli A, La Vecchia C, Bamfi F. Asthma mortality and long-acting beta2-agonists in five
major European countries, 1994-2004. J Asthma 2009 46 : 546-551
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Naldi L, Chatenoud L Registry research in dermatology. Dermatol Clin 2009 27 : 185-19
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Naldi L, Chatenoud L, Belloni A, Peserico A, Balato N, Virgili A R, Bruni P L, Ingordo V, Lo Scocco G, Solaroli C,
Schena D, Di Landro A, Pezzarossa E, Arcangeli F, Gianni C, Betti R, Carli P, Farris A, Barabino G F, La Vecchia C,
Parazzini F Medical history, drug exposure and the risk of psoriasis. Evidence from an Italian case-control study
Dermatology 2008 216 : 125-132
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Valentini L G, Casali C, Chatenoud L, Chiaffarino F, Uberti Foppa C, Broggi G Surgical site infections after elective
neurosurgery: a survey of 1747 patients. Neurosurgery 2008 62 : 88-95
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Chatenoud L, Mosconi P, Malvezzi M, Colombo P, La Vecchia C, Apolone G. Impact of a major thermoelectric plant on
self-perceived health status. Prev Med. 2005;41:328-33.
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•
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Naldi L, Chatenoud L, Linder D, Belloni Fortina A, Peserico A, Virgili AR, et al. Cigarette smoking, body mass index,
and stressful life events as risk factors for psoriasis: results from an Italian case-control study. J Invest Dermatol.
2005;125:61-7.
Bosetti C, Malvezzi M, Chatenoud L, Negri E, Levi F, La Vecchia C. Trends in cancer mortality in the Americas, 19702000. Ann Oncol 2005; 16: 489-511.
Silvano Gallus was born in Milan on the 20th of November 1970, and got his degree in Computer
Science in 1999 at the University of Milan.
Work experiences: Chief of the Unit of Epidemiology for Clinical Research of the Department of
Epidemiology (since 2006); computer analyst, graphic designer, and statistical and epidemiological
consultant, Milan and Bergamo (since 2002); researcher at the Laboratory of Epidemiology (since 1997);
creator, designer and webmaster of the website of one of the major Italian public hospital, Milano (19992002).
Areas of interest: Design, data managing, and statistical analyses of case-control studies on the
associations between several risk factors (including in particular tobacco smoking, alcohol drinking and
Mediterranean diet) and risk of cancer, coronary heart disease and several other conditions. Analyses of
occupational cohort studies. Monitoring of prevalence and trends of smoking habit and obesity in Italy
and Europe. Author/coauthor of over 160 publications in peer-reviewed journals since 1998.
Since 2008, Dr Gallus is Associate Editor (Deputy Section Editor since 2010) of the journal BMC Public
Health, and is member of the editorial board of the following journals: The Open Obesity Journal (since
2008), The Open Demography Journal (since 2009), World Journal of Gastrointestinal Oncology (since
2009), World Journal of Dermatology (since 2010).
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Parente F, Molteni M, Marino B, Colli A, Ardizzone S, Greco S, Sampietro G, Foschi D, Gallus S. Are colonoscopy and
bowel ultrasound useful for assessing response to short-term therapy and predicting disease outcome of moderate-tosevere forms of ulcerative colitis?: a prospective study. Am J Gastroenterol. 2010;105:1150-7.
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Gallus S, Naldi L, Carli P, La Vecchia C; Italian Group for Epidemiologic Research in Dermatology (GISED). Nevus
count on specific anatomic sites as a predictor of total body count: a survey of 3,406 children from Italy. Am J
Epidemiol. 2007;166:472-8.
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Gallus S, Scotti L, Negri E, Talamini R, Franceschi S, Montella M, Giacosa A, Dal Maso L, La Vecchia C. Artificial
sweeteners and cancer risk in a network of case-control studies. Ann Oncol. 2007;18:40-4.
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Gallus S, Schiaffino A, La Vecchia C, Townsend J, Fernandez E. Price and cigarette consumption in Europe. Tob
Control. 2006;15:114-9.
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Gallus S, Zuccaro P, Colombo P, Apolone G, Pacifici R, Garattini S, La Vecchia C. Effects of new smoking regulations
in Italy. Ann Oncol. 2006;17:346-7.
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Clifford GM, Gallus S, Herrero R, Muñoz N, Snijders PJ, Vaccarella S, Anh PT, Ferreccio C, Hieu NT, Matos E,
Molano M, Rajkumar R, Ronco G, de Sanjosé S, Shin HR, Sukvirach S, Thomas JO, Tunsakul S, Meijer CJ, Franceschi
S; IARC HPV Prevalence Surveys Study Group. Worldwide distribution of human papillomavirus types in cytologically
normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet.
2005;366:991-8.
ACTIVITIES
The Department of Epidemiology is involved in the epidemiology of several common cancers
(including cancers of the breast, female genital tract, respiratory and digestive sites, prostate and
urinary organs, lymphoid malignancies, melanoma, etc.) and of cardiovascular diseases, both
through a descriptive and an analytical approach. Among the activities of descriptive
epidemiology are the analysis of temporal trends and geographical distribution of mortality
from cancer, cardiovascular diseases, and other selected conditions, in Italy and Europe; the
analysis of trends in tobacco consumption in the Italian population, and the corresponding
effects on incidence and mortality from lung and other tobacco-related neoplasms. The analytic
epidemiology activities include the conduction and analysis of case-control studies, aimed at
identifying and better quantifying the association between genetic factors (family history),
selected lifestyle habits (diet, tobacco, alcohol, etc.), use of exogenous hormones and exposure
to various substances and the development of various forms of cancers and cardiovascular
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diseases. In particular, the Department works on the analysis of dietary correlates of cancer and
cardiovascular disease risk; quantification of health effects of tobacco smoking, alcohol
consumption and implications for prevention; epidemiological studies on the risk related to oral
contraceptive and hormone replacement therapy use; evaluation of the impact of screening in
the early diagnosis and prevention of cancer. Other activities include: the conduction of
quantitative reviews and meta-analysis of published data; the re-analysis of original data from
epidemiological studies of cancers of the oral cavity and pharynx, pancreas, thyroid, breast,
ovary, and cervix; the analysis of historical cohort studies of occupational exposures to aromatic
amines, asbestos, herbicides and other known or potential carcinogens; monitoring and
prevention of injuries; epidemiological and clinical studies in dermatology, pediatrics and
oncology in collaboration with other Italian groups. Other Department’s activities are related to
the development of medical websites, the study of the quality of medical information available
on the Internet, and the training and research on issues related to medical informatics and those
concerning the use in the medical field of the Internet, the social media, and the web 2.0
applications.
MAIN FINDINGS
Diets rich in foods of animal origin and animal fats were positively, and those rich in fruit,
vegetables and vegetable fats inversely related to oral and pharyngeal cancer risk.
Similarly, a diet rich in animal products and animal fats was directly related to laryngeal cancer
risk, while one rich in fruit and vegetables was inversely associated.
We found that a lower BMI enhanced smoking- and drinking-related odds ratios for oral
cavity/pharyngeal cancer, but did not modify smoking and drinking odds ratios for laryngeal
cancer.
We found that quitting tobacco smoking and alcohol drinking resulted in a head and neck cancer
risk reduction, mainly after ≥20 years of quitting.
Intake of green tea is not associated with gastric cancer risk. However, the temperature of green
tea may play a role in the etiology of the disease.
We found that dietary proanthocyanidins have a favorable role on gastric cancer risk.
Our findings do not support the inverse relation between aspirin use and gastric cancer reported
in a recent meta-analysis.
We found a direct association between metabolic syndrome and both colon and rectal cancers in
men, but not in women.
We observed an unfavorable role on colorectal cancer of a dietary pattern based on high intake
of starch, and a protective role of dietary patterns characterized by vitamins and fiber, and
unsaturated fats.
We found an increased risk of colon cancer for higher intake of polyunsaturated fat, trans-fat,
lactose, sucrose and cholesterol.
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Our case-control study of pancreatic cancer reported no association with dietary acrylamide
intake.
Occupational and recreational physical activity was not associated to a decreased risk of
pancreatic cancer in our study.
Alcohol consumption was associated to increased pancreatic cancer risk, but the ORs were
significant only among heavy drinkers. The risk was over 4-fold higher in heavy smokers and
heavy drinkers in comparison with never smokers who drunk no or low amounts.
Our findings support a favorable role of vitamins E and C, selected carotenoids, and folate on
pancreatic cancer risk.
We confirmed that soft drink consumption is not materially related to pancreatic cancer risk.
We observed no association between regular aspirin use and pancreatic cancer risk, although our
results suggested a possible protective effect for long-term current users.
We found that diabetes and smoking are related to pancreatic cancer risk, with a multiplicative
effect between the two factors.
There is an inverse association between fruit and vegetables and pancreatic cancer risk, and a
direct one with meat.
A diet poor in animal proteins and rich in sugars (mainly derived from fruit) appears to have a
beneficial effect on pancreatic cancer risk.
A case-control study of endometrial cancer showed a direct association with the metabolic
syndrome.
Our data suggest the potential importance of lignin intake in the prevention of endometrial
cancer at Italian consumption levels.
Our data support earlier findings of an increase in risk of endometrial cancer with duration of
use of fertility drugs.
We found a lack of association between alcohol consumption and endometrial cancer risk in our
case-control study and in a meta-analysis including other 19 case-control and 7 cohort studies
(more than 13,000 cases).
We added relevant information on the absence of a consistent association between aspirin use
and endometrial cancer risk, even in high-risk overweight and obese women.
We found that a diet low in trans-fat could reduce prostate cancer risk.
Adherence to the Mediterranean diet in an Italian population showed no significant change over
the last 15 years in both men and women.
Our case-control study indicated that the metabolic syndrome, as well as its components, are
associated with an increased risk of cataract extraction in an Italian population.
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Glycemic index and glycemic load were inversely related to body mass index and not related to
waist to hip ratio in an Italian population.
A review on flavonoids and cancer risk provided evidence of a protective effect of flavanones
on upper aerodigestive tract cancers, flavonols, anthocyanidins and proanthocyanidins on
colorectal cancer, flavonols and flavones on breast cancer, isoflavones on ovarian cancer, and
flavonols on renal cancer.
Our findings indicated that citrus fruit has a protective role against cancers of the digestive and
upper respiratory tract.
Several aspects of the Mediterranean diet were favorable on risk of various cancers, particularly
of the digestive tract.
A meta-analysis of epidemiological studies on dietary acrylamide and human cancer reported a
lack of association with most neoplasms. The main association which will require further
monitoring involves kidney cancer.
In a meta-analysis of observational studies, a significant reduction in the risk of oral and
pharyngeal cancer of about 35% emerged for highest coffee drinkers as compared to lowest
drinkers, while no relation was found between coffee drinking and laryngeal and esophageal
cancer.
In a meta-analysis of 31 observational studies on alcohol and cancers of the oral cavity and
pharynx, we observed higher alcohol-related RRs for pharyngeal than for oral cancer,
particularly at higher doses.
A meta-analysis of case–control studies suggested a moderate favorable effect of coffee
consumption on colorectal cancer risk. This may reflect a real protection, but can also partly or
largely be due to reverse causation.
A collaborative analysis provided evidence that cigar smoking is associated with an excess risk
of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless
tobacco use.
In a review of all studies of alcohol and oral and pharyngeal cancers, we observed a strong
dose–response effect on the intensity of alcohol use, but no apparent association for the duration
of alcohol use.
A significant positive association with non-Hodgkin lymphoma was found in higher
socioeconomic status subjects.
CHD and CVD mortality steadily declined in Europe, except in Russia, where rates were 10- to
15-fold higher than those of France, Italy or Sweden. Hungary and Poland, but also Scotland,
where CHD trends were less favorable than in other western European countries, also emerge as
priorities for preventive interventions.
Though oral and pharyngeal mortality in Europe has declined in the last decade in men, there
were still rises in a few central and eastern European countries, reaching exceedingly high rates
in Hungary and Slovakia.
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In Brazil, total cancer mortality rates increased over the last decades in both sexes. Particularly
high rates were registered in the last decade for head and neck cancers in men and cervix in
women, cancers largely avoidable through prevention screening and early diagnosis.
Overall, since 1970, rates for all childhood cancers dropped in both sexes in North America and
Japan. In middle and low income countries, for leukemia, bone and kidney cancer, rates
registered in 2005- 2007, are comparable to those registered in more developed areas in the
early 1980s.
High risk-populations in terms of risk factors related to cardiovascular mortality should give the
highest priority to achieving favorable shifts in all modifiable risk factors.
Analyzing cancer mortality in Europe during 2000-2004, we found a decline in overall cancer
mortality from 185.2 to 168.0/100 000 (world standard, 29%) in men and from 104.8 to 96.9
(28%) in women.
Although the reduction in postmenopausal hormone therapy use is a plausible explanation for
the recent decline in breast cancer incidence observed in Europe and North America, the issue
remains open to discussion.
In an age-period-cohort analysis, we observed a leveling of the epidemic of oral cancer for men
in most European countries, including Hungary and other central European countries where
mortality from this cancer was exceedingly high.
In another age-period-cohort analysis, we found that the favourable trends in gastric cancer
mortality observed in recent years are likely to continue in the close future.
In an analysis for breast cancer trends from Cordoba, Argentina, rates over most recent calendar
years decreased, mainly in the most urbanized districts.
Mortality from childhood cancer continued to decline over more recent years in most European
countries. Some further improvement in childhood cancer mortality in eastern Europe is
achievable through more widespread and better adoption of currently available treatments.
The recent decreases in colorectal cancer mortality rates in several European countries are likely
due to improvements in (early) diagnosis and treatment, with a consequent higher survival from
the disease.
Changes in breast cancer mortality after 1988 varied widely between European countries, and
the UK is among the countries with the largest reductions.
In South-eastern Europe, liver cirrhosis mortality was 10-20 times higher than in most other
European states.
Using data from two surveys on more than 3000 individuals representative of the Italian adult
population, we found for the first time, after 5 decades, a significant increase in smoking
prevalence.
Countries of the European Union with a relatively stricter implementation of policies to control
tobacco have lower smoking prevalence, lower self-reported exposure to SHS and higher
support towards smoking bans in all workplaces.
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Supplementation with n-3 polyunsaturated fatty acids ameliorated depressive symptoms and
quality of life in the treatment of depressed elderly female patients.
Influenza vaccination among oncohematological children should be strongly recommended only
for those who have been off therapy for less than 6 months.
The direct involvement of parents significantly increased children acceptance of nasal swabs use
to detect influenza virus, thus simplifying collection, without reducing the influenza virus
detection rate.
In a survey of Italian adolescents and parents, the likelihood of HPV infection was
underestimated. This was associated with a lower propensity towards HPV vaccine.
In a meta-analysis on the literature on risks factors for falls in older people we identified some
indicators of disability that strongly predict the risk of falling.
In a prospective study, we found that bowel ultrasound (US) may be used as a surrogate of
colonoscopy in assessing the short-term response of severe forms of UC to therapy. Both US
score and endoscopic score after 3 months of steroid therapy predict outcome of disease at 15
months.
In Milan, the Emergency Medical System provides support to patients having an out-of-hospital
cardiac arrest with characteristics comparable with those reported in other large urban areas, but
the time from arrival-to-first CPR was longer than recommended by current guidelines.
Serum amyloid A protein levels were predictive of an elevated risk of lung cancer, supporting
the general view that inflammation is implicated in lung cancer development.
Bronchial diverticula are a frequent finding in the major airways of smokers, and they are
associated with other markers of smoking-related damage.
Screening for lung cancer using airflow obstruction with FEV1% is a strategy worth future
consideration.
In a cohort of workers exposed to extensively high doses of aromatic amines, 56 deaths from
bladder cancer were observed, compared with 3.4 expected.
The incidence of second HN cancers does not increase with age, but remains constant, or if
anything, decreases with advancing age.
Preliminary results from 2 case-control studies conducted in Italy and Spain suggest a weak – if
any – association between colorectal cancer and disinfection by-products.
The excess risks of adverse pregnancy outcomes in relation to particulate matter, if any, are
small, and it is unclear whether they are causal, due to misclassification of the exposure or some
sources of bias/residual confounding.
The evidence that human exposure to paraquat pesticide increases the risk for Parkinson Disease
is rather limited.
ANNUAL REPORT
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IRFMN
Associazione Italiana di Oncologia Medica (AIOM)
Accademia Nazionale di Medicina, Genova
Agenzia giornalismo scientifico Zadig, Milano
Arcispedale S. Maria Nuova, Reggio Emilia
Associazione Nazionale dei Medici Cardiologi Ospedalieri (ANMCO)
Azienda Unità Sanitaria Locale di Ravenna
Centro Cardiologico Monzino, Milano
Centro Studi Comunicazione sul Farmaco, Milano
Centro di Riferimento Oncologico, Servizio di Epidemiologia e Biostatistica, Aviano (PN)
Comune di Milano, Direzione centrale salute, Settore politiche per la Salute
Federazione Italiana delle Associazioni di Volontariato in Oncologia (FAVO)
Fondazione LuVI
Fondazione Politecnico di Milano
Fondazione SmithKline, Milano
Gruppo Italiano per lo Studio della Sopravivenza nell’Infarto miocardico (GISSI)
Gruppo Italiano Studi Epidemiologici in Dermatologia GISED, Bergamo
Gruppo Italiano Documentalisti dell’Industria Farmaceutica e degli Istituti di Ricerca
Biomedica
Gruppo Studi Tumori Urologici (GSTU)
International Centre for Pesticides and Health Risk Prevention, Milano
Istituto Auxologico Italiano, Divisione Malattie Metaboliche III, IRCCS, Piancavallo (VB)
Istituto Auxologico Italiano, Laboratorio Sperimentale di Ricerche Endocrinologiche (LSRE),
IRCCS, Milano
Istituto DOXA, Milano
Istituto Europeo di Oncologia, Divisione di Epidemiologia e Biostatistica, Milano
Istituto Europeo di Oncologia, Divisione di Chirurgia Cervico Facciale, Milano
Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione (INRAN), Roma
Istituto Nazionale Neurologico “Carlo Besta”, Milano
Istituto Nazionale per lo Studio e la Cura dei Tumori, Oncologia Sperimentale, Unità di Eredità
Poligenica, Milano
Istituto Superiore di Sanità, Osservatorio Fumo Alcol Droga, Roma
Istituto Tumori “Fondazione Pascale”, Servizio di Epidemiologia, Napoli
Novartis Vaccines SpA, Siena
Ordine dei Medici della Provincia di Bari
Ospedale Casa Sollievo della Sofferenza San Giovanni Rotondo
Ospedale Niguarda Ca’ Granda, Dipartimento Trapianti di Fegato, Milano
Ospedale Niguarda Ca’ Granda, Istituto di Fisiologia Clinica CNR, Sezione di Milano, Milano
Ospedali Riuniti di Bergamo
Ospedale Alessandro Manzoni, Unità di Gastroenterologia, Lecco (LC)
Ospedale Luigi Sacco, Az Osp - Polo Universitario, Milano
Policlinico di Monza, Unità Operativa di Endoscopia I, Monza (MB)
Prima Clinica Ostetrico Ginecologica, Mangiagalli, Milano
Regione Lombardia, U.O. Governo dei servizi sanitari territoriali e politiche di appropriatezza e
controllo Struttura Sistemi di remunerazione e Osservatorio Epidemiologico Direzione Generale
Sanità
Società Italiana Attività Regolatorie
Unione Nazionale dei Giornalisti Scientifici Italiani
ANNUAL REPORT
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2010
IRFMN
Università Bocconi di Milano, Dipartimento di Analisi Istituzionale e Management Pubblico,
Milano
Università Cattolica del Sacro Cuore, Unità di Epidemiologia genetica e Biologia Molecolare,
Istituto di Igiene, Roma
Università degli Studi di Milano - Bicocca, Dipartimento di Statistica, Milano
Università degli Studi di Milano-Bicocca, I Clinica Otorinolaringoiatria, DNTB, Monza
Università di Milano, Clinica Pediatrica De Marchi, Milano
Università di Milano, Dipartimento di Medicina del Lavoro, Sezione di Statistica Medica e
Biometria, Milano
Università di Milano, Prima Clinica Ostetrico Ginecologica, Milano
Università di Pavia, Azienda di Servizi alla Persona, Pavia
Università di Torino, Istituto di Medicina del Lavoro, CTO, Torino
Università di Verona, Clinica Ostetrico Ginecologica, Verona
Catalan Institute of Oncology, Institut d’Investigaciò Biomédica de Bellvitge (IDIBELL),
Cancer Prevention and Control Unit, L’Hospitalet de Llobregat, Spain
Center of Oncology, Dept. of Epidemiology and Cancer Prevention, Warsaw, Poland
Centre for Research in Environmental Epidemiology (CREAL) and Municipal Institute of
Medical Research (IMIM), Barcellona, Spain
Evidence and Risk Assessment Division, Centre for Chronic Disease Prevention and Control,
Public Health Agency of Canada, Ottawa, Ontario, Canada
Harvard School of Public Health, Department of Epidemiology, Boston, USA
Hellenic Health Foundation, Greece
Hôpital Necker - Enfants Malades, Centre of the Association Claude Bernard on Auto-immunes
diseases, Parigi, France
Institute de Academie des Sciences, Paris, France
International Agency for Research on Cancer, Lione, France
International Epidemiology Institute (IEI), Rockville, USA
International Life Science Institute (ILSI), Bruxelles, Belgium
International Prevention Research Institute (IPRI), Lyon, France
Karolinska Institute, Department of Medical Epidemiology and Biostatistics, Stockholm,
Sweden
National Cancer Institute, Environmental Studies Section, Bethesda, USA
National Cancer Institute, Radiation Epidemiology Branch, Bethesda, USA
National School of Public Health, WHO, Atene, Greece
Registre Vaudois des Tumeurs, Institut Universitaire de Médecine Sociale et Préventive,
Losanna, Switzerland
Senologic International Society
Society for Internet in Medicine
The Tisch Cancer Institute and Institute for Translational Epidemiology, Mount Sinai School of
Medicine, New York, NY, USA
Tobacco Free Research Institute, Dublino, Ireland
UNDP/UNFPA/WHO/WORLD Bank special programme of research development and research
training in human reproduction, Ginevra, Svizzera
Universitat Pompeu Fabra, Department of Experimental and Health Sciences, Barcellona, Spain
ANNUAL REPORT
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IRFMN
University of Athens Medical School, Department of Hygiene and Epidemiology, Atene,
Greece
University of Cordoba, Faculty of Medical Diseases, Cordoba, Argentina
University of Las Palmas de Gran Canaria, Department of Clinical Sciences, Las Palmas de
Gran Canaria, Spain
Vanderbilt University, Department of Medicine, School of Medicine, Nashville, TN, USA
Advances in Therapy (Eva Negri)
Alimentazione e Prevenzione (Carlo La Vecchia)
Annals of Oncology (Carlo La Vecchia, Associate Editor)
Archives of Medical Science (Carlo La Vecchia)
BMC Public Health (Silvano Gallus, Associate Editor)
Cancer Letter (Carlo La Vecchia, Associate Editor)
Current Cancer Therapy Reviews (Carlo La Vecchia)
Dermatology Research and Practice (Carlo La Vecchia)
Digestive and Liver Disease (Carlo La Vecchia)
Economia Politica del Farmaco (Carlo La Vecchia)
European Journal of Cancer Prevention (Carlo La Vecchia, Associate Editor)
European Journal of Clinical Nutrition (Carlo La Vecchia)
European Journal of Nutrition (Carlo La Vecchia)
Evidence Based Dermatology (Carlo La Vecchia, Liliane Chatenoud)
In Scope Oncology & Haematology (Carlo La Vecchia)
ISRN Cardiology (Eugenio Santoro)
Maturitas (Carlo La Vecchia)
Nutrition and Cancer (Carlo La Vecchia)
Open Cancer Journal (Carlo La Vecchia)
Oral Oncology (Carlo La Vecchia)
Portale Partecipasalute.it – http://www.partecipasalute.it (Eugenio Santoro)
Revisiones en Ginecologìa y Obstetricia (Carlo La Vecchia)
Revista Española de Nutriciò Comunitaria (Carlo La Vecchia)
Revue d’Epidémiologie et de Santé Publique (Carlo La Vecchia)
Società Italiana Attività Regolatorie News, SIARNews (Eugenio Santoro)
The Open Obesity Journal (Silvano Gallus)
Tumori (Carlo La Vecchia)
World Journal of Gastrointestinal Oncology (Silvano Gallus)
Acta Dermato-Venereologica, Acta Psychiatrica Scandinavica, Alcologia, American Journal of
Clinical Nutrition, American Journal of Epidemiology, Annals of Epidemiology, Annals of
Oncology, Archives of Internal Medicine, BMC Public Health, British Journal of Cancer,
British Journal of Nutrition, British Medical Journal, Bulletin of the World Health Organization,
Canadian Journal of Physiology and Pharmacology, Cancer, Cancer Causes and Control, Cancer
Detection and Prevention, Cancer Epidemiology Biomarkers and Prevention, Computer
Methods and Programs in Biomedicine, Diabetes/Metabolism Research and Reviews, Digestive
ANNUAL REPORT
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2010
IRFMN
Liver Disease, Epidemiologia & Prevenzione, Epidemiology, Epidemiology & Biostatistic,
European Heart Journal, European Journal of Cancer, European Journal of Cancer Prevention,
European Journal of Clinical Nutrition, European Journal of Epidemiology, European Journal of
Public Health, Evidence-Based Healthcare and Public Health, Gynecological Endocrinology,
Gut, Hepatology, Human Reproduction, International Journal of Cancer, International Journal
of Environmental Research and Public Health, International Journal of Epidemiology,
International Journal of Obesity, JAMA, Journal of American College of Nutrition, Journal of
Clinical Endocrinology and Metabolism, Journal of Clinical Epidemiology, Journal of
Epidemiology and Community Health, Journal of Investigative Dermatology, Journal of
Medical Economics, Journal of Medical Internet Research , Journal of the National Cancer
Institute, Lancet Oncology, Lung Cancer, Maturitas, Melanoma Research, Nicotine & Tobacco
Research, Nutrition and Cancer, Obstetric and Gynecology, Oncology, PLoS ONE, Preventive
Medicine, Public Health, Public Health Nutrition, QJM, Radiation Research, Revue
d’Epidèmiologie et de Santé Publique, The Breast, The Cancer Journal, The Lancet, The Open
Obesity Journal, Tobacco Control, Tumori, World Journal of Gastroenterology.
Advisory Committee of the Oxford Collaborative group on Aetiological Factors in Cancers of
the Female Genital Tract
Comitato Scientifico del Gruppo Italiano Studi Epidemiologici in Dermatologia
Comitato Scientifico della Società Italiana di Colposcopia e Patologia Cervico Vaginale
Comitato Scientifico del portale www.familyhealth.it
Data and Safety Monitoring Board of the “Phase II therapeutic trial with a humanized
nonmitogenic CD3 (ChAgly CD3) monoclonal antibody in recently diagnosed type I diabetic
patients”
Executive Committee, International Head and Neck Cancer Epidemiology (INHANCE)
consortium
Ministero della Salute, Sottocomitato fumo
Scientific Review Committee del UND/WHO/World Bank Human Reproduction Programme
EVENT ORGANIZATION
Istituto di Ricerche Farmacologiche Mario Negri, Milan; Conference: “Presentazione trial
sull’effetto del consumo di chewing-gum sull’appetito e il consumo di snack”. 15 January 2010.
Corso “La ricerca bibliografica su database biomedici”, organizzato in collaborazione con
l’ASL di Bergamo
Dipartimento Cure Primarie e Continuità Assistenziale, Bergamo 11 February 2010
V° edizione del corso ECM “"La ricerca bibliografica su database biomedici", Istituto di
Ricerche Farmacologiche “Mario Negri”, Milano, 8 June 2010
V ° edizione del corso ECM "Internet e l’aggiornamento professionale in ambito medico",
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 9 June 2010
V ° edizione del corso ECM "Il web 2.0 al servizio della formazione e dell’aggiornamento del
medico", Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 10 June 2010
ANNUAL REPORT
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2010
IRFMN
V ° edizione del corso ECM "Twitter, Facebook, Youtube e i nuovi social media per
l’aggiornamento del medico e dell’operatore sanitario", Istituto di Ricerche Farmacologiche
“Mario Negri”, Milano, 11 June 2010
Corso “Web 2.0 e social media in medicina” organizzato presso il Centro Cardiologico
Monzino di Milano, 5,19 October 2010
Corso di formazione e aggiornamento per i giornalisti “Internet e Medicina: a caccia di salute
sul web”, organizzato in collaborazione con la Unione Nazionale dei Giornalisti Scientifici
Italiani (UNAMSI), Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 16 October
2010
VI° edizione del corso ECM “"La ricerca bibliografica su database biomedici", Istituto di
Ricerche Farmacologiche “Mario Negri”, Milano, 2 November 2010
VI° edizione del corso ECM "Internet e l’aggiornamento professionale in ambito medico",
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 3 November 2010
VI° edizione del corso ECM "Il web 2.0 al servizio della formazione e dell’aggiornamento del
medico", Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 4 November 2010
VI° edizione del corso ECM "Twitter, Facebook, Youtube e i nuovi social media per
l’aggiornamento del medico e dell’operatore sanitario", Istituto di Ricerche Farmacologiche
“Mario Negri”, Milano, 5 November 2010
Corso “Aggiornarsi in oncologia con gli strumenti del web 2.0” organizzato dal
personale del dipartimento in collaborazione con l’Associazione Italiana Oncologia
Medica e svolto nell’ambito del XII Congresso Nazionale dell’Associazione Italiana
Oncologia Medica, Roma 6 November 2010
Corso “Il web 2.0 e i social media come strumento di comunicazione in sanità” promosso dalla
Scuola Umbra di Amministrazione Pubblica, Perugia 10 November 2010
Corso “Il web 2.0 e i social media al servizio della formazione e dell’aggiornamento del medico
e dell’operatore sanitario” organizzato presso l’Azienda Unità Sanitaria Locale di Ravenna,
Ravenna 14-15 December 2010
Corso “L’accademia del cittadino: valutare la qualità e la sicurezza dei servizi sanitari per fare
scelte consapevoli e partecipare al miglioramento” – Modulo 3: Informazione e comunicazione
sulla salute. Il ruolo della associazioni nella costruzione dell’alleanza tra cittadino e sistema
sanitario” organizzato da Partecipasalute e Regione Toscana. Titolo della relazione: “Facebook,
blog, wiki: le informazioni di salute corrono sul web 2.0”, Montecatini Terme 21 January 2010.
Corso “Le nuove tecnologie al servizio dell’efficacia e dell’efficienza in diabetologia”,
promosso da Roche Diagnostics, Buttrio (UD) 22-23 January 2010
Convegno. Cibo degli dei, cibo dei demoni – alimentazione fra salute e malattia. “Cibi contro il
cancro e cibi che lo fanno venire. Cosa c’è di vero? Lugano, Svizzera 28 January 2010
ANNUAL REPORT
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2010
IRFMN
International scientific workshop. The truth about wine. “Alcohol and health, with focus on
moderate doses” e ”Wine consumption and longevity”. Castello di Grinzane Cavour (CN) 5-7
February 2010
Open day. Hiwate. Health impacts of long term exposure to disinfection by-products in drinking
water. London, UK 23 February 2010
43rd Annual Meeting of the Italian Association for the Study of the Liver. “ Coffee and liver
diseases”. Roma, 24 February 2010
Convegno “Alleati per la salute”, Roma 5-6 March 2010. Titolo della relazione”Comunicare il
non profit: Internet e i Social Network”
Corso di aggiornamento. Gli studi caso-controllo: dal disegno agli strumenti epidemiologicostatistici. “Lettura di un articolo scientifico ed esercitazione: disegnare uno studio casocontrollo””Calcolo della numerosità campionaria in uno studio caso-controllo. Particolari tipi di
studi caso-controllo”. Roma 9 March 2010
Pancreatic cancer case-control (PANC4) consortium. “Non-cigarette tobacco use and pancreatic
cancer”. Rockville, MD 18 March 2010
European Breast Cancer Conference. EBCC7. ”Impact of lifestyle on breast cancer”.
Barcellona, Spagna 24-27 March 2010
Corso, “Siti, strumenti ed applicazioni web 2.0 in ambito medico” promosso dalla Biblioteca
Medica della AIL Biella-Fondazione Clelio Angelino onlus, Biella 14-15 aprile 2010.
VII International Nutrition and dietetics Congress. “Mediterranean diet and cancer”. Istanbul,
Turchia 14-18 April 2010
Corso “Internet e l’aggiornamento professionale in ambito medico”, promosso dal servizio
formazione del personale medico della Provincia Autonoma di Bolzano, Bolzano 23 April 2010
Alimentazione, stili di vita e promozione della salute. “Componenti della frutta e verdura e
prevenzione del cancro”. Bologna, 24-27 Aprile2010
Bocconi University, Milan; Master course: “Epidemiology of tobacco in Italy, with a focus on
the effects of the smoking ban legislation”. Milano. 4 Maggio 2010.
Master Universitario di I° livello in “Comunicazione e Salute nei Media Contemporanei”,
Università degli Studi di Milano, facoltà di Farmacia, anno accademico 2009-2010. Ruolo di
docenze nel modulo “Il Web 2.0 come strumento per la comunicazione della salute", Milano 7
May 2010
V Giornata nazionale del malato oncologico promossa dalla Federazione Italiana delle
Associazioni di Volontariato in Oncologia (FAVO). Titolo della relazione: Le associazioni dei
pazienti nell’era dei social network e dei social media”, Roma 15 May 2010
PPACTE Meeting: “WP2: European Survey on economic aspects of smoking”. IARC, Lyon,
France. 16 May 2010.
ANNUAL REPORT
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2010
IRFMN
IARC Handbook Meeting: “Chapter 5; tax, price and adult tobacco use”. IARC, Lyon, France.
17 May 2010.
Minimaster “Come leggere un lavoro clinico – Ricerca bibliografica online” organizzato
dall’Associazione Nazionale Medici Cardiologi Ospedalieri”, Firenze 19 May 2010. Titolo della
relazione “Web 2.0 e banche dati: utilizzo di feed RSS, aggregatori di notizie e social
bookmarks”
I edizione Convegno Nazionale Fondazione GSTU (Gruppo Studi Tumori Urologici).
“L’oncologia dei nostri giorni: fra comunicazione e comunicabilità”. Titolo della relazione
“Strumenti di informazione sanitaria disponibili su Internet: come orientarsi”, Palermo 21 May
2010
XII Convegno nazionale tabagismo e servizio sanitario nazionale. “Fumo e donne: nulla è
peggio per la loro salute. Roma, 31 May 2010
Convegno “Medicina e Media: sfide per una comunicazione di qualità” organizzato
dall’Università degli Studi di Padova, Padova 8 June 2010. Titolo della relazione: “Internet e
web 2.0: cosa cambia per la comunicazione in medicina”.
Convegno “I nuovi canali del ‘informazione scientifica tra e-detailing e TV digitale terrestre”,
Business International. Titolo della relazione “Social Networking in Sanità: come scambiare
esperienze e condividere conoscenze mediche e sanitarie attraverso la rete”, Roma 16 June
2010.
1° European Focus Meeting. Excellence in young women breast care. “Epidemiologia del
carcinoma mammario” (La Vecchia moderatore), Famigliarità, ereditarietà e counseling
genetico (Negri). Castel dell’Ovo, Napoli, 24-25 June 2010
IPRI-Dundee University Summer School of epidemiology. “Exposure assessment”,
”Introduction to bias”Dundee, UK, 5-7 July 2010
Meeting “The International meta-analysis on lung cancer screening: recent data”- Peter B. Bach.
Fondazione IRCCS Istituto Nazionale dei Tumori. Milano, 22 July 2010
Prevention, from theory to policy. “Lifestyle and cardiovascular risk”. Losanna, Svizzera. 7
September 2010
ESBRA Nordmann Award & ISBRA Satellite Meeting Alcohol & Cancer. “Epidemiology of
alcohol cancer”. Heidelberg 17-18 September 2010
I° edizione del corso “Gli strumenti del web 2.0 per la distribuzione e la condivisione
dell’informatica medica”, promosso dall’Arcispedale Santa Maria Nuova, Azienda Ospedaliera
di Reggio Emilia, Reggio Emilia 22 September 2010
II World Congress of Public Health Nutrition. “Application of low-calorie sweeteners, safety
and contributions to health. Porto, Portogallo. 23-25 September 2010
Europa Donna Breast Cancer Advocacy Leader Conference: reducing health inequalities and
fostering healthy ways of life. “Epidemiology and facts about lifestyle and breast cancer
prevention. Milano. 25 September 2010
ANNUAL REPORT
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2010
IRFMN
II° edizione del corso “Gli strumenti del web 2.0 per la distribuzione e la condivisione
di Reggio Emilia, Reggio Emilia 1 October 2010
Corso “Le nuove tecnologie al servizio dell’efficacia e dell’efficienza in diabetologia”,
promosso da Roche Diagnostics, Cavenago 1-2 October 2010
Convegno. Alimentazione e tumori: dalla prevenzione al support nutrizionale. “Componenti
della dieta utili nella prevenzione dei t umori”. Milano. 8 October 2010
Breast cancer conference. Swedish Cancer Society. “Impact of lifestyle on breast cancer”.
Stoccolma, Svezia. 15 October 2010
Vivere in salute alla Bocconi. “La prevenzione come strumento utile al fine di ridurre i rischi di
malattie”. Milano. 18 October 2010
Dental Lessons. “Alcohol e colluttori: dati epidemiologici”. Roma. 19 October 2010
3rd International Congress on Nutrition and Cancer. “Overweight, diabetes and Cancer risk”.
Bodrum, Turkey. 20-24 October 2010
III° edizione del corso “Gli strumenti del web 2.0 per la distribuzione e la condivisione
di Reggio Emilia, Reggio Emilia 20 October 2010
II edizione Convegno Nazionale Fondazione GSTU (Gruppo Studi Tumori Urologici).
“L’oncologia dei nostri giorni: fra comunicazione e comunicabilità”. Titolo della relazione
“Strumenti di informazione sanitaria disponibili su Internet: come orientarsi”, Catania 30
October 2010
Conference EUROEPI: “Impact of cigarette price on demand for tobacco products”. Florence, 8
November 2010.
Conference EUROEPI: “Colorectal cancer and disinfection by-products in Italy and Spain”.
Florence, 7 November 2010.
XXXIV Congresso AIE 2010. Associazione Italiana Epidemiologia. Consumo di caffè e tè e
rischio di tumore alla testa e collo: una pooled analysis di studi del consorzio INHANCE (The
International Head and Neck Cancer Epidemiology). Firenze. 9 November 2010
Conferenza “Da LightHouse al web 2.0: il futuro dell’informazione biomedica in Lombardia”,
conferenza annuale del Sistema Bibiotecario Biomedico Lombardo (SBBL). Titolo della
relazione “Il ruolo del web 2.0 e dei social media nella diffusione dell’informazione
biomedica”, Milano 16 November 2010.
XVI Congress of International Federation of Health Records Organizations (IFHRO), Milano
15-19 November 2010. Titolo relazione: “Personal Health Record and web 2.0: a new way for
patients and citizens to collect, handle, and share their own health data”
Convegno “Comunicazione sociale per la salute: salute 2.0 esperienze e interrogativi” promosso
dalla Agenzia Informazione e Ufficio Stampa della Giunta Regionale Emilia Romagna in
collaborazione con l’Università di Bologna e Fondazione Pubblicità e Progresso. Titolo della
ANNUAL REPORT
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IRFMN
relazione “Partecipazione, formazione e salute:l’esperienza del portale partecipasalute.it”,
Bologna 26 November 2010
Seminario “La registrazione dei trial clinici: come e perché effettuarla e come interrogare i
database”, Ospedale Maggiore di Bologna, Bologna 2 Dicember 2010
Convegno “Questioni di cuore: l’infarto miocardico nell’era della comunicazione globale”
promosso dalla Azienda Unità Sanitaria locale di Forlì. Titolo della relazione “La
comunicazione e gli ammalati (potenziali) di domani: web, iphone, ipad, centro di ascolto,
condivisione delle immagini, second opinion”, Forlì 4 December 2010
Convegno “Innovazioni tecnologiche in medicina sportiva”, promosso dalla Federazione
Medico Sportiva Italiana (FMSI) Puglia e Basilicata, Matera 3-4 December 2010. Titolo della
relazione “Il web 2.0: filosofia e strumenti”.
Master Universitario di I° livello in Ricerca Clinica, Università degli Studi di Milano, anno
accademico 2010-2011. Ruolo di docenze nel modulo “Internet e le nuove tecnologie per
l’aggiornamento medico-scientifico”, Milano 9 December 2010
EU-FP6 Project HiWATE Final Meeting. 22-24 February 2010 Londra
AIFA
Arcispedale Santa Maria Nuova, Azienda Ospedaliera di Reggio Emilia
Associazione Italiana Oncologia Medica
Associazione Italiana per la Ricerca sul Cancro (AIRC)
Azienda Sanitaria Locale di Bergamo
Azienda Unità Sanitaria Locale di Ravenna
Centro Cardiologico Monzino
Comune di Milano
Lega Italiana Lotta contro i Tumori (LILT)
European Commission (FP7)
European Research Council (ERC)
Fondazione Politecnico di Milano
GISED
Regione Lombardia
Weber Shandwich
Consorzio Assomela
ISA
Perfetti Van Melle
Provincia Autonoma di Bolzano
Roche Diagnostics
Scuola Umbra di Amministrazione Pubblica
Unione Nazionale dei Giornalisti Scientifici Italiani
ANNUAL REPORT
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2010
IRFMN
Deandrea S, Foschi R, Galeone C, La Vecchia C, Negri E, Hu J.
Is temperature an effect modifier of the association between green tea intake and gastric cancer
risk?
Eur. J. Cancer Prev 19:18–22 (2010)
Parazzini F, Ricci E, Chiaffarino F, Cipriani S, Tozzi L, Fedele L
Induced abortion and risk of preterm birth.
Gynecol Obstet Invest. 69:40-45 (2010).
Tavani A, Scotti L, Bosetti C, Dal Maso L, Montella M, Ramazzotti V, Negri E, Franceschi S,
La Vecchia C.
Aspirin and risk of renal cell cancer in Italy.
Eur. J. Cancer Prev., 19: 272-274 (2010)
Bosetti C, Niewenhuijsen M, Gallus S, Cipriani S, La Vecchia C, Parazzini F.
Ambient particulate matter and preterm birth or birth weight: review of the literature.
Arch Toxicol. 2010;84:447-60.
Pelucchi C, Galeone C, Negri E, La Vecchia C.
Trends in adherence to the Mediterranean diet in an Italian population between 1991 and 2006.
Eur J Clin Nutr, 64: 1052-1056 (2010)
Powles J, Shroufi A, Mathers C, Zatonski W, La Vecchia C, Ezzati M
National cardiovascular prevention should be based on absolute disease risks, not levels of risk
factors.
EJPH, 20: 103–106 (2010)
Bidoli E, Pelucchi C, Zucchetto A, Negri E, Dal Maso L, Polesel J, Montella M, Franceschi S,
Serraino D, La Vecchia C, Talamini R.
Fiber intake and endometrial cancer risk.
Acta Oncol. 49: 441–446 (2010)
Bravi F, Edefonti V, Bosetti C, Talamini R, Montella M, Giacosa A, Franceschi S, Negri E,
Ferraroni M, La Vecchia C, Decarli A.
Nutrient dietary patterns and the risk of colorectal cancer: case-control study.
Cancer Causes Control, 21: 1911-1918 (2010)
Rossi M, Negri E, Parpinel M, Lagiou P, Bosetti C, Talamini R, Montella M, Giacosa A,
Franceschi S, La Vecchia C.
Proanthocyanidins and the risk of colorectal cancer in Italy.
Gaudet MM, Olshan AF, Chuang SC, Berthiller J, Zhang ZF, Lissowska J, Zaridze D, Winn
DM, Wei Q, Talamini R, Szeszenia-Dabrowska N, Sturgis EM, Schwartz SM, Rudnai P, ElufNeto J, Muscat J, Menezes A, Matos E, Bucur A, Levi F, Lazarus P, La Vecchia C, Koifman S,
Kelsey K, Herrero R, Hayes RB, Franceschi S, Wunsch-Filho V, Fernandez V, Fabianova E,
Daudt AW, Dal Maso L, Curado MP, Chen C, Castellsague X, Benhamou S, Boffetta P,
Brennan P, Hashibe M.
ANNUAL REPORT
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2010
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Body mass index and risk of head and neck cancer in a pooled analysis of case-control studies
in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium.
Int J Epidemiol, 39: 1091-1102 (2010)
Deandrea S, Lucenteforte E, Bravi F, Foschi R, La Vecchia C, Negri E.
Risk factors for falls in community-dwelling older people. A systematic review and metaanalysis.
Epidemiology, 21: 658-668 (2010)
Foschi R, Pelucchi C, Dal Maso L, Rossi M, Levi F, Talamini R, Bosetti C, Negri E, Serraino
D, Giacosa A, Franceschi S, La Vecchia C.
Citrus fruit and cancer risk in a network of case–control studies
Cancer Causes Control, 21:237–242 (2010)
Marron M, Boffetta P, Zhang Z-F, Zaridze D, Wunsch-Filho V, Winn DM, Wei Q, Talamini R,
Szeszeia-Dabrowska N, Sturgis EM, Smith E, Schwartz SM, Rudnai P, Purdue M, Olshan AF,
Eluf-neto J, Menezes A, Mclean M, Matos E Mates IN, Lissowska J, Levi F, Lazarus P, La
Vecchia C, Koifman S, Kelsey K, Herrero R, Hayes RB, Franceschi S, Fernandez L, Fabianova
E, Daudt AW, Da Maso L, Curado MP, Cadoni G, Chen C, Castellsague X, Boccia S,
Benhamou S, Ferro G, Berthiller J, Brennan J, Moller H, Hashibe M.
Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk.
Int. J. Epidemiol, 39: 182-196 (2010)
Talamini R, Polesel J, Gallus S, Dal Maso L, Zucchetto A, Negri E, Bosetti C, Lucenteforte E,
Boz G, Franceschi S, Serraino D, La Vecchia C.
Tobacco smoking, alcohol consumption and pancreatic cancer risk: a case-control study in Italy.
Eur. J. Cancer, 4 6 : 3 7 0 –3 7 6 (2010)
La Vecchia C, Bosetti C, Lucchini F, Bertuccio P, Negri E, Boyle P, Levi F.
Cancer mortality in Europe, 2000-2004, and an overview of trends since 1975.
Ann. Oncol., 21: 1323-1360 (2010).
Chatenoud L, Bertuccio P, Bosetti C, Levi F, Curado PM, Malvezzi M, Negri E, La Vecchia C.
Trends in cancer mortality in Brazil, 1980-2004.
Eur J Cancer Prev. 19:79-86. (2010)
Rossi M, Rosato V, Bosetti C, Lagiou P, Parpinel M, Bertuccio P, Negri E, La Vecchia C.
Flavonoids, proanthocyanidins and the risk of stomach cancer.
Lucenteforte E, Talamini R, Bosetti C, Polesel J, Franceschi S, Serraino D, Negri E, La Vecchia
C.
Macronutrients, fatty acids, cholesterol and pancreatic cancer.
Eur. J. Cancer, 46: 581-587 (2010)
Lubin JH, Gaudet MM, Olshan AF, Kelsey K, Zhang Z-F, Winn D, Wei Q, Talamini R,
Szeszenia-Dabrowska N, Sturgis EM, Smith E, Shangina O, Schwartz SM, Rudnai P, Neto JE,
Muscat J, Morgenstern H, Menezes A, Matos E, Mates IN, Lissowska J, Levi F, Lazarus P,
Vecchia C, Koifman S, Herrero R, Franceschi S, Wünsch-Filho V, Fernandez L, Fabianova E,
Daudt AW, Dal Maso L, Curado MP, Chen C, Castellsague X, Brennan P, Boffetta P, Hashibe
M, Hayes RB.
ANNUAL REPORT
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Body mass index, cigarette smoking and alcohol consumption and risk of cancer of the larynx,
pharynx and oral cavity: modeling risk in pooled case-control data.
Am. J. Epidemiol, 171:1250–1261 (2010)
Morici N, De Luca G, Lucenteforte E, Chatenoud L, Lorito F, Palgiosa A, La Vecchia C,
Sesana G.
Emergency Medical System response to out-of hospital cardiac arrest in Milan, Italy.
Eur. J. Emergency Med., 17: 234-236 (2010)
Bosetti C, Bertuccio P, Chatenoud L, Levi F, Negri E, La Vecchia C.
Childhood cancer mortality in Europe, 1970-2007.
Eur. J. Cancer, 4 6 : 3 8 4 –3 9 4 (2010)
Edefonti V, Bravi F, Garavello W, La Vecchia C, Parpinel M, Franceschi S, Dal Maso L,
Hashibe M, Bosetti C, Boffetta P, Ferraroni M, Decarli A.
Nutrient-based dietary patterns and laryngeal cancer: evidence from an exploratory factor
analysis
Cancer Epidemiol Biomarkers Prev, 19: 18-27 (2010)
Sverzellati N, Ingegnoli A, Calabrò E, Randi G, La Vecchia C, Marchianò A, Kuhnigk JM,
Hansell DM, Zompatori M, Pastorino U.
Bronchial diverticula in smokers on thin-section CT.
Eur. Radiol., 20: 88-94 (2010)
Rondanelli M, Giacosa A, Opizzi A, Pelucchi C, La Vecchia C, Montorfano G, Negroni M,
Berra B, Politi P, Rizzo AM.
Effect of omega-3 fatty acids supplementation on depressive symptoms and on health-related
quality of life in the treatment of elderly women with depression. A double-blind, placebocontrolled, randomized clinical trial.
J. Am. College Nutr., 29: 55-64 (2010)
Garavello W, Bertuccio P, Levi F, Lucchini F, Bosetti C, Negri E, La Vecchia C.
The oral cancer epidemic in central and eastern Europe.
Int. J. Cancer. 127: 160–171 (2010)
Polesel J, Talamini R, Negri E, Bosetti C, Boz G, Lucenteforte E, Franceschi S, Serraino D, La
Vecchia C.
Dietary habits and risk of pancreatic cancer: An Italian case-control study.
Cancer Causes Control, 21:493–50, (2010)
Niclis C, del Pilar Diaz M, La Vecchia C.
Breast cancer mortality trends and patterns in Cordoba, Argentina 1986-2006.
Eur. J. Cancer Prev., 19: 94-99 (2010)
Pelucchi C, Levi F, La Vecchia C.
The rise and fall in menopausal hormone therapy and breast cancer incidence.
The Breast, 19: 198-201 (2010)
Tramacere I, Scotti L, Jenab M, Bagnardi V, Bellocco R, Rota M, Corrao G, Bravi F, Boffetta
P, La Vecchia C.
Alcohol drinking and pancreatic cancer risk: a meta-analysis of the dose-risk relation.
Int. J. Cancer, 126: 1474–1486 (2010)
ANNUAL REPORT
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Calabrò E, Randi G, La Vecchia C, Sverzellati N, Marchianò A, Villani M, Zompatori M,
Cassandro R, Harari S, Pastorino U.
Lung function predicts lung cancer risk in smokers: a tool for targeting screening programs.
Eur. Respir. J., 35: 146-151 (2010)
Galeone C, Turati F, La Vecchia C, Tavani A.
Coffee consumption and risk of colorectal cancer: a meta-analysis of case-control studies.
Edefonti V, Bravi F, La Vecchia C, Randi G, Ferraroni M, Garavello W, Franceschi S,Talamini
R, Boffetta P, Decarli A.
Nutrient-based dietary patterns and the risk of oral and pharyngeal cancer
Oral Oncol, 46: 343-348 (2010)
Galeone C, Petracci E, Pelucchi C, La Vecchia C, Tavani A.
Metabolic syndrome, its components and risk of age-related cataract extraction: a case-control
study in Italy.
Ann. Epidemiol., 20:380–384 (2010)
Rossi M, Bosetti C, Negri E, Lagiou P, La Vecchia C.
Flavonoids , proanthocyanidins and cancer risk: a network of case-control studies from Italy.
Nutr Cancer, 62: 871-877 (2010)
Rossi M, Lipworth L, Polesel J, Negri E, Bosetti C, Talamini R, McLaughlin J, La Vecchia C.
Dietary glycemic index and glycemic load and risk of pancreatic cancer: a case-control study.
Ann Epidemiol, 20: 460-465 (2010)
Negri E.
Sun exposure, vitamin D and risk of Hodgkin and non Hodgkin lymphoma.
Nutr Cancer, 62: 878-882 (2010)
Rota M, Bellocco R, Scotti L, Tramacere I, Jenab M, Corrao G, La Vecchia C, Boffetta P,
Bagnardi V
Random-effects meta-regression model for studying nonlinear dose-response relationship
Stat Med, 29: 2679-2687 (2010)
Goldstein BY, Chang S-C, Hashibe M, La Vecchia C, Zhang Z F
Alcohol consumption and cancer of the oral cavity and pharynx from 1988 to 2009: an update
Eur J Cancer Prev, 19: 431-465 (2010)
Grulich A E, Vajdic C M , Falster M O, Kane E , Smedby K E, Bracci P M, De Sanjose S,
Becker N, Turner J, Martinez-Maza O, Melbye M, Engels E A, Vineis P, Seniori Costantini A,
Holly E A, Spinelli J J, La Vecchia C, Zheng T, Chiu B C H, Dal Maso L, Cocco P, Maynadie
M, Foretova L, Staines A, Brennan P, Davis S, Severson R, Cerhan J R, Breen E C, Birmann B,
Cozen W
Birth order and risk of non-Hodgkin lymphoma – true association or bias?
Am J Epidemiol, 172: 621-630 (2010)
Hu J, La Vecchia C, Gibbons L , Negri E, Mery L, Canadian Cancer Registries Epidemiology
Research Group
Nutrients and risk of prostate cancer
ANNUAL REPORT
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Nutr Cancer, 62: 710-718 (2010)
F. Parente, M. Molteni, B. Marino, A. Colli, S. Ardizzone, S. Greco, G. Sampietro, D. Foschi,
S. Gallus.
Are colonoscopy and bowel ultrasound useful to assess response to short-term therapy and
predict disease outcome of moderate to severe forms of ulcerative colitis ? A prospective study
Am J Gastroenterol, 105: 1150-1157 (2010)
Pelucchi C, Negri N, Talamini R, Levi F, Giacosa A, Crispo A, Bidoli E, Montella M,
Franceschi S, La Vecchia C
Metabolic syndrome is associated with colorectal cancer in men
Eur J Cancer, 46: 1866-1872 (2010)
Hu J, La Vecchia C, Negri E, Mery L
Nutrients and Risk of Colon Cancer
Cancer, 2: 51-67 (2010)
Bosetti C, Bravi F, Talamini R, Montella M, Negri E, La Vecchia C.
Aspirin and risk of endometrial cancer: a case-control study from Italy.
Eur J Cancer prev, 19: 401-403 (2010)
Bonifazi M, Gallus S, Bosetti C, Polesel J, Serraino D, Talamini R, Negri E, La Vecchia C.
Aspirin use and pancreatic cancer risk
Eur J Cancer Prev, 19: 352-354 (2010)
Martínez-Sáncheza,JM, Fernándeza,E, Fua,M, Gallus S, Martíneza,C, Sureda X, La Vecchia C,
Clancy L
Smoking behaviour, involuntary smoking, attitudes towards smoke-free legislation, and tobacco
control activities in the European Union.
PLoS ONE, 5: e13881 (2010)
Esposito S, Cecinati V, Scicchitano B, Delvecchio GC, Santoro N, Amato D, Pelucchi C,
Jankovic M, De Mattia D, Principi N.
Impact of influenza-like illness and effectiveness of influenza vaccination in oncohematological
children who have completed cancer therapy.
Vaccine. 28: 1558-1565 (2010)
Galeone C, Tavani A, Pelucchi C, Turati F , Winn DM,
Levi F, Yu G-P, Morgenstern H, Kelsey K, Dal Maso L, Purdue MP, McClean M, Talamini R,
Hayes RB, Franceschi A, Schantz S, Zhang Z-F, Ferro G, Chuang S-C, Boffetta P, La Vecchia
C, Hashibe M
Coffee and tea intake and risk of head and neck cancer: pooled analysis in the international head
and neck cancer Epidemiology consortium.
Cancer Epidemiol Bio Prev, 19: 1723-36 (2010)
Tramacere I, Negri E, Bagnardi V, Garavello W, Rota M, Scotti L, Islami F, Corrao G, Boffetta
P, La Vecchia C
A meta-analysis of alcohol drinking and oral and pharyngeal cancers: 1. Overall results and
dose-risk relation
Oral Oncol, 46: 497–503 (2010)
Zatonski W, Sulkowska U, Manczuk M, Rehm J, Boffetta P, Lowenfels AB, La Vecchia C.
ANNUAL REPORT
208
2010
IRFMN
Liver cirrhosis mortality in Europe, with special attention to Central and Eastern Europe.
Eur Addiction Res, 16:193-201 (2010)
Autier P; Boniol M; La Vecchia C; Vatten L; Gavin A; Héry C; Heanue M
Disparities in breast cancer mortality trends between thirty European countries
BMJ, 341: c3620 (2010)
doi:10.1136/bmj.c3620
Chatenoud L, Bertuccio P, Bosetti C, Levi F, Negri E, La Vecchia C
Childhood cancer mortality in America, Asia, and Oceania, 1970 through 2007
Cancer, 116: 5063-5074 (2010)
Peleteiro B, Lunet N, Carrilho C, Durães C, Machado JC, La Vecchia C, Barros H.
Association between cytokine gene polymorphisms and gastric precancerous lesions: systematic
review and meta-analysis.
Cancer Epidemiol Biomarkers Prev, 19: 762-776 (2010)
Turati F, Gallus S, Tavani A, Tramacere I, Polesel J, Talamini R, Montella M, Scotti L,
Franceschi S, La Vecchia C
Alcohol and endometrial cancer risk: a case-control study and a meta-analysis
López-Miranda J, Pérez-Jiménez F, Ros E, De Caterina R, Badimón L, Covas MI, Escrich E,
Ordovás JM, Soriguer F, Abiá R, Alarcón de la Lastra C, Battino M, Corella D, ChamorroQuirós J, Delgado-Lista J, Giugliano D, Esposito K, Estruch R, Fernandez-Real JM, Gaforio JJ,
La Vecchia C, Lairon D, López-Segura F, Mata P, Menéndez JA, Muriana FJ, Osada J,
Panagiotakos DB, Paniagua JA, Pérez-Martinez P, Peinado MA, Pineda-Priego M, Poulsen HE,
Quiles JL, Ramírez-Tortosa MC, Ruano J, Serra-Majem L, Solá R, Solanas M, Solfrizzi V, R de
la Torre-Fornell, Trichopoulou A, Uceda M, Villalba-Montoro JM, Villar-Ortiz JR, Visioli F,
Yiannakouris N.
Olive oil and health: Summary of the II international conference on olive oil and health
consensus report, Jaen and Cordoba (Spain) 2008
Nutr Metab Cardiovasc Dis., 20: 284-294 (2010)
Malvezzi M, Bonifazi M, Bertuccio P, Levi F, La Vecchia C, Decarli A, Negri E
An Age-Period-Cohort Analysis of Gastric Cancer Mortality from 1950 to 2007 in Europe.
Ann Epidemiol, 20: 898-905 (2010)
Peleteiro B, Lunet N, Barros R, La Vecchia C, Barros H.
Factors contributing to the underestimation of Helicobacter pylori-associated gastric cancer risk
in a high-prevalence population.
Cancer Causes Control. 21:1257–1264 (2010)
The ESHRE Capri Workshop Group (In appendix: E Negri and C La Vecchia)
Bone fractures after menopause.
Human Reproduction Update, 16: 761-773 (2010)
Ricci E, Cipriani S, Chiaffarino F, Malvezzi M, Parazzini F.
Effects of soy isoflavones and genistein on glucose metabolism in perimenopausal and
postmenopausal non-Asian women: a meta-analysis of randomized controlled trials
Menopause, 17: 1080-1086 (2010)
ANNUAL REPORT
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Lucenteforte E, Garavello W, Bosetti C, La Vecchia C.
Dietary factors.
In: Epidemiology, pathogenesis, and prevention of head and neck cancer. (Olshan AF, editor),
Springer, New York. pp 117-136 (2010).
Parazzini F, Pelucchi C, Talamini R, Montella M, La Vecchia C
Use of fertility drugs and risk of endometrial cancer in an Italian case-control study.
Eur J Cancer Prev, 19: 428-430 (2010)
Turati F, Garavello W, Tramacere I, Bagnardi V, Rota M, Scotti L, Islami F, Corrao G, Boffetta
P, La Vecchia C, Negri E
A meta-analysis of alcohol drinking and oral and pharyngeal cancers. Part 2: Results by subsites
Oral Oncol, 46: 720-726 (2010)
Berry Sir C, La Vecchia C, Nicotera P
Paraquat and parkinson’s disease
Cell Death Differentiation, 17: 1115-1125 (2010)
Randi G, Edefonti V, Ferraroni M, La Vecchia C, Decarli A.
Dietary patterns and the risk of colorectal cancers and adenomas.
Nutrit Review, 68:389-408 (2010)
Bertuccio P, Bravi F, Bosetti C, Negri E, La Vecchia C
Aspirin and gastric cancer risk
Eur J Cancer Prev, 19: 426-427 (2010)
Islami F, Tramacere I, Rota M, Bagnardi V, Fedirko V , Scotti L, Garavello W, Jenab M,
Corrao G, Straif K, Negri E, Boffetta P, La Vecchia C
Alcohol drinking and laryngeal cancer: overall and dose-risk relation- a systematic review and
meta-analysis
Oral Oncol, 46: 802-810 (2010)
Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC, Skouby SO, Zikan M, Dusek
L, Crosignani P
Hormonal contraception and risk of cancer.
Hum Repr Update, 16: 631-650 (2010)
Bosetti C, Rossi M, Pelucchi C, La Vecchia C.
Mediterranean diet and cancer.
CML Kidney Cancer, 2: 69-76 (2010)
La Vecchia C.
Intake of artificially sweetened soft drinks and risk of preterm delivery.
Am J Clin Nutr 92: 1540 (2010)
Ricci E, Cipriani S, Chiaffarino F, Malvezzi M, Parazzini F
Soy isoflavones and bone mineral density in perimenopausal and postmenopausal western
women: a systematic review and meta-analysis of randomized controlled trials.
J Women’s Health, 19: 1609-1617 (2010)
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McLaughlin JK, LaVecchia C, Tarone RE, Lipworth L, Blot WJ
Re: False-positive results in cancer epidemiology: a plea for epistemological modesty (response
to Cogliano).
JNCI, 102: 134-135 (2010)
McLaughlin JK, Lipworth L, Tarone RE, La Vecchia C, Blot WJ, Boffetta P
Authors’ response: A further plea for adherence to the principles underlying science in general
and the epidemiologic enterprise in particular (by Hauptmann and Ronckers)
Int J Epid, 39: 1679-1680 (2010)
Parazzini F, Chiaffarino F, Chatenoud L, Cipriani S, Ricci E, Chiantera V, Bortolus R,
Maffioletti C.
Exposure to Video DisplayTerminals and Risk of Small-for-Gestational-Age Birth
J Environ Health 72: 24-27 (2010)
Rossi M, Talamini R, Lagiou P, Franceschi S, La Vecchia C.
Glycemic index and glycemic load in relation to body mass index and waist to hip ratio.
Eur J Nutr, in press
http://www.ncbi.nlm.nih.gov/pubmed/20390288
Gallus S, Tramacere I, Boffetta P, Fernandez E, Rossi S, Zuccaro P, Colombo P, La Vecchia C.
Temporal changes of under-reporting of cigarette consumption in population-based studies.
Tobacco Control, in press
Cremona M, Calabrò E, Randi G, De Bortoli M, Mondellini P, Sozzi G, Pierotti MA, La
Vecchia C, Pastorino U, Bongarzone I.
Elevated levels of the acute-phase serum amyloid A are associated with heightened lung cancer
risk.
Cancer, in press.
Bagnardi V, Randi G, Lubin J, Consonni D, Lam TK, Subar AF, Goldstein A, Wacholder S,
Goldin L, Bergen A, Tucker M, Decarli A, Caporaso N, Bertazzi PA, Landi MT.
Alcohol consumption and lung cancer risk in the “Environment and Genetics in Lung cancer
Etiology (EAGLE) study.
Am. J. Epidemiol., in press
Ricci E, Chiaffarino F, Cipriani S, Malvezzi M, Parazzini F.
Diet in pregnancy and risk of small for gestational age birth: results from a retrospective casecontrol study in Italy.
Maternal Child Nutr., in press.
http://www3.interscience.wiley.com/journal/122651373/abstract?CRETRY=1&SRETRY=0
Bravi F, Polesel J, Bosetti C, Talamini R, Negri E, Dal Maso L, Serraino D, La Vecchia C.
Dietary intake of selected micronutrients and the risk of pancreatic cancer: an Italian casecontrol study.
Ann Oncol, in press.
Pira E, Piolatto G, Negri E, Romano C, Boffetta P, Lipworth L, McLaughlin JK, La Vecchia C
ANNUAL REPORT
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Bladder cancer mortality of workers exposed to aromatic amines: a 58-year follow-up
J Natl Cancer Inst, in press
http://www.ncbi.nlm.nih.gov/sites/pubmed/20548022
Rossi M, Negri E, La Vecchia C, Campos H
Smoking habits and the risk of nonfatal acute myocardial infarction in Costa Rica
Eur J Card Prev Rehabil, in press
Cecinati V, Esposito S, Scicchitano B, Dalvecchio G C , Amato D, Pelucchi C, Jankovic M,
Mattia D D, Principi N
Effectiveness of recall systems for improving influenza vaccination coverage in children with
oncohematological malignancies.
Human Vaccine, in press
http://www.ncbi.nlm.nih.gov/sites/entrez/19946216
Rosato V, Zucchetto A, Bosetti C, Dal Maso L, Montella M, Pelucchi C, Negri E, Franceschi S,
La Vecchia C
Metabolic syndrome and endometrial cancer risk
Ann Oncol, in press
Pelucchi C, Esposito S, Galeone C, Semino M, Sabatini C, Picciolli I, Consolo S, Milani G,
Principi N
Knowledge of human papillomavirus infection and its prevention among adolescents and
parents in Italy
BMC Public Health, in press
Bosetti C, Scelo G, Chuang S - C, Tonita J M , Tamaro S, Jonasson J G , Kliewer E V ,
Hemminki K, Weiderpass E , Pukkala E, Tracey E , Olsen J H , Pompe-Kirn V , Brewster D H ,
Martos C , Chia K - S , Brennan P, Hashibe M, Levi F, La Vecchia C, Boffetta P
High constant incidence rates of second primary cancers of the head and neck: a pooled analysis
of 13 cancer registries
Int J Cancer, in press
Pelucchi C, Galeone C, Talamini R, Negri E, Polesel J, Serraino D, La Vecchia C
Dietary acrylamide and pancreatic cancer risk in an italian case-control study.
Ann Oncol, in press
Bertuccio P, La Vecchia C, Silverman D, Petersen G, Bracci P, Negri E, Donghui L, Risch H A
, Olson S H , Gallinger S, Miller A B, Bueno-De-Mesquita H B, Talamini R, Polesel J,
Ghadirian P, Baghurst P A, Zatonski W, Fontham E , Bamlet W R, Holly E A, Lucenteforte E,
Hassan M, Yu H , Kurtz R C , Cotterchio M, Su J , Maisonneuve P, Duell E J, Bosetti C,
Boffetta P
Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: a re-analysis from the
International Pancreatic Cancer Case-Control Consortium (PanC4)
Ann Oncol, in press
Esposito S, Molteni CG, Daleno C, Valzano A, Tagliabue C, Galeone C, Milani G, Fossali E,
Marchisio P, Principi N.
Collection by trained pediatricians or parents of mid-turbinate nasal flocked swabs for the
detection of influenza viruses in childhood.
ANNUAL REPORT
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Virology Journal 2010, 7:85
Bertuccio P, Levi L, Lucchini F, Chatenoud L, Bosetti C, Negri E, La Vecchia C
Coronary heart and cerebrovascular disease mortality in young adults: recent trends in Europe
Eur j cardiovascular prev, in press
Bosetti C, Levi F, Rosato V, Bertuccio P, Lucchini F, Negri E, La Vecchia C
Recent trends in colorectal cancer mortality in Europe
Lipworth L, Zucchetto A, Bosetti C, Franceschi S, Talamini R, Serraino D, McLaughlin J K, La
Vecchia C, Negri E
Diabetes mellitus and other medical conditions and pancreatic cancer: a case-control study
Diabetes Metab Res Rev, in press
Bonifazi M, Malvezzi M, Bertuccio P, Edefonti V, Garavello W, Levi F, La Vecchia C, Negri E
Age-Period-Cohort Analysis of Oral Cancer Mortality in Europe: the End of an Epidemic?
Oral Oncol, in press
Tramacere I, La Vecchia C, Negri E
Tobacco smoking and esophageal and gastric cardia adenocarcinoma: A metaanalysis
Epidemiology, in press
Gallus S, Turati F, Polesel J, Talamini R, Franceschi S, La Vecchia C
Soft drinks, sweetened beverages and risk of pancreatic cancer
Cancer Causes and Control, in press
Gallus S, Tramacere I, Pacifici R, Zuccaro P G, Colombo P, Ghislandi S, La Vecchia C
Smoking in Italy 2008-2009: a rise in prevalence related to the economic crisis?
Prev Med, in press
Fedirko V , Tramacere I, Bagnardi V, Rota M, Scotti L, Islami F, Negri E, Straif K, Romieu I,
La Vecchia C, Boffetta P, Jenab M
A meta-analysis of alcohol drinking and colorectal cancer risk: a dose-response analysis of
published studies
Ann Oncol, in press
Hu J, La Vecchia C, Morrison H, Negri E, Mery L, Canadian Cancer Registries Epidemiology
Research Group
Salt, processed meat and the risk of cancer.
Eur J Cancer Prev, in press
Islami F, Fedirko V, Tramacere I, Bagnardi V, Jenab M, Scotti L, Rota M, Corrao G, Garavello
W, Schuz J, Straif K, Negri E, Boffetta P, La Vecchia C
Alcohol drinking and esophageal squamous cell carcinoma with focus on light-drinkers and
never-smokers – A systematic review and meta-analysis
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Pelucchi C, Zucchetto A, Tavani A, Dal Maso L, Serraino D, La Vecchia C.
Physical activity and pancreatic cancer risk.
Randi G, Malvezzi M, Levi F, Ferlay J, Negri E, Franceschi S, La Vecchia C.
Re: Classification of biliary tract cancer (BTC): evaluation of all entities.
Ann. Oncol., in press.
Turati F, Galeone C, La Vecchia C, Tavani A.
Coffee and Cancers of the Upper Digestive and Respiratory Tracts: Meta-analyses of
observational studies
Ann Oncol, in press
Pelucchi C, et al.
Exposure to acrylamide and human cancer-a review and meta-analysis of epidemic studies.
Ann Oncol, in press
Santoro E. Dai social network ai social media. Ricerca & Pratica 2010 ; n.154 : 159-160
Santoro E. Medpedia: il Wikipedia della medicina. Ricerca & Pratica 2010 ; n.153 : 123-124
Santoro E. La medicina viaggia su YouTube. Ricerca & Pratica 2010 ; n.151 : 27-28
Santoro E. Wikipedia o wiki medici? Ricerca & Pratica 2010 ; n.152 : 69-70
Santoro E. La newsletter web 1.0 del Ministero della Salute. Ricerca & Pratica 2010 ; n. 155 :
202-203
Santoro E. E’ indispensabile il coinvolgimento dei medici. Avvenire Medico 2010;8:13-14
Santoro E. Web 2.0 e diabete: il nuovo web al servizio dell’aggiornamento del medico. Giornale
Italiano di Diabetologia e Metabolismo 2010; 30:45-48
Santoro E. Internet, web 2.0 e malati cronici: i risultati di un’indagine. Partecipasalute 2010;
http://www.partecipasalute.it/cms_2/node/1467
Santoro E. La cartella clinica delude le aspettative. Partecipasalute 2010;
Santoro E. Per Big Pharma il futuro del marketing è su Facebook? Partecipasalute 2010;
Santoro E. Niente e-mail tra medico e paziente. Partecipasalute 2010;
Santoro E. La salute ai tempi del web 2.0. Il Sole 24 Ore Sanità 29 giugno – 5 luglio 2010; 1617
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Santoro E. Fascicolo elettronico, il mezzo flop inglese. Il Sole 24 Ore Sanità 19-25 ottobre
2010; 12
OTHER PUBLICATIONS (2010)
Levi F, La Vecchia C.
Cancer of the prostate
In: Tobacco - Science, policy and public health, 2e. (Chapter 19 and Prelims)
Rossi M, Negri E, Bosetti C, Pelucchi C, La Vecchia C.
Epidemiology behind fruit and vegetable consumption and cancer risk with a focus on
flavonoids.
In: Plant phenolics and human health. Biochemistry, Nutrition and Pharmacology. (Cesar G.
Fraga, ed.). John Wiley & Sons. Inc., Hoboken, New Jersey. pp. 471-487 (2010)
RESEARCH ACTIVITIES
Laboratory of General Epidemiology
CASE-CONTROL STUDIES ON CANCER
Dietary patterns and upper aero-digestive tract cancers
In a case-control study of laryngeal cancer, we identified five major dietary patterns named
“animal products”, “starch-rich”, “vitamins and fiber”, “vegetable unsaturated fatty acids”, and
“animal unsaturated fatty acids”. The vitamins and fiber dietary pattern was inversely associated
with laryngeal cancer, whereas the animal products and the animal unsaturated fatty acids
patterns were directly associated with it. There was no significant association between the
vegetable unsaturated fatty acids and the starch-rich patterns and laryngeal cancer risk. These
findings suggest that diets rich in animal products and animal fats are directly related, and those
rich in fruit and vegetables inversely related, to laryngeal cancer risk.
A similar analysis of oral and pharyngeal cancer indicated that diets rich in animal origin and
animal fats are positively, and those rich in fruit and vegetables, and vegetable fats inversely
related to oral and pharyngeal cancer risk.
Green tea and gastric cancer
We considered the relationship between green tea and gastric cancer risk in Harbin, China, an
area with high baseline risk of stomach cancer. No association emerged when tea consumption
alone was considered. When tea consumption was further classified according to the
temperature, however, the odds ratio (OR) was 0.19 for cold tea intake ≥750 g/year and 1.27 for
hot tea intake as compared to non drinkers.
Flavonoids, proanthocyanidins and gastric cancer
Flavonoids have been suggested to be responsible for the potential beneficial properties of fruit
and vegetables on stomach cancer risk. We analyzed data from a case-control study conducted
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in Italy including 230 cases with incident gastric cancer and 547 controls. Using logistic
regression models, strong inverse relations were found for proanthocyanidins. The OR for the
highest versus the lowest quintile was 0.44 for monomers and dimers combined, and 0.36 for
polymers with three or more mers. Further adjustment for fruit and vegetables, or vitamin C, did
not materially change these associations.
Aspirin and gastric cancer risk
Studies on the relation between aspirin and non-steroideal anti-inflammatory drugs (NSAIDs),
and the risk of gastric cancer are inconsistent. We analyzed data of our case-control study
conducted in Northern Italy in 1997-2007, based on 230 cases and 547 controls. Regular use of
aspirin was reported by 21 (9.2%) cases and 46 (8.5%) controls, and was not related with risk of
gastric cancer (OR=1.09 95% confidence interval, CI: 0.61–1.94). No associations were found
with duration of use, age at first use, time since first use, and time since last use.
Nutrients and colon cancer
We were also involved in a nationwide case-control studies from 8 Canadian provinces. With
reference to colon cancer, intake of polyunsaturated fat, trans-fat and cholesterol were
significantly associated with the risk of colon cancer. The association was stronger with
proximal colon cancer. An increased risk was also observed with increasing intake of sucrose
for both proximal and distal colon cancers. An elevated risk of proximal colon cancer was also
found with increased lactose intake.
Dietary patterns and colorectal cancer
In an Italian case-control study we identified five nutrient-based dietary patterns, and we
investigated their role on colorectal cancer risk. Direct associations were observed between the
“Starch-rich” pattern and both cancer of the colon (OR=1.68) and rectum (OR=1.74). Inverse
relations were found between the “Vitamins and fiber” pattern and rectal cancer (OR=0.61),
between the “Unsaturated fats (animal source)” and the “Unsaturated fats (vegetable source)”
and cancer of the colon (OR=0.80 and OR=0.79, respectively). The “Animal products” pattern
was not associated with colorectal cancer.
Proanthocyanidins and colorectal cancer
In vitro and animal studies suggest that proanthocyanidins decrease cancer risk, particularly
colorectal cancer. We analyzed data from an Italian case-control study on 1953 incident cases of
colorectal cancer and 4154 controls. Using logistic regression methods, we found a decreased
risk of cancer with increasing intake of proanthocyanidins. The OR for the highest quintile
compared to lowest was 0.88 for monomers, 0.75 for dimers, 0.84 for trimers, 0.80 for polymers
with 4-6 meres, 0.79 for polymers with 7-10 meres, and 0.69 for polymers with more than 10
meres. The associations appeared stronger for the rectum than the colon. Our results may
explain the protective effect of fruit and vegetables on these tumors.
Metabolic syndrome and colorectal cancer
We analysed data from a multicentre case-control study conducted in Italy and Switzerland,
including 1378 cases of colon cancer, 878 cases of rectal cancer and 4661 controls to assess the
relation between metabolic syndrome (MetS) and its components and colorectal cancer. MetS
was defined according to the International Diabetes Federation criteria. With reference to each
component of the MetS, the ORs of colorectal cancer were increased in men only. Accordingly,
colorectal cancer risk was increased in men (OR=1.86), but not women (OR=1.13), with MetS.
Results were similar for colon and rectal cancers. This study supported a direct association
between MetS and both colon and rectal cancers in men, but not in women.
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Dietary habits and pancreatic cancer
In the case-control study on pancreatic cancer we investigated the role of dietary habits.
Frequent meat consumption was associated to a two-fold increased risk of pancreatic cancer; the
risk was significant for meat cooked by boiling/stewing or broiling/roasting. Added table sugar
(OR = 2.23) and potatoes (OR = 1.79) were significantly related to pancreatic cancer. A
significant inverse association emerged for non-citrus fruits (OR = 0.41), cooked vegetables
(OR = 0.57), and, possibly, for pulses (OR = 0.59). The present study supports an inverse
association between fruit and vegetables and pancreatic cancer risk, and it confirms a direct
relation with meat.
Macronutrients, fatty acids, cholesterol and pancreatic cancer
A positive association was found between pancreatic cancer and animal proteins (OR=1.85 for
the highest versus the lowest quintile of intake; p for trend=0.039), whereas a negative
association was observed for sugars (OR=0.52; p for trend=0.003). Non-significant negative
associations emerged for vegetable proteins (OR=0.69) and polyunsaturated fatty acids
(OR=0.67). A diet poor in animal proteins and rich in sugars (mainly derived from fruit)
appears to have a beneficial effect on pancreatic cancer risk.
Micronutrients and pancreatic cancer
Several studies have reported an inverse relation between fruit and vegetables and pancreatic
cancer, but no specific component of these foods has been clearly identified as beneficial. We
estimated the intakes of selected vitamins, carotenoids and minerals, using an Italian food
composition database applied on information collected through a food frequency questionnaire.
We observed inverse associations with vitamin E (OR=0.60), vitamin C (OR=0.44), folate
(OR=0.56), and potassium (OR=0.57). Non significant protections were also observed for αcarotene, β-carotene, and β-cryptoxanthin, while no relation was found with retinol, lycopene,
lutein/zeaxanthin, total carotenoids, vitamin D, thiamin, riboflavin, niacin, vitamin B6, calcium,
phosphorus, iron, zinc, and sodium.
Dietary acrylamide and pancreatic cancer
In the same database of pancreatic cancer, we investigated the relation with dietary acrylamide
exposure. The OR of pancreatic cancer for an increase in acrylamide intake of 10 µg/day was
1.01. No meaningful difference between ORs was found in strata of smoking habit, alcohol
drinking, body mass index (BMI) and other selected covariates. Thus, this study found no
association between dietary acrylamide and pancreatic cancer.
Soft drinks, sweetened beverages and pancreatic cancer
We considered the association between carbonated drink consumption and pancreatic cancer
risk in an Italian case-control study conducted on 326 pancreatic cancer cases and 652 matched
controls. We also combined the results from all the studies on soft drinks or sweetened
beverages and pancreatic cancer published before June 2010, using a meta-analytic approach. In
the case-control study, compared with non-drinkers, the multivariate OR was 1.02 for
carbonated drink consumers and 0.89 for regular consumers. From the literature search, we
identified 4 other case-control (1919 cases) and 6 cohort studies (2367 cases). The pooled
relative risks (RR) for soft drink consumers vs. non-consumers were 0.97 for case-control, 1.05
for cohort, and 1.02 for all studies.
Physical activity and pancreatic cancer
We also analyzed data on physical activity and pancreatic cancer risk. For the highest vs. lowest
level of occupational physical activity, the ORs were 1.24 at age 15-19, 1.21 at age 30-39 and
1.41 at age 50-59, with no significant trend in risk at any age considered. The corresponding
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ORs for recreational physical activity were 1.44 at age 15-19, 1.52 at age 30-39 and 1.39 at age
50-59. Therefore, occupational and recreational physical activity were not associated to a
decreased risk of pancreatic cancer in our study.
Tobacco, alcohol and pancreatic cancer
Tobacco smoking is the major established risk factor for pancreatic cancer, whereas the role of
alcohol consumption is still open to debate. In our case-control study including 326 cases with
pancreatic cancer and 652 controls, pancreatic cancer was associated to current smoking
(OR=1.68), and the risk rose with increasing number of cigarettes/day (OR=2.04 for 20
cigarettes/day). No association emerged for former smokers. Alcohol consumption was
associated to increased pancreatic cancer risk, but ORs were significant only among heavy
drinkers. The risk was 4.3-fold higher in heavy smokers and heavy drinkers in comparison with
never smokers who drunk <7 drinks/week.
Diabetes mellitus, other medical conditions and pancreatic cancer
We considered diabetes and other medical conditions in relation to pancreatic cancer risk among
two datasets collected between 1983 and 2008 and including 683 cases. Diabetes was associated
with pancreatic cancer risk, and the association was significant for diabetes diagnosed up to 10
years before pancreatic cancer. As compared to non-diabetic non-smokers, the OR was 1.85
among non-diabetic current smokers, 2.18 among diabetic never/former smokers, and rose to
4.67 among diabetic current smokers, indicating a multiplicative effect between these two risk
factors. Pancreatic cancer was also significantly associated with pancreatitis, primarily among
those diagnosed within 2 years.
Aspirin use and pancreatic cancer
We analyzed the role of aspirin use in pancreatic carcinogenesis using data from a hospitalbased case-control study (308 cases e 477 controls) conducted in Italy between 1991 and 2008.
A total of 22 cases (7%) and 37 controls (8%) reported regular aspirin use, with a corresponding
adjusted OR of 0.87. A slight protection, although not significant, was observed for duration of
use > or =5 years (OR=0.53) and for time since first use > or =10 years (OR=0.69). The risk of
pancreatic cancer was significantly below unity for current users of > or =5 years (OR=0.23).
Dietary fiber and endometrial cancer
The epidemiological evidence on the relation between dietary fiber intake and endometrial
cancer is contradictory. We further investigated the issue in a case-control study of 454 women
with incident, histologically confirmed, endometrial cancer and 908 controls. Information on
diet was elicited using a validated food frequency questionnaire. Lignin intake was significantly
inversely related to endometrial cancer (OR=0.6 for the highest vs. the lowest quintile of
intake), whereas total fiber intake was not associated with risk. Data suggest the potential
importance of lignin intake in the prevention of endometrial cancer at Italian consumption
levels.
Metabolic syndrome and endometrial cancer
The same case-control study - conducted between 1992 and 2006 in the provinces of Milan,
Pordenone and Naples - showed a significant association between the metabolic syndrome (a
cluster of central obesity, diabetes, hyperlipidemia, hypertension) and risk of endometrial
cancer. According to different definitions of the metabolic syndrome, women with at least three
components of the syndrome were 3 to almost 9 times more likely to develop endometrial
cancer than women with no component.
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Aspirin and risk of endometrial cancer
We provided additional information on the role of aspirin on endometrial cancer. Regular
aspirin use was reported by 28 (6.3%) cases and 46 (6.8%) controls, corresponding to a non
significant multivariate OR of 0.65. There was no consistent pattern of risk with duration of use,
nor with age at first use, time since first use or time since last use. Further, there was no
difference in risk estimates across strata of BMI. This study -the first one from a population
outside North America- adds relevant information on the absence of a consistent association
between aspirin use and endometrial cancer risk, even in high-risk overweight and obese
women.
Use of fertility drugs and endometrial cancer
The same case-control study analyzed time-related aspects of the use of fertility drugs in
association to the risk of endometrial cancer. The OR of endometrial cancer for ever use of
fertility drugs was 3.26. The risk was higher for duration of use 12 months or more (OR= 6.10),
time since last use 25 years or less before the interview (OR= 5.30), and for age at first use less
than 30 years (OR= 5.14). Thus, our data support earlier findings of an increase in risk of
endometrial cancer with duration of use of fertility drugs.
Nutrients and prostate cancer
In a companion study of prostate cancer, an increased risk was observed with increasing intake
of sucrose and disaccharides. In contrast, men in the highest quartile of cholesterol intake were
at lower risk of prostate cancer. No association was found with intake of total proteins, total fat,
monounsaturated fats, polyunsaturated fats, monosaccharides, and total carbohydrates. The
findings provide evidence that a diet low in trans-fat could reduce prostate cancer risk.
Citrus fruit and cancer
Our findings indicated that citrus fruit has a protective role against cancers of the digestive and
upper respiratory tract. No association was found with breast, endometrial, ovarian, prostate and
renal cell cancer (RCC).
Flavonoids, proanthocyanidins and cancer
We considered flavonoids and proanthocyanidins in a network of Italian case-control studies
including about 10,000 incident cases of selected cancers, and over 16,000 controls. Using
logistic regression analysis, these studies provide evidence of a protective role of flavanones on
upper aerodigestive tract cancers, flavonols, anthocyanidins and proanthocyanidins (in
particular, those with higher degree of polymerization) on colorectal cancer, flavonols and
flavones on breast cancer, isoflavones on ovarian cancer, and flavonols on renal cancer. No
association between flavonoids and prostate cancer emerged.
Glycemic index and glycemic load and to body mass index and waist to
hip ratio
High-glycemic index (GI) diet has been associated with obesity, but epidemiological data are
inconsistent. We investigated the relation between GI and glycemic load (GL) with BMI and
waist-to-hip ratio (WHR), using data of 7,724 patients from the control group of a network of
hospital-based case-control studies from Italy. Mean BMI decreased from the lowest to the
highest tertile of GI from 26.59 to 26.18 kg/m2 in men (p ~ 0.005), and from 25.81 to 25.09
kg/m2 in women (p < 0.001). With respect to GL tertiles, the corresponding values were 26.41
and 26.25 kg/m2 in men (p ~ 0.51), and 26.01 and 24.93 kg/m2 in women (p <0.001). No
consistent association was found with WHR.
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Trends in adherence to the Mediterranean diet
We investigated whether adherence to the Mediterranean diet changed during the period 19912006 in an Italian population. Subjects included in the study were 3247 adults with a wide
spectrum of acute conditions unrelated to long term modifications of diet. For each subject, we
computed a Mediterranean diet score on the basis of nine a priori defined peculiar
characteristics of the Mediterranean dietary pattern. Adherence to the Mediterranean diet
showed no significant change over the last 15 years in both sexes. Subjects aged 55-64
years, those with high education, and those born in central and southern Italy showed the
highest adherence to the Mediterranean diet.
POOLED- AND META-ANALYSES AND REVIEW PAPERS
Alcohol drinking and oral and pharyngeal cancers
We performed a review of all studies of alcohol, oral and pharyngeal cancers published between
1988 and 2009. A strong dose–response effect on the intensity of alcohol use was reported in
most of the studies. However, no apparent association was observed for the duration of alcohol
use. A decreased risk of approximately 10 to 15 years was associated with alcohol cessation.
Similar associations have been observed among nonsmokers in over 20 studies. In general, the
dominant type of alcohol consumption in each population was associated with the greatest
increase in risk.
We also conducted a meta-analysis of available data on the association between alcohol
drinking and oral and pharyngeal cancer (OPC) risk, published up to September 2009. We
identified 43 case-control and 2 cohort studies, including a total of 17,085 OPC cases. The
pooled RR was 1.21 (95% CI, 1.10-1.33) for ≤1 drink per day, and rose to 5.24 (95% CI, 4.366.30) for heavy alcohol drinking (≥4 drinks per day). The dose-risk analysis resulted in RR of
1.29 for 10 g ethanol/day, 3.24 for 50 g ethanol/day, 8.61 for 100 g ethanol/day, and 13.02 for
125 g ethanol/day. This meta-analysis provided more precise evidence of a gross excess of OPC
risk for heavy alcohol drinkers. It also indicated an increased risk for moderate doses, i.e. ≤1
drink or 10 g ethanol/day.
Alcohol drinking and esophageal squamous cell carcinoma
We conducted a systematic review and meta-analysis using 40 case-control and 13 cohort
studies that reported the risk of esophageal squamous cell carcinoma (ESCC) associated with
alcohol drinking for at least 3 levels of consumption. In studies adjusted for age, sex, and
tobacco smoking, the RR and 95% CI for the association between light alcohol drinking
(≤12.5g/d) and risk of ESCC was 1.38 (1.14-1.67). The association was slightly stronger in
Asian countries than in other populations. The adjusted RRs (95% CIs) were 2.62 (2.07-3.31)
for moderate drinking (>12.5-<50g/d) and 5.54 (3.92-7.28) for high alcohol intake (≥50g/d); the
RRs were slightly higher in non-Asian populations. In prospective studies, the RR (95% CI)
was 1.35 (0.92-1.98) for light, 2.15 (1.55-2.98) for moderate, and 3.35 (2.06-5.46) for high
alcohol intakes; light drinking showed an association with ESCC in Asia (5 studies) but not in
other regions (3 studies). Among never-smokers (9 studies), the RR (95% CI) was 0.74 (0.471.16) for light, 1.54 (1.09-2.17) for moderate, and 3.09 (1.75-5.46) for high intakes. This metaanalysis further corroborated the association of moderate and high alcohol intake with risk of
ESCC and provided risk estimates based on multiple prospective studies. Light alcohol intake
appeared to be associated to ESCC mainly in studies in Asia, which suggests a possible role of
genetic susceptibility factors.
Tobacco smoking and esophageal and gastric cardia adenocarcinoma
We conducted a meta-analysis of 33 studies published up to January 2010 on the association
between tobacco smoking and esophageal and gastric cardia adenocarcinoma risk. Compared to
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never smokers, the pooled RR was 1.76 for ever, 2.32 for current, and 1.62 for ex-smokers. No
significant difference emerged between esophageal (RR=1.85 for ever vs never smokers) and
gastric cardia (RR=1.76) adenocarcinoma. We found a direct association with quantity
(RR=2.48 for ≥20 cig/day) and duration (RR=2.32 for ≥40 years) of cigarette consumption. This
meta-analysis showed a significant excess of esophageal and gastric cardia adenocarcinoma risk
for smokers.
Alcohol drinking and laryngeal cancer
We conducted a meta-analysis on the association between alcohol drinking and laryngeal cancer
risk. Forty studies (38 case-control, 2 cohort) reporting at least three levels of consumption were
included. Overall, alcohol drinking versus non-drinking was associated with an approximately
2-fold increase in risk of laryngeal cancer (RR=1.90; 95% CI: 1.59-2.28). While light alcohol
drinking (≤1 drink/day) did not show any significant association with risk of laryngeal cancer
(12 studies. RR=0.88; 95% CI: 0.71-1.08), moderate drinking (>1 to <4 drinks/day) was
associated with a 1.5-fold increase in risk (35 studies. RR=1.47; 95% CI: 1.25-1.72) and heavy
drinking (≥4 drinks/day) was associated with a 2.5-fold increased risk (33 studies. RR=2.62;
95% CI: 2.13-3.23). Thus, this meta-analysis showed a significant and positive association
between alcohol drinking and laryngeal cancer risk, even at moderate doses.
Alcohol drinking and colorectal cancer risk
A meta-analysis with dose-risk estimation was performed to evaluate the association between
alcohol drinking and colorectal cancer risk from published epidemiological literature. We
identified 27 cohort and 34 case-control studies. The summary RR was 1.21 (95% CI, 1.131.28) for moderate alcohol drinking (>1 to 3 drinks/day), and 1.52 (95% CI, 1.27-1.81) for
heavy alcohol drinking (≥4 drinks/day). The RR for moderate drinkers, compared to non- or
occasional drinkers, was stronger for men (RR=1.24, 95% CI, 1.13-1.37) than for women
(RR=1.08, 95% CI, 1.03-1.13). For heavy drinkers, the association tended to be stronger in
Asian studies (RR=1.81, 95% CI, 1.33-2.46) compared to studies conducted in other
geographical regions, and in particular in Europe (RR=1.16, 95% CI, 0.95-1.43). The dose-risk
analysis found RRs of 1.07 (95% CI, 1.04-1.10), 1.18 (95% CI, 1.12-1.25), 1.38 (95% CI, 1.281.50), and 1.82 (95% CI, 1.41-2.35) for 10, 25, 50, and 100 g/day of alcohol, respectively. This
meta-analysis provided strong evidence for a positive association between colorectal cancer risk
and alcohol drinking, even at relatively low doses.
Dietary patterns and colorectal adenomas and cancer
We conducted a systematic review of dietary patterns and colorectal disease and cancer. Dietary
patterns named as healthy, prudent, fruit and vegetables, fat-reduced/diet foods,
vegetable/fish/poultry, fruit/whole grain/dairy, and healthy eating index-2005, recommended
food and Mediterranean diet scores were all associated with reduced risk of colorectal cancer. In
contrast, diets named Western, pork-processed meat-potatoes, meat-eaters, meat and potatoes,
traditional patterns, and dietary risk and life summary scores were associated with increased risk
of colorectal cancer. Dietary patterns for adenomas were consistent with those identified for
colorectal cancer.
Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer in
the PANC4 consortium
We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk
of pancreatic cancer using data from 11 case–control studies (6,056 cases and 11,338 controls)
within the International Pancreatic Cancer Case-Control Consortium (PanC4). Compared with
never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2–2.3), i.e. comparable
to that of cigarette-only smokers (OR 1.5; 95% CI: 1.4–1.6). The OR was 1.1 (95% CI: 0.69–
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1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount
of cigar smoked per day (OR 1.82 for ≥10 grams of tobacco), although not with duration. The
OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI:
0.75–1.3).
Selected aspects of Mediterranean diet and cancer
We reviewed the role of the Mediterranean diet on cancer risk in our series of case-control
studies. Several aspects of the Mediterranean diet (i.e., high vegetable and fruit consumption,
high fish, low meat intake, use of olive oil, whole grain foods consumption) were favourable on
risk of various cancer, particularly those of the digestive tract.
Acrylamide exposure and human cancer
We performed a critical review and meta-analysis of studies considering exposure to acrylamide
and cancer risk. We identified 25 publications providing relevant results. The summary RRs for
an increase of 10 µg/day of dietary acrylamide intake were close to unity for all the cancers
considered, ranging from 0.98 for esophageal cancer to 1.01 for colon, endometrial, ovarian and
kidney cancer. None of the estimates was significant. The combined standardized mortality
ratios for high occupational acrylamide exposure were 1.67 for pancreatic cancer and 2.22 for
kidney cancer. Available studies consistently suggest a lack of an increased risk of most types
of cancer from exposure to acrylamide. The main association which requires further monitoring
involves kidney cancer.
InterLymph study
We participated to a consortium study of non-Hodgkin lymphoma (NHL) worldwide. In this
pooled analysis, these was no significant association between increasing birth order and risk of
NHL. However, a significant association was present for a number of B- and T-cell NHL
subtypes. A significant positive association was present in higher socioeconomic status
participants only. Results were very similar for the related variable of sibship size. The known
correlation of high birth order with low socioeconomic status suggests that selection bias related
to socioeconomic status may be responsible for the association between birth order and NHL.
Ambient particulate matter and preterm birth or low birth weight
We reviewed epidemiologic evidence on maternal exposure to particulate matter (PM) and
adverse pregnancy outcomes, up to June 2009. We identified a total of 30 papers, including 13
with information on preterm birth, 17 on low birth weight (LBW) or very low birth weight
(VLBW), and 4 on small for gestational age (SGA). Eight studies on preterm birth, 11 studies
on LBW/VLBW and two studies on SGA reported some increased risk (by about 10-20%) in
relation to exposure to PM; no meaningful associations was found in the remaining studies.
However, even in studies reporting some excess risk, this was inconsistent across exposure
levels and pregnancy periods. Epidemiologic studies on maternal exposure to PM during
pregnancy thus do not provide convincing evidence of an association with the risk of preterm
birth and LBW/VLBW and SGA.
OTHER PROJECTS
HI-WATE project - Colorectal cancer and disinfection by-products in Italy
and Spain
Experimental data suggest that disinfection by-products (DBPs) are possible colorectal carcinogens, but
epidemiological evidence is inconclusive. To evaluate colorectal cancer risk in relation to long-term DBP
exposure we conducted a case-control study in the greater Milan area and the provinces of
Pordenone and Udine, Italy, and the metropolitan area of Barcelona, Spain. Cases are incident,
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histologically confirmed colon and rectal patients, aged 20-85 years and resident in the study
areas. Controls are hospital-based (Italy) or population-based patients (Spain) matched to cases
by age and sex. Besides data on known or potential risk factors of colorectal cancer, information
is collected on residential and water source history, water consumption and use, including
ingestion, showering, bathing, dishwashing and swimming pool attendance. Retrospective data
on DPB (mainly trihalomethane, THM) levels in the study areas is collected through local water
companies. Based on 400 cases and 363 controls from Italy, and 500 cases and 436 controls
from Spain, 46% of Italian subjects and 56% of Spanish subjects drunk water from public water
at the longest residence (mean duration 37 years in Italy and 35 years in Spain); the remaining
consumed water from bottles or other sources. The multivariate OR for subjects drinking water
from public supplies as compared to those drinking bottled water was 1.17 (95% CI, 0.87-1.58)
in Italy and 1.18 (95% CI, 0.79-1.77) in Spain. Taking long compared to short shower yield an
OR of 1.16 (95% CI, 0.83-1.63) in Italy and of 1.04 (95% CI, 0.80-1.40) in Spain. Mean THM
levels in Italy were <10 μg/l, and ranged between 17.6 and 134 μg/l in Spain. No clear dose-risk
relations between residential THM exposure and colorectal cancer risk were observed.
Preliminary results suggest a weak – if any – association between colorectal cancer and DBPs.
The MILD trial
We have collaborated with the Multicentric Italian Lung Diagnosis (MILD) trial, a randomised
trial of CT scan in lung cancer disease, plus smoking cessation assistance to both intervention
and control subjects. In this study, serum amyloid A (SAA) protein was strongly related to lung
cancer risk. Thus, SAA levels were predictive of an elevated risk of lung cancer, supporting the
general view that inflammation is implicated in lung cancer development.
In another analysis of the MILD trial, subjects with grade 2 bronchial diverticula were heavier
smokers, reported a history of coughing more frequently, and showed more severe functional
impairment, greater extent of emphysema and more severe bronchial wall thickening compared
with subjects with grade 1 and those without bronchial diverticula. Thus, bronchial diverticula
are a frequent finding in the major airways of smokers, and they are associated with other
markers of smoking-related damage.
In a third analysis, even a relatively small reduction in FEV1 % was found to be a significant
predictor of increased lung cancer risk. Thus, screening for lung cancer using airflow
obstruction with FEV1% is a strategy worth future consideration.
Influenza vaccination in children
In a study investigating the best recall system to improve influenza vaccination coverage in
children with oncohematological malignancies, 205 subjects were randomised to one of three
intervention groups: i) call by a known pediatrician from the Oncohematological Unit and
vaccination in the same Unit; ii) call by a known pediatrician from the Oncohematological Unit
and vaccination in a general pediatric clinic by an unknown paediatrician; iii) call by a
pediatrician not previously involved in caring for the children and vaccination in a general
pediatric clinic by an unknown paediatrician. The results showed that all of the recall strategies
were useful in increasing influenza vaccination coverage, particularly the first one, but the
efficacy was optimal only in the children who had interrupted chemotherapy for less than six
months.
In the same study, it was found that the clinical and socio-economic impact of influenza-like
illness and the effectiveness of influenza vaccination in children with oncohematological
disease were related to the length of the off therapy period, and seemed to be significantly
greater in those who had been off therapy for less
than 6 months in comparison with healthy controls. This suggests that the administration of
influenza
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vaccination should be strongly recommended only among oncohematological children who
have been
off therapy for less than 6 months.
Another investigation from the same study evaluated the efficiency of pediatric mid-turbinate
nasal flocked swabs to detect influenza viruses used by parents in 203 children aged 6 months to
5 years with signs and symptoms of respiratory disease. Two nasal samples were collected from
each child in a randomised sequence: one by a trained pediatrician and one by a parent. In
comparison with the pediatrician-collected samples, the sensitivity and specificity of the
parental collections were respectively 89.3% and 97.7%. The children were significantly more
satisfied with the parental collections. This study showed that mid-turbinate nasal flocked swabs
specifically designed for infants and children can be used by parents without reducing the
influenza virus detection rate.
Mortality of workers exposed to aromatic amines
We have updated to 58 years the follow-up of a cohort of workers exposed to extensively high
doses of aromatic amines. Overall, 56 deaths from bladder cancer were observed, compared
with 3.4 expected (standardized mortality ratio, SMR = 16.5, 95% CI, 12.4 to 21.4). The SMR
for bladder cancer increased with younger age at first exposure and increasing duration of
exposure. Although the SMR for bladder cancer steadily decreased with time since exposure
stopped, the absolute risk remained approximately constant at 3.5 deaths per 1000 man-years up
to 29 years after exposure stopped. Excess risk was apparent 30 years or more after last
exposure.
Incidence rates of second primary cancers of the head and neck
Scanty data are available on the incidence of second cancers of the head and neck (HN) and its
pattern with age. We investigated this issue using data from a multicentric study of 13
population-based cancer registries from Europe, Canada, Australia and Singapore for the years
1943-2000. A total of 99,257 patients had a first primary HN cancer, contributing to 489,855
person-years of follow-up. A total of 1,294 of the patients (1.3%) were diagnosed with second
HN cancers. Male incidence rates of first HN cancer steeply increased from 0.68/100,000 at age
30-34 to 46.2/100,000 at age 70-74, and leveled off at older age; female incidence increased
from 0.50/100,000 at age 30-34 to 16.5/100,000 at age 80-84. However, age-specific incidence
of second HN cancers after a first HN cancer in men was around 200-300/100,000 between age
40-44 and age 70-74 and tended to decline at subsequent ages (150/100,000 at age 80-84); in
women, incidence of second HN cancers was around 200-300/100,000 between age 45-49 and
80-84. The incidence of second HN cancers does not increase with age, but remains constant, or
if anything, decreases with advancing age.
Knowledge and prevention of HPV infection
A study was aimed to investigate the knowledge of Italian adolescents and parents concerning
human papillomavirus (HPV) infection and its prevention. Both students and parents
underestimated the likelihood of HPV infection, and this was associated with a lower propensity
for vaccination. This is an important indication for future training programmes concerning HPV
prevention designed to increase the acceptance of HPV vaccine in families.
Effect of omega-3 supplementation on depression in elderly women
In a randomized controlled trial, it was investigated whether a supplement containing long chain
omega-3 polyunsaturated fatty acids improved depressive symptoms and health-related quality
of life in depressed elderly patients. The mean Geriatric Depression Scale at 8-week was
significantly lowered for the n-3 group. Supplementation with n-3 polyunsaturated fatty acids
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was found to be efficacious in the amelioration of depressive symptoms and quality of life in the
treatment of depressed elderly female patients.
Menopausal hormone therapy and breast cancer incidence
Recent studies conducted in different areas of North America and Europe showed a 5-10%
decline in the incidence of breast cancer. This followed reductions up to 70% in menopause
hormone therapy (HT) use after 2002. The observation that the decline in breast cancer
incidence was larger in (or limited to) women aged ≥50 years weighs in favour of an effect of
reduced HT use. However, changes in screening are also likely to play a role in the decreasing
incidence of breast cancer observed in several countries. Thus, the reasons of the falls in
incidence of breast cancer remain open to discussion.
Cytokine gene polymorphisms and gastric precancerous lesions
In a meta-analysis of studies of cytokine gene polymorphisms and gastric cancer from Portugal
and Mozambique, the IL1RN*22 genotype seems to consistently increase the risk of gastric
precancerous lesions, supporting a role for this polymorphism in the early stages of gastric
carcinogenesis.
Paraquat and Parkinson’s disease
We reviewed data on Paraquat (PQ) and Parkinson’s disease (PD). Several studies have
suggested that pesticide exposure and life in rural areas are significant risks factors for PD.
Among other pesticides, PQ has been linked to PD by epidemiological studies and experimental
work in rodents, in which it causes lesions in the substantia nigra, pars compacta. However, the
evidence that human exposure to the chemical results in an increased risk for PD is rather
limited and based on insufficient epidemiological data.
Emergency Medical System response to out-of-hospital cardiac arrest in
Milan, Italy
The objective of this study was to investigate how rapidly the Emergency Medical System
provides life support to 1426 patients having an out-of-hospital cardiac arrest in Milan, Italy
between January 2007 and October 2008. The mean time interval from collapse-to-first shock
was 18.67± 5.37 min. The mean Emergency Medical System unit response time interval was
7.07± 3.14 min; time elapsed from arrival-to first CPR was 7.75± 4.32 min. The dispatch to
arrival and dispatch to CPR intervals are comparable with those reported in other large urban
areas, but the time from arrival-to-first CPR was longer than recommended by current
guidelines.
TOBACCO CONTROL
Smoking in Italy 2008-2009
Two surveys on smoking were conducted in 2008 and 2009, i.e., before and during the
economic crisis. Each survey was based on a sample of more than 3000 individuals,
representative of the Italian population aged 15 years or over. Compared to 2008, there was a
significant increase in smoking prevalence overall (25.4% in 2009 vs 22.0% in 2008; <0.01),
among men (28.9% in 2009 vs 26.4%, p=0.13), and among women (22.3% in 2009 vs 17.9% in
2008; <0.01). The proportion of ever smokers did not change, whereas that of ex-smokers
decreased (18% in 2008 vs 15% in 2009). For the first time after several decades, in 2009
smoking prevalence increased in both sexes in Italy. This may be at least in part due to relapses
of former smokers, because of stress related to the economic crisis.
Smoking behavior, involuntary smoking, attitudes towards smoke-free
legislations, and tobacco control activities in the European Union
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We estimated the correlation between the Tobacco Control Scale (TCS; a scale that measures
the six most important cost-effective policies on tobacco control in each country) and selected
smoking patterns in the 27 countries of the European Union (EU27) in 2008. The correlation
between smoking prevalence and TCS score was negative (r = -0.42); the correlation between
TCS score and support to smoking bans in all workplaces was positive. The correlation between
TCS score and self-reported exposure to SHS was negative, but statistically non-significant.
Temporal changes of under-reporting of cigarette consumption in
population-based studies
We monitored trends in under-reporting of smoking in Italy over the last two decades, using 9
representative population-based surveys on smoking conducted in Italy in 1990 and annually
between 2001 and 2008, covering 26,397 individuals. The difference in cigarette consumption
between legal sale and self-reported data has substantially increased in Italy, from
approximately 1% in 1990, 25% in 2001 and up to 35% in 2008. This reflects increasing underreporting of cigarette consumption mainly due to a decreasing social acceptability of smoking.
The difference in cigarette consumption between legal sale and self-reported data has
substantially increased over the last two decades in Italy, reflecting increasing under-reporting
of cigarette consumption mainly due to a decreasing social acceptability of smoking.
PUBLIC HEALTH PREVENTION AND INFORMATION
The major products of our activity have also been published in the lay press, in order to increase
the project impact on prevention and public health.
Laboratory of Epidemiological Methods
MONITORING OF CANCER MORTALITY
Update of the systematic analysis of cancer mortality in Europe for 20002004
We analysed cancer mortality in 34 European countries during 2000–2004, with an overview of
trends in 1975–2004 using data from the World Health Organization (WHO). From 1990–1994
to 2000–2004, overall cancer mortality in the EU declined from 185.2 to 168.0/100 000 (world
standard, 29%) in men and from 104.8 to 96.9 (28%) in women, with larger falls in middle age.
Total cancer mortality trends were favourable, though to a variable degree, in all major
European countries. The major determinants of these favourable trends were the decline of lung
(216%) and other tobacco-related cancers in men, together with the persistent falls in gastric
cancer, and the recent appreciable falls in colorectal cancer. In women, relevant contributions
came from the persistent decline in cervical cancer and the recent falls in breast cancer
mortality, particularly in northern and western Europe. Favourable trends were also observed for
testicular cancer, Hodgkin lymphomas, leukaemias, and other neoplasms amenable to treatment,
though the reductions were still appreciably smaller in eastern Europe.
Age-period-cohort analysis of oral cancer mortality in Europe
To update trends in oral cancer mortality and analyse the recent epidemic in central Europe,
official death certifications for oral and pharyngeal cancer for 37 European countries were
derived over the period 1970-2007, and an age-period-cohort model was fitted for selected
countries. Male oral cancer mortality continued to decline in most European countries, and,
more importantly, it also started to decline in some of the countries with the highest male rates,
i.e. Hungary (18.9/100 000) and Slovakia (15.8/100 000); persisting rises were, however,
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observed in Belarus, Bulgaria and Romania. In women rates were lower than in men and
showed no appreciable trend over the recent period in the EU. The estimated effects of age,
period of death and cohort of birth for most selected countries showed a fall in effects from the
cohorts born after the 1950’s. For the period effect there was a rise for the earlier periods, an
inversion in the 1990's and a continuous fall up to the last studied period. Only some former
non-market economy countries, like Romania, Ukraine and Lithuania, had rising cohort effect
trends up to most recent generations. The major finding of analysis is the leveling of the
epidemic for men in most European countries, including Hungary and other central European
countries where mortality from this cancer was exceedingly high. This essentially reflects the
changes in alcohol and tobacco consumption patterns in various populations.
The oral cancer epidemic in central and eastern Europe
We analyzed oral and pharyngeal cancer mortality in 38 European countries over the period
1975–2004. Joinpoint analysis was used to identify significant changes in trends. In the EU,
male mortality rates rose by 2.1% per year between 1975 and 1984, by 1.0% between 1984 and
1993, and declined by 1.3% between 1993 and 2004, to reach an overall age-standardized rate
of 6.1/100,000 in 2000–2004. Mortality rates were much lower in women, and the rate in the
EU rose by 0.9% per year up to 2000, and leveled off to 1.1/100,000 in 2000–2004. In France
and Italy, which had the highest rates in the past, male rates have steadily declined during the
last two decades (annual percent change, APC=-4.8% in 1998–2004 in France and -2.6% in
1986–2003 in Italy). Persisting rises were, however, observed in several central and eastern
European countries, with exceedingly high rates in Hungary (21.1/100,000; APC=6.9% in
1975–1993 and 1.4% in 1993–2004) and Slovakia (16.9/100,000; APC=0.1% in 1992–2004).
The highest rates for women were in Hungary (3.3/100,000; APC=4.7% in 1975–2004) and
Denmark (1.6/100,000; APC=1.3% in 1975–2001). Oral and pharyngeal cancer mortality
essentially reflects the different patterns in tobacco smoking and alcohol drinking, including
drinking patterns and type of alcohol in central Europe.
Age-period-cohort analysis of gastric cancer mortality in Europe
In order to analyse the favourable trends in gastric cancer mortality in Europe, we applied an
age-period-cohort regression model to official, certified gastric cancer mortality data from 42
countries of the European region and the EU as a whole, from 1950 to 2007. We found that
Central and northern European countries, such as France, the UK, Sweden and Switzerland that
had very low mortality rates in the 2005-2007 period (between 4.5 and 5.5 / 100,000 men and
1.5 and 2.5 /100,000 women), showed steep descending period effects and cohorts that fell
steeply from the earliest cohorts to those born after the 1940’s where they stabilised.
Conversely, many former non-market economy countries had rates greater than 20/100,000 in
men and 10/100,000 in women. In these countries cohort effect falls were only seen later but the
fall gradient remained stable throughout recent cohorts. Mortality rates were also found to be
high in some countries of Southern and eastern Europe. The observed falls in gastric cancer
mortality are driven by downward trends in the effects of both cohorts and periods, although
these are stronger in the former, indicating that these favourable trends should continue in the
foreseeable future, particularly in those countries that still had high mortality rates, while in
some countries with very low rates there appears to be an asymptote in cohort effects born after
the 1940’s.
Colorectal cancer mortality in Europe
We updated to 2007 colorectal cancer mortality trends in Europe using data from the WHO. In
the EU, between 1997 and 2007 mortality from colorectal cancer declined by around 2% per
year, from 19.7 to 17.4/100,000 men (world standardized rates) and from 12.5 to 10.5/100,000
women. Persisting favourable trends were observed in countries of western and northern
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Europe, while there were more recent declines in several countries of eastern Europe
particularly in women (but not in Romania and the Russian Federation). In 2007, a substantial
excess in colorectal cancer mortality was still observed in Slovakia, Hungary, Croatia, the
Czech Republic and Slovenia in men (rates over 25/100,000), and in Hungary, Norway,
Denmark and Slovakia in women (rates over 14/100,000). Colorectal mortality trends were
more favourable in the young (30-49 years) from most European countries, with a decline of 2%
per year since the early 1990s in both men and women from the EU.
Disparities in breast cancer mortality trends in Europe
We also separately considered mortality from breast cancer. Changes in breast cancer mortality
after 1988 varied widely between European countries, and the UK is among the countries with
the largest reductions. Women aged <50 years showed the greatest reductions in mortality, also
in countries where screening at that age is uncommon. The increasing mortality in some central
European countries reflects avoidable mortality.
Liver cirrhosis mortality in Europe
With reference to liver cirrhosis, an increase of the burden of mortality appeared in Eastern
Europe in two specific areas: South-eastern Europe and North-eastern Europe. In the first group
of countries, liver cirrhosis mortality was 10-20 times higher than in most other European states,
levels never before observed in Europe.
Childhood cancer mortality in Europe
We analyzed mortality data derived from the WHO for all childhood neoplasms and selected
cancers in 30 European countries up to 2007. Between 1990-1994 and 2005-2007, mortality
from all neoplasms steadily declined in most European countries (from 5.2 to 3.5/100,000 boys
and from 4.3 to 2.8/100,000 girls in the EU). In 2005-2007, however, mortality rates from
childhood cancers were still higher in countries from Eastern (4.9/100,000 boys and 3.9/100,000
girls) and Southern (4.0/100,000 boys and 3.1/100,000 girls) Europe than in those from Western
(3.1/100,000 boys and 2.5/100,000 girls) and Northern (3.2/100,000 boys and 2.5/100,000 girls)
Europe. Similar temporal trends and geographic patterns were observed for leukaemias, with
declines from 1.7 to 0.9/100,000 boys and from 1.3 to 0.7/100,000 girls between 1990-1994 and
2005-2007 in the EU. For kidney cancer and NHL mortality rates were low and have been
declining in larger European countries over the last 15 years. The pattern of trends was less
clear for bone cancer, with no systematic downward trends at age 0-14, though some fall was
evident at age 15-19. Thus, mortality from childhood cancer continued to decline over more
recent years in most European countries. However, the mortality rates in Eastern - but also
Southern - European countries in the mid 2000's were similar to those in the Western and
Northern European ones in the early 1990's.
Coronary heart and cerebrovascular disease mortality in young adults, in
Europe
We analyzed trends in mortality from coronary heart diseases (CHD) and cerebrovascular
diseases (CVD) at age 35-44 in the EU as a whole and in 12 selected European countries, over
the period 1980-2007. With joinpoint regression analysis we identified significant changes in
trends and estimated average annual percent changes (AAPC). CHD mortality rates at ages 3544 years have decreased in both sexes since the 1980s for most countries, except for Russia
(130/100,000 men and 24/100,000 women, in 2005-07). The lowest rates (around 9/100,000
men and 2/100,000 women) were in France, Italy and Sweden. In men, the steepest declines in
mortality were in the Czech Republic (AAPC=-6.1%), the Netherlands (-5.2%), Poland (-4.5%)
and England and Wales (-4.5%). Patterns were similar in women, though with appreciably
lower rates. The AAPC in the EU was -3.3% for men (rate=16.6/100,000 in 2005-07) and -2.1%
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for women (rate=3.5/100,000). For CVD, Russian rates in 2005-07 were 40/100,000 men and
16/100,000 women, 5- to 10-fold higher than in most western European countries. The steepest
declines were in the Czech Republic and Italy for men, in Sweden and the Czech Republic for
women. The AAPC in the EU was -2.5% in both sexes, with steeper declines after the mid-late
1990's (rates=6.4/100,000 men and 4.3/100,000 women in 2005-07).
Trends in cancer mortality in Brazil, 1980-2004
We have also considered trends in cancer mortality in Brazil since 1980. Age-standardized
mortality rates between 1980 and 2004, derived from the WHO database, were computed for all
cancers and 24 major cancer sites in Brazil. Total cancer mortality rates increased over the last
decade in men to reach 101.2/100,000, and in women 71.3/100,000. In men, upward trends were
observed for cancers of the oral cavity and pharynx with a rate of 5.9/100,000 in 2000–2004,
intestines (whose rate, however was low, i.e. 7.6), prostate (12.2), and leukemias (3.4). Breast
cancer mortality leveled off at around 10/100,000 in the last decade, whereas declines were
observed for cancers of the uterus, whose rate (8.3) however, remained comparatively high.
Declines were observed for stomach cancer in both sexes, with rates of 11.1 in men and 4.6 in
women. In conclusion, most rates were comparatively low, but key issues were the high
rates of head and neck cancers in men and (cervix) uterine cancer in women, i.e., in
principle cancers that are largely avoidable through prevention, screening and early
diagnosis.
Trends in breast cancer mortality in Argentina
In an analysis for breast cancer trends from Cordoba, Argentina, rates over most recent calendar
years decreased, mainly in the most urbanized districts. Age–period–cohort models for Cordoba
province and Cordoba Capital showed a favorable cohort effect for generations born after 1955,
in the absence of a clear interpretation.
Childhood cancer mortality in America, Asia, and Oceania
In this article we analyzed and compared patterns in childhood cancer mortality in 24 developed
and middle-income countries in America, Asia, and Oceania between 1970 and 2007.
Childhood age-standardized mortality rates were derived from the WHO database for all
neoplasms, bone and kidney cancer, NHL, and leukemias. Since 1970, rates for all childhood
cancers dropped from approximately 8 to 3 per 100,000 boys and from 6 to 2 per 100,000 girls
in North America and Japan. Latin American countries registered rates of about 5 and 4 per
100,000 boys and girls respectively for 2005 through 2007, similar to the rates registered in
more developed areas in the early 1980s. Similar patterns were observed for leukemias. Highest
bone cancer rates for 2005 through 2007 were registered in Argentina, in Mexico for kidney
cancer and in Colombia for NHL, whereas the lowest rates were registered by Japan for kidney
and by Japan and the United States for NHL. Improvements in the adoption of current
integrated treatment protocols in Latin American and other lower- and middle-income countries
worldwide would avoid a substantial proportion of childhood cancer deaths.
OTHER PROJECTS
Risk factors for falls in community-dwelling older people
We performed a systematic review and meta-analysis on the literature on risk factors for falls in
community-dwelling older people. We identified a total of 74 studies, considering several risk
factors including sociodemographic, mobility, sensory, psychologic, and medical factors, and
medication use. The strongest associations were found for history of falls (OR=2.8 for all
fallers; OR=3.5 for recurrent fallers), gait problems (OR =2.1 and 2.2), walking aids use
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(OR=2.2 and 3.1), vertigo (OR=1.8 and 2.3), Parkinson disease (OR=2.7 and 2.8), and
antiepileptic drug use (OR=1.9 and 2.7).
Follow-up of subjects enrolled in case-control studies
The main aim of this project is to collect follow-up information on vital status and, when
needed, cause of death for subjects included in the case-control studies, in order to obtain a
prospective study from retrospectively collected data and to analyse factors influencing survival
from several cancers. We thus collected information on vital status of the subjects with
pancreatic cancer included in our database, by contacting the competent institutional sources
(Municipalities, Local Health Units, General Registry Offices).
Random-effects meta-regression models for studying nonlinear doseresponse relationship
A fundamental challenge in meta-analyses of published epidemiological dose-response data is
the estimate of the function describing how the risk of disease varies across different levels of a
given exposure. We developed a method, based on a two-step process, that addresses
simultaneously the following issues: within studies variability, between studies heterogeneity,
and nonlinear trend components. First, two-term fractional polynomial models are fitted within
each study included in the meta-analysis, taking into account the correlation between the
reported estimates for different exposure levels. Second, the pooled dose-response relationship
is estimated considering the between studies heterogeneity, using a bivariate random-effects
model.
Vitamin D and cancer risk
The epidemiological literature on sun exposure, vitamin D and lymphomas has been reviewed.
Similarities in the epidemiology of melanoma and NHL led to the hypothesis that UV exposure
increases the risk of NHL. Epidemiologic studies, however, have not confirmed this hypothesis.
If anything, an inverse association with recreational sun exposure emerged. Sun exposure is a
major determinant of vitamin D status. Studies investigating the association of dietary or serum
vitamin D with NHL are scanty and inconsistent, and the vitamin D-NHL relation remains
therefore largely undefined.
Strategies for prevention of cardiovascular mortality
An analysis of prevalence of risk factor and national cardiovascular mortality in Europe
indicated that high-risk populations should give the highest priority to achieving favourable
shifts in all modifiable risk factors. Irrespective of the level of any particular risk factor, the
rewards will be greatest in these populations.
Laboratory of Epidemiology of Chronic Diseases
CASE-CONTROL STUDIES
Organization for data and biological sample collection for case-control
studies
Data collection of epidemiological data is going on and it includes: 1) interview and interviewer
management and training activity for new interviewers; 2) contacts with hospital department
and ethical committee for study approval and conduction; 3) check and codification of patient
questionnaires; 4) diagnosis and histological exam check; 5) organization and management of
biological sample collection; 6) data input management.
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Ongoing case-control studies include: cancer of the oral cavity, pharynx, larynx, esophaguscardias, biliary tract, colorectum, bladder, lymphomas, myelomas and sarcomas.
The overall updated dataset include about: 1250 cases of cancers of oral cavity and pharynx,
700 of the esophagus, 1100 of the stomach, 6500 of the colorectum, 600 of the liver, 120 of the
biliary tract, 600 of the pancreas, 850 of the larynx, 500 cutaneous malignant melanoma, 7000
of the breast, 1000 of the cervix, 1000 of the endometrium, 200 of trophoblastic gestational
disease, 200 of the vulva, 2000 of the ovary, 1300 of the prostate, 700 of the bladder, 800 of the
kidney and renal pelvis, 600 of the thyroid, 200 of Hodgkin disease, 500 of non-Hodgkin
disease, 200 of sarcomas, 300 of myelomas and about 18,000 controls. Biological sample
collection, aimed to study genetic polymorphisms, includes cancers of the oral cavity, pharynx,
larynx, bladder and colorectum.
Aspirin use and renal cell cancer
Aspirin has been related to decreased risk of several cancers, but studies on the relation with the
risk of renal cell cancer (RCC) are inconsistent. We analyzed data of our case-control study.
Regular use of aspirin for at least six months was reported by 67 cases and 99 controls and was
not related with risk of RCC (OR = 0.98). The lack of association was consistent in both sexes,
in two strata of age, in users for less than 3 years or 3 years or longer, and among users of
aspirin as analgesic or for cardiovascular disease prevention.
Metabolic syndrome and cataract extraction
We explored the relationship between age-related cataract extraction and the metabolic
syndrome or its various components separately and in various combinations in an Italian casecontrol study, including 761 cases and 1522 hospital controls. The ORs were 1.41 for a history
of central obesity, 1.42 for hypertension, 1.25 for hyperlipidemia, and 1.16 for diabetes. Patients
with the metabolic syndrome had an increased risk of cataract, with an OR of 2.01 (95% CI,
1.43–2.83).
META-ANALYSIS
Coffee and cancers of the upper aero-digestive tract
We performed a meta-analysis on coffee consumption and risk of cancers of the upper aerodigestive tract, comparing the highest vs the lowest categories of coffee intake. For oral and
pharyngeal cancer, laryngeal cancer and esophageal squamous cell carcinoma, we selected only
studies with age, sex and smoking adjustments; for esophageal adenocarcinoma those with age,
sex and BMI (or energy) adjustments. We found a significant reduction in the risk of oral and
pharyngeal cancer of about 35% in highest coffee drinkers as compared to lowest drinkers, but
no relation of coffee drinking with laryngeal and esophageal cancer.
Alcohol drinking and oral and pharyngeal cancer
We conducted a meta-analysis to provide a quantification of the association of alcohol
consumption with oral and pharyngeal cancer separately, as well as with their subsites. We
found higher alcohol-related RRs for pharyngeal than for oral cancer, particularly at higher
doses: compared to non- or occasional drinkers, the pooled RRs for ≥4 drinks/day were 4.64 for
oral (17 studies) and 6.62 for pharyngeal (17 studies) cancer. The association with cancer of the
tongue was similar to that of oral cancer and weaker than that with hypopharyngeal and
oropharyngeal cancers.
Coffee consumption and colorectal cancer
A meta-analysis of case–control studies on coffee consumption and colorectal cancer risk was
conducted. Twenty-four eligible studies published before May 2010 were identified, including a
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total of 14,846 cases of colorectal, colon or rectal cancer. Compared to non/occasional drinkers,
the ORs for drinkers were 0.83 (95% CI, 0.73–0.95) for colorectal, 0.93 (95% CI, 0.81–1.07)
for colon and 0.98 (95% CI, 0.85–1.13) for rectal cancer, with significant heterogeneity among
studies. The results of this meta-analysis of case–control studies suggested a moderate favorable
effect of coffee consumption on colorectal cancer risk.
Alcohol drinking and pancreatic cancer
We performed a meta-analysis of relevant dose-risk results on the association between alcohol
consumption and pancreatic cancer risk. The pooled RR was 0.92 for <3 drinks/day and 1.22 for
≥3 drinks/day. The increased risk for heavy drinking was similar in women and men, but
apparently stronger in cohort studies (RR=1.29), in studies with high quality index (RR=1.30),
and did not appear to be explained by residual confounding by either history of pancreatitis or
tobacco smoking. Given the moderate increase in risk and the low prevalence of heavy drinkers
in most populations, alcohol appears to be responsible only for a small fraction of all pancreatic
cancers.
Alcohol and endometrial cancer
We analyzed data from our case-control study including 454 endometrial cancer cases and 908
controls, finding that alcohol drinking was not associated with the risk of this cancer, even for
relatively high doses (OR=1.19 for ≥15 drinks/week, compared with never drinking). A lack of
association was also observed for any type of alcoholic beverages (wine, beer and spirits). We
also performed a meta-analysis on alcohol and endometrial cancer, including other 19 casecontrol and 7 cohort studies (for a total of 13,120 cases). Compared to non/low drinkers, the
pooled RRs were 0.95 (95% CI 0.88-1.03) for drinkers and 1.12 (95% CI 0.87-1.45) for heavy
drinkers.
OTHER PROJECTS
INHANCE study
We were also actively involved in the International Head and Neck Cancer Epidemiology
(INHANCE) consortium, which includes data from 33 head and neck cancer studies worldwide,
and a total of about 25,000 cases of 33,000 controls.
In an analysis for the INHANCE consortium, including over 8.000 cases, a lower BMI
enhanced smoking- and drinking-related ORs for oral cavity/pharyngeal cancer (P < 0.01),
while BMI did not modify smoking and drinking ORs for laryngeal cancer.
Likewise, in the INHANCE dataset, quitting tobacco smoking for 1–4 years resulted in a head
and neck cancer risk reduction (OR=0.70), with the risk reduction due to smoking cessation
after ≥20 years, reaching the level of never smokers. For alcohol use, a beneficial effect on the
risk of head and neck cancer was only observed after ≥20 years of quitting (OR=0.60, 95% CI,
0.40–0.89 compared with current drinking).
Only a few studies explored the relation between coffee and tea intake and head and neck
cancers, with inconsistent results. In the INHANCE consortium, including 5139 cases and 9028
controls with information on the issue, we found that coffee intake was inversely related with
the risk of cancer of the oral cavity and pharynx: the ORs were 0.96 (95% CI, 0.94–0.98) for an
increment of 1 cup per day and 0.61 (95% CI, 0.47–0.80) in drinkers of >4 cups per day versus
nondrinkers. No association of coffee drinking was found with laryngeal cancer. Data on
decaffeinated coffee were too sparse for detailed analysis, but indicated no increased risk. Tea
intake was not associated with head and neck cancer risk.
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Definition and management of a cohort of residents in Asti for the
cardiovascular risk evaluation
The study is conducted with the collaboration of the ALMA association and the “Ordine dei
Medici di Asti” and includes data collection and first analysis of follow-up.
Laboratory of Medical Informatics
Development of a medical collaborative platform
In collaboration with the Arcispedale S. Maria Nuova of Reggio Emilia a project with the
following three aims has been started: the training of the medical staff working at the
Arcispedale hospital in using web 2.0 tools and social media for professional education and
update; the designing of tools to allow physicians to share medical knowledge; the development
of a collaborative platform to allow physicians to share evidence-based medical practices,
practice management information and other relevant medical information, and to discuss clinical
cases. As of today, more than 80 physicians, health professionals and medical librarians have
been trained on these issues. In addition, in collaboration with the Medical Library of the
Arcispedale S. Maria Nuova of Reggio Emilia, we have developed a blog where physicians may
access to and discuss on selected evidence-based medical literature. A collaborative platform for
sharing medical slides, images and videos is planned to be developed during 2011.
Maintenance of the CARDIO.CARE, ONCO.CARE, GASTRO.CARE,
NEURO.CARE, PNEUMO.CARE, BPCO.CARE, PAIN.CARE and
DERMA.CARE websites
These indexes have been developed by the Laboratory of Medical Informatics in order to
collect, classify, evaluate, and describe the most useful medical information on the web, and to
provide Internet users with an easy means to surf the net. Several medical areas are covered
including oncology (http://www.oncocare.it), neurology (http://www.neurocare.it),
gastroenterology (http://www.gastrocare.it), cardiology (http://www.cardiocare.it),
pulmonology (http://www.pneumocare.it, http://www.bpcocare.it ), the pain care and
management (http://www.paincare.it), and dermatology (http://www.dermacare.it). The project
is in collaboration with intramural departments (Department of Oncology, Laboratory of
Neurological Disorders and Department of Cardiovascular Research, Laboratory of General
Practice Research, Laboratory of Translational and Outcome Research in Oncology) and
extramural research groups (Italian Group for Epidemiologic Research in Dermatology,
GISED). During 2010, information about the use of web 2.0 tools and technologies (such as
podcast, RSS feeds, blogs, webcasts, and webinars) by the indexed websites has been collected.
RSS feeds and podcasting services have been activated on the CARE websites in order to allow
the users to access to the corresponding applications available on the classified websites.
Studies on the typology of the web 2.0 applications in medicine
The Laboratory of Medical Informatics is involved in studies and surveys which aim is to
describe the typology of the web 2.0 applications and tools (including social networks, podcasts,
feed RSS, blogs, and wikis) in medicine available on the net, and how these are perceived by
the medical community.
Internet as a research and formative tool on the chronic pain in cancer
patient
This research project was born in the framework of the project "Pain in the patient with cancer",
in collaboration with the Laboratory of Medical Research and Consumer Involvement and the
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Laboratory of Translational and Outcome Research in Oncology. Its aim is to make available
for doctors, patients and families correct information about therapies for cancer pain and to
produce greater tests on the effectiveness of therapies based on the use of analgesic drugs. This
project is articulated in two main activities:
Paincare, set-up a catalogue of selected web pages dedicated to the cancer pain and relative
periodical up-to-date, http://www.paincare.it;
Adaptation of the methods and instruments of Evidence Based Medicine to the resources
available on the Internet about chronic pain in patients with cancer. This is done through a
specific questionnaire. We are also considering the opportunity to set up a new Italian cancer
pain website.
Training activities
In 2010, the Laboratory of Medical Informatics continued its training activity on issues related
to the use of the Internet in medicine, and extended it to the use of the recent social media and
web 2.0 technologies and tools in the medicine area. The members of the laboratory staff
activated (or attended as invited teachers) a number of training courses, workshops, and master
courses. Onsite CME courses for the Italian physicians have also been organized using the
training/educational facilities and equipment available at the Mario Negri Institute.
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DEPARTMENT OF PUBLIC HEALTH
STAFF
Head Department
Maurizio BONATI, MD.
"Angelo & Angela Valenti" Centre for Health Economics (CESAV)
Head of Laboratory
Livio GARATTINI, Econ.D.
Laboratory of Clinical Epidemiology
Head of Laboratory
Guido BERTOLINI, MD.
Clinical Knowledge Engineering Unit
Head Unit
Davide LUCIANI, MD.
Computer Methods and Programs for Clinical Research Unit
Head Unit
Abramo ANGHILERI, IT.
Laboratory for Mother and Child Health
Head Laboratory
Maurizio BONATI, MD.
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CURRICULA
Maurizio Bonati has a Medical School degree at the University of Milan.
Areas of interest: Monitoring and epidemiological evaluation of drug utilisation and effects of drugs and
vaccines in motherhood and childhood. Research methodology in general hospital and paediatric
community practice. Transfer of information to the community. Epidemiology of paediatric and perinatal
care.
Past and present roles both at the Mario Negri Institute and in other institutions: 1973-77 Research Fellow
at the IRFMN, within the Neurochemistry Lab.; 1977-85 Research Assistant at the IRFMN, within the
Clinical Pharmacology Lab.; 1986-93 Chief of the Perinatal Clinical Pharmacology Unit at the IRFMN;
Advisor to WHO for the Drug Utilization Research Group (pregnancy, paediatrics and breastfeeding);
1987-92 coordinator of the International Cooperative Study of Drug Use in Pregnancy, under the auspices
of WHO and the support of EEC; 1992-93 co-editor of The Kangaroo; 2000-05 coordinator of the
European Cooperative Study: “Development of the European register of clinical trials on medicines for
children” (DEC-net), under the 5th Framework Programme’s Quality of life and Management of Living
Resources; since 1989 he has been director of the Centre for Drug Information; since 1993 head of the
Lab. for Mother and Child Health; since 1997 teacher for the Lombardy region’s professional training
courses; since 2000 teacher for the Lombardy region’s professional training courses; since 2002 Editor of
the Ricerca & Pratica scientific journal; since 2003 professor of the School of Specialisation in
Paediatrics - University of Milan Bicocca; teacher at the annual European course “Evaluation of
Medicinal Products in Children” (promoted by ESDPPP and Eudipharm); from May 2008 Head of
Department Public Health at the "Mario Negri" Institute for Pharmacology Research; since 2010
coordinator of the European Cooperative Study “COHEMI-Coordination resources to Assess and
Improve health status of migrants from Latin America”, under the 7th Framework Programme for
Research and Technological Development (Programme Cooperation- Health).
•
Santoro E, Rossi V, Pandolfini C, Bonati M. DEC-net: the development of the European Register of Clinical Trials on
Medicines for Children. Clinical Trials 2006;3:366-375.
•
Clavenna A, Rossi E, De Rosa M, Bonati M. Use of Psychotropic Medications in Italian Children and adolescents. Eur J
Pediatr 2007;166:339-47.
•
Maschi S, Clavenna A, Schiavetti B, Campi R, Bernat M, Bonati M. Neonatal outcome following pregnancy exposure to
antidepressants: a prospective controlled cohort study. BJOG 2008;115:283-289.
•
Usala T, Clavenna A, Zuddas A, Bonati M. Randomised controlled trials of Selective Serotonin Reuptake Inhibitors in
treating depression in children and adolescents: a systematic review and meta-analysis. European
Neuropsychopharmacology 2008;18:62-73.
•
Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfeeding: a review of the evidence. Pediatrics
2009;124:e547-e556.
•
Fortinguerra F, Maschi S, Clavenna A, Bonati M. Pain management in the paediatric population. The regulatory
situation in Europe. Arch Dis Child 2010;95:749-753.
Livio Garattini: got his degree in Economics in March 1983 at the Bocconi University in Milan.
Educational activities: “King’s Fund College”, London: courses of health care management; “Centre for
Health Economics”, York: review of publications on the English NHS; “Ecole Nationale de la Santé
Publique”, Rennes: courses of health policy.
Areas of interest: Health Economics and Health Policy Analysis.
At present he is the Director of CESAV (Centre of Health Economics A. e A. Valenti - M. Negri
Institute); 1981-1983: researcher at M. Negri Institute; 1983-1984: clerk at Banca Commerciale Italiana
in Milan; 1984- 1985: junior consultant at “Sogess srl” in Milan; 1985-1990: researcher at Bocconi
University in Milan.
• Cornago D, Li Bassi L, De Compadri P, Garattini L. Pharmacoeconomic studies in Italy: a critical review of the
literature. The European Journal of Health Economics 2007;8(2):89-95.
• Garattini L, Cornago D, De Compadri P. Pricing and reimbursement of in-patent drugs in seven European countries: A
comparative analysis. Health Policy 2007;82:330-339.
• Garattini L, Motterlini N, Cornago D. Prices and distribution margins of in-patent drugs in pharmacy: A comparison in
seven European countries. Health Policy 2008;85(3):305-313.
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•
•
•
Garattini L, Casadei G. Health technology assessment: for whom the bell tolls? The European Journal of Health
Economics 2008;9(4):311-312.
Garattini L, Casadei G, Freemantle N. Continuing medical education funding and management in Europe: room for
improvement? (Editorial) JME 2009;12(1):56-59.
Garattini L, Gritti S, De Compadri P, Casadei G. Continuing Medical Education in six European countries: A
comparative analysis. Health Policy 2010;94(3):246-54.
Guido Bertolini got his Medical degree in 1989 at the University of Bologna, and the specialization in
Pharmacological Research in 1993 at the “Mario Negri” Institute and in Gastroenterology in 1994 at the
University of Pavia.
He founded and chaired from 1997 to 2000 the School of Clinical Methodology and Quality of Care
Improvement at the Ospedali Riuniti di Bergamo and the Istituto di Ricerche Farmacologiche Mario
Negri. From 1999 to 2003 he has been contract professor at the post-doctoral schools in Anaesthesia and
Intensive Care, University of Brescia and Milano; from 2002 to 2005 he has been contract professor of
Educational Science at the Faculty of Lettere e Filosofia, University of Bergamo.
Current research interests: Clinical Research Methodology, Continuous Quality of Care Assessment and
Improvement, Health services research and outcome, Medical decision making, Medical Education.
These interests are mainly developed within the fields of Intensive Care Medicine and Rare Diseases.
Since 1997 he chairs the GiViTI Coordinating Center for research in intensive care medicine. He has been
Head of the Unit of Epidemiology and Education for Clinical Practice at the “Mario Negri” Institute and
since 2001 he is the Head of the Laboratory of Clinical Epidemiology. From 2001 to 2005 he has been
Vice-chairman of the Research Group on Cost-effectiveness, Section on Health Services Research and
Outcomes – European Society of Intensive Care Medicine and, from 2001 to 2005, he has been President
of the Scientific Committee of the “Ospedale maggiore” in Crema.
•
Bertolini G, Rossi C, Anghileri A, Livigni S, Addis A, Poole D. Use of drotrecogin alfa (activated) in Italian intensive
care units: the results of a nationwide survey. Intensive Care Med 2007;33:426-434.
•
Malacarne P, Langer M, Nascimben E, Moro ML, Giudici D, Lampati L, Bertolini G, GiViTI. Building a continuous
multicenter infection surveillance system in the intensive care unit: findings from the initial data set of 9,493 patients
from 71 Italian intensive care units. Crit Care Med 2008;36:1105-1113.
•
Poole D, Bertolini G, Garattini S. Errors in the approval process and post-marketing evaluation of drotrecogin alfa
(activated) for the treatment of severe sepsis. Lancet Infect Dis 2009;9:67-72.
•
Guido Bertolini, Simona Boffelli, Paolo Malacarne, Mario Peta, Mariano Marchesi, Camillo Barbisan, Stefano
Tomelleri, Simonetta Spada, Roberto Satolli, Bruno Gridelli, Ivo Lizzola, Davide Mazzon. End-of-Life Decision-Making
and Quality of ICU Performance: An Observational Study in 84 Italian Units. Intensive Care Med. 2010 Sep;36(9):1495504.
•
J.C. Marchall, K. Reinhart, D. Angus, A. Argent, G. Bernard, G. Bertolini, S. Bhagwanjee, J.P. Cobb, D.J. cook, D.
Fedson, S. Finfer, R. Fowler, C. Gomersall, E. Jimenez, N. Kissoon, D. McAuley, S. Opal, J.L. Vincent, S. Webb.
InFACT: a global vritical care clinical research reponse to severe pendemic H1N1. Lancet. 2010 Jan 2;375(9708):11-3.
•
Marchall JC, Reinhart K, Angus D, Argent A, Bernard G, Bertolini G, Bhagwanjee S, Cobb JP, Cook,
Fedson D, Finfer S, Fowler R, Gomersall C, Jimenez E, Kissoon N, McAuleyD, Opal S, Vincent JL, Webb
S. InFACT: a global vritical care clinical research reponse to severe pendemic H1N1. Lancet 2010 Jan
2;375(9708):11-3.
Davide Luciani got his Medical Degree at the University of Bologna in 1995, and the post-doctoral
certificate in "Tropical Medicine and Hygiene" at the University of Liverpool in 1997. In 2001, he spent
one year at the Department of Statistical Science (University College London). Bayesian probabilistic
applications, decision theory and the graphical approach to pathophysiological modelling represent his
main interests. Within his research activity, these skills are meant as the main methodological
ingredients in the formalization of clinical reasoning, in order to improve its effectiveness and to exploit
its educational value.
Since 2005 he is responsible of the Unit of Clinical Knowledge Engineering.
•
Luciani D, Marchesi M, Bertolini G. The role of Bayesian Network in the diagnosis of pulmunary embolism. J Thromb
Haemost 2003;1:698-707.
•
Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of
thrombosis in the antiphospholipid syndrome. Blood 2003;102 (8):2717-23.
•
Luciani D, Cavuto S, Antiga L, Miniati M, Monti S, Pistolesi M, Bertolini G. Bayes pulmonary embolism assisted
diagnosis: a new expert system for clinical use. Em Med J 2007;24:157-164.
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•
•
•
M.Cesana, R.Cerutti, E.Grossi, E.Fagiuoli, M.Stabilini, F.Stella, D Luciani. Bayesian Data Mining Techniques: The
Evidence Provided by Signals Detected in Single-Company Spontaneous Reports Databases. Drug Information Journal
2007;41:11-21.
Latronico N, Bertolini G, Guarneri B, Botteri M, Peli E, Andreoletti S, Bera P, Luciani D, Nardella A, Vittorielli E,
Simini B, Candiani A Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian
multi-centre CRIMYNE study. Crit Care 2007;11(1):R11.
Bertolini G, Luciani D, Biolo G Immunonutrition in septic patients: A philosophical view of the current situation. Clin
Nutr 2007;26:25-29.
Abramo Anghileri got his high-school certificate at the ITIS P. Paleocapa of Bergamo in 1997 and
attended several courses in information technology (IT) applied to health care. Since 2001 he coordinates
the IT activities of the Laboratory of Clinical Epidemiology at the Mario Negri Institute for
Pharmacological Research. His main area of interest is informatics applied to clinical research. Since
2009, he is the head of the Unit of Computer Methods and Programs for Clinical Research of the
Laboratory of Clinical Epidemiology.
•
•
•
•
•
Boffelli S, Rossi C, Anghileri A, Giardino M, Carnevale L, Messina M, Neri M, Langer M, Bertolini G. Continuous
quality improvement in intensive care medicine. The GiViTI Margherita project - Report 2005. Minerva Anestesiol 2006;
72: 419-432.
Bertolini G, Rossi C, Anghileri A, Livigni S, Addis A, Poole D. Response to the letter by Williams et al. Intensive Care
Med 2007; 33(8): 1490-1
Bertolini G, Rossi C, Anghileri A, Livigni S, Addis A, Poole D. Use of drotrecogin alfa (activated) in Italian intensive
care units: the results of a nationwide survey. Intensive Care Med 2007; 33(3): 426-34
Di Bartolomeo S, Valent F, Rossi C, Beltrame F, Anghileri A, Barbone F. Geographical differences in mortality of
severely injured patients in Italy. Eur J Epidemiol 2008
Poole D, Rossi C, Anghileri A, Giardino M, Latronico N, Radrizzani D, Langer M, Bertolini G. External validation of
the simplified acute physiology score (SAPS3) in a cohort of 28.357 patients from 147 Italian intensive care units.
Intensive Care Medicine (2009)35:1916-1924
ACTIVITIES
The main aim of the Public Health Department is to understand which factors affect the health
of individuals or entire populations and to define effective interventions for responding to their
health needs. Special emphasis is therefore placed on prevention, so that the risks of contracting
illness are lowered, and on the dissemination of independent, evidence-based information.
The department’s effort cannot disregard the National Health System, however, which must
guarantee access to, and quality of, care that is based on principles of equity and appropriateness
and must guarantee it especially to the more vulnerable patient groups. It is in this context that
the Public Health Department carries out its activities.
In addition to its formal research activity, the department participates in, and organises,
initiatives involving information dissemination, training, and debate aimed at healthcare
operators and social care workers, but also at the general population. These activities are also
supported by the publication of the department’s two journals: Ricerca&Pratica and Quaderni
di Farmaco Economia.
During 2009, 34 people worked in the Department
"A. and A. Valenti" Centre for Health Economics (CESAV)
The "Angelo e Angela Valenti" Centre for Health Economics (CESAV) was established in 1992
at the "M. Negri Institute" and based at Villa Camozzi- Ranica (Bergamo)-Italy. CESAV is
primarily a research centre, but also does educational work. The centre is involved in health
economics and health policy research. The main areas of research are: Economic Evaluation of
Health Care Programs (i.e. assessment of costs and benefits of alternative health care treatments
and services) and Comparative Health Policy Analysis (i.e. study of domestic and foreign health
care systems, in particular aimed at identifying possible innovations for European countries).
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The general aim of the Laboratory of Clinical Epidemiology is to contribute to the improvement
of health care in different medical fields. The guiding principles are mainly two: to help
physicians in using the available knowledge and resources at their best, and to contribute to the
growth of applied knowledge for clinical practice. The Laboratory operates in the field of
Intensive Care Medicine and Rare Diseases.
Within the Laboratory, the Unit of Clinical Knowledge Engineering aims to bring the value of
clinical reasoning out, through the implementation of probabilistic models for its formalization,
thus favouring the evaluation and the continuous improvement of complex clinical activities.
The main area of activity of the Unit of Computer Methods and Programs for Clinical Research
is the development of an electronic health record for the ICU that would be able to conjugate the
needs of clinical practice with those of clinical research, with the aim of closing the gap
between the two.
The main objective of the Laboratory for Mother and Child Health is to ensure a better mother
and child well-being by undertaking interdisciplinary and collaborative work in the field.
Four broad areas, or spheres, of research have been selected:
- monitoring and epidemiological evaluation of utilisation and effects of drugs and vaccines;
- research methodology in general hospital and paediatric community practice;
- public health determinants of children’s well-being;
- transfer of health information to the community.
Special attention is given to activities involving countries in the north and south of the world.
In addition to the formal research activities, the Laboratory promotes initiatives in the public
health field, in particular those involving mother and child health care.
The initiatives involve the participation in, and the organisation of, educational, training, and
information-dissemination activities.
The critical and active transfer of scientific knowledge is a continuous, daily stimulus to the
Laboratory’s activity.
Public and private institutions, other health care organizations (Ministry of Health, Regional and
Local Health Authorities, Hospital Trusts).
−
−
−
−
−
−
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo
Ospedale A. Manzoni, U.O. Anestesia e Rianimazione 1, Lecco.
Ospedale Regionale S. Maria dei Battuti Cà Foncello, Dipartimento di Neurologia,
Treviso
Ospedale San Giovanni Bosco, Servizio Anestesia e Rianimazione, Torino
Università degli Studi di Brescia, Dipartimento di Specialità Chirurgiche, Scienze
Radiologiche e Medico Forensi, Cattedra di Anestesia.
Università di Firenze, Facoltà di Medicina e Chirurgia,Cattedra di Fisica e Informatica
Medica.
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−
Università di Milano
Comunicazione.
Bicocca,
Dipartimento
di
Informatica
Sistemistica
e
−
−
−
−
−
−
−
−
−
−
−
−
−
−
Centre for Child Health, (CSB)
Cultural Paediatric Association, (ACP)
Federfarma Lombardia
Hospital of Bergamo “Ospedali Riuniti”, Poison Control Centre, Unit Clinical
Toxicology
Italian Drug Agency, (AIFA)
Italian Global Health Watch (OISG)
Italian National Institute of Health (ISS)
Italian Society of Preparers Pharmacists (SIFAP)
Italian Society of Clinical Pharmacy (SIFO)
Il Pensiero Scientifico Editore
Lombardy Region, Ministry of Health
Operating unity of Neuropsychiatry of the childhood and of the adolescence,
Foundation “Policlinico di Milano”, (UONPIA)
University of Cagliari, Department of Neuroscience, Clinic of Child and Adolescent
Neuropsychiatry
University of Milan-Bicocca, Faculty Medicine, Paediatric Clinic
−
−
−
−
−
−
−
−
−
−
CES (Collège des Economistes de la Santé) of Paris
Corvinus University of Budapest
Global Fund of Geneva
WidO of Bonn
Servicio Canario de la Salud, S/C de Tenerife
University of Birmingham
University of Hannover
University of York
University Pompeu Fabra of Barcelona
University Erasmus of Rotterdam
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−
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Centre for Intensive Care Medicines, Bloomsbury Institute, London, UK
Clinic of Anesthesiology and Intensive Therapy, Jena, Germany
Machine Intelligence Group, University di Aalborg, Denmark
Institute of Anesthesia and Intensive Cares, Semmelweis University, Budapest,
Hungary
Department of Anesthesiology and Intensive Cares, University of Warsaw, Poland
Department of Intensive Care, Hospital Generale di Novo Mesto, Slovenia
Department of Pneumologia and Intensive Cares, Hospital Generale di Nicosia, Cyprus
Laboratory of Experimental Physiopathology, Academic Unity of Sciences of the
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−
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−
−
Health, University of the Studies Extremo Sul Catarinense, Criciúma, SC, Brasil
Department of Anesthesiology and Intensive Cares, University of Toronto, Canada
Intensive Medicine, Regional Hospital of Lugano, Switzerland
Intensive Medicine, Regional Hospital Beata Vergine, Mendrisio - Ticino, Switzerland
Terapia Intensiva Pediatrica, Soroka University Medical Center, Beer-Sheva, Israele
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Centre for Tropical Diseases (CECOMET), Ecuador
Clínica Infantil Colsubsidio, Bogotà, Colombia
European Medicines Agency (EMA)
European Society for Developmental, Perinatal and Paediatric Pharmacology.
(ESDPPP)
European Union (EU)
Hospital Robert Debré, Paris, France
International Society of Drug Bulletins (ISDB)
World Health Organization (WHO)
University of Nottingham, Derbyshire Children’s Hospital, Derby, United Kingdom
INTERNATIONAL:
Acta Bio Medica; Applied Health Economics and Health Policy; Biomedical Statistics and
Clinical Epidemiology; BMC-Health Services Research; Health Policy; Journal of Medical
Economics; The European Journal of Health Economics.
NATIONAL:
FarmacoEconomia
News;
Farmeconomia
e
Percorsi
Terapeutici;
L'Internista;
PharmacoEconomics Italian Research Articles; Quaderni di FarmacoEconomia.
INTERNATIONAL:
Intensive Care Medicine
NATIONAL:
Ricerca & Pratica;
Dedalo. Gestire i sistemi complessi in sanità.
INTERNATIONAL:
European Journal Clinical Pharmacology; Journal of Clinical Pharmacology &
Pharmacoepidemiology; Saludarte.
NATIONAL:
Dialogo sui Farmaci; Disturbi d’Attenzione e Iperattività; Quaderni ACP; Quaderni di
Farmacoeconomia; Ricerca & Pratica.
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Applied Health Economics and Health Policy; BMC-Health Services Research; Health Policy;
PharmacoEconomics; The European Journal of Health Economics.
INTERNATIONAL:
British Medical Journal; Intensive Care Medicine; Critical Care Medicine; American Journal of
respiratory and Critical Care Medicine.
NATIONAL:
Ricerca & Pratica
INTERNATIONAL:
Acta Paediatrica; African Health Sciences; Annals of African Medicine; Annals of African
Medicine; Antimicrobial Agents and Chemoterapy; BMC Public Health; BMC Pulmonary
Medicine; British Journal of Clinical Pharmacology; Current Drug Metabolism; Drug
Metabolism Letters; European Journal of Clinical Pharmacology; Health and Quality of Life
Outcome; Journal of Infection and Public Health; Pharmaceuticals; Pediatrics; Swiss National
Foundation.
NATIONAL:
Dialogo sui Farmaci; Medico e Bambino; Quaderni ACP.
− Ethical committee A.O. “Bolognini” in Seriate (Bergamo)
− National Health Plan Research Commission, Trent Autonomous Province
− Scientific Council of the Health and Illness Interdisciplinary Research Centre
− Scientific Commitee of the Lombardy Region on cancer research
− Ethical committee A.O. "Ospedale Maggiore" of Crema
− Technical Commission for the management, update, and elaboration of the
Regional
− Therapeutic Formulary, Valle d'Aosta Autonomous Region
− Breastfeeding Promotion Work Group, Lombardy Region
− Scientific Advisory Board (PRIOMEDCHILD)
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EVENT ORGANIZATION
Regional Congress of Pharmacoeconomics: “Economia del farmaco: fra soluzioni tecniche e
decisioni politiche”, May 25-26, Ranica (BG).
Regional Congress of Pharmacoeconomics “Politiche vaccinazione HPV regionali: esperienze
a confronto”, October 22, Milan.
Congress, Meeting annuale GiViTI, October 27-29, Pesaro.
Workshop, Startup Meeting Crimyne2, April 16, Milan.
Workshop, Meeting Compact, May 12, Milan.
Workshop, Meeting MargheritaTre, May 18-19, Milan.
Course, Statistica applicata alla Ricerca biomedica, from September to December, Ranica (BG).
Congress “Modelli innovativi di intervento nella crisi acuta in adolescenza” Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico e Laboratory for Mother and Child Health,
IRFMN, Milan.
Congress “Bisogni comunicativi complessi e partecipazione nei contesti di vita” Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico e Laboratory for Mother and Child Health,
IRFMN, Milan.
May
Congress, “Societal impact of pain”, Bruxelles.
Congress, “Le vaccinazioni alla luce delle più recent innovazioni”, Ranica.
July
Congress, “Adozione del PDT HIV e determinanti costo-efficaci nella terapia antiretrovirale”,
Monza.
September
Congress, “Risk sharing: il prezzo dell’innovazione”, Milan.
October
Course, “5° Corso di aggiornamento: novità e criticità nell’attività regolatoria dei farmaci”,
Rome.
Congress, “Bioequivalenza e pregiudizio-Un’esperienza di informazione condivisa sul farmaco
equivalente”, Comano Terme (TN).
November
Congress, “ISPOR 13° Annual European Congress”, Prague.
Congress, “Farmaci a brevetto scaduto: tecnologia farmaceutica, appropriatezza e strumenti di
governo”, Legnago (VR).
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Congress, “Economia, Politica del Farmaco e HTA”, Udine.
January
Meeting, MargheritaTre; Palermo.
Congress, MargheritaDue; Lugano.
February
Congress, National meeting PROSAFE; Lubiana.
Congress, ‘Formazione del medico’; Bolzano.
March
Congress, Progetto StART Piemonte; Torino.
Congress, National meeting PROSAFE; Budapest.
Meeting, Presentazione Margheirta Tre; Carrara.
April
Workshop: Startup Crimyne 2; Ranica (BG).
Meeting: Presentazione Margheirta Tre; Tortona.
Meeting: Presentazione Margheirta Tre; Massa.
May
Congress, Progetto StART Lombardia; Milano.
Workshop, Meeting Compact; Milano.
Workshop, Meeting MargheritaTre; Milano.
Congress, Progetto StART Toscana; Firenze.
Congress, Congresso Nazionale SIARED ; Cagliari.
June
Congress, Convegno CPFA; Vicenza.
August
Meeting: Presentazione Margheirta Tre; Massa.
September
Seminar, Scuola specializzazione; Milano.
October
Congress, Terzo Simposio Nazionale sulle decisioni di fine vita: Le testimonianze;
Sottomarina di Chioggia
Master Nefrologia; Bergamo.
Congress, Appropriatezza dei ricoveri in Terapia Intensiva, Tuscany; Lucca.
Congress, Meeting GiViTI 2010; Pesaro.
November
Congress, National meeting PROSAFE; Varsavia.
Congress, Tecnical meeting PROSAFE; Lubiana.
January
Le prospettive della ricerca in campo pediatrico. Congress “Dove va la pediatria?”.
Associazione Pediatria di Comunità (APeC), Cesena (FC).
March
Come superare il problema dell’off-label. Course: “La prescrizione off-label in età pediatrica:
evidenze scientifiche, aspetti medico-legali e comunicazione efficace”. OCM Comunicazioni;
Verona.
ANNUAL REPORT
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2010
IRFMN
Il profilo epidemiologico del bambino con spettro autistico. National Congress: “Attualità
sull’autismo: dai modelli interpretativi all’efficacia del trattamenti”. ULSS 10 Veneto
Orientale, Comune di San Donà di Piave; San Donà di Piave (VE).
April
Farmaci in gravidanza e durante l’allattamento. Congress “Allattamento Materno e Ospedale
Amici dei Bambini: Dieci Passi Insieme per la qualità del percorso nascita”. UNICEF, SIGO
(Società Italiana di Ginecologia e Ostetricia); Palermo.
L’appropriatezza (efficacia, sicurezza, costo) dell’utilizzo dei farmaci in età pediatrica.
Farmaci off-l’abel in ambito pediatrico. Course “Il medico di continuità Assistenziale e
l’appropriato uso dei farmaci”. ASL provincia di Bergamo Dipartimento Cure Primarie e
Continuità Assistenziale; Bergamo.
Il ruolo del mediatore culturale in neuropsichiatria infantile. National Course of “Mediazione
Transculturale”. INMP (Istituto Nazionale Salute, Migrazione e Povertà); Rome.
Sfide nel trattamento della malaria nei bambini. II International Congress “Lotta alla malaria
in Africa e infuso di Artemisia annua L.”. ICEI (Istituto Cooperazione Economica
Internazionale); Rome.
Educazione e istituzione: fattori essenziali per lo sviluppo e il benessere dei bambini.
Congress “Conclusione della campagna di prevenzione incidenti in casa, a scuola, negli
ambienti di svago, sulla strada, sull’uso improprio di psicofarmaci, videogiochi, Personal
Computer, alimentazione”. MOICA (Movimento Italiano Casalinghe); Treviso.
The TINN survey in european neonatal intensive care units (NICUs). Ciprofloxacin safety in
infants newborns. General Meeting “TINN Period 1”. TINN (Treat Infections In Neonates);
Paris (F).
Vietato ammalarsi: povertà e discriminazione nell’accesso delle cure sanitarie. XVI Course
multidisciplinare di educazione ai diritti. UNICEF; Milan.
May
Costo/efficacia: parametro efficace? Come si misura la sostenibilità dell’intervento nei paesi
poveri? Round Table. Convegno “Gratuità e qualità delle cure: il Progetto EMERGENCY”.
Commissione Straordinaria per i Diritti Umani del Senato, EMERGENCY; Rome.
Crisi acuta in adolescenza: lo scenario italiano ed esperienze internazionali. Congress
“Modelli innovativi di intervento nella crisi acuta in adolescenza”. Fondazione IRCCS Ca’
Granda (Ospedale Maggioer Policlinico, ASL Milano; Milan.
I farmaci: quali evidenze. Workshop “Opzioni chirurgiche per il bambino e l’adolescente
obeso”. ICP (Istituti Clinici di Perfezionamento), Ospedale dei Bambini Buzzi; Milan.
Reazioni avverse in gravidanza e pediatria. Master and Course “Perfezionamento in
Farmacovigilanza” “Gestione del farmaco sul territorio e farmacosorveglianza”. SEFAP
(Servizio di Epidemiologia e Farmacologia Preventiva) Università degli Studi di Milano
Dipartimento di Scienze Farmacologiche; Milan.
Farmaci essenziali, politiche ed uso nei paesi poveri. VIII Course “In memoria di Antonio
Terrizzi”. Medici in Africa; Genoa.
Lettura: implicazioni cliniche e generalizzazione dei risultati degli RCT’s. 7° National
Congress SIARED; Villasimius (CA).
Farmaci, test diagnostici e screening: i rischi nelle decisioni mediche. Incontro Formazione
Giornalisti. Ordine dei Giornalisti di Milano; Milan.
June
Determinants of the drug utilization profile in the pediatric population in Italy’s Lombardy
Region. Course: “Indagine sul consenso prescrittivo nella pediatria di famiglia: considerazioni
e proposte”. Regione Lombardia ASL Monza e Brianza; Monza (MB).
L’uso razionale degli psicofarmaci in età evolutiva. GCP e buona pratica clinica. Il
monitoraggio delle reazioni avverse da farmaci. Seminari del lunedì. Fondazione “Istituto
Neurologico Nazionale C. Mondino”, Dipartimento di Scienze Neurologiche Università di
Pavia; Pavia, (PV).
ANNUAL REPORT
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2010
IRFMN
La ricerca clinica nella pediatria di famiglia. Course “La sperimentazione clinica in pediatria”
ASL Roma E, Ospedale S.Spirito in Sassia; Rome.
July
Paediatric Clinical Pharmacology in Italy. Congress “PAEDIATRIC Clinical Pharmacology
and Child Health”. The Medical School Royal Derby Hospital, NHS Fondation Trust; Derby
(UK).
September
Round Table. Regional Congress “Prescrizioni di antibiotici in pediatria: si può migliorare?
Valutazione di un’esperienza veneta di percorsi diagnostico terapeutici”. Regione del Veneto,
Unità di Informazione sul Farmaco, Azienda ULSS 20 Verona; San Bonifacio (VR).
La prescrizione dei farmaci in età pediatrica. Il profilo prescrittivo in età pediatrica in Regione
Lombardia. Course ASL Milano Due “Una lista di farmaci essenziali basata sulle attitudini
prescrittive dei pediatri”. Azienda Sanitaria Locale della Provincia di Milano 2; Milan.
Il network e la ricerca. Congress “Network Neonatale Italiano: cure, esiti e ricerca per i
neonati pretermine”. SIN (Società Italiana Neonatologia), Network Neonatale Italiano; Roma.
La realtà dei centri di riferimento a due anni dall’avvio del Registro Nazionale. Registro
regionale dell’ADHD. Giornate di studio e approfondimento “Lavorare insieme nell’ADHD.
Esperienze dei centri di riferimento della Lombardia”. Regione Lombardia, ASL di Brescia,
UONPIA Ospedale dei Bambini e Ospedale Civile di Brescia; Iseo (BS).
October
La valutazione degli esiti nelle situazioni complesse. Course “Bisogni comunicativi complessi
e partecipazione nei contesti di vita”. ASL Milano, Fondazione RCCS Ca’ Granda Ospedale
Maggiore Policlinico, Azienda Ospedaliera Treviglio; Milan (MI).
November
I farmaci off-label in età pediatrica. Congress “Progetto MEAP. La terapia farmacologica in
pediatria: dall’empirismo alla razionalizzazione”. Regione Lombardia Sanità; Milan.
December
Le caratteristiche della farmacocinetica in età pediatrica. Sperimentazione clinica in pediatria.
Course “Utilizzo appropriato dei farmaci nelle patologie oncologiche dell’età pediatrica e
adolescenziale”. CRO Aviano (Centro di Riferimento Oncologico) Istituto Nazionale Tumori;
Aviano (PN).
−
−
−
−
−
−
−
−
Abbott
AIFA
Grunenthal-Prodotti Formenti
Merck Serono
Sanofi Aventis
Sanofi Pasteur MSD
Schering Plough
Vivisol
− ARESS Piemonte
− ASL TO-2 Piemonte
ANNUAL REPORT
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IRFMN
−
−
−
−
−
−
−
−
−
Azienda ULSS 16, Padova – Italia
Bellco SpA
Draeger Italia
Regione Lombardia
Regione Toscana
Commissione Europea DG SANCO
Hill-Rom
Brahms
Astellas
− A.O. Spedali Civili of Brescia
−
−
Boehringer Ingelheim
European Union
−
−
−
−
Italian Drug Agency, (AIFA)
Province of Milan
Regional Health Ministry - Lombardy Region
Regional Health Ministry - Valle d’Aosta Region
− IRCCS Burlo Garofolo, Trieste
− IRCCS Cà Granda Hospital Maggiore Policlinico, Milan
Garattini L, Gritti S, De Compadri P, Casadei G. Continuing Medical Education in six European countries: A comparative
analysis. Health Policy 2010; 94(3):246-254.
Garattini L, Casadei G. Letter to the Editor. (2nd) Vaccine 2010; 28:880.
Koleva D, Cortelazzo S, Toldo C, Garattini L. Health Care Costs of Multiple Myeloma: an Italian Study. European Journal
of Cancer Care (e-pub); 2010.
Garattini L, Koleva D, Casadei G. Modeling in pharmacoeconomic studies: Funding sources and outcomes. International
Journal of Technology Assessment in Health Care 2010;26(3):330-333.
Virgili G, Koleva D, Garattini L, Banzi R, Gensini GF. Utilities and QALYs in health economic evaluations: glossary and
introduction. Internal and Emergency Medicine 2010;5:349-352.
Csomos A, Varga S, Bertolini G, Hibbert C, Sandor J, Capuzzo M, Guidet BR. Intensive care reimbursement practices:
results from the ICUFUND survey. Intensive Care Med 2010 Oct;36(10):1759-64.
Guido Bertolini, Simona Boffelli, Paolo Malacarne, Mario Peta, Mariano Marchesi, Camillo Barbisan, Stefano Tomelleri,
Simonetta Spada, Roberto Satolli, Bruno Gridelli, Ivo Lizzola, Davide Mazzon. End-of-Life Decision-Making and Quality of
ICU Performance: An Observational Study in 84 Italian Units. Intensive Care Med 2010 Sep;36(9):1495-504.
Cogo PE, Poole D, Codazzi D, Boniotti C, Capretta A, Langer M, Luciani D, Rossi C, Bertolini G.Outcome of children
admitted to adult intensive care units in Italy between 2003 and 2007. Intensive Care Med 2010Aug;36(8):1403-9.
Corona A, Bertolini G, Lipman J, Wilson P, Singer M. Use and impact of antibiotics on outcome in bacteraemic critical
ANNUAL REPORT
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2010
IRFMN
illness: the BActeraemia study in intensive care (BASIC). J Antimicrob Chemother 2010Jun;65(6):1276-85.
Bruno Giometto; Wolfgang Grisold; Roberta Vitaliani; Francesc Graus; Jérôme Honnorat; Guido Bertolini; for the PNS
Euronetwork. Paraneoplastic Neurologic Syndrome in the PNS Euronetwork Database: A European Study From 20 Centers.
Arch Neurol 2010;67(3):330-335.
P. Malacarne, D. Boccalatte, A. Acquarolo, F. Agostini, A. Anghileri, M.Giardino, D. Giudici, M. Langer, S. Livigni, E.
Nascimben, C. Rossi, G. Bertolini. Epidemiology of Nosocomial Infection in 125 Italian Intensive Care Units. Minerva
Anestesiologica 2010 Gennaio;76(1):13-23.
J.C. Marchall, K. Reinhart, D. Angus, A. Argent, G. Bernard, G. Bertolini, S. Bhagwanjee, J.P. Cobb, D.J. Cook, D. Fedson,
S. Finfer, R. Fowler, C. Gomersall, E. Jimenez, N. Kissoon, D. McAuley, S. Opal, J.L. Vincent, S. Webb. InFACT: a global
vritical care clinical research reponse to severe pendemic H1N1. Lancet 2010 Jan 2;375(9708):11-3.
Bianchi M, Clavenna A, Bonati M. Inter-country variations in anti-asthmatic drug prescriptions for children.
Systematic review of studies published during the 2000–2009 period. Eur J Clin Pharmacol 2010;66: 929-36.
Bonati M. Commentary. Evidence-Based Mental Health 2010;13:43.
Bonati M, Pandolfini C. Safety of ciprofloxacin in neonates with sepsis. Adverse Drug Reactions Bulletin
2010:265:1019-1022.
Clavenna A, Pandolfini C, Bianchi M, Bonati M. Do children really need more research on respiratory drugs? Acta
Paeditr 2010;99:1445-46.
Clavenna A, Sequi M, Bonati M. Drug prescribing by Italian family paediatricians: an exception? Acta Paediatr
2010;99:754-757.
Clavenna A, Sequi M, Bonati M. Differences in the drug prescriptions to children by Italian paediatricians and
general practitioners. Eur J Clin Pharmacol 2010;66:519-524.
Fortinguerra F, Maschi S, Clavenna A, Bonati M. Pain management in the paediatric population. The regulatory
situation in Europe. Arch Dis Child 2010;95:749-753.
Panei P, Arcieri R, Bonati M, Bugarini M, Didoni A, Germinario E. Safety of psychotropic drug prescribed for
attention-deficit/hyperactivity disorder in Italy. Adverse Drug Reaction Bulletin 2010;260:999-1002.
Clavenna A, Gangemi M, Casadei G, Garattini L, Bonati M. Efficacia del beclometasone versus placebo nella profilassi del
wheezing virale in età prescolare. Ricerca & Pratica 2010; 26: 19-25.
Padula A, Casadei G, Motterlini N, Garattini L . Vaccinazione antinfluenzale in ambiente di lavoro: una valutazione
economica. Quaderni di Farmaco Economia 2010; 11:9-15.
Garattini L, Koleva D, Casadei G . L’applicazione dei modelli di Markov in farmacoeconomia. Quaderni di Farmaco
Economia 2010; 12:7-12.
Gallus S, Apolone G, Padula A, Casadei G, Motterlini N, Garattini L . Quaderni di Farmacoeconomia risponde ai lettori.
Quaderni di farmaco economia 2010; 12:24-31.
Garattini L, Casadei G . Cure H: far bene la gara fa bene alla spesa. Sanità del Sole 24Ore 26 Gennaio 2010 pag. 11.
Garattini L . Finanziaria 2010. Dialogo sui Farmaci 2010; 1:25-26.
Garattini L, Casadei G . Cure H: far bene la gara fa bene alla spesa. Ricerca & Pratica 2010; 26: 75-80.
ANNUAL REPORT
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2010
IRFMN
Garattini L . Riunificare i tetti di spesa per responsabilizzare chi fa i prezzi. Sanità del Sole 24Ore 1-7 Giugno 2010
pag.6-7.
Garattini L, Casadei G . No alla riserva indiana per gli equivalenti. Sanità del Sole 24Ore 15-21 Giugno 2010 pag. 7.
Garattini L, Casadei G . Ma attenti alla spesa ospedaliera. L’Espresso 3 Settembre 2010 pagg.137-138.
Casadei G, Garattini L . Contratti d’esito, puntualizzare le verifiche. Sanità del Sole 24Ore 7-13 Settembre 2010 pag.
19.
Clavenna A, Gangemi M, Casadei G, Garattini L, Bonati M . Efficacia del beclometasone versus placebo nella
profilassi del wheezing virale in età prescolare. Ricerca & Pratica 2010; 151:21.
Casadei G, Garattini L . Spesa farmaceutica e manovra finanziaria: riflessioni. Ricerca & Pratica 2010; 26:135-140.
Garattini L . Mercato, Salute e Povertà. Club3-Vivere in armonia Dicembre 2010 pag. 129.
De Compadri P, Koleva D . Costi nosocomiali del condiloma acuminato, con particolare riferimento alla Regione
Lombardia. Farmacoeconomia News 2010; 1:23-30.
De Compadri P . Corticosteroidi Inalati somministrati a bambini in età pre-scolare con manifestazioni asmatiche
durante infezione delle vie respiratorie superiori: valutazione economica budesonide. Quaderni di Farmaco
Economia 2010; 13:7-14.
Casadei G . Stato, Regioni e Concorrenza. Quaderni di Farmaco Economia 2010; 11:5-7.
Casadei G . Spesa, federalismo e varie. Quaderni di Farmaco Economia 2010; 12:4-6.
Gritti S . Valutazione economica della vaccinazione antinfluenzale in ambiente di lavoro. Ricerca & Pratica 2010;
26(3):130-131.
Guido Bertolini. Per un medico nuovo: saper collaborare, saper apprendere, saper sapere. Recenti Progressi in
Medicina, Luglio-Agosto 2010:303-304.
Guido Bertolini. La fibrosi cistica e l’evoluzione della specie. R&P 2010;26:161-173.
Abramo Anghileri, Michele Giardino, Guido Bertolini. Margherita Due: l’assistenza informatica. R&P 2010; 26: 3839.
Bertolini G. Imparare dall’errore. Appunti per una riflessione in medicina. Medico e bambino 2010; 29:566-568.
Bianchi M. Variabilità dell’inosina monofosfato deidrogenasi nei pazienti con trapianto di rene in terapia cronica con
micofenolato mofetile. R&P 2010;152:67.
Bonaccorsi A. Farmaci in prima pagina. R&P 2010;152:78-80.
Bonaccorsi A. Displasia broncopolmonare e danno cerebrale nei neonati prematuri: una relazione complessa. R&P
2010;152:66.
Bonaccorsi A. Farmaci in prima pagina (traduzione). R&P 2010;152:75-80.
Bonaccorsi A. Innovazione e brevetti nella synthetic biology. R&P 2010;26:207-209.
Bonati M. Uso e abuso degli pasicofarmaci nella ricerca e nell’assistenza ai minori e agli adulti. In: 1978-2008
Trent’anni di sanità tra bioetica e prassi quotidiana. Regione Toscana, Firenze 100-103; 2010.
Bonati M. Il 90 per cento dei ‘lettori’ legge solo l’abstract. R&P 2010;26:43-44.
ANNUAL REPORT
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IRFMN
Bonati M, Severino F, Bagnati R, Carrà A, Roberto F. Sfide nel trattamento della malaria nei bambini. R&P
2010;152:163-164.
Campi R, Bonati M. I bambini ci guardano e ... aspettano ancora. R&P 2010;152:47-49.
Clavenna A. Utilità clinical dei criteri di Roma per la gestione dei disturbi funzionali gastrointestinali nelle cure
primarie pediatriche. R&P 2010;152:66.
Clavenna A, Bonati M. La ricerca indipendente; faranno apposta? Quaderni acp 2010;17:191-192.
Clavenna A, Bonati M, Sequi M, Nobili A, Franchi C, Tettamanti M, Bortolotti A, Merlino L, Fortino I. La
prescrizione di farmaci per i bambini e gli anziani in Regione Lombardia. R&P 2010;151:9-18.
Clavenna A, Bonati M. Troppe inadempienze ritardano la sperimentazione clinica nel territorio. Quaderni acp
2010;17:49.
Clavenna A, Fortinguerra F. Psicofarmaci in allattamento: per un terzo dei medicinali non ci sono evidenze. Quaderni
ACP 2010;17:35.
Clavenna A, Fortinguerra F. Lista dei farmaci cardiovascolari per i bambini: un passo per superare gli off label.
Quaderni acp 2010;17:82.
Clavenna A, Fortinguerra F. Beta-agonisti a lunga durata d’azione: mai più da soli nella terapia dell’asma. Quaderni
acp 2010;17:131.
Clavenna A, Fortinguerra F. Mucolitici e propiltiouracile: aggiornamenti sulla sicurezza di impiego nei bambini.
Quaderni acp 2010;17:181.
Clavenna A, Fortinguerra F. Quando il farmaco è somministrato per far male: un problema in aumento negli Stati
Uniti. Quaderni acp P 2010;17:227.
Clavenna A, Gangemi M, Casadei G, Garattini L, Bonati M. Efficacia del beclometasone versus placebo nella
profilassi del wheezing virale in età prescolare. R&P 2010;151:21.
Clavenna A, Sequi M, Bortolotti A, Fortino I, Merlino L, Bonati M. Farmaci essenziali e attitudini prescrittive dei
pediatri. M&B 2010;29:565-569.
De Compadri P, Clavenna A. Corticosteroidi Inalati somministrati per manifestazioni asmatiche in età prescolare:
valutazione economica budesonide. Quaderni di Farmacoeconomia 2010;13:7-14.
De Fiore L, Bonati M. La fiera dei congressi. R&P 2010;151:3-8.
Didoni A. “A colloquio”. R&P 2010;151:32.
Didoni A. Una madre e una figlia alla ricerca delle proprie identità. R&P 2010;152: 74.
Fortinguerra F. Pittogrammi gratuiti per farmacie e ospedali. R&P 2010;151:28-29.
Fortinguerra F. Prescribe nel regno di Sua Maestà. R&P 2010;151:201.
Fortinguerra F. Nuovi farmaci sottoposti a studi clinici pediatrici in UE: a che punto siamo? Giornale italiano di
Farmaci Clinica 2010;24:55-56.
Fortinguerra F. L’EMA presenta una sezione pediatrica rinnovata all’interno del suo sito web. Giornale italiano di
Farmaci Clinica 2010;24:116-117.
Fortinguerra F. Uso di formulazioni orali non appropriate negli studi clinici pediatrici Giornale italiano di Farmaci
Clinica 2010;24:
Fusco F, Sambugaro D, Clavenna A. L’invermictina per os nella pediculosi di difficile trattamento. M&B 2010;
http://www.medicoebambino.com/?id=AP1005_10.html.
ANNUAL REPORT
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IRFMN
Marchetti F, Ronfani L, Maestro A, Rovere F, Zanon D, Arrighini A, Bertolani P, Biban P, Da Dalt L, Di pietro P,
Renna S, Guala A, Mannelli F, Pazzaglia A, Messi G, Perri F, Reale A, Tondelli MT, Urbino AF, Valletta E, Vitale
A, Zangardi T, Clavenna A, Bonati M. Trial controllato randomizzato multicentrico di valutazione comparativa
dell’ondansetron verso domperidone per il trattamento sintomatico del vomito acuto da gastroenterite nel bambino:
protocollo di studio. M&B 2010; http://www.medicoebambino.com/?id=PST1009_10.html.
Severino F, Bonati M. Migranti e salute: tra diritto (alle cure) e reato (di clandestinità). R&P 2010;152:50-61.
Working Group Pediatrico dell’AIFA, Bonati M. La prima lista dei farmaci cardiovascolari autorizzati per un uso
pediatrico. M&B 2010;29:172-176.
Working Group Pediatrico della’AIFA, Bonati M. Farmaci cardiovascolari: la prima lista di farmaci autorizzati per
un uso pediatrico. Clinica e management 2010;2:9-12.
OTHER PUBLICATIONS (2010)
Rossi C, Di Gangi S, Bertolini G. Progetto Margherita - Promuovere la ricerca e la valutazione in Terapia Intensiva
RAPPORTO 2009. Bergamo: Edizioni Sestante, 2010. [report]
Bonati M, Garattini S. Malattie Tropicali dimenticate. In: rapporto di Medici Senza Frontiere. “Le crisi umanitarie
dimenticate dai media 2009”. Marsilio Editori spa, Venezia, 2010;94-100. [chapter book]
Bonati M. Lo specialista risponde. In: Il grande libro italiano della gravidanza. Rizzoli, Milano, 2010;252-253.
[chapter book]
Clavenna A, Braguglia A. Peculiarità della farmacocinetica nel neonato. In: Farmacoterapia Neonatale. Guida pratica
con supporto interattivo. I edizione 2009. Editore Biomedia, Milano 2009;4-6. [chapter book]
Bonati M, Campi R. Quale futuro per chi nasce e cresce oggi nel mezzogiorno? Saluteinternazionale.info 17 febbraio
2010;
http://saluteinternazionale.info/2010/02/quale-futuro-per-chi-nasce-e-cresce-oggi-nel-mezzogiorno/.
[Information in the Media]
Fattore E, Davoli E, Bonati M. Il fantasma della discarica. Il Sole 24 Ore Sanità 30 novembre - 6 dicembre 2010; pag.
14-15 [Information in the Media]
Per un uso razionale dei farmaci. Controparte: Assessorato alla Sanità, Regione Lombardia. [report]
Registro Nazionale ADHD. Controparte : AIFA. [report]
Formazione farmaco epidemiologia pediatrica. Controparte: Boehringer Ingelheim S.p.A. [report]
During 2009 the laboratory’s activities were covered by the national media 40 times
RESEARCH ACTIVITIES
Educational activity
Educational activities are developed only if related to research studies, in order to offer
original contributions which naturally reinforce the research aims.
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Economic Evaluation of Health Care Programs
The aim of this research area is to assess the costs of pathologies and the cost-effectiveness
ratios of the diagnostic/therapeutic existing alternatives. In general, analyses can be
classified into two groups: partial economic evaluations (e.g. cost of illness analysis) and full
economic evaluations (e.g. cost-effectiveness analyses).
Comparative Health Policy Analysis
The aim of this research area is to study the organization of health care systems, in order to
draw lessons from international comparisons. This is particularly important in a "market"
like health care where economic competition lacks by definition and therefore public
regulation plays a crucial role.
Quality of care in the Intensive Care Units
The main purpose of these research projects is the assessment and improvement of the
quality of care in Italian Intensive Care Units (ICUs). It is a multi-annual project promoted
on behalf of GiViTI, a collaborative network composed by more than half of the Italian ICUs
and coordinated by the Laboratory. The main focus is the Project Margherita. Its aim is the
continuous evaluation of the quality of care and it is based on a free software developed by
the Laboratory and distributed to all the ICUs adhering to the GiViTI group. The software
has been realized on a modular structure, which enables to easily integrate the basic data
collection (the “core” of Margherita) with the data collection of specific research projects
(the “petals” of Margherita).
Since January 2011, Margherita became an international project. Thanks to funding from the
European Union have in fact been able to develop new software and to distribute the project
to six countries: Slovenia, Hungary, Poland, Cyprus, Brazil and Israel.
Appropriateness of the Intensive Care Units
ICU is a high technology environment, that requires a high number of high-level personnel.
Hence, the cost of these units is extremely important and a special attention not to waste
resources is mandatory. In this field, the Laboratory launched a study to assess the level of
appropriateness of the use of ICU beds, in four Italian regions: Lombardia, Piemonte,
Toscana e Campania. Such an evaluation is based on the understanding that the level of care
provided by an ICU should correspond to the level of care it can theoretically provide, given
the available resources. In this framework, patients are classified as requiring high-, low-, or
ordinary-care, and beds are independently classified are high- or low-level. The
appropriateness evaluation protocol adopted verify the concordance between these two
separate classifications.
Influenza A/H1N1 in ICU
On 11 June 2009 the World Health Organization confirmed the presence of a new pandemic
influenza A, caused by a H1N1 virus. The first experiences showed that this influenza was
characterized by a higher incidence of severe viral pneumonia in children, middle-aged
patients, and pregnant women and, apparently, by a higher mortality than expected in a
normal influenza season. This caused a generalized alarm all over the world.
On October 2009 the GiViTI group, coordinated by the Laboratory of Clinical
Epidemiology, set up the H1N1 registry, with the aim to assess the characteristics and
outcome of affected patients, the impact of the pandemic influenza on the activity of Italian
ICUs from September 2009 to April 2010, and the correspondence between the generalized
alarm on this phenomenon and what really took place in Italian ICUs.
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Studies on Multiple Organ Failure pathological processes
The Laboratory of Clinical Epidemiology has lead several investigations to clarify which
pathophysiological mechanisms induce multiple organ failure, a condition still burdened
with high mortality. Among these, the investigation on the neuromuscular impairment in
critical patients (the observational study 'Crimyne'), the study on the impact of enteral
feeding, and the new treatments proposed for severe sepsis (Xigris and the removal of
inflammation mediators through specific filter applied to circuit of plasma-filtration).
The value of a strict glycemic control of critical patients has been recently emphasized, given
its connection to a drug like insulin that, in spite of its large availability and low cost,
induces a relevant reduction of mortality in ICU. The Unit of Clinical Knowledge
Engineering has developed a model based on a differential equations system whose aim is to
support the physician in dosing both insulin and glucose infusions, in order to extend the
possibility of a strict control even to patients with a high risk of hypoglycaemia. This model
represents a precious opportunity to investigate the pathophysiological mechanisms behind
the benefits of insulin already demonstrated at an empirical level, allowing the explanation
of the dynamic behaviour of glycemic fluctuations on the basis of the patient's metabolic
profile.
The reconstruction of clinical reasoning in the medical practice and
education
This area represents the main concern of the Unit of Clinical Knowledge Engineering, whose
objective is the valorization of clinical reasoning in solving complex clinical problems.
The diagnosis of pulmonary embolism still represents a relevant clinical challenge, due to
the complexity of the patient's clinical presentation and the variability of diagnostic
resources among Centres. In this regards, we are conducting an Italian multicenter study,
involving mainly Emergency Units, with the aim of prospectively validating the diagnostic
software BayPAD (Bayes Pulmonary embolism Assisted Diagnosis). Such a tool, relying on
a probabilistic model covering 72 clinical variables and doing without the need to input all
the contemplated observations, would overcome the main reasons which prevented ordinary
clinical guidelines to be largely accepted. Moreover, the results of the retrospective
validation of the system have been obtained.
The Unit started a project for the realization of a software assisting the physician in tracing
back the basis of his clinical decisions before the description provided by clinical reports,
among those that are typical of particular medical specialty. The software has the double
target to create specific applications based on probabilistic models representing complex
clinical decision problems, and to involve physicians in their construction. The last target is
achievable given the strong analogy between the causal structure of the exploited models
(bayesian networks) and the pathophysiological structure of medical knowledge. By this, it
will be given the chance to adopt this system within medical training projects, with a special
attention to e-learning programs.
Clinical Epidemiology of rare diseases and orphan medicine
Our purpose is to find out and describe clinical and research problems related either to rare
diseases or to neglected aspects of well-known diseases. We also focus on the needs of the
patients with rare diseases. A specific project is connected with this research activity: “PNS
– Euronetwork”. It is a European project on paraneoplastic neurological syndromes that is
financed by the Fifth and Sixth Framework Program of the European Community. Its
purposes are various: to develop a network of reference centers for these pathologies all
sharing a common database; to organize a sample bank of biological fluids and cerebrospinal
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liquid to point out the best antibody indicators for the diagnosis and prognosis of these
patients; to realize some research projects on the treatment of this syndrome.
An electronic health record to promote research in Intensive Care
Medicine
The main aim of this project is to develop an electronic health record (EHR) the allows the
assessment of indicators of the process of care in the ICU. A multidisciplinary team of
intensivists, ICU nurses, epidemiologists, statisticians, and IT specialists, had the
responsibility of planning the HER, that is now already shared by 15 Italian ICUs.
Efficacy of Nebulised Beclometasone versus placebo in preventing viral
wheezing in pre-school children. (ENBe)
The Laboratory for Mother and Child Health coordinates the “Efficacy Of Nebulised
Beclometasone Versus Placebo In Preventing Viral Wheezing In Pre-School Children”
(ENBe) randomised controlled trial.
The study is funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA)
with a grant for independent research on drugs and it is performed in collaboration with the
Associazione Culturale Pediatri and the "Angelo and Angela Valenti" Centre for Health
Economics (CESAV).
The ENBe study involves 36 family paediatricians in 9 Italian local health units (LHU)
representative of geographical distribution and setting.
The aim of the study is to evaluate the safety and effectiveness of beclometasone in
preventing wheezing in viral upper respiratory tract infection (URTI).
A total of 576 children 1-5 years old, with at least one episode of viral wheezing in the
previous 12 months, will be enrolled. Children with steroid hypersensitivity, chronic
respiratory disease (e.g. cystic fibrosis, broncho-pulmonary dysplasia), presence of wheezing
at the entry visit or using inhaled and/or oral corticosteroid use in the preceding month will
be excluded.
Patients will be randomly allocated to receive beclometasone suspension 400 mcg b.i.d or
placebo b.i.d.
Active drug and placebo will be administered through a nebuliser, in the morning and in the
evening. The duration of the treatment will be 10 days, and a 6-month follow up period will
be performed to monitor the recurrence of respiratory tract infections and viral wheezing.
The percentage of children with wheezing (diagnosed by the paediatrician) during the URTI
episode will be the primary outcome measure.
The bureaucratic procedures for obtaining the authorization by each LHU ethics committee
lasted a total of 19 months and only in October 2010 it was possible to start the patient
enrollment.
On 9 January 2011, 13 weeks after the beginning of the study, 615 eligible children were
visited, 218 of which (35%) were enrolled: 137 were males and 81 females, with an average
age of 2.7 years.
Pharmacoepidemiology in the Lombardy Region
The Laboratory for Mother and Child Health is involved in the analysis of the drug
prescription profile in children and adolescents in the EPIFARM (Epidemiologia del
farmaco) project funded by the Lombardy Region.
The main results of the project are summarised below:
• During 2008, 826,727 children and adolescents < 18 years old (51% of the population)
received at least one drug prescription.
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•
The highest prevalence of drug prescription was observed in the 1-5 year old range
(average value 68%), and then decreased to 40% in the 12-17 year range. Each treated
child received an average of 3 prescriptions and 4 packages.
• Antibiotics were the most commonly prescribed therapeutic class (41% of the
population), followed by anti-asthmatics (15%) and anti-histamines (5%).
Amoxicillin+clavulanic acid was the most prescribed drug (21% of children) , followed
by amoxicillin (12%) and inhaled beclometasone (9%).
• Only 42 out of 746 drugs were prescribed by at least 50% of the paediatricians. Six
drugs were prescribed by all the paediatricians (amoxicillin+clavulanic acid,
amoxicillin, beclometasone, clarithromycin, salbutamol, and cefaclor)
• Quantitative and qualitative differences in the prescription profile were found between
different local health units (LHU). The prevalence ranged between 41% in Milan and
56% in Valle Camonica.
• In general, the LHUs with a greater prevalence of drug prescriptions were also
characterised by a lower degree of appropriate prescriptions This is particularly evident
in the case of antibiotic: the average ratio of children treated with penicillins/children
treated with cephalosporins by paediatrician in Milan LHU was 4.7 (median 4.1,
interquartile range: 3.0-5.8), while the average ratio penicillin/cephalosporin treated
children by paediatrician in Brescia was 1.9 (median 1.7, interquartile range 1.2-2.2).
The quantitative and qualitative differences observed in a quite homogeneous context like
Lombardy region suggest that educational interventions for physicians and parents with the aim
to improve the rational use of drugs should be adapted to the local setting.
Prescription, efficacy, and safety of psychotropic drugs in the Italian
paediatric population
Diagnostic and therapeutic approaches in children and adolescents with
neuropsychiatric disorders in the Local Health Unit of Verona, Italy.
Aims. The safety and effectiveness of psychotropic drug use in the paediatric population are
widely debated, in particular because of the lack of data concerning the long term effects. In
Italy the prevalence of psychotropic drug prescriptions increased in the 2000-2002 period
and decreased afterwards. In such a context, a study with the aim to estimate the prevalence
of psychotropic drug prescription in the paediatric population and to describe diagnostic and
therapeutic approaches was performed.
Methods. The study population was composed of 76,000 youths <18 years of age living in
an area covered by the Local Health Unit of Verona, Italy. Children and adolescents
receiving psychotropic drug prescriptions were identified. Questionnaires were sent to the
prescribers with the aim to collect data concerning diagnostic and therapeutic approaches,
and care strategies.
Results. Between 1 January 2005 and 31 December 2006, 111 youths (0.8 per 1,000)
received at least one psychotropic drug prescription. Nintyone youths received
antidepressants and 25 received antipsychotics. Only 29 patients were under the care of child
and adolescent outpatient psychiatric services. Information concerning diagnostic and
therapeutic approaches, and care strategies, were collected for 52 patients (47%). Anxietydepressive syndrome and attention disorders were the diseases for which psychotropic drugs
were most commonly prescribed. In all, 85% youths received also psychological support and
20% were prescribed drugs for 2 or more years. Child psychiatrists made the first diagnosis
in 50% of the cases, but in 1/3 of the cases the parents met with 2 or more physicians before
the diagnostic procedure was completed.
Conclusions. Despite the low prevalence of drug prescriptions, the finding that most
children were not cared for by child and adolescent psychiatric services is of concern and
calls for a systematic continuous monitoring of psychopharmacological treatments.
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Migration and psychological difficulties in growth and adulthood
The project involves seven Childhood and Adolescence Neuropsychiatry Units (UONPIAs)
of Milan, 2 psychiatric services and the family, childhood and school-age service of Milan’s
local health unit, Milan’s social and educational services, the “Cesare Beccaria” Penal
Institute for Minors, 7 third-sector organizations, the Provincial School Office and the
“Mario Negri” Institute. The project aims to improve the response to the specific problems of
the school-aged migrant population, with particular attention to adolescents and minors who
arrived in Italy unaccompanied by family members.
During 2010 data concerning 727 patients were collected and analyzed, most of whom are
males, aged between 0 and 23 years (mode: 7 years). 64, 9% were born in Italy. In 40.2% of
the cases the school sent the children to the services, most commonly for academic
difficulties, behavioral problems, and language or communication problems.
In 53% of cases, migrant patients, who are not Italian citizens, have regular residence
permits. Patients generally have a good knowledge of Italian. The mother tongue is Italian
only in 10.7% of patients. The patients’ parents were generally born abroad, migrated
without the family of origin (50%) in order to search for a job, and both hold a residence
permit in 40% of cases.
Complex communication needs and participation
(CAA: Augmentative Alternative Communication)
Children who do not speak or who can only say a few words, children who have difficulty in
understanding another’s words... There are about 8000 people between 0 and 18 years in the
Lombardy Region that suffer from communication disorders, some for a few months, others
for years, some forever. In Italy there are almost 50,000. Some also have mobility problems,
others a genetic syndrome or autistic disorder. For all, growing up without the ability to
communicate is very tough, and it is essential to find ways of making it possible to
communicate without use of the voice, through measures of support (augmentative
communication). Symbol-based systems, as well as images, can be used, in which all the
figures are written above the word or the verb they represent. The child is therefore able to
recognize the images and the interlocutor to read the words.
Digital tools programmed to “lend” a voice when necessary can be used, as well as
information technology and computer technology adapted to personal needs and systems that
allow people who cannot use the alphabet or cannot use a pen, to read and write. Anyone
who needs to communicate with a child must use a language (written, spoken, visual)
appropriate to the child’s ability and this should be implemented and guaranteed forever. For
this reason, it is not enough to train specific operators, but it is necessary to also involve
parents and teachers. To date, only a few patients can access the required support
interventions for communication, and this generally occurs very late for the shortage of
adequately trained personnel within departments of Child and Adolescent Psychiatry.
To meet these unaddressed needs, Milan’s Local Health Unit (ASL) has launched a specific
project, financed by the Lombardy Region for the years 2010-2012, involving 15 Child and
Adolescent Psychiatry Units of the region. In this context, a conference was organized on
October 21st by the the IRCCS “Ca’ Granda” Ospedale Maggiore Policlinico di Milano
Foundation’s Centro Sovrazonale di Comunicazione Aumentativa (Supranational Centre for
Augmentative Communication), in collaboration with Milan’s Local Health Unit (ASL),
Treviglio’s UONPIA (Infant and Adolescent Neuropsychiatry Operational Unit), and the
Laboratory for Mother and Child Health of the Mario Negri Institute for Pharmacological
Research.
The conference addressed the complex communication needs in children, described what
represents an augmentative communication intervention, and how it can be applied to certain
situations in order to become a possible resource for all children. The project was presented
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in detail and a series of experiences already in place that led to the structuring of the project
were described.
Fp7 Projects
1) TINN – Treat Infections in NeoNates
The TINN project, Treat Infections in Neonates, is part of the European Union’s Seventh
Framework Project and is aimed at gathering the experience in the neonatal research field of
numerous centres across Europe in order to produce detailed evidence on the safety and
efficacy of ciprofloxacin and fluconazole use in neonatal sepsis. The final goal of the project
is to obtain a Pediatric Use Marketing Authorization (PUMA) for the two drugs.
A survey on the use of ciprofloxacin and fluconazole by neonatal intensive care units
(NICU) in Europe was conducted in the first phase of the project, from December 2009 to
June 2010. A total of 200 NICUs participated, representing 32 countries. The countries
represented by the greatest number of NICUs (disregarding country size), were Italy, the
United Kingdom, and France.
The survey results highlight a heterogeneous picture of the therapeutic schemes and
indications for use of the two drugs, both between and within countries. Significant doubts
on the part of clinicians concerning safety and efficacy issues were also revealed,
highlighting a need for additional evaluation and information on the optimal use of the drugs.
The survey, however, also found a notable interest on the part of NICUs across Europe in
participating in studies on the two drugs in order to obtain the necessary, lacking
information.
2) COHEMI
Coordinating resources to assess and improve health status of migrants from Latin AmericaCOHEMI Project- HEALTH.2010.3.4-5
European health systems are committed to meeting the challenge of understanding the needs
of migrant populations and adapting their services to meet these needs. The difficulties
inextricably linked to this challenge are caused by the complexity of migration patterns and
the differences between migrant population across EU countries. At present, the limited
available data show that attempts to incorporate migrants’ health needs, in particular those of
migrants from non-EU countries, into EU health systems have remained scattered and
uncoordinated.
In January 2011 started the project COHEMI-Coordination resources to Assess and Improve
health status of migrants from Latin America, a three-year project, funded under the 7th
Framework Programme for Research and Technological Development (Programme
Cooperation- Health), which sees the Mario Negri Institute coordinator of a major
consortium of 10 partners located between Europe and Latin America.
COHEMI’s general objective is to coordinate referral centres dealing with specific Latin
American (LA) diseases in order to:
− provide an analysis of health systems and legislation on migrants and assess the
determinants of health
− by evaluating 3 types of diseases typical of LA countries
− in order to produce new procedures and suggestions shared at migration policies level,
that take into account the specific cultural needs of migrants.
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NEONATOLOGY
Part of the Laboratory’s effort is currently dedicated specifically to the neonatological area.
In addition to the TINN project, Treat Infections in Neonates (see dedicated section), there
are three projects underway, two of which related to developing countries:
A literature review on the use of drugs in neonatal intensive care units in low to middle
income countries.
An assessment of mortality and duration of stay of neonates admitted to the largest neonatal
intensive care unit in Nicaragua, after modification of the strategy used to employ
mechanical ventilation.
A literature review on the use of moderate cerebral hypothermia for prevention of brain
injury, with particular attention to neonatal hypoxic-ischaemic encephalopathy.
“Io e l’Asma” Project
Under an agreement with the Hospital of Brescia, the data collected during the "Io e l’asma"
project, performed by the Bronchopneumology Unit of the Hospital, were evaluated.
The aim of the project is to create multidisciplinary network of different figures (physicians,
nurses, parents, teachers, educators) who share common educational and therapeutic
approaches for the management of asthma.
During the September 2007-September 2010 period a total of 515 children (64% male) have
made at least three visits to the Bronchopneumology Unit.
40% of the children had adequate control of asthma at the baseline visit, a figure that
increased to 76% at the time of the third visit (after 12-16 weeks). The degree of asthma
control improved in 47% of children and was adequately maintained in 34% of cases. The
rate of hospitalization and of school absences due to asthma in children followed at the clinic
were reduced (from 7.6 to 2.7%, and from 13.4 to 6.1%, respectively).
30% of children did not need any controller medication, while 62% of children receiving
drug therapy were treated with an inhaled steroid (fluticasone) at low doses.
After attending the unit all children used spacer device appropriate for the age, and in 2/3 of
the cases the symptoms were recorded on a daily diary.
This pilot study documented that the multidisciplinary approach used within the "Io e
l’asma" project was effective in improving and maintaining an adequate control of asthma
symptoms in more than 80% of children.
National ADHD Register
The National Register for ADHD in children has been active since June 2007. The register
monitors the diagnostic, therapeutic, and health care approaches and evaluates the adverse
effects of two drugs; methylphenidate and atomoxetine. These two drugs are marketed in
Italy for the treatment of ADHD in children and adolescents. The register was initially
supposed to be active for two years (2008-9), but its duration was extended to three (to the
end of June 2010).
The register is a tool with great potential for responding, in an appropriate manner and at the
national level, to specific, unmet health needs in youth with ADHD (and their families).
The Laboratory for Mother and Child health, as part of the scientific committee, participated
in writing the protocol that defines the National ADHD Register’s structure and activities
and in monitoring it. The Laboratory is currently involved in monitoring the data present in
the register and in creating the data reports for the health operators working in the services
involved. The Lab is especially involved in supporting the creation of a functional network
of referral centers.
The Lombardy Region, with 300 patients, is the first region in number of patients monitored
by the national register. There are 229 patients with a first methylphenidate and atomoxetine
prescription (76%), reported by 15 of 22 referral centres (68%) indicated by the Lombardy
Region: 57 were present in 2007, 82 in 2008, 42 in 2009, and 39 in 2010. In all, 88% of
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patients are male, aged between 5 and 17 years (median 11 years, mode 12). For 129 patients
(56,3%) at least one familiarity was found, in particular: 12 with ADHD, 24 with ADHD and
learning disabilities, and 17 with learning disabilities. In agreement with the protocol’s
indications, 66 patients were evaluated with a multidimensional approach (28,8% of the
total, with K-SADS, CPRS, CTRS e WISC).
The most common diagnosis was complex ADHD (79,5%), compared to the disorder
characterized prevalently by attention deficit (14,4%), or hyperactivity (4,4%). In 54 cases
(23,6% of the total) no comorbidities were found, while in 100 cases one was found and in 1
case five were found. The most common comorbidities were learning disorders (49,8%) and
oppositional defiant disorder (34,5%). Both were diagnosed in 34 patients (14,8% of total).
In all, 149 patients began treatment with atomoxetine (65%) and 80 with methylphenidate.
Adverse effects were found in 109 patients (47,6% of the total).
The laboratory set up ADHDNews, a newsletter aimed at providing interested health
operators with a monthly bibliographic update of the recent scientific literature via email.
This initiative is part of the Italian Medicines Agency’s (AIFA) independent research project
implemented in collaboration with the Istituto Superiore di Sanità and called “Long term
safety of drugs used to treat school-aged children with Attention Deficit Hyperactivity
Disorder and epidemiology of the disorder in the Italian population”. A total of 24 issues of
ADHDNews have been produced so far and 277 people have registered to receive the update
(125 psychiatrists and neuropsychiatrists, 48 family physicians, 36 psychologists and speech
therapists, 32 pediatricians, 7 pharmacists, 7 school workers, and 22 “other”). The newsletter
identified more than 1010 scientific articles.
The Lombardy Region’s ADHD Register
Thanks to the network created after the abovementioned project, it was possible for the
referral centres to actively put forward a three-year project “Sharing diagnostic-therapeutic
approaches for ADHD in Lombardy”. The project, whose coordinator is the UONPIA A.O.
Spedali Civili of Brescia, began in January 2010, involves 18 referral centres, and is funded
by the Lombardy Region.
In this project, the laboratory’s role is to build a new registry, that will be more practical than
the national one, in order to increase the centers’ compliance in providing information, with
the aim to improve data quality.
The Registry will also be extended not only to patients with a diagnosis of ADHD in drug
treatment with methylphenidate or atomoxetine, but to all those who belong to the center
with suspected ADHD.
The registry will then permit the:
−
−
−
−
−
Quantification of the workload
Monitoring of diagnostic paths
Outlining of the prevalence of the disorder
Monitoring of also non-drug treatment programs
Maintenance of pharmacovigilance by extending the monitoring on the use of
the drugs, including drugs other than atomoxetine and methylphenidate.
The registry will most likely be accessible from the early months of 2011.
Workgroup on the Convention for child and adolescent rights.
The Laboratory for Mother and Child Health is part of the Working Group for the
Convention on the Rights of the Child (CRC) in Italy. This year the CRC Group has
published the 2nd Supplementary Report in English and sent it to the 'NGO Group
for the CRC, which will forward it to the UN Committee that will consider Italy in
2011.
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The English version of the 2nd supplementary report can be downloaded at:
http://gruppocrc.net/IMG/pdf/2_Rapporto_CRC_2010_StC.pdf.
The 2nd Supplementary Report on the Rights of the Child in Italy in Italian was
presented November 18, 2009, on the occasion of the twentieth anniversary of the
CRC.
CRC Group, as happened in 2003 and 2006, will attend the pre-session (closed-door
meeting between the members of the UN and representatives of NGOs) and the
sessions will be held in 2011.
EAHC (Executive Agency for Health and Consumers).
The Laboratory for Mother and Child Health collaborated in writing the Health and social
care chapter of the First European child health report for the age group of 0-12 years in
European countries, funded by the Executive Agency for Health and Consumers of the
European Union. In particular, the Laboratory was involved in evaluating the policies
concerning the access to health care for migrant people developed by European and EFTA
countries, and the drug prescription profile in paediatric population.
Ricerca & Pratica
Ricerca & Pratica was born in January, 1985, as a manifestation of the . Mario Negri.
Institute for Pharmacological Research. Today, the journal is part of the International Society
of Drug Bulletins (ISDB), which represents independent journals.
For more than twenty years, the journal has represented an arena for all those professionals
who collect data and carry out studies in general practice with the aim to increase their
knowledge and to improve their practice. Ricerca & Pratica is also appreciated for its ability
to go beyond the merely clinical aspect of medicine, without, however, forgetting that it is to
this aspect that the readers dedicate most of their time and effort.
Through its activity, Ricerca & Pratica can therefore represent an exclusive, independent
observation point. It is also an area that promotes contemplation, evaluation, and information
by applying . tools. such as data trustworthiness and importance, the balance between
benefits and risks and between benefits and costs, independence from conflicts of interest,
and the realistic objective to contribute to a progressive, equally distributed improvement in
the population’s health.
Co-operation with countries with limited resources
As an expression, test, and original method of expression of the choice to make the
Laboratory’s research transferable and accessible to all populations, the Laboratory
promoted and provided assistance to projects in, and for, the . South of the world. , also in
collaboration with the World Health Organization. The technical and organisational support
for local groups and international non-governmental organisations for carrying out sociosanitary projects in countries with limited resources, especially Colombia, Ecuador, Brazil,
Bolivia, Cuba, Vietnam and the Balkans, continues.
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LABORATORY OF REGULATORY
POLICIES
STAFF
Head
Vittorio BERTELE’, M.D.
Senior resercher
Rita BANZI, Chem Pharm. D, PhD
Research fellow
Brian GODMAN, BSc
Visiting scientist
Roberta Joppi, Chem Pharm. D
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CURRICULUM
Vittorio Bertele’ is a clinical pharmacologist. He got his MD degree in 1977 and the specialization in
Internal Medicine in 1982, both at the Milan University Medical School. He was research fellow at the
Harvard Medical School and then worked at the Milan University and the “Mario Negri” Institute.
His main areas of interest have been clinical pharmacology of drugs active on the haemostatic and
vascular system1,2, epidemiology of interventions in the cardiovascular area, and clinical trials and drug
utilization studies in the cardiovascular area3,4. He was CPMP expert at the EMEA, member of the
Committee for Drug Price Negotiation at the Italian Ministry of Health, and member of the TechnicalScientific Committee at the Italian Drug Agency. At present he is head of the Regulatory Policies
Laboratory at the "Mario Negri" Institute, secretariat of the ECRIN Scientific Board, and member of the
Italian Horizon Scanning Center5-10.
1. Bertele' V., Falanga A., Tomasiak M., Dejana E., Cerletti C., De Gaetano G. Platelet
thromboxane synthetase inhibitors with low doses of aspirin: Possible resolution of the
"aspirin dilemma". Science 1983; 220: 517-519
2. Bertele' V., Falanga A., Tomasiak M., Chiabrando C., Cerletti C., De Gaetano G.
Pharmacological inhibition of thromboxane synthetase and platelet aggregation:
Modulatory role of cyclooxygenase products. Blood 1984; 63: 1460-1466 (1984).
3. The i.c.a.i. Group (Gruppo di studio dell'Ischemia cronica Critica degli Arti Inferiori).
Prostanoids for chronic critical leg ischemia: A randomized, controlled, open-label trial with
prostaglandin E1. Ann Int Med 1999; 130: 412-421
4. Garattini S, Bertele’ V. Adjusting regulatory rules to public health needs. Lancet 2001; 358: 6467
5. Garattini S, Bertele' V. Efficacy, safety, and cost of new anticancer drugs. BMJ 2002; 325: 269271
6. Garattini S, Bertele’ V, Li Bassi L. How can research ethics committees protect patients better?
BMJ 2003; 326:1199–201
7. Joppi R, Bertele' V, Garattini S. Disappointing biotech. BMJ 2005; 331: 895-897
8. Garattini S, Bertele' V. Non-inferiority trials are unethical because they disregard patients'
interests. Lancet 2007; 370 : 1875-1877
9. Garattini S, Bertele' V. Homoeopathy: not a matter for drug-regulatory authorities. Lancet 2009;
374 : 1578-1580
10. Garattini S, Bertele' V. Europe's opportunity to open up drug regulation. BMJ 2010; 340:c1578
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ACTIVITIES
Critical appraisal of clinical methodology
Cooperation to the development and functioning of the pan-European Infrastructure for clinical
trials (ECRIN, European Clinical Research Infrastructure Network) achieved by the ECRIN
Scientific Board Secretariat and the European Correspondent for Italy
Coordination of the Task 9.3 “Identification of key steps on monitoring activities” within the
WP9 of the ECRIN, European Clinical Research Infrastructure Network
Critical evaluation of the benefit-risk profile of drugs
Assessment of emerging technologies
Optimisation of drug use and healthcare fund stewardship including potential reforms and
initiatives to achieve this
Critical appraisal and recommendations for European Pricing and Reimbursement systems
including generics, interchangeable products within a class and new innovative medicines
Cooperation to the design and conduct of pharmacovigilance and pharmacoepidemiology
studies in Europe
Evaluation of the appropriateness of drug legislation, institutions, and regulatory procedures
with respect to public health needs.
Cooperation to the development and to the solution of regulatory issues in developing countries.
MAIN FINDINGS
Critical appraisal of clinical research methodological aspects as the adoption of
equivalence/non-inferiority design in clinical trials
Critical evaluation of transnational clinical research projects to be conducted with the
methodological and operating support of ECRIN (European Clinical Research Infrastructure
Network).
Development of Pan-European strategies for the rational use of new and existing drugs
including policies to enhance the managed entry of new drugs as well as reduce prescribing of
more expensive interchangeable single sourced products in a class once generics are available:
establishment of the Piperska Group
Development of new models and strategies to optimise the managed entry of new drugs
including suggestions for risk sharing arrangements in the future given current concerns. This
co-ordinated via the Piperska group
Recommendations for Pan-European pricing policies for generics as well as interchangeable
brands in a class once generics are available
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Assessment of emerging technologies in the frame of the Italian Horizon Scanning Project
which provides decision makers with timely information on the potential clinical impact and
cost-effectiveness of new health technologies
Critical review of drug documentation at the basis of marketing authorizations.
Critical review of the criteria to assess pharmaceutical innovation and include new drugs in the
national reimbursement schemes.
Participation in the ENCePP (European Network of Centres of Pharmacovigilance and
Pharmacoepidemiology) and the PROTECT consortium which under the coordination of the
European Medicines Agency (EMA) aims at improving design and conduct of
pharmacovigilance activities and pharmacoepidemiological studies in Europe. The PROTECT
consortium is also developing and testing innovative methods to integrate and present
information on drug-related benefits and risks
Raising awareness among interested parties about the deficiencies of the present EU
pharmaceutical legislation and about our proposals to improve it in the public health interest.
Italian Drug Agency (AIFA)
Department of Health Lombardy Region
Italian Horizon Scanning Project
European Medicine Agency (EMA)
European Clinical Research Infrastructure Network (ECRIN)
European Network of Centres in Pharmacoepidemiology and Pharmacovigilance (ENCePP)
Piperska network involving health authority and health insurance personnel from acoss Europe
to enhance the rational use of new and existing drugs
Karolinska Institutet, Division of Clinical Pharmacology, Department of Laboratory Medicine,
and Centre for Pharmacoepidemiology; Department of Drug Management and Informatics, SE
University of Liverpool Management School, Prescribing Research Group, UK
Cochrane Collaboration
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International Information Network on New and Emerging Health Technologies (EuroScan)
World Health Organisation (Department of Essential Drugs and Medicines Policy)
Association of South East Asian Nations (ASEAN)
Ricerca & Pratica
Dialogo sui Farmaci
Frontiers in Clinical Trials and Pharmacotherapy (associate editor)
Frontiers in Pharmacology: Pharmacoeconomics and Outcomes Research (Associate
Editor)
European Clinical Research Infrastructure Network (ECRIN) Scientific Board, Secretariat
Scientific Committee of the Italian Horizon Scanning Project
•
Garattini S, Bertele' V. Bevacizumab and ranibizumab. A matter of public interest. BMJ 2010 341 :
c3721
•
Garattini S, Bertele' V. Dutasteride and prostate cancer. Reply to. N Engl J Med 2010 363 : 794
•
Garattini S, Bertele' V. Europe's opportunity to open up drug regulation. BMJ 2010 340 : c1578
•
Garattini S, Bertele' V. Alternative medical practices: flashbacks from the dark ages. Eur J Intern
Med 2010 21 : 245-246
•
Garattini S, Bertele' V. Rosiglitazone and the need for a new drug safety agency. BMJ 2010 341 :
c5506
•
Garattini S, Bertele' V. Health authorities should drive clinical research. Public Service Review
European Union 2010 20 : 162-163
•
Adamski J, Godman B, Ofierska-Sujkowska G, Osinska B, Herholz H, Wendykowska K,Laius O,
Jan S, Sermet C, Zara C, Kalaba M, Gustafsson R, Garuoliene K, Haycox A, Garattini S, Gustafsson
LL. Review of risk sharing schemes for pharmaceuticals: considerations, critical evaluation and
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recommendations for European payers. BMC Health Services Research 2010, 10:153
doi:10.1186/1472-6963-10-153
•
Godman B, Shrank W, Wettermark B, Andersen M, Bishop I, Burkhardt T, Garuoliene K, Kalaba M,
Laius O, Joppi R, Sermet C, Schwabe U, Teixeira I, Tulunay FC, Wendykowska K, Zara C,
Gustafsson LL. Use of generics – a critical cost containment measure for all healthcare professionals
in Europe? Pharmaceuticals 2010; 3:2470-94 doi 10.3390/ph/3082470 ISSN 1424-8247
•
Wettermark B, Godman B, Eriksson C, van Ganse E, Garattini S, Joppi R, Malmström RE, Paterson
K, Gustafsson LL. Einführung neuer Arzneimittel in europäische Gesundheitssysteme. GGW
2010;10(3):24–34 (Introduction of new medicines into European healthcare systems)
•
Godman B, Wettermark B. Commentry – ‘Cost awareness when prescribing treatment’. British
Journal of Healthcare Management 2010;16( 2); 72
•
Wettermark B, Elseviers M, Godman B, Ronning M, Tilson L, Vlahovic-Palcevski V.
Methodological challenges in cross-national comparisons in drug utilisation. Pharmacoepidemiology
and Drug Safety 2010:19:S16.DOI: 10.1002/pds
•
P. K. Cheema, S. Gavura, B. Godman, L. Yeung, M. E. Trudeau. Global variations in reimbursement
of new cancer therapeutics: Improving access through risk-sharing agreements. J Clin Oncol 28:15s,
2010 (suppl; abstr 6050).
•
Godman B, Shrank W, Andersen M, Berg C, Bishop I, T. Burkhardt T, Garuolienè K, Herholz H,
Joppi R, Kalaba M, Laius O, McGinn D, Samaluk V, Sermet C, Schwabe U,Teixeira I, Tilson L,
Tulunay FC, Vlahović-Palčevski V, Wendykowska K, Wettermark B, Zara C, Gustafsson LL.
Comparing policies to enhance prescribing efficiency in Europe through increasing generic
utilisation: changes seen and global implications. Expert Rev. Pharmacoeconomics Outcomes Res
2010; 10: 707–722
•
Godman B, Buscics A, Burkhardt T, Schmitzer M, Wettermark B, Wieninger P. Initiatives to
enhance renin-angiotensin prescribing efficiency in Austria; impact and implications for other
countries. Expert Rev Pharmacoeconomics and Outcomes Research 2010;10: 199-207
•
Sermet C, Andrieu V, Godman B, Van Ganse E, Haycox A, Reynier JP. Ongoing pharmaceutical
reforms in France; implications for key stakeholder groups. Applied Health Economics and Health
Policy 2010;8:7-24
•
Wettermark B, Persson M, Wilking N, Kalin M, Korkmaz S, Hjemdahl P, Godman B, Petzold M
Gustafsson LL for the Regional Drug Expert Consortium. Forecasting drug utilization and
expenditure in a metropolitan health region. BMC Health Services Research 2010, 10:128
•
McGinn D, Godman B, Lonsdale J, Way R, Wettermark B, Haycox A. Initiatives to enhance the
efficiency of statin and proton pump inhibitor prescribing in the UK; impact and implications. Expert
Rev Pharmacoeconomics and Outcomes Res 2010; 10: 73-85
•
Moon J, Flett A, Godman B, Grosso A, Wierzbicki A. Getting better value from the NHS drug
budget. BMJ 341:c6449 2010.
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RESEARCH ACTIVITIES
Critical appraisal of clinical methodology
Raising awareness about potential biases in clinical research
Critical evaluation of the EU pharmaceutical legislation
Raising awareness among interested parties about the deficiencies of the present EU
pharmaceutical legislation and about our proposals to improve it in the public health interest
Development of a Pan-European Infrastructure for clinical trials
Participation in a distributed infrastructure linking national networks of clinical research centres
and clinical trials units (ECRIN, European Clinical Research Infrastructure Network) which
provides integrated ‘one-stop shop’ services to investigators and sponsors in multinational
studies.
Critical appraisal of ongoing reforms including pricing reforms in major
European countries
Evaluation of ongoing reforms across Europe to enhance generic prescribing rates, drive down
generic prices and corresponding originator brands, as well as potential prices of
interchangeable brands once standards become available as generics, and the potential for cross
cultural learnings to release valuable resources to fund increased volumes and new innovative
drugs in the future without prohibitive increases in general taxation or health insurances to
continue to provide equitable and comprehensive healthcare in Europe
Development of Pan-European strategies for rational use of drugs
Enhancing rational use in line with an approach that has become known as the ‘four Es’,
namely: economics; enforcement; education and engineering to further fund increased volumes
and new valuable innovative drugs. In addition, development of new models to optimize the
managed entry of new drugs including horizon scanning and critical drug evaluation pre-launch
(below) and post launch activities
Development of Pan-European strategies for pharmacovigilance
Developing and testing innovative methods to integrate and present information on benefits and
risks in order to provide all stakeholders (patients, prescribers, regulators and pharmaceutical
companies) with accurate and useful information on drug-related risks and benefits
Assessment of emerging technologies
Collecting information on emerging medicines with respect to their potential clinical impact and
their cost effectiveness and ranking the new products according to their possible marketing
authorization date, their potential innovation grade, therapeutic and economic impact, possible
price and NHS sustainability with the aim to provide decision makers with timely information
on the potential clinical impact and cost effectiveness of new health technologies
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CENTRE OF COMPUTER SCIENCE
ENGINEERING
STAFF
Research and Communication Informatics
Head of Division
ROSSI Lorenzo Marco
Division of I.C.T. Services and Management
Head of Division
BAZZI Davide
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CURRICULA
Lorenzo Marco Rossi graduated in Biomedical Engineering with specialization in
Hospital Clinical Instrumentation at Politecnico of Milan. He has been working with the
Institute Mario Negri since 1998.
Main areas of interest are:
1.Planning and realization of software for clinical research
2.Planning and realization of software system for in-plant automatization
3.Planning and realization of products for multimedia divulgation
Davide Bazzi graduated in Informatics with ABACUS specialization at Istituto Tecnico
Industriale Statale of Corsico. He has been working with the Institute of Mario Negri
since 1997.
Main areas of interest are:
1. Planning, realization and management of communication Network and Data Center
2. Definition and management of technological innovation for ICT systems
4. Planning and realization of technological innovation for ICT systems
3. Definition and application of organization’s methodologies and processes for the
Informatics Security Management
ACTIVITIES
In order to fulfill even more specialization needs in informatics development, the Centre
of Computer Science Engineering is organized, considering the acquired skills, in three
distinct division bound each other by a strong collaborative relationship.
The Centre of Computer Science Engineering gathering informatics multidisciplinary
aspects promotes and propose itself to coordinate and harmonize the development of the
tools for the management information, improving the integration between informative
procedures making more efficacious communication process and management of
scientific and administrative datas, in order to support and fasten decisional,
management, clinical trials and scientific processes.
RESEARCH ACTIVITIES
Implementation of Clinical Trials’ gathering forms (E-CRF)
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Lab. Translational and Outcome Research in Oncology (Dep. Oncology)
Trial CERP
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Lab. Clinical Trials (Dep. Oncology)
Amendment trial FOLFOX
Trial ITACAS 2
Lab. New Drug Development Strategies (Dep. Oncology)
-
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Trial MUCOSITIS
Maintenance and management of data gathering forms for the following clinical
trials
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Lab. Neurological Disorders (Dip. Neuroscience):
Registro Europeo SLA
Trial L-ACETYLCARNITINE
Trial ANTIEPILETTICI
Trial EPILESSIA E STROKE
Trial EPO VS MP IN SPINAL SHOCK
Trial VALPROATO
Trial THEOREM
Trial ANTIEPILETTICI
Trial ADONE
Trial EDU-COM
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Lab. Clinical Trials (Dip. Oncology)
Trial FOLFOX
Trial TOP
Trial COMETS
Trial TAILOR
Trial HEAD & NECK
Trial GLAUCOMA PEDIATRICO
Amendment to Trial TAILOR
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Lab. New Drug Development Strategies (Dip. Oncology)
Trial MAPS
Trial STARPAN
Trial TRIAC
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Dip. Epidemiology
Trial CADASIL
-
Lab. Quality Assessment of Geriatric Therapies and Services
Trial GISAS
Patients registry for Polipathologies and Politherapies – SIMI web
Web based applications connected to the projects
−
−
−
−
−
Design and realization of Monitoring Instruments for the current Trials Gathering
Data Program
Order Handling System (Statistics Module)
Management of the Database hostings datas about recovers, prescriptions and
examinations provided from Regione Lombardia for covenant data analysis.
Support to data processing in recipes analysis for Regione Lombardia
Creation of utility for the software of Interaction between Drugs
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−
Other projects
Web based applications connected to the projects
New database for the Institute Donators
Updates of statistics for the Institute Distributed Publications
•
Management of the database and credits of ECM
•
Clinical Trial Register for the Institute
•
Administration of the management system for the entrance exams of the Regione
Lombardia school
•
Administration of the management system for the entrance exams for PhD
•
Utility for School Administration
•
•
Multimedia Communication
-
Management of multimedia contents for Institutional website
Video editing and DVD realization for Presentations
Websites
−
−
Management of the Official Institute’s website
Management of linked websites
Informatics Infrastructures
−
−
−
−
−
−
−
Realization of physical-to-virtual migration and stabilization of server on virtual
platform
Realization of support infrastructure (server and database) for Valhidate project
Migration of the new e-mail system on virtualized platform
Coordination of activities for setup and starting of the new Km Rosso site’s
Informatics and Telecommunications
Activation completed for new linking infrastructures between sites on MPLS
network
Realization of a new backup system (disk-to-disk) in secondary server farm destined
to a disaster recovery site
Ordinary activities of helpdesk and Informatics Infrastructures and
Telecommunications management
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ITALIAN COCHRANE CENTRE
STAFF
Head
Alessandro LIBERATI, M.D.
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CURRICULUM
Alessandro Liberati obtained his MD Degree in 1978 at the University of Milano and his post doctoral
degree in Hygiene and Preventive Medicine in 1981 at the same university.
Teaching activities: Primary responsibility of several academic and non academic training courses on the
methodology of clinical research and systematic reviews/metanalyses. He is Director of the advanced
Master “Evidence based medicine e metodologia della ricerca sanitaria”, at the Università degli Studi di
Modena e Reggio Emilia.
Areas of scientific expertise: methodology of clinical research with particular reference to controlled
clinical trials, epidemiological methods for research synthesis (systematic reviews and metanalyses);
methods of practice guidelines production and implementation, evaluation of ethical implications of
clinical research.
Past and current roles at the Mario Negri Institute: 1980-1986 Junior researcher at the Laboratory of
Clinical pharmacology; 1987-1989 Head, Unit of Clinical Epidemiology and Health Services Research;
1990-1998 Head Laboratory of Clinical Epidemiology; since 1994 he is Director of the Italian Cochrane
Centre; since 1998 he is Associate Professor of Clinical Biostatistics and Epidemiology at the University
of Modena and Reggio Emilia; since 1997 he is President of the Associazione per la Ricerca sulla
Efficacia dell’Assistenza Sanitaria - Centro Cochrane Italiano (AREAS-CCI); he collaborates since 2004
with the Social and Health Regional Agency of Emilia Romagna; since 2004 he is Member of the
Commissione Nazionale Ricerca Sanitaria; since 2005 he is Member of the Commissione Ricerca e
Sviluppo dell’Agenzia Italiana del Farmaco (AIFA).
•
•
•
•
•
•
•
•
•
•
•
Liberati A et al (Italian Medicines Agency (AIFA) Research & Development Working group). Feasibility and challenges
of independent research on drugs: the Italian medicines agency (AIFA) experience Eur J Clin Invest 2010; 40 (1): 69-86
Banzi R, Liberati A, Moschetti I, Tagliabue L, Moja L, A review of online evidence-based practice point of care
information summary providers. J Med Internet Res 2010; 7:12 (3)
Parmelli E, Papini D, Moja L, Bandieri E, Belfiglio M, Ciccone G, De Palma R, Leoni M, Longo G, Magrini N,
Moschetti I, Liberati A, Updating clinical recommendations for breast, colorectal and lung cancer treatments: an
opportunity to improve methodology and clinical relevance Ann Oncol 2010
Moher D, Liberati A Reporting systematic reviews and meta-analyses: Asking authors, peer reviewers, editors and
funders to do better Med Clin 2010
Colombo C, Mosconi P, Buratti MG, Liberati A, Donati S, Mele A, Satolli R, Press coverage of hormone replacement
therapy and menopause. Eur J Obstet Gynecol Reprod Biol 2010
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA GROUP Preferrred reporting items for systematic reviews
and meta-analysis. The PRISMA Statement. Int J Surg 2010; 8: 336-41
Liberati A, D'Amico R, Commentary: The dabate on non inferiority trials: "when meta-analysis alone is not helpful" Int
J Epidemiol 2010; 39: 1582-3
Colombo C, Satolli R, Liberati A, Mosconi P, Giurie dei cittadini Working Group. Treating prehypertension. Citizens'
juries in health care. BMJ 2010; 22: 341
Traversa G, Sagliocca L, Liberati A, Martini N, The need to promote independent research on drugs. Ann Oncol 2010;
21: 2295
Liberati A, So many questions, so few answers. Inerview by Les Olson. Bull World Health Organ 2010; 88: 568
Moher D, Liberati A, Reporting systematic reviews and meta-analysies: asking authors, peer reviewers, editors and
funders to do better. Med Clin (Barc) 2010; 135: 505
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INTRODUCTION TO THE CENTRE'S ACTIVITIES
The Italian Cochrane Centre (ICC) (http://www.cochrane.it) was founded in 1994 and is
affiliated to the Cochrane Collaboration (CC). The CC is an international non profit
organization that prepares, maintains and promotes systematic reviews of the effects of health
care interventions. The main product of the Cochrane Collaboration is the Cochrane Library, a
monthly publication containing Cochrane systematic reviews and other relevant databases of
other siblings international organizations.
The objectives of the ICC are centered around supporting various activities of the Cochrane
Collaboration within Italy. In particular:
a) to disseminate the knowledge of CC and CC activities throughout Italy;
b) to provide methodological and practical support to all individuals and groups who are
interested in collaborating with the CC;
c) to develop methodological projects to progress scientific knowledge on “science of research
synthesis”
d) to contribute to the adoption and dissemination of Evidence-based Medicine (EBM) and
Evidence based Health Care (EBHC) in Italy.
e) to collaborate with NHS to improve the quality of clinical and epidemiological research.
The ICC has created a national network with researchers and health care providers who are
producing systematic reviews for the Cochrane Collaboration and are actively involved in other
activities related to the dissemination of evidence based medicine.
Collaboration with Agenzia Italiana del Farmaco (AIFA) in information projects
Collaboration with Agenzia Sanitaria e Sociale Regione Emilia Romagna to production
guidelines and raccomendations in clinical oncology.
Istituto Neurologico "Carlo Besta", Milano
Agenzia Sanitaria Regionale, Regione Emilia Romagna, Bologna
Università degli Studi di Modena e Reggio Emilia, Modena
Università degli Studi di Milano, Milano
Dipartimento di Epidemiologia della Regione Lazio, Roma
Osservatorio epidemiologico della Direzione sanità e servizi sociali della Regione Umbria,
Perugia
Istituto Ortopedico “Galeazzi”, Milano
Istituti Ortopedici Rizzoli, Bologna
The Cochrane Collaboration, Oxford, UK
Centre for Reviews and Dissemination, University of York, York, UK
British Medical Journal Publishing Group, London, UK
Centre for Statistics in Medicine, Oxford, UK
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Thomas Chalmers Centre for Systematic Reviews, Ottawa, Canada
The Campbell Collaboration, Philadelphia, USA
Centre for Evidence-Based Medicine, Oxford, UK
Institute of Health and Society, Newcastle University, Newcastle, UK
Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Canada
Department of Epidemiology and Community Medicine, Faculty of Medicine, University of
Ottawa, Ottawa, Canada
Evidence Based Health Policy and Research, Journal of Clinical Epidemiology, Journal of
Health Services Research, BMJ Evidence Centre (BMJ Publishing Group), European Journal of
Clinical Investigation
Annals of Internal Medicine, British Medical Journal, JAMA, Evidence Based Health Policy
and Research, Canadian Medical Association Journal, PLoS Medicine. International Journal of
Epidemiology.
EVENT ORGANIZATION
Corso di perfezionamento avanzato in “Revisioni sistematiche e meta-analisi – metodologia
Cochrane” –
November 2010- March 2011
Master in “Promozione e Governo della Ricerca nella Aziende Sanitarie”
March – December 2010, Modena
Workshop: November 14 2010, Modena
- Cochrane Collaboration e miglioramento della pratica clinica
- Assistenza pazienti con ictus
XIV Annual Meeting of the Italian Cochrane Network "Orientare e informare le decisioni nel
campo degli interventi complessi"
November 15 2010, Modena
PARTICIPATION IN EVENTS IN WHICH THE CENTRE WAS
INVOLVED
Clinical Trial Day
May 19 2010, Milano
Course “Dalle evidenze alle raccomandazioni per la pratica clinica: istruzioni per l’uso”
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May 30 – 31 2010, Ischia
Annual Continental European Cochrane Entities Meeting (CECEM)
June 2 – 4 2010, Perugia
Annual Croatian Cochrane Simposium
June 26 – 27, Spalato
XII Cochrane Colloquium
October 18 – 22 2010, Keystone, Colorado
Istituto di Ricerche Farmacologiche Mario Negri, Milano
Università degli studi di Modena e Reggio Emilia
Agenzia sanitaria e sociale regionale, Regione Emilia-Romagna, Bologna
Università degli Studi di Milano, Milano
SELECTION OF SCIENTIFIC PUBLICATIONS FROM 2010
All publications of the Italian Cochrane Center are available on web site www.cochrane.it.
Spagnolo P, Del Giovane C, Luppi F, Cerri S, Balduzzi S, Walters EH, D'Amico R, Richeldi L.
Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database of Systematic
Reviews 2010; Issue 9: CD003134
Iorio A, Matino D, D'Amico R, Makris M, Recombinant Factor VIIa concentrate versus
plasma derived concentrates for the treatment of acute bleeding episodes in people with
haemophilia and inhibitors. Cochrane Database of Systematic Reviews 2010; Issue 8:
CD004449
Liberati A, D'Amico R, Commentary: The dabate on non inferiority trials: "when metaanalysis alone is not helpful" Int J Epidemiol 2010; 39: 1582-3
Colombo C, Satolli R, Liberati A, Mosconi P, Giurie dei cittadini Working Group. Treating
prehypertension. Citizens' juries in health care. BMJ 2010; 22: 341
Traversa G, Sagliocca L, Liberati A, Martini N, The need to promote independent research
on drugs. Ann Oncol 2010; 21: 2295
Liberati A, So many questions, so few answers. Inerview by Les Olson. Bull World Health
Organ 2010; 88: 568
Moher D, Liberati A, Reporting systematic reviews and meta-analysies: asking authors,
peer reviewers, editors and funders to do better. Med Clin (Barc) 2010; 135: 505
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IRFMN
Corbetta D, Sirtori V, Moja L, Gatti R, Constraint - induced movement therapy in stroke
patients: systematic review and meta-analysis. Eur J Phy Rehabil Med 2010; 46: 537-44
Dall'Olmo L, Moja L, Treatment for non-dysplastic Barrett's oesophagus: a well informed,
demanding patient. Int Emerg Med 2010; 5: 433-5
Macura A, Abraha I, Kirkham J, Gensini GF, Moja L, Iorio A, Selective outcome reporting:
telling and detecting true lies. The state of the science. Int Emerg Med 2010; 5: 151-5
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA GROUP Preferrred reporting
items for systematic reviews and meta-analysis. The PRISMA Statement. Int J Surg 2010;
8: 336-41
Moja L, Clinicla trials: trial registration cannot alone trasform scientific conduct. Nat Rev
Urol 2010; 7: 7-8
Colombo C, Mosconi P, Buratti MG, Liberati A, Donati S, Mele A, Satolli R, Press coverage
of hormone replacement therapy and menopause. Eur J Obstet Gynecol Reprod Biol 2010
Virgili G, Koleva D, Garattini L, Banzi R, Gensini GF, Utilities and QALYs in health
economic evaluations: glossary and introduction. Internal Emerg Med 2010; 5: 349-352
Banzi R, Liberati A, Moschetti I, Tagliabue L, Moja L, A review of online evidence-based
practice point of care information summary providers. J Med Internet Res 2010; 7:12 (3)
Parmelli E, Papini D, Moja L, Bandieri E, Belfiglio M, Ciccone G, De Palma R, Leoni M,
Longo G, Magrini N, Moschetti I, Liberati A, Updating clinical recommendations for breast,
colorectal and lung cancer treatments: an opportunity to improve methodology and
clinical relevance Ann Oncol 2010
Moher D, Liberati A Reporting systematic reviews and meta-analyses: Asking authors, peer
reviewers, editors and funders to do better Med Clin 2010
Italian Medicines Agency (AIFA) Research & Development Working group. Feasibility and
challenges of indipendent research on drugs: the Italian medicines agency (AIFA)
experience Eur J Clin Invest 2010; 40 (1): 69-86
Moja L. Trial registration cannot alone transform scientific conduct. Nature reviews.
Urology 2010;7(1):7-8
Sirtori V, Corbetta D, Moja L, Gatti R. Constraint-induced movement therapy for upper
extremities in patients with stroke. Stroke 2010;47:e57-e58
RESEARCH ACTIVITIES
Educational and dissemination activities
The ICC is a partner of the Thomas C. Chalmers Interuniversity Center together with eight
Italian schools of medicine. This network’s main objective is to disseminate systematic reviews
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knowledge, production and use within the academia activities. In particular, many post-graduate
courses were organized on EBM, clinical trial and systematic review methodology, and the
GRADE approach to develop clinical guideline. In the context of the Thomas C. Chalmers
activities, the ICC has organized a post-graduate advanced course on systematic reviews,
“Corso di Perfezionamento avanzato in revisioni sistematiche e meta-analisi per la produzione
di linee guida – metodologia Cochrane”, second edition.
In collaboration with PartecipaSalute project, the ICC translates the Cochrane Library press
releases and disseminates them to scientific journalists, doctors and consumers (through the
PartecipaSalute website).
Research activities
ICC researchers are involved in methodological projects focused on the study of the quality of
Systematic Reviews.
The ICC is involved in many multidisciplinary projects:
- Point-of-Care information tools: to describe and evaluate information tools used by
clinicians during their practice. Specifically the project focuses on editorial quality,
evidence-based methodology and updating of Point-of-Care products.
- GRADE: international collaboration with the GRADE working Group to develop and
transparent methodology on evidence quality and strength of recommendation
assessment, used in the production of the clinical guideline.
- PRISMA: publication of a reporting guideline to evaluate the completeness of
systematic review reporting.
- E-learning: two systematic reviews on efficacy of e-learning to improve the knowledge
of students and health professionals in health care.
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THE CATULLO AND DANIELA
BORGOMAINERIO CENTER
One of the buildings on the Mario Negri Institute campus is The Catullo and Daniela
Borgomainerio Center built in 1987 thanks to a donation from Mrs. Angela Marchegiano
Borgomainerio. This is a Center for the study of rare childhood diseases and even today some of
the laboratories housed in the building still conduct this research. For example, the study of new
therapies used to treat a very rare form of acute myeloid leukemia, know as acute promyelocytic
leukemia. A number of new studies are being done to identify new drugs having different
mechanisms able to synergize with trans retinoic acid.
Research on epidemiological childhood leukemia is also done at the Borgomainerio and a
similar line of research involves testicular cancer in adolescents and young adults.
We also do research aimed at finding evidence based therapies for children.
Paediatric research activities done at the Borgomainerio Center are also performed in
collaboration with groups located at other Institute locations including, The Aldo and Cele
Daccò Center for Clinical Research on Rare Diseases at Ranica in Bergamo, the Regional
Centre for Drug Information (CRIF) and the Laboratory for Mother and Child Health
(Department of Public Health) which are both located in Milan.
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THE LIBRARY
STAFF
Head Librarian
Vanna Pistotti
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The Library, specialised in pharmacology and clinical epidemiology, was founded in 1963
thanks to a generous donation from the Gustavus and Louise Pfeiffer Research Foundation, in
Denville, New Jersey, USA.
Numerous public and private organisations help keep it operative, through donations in money
or books, and subscriptions to periodicals.
STAFF
One Head and two Assistants plus a clerical worker
WHAT THE LIBRARY OFFERS
The library has a collection of about 5000 textbooks, monographs and congressional
proceedings, and 150 periodicals of which a major part are in an electronic format. The books
are classified according to the US National Library of Medicine Classification and the Medical
Subject headings of Medline (MeSH). Besides the internal collection, the Library has access to
the National Periodical Catalogue and to other Library systems (SBBL, GIDIF-RBM).
DATABESES AND ELECTRONIC JOURNALS
From every computer in the Institute it is now possible to have access to more than 2000
electronic journals and to three of the most important databases, PubMed, the Cochrane Library
and Embase.
SPECIAL PROJECTS
The Library cooperates to the realisation of the Italian Information Specialists’ (GIDIF,
RBM) journal catalog which is updated annually and to the catalog of the Lombardy
Biomedical Library Consortium, a network that serves, through Internet, the scientific
community in this District.
It collaborates to the Institute web site, particularly taking care of the Publications section, both
scientific and lay press.
TRAINING
Every year courses on the use of the database and electronic journals are organised. These
courses are designed for use by those working at the Institute but outsiders who are interested
may attend.
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CONTRACTS
Since 1994 the library has been part of the Lombard Biomedical Library System. 14 university
and research organisation libraries in Lombardy take part in this project, which allows easy, free
access to scientific information to over 140 centres and institutions the Lombardy Region.
EVENTS AND COURSES
Corso “La ricerca bibliografica su database biomedici”, organizzato in collaborazione con
l’ASL di Bergamo Dipartimento Cure Primarie e Continuità Assistenziale, Bergamo 11 febbraio
2010
V° edizione del corso ECM “"La ricerca bibliografica su database biomedici", Istituto di
Ricerche Farmacologiche “Mario Negri”, Milano, 8 giugno 2010
V ° edizione del corso ECM "Internet e l’aggiornamento professionale in ambito medico",
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 9 giugno 2010
Corso di formazione e aggiornamento per i giornalisti “Internet e Medicina: a caccia di salute
sul web”, organizzato in collaborazione con la Unione Nazionale dei Giornalisti Scientifici
Italiani (UNAMSI), Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 16 ottobre
2010
VI° edizione del corso ECM “"La ricerca bibliografica su database biomedici", Istituto di
Ricerche Farmacologiche “Mario Negri”, Milano, 2 novembre 2010
VI° edizione del corso ECM "Internet e l’aggiornamento professionale in ambito medico",
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 3 novembre 2010
Minimaster “Come leggere un lavoro clinico – Ricerca bibliografica online” organizzato
dall’Associazione Nazionale Medici Cardiologi Ospedalieri”, Firenze 19 maggio 2010. Titolo
della relazione “La ricerca bibliografica su database biomedici"
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Negri Bergamo Laboratories
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REPORT 2010
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DEPARTMENT OF MOLECULAR
MEDICINE
STAFF
Head
Ariela BENIGNI, Biol.Sci.D., Ph.D.
Laboratory of Cell Biology and Xenotransplantation*
Head
Marina MORIGI, Biol.Sci.D., Ph.D.
Unit of Platelet-Endothelial Cell Interaction
Head
Miriam GALBUSERA, Biol.Sci.D.
Laboratory of Immunology and Genetics of Organ Transplantation and
Rare Diseases
Head
Marina NORIS, Chem.Farm.D., Ph.D.
Unit of Cellular biology of Autoimmunity and Transplant Rejection
Head
Sistiana AIELLO, Biol.Sci.D
Unit of Cellular and Molecular Biology of Transplantation Tolerance
Head
Federica CASIRAGHI, Chemist
Laboratory of Experimental Models of Kidney Diseases*
Head
Carla ZOJA, Biol.Sci.D., Ph.D.
Unit of Pathology and Immunophatology
Head
Mauro ABBATE, M.D.
Laboratory of Cell and Gene Therapy*
Head
Susanna TOMASONI, Biol.Sci.D., Ph.D.
Unit of Advanced Microscopy
Head
Elena GAGLIARDINI, Biol.Sci.D., Ph.D.
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st
*Since November 1 2010, the following Laboratories have changed
name:
Laboratory of Cell Biology and Xenotransplantation is now entitled Laboratory of Cell
Biology and Regenerative Medicine
Laboratory of Experimental Models of Kidney Diseases is now entitled Laboratory of
Pathophysiology of Experimental Renal Disease and Interaction with other Organ
systems
Laboratory of Cell and Gene Therapy is now entitled Laboratory of Gene Therapy and
Cellular Reprogramming
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CURRICULA
Ariela Benigni got the Biol.Sci. degree in 1979 at the University of Milano, Italy, and the Ph.D. at
Maastricht University, Netherlands, in 2001.
Educational training: in 1979 Post Doctoral Fellow, Istituto di Ricerche Farmacologiche Mario Negri
(IRFMN), Laboratory of Cancer Chemotherapy, Milan, Italy; in 1980-1981 Post Doctoral Fellow,
Associazione Bergamasca per lo Studio delle Malattie Renali, Laboratory of the Division of Nephrology
and Dialysis, Ospedali Riuniti di Bergamo, Italy; in 1982 Post Doctoral Fellow, Centre Regional de
Transfusion Sanguigne de Strasbourg, France.
Areas of interest: vasoactive and inflammatory mediators of progressive renal injury with a particular
emphasis on endothelin-1; combined treatment of antipertensive and renoprotective drugs to halt
progressive renal injury; use of stem cells for tissue regeneration in acute renal failure in vivo e in vitro
gene transfer; prevention of acute graft rejection through gene therapy; induction of kidney transplant
tolerance by gene therapy; correction of genetic deficiency in rare diseases.
Employement: in 1983 Scientist, IRFMN, Laboratory of Kidney Disease, Bergamo, Italy; in 19901994 Head Laboratory of Prostaglandin and Leukotriene Metabolism, IRFMN, Bergamo, Italy;
from January 1991 Scientific Secretary, IRFMN, Bergamo, Italy; in 1994-1999 Head Laboratory of
Vasoactive and Inflammatory Mediators of Tissue damage, IRFMN, Bergamo, Italy; from January
2000 Head, Department of Molecular Medicine, IRFMN, Bergamo, Italy; from March 2007
Consultant World Health Organization (WHO) for the multicentre observational study “Screening
for Pre-eclampsia: evaluation of the predictive ability of angiogenic factors for Pre-eclampsia”;
during 2007 Senior Fellow at the University of Oxford, Nuffield Department of Obstetrics &
Gynaecology.
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Gagliardini E, Conti S, Benigni A, Remuzzi G, Remuzzi A. Imaging of the porous ultrastructure of the glomerular epithelial
filtration slit. J Am Soc Nephrol. 2010;21:2081-2089.
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H. Mischak, G. Allmaier, R. Apweiler, T. Attwood, M. Baumann, A. Benigni, S.E. Bennett, R. Bischoff, E. BongcamRudloff, G. Capasso, J.J. Coon, P. D'Haese, A.F. Dominiczak, M. Dakna, H. Dihazi, J.H. Ehrich, P. Fernandez-Llama, D.
Fliser, J. Frokiaer, J. Garin, M. Girolami, W.S. Hancock, M. Haubitz, D. Hochstrasser, R.R. Holman, J.P. Ioannidis, J.
Jankowski, B.A. Julian, J.B. Klein, W. Kolch, T. Luider, Z. Massy, W.B. Mattes, F. Molina, B. Monsarrat, J. Novak, K. Peter,
P. Rossing, M. Sánchez-Carbayo, J.P. Schanstra, O.J. Semmes, G. Spasovski, D. Theodorescu, V. Thongboonkerd, R.
Vanholder, T.D. Veenstra, E. Weissinger, T. Yamamoto, A. Vlahou. Recommendations for biomarker identification and
qualification in clinical proteomics. Sci Transl Med. 2010;2:46ps42
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Benigni, P. Cassis, G. Remuzzi. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol
Med. 2010; 2;247-257. Review
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Benigni, M. Morigi, G. Remuzzi. Kidney regeneration. Lancet. 2010;375:1310-1317.
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F. Prefumo, G. Pagani, N. Fratelli, A. Benigni, T. Frusca.Increased concentrations of antiangiogenic factors in mirror
syndrome complicating twin-to-twin transfusion syndrome. Prenat Diagn. 2010;30:378-379.
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B. Smeets, ML. Angelotti, P. Rizzo, H. Dijkman, E. Lazzeri, F. Mooren, L. Ballerini, E. Parente, C. Sagrinati, B.
Mazzinghi, E. Ronconi, F. Becherucci, A. Benigni, E. Steenbergen, L. Lasagni, G. Remuzzi, J. Wetzels, P. Romagnani.
Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am
Soc Nephrol. 2009;20:2593-2603.
Marina Morigi got her Biol.Sci. degree in 1987 at the University of Milano, Milano, Italy and the Ph.D.
at Maastricht University, Netherlands, in 2005.
Educational training: in 1984-1987 Research training, IRFMN, Bergamo, Italy; in 1987-1995 Post
Doctoral Fellow, IRFMN, Bergamo, Italy; in 1991 Stage at Brigham and Women’s Hospital, Laboratory
of Dr. P. Marsden, Boston, USA.
Employement: since 1995 Scientist, IRFMN, Bergamo, Italy; in 1996-1999 Head, Unit of Renal and
Endothelial Cell Biology; since 2000 Head, Laboratory of Cell Biology and Xenotransplantation,
IRFMN, Bergamo, Italy.
Areas of interest: Stem cell therapy and tissue regeneration: the potential of adult stem cells of different
origin, and renal progenitor cells to differentiate and to regenerate renal tissue in acute and chronic
experimental models of renal disease. Stem cell therapy with embryonic stem cells to cure acute and
chronic renal diseases and to correct genetic defects in experimental mouse models. Kidney
Organogenesis. Role of Shigatoxin in the pathogenesis of endothelial dysfunction and microvascular
thrombosis in Hemolytic Uremic Syndrome. In vitro model of hyperacute xenograft rejection (porcine
endothelium exposed to human serum as a source of xenoreactive natural antibodies and complement).
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Renal toxicity of the proteins filtered through the capillary barrier: in vitro model to study intracellular
signals, gene expression and production of inflammatory mediators in cultured proximal tubular cells
and glomerular epithelial cells.
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Morigi M, Buelli S, Zanchi C, Longaretti L, Macconi D, Benigni A, Moioli D, Remuzzi G, Zoja C. Shigatoxin-induced
endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol. 2006 Dec;
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169(6):1965-75.
Morigi M, Benigni A, Remuzzi G, Imberti B. The regenerative potential of stem cells in acute renal failure. Cell
Transplant. 2006;15 Suppl 1:S111-7. Review.
Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, Sonzogni A,
Perico N, Remuzzi G, Noris M. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a
semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008 Sep 15;181(6):3933-46.
Morigi M, Introna M, Imberti B, Corna D, Abbate M, Rota C, Rottoli D, Benigni A, Perico N, Zoja C, Rambaldi A,
Remuzzi A, Remuzzi G. Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and
prolong survival in mice. Stem Cells. 2008 Aug;26(8):2075-82. Epub 2008 May 22.
Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, Remuzzi A, Benigni A. Bone marrow-derived
mesenchymal stem cells improve islet graft function in diabetic rats. Transplant Proc. 2009 Jun;41(5):1797-800.
Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M,
Coffman TM, Remuzzi G. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. 2009
Mar;119(3):524-30.
Zoja C, Buelli S, Morigi M. Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial
dysfunction. Pediatr Nephrol. 2010 Nov;25(11):2231-40. Epub 2010 Apr 28.
Benigni A, Morigi M, Remuzzi G. Kidney regeneration. Lancet. 2010 Apr 10;375(9722):1310-7.
Morigi M, Rota C, Montemurro T, Montelatici E, Lo Cicero V, Imberti B, Abbate M, Zoja C, Cassis P, Longaretti L,
Rebulla P, Introna M, Capelli C, Benigni A, Remuzzi G, Lazzari L. Life-sparing effect of human cord bloodmesenchymal stem cells in experimental acute kidney injury. Stem Cells. 2010 Mar 31; 28(3):513-22.
Marina Noris got her degree in Pharmaceutical Chemistry and Technologies in 1986 at the University
of Rome “La Sapienza) and the Ph.D. at Maastricht University, Netherlands, in 2005.
Educational training: in 1984-1986 Fellow, Istituto di Chimica Farmaceutica e Tossicologica, University
of Rome, Italy; in 1986-1987 Post Doctoral Fellow, Istituto di Chimica Farmaceutica e Tossicologica,
University of Rome, Italy; in September 1987-March 1994 Post Doctoral Fellow, IRFMN, Unit of
Mediators of Inflammation and Tissue Damage, Laboratory of Kidney Disease, Bergamo, Italy.
Areas of interest: immunology of transplantation, tolerance induction; genetics of hemolytic uremic
syndrome, thrombotic thrombocytopenic purpura, focal segmental glomerulosclerosis, diabetic
nephropathy, role of nitric oxide and arginine dysfunctions in uremia and in pre-eclampsia.
Employment: in 1994-1996 Head, Unit of Endothelial Cell Pathophysiology, IRFMN, Bergamo, Italy;
1996-1999 Head, Laboratory of Cellular and Molecular Biology of the immune response and
autoimmunity, IRFMN, Italy; from January 2000: Head, Laboratory of Immunology and Genetics of Rare
Diseases and Organ Transplantation, Department of Molecular Medicine, IRFMN, Bergamo, Italy.
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Noris M, Remuzzi G. Atypical Hemolytic Uremic Syndrome N Engl J Med. 2009 Oct 22;361(17):1676-87.
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Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, Todeschini M,
Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. The Toll-IL1R member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts. J Immunol. 2009 Oct 1;183(7):424960.
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Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D,
Zoja C, Remuzzi G, Conway EM. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009
Jul 23;361(4):345-57.
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Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M, Caprioli
J, Caruso RM, Artuso R, Remuzzi G, Noris M. Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc Natl
Acad Sci U S A. 2008;105(7):2538-43.
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Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F,
Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: the impact
of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006; 108(4):1267-79.
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Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G, on behalf of the International
Registry of Familial and Recurrent HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet. 2003;
362:1542-47.
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Susanna Tomasoni got her Biological Science degree in 1991 at the University of Milan and the Ph.D. at
the University of Bologna in 1995.
Educational training: in 1989-1991 Graduate student, University of Milan; in 1991-1994 PhD student,
University of Milan; in 1994 Research Fellow, Renal Division, Brigham & Women’s Hospital, Harvard
Medical School, Boston, USA; 1995-1998: Post Doctoral Fellow, IRFMN, Bergamo, Italy.
Areas of interest: construction of adenoviral vectors for gene therapy; in vitro and in vivo gene transfer
techniques; use of adenoviral and adeno-associated viral vectors to prevent acute and chronic allograft
rejection; induction of kidney transplant tolerance by cell and gene therapy; correction of genetic
deficiency in rare diseases by gene therapy; involvement of microRNAs in the progression of renal
disease; generation of induced-pluripotent stem cell from adult somatic cells; mesenchymal stem cellderived exosomes as mediators of cell-to-cell communication.
Employment: in 1998-2000 Scientist; from 2000 Head, Unit of Gene Therapy; from 2010 Head,
Laboratory of Cell and Gene Therapy; IRFMN, Bergamo, Italy.
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Trionfini P, Tomasoni S, Galbusera M, Motto D, Longaretti L, Corna D, Remuzzi G, Benigni A. Adenoviral-mediated
gene transfer restores plasma ADAMTS13 antigen and activity in ADAMTS13 knockout mice. Gene Therapy. 2009; 16:
1379-85.
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Tomasoni S, Remuzzi G, Benigni A. Allograft rejection: acute and chronic studies. Contrib Nephrol. 2008; 159:122-34.
Review.
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Imberti B, Morigi M, Tomasoni S, Rota C, Corna D, Longaretti L, Rottoli D, Valsecchi F, Benigni A, Wang J, Abbate
M, Zoja C, Remuzzi G. Insulin-like growth factor-1 sustains stem cell mediated renal repair. J Am Soc Nephrol. 2007;
18: 2921-8.
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Benigni A, Tomasoni S, Turka LA, Longaretti L, Zentilin L, Mister M, Pezzotta A, Azzollini N, Noris M, Conti S,
Abbate M, Giacca M, Remuzzi G. Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched
renal allografts from chronic rejection. J Am Soc Nephrol. 2006, 17: 1665-72.
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Tomasoni S, Aiello S, Cassis L, Noris M, Longaretti L, Cavinato R, Azzollini N, Pezzotta A, Remuzzi G, Benigni A.
Dendritic cells genetically engineered with adenoviral vector encoding dnIKK2 induce the formation of potent CD4+ Tregulatory cells. Transplantation. 2005; 79: 1056-61.
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Tomasoni S, Azzollini N, Casiraghi F, Capogrossi M C, Remuzzi G, Benigni A. CTLA4Ig gene transfer prolongs
survival and induces donor-specific tolerance in a rat renal allograft. J Am Soc Nephrol. 2000; 11: 747-52.
Carlamaria Zoja got her Biol.Sci. degree at the University of Milano, Italy, in 1979 and the Ph.D. at
the University of Maastricht, The Netherlands in 2001.
Educational Training: in 1979-1981 Post Doctoral Fellow, ‘Associazione Bergamasca per lo studio delle
Malattie Renali’, Laboratory of the Division of Nephrology and Dialysis, Ospedali Riuniti di Bergamo,
Italy; in 1981-1983 Post Doctoral Fellow, Center for Thrombosis and Vascular Research, Department of
Research Katholieke Universiteit, Leuven, Belgium; in 1983-1985: Post Doctoral Fellow, IRFMN,
Laboratory of Kidney Disease, Bergamo, Italy; in 1988 stage at Case Western Reserve University,
Cleveland, Ohio, USA; in 1989 stage at Brigham and Women’s Hospital, Boston, USA.
Areas of interest: experimental models of kidney diseases of immunological and non immunological
origin; vasoactive and inflammatory mediators of renal disease progression; role of proteinuria in
progressive kidney damage; protection of renal disease progression by a multidrug approach; novel
immunosuppressive and anti-inflammatory strategies for the treatment of lupus nephritis; role of
Shigatoxin in the pathogenesis of endothelial dysfunction in Hemolytic Uremic Syndrome.
Employement: since 1985 Scientist, IRFMN, Bergamo, Italy; in 1990-1994: Head, Unit of Experimental
Modelling for Human Renal Diseases, Laboratory of Kidney Diseases, IRFMN, Bergamo, Italy; since
1995: Head, Laboratory of Experimental Models of Kidney Diseases, IRFMN, Bergamo, Italy. In
November 2010 Lab denomination changed to ‘Laboratory of Physiopathology of Experimental Renal
Disease and Interaction with other Organ Systems’.
In 2004-2007 member Editorial Board, Journal of the American Society of Nephrology. Since January
2010 Leader WP5.2, SysKid collaborative project (FP7.
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C. Zoja, D. Corna, D. Camozzi, D. Cattaneo, D. Rottoli, C. Batani, C. Zanchi, M. Abbate, G. Remuzzi. How to fully
protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol
2002;13:2898-2908.
R. Donadelli, C. Zanchi, M. Morigi, S. Buelli, C. Batani, S. Tomasoni, D. Corna, D. Rottoli, A. Benigni, M. Abbate, G.
Remuzzi, C. Zoja. Protein overload induces fractalkine upregulation in proximal tubular cells through NF-kB and p38
MAPK dependent pathways. J Am Soc Nephrol 2003; 14:2436-2446.
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C.Zoja, F.Casiraghi, S.Conti, D.Corna, D.Rottoli, R.A.Cavinato, G.Remuzzi, A.Benigni. Cyclin-Dependent kinase
inhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus. Arthritis & Rheumatism 2007;
56; 1629-1637.
C.Zanchi, C.Zoja, M. Morigi, F.Valsecchi, XY Liu, D. Rottoli, M. Locatelli, S. Buelli, A.Pezzotta, P.Mapelli, J.
Geelen, G.Remuzzi, J.Hawiger J. Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to
Shiga toxin. J Immunol. 2008; 181:1460-9.
N.Perico, C.Zoja, D.Corna, D. Rottoli, F.Gaspari, L.Haskell, G.Remuzzi.V1/V2 Vasopressin receptor antagonism
potentiates the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction. Kidney Int.
2009; 76:960-7.
C.Zoja, D.Corna, E.Gagliardini, S.Conti, L.Arnaboldi, A. Benigni, G.Remuzzi G. Adding a statin to a combination of
ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which translates into full renoprotection. Am
J Physiol Renal Physiol. 2010; 299:F1203-11.
Mauro Abbate obtained his M.D. degree in 1988 at the University of Brescia, Italy.
Educational training: in 1984-1988 Graduate Student, IRFMN, Bergamo, Italy; in 1988-1992 Post
Doctoral Fellow, IRFMN, Bergamo, Italy; in 1992-1994 Research Fellow, The Renal Unit,
Massachusetts General Hospital, HMS, Boston, USA.
Areas of interest: renal disease progression: the role of proteinuria, complement, and mediators of injury
in progressive kidney damage; mechanisms of glomerular injury; anti-GBM glomerulonephritis;
mechanisms of tubular injury; kidney fibrosis; the renal biopsy; membranous nephropathy.
Employement: in 1996 - 2000: Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of Renal
Pathology and Immunopathology, IRFMN, Bergamo, Italy.
− Buelli S, Abbate M, Morigi M, Moioli D, Zanchi C, Noris M, Zoja C, Pusey CD, Zipfel PF, Remuzzi G. Protein load
impairs factor H binding promoting complement-dependent dysfunction of proximal tubular cells. Kidney Int. 2009
May;75(10):1050-9.
− Ruggenenti P, Cravedi P, Sghirlanzoni MC, Gagliardini E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G.
Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol. 2008
Nov;3(6):1652-9.
− Abbate M, Zoja C, Corna D, Rottoli D, Zanchi C, Azzollini N, Tomasoni S, Berlingeri S, Noris M, Morigi M, Remuzzi
G. Complement-mediated dysfunction of glomerular filtration barrier accelerates progressive renal injury. J Am Soc
Nephrol. 2008 Jun;19(6):1158-67.
− Macconi D, Abbate M, Morigi M, Angioletti S, Mister M, Buelli S, Bonomelli M, Mundel P, Endlich K, Remuzzi A,
Remuzzi G. Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target
for renoprotective intervention. Am J Pathol. 2006 Apr;168(4):1073-85.
− Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006
Nov;17(11):2974-84. Review
− Abbate M, Zoja C, Morigi M, Rottoli D, Angioletti S, Tomasoni S, Zanchi C, Longaretti L, Donadelli R, Remuzzi G.
Transforming Growth Factor-beta 1 Is Up-Regulated by Podocytes in Response to Excess Intraglomerular Passage of
Proteins: A Central Pathway in Progressive Glomerulosclerosis. Am J Pathol. 2002;161,2179-93.
Sistiana Aiello got the Biol.Sci. degree in 1993 at the University of Milano, Italy, and the Specialization
in Pharmacology Research in 1996, at IRFMN, Bergamo, Italy.
Educational training: in 1990-1993 research training, IRFMN, Bergamo; in 1993-2000 post doctoral
fellow, IRFMN, Bergamo.
Areas of interest: transplant immunology with a particular interest on dendritic cell biology and
mechanisms by which T regulatory cells arise and work; in vitro and in vivo studies on new compounds
with immunosuppressive capacity or capable to prevent ischemia/reperfusion tissue injury; vasoactive and
inflammatory mediators of progressive renal injury with a particular emphasis on platelet activating factor
(PAF) and nitric oxide (NO).
Employement: since 2000 Scientist within Laboratory of Immunology and Genetics of Rare disease and
Organ Transplantation; IRFMN, Bergamo; since 2006 Head, Unit of Cellular Biology of Autoimmunity
and Transplant Rejection, IRFMN, Transplant Research Center “Chiara Cucchi de Alessandri e Gilberto
Crespi”, Ranica.
Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, Todeschini M,
Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. The Toll-IL1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts. J Immunol. 2009, 183(7): 4249-60.
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-
Nephrol. 2009;20(1):123-30.
Pezzotta A, Mister M, Monteferrante G, Cassis L, Azzollini N, Aiello S, Satta M, Benigni A, Remuzzi G, Noris M. Effect of
seliciclib (CYC202, R-roscovitine) on lymphocyte alloreactivity and acute kidney allograft rejection in rat. Transplantation.
2008; 85(10):1476-82.
Aiello S, Cassis P, Cassis L, Tomasoni S, Benigni A, Pezzotta A, Cavinato RA, Cugini D, Azzollini N, Mister M, Longaretti
L, Thomson AW, Remuzzi G, Noris M. DnIKK2-transfected dendritic cells induce a novel population of iNOS-expressing
CD4+CD25- cells with tolerogenic properties. Transplantation. 2007; 83:474-84.
Tomasoni S, Aiello S, Cassis L, Noris M, Longaretti L, Cavinato RA, Azzollini N, Pezzotta A, Remuzzi G, Benigni A.
Dendritic cells genetically engineered with adenoviral vector encoding dnIKK2 induce the formation of potent CD4+ T
regulatory cells. Transplantation. 2005;79:1056-61.
Federica Casiraghi has obtained his degree in Industrial Chemistry in 1988, and the degree in Clinical
Monitoring and in Biochemical Research in 1993-1994 at IRFMN, Bergamo, Italy.
Educational Training: 1989-1994 research fellow, IRFMN, Bergamo.
Areas of interest: Transplant immunology with particular focus on pharmacological and cellular therapies
for induction and maintenance of transplantation tolerance. Characterization of regulatory T cells in renal
transplant patients and in experimental models of allograft tolerance. Impact of different
immunosuppressive drugs on T cell function in renal transplant patients. Vasoactive and inflammatory
mediators of progressive renal injury with a particular emphasis on arachidonic acid metabolites.
Employment: since 1994 Scientist within Laboratory of Immunology and Genetics of Rare Disease and
Organ Transplantation, IRFM, Bergamo; since 2006 Head, Unit of Cellular and Molecolar Biology of
Transplantation Tolerance, Transplant Research Center “Chiara Cucchi de Alessandri e Gilberto Crespi”,
Ranica.
Selected Publications:
− Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P,
Cortinovis M, Marasà M, Golay J, Noris M, Remuzzi G. Autologous Mesenchymal Stromal Cells and Kidney
Transplantation: A Pilot Study of Safety and Clinical Feasibility. Clin J Am Soc Nephrol. 2010 Oct 7. [Epub ahead of
print
− Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, Todeschini
M, Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. The
Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts. J Immunol. 2009
183(7): 4249-60.
− Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, Sonzogni A,
Perico N, Remuzzi G, Noris M. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a
semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008;181(6):3933-46.
− Noris M, Casiraghi F, Todeschini M, Cravedi P, Cugini D, Monteferrante G, Aiello S, Cassis L, Gotti E, Gaspari F,
Cattaneo D, Perico N, Remuzzi G. Regulatory T Cells and T Cell Depletion: Role of Immunosuppressive Drugs. J Am
Soc Nephrol. 2007; 18 (3):1007-18.
− Ruggenenti P, Perico N, Gotti E, Cravedi P, D'Agati V, Gagliardini E, Abbate M, Gaspari F, Cattaneo D, Noris M,
Casiraghi F, Todeschini M, Cugini D, Conti S, Remuzzi G. Sirolimus versus cyclosporine therapy increases circulating
regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft
injury. Transplantation. 2007, 84(8):956-64.
Elena Gagliardini got her Biological Science degree in 1998 at the University of Milan and the Ph.D. at
the Open University of London, UK, in 2006.
Educational training: in 1996-1998 graduate student, IRFMN, Bergamo, Italy; in 1998-2006 Research
Fellow, IRFMN, Bergamo, Italy.
Areas of interest: vasoactive and inflammatory mediators of progressive renal injury; combined treatment
of antipertensive and renoprotective drugs to halt and also regress progressive renal injury; mechanisms
underlying tissue regeneration; ultrastucture and function of glomerular filter in physiological or
pathological conditions.
Employment: from 1996 Scientist, IRFMN, Bergamo, Italy; from 2010 Head, Unit of Advanced
Microscopy, IRFMN, Bergamo, Italy
•
Imaging of the porous ultrastructure of the glomerular epithelial filtration slit. Gagliardini E, Conti S, Benigni A,
Remuzzi G, Remuzzi A. J Am Soc Nephrol. 2010 Dec;21(12):2081-9.
•
Adding a statin to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which
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•
•
•
•
translates into full renoprotection. Zoja C, Corna D, Gagliardini E, Conti S, Arnaboldi L, Benigni A, Remuzzi G. Am J
Physiol Renal Physiol. 2010 Nov;299(5):F1203-11.
Podocyte repopulation contributes to regression of glomerular injury induced by ACE inhibition. Macconi D, Sangalli F,
Bonomelli M, Conti S, Condorelli L, Gagliardini E, Remuzzi G, Remuzzi A. Am J Pathol. 2009 Mar;174(3):797-807
ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease.
Remuzzi A, Gagliardini E, Sangalli F, Bonomelli M, Piccinelli M, Benigni A, Remuzzi G. Kidney Int. 2006
Apr;69(7):1124-1130.
Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy. Benigni A,
Gagliardini E, Tomasoni S, Abbate M, Ruggenenti P, Kalluri R, Remuzzi G. Kidney Int. 2004 Jun;65(6):2193-200.
Changes in glomerular perm-selectivity induced by angiotensin II imply podocyte dysfunction and slit diaphragm protein
rearrangement. Benigni A, Gagliardini E, Remuzzi G. Semin Nephrol. 2004 Mar;24(2):131-40. Review.
Miriam Galbusera got her Biol.Sci. degree in 1981 at the Università degli Studi di Milano.
Educational training: in 1981-1983 Post Doctoral Fellow, Istituto di Patologia Speciale Medica
dell'Università degli Studi di Milano, Italy; in 1985 - 1989 Post Doctoral Fellow, IRFMN, Bergamo,
Italy; in 1989-1991 Post Doctoral Fellow at Scripps Clinic and Research Foundation, Laboratory of
Thrombosis and Hemostasis, La Jolla, CA, USA; in 1991-1995 Post Doctoral Fellow, IRFMN, Bergamo,
Italy.
Areas of interest: ADAMTS-13 and VWF in thrombotic microangiopathies, VWF biochemistry,
xenotransplantation, platelet-endothelial cell interaction under flow condition, platelet pathophysiology in
uremia, receptor studies in kidney and platelets.
Employement: 1995 - 1999: Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of PlateletEndothelial Cell Interaction, IRFMN, Bergamo, Italy.
− Trionfini, P, Tomasoni S, Galbusera M, Motto D, Longaretti L, Corna D, Remuzzi G, Benigni A. Adenoviral-mediated gene
transfer restores ADAMTS13 plasma levels and activity in knockout mice. Gene Therapy. 2009; 16:1373-9.
− Galbusera M, Remuzzi G, Boccardo P. Treatment of bleeding in the dialysis patients. Semin Dial. 2009; 22:279-86.
− Galbusera M, Noris M, Remuzzi G. Inherited thrombotic thrombocytopenic purpura. Haematologica. 2009; 94:166-70.
− Bresin E, Gastoldi S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G, Galbusera
M. Rituximab to prevent relapses in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13
autoantibodies. Thromb Haemost. 2009; 101:233-8.
− Benigni A, Caroli C, Longaretti L, Gagliardini E, Zoja C, Galbusera M, Moioli D, Romagnani P, Tincani A, Andreoli L,
Remuzzi G. Renal tubular TLR9 is involved in the development of tubulointerstitial injury of systemic lupus. Arthritis Rheum.
2007; 56:1569-78.
− Donadelli R, Banterla F, Galbusera M, Capoferri C, Bucchioni S, Gastoldi S, Ruggeri ZM, Bresin E, Scheiflinger F, Rossi E,
Remuzzi G, Noris M. In vitro and in vivo consequences of mutations in the von Willebrand factor cleaving protease
ADAMTS13 in thrombotic microangiopathies. Thromb Haemost. 2006; 96:454-64.
INTRODUCTION TO THE DEPARTMENT'S ACTIVITIES
The Department of Molecular Medicine was established in 1999 at the Negri Bergamo
laboratories to coordinate the work of four laboratories and five units. The activities of the
Department of Molecular Medicine are strictly interrelated with those of the Department of
Renal Medicine of the Clinical Research Center for Rare Diseases Aldo e Cele Daccò.
The following major objectives have been pursued:
1) identification of mediators and mechanisms responsible for the relentless decline of renal
function in kidney diseases and development of therapeutic interventions to slow or even halt
the disease progression to end-stage renal failure;
2) understanding the mechanisms underlying endothelial cell dysfunction in thrombotic
microangiopathies and hyperacute rejection of xenograft
3) finding new strategies for modulating the immune response and preventing acute and chronic
rejection of kidney allograft as well as exploration of immunological pathways leading to donor
specific unresponsiveness and tolerance of the graft;
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4) investigation of the molecular and genetic basis of rare diseases such as hemolytic uremic
syndrome/thrombotic thrombocytopenic purpura and pre-eclampsia and search for diseasesusceptibility genes or gene polymorphisms predicting the patient's response to drug therapy in
more common and complex polygenic disorders.
Such goals have been pursued using various approaches: 1) experimental models of kidney
diseases of immunological and non-immunological origin mimicking human renal diseases to
study vasoactive and inflammatory mediators and to test novel antiproteinuric and
renoprotective drugs; 2) in vitro cultures of renal cells to address the toxicity of protein overload
reproducing the condition of exaggerated protein traffic of proteinuric progressive
nephropathies; 3) in vitro models to assess the interaction of vascular endothelial cells with
leukocytes and platelets under controlled flow conditions; 4) experimental models of kidney
allotransplant to study immunological processes responsible for acute and chronic rejection, the
nephrotoxicity of immunosuppressor drugs as well as to explore pathways responsible for
accomodation; 5) gene transfer of viral constructs carrying genes encoding immunomodulatory
molecules to overcome acute rejection of allotransplantation avoiding immunosuppression; 6)
identification of candidate genes with linkage analysis and search for mutations as well as
assessment of gene polymorphisms.
Mesenchymal
stromal
cell
infusion
inhibits
memory
favouring regulatory cell expansion in kidney transplant recipients.
lymphocytes
while
Identified the ultrastructure of the glomerular filtration pores whose alterations might be
responsible for the increased filtration of plasma proteins in glomerular disease.
A triple therapy to protect the diabetic kidney.
Alterations in thrombomodulin – a coagulation protein Hemolytic Uremic Syndrome.
worsens Shigatoxin-associated
Human amniotic fluid stem cell therapy ameliorates the outcome of experimental acute kidney
injury and improves animal survival.
Embryonic kidneys transplanted in rats with chronic renal injury develop new renal structures
and contribute to regeneration of damaged tissue.
Inhibiting ACE promotes renal repair by limiting progenitor cell proliferation and restoring the
glomerular niche
Consorzio per la Ricerca sul Trapianto di Organi, Tessuti, Cellule e Medicina Rigenerativa
CORIT, Padova
Laboratorio di Biologia dello Sviluppo, Dipartimento di Biologia Animale, Università degli Studi
di Pavia, Pavia
Stem Cell Processing Laboratory, Clinic of Paediatric Oncohematology, University of Padova
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Sezione di Istologia e Embriologia, Dipartimento di Medicina Sperimentale, Università degli
Studi di Parma, Parma
Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia
Laboratorio di Terapia genica e cellulare, G. Lanzani, Divisione di Ematologia, Ospedali Riuniti
di Bergamo
Laboratorio di Tecnologie della Riproduzione, AVANTEA Srl, Cremona
Laboratorio di Virologia, Istituto Nazionale per le Malattie Infettive L. Spallanzani, Roma
Centro Trasfusionale e di Immunologia dei Trapianti, IRCCS Ospedale Maggiore, Milano
Dipartimento di Biotecnologie, Università di Verona
Dipartimento di Istologia Microbiologia e Biotecnologie Mediche, Università di Padova
Dipartimento di Patofisiologia Clinica, Sezione di Nefrologia, Università di Firenze
International Centre for Genetic Engineering and Biotechnology, Molecular Medicine Group,
Trieste
U.O. di Ostetricia e Ginecologia, Azienda Ospedaliera Spedali Civili di Brescia
I.R.C.C.S. Policlinico San Matteo, Pavia
Istituto di Medicina Interna e Geriatria e Centro di Ricerca Emostasi, Università Cattolica,
Roma
Dipartimento di Fisiologia e Patologia, Università di Trieste
Centro Regionale Indicatori biochimici di tumori, Associazione ABO, AULSS 12, Ospedale
Civile, Venezia
Academisch Ziekenhuis Maastricht, Interne Geneeskunde, Maastricht, Olanda
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA
Children's Hospital and Regional Medical Center, University of Washington, Seattle, USA
Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse,
NY, USA
Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, USA
Deparment of Medicine, Division of Rheumatology, Washington University School of
Medicine, St. Louis, USA
Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, North
Carolina, USA
Erasmus University of Rotterdam, Olanda
Hans-Knoll Institute for Natural Products Research, Jena, Germania
Hospital of Bellvitge, Barcelona, Spagna
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of
Medicine, Palo Alto, USA
Klinikum der Ludwig Maximillians Universitat Munchen, Germania
Max Delbruck Center for Molecular Medicine, Berlin, Germania
Max-Plank Gesellschaft zur Forderung der Wissenshaften, Hpi of experimental
endocrinology, Hannover, Germania
Medical University of Innsbruck, Austria
MISOT (Mesenchymal Stem Cells in Solid Organ Transplantation) study group
Pediatric Nephrology Division, Center for Pediatrics and Adolescence Medicine, Heidelberg,
Germany
Rosalind Franklin University of Medicine and Science, Chicago, USA
Surgery Unit, Great Ormond Street Hospital and Institute of Child Health, University College
London, UK
UCD Conway Institute, University College Dublin, Ireland
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University of British Columbia, Vancouver, Canada
University of Colorado Cardiovascular Institute, Denver, USA
University of Groningen, Olanda
University of Liverpool, School of Biological Sciences, UK
University of Pittsburgh School of Medicine, Pittsburgh, USA
Wake Forest Institute of Regenerative Medicine, Wake Forest University of School of
Medicine, Winston-Salem, NC, USA
Weizmann Institute of Science, Rehovot, Israele
World Health Organization, Geneva, Svizzera
International Journal of Artificial Organs
American Journal of Kidney Diseases
American Journal of Transplantation
Archives of Medical Science
Cell transplantation
Cytotherapy
Diabetologia
Drug Discovery Today
Experimental Gerontology
Kidney International
Journal of Clinical Investigation
Journal of Immunology
Journal of Nephrology
Journal of the American Society of Nephrology
Laboratory Investigation
Molecular Medicine
Nature Reviews Nephrology
Nephrology, Dialysis and Transplantation
New England Journal of Medicine
Pediatric Nephrology
Plos One
Proteomics
Stem Cells and Development
The Lancet
Tissue and Cell
Transplant Immunology
Transplantation
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PARTICIPATION IN EVENTS IN WHICH THE DEPARTMENT WAS
INVOLVED
Star-T Rek Annual Meeting, Firenze, February 16 2010
EVOLVA meeting, Zurigo, March 2, 2010
SysKid Meeting, FP7, Vienna, March 8-9 2010
International Society of Nephrology, ISN Nexus Symposium; Kyoto, Japan, April 15-18, 2010
American Transplant Congress, San Diego, CA, May 1-5, 2010
2nd Meeting of the Forum of Italian Researchers on Mesenchymal and Stromal Stem Cells,
Modena, May 3 2010
Curarsi con le cellule, Bergamo, May 22, 2010
Tavola Rotonda su Next Generation sequencing, Bergamo, May 24, 2010
Stem Cells and the Kidney, Genova, June 18-19, 2010
SysKid Meeting , FP7, Munich, Germany, June 24, 2010
XLVII ERA-EDTA Congress, Munich, Germany June 25-28, 2010
Renal Biopsy in Medical Diseases of the Kidneys, 33rd Annual Postgraduate Medicine Course,
August 4- 7, 2010, Columbia University, New York
Grandangolo 2010 in Nefrologia, Dialisi e Trapianto, Bologna, September 15, 2010
II Meeting Internazionale: Modern trends in Andrologia e Riproduzione Assistita - Taranto
September, 17-18, 2010
12th Cambridge Massachusetts Biennial meeting of the International society for applied
cardiovascular biology, Boston, USA, September 22-25, 2010
International Stem Cell Symposium, Seoul, Korea, October 2, 2010
51° Congresso Nazionale Società Italiana di Nefrologia, Rimini, October 6-9, 2010
Renal Master Class, Ranica, Bergamo, October 7-8, 2010
PodoNet Symposium on Podocyte Disorders at the Meeting of the Turkish Society of Pediatric
Nephrology Ankara , Turkey, October 8, 2010
New paradigma in hypertension research, American Heart association HBPR, Washington,
USA, October 13, 2010
43rd Annual Meeting, American Society of Nephrology, Denver, November 16-21,
2010
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First European Conference on Mesenchymal Stem Cells, Toulouse, France, November 18-20,
2010
Second International Symposium on Albuminuria, Amsterdam, December 12-14, 2010
Comitato Telethon Fondazione ONLUS
Commissione Europea FP6 e FP7, Programma E-RARE
Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR)
Fondazione ART per la Ricerca sui Trapianti ONLUS
Fondazione Cariplo
Fondazione Compagnia di San Paolo
Fondazione Chiesi
F. Hoffman – La Roche Ltd
Ablynx NV
ACRAF (Aziende Chimiche Riunite Angelini Francesco Spa)
Alexion Pharmaceuticals
Evolva AG
Genzyme Corporation (Genzyme Renal Innovations Program)
Genzyme Europe B.V.
LFB Biotechnologies
Reata Pharmaceuticals
Sigma-Tau SpA
Zoja C, Corna D, Gagliardini E, Conti S, Arnaboldi L, Benigni A, Remuzzi G. Adding a statin
to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes,
which translates into full renoprotection. Am J Physiol Renal Physiol. 2010 Nov;299(5):F120311.
Zoja C, Buelli S, Morigi M. Shiga toxin-associated hemolytic uremic syndrome:
pathophysiology of endothelial dysfunction. Pediatr Nephrol. 2010 Nov;25(11):2231-40.
Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P,
Rizzo P, Cortinovis M, Marasà M, Golay J, Noris M, Remuzzi G. Autologous Mesenchymal Stromal
Cells and Kidney Transplantation: A Pilot Study of Safety and Clinical Feasibility. Clin J Am Soc
Nephrol. 2010 Oct 7. [Epub ahead of print]
Cugini D and Noris M. Toward a B-cell signature of tolerance? Commentary on Kidney Int. 2010
Sep;78(5):435-7.
Aiello S, Noris M. Klotho in acute kidney injury: biomarker, therapy, or a bit of both?
Kidney Int. 2010 Dec;78(12):1208-10
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Benigni A, Morigi M, Remuzzi G. Kidney Regeneration. Lancet 2010;375:1310-7.
Cassis P, Conti S, Remuzzi G, Benigni A. Angiotensin receptors as determinants of life span.
Pflugers Arch. 2010 Jan;459(2):325-32. Review
R. Schiffmann, S. Waldek, A. Benigni, C. Auray-Blais. Biomarkers of Fabry disease
nephropathy. Clin J Am Soc Nephrol. 2010;5:360-364.
A. Benigni, M. Morigi, G. Remuzzi. Kidney regeneration. Lancet. 2010;375:1310-1317.
F. Prefumo, G. Pagani, N. Fratelli, A. Benigni, T. Frusca.Increased concentrations of
antiangiogenic factors in mirror syndrome complicating twin-to-twin transfusion
syndrome. Prenat Diagn. 2010;30:378-379.
M. Morigi, C. Rota, T. Montemurro, E. Montelatici, V. Lo Cicero, B. Imberti, M. Abbate,
C. Zoja, P. Cassis, L. Longaretti, P. Rebulla, M. Introna, C. Capelli, A. Benigni, G.
Remuzzi, L. Lazzari. Life-sparing effect of human cord blood-mesenchymal stem cells in
experimental acute kidney injury. Stem Cells. 2010;28:513-522.
A. Benigni, P. Cassis, G. Remuzzi. Angiotensin II revisited: new roles in
inflammation, immunology and aging. EMBO Mol Med. 2010; 2;247-257. Review
H. Mischak, G. Allmaier, R. Apweiler, T. Attwood, M. Baumann, A. Benigni, S.E. Bennett, R.
Bischoff, E. Bongcam-Rudloff, G. Capasso, J.J. Coon, P. D'Haese, A.F. Dominiczak, M. Dakna,
H. Dihazi, J.H. Ehrich, P. Fernandez-Llama, D. Fliser, J. Frokiaer, J. Garin, M. Girolami, W.S.
Hancock, M. Haubitz, D. Hochstrasser, R.R. Holman, J.P. Ioannidis, J. Jankowski, B.A. Julian,
J.B. Klein, W. Kolch, T. Luider, Z. Massy, W.B. Mattes, F. Molina, B. Monsarrat, J. Novak, K.
Peter, P. Rossing, M. Sánchez-Carbayo, J.P. Schanstra, O.J. Semmes, G. Spasovski, D.
Theodorescu, V. Thongboonkerd, R. Vanholder, T.D. Veenstra, E. Weissinger, T. Yamamoto,
A. Vlahou. Recommendations for biomarker identification and qualification in clinical
proteomics. Sci Transl Med. 2010;2:46ps42.
M. Sandovici, L.E. Deelman, A. Benigni, R.H. Henning. Towards graft-specific immune
suppression: Gene therapy of the transplanted kidney. Adv Drug Deliv Rev. 2010;62:13581368.
Gagliardini E, Conti S, Benigni A, Remuzzi G, Remuzzi A. Imaging of the porous
ultrastructure of the glomerular epithelial filtration slit. J Am Soc Nephrol. 2010;21:2081-2089.
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RESEARCH ACTIVITIES
The kidney's capability to regenerate by forming new nephrons, a characteristic of teleost and
elasmobranch fish, was lost during the evolution of species. In humans, the kidney has been
considered a terminally differentiated organ with low proliferative potential. However, as we
reported in a recent review ( Lancet, 375: 1310-1317, 2010), studies in rodents suggest that,
after an acute kidney injury, progenitors present in renal tissue or derived from bone marrow are
able to activate molecular and cellular processes of regeneration. In this context, our research
focused on studying whether and how adult stem cells of different origin or embryonic kidney
tissues are able to regenerate and protect the kidney in models of acute and chronic kidney
injury. Identification of renal progenitors in the adult tissue will allow to find new potential
targets for regenerative therapies.
Laboratory of Cell Biology and Xenotransplantation
Human amniotic fluid stem cells ameliorate the outcome of
experimental acute kidney injury and animal survival.
Transplantation of bone marrow or cord blood mesenchymal stem cells (MSCs) has been
indicated as a powerful tool for cell-based treatment of acute kidney injury (AKI). However,
bone marrow collection is associated with patient’s discomfort and isolation of MSCs from cord
blood is not invariably successful. By contrast, broadly multipotent stem cells, sharing
characteristics with embryonic stem cells, can be easily obtained from amniotic fluid. Here we
studied the regenerative potential of human amniotic fluid stem (hAFS) cells in mice with
cisplatin-induced AKI. Infusion of hAFS cells in cisplatin-mice limited tubular damage and
improved renal function, although not to control level, and prolonged animal survival. Human
AFS cells engrafted injured kidney predominantly in peritubular region without acquiring
tubular epithelial markers. Human AFS cells exerted antiapoptotic effect, activated Akt and
stimulated proliferation of tubular cells possibly via local release of factors that we documented
in vitro to be produced by hAFS cells. The therapeutic potential of hAFS cells was enhanced by
cell pre-treatment with GDNF which, markedly ameliorated tubular injury and renal function by
increasing stem cell homing to tubulo-interstitial area. By in vitro studies, GDNF increased
hAFS cell production of growth factors, motility and expression of receptors involved in cell
homing and survival. These findings indicate that hAFS cells can promote functional recovery
and contribute to renal regeneration in AKI mice via local production of mitogenic and prosurvival factors. The effects of hAFS cells can be remarkably enhanced by GDNF
preconditioning.
Kidney Organogenesis Activates Regeneration in a Rat Model of
Progressive Renal Disease
Transplanted embryonic kidneys, metanephroi, were shown to develop renal structures in
healthy animals. Here, in the context of chronic renal injury, we investigated the developmental
capacity and the regenerative potential of metanephroi transplanted under the kidney capsule of
rats with progressive renal disease. Six weeks post-transplantation, metanephroi developed
tubuli and glomeruli, and produced diluted urine in cyst-like structures. In renal tissues, adjacent
to the graft, proliferation and vascular density augmented together with a decrease of apoptosis
and oxidative stress. Grafted animals showed tubuli positive to molecules normally expressed in
immature renal tissue or in maturing nephrons and regenerating tubuli. Co-transplanted
mesenchymal stem cells enhanced metanephros-induced cell proliferation, vascular density and
graft filtering activity. Our data highlight that nephrogenesis occurres in chronically injured
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animals and activates regenerative processes. Moreover, mesenchymal stem cells revealed the
capacity to speed-up and support renal recovery.
Inhibiting ACE promotes renal repair by limiting progenitor cell
proliferation and restoring the glomerular niche
In collaboration with the Unit of Advanced Microscopy
In the present study we have identified in rat kidneys a renal progenitor cell population localized
in the inner surface of the Bowman’s capsule. Accordingly with previous observation in human
biopsies, the Bowman’s capsule of healthy glomeruli is constituted by three different cell
populations: immature renal progenitors, visceral epithelial cells or podocytes, and transitional
cells which co-express markers of both the other cell populations. Under physiological
condition renal progenitor cells may differentiate into podocytes and may be responsible for the
generation of new podocytes. By using an experimental model of progressive nephropathy, we
have observed that during the course of the disease renal progenitor cells undergo excessive
proliferation, detach from the Bowman’s capsule and invade the glomerular capillary tuft thus
contributing to the formation of hyperplastic lesions. Treatment with the anti-hypertensive drug
ACE inhibitor induces renal repair by significantly reducing the number and the extension of
hyperplastic glomerular lesions. ACE inhibitor induces renoprotection by limiting renal
progenitor cell activation and restoring the glomerular niche. Accordingly, progenitor cells in
treated animals were no longer detectable within glomerular lesions but were localized along the
Bowman’s capsule to a pattern similar to controls. These results shed light on the mechanisms
of glomerular injury and repair, and indicate the inhibition of angiotensin II synthesis as a
potential selective way to enhance the intrinsic ability of the kidney to regenerate.
Laboratory of Experimental Models of Kidney Diseases
Adding a statin to a combination of ACE inhibitor and Angiotensin II
receptor blocker normalizes proteinuria in experimental diabetes which
translates into full renoprotection
In collaboration with the Unit of Advanced Microscopy
The activation of renin angiotensin system (RAS) plays a key role in favoring mechanisms
leading to kidney function loss in several nephropathies and in diabetes. The capacity of RAS
inhibitors to delay progression of diabetic nephropathy depends on the time at which therapy is
started. A multimodal intervention is required to afford renoprotection in overt diabetic
nephropathy. We assessed the effects of maximal RAS inhibition by angiotensin converting
enzyme (ACE) inhibitor plus angiotensin II type I receptor blocker (ARB) in combination with
statin in rats with overt diabetic nephropathy. Uninephrectomized rats made diabetic by
streptozotocin were orally treated from 4 (when proteinuria and renal lesions had developed) to
8 months with vehicle, lisinopril plus candesartan, lisinopril plus candesartan plus rosuvastatin
or rosuvastatin alone. Results showed that combined therapies were more renoprotective than
single therapies. Systolic blood pressure increased in diabetic rats and was significantly lowered
by combined therapies. Dual RAS blockade significantly reduced proteinuria with respect to
vehicle. Addition of statin further lowered proteinuria to control levels. Glomerulosclerosis was
ameliorated by RAS inhibitors or statin, and regression was achieved by the addition of statin.
Loss of podocytes of diabetic rats was limited by ACE inhibitor plus ARB, while normalized by
the three drugs. Defective nephrin expression of diabetes was increased by dual RAS blockade
or statin, and restored by the triple therapy. Tubular damage, interstitial inflammation, and the
expression of the fibrotic markers TGFβ and phosphorylated Smad 2/3 in tubuli were
significantly reduced by the triple regimen. These data suggest a strategy to target proteinuria to
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try to achieve regression of renal disease in diabetic patients who do not fully benefit RAS
inhibition alone.
Lack of the lectin-like domain of thrombomodulin worsens Shigatoxin
(Stx)-induced HUS in mice.
In collaboration with the Laboratory of Immunology and Genetic of Rare Diseases and
Organ Transplantation
Mutations of thrombomodulin (TM), a transmembrane endothelial cell glycoprotein with
anticoagulant, anti-inflammatory and cytoprotective properties, have been recently implicated in
the development of atypical HUS. We and others have found that in vitro TM expression was
decreased in microvascular endothelial cells exposed to Stx, the causative agent of diarrheaassociated HUS (D+HUS), suggesting that impaired TM activity/levels may play a role also in
D+HUS. In a murine model of Stx-HUS we studied the effect on disease course and severity of
deletion of the lectin-like domain of TM that is critical for its anti-inflammatory and
cytoprotective properties. Disease was induced by co-injection of Stx2 and LPS in mice lacking
the lectin-like domain (TMLed/Led mice) or in wild type mice (TMwt/wt ). TMLed/Led mice had
higher mortality after Stx2/LPS than TMwt/wt mice. TMLed/Led mice exhibited more severe
thrombocytopenia and renal failure compared to TMwt/wt. In TMLed/Led mice, intraglomerular
fibrinogen deposits were detected earlier (at 3h) than in TMwt/wt mice (at 6h). More abundant
fibrinogen deposits were also found in the brain of TMLed/Led mice. Lack of the lectin-like
domain of TM resulted in a stronger inflammatory reaction in the kidney after Stx2/LPS, with a
higher number of neutrophils infiltrating glomeruli and renal interstitium. Interstitial
accumulation of monocytes/macrophages was also more abundant. These data document that
TMLed/Led mice exhibited earlier onset of HUS that, over the follow-up, was worse than in the
TMwt/wt mice, suggesting that loss of TM function may increase susceptibility to the
development of thrombotic microangiopathic lesions after Stx infection. These findings suggest
that TM may be a therapeutic target for D+HUS.
Laboratory of Immunology and Genetic of Rare Diseases and
Organ Transplantation
Autologous Mesenchymal Stromal Cells and Kidney Transplantation: A pilot
study of safety and clinical feasibility
Multipotent mesenchymal stromal cells (MSCs) possess powerful immunomodulatory activity
highlighting the potential for their clinical translation as a novel cell-based approach in solid
organ transplantation. A safety and clinical feasibility study (ClinicalTrials.gov, NCT00752479)
of autologous MSC infusion in recipients of kidneys from living-related donors is ongoing at
our Centre. We reported on the first two patients. Patients were given T cell-depleting induction
therapy and maintenance immunosuppression with cyclosporine and mycophenolate mofetil. On
day 7 posttransplant, MSCs were administered intravenously. In both MSC-treated patients
serum creatinine levels increased 7 to 14 days after cell infusion. A graft biopsy in patient 2
excluded acute graft rejection, but showed a focal inflammatory infiltrate, mostly granulocytes.
In patient 1 protocol biopsy at 1-year posttransplant showed a normal graft. Both MSC-treated
patients are in good health with stable graft function. A progressive increase of the percentage
of CD4+CD25highFoxP3+CD127- Treg and a marked inhibition of memory CD45RO+RA-CD8+ T
cell expansion were observed posttransplant. Patient T cells showed a profound reduction of
CD8+ T cell activity.
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Findings from this study in the two patients show that MSC infusion in kidney transplant
recipients is feasible, allows enlargement of Treg in the peripheral blood, and controls memory
CD8+ T cell function. Future clinical trials with MSCs to look with the greatest care for
unwanted side effects is advised.
Relative role of genetic complement abnormalities in sporadic and familial
aHUS and their impact on clinical phenotype
Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia,
thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxinproducing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a
poor prognosis. Genetic complement abnormalities have been found in aHUS.
We screened 273 consecutive patients with aHUS for complement abnormalities and studied
their role in predicting clinical phenotype and response to treatment. We compared mutation
frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases.
In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH)
polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH
polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a
genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of
CFH and more severe disease than sporadic cases. Patients with CFH or THBD
(thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor
protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced
remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or
autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS
recurred frequently after kidney transplantation except for patients with MCP mutations.
Results underline the need of genetic screening for all susceptibility factors as part of clinical
management of aHUS and for identification of patients who could safely benefit from kidney
transplant.
Laboratory of Cell and Gene Therapy
Mechanism of cell-to-cell communication between MSc and damaged
tubular cells
In collaboration with the Laboratory of Cell Biology and Xenotransplantation
Recent studies demonstrated that exogenous bone marrow-mesenchymal stem cells (BM-MSCs)
may contribute to the recovery of tissue injury in several organs. We demonstrated that
administration of mouse BM-MSC in a mouse model of cisplatin-induced acute kidney injury
(AKI) ameliorates renal dysfunction and repairs tubular damage. This effect is possibly due to
the ability of MSCs to promote renal tubular cell proliferation. The low number of MSC found
within the renal tissue after injury together with the increased proliferation of tubular cells
suggest that MSCs may exert their effects by a paracrine action on resident cells.
One of the projects of the Department is to characterize the signalling mediators involved in the
mechanism of cell-to-cell communication between MSCs and damaged tubular cells (growth
factors, exosomes and microvesicles). We demonstrated that mouse and human BM-MSC
release microvesicles (MV) and exosomes in the microenvironment. MV/exosomes were
isolated from conditioned medium by serial ultracentrifugation and their identity was confirmed
by electron microscopy. MV/exosomes are enriched in microRNA, mRNA and proteins. By in
vitro experiments, we demonstrated that MV/exosomes horizontally transfer their mRNAs to
damaged tubular cells, increasing their proliferation. We are now evaluating the possible
pathways involved in such an effect and which pathways are modulated in targeted cells
exposed to MSC-derived MV/exosomes.
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Induction of pluripotent stem cells from somatic cells
In collaboration with the Laboratory of Cell Biology and Xenotransplantation
The therapeutic effects of human embryonic stem cells (hES cells) have been reported in several
animal models of degenerative diseases, but only in January 2009 the US FDA approved the
first clinical trial for treating patients affected by spinal cord injury with hES cells. The clinical
applications of hES cells are associated with some obstacles: the immune rejection after
transplantation and ethical concerns about the use of embryos. The induced pluripotent stem
cells (iPS) technology could overcome the obstacles associated with hES cells. The iPS cells
refer to pluripotent stem cells that are artificially induced from differentiated cells by
introducing four transcription factors (OCT4, KLF4, SOX2 and cMyc) highly expressed in hES
cells. Several methods have been used to deliver the four transcription factors into the somatic
cells, but the plasmid-based transfection seems to be safer because it can avoid the integration
into the host genome. On the basis of these evidences, our group cloned the four transcription
factors in a single plasmid vector that ensures the same expression level for all factors into the
differentiated cells. We have chosen to reprogram human adult dermal fibroblast cells because
they are easy to obtain from patients. Preliminary experiments led to only partially
reprogrammed iPS-like colonies. To overcome this problem we are now trying to improve
transfection efficiency and the cell culture protocols. Recently, it has been reported that
transfection with the RNA for the four transcription factors can reprogram adult cells with a
high efficiency. This method seems to be safer then plasmid vector because the RNA can’t
integrate in the host genome. Given these data, our group is trying to optimize the in vitro RNA
transcription technique in order to generate a unique RNA with all the four reprogramming
factors. The final goal of our research will be to obtain iPS cells from patients affected from rare
genetic diseases in order to get an in vitro model of the disease to study and correct the genetic
defect.
MicroRNAs Involvement in the progression of the renal disease
In collaboration with the Laboratory of Renal Biophysics (Department of
Bioengineering)
MicroRNAs are small, endogenously expressed non-coding RNA molecules that
regulate target gene expression through translation repression or messenger RNA
degradation. MicroRNAs are involved in a number of physiological processes like
development, cellular proliferation, and apoptosis but also in pathological conditions
such as in cardiovascular diseases and in cancer. One of the research lines of the
Department is the identification of possible microRNAs modulated during the
progression of renal disease in order to find gene and mechanisms predisposing to the
renal damage. Munich Wistar Fromter (MWF) rats represent a genetic experimental
model of spontaneous glomerulosclerosis, characterized by superficial glomeruli,
reduced number of nephrons, increased glomerular volume and proteinuria. The male
MWF rats develop hypertension, massive proteinuria and glomerulosclerosis with age.
The reduction in podocytes number is an important determinant of podocytes
dysfunction and progressive impairment of the glomerular permselectivity that leads to
renal scarring. Taking advantage of this model, we performed a microRNA expression
profile in isolated glomeruli and identified microRNAs differentially expressed in MWF
rats in respect to control rats. We focused our attention on the most upregulated
microRNA and, using different algorithms, we computationally predicted possible
microRNA targets.
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Gene therapy to correct Thrombotic Thrombocytopenic Purpura
In collaboration with the Department of Bioengineering
Thrombotic Thrombocytopenic Purpura is a rare thrombotic microangiopathy characterized by
anemia and thrombocytopenia. The disease manifests prevalent, but not exclusive, neurologic
symptoms and renal dysfunction. TTP is caused by deficiency of ADAMTS13 activity.
ADAMTS13 is a plasma protein that regulates thrombi formation by cleaving von Willebrand
(vWF) factor multimers secreted from endothelial cells. The treatment of choice for patients
with familial TTP is plasma infusion that, however, exposes patients to high risk of infections,
fluid volume overload and allergies. These limitations prompted us to look for an alternative
therapy. Recently, we demonstrated that gene therapy restores ADAMTS13 plasma levels and
activity in knockout mice. Indeed, intravenous administration of a recombinant adenoviral
vector encoding for human ADAMTS13 into ADAMTS13-/- mice induces the release into the
plasma of large amounts of functionally active ADAMTS13 protein, able to reduce the thrombi
area in respect to control mice. Despite these promising results the use of an adenoviral vector
as a gene transfer tool causes the production of antibodies against both the adenovirus and the
transgene reducing the expression and activity of the recombinant protein in the long-term. In
order to ameliorate our gene therapy approach we are now evaluating alternative gene delivery
strategies based on the use of transposons. We are going to use the Sleeping Beauty (SB) system
consisting of a plasmid containing ADAMTS13 cDNA flanked by inverted terminal repeats
(ITR) typical of the SB transposon and a plasmid encoding for the transposase, a protein able to
“cut” DNA at the level of the ITRs and to “paste” it into the genome. Of note, no dominant
adverse effects associated with SB vectors integration have been observed in experimental
animal and this system allows long-term expression of the transgene. Moreover, in order to
overcome transgene expression in dendritic cells responsible for T cells activation, we inserted
the target sequence for microRNA (miR)142-3p in the 3’UTR of the ADAMTS13 cDNA. The
miR142-3p is present in dendritic cells but not in hepatocytes. The perfect complementarity
between the microRNA and its target sequence will suppress the expression of ADAMTS13 in
dendritic cells, preserving ADAMTS13 into the hepatocytes, the constitutive site of
ADAMTS13 production.
Imaging of the porous ultrastructure of the glomerular epithelial filtration
slit
The ultrastructure of the glomerular filtration pores is still controversial. In the last 30 years,
observations from transmission electron microscopy (TEM) and theoretical analysis of solute
clearance produced conflicting results. In this study, the employment of a sophisticated
technological approach permitted to observe details never detected in the past. Here, we used
scanning electron microscopy (SEM) of last generation (Cross-Beam Supra con colonna
Gemini, Carl Zeiss, Oberkochen, Germania) with a high-sensitivity detector to image the
deepest regions of the filtration pores. In contrast to previous TEM imaging, we observed, in
kidney samples of control animals, circular and ellipsoidal pores mainly located in the central
region of the podocyte junctions. The normal mean pore radius estimated by digital
morphometric analysis had a log-normal distribution, with an average value of 12.1 nm. Of
note, in the kidney of proteinuric rats, the mean pore radius values were also log-normally
distributed with the presence, however, of some very large pores, exceeding the sizes observed
in normal conditions. These exceptionally large pores may be responsible for the increased
filtration of plasma proteins in glomerular disease.
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DEPARTMENT OF BIOMEDICAL
ENGINEERING
STAFF
Head
Andrea REMUZZI, Eng. D.
Laboratory of Renal Biophysics
Head
Daniela MACCONI, Biol.Sci.D.
Laboratory of Biomedical Technologies
Head
Bogdan ENE-IORDACHE, Eng.D.
Unit of Tissue Engineering
Head
Marina FIGLIUZZI, Biol.Sci.D.
Unit of Medical Imaging
Head
Luca ANTIGA, Ph.D.
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CURRICULA
Andrea Remuzzi got his degree in Mechanical (Biomedical) Engineering in 1979, Politecnico di Milano.
Research experience: 1980 Politecnico di Milano, Dipartimento di Ingegneria Biomedica; 1981 Istituto
Mario Negri (Milano), Laboratorio di Farmacologia Cardiovascolare; 1982-83 Massachusetts Institute of
Technology, Mechanical Engineering Department, Cambridge, USA.
Areas of interest: biological transport phenomena, mathematical models, renal pathophysiology, cellular
response to mechanical stimulation, tissue engineering, pancreatic islet transplantation, clinical databases,
computational fluid dynamics.
Chronology of appointment: From 1984 to 1986 Ricercatore Istituto Mario Negri (Bergamo), Laboratorio
di malattie renali, 1986-1989 Head, Unità di Bioingegneria, Istituto Mario Negri, 1989-1993 Head,
Laboratorio di Bioingegneria, Istituto Mario Negri, 1993-1999 Head, Dipartimento di Ricerca Renale,
Istituto Mario Negri, from 2000 Head, Dipartimento di Bioingegneria, Istituto Mario Negri. From 1998 to
2007 contract professor of Bioengineering, Politecnico di Milano. For 2007 Professor of Bioengineering,
University of Bergamo.
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Davies PF, Remuzzi A, Gordon EJ, Dewey CF Jr, Gimbrone MA Jr. Turbulent fluid shear stress induces vascular
endothelial cell turnover in vitro. Proc Natl Acad Sci U S A. 1986 Apr;83(7): 2114-7. PMID: 3457378
Remuzzi A, Puntorieri S, Battaglia C, Bertani T, Remuzzi G. Angiotensin converting enzyme inhibition ameliorates
glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest. 1990
Feb;85(2):541-9. PMID: 1688888
Noris M, Morigi M, Donadelli R, Aiello S, Foppolo M, Todeschini M, Orisio S, Remuzzi G, Remuzzi A. Nitric oxide
synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res. 1995 Apr;76(4):536-43. PMID:
7534657
Giavazzi R, Foppolo M, Dossi R, Remuzzi A. Rolling and adhesion of human tumor cells on vascular endothelium
under physiological flow conditions. J Clin Invest. 1993 Dec;92(6):3038-44. PMID: 7504697
Antiga L, Ene-Iordache B, Remuzzi A. Computational geometry for patient-specific reconstruction and meshing of
blood vessels from MR and CT angiography. IEEE Trans Med Imaging. 2003 May;22(5):674-84. PMID: 12846436
Remuzzi A, Gagliardini E, Sangalli F, Bonomelli M, Piccinelli M, Benigni A, Remuzzi G. ACE inhibition reduces
glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease. Kidney Int. 2006
Apr;69(7):1124-30.
Ruggenenti P, Remuzzi A, Remuzzi G. Decision time for pancreatic islet-cell transplantation. Lancet. 2008 371:883-4.
Antiga L, Piccinelli M, Fasolini G, Ene-Iordache B, Ondei P, Bruno S, Remuzzi G, Remuzzi A. Computed tomography
evaluation of autosomal dominant polycystic kidney disease progression: a progress report. CJASN 2006 1:754-60.
Cornolti R, Figliuzzi M, Remuzzi A. Effect of micro-and macroencapsulation on oxygen consumption by pancreatic
islets. Cell Transplant. 2009; 18(2): 195-201.
Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V, Crippa L, Avezza F,
Fiordaliso
F, Salio M, Lauria G, Lombardi R, Cavaletti G. Regression of diabetic complications by islet transplantation in the rat.
Diabetologia 2009 sep 30; 52: 2653-2661.
Cornolti R, Cattaneo I, Trudu M, Figliuzzi M, Remuzzi A. Effect of islet transplantation on metabolic glucose control
in rats
with diabetes. Diabetes Technol Ther. 2009 Dec; 11(12):805-11
Gagliardini E, Conti S, Benigni A, Remuzzi G, Remuzzi A.
Imaging of the Porous ultrastructure of the glomerular epithelial filtration Slit. Journal American Society Nephrology
21: 20812089, 2010.
Daniela Macconi got her Biol.Sci.D. degree in Milan in the 1983.
Research experience: 1977-81 CNR Institute of Neuroscience - Cell Mol Pharmacology - and Department
of Medical Pharmacology, University of Milan, Milan, Italy; 1982-83 Laboratory of the Division of
Nephrology and Dialysis, Ospedali Riuniti di Bergamo, Bergamo, Italy; 1984-85 University of Michigan,
Medical School, Department of Pathology, Medical Science I, Ann Arbor Michigan, USA; 1985-89
Mario Negri Institute for Pharmacological Research, Laboratory of Kidney Disease, Bergamo, Italy.
Areas of interest: glomerular permeability, renal disease progression, podocytes, angiotensin II, reactive
oxygen species
Chronology of appointment: From 2000 Head Laboratory of Renal Biophysics, Department of
Biomedical Engineering; 1994-2000 Head, Unit of Inflammatory Mediator of Leukocyte Origin; 198994 Scientist, 1985-89 post-doctoral fellow Mario Negri Institute for Pharmacological Research, Bergamo,
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Italy; 1982-83 fellow Laboratory of the Division of Nephrology e Dialysis, Ospedali Riuniti di Bergamo,
Bergamo, Italy
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Macconi D. Targeting the renin angiotensin system for remission/regression of chronic kidney disease. Histol
Histopathol 25:655-68, 2010. Review
Macconi D, Sangalli F, Bonomelli M, Conti S, Condorelli L, Gagliardini E, Remuzzi G, Remuzzi A. Podocyte
repopulation contributes to regression of glomerular injury induced by ACE inhibition. Am J Pathol 174:797-807, 2009
Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E, Noris M, Buelli S, Zoja C, Corna D, Mele C,
Fanelli R, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic
peptides. J Am Soc Nephrol 20:123-30, 2009.
Macconi D, Abbate M, Morigi M, Angioletti S, Mister M, Buelli S, Bonomelli M, Mundel P, Endlich K, Remuzzi A,
Remuzzi G: Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target
for renoprotective intervention. Am J Pathol 168:1073-85, 2006.
Macconi D, Bonomelli M, Benigni A, Plati T, Sangalli F, Longaretti L, Conti S, Kawachi H, Hill P, Remuzzi G,
Remuzzi A. Pathophysiologic implications of reduced podocyte number in a rat model of progressive glomerular injury.
Am J Pathol 68:42-54, 2006.
Morigi M, Buelli S, Zanchi C, Longaretti L, Macconi D, Benigni A, Moioli D, Remuzzi G, Zoja C. Shigatoxin –induced
endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol 169:1965-75, 2006
Morigi M, Macconi D, Zoja C, Donadelli R, Buelli S, Zanchi C, Ghilardi M, Remuzzi G: Protein overload-induced NFkappaB activation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway. J Am Soc Nephrol
13:1179-89, 2002
Macconi D, Ghilardi M, Bonassi ME, Mohamed EI, Abbate M, Colombi F, Remuzzi G, Remuzzi A: Effect of
angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula
occludens-1 in MWF rats. J Am Soc Nephrol 11:477-89, 2000.
Bogdan Ene-Iordache got his M.Sc. in Mechanical Engineering in 1990 at the Petroleum & Gas
University in Ploiesti (Romania). In 1992 he joined the Bioengineering Laboratory at NegriBERGAMO
Laboratories.
Main interests: renal research (hemodynamics and remodeling of the arteriovenous fistula for vascular
access, morfometry of renal glomeruli) and controlled clinical trials (data management and data analysis).
Other research interests include clinical research informatics (web-based applications) and applied
clinical informatics (development of Electronic Health Record - EHR).
Roles: since January 2000 is the Head of the Biomedical Technologies Laboratory, Department of
Biomedical Engineering. He is coordinating the IT activities in the Clinical Research Center for Rare
Diseases “Aldo e Cele Daccò”.
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Ene-Iordache B, Imberti O, Foglieni O, Remuzzi G, Bertani T and Remuzzi A. Effects of
angiotensin-converting enzyme inhibition on glomerular capillary wall ultrastructure in
MWF/Ztm rats. J Am Soc Nephrol 5: 1378-1384, 1994.
Ene-Iordache B and Remuzzi A. Numerical analysis of blood flow in reconstructed glomerular
capillary segments. Microvasc Res 49: 1-11, 1995.
Ene-Iordache B, Mosconi L, Remuzzi G, Remuzzi A. Computational fluid dynamics of a
vascular access case for hemodialysis. J Biomech Eng 123(3): 284-292, 2001.
Ene-Iordache B, Mosconi L, Antiga L, Bruno S, Anghileri A, Remuzzi G, Remuzzi A. Radial
artery remodeling in response to shear stress increase within arteriovenous fistula for
hemodialysis access. Endothelium 10(2): 95-102, 2003.
Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi
F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi
G for the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators.
Preventing microalbuminuria in type 2 diabetes. NEJM 351(19): 1941-1951, 2004.
Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G and Remuzzi A.
Developing regulatory-compliant electronic case report forms for clinical trials: experience with
the DEMAND trial. J Am Med Inform Assoc, 16(3):404-408, 2009.
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Marina Figliuzzi got her Biol.Sci.D. degree in Milan in the 1991.
Research experience :1991-94 Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Areas of interest: techniques of kidney decellularization, isolation of pancreatic islets from human,
bovine, pig and rat pancreas, cell culture, immunoisolation devices for pancreatic islets, differentiation of
progenitor pancreatic cells in insulin containing cells, immunhistochemistry.
Chronology of appointment: From 2000 Head Unit of Tissue Engineering, Department of Biomedical
Engineering; 1991-2000 fellow laboratory of Renal research, Mario Negri Institute for Pharmacological
Research, Bergamo, Italy.
• Figliuzzi M, Bonandrini B, Cattaneo I, Remuzzi G, Remuzzi A. Effect of inborn pancreatic islet
deficit in the Munich Wister Frömter rat. Islets. 2010 Sep 1;2(5):318-22.
• Cornolti R, Cattaneo I, Trudu M, Figliuzzi M, Remuzzi A.Effect of islet transplantation on
metabolic glucose control in rats with diabetes.Diabetes Technol Ther. 2009 Dec;11(12):805-11.
• Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V,
Crippa L, Avezza F, Fiordaliso F, Salio M, Lauria G, Lombardi R, Cavaletti G. Regression of
diabetic complications by islet transplantation in the rat. Diabetologia. 2009 Dec;52(12):26532661.
• Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, Remuzzi A, Benigni A. Bone
marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats. Transplant
Proc. 2009 Jun;41(5):1797-800.
• Cornolti R, Figliuzzi M, Remuzzi A. Effect of micro- and macroencapsulation on oxygen
consumption by pancreatic islets.Cell Transplant. 2009;18(2):195-201.
• Figliuzzi M, Adobati F, Cornolti R, Cassis P, Remuzzi G, Remuzzi A.Assessment of in vitro
differentiation of bovine pancreatic tissue in insulin-expressing cells. JOP 9(5):601-11, 2008.
• Figliuzzi M, Plati T, Cornolti R, Adobati F, Fagiani A, Rossi L, Remuzzi G, Remuzzi A.
Biocompatibility and function of microencapsulated pancreatic islets. Acta Biomater. 2006
Mar;2(2):221-7.
• Figliuzzi M, Cornolti R, Plati T, Rajan N, Adobati F, Remuzzi G, Remuzzi A: Subcutaneous
xenotransplantation of bovine pancreatic islets. Biomaterials. 26:5640-47, 2005.
• Figliuzzi M, Zappella S, Morigi M, Rossi P, Marchetti P, Remuzzi A: Influence of donor age on
bovine pancreatic islet isolation. Transplantation. 70:1032-37, 2000
Luke Antiga graduated in 1999 in Biomedical Engineering and got his PhD in Bioengineering in 2003,
Politecnico di Milano, having worked at the research laboratory of Biomedical Technology, Department
of Bioengineering Institute Mario Negri.
Training activities: 2003 Post-doctoral fellow at Imaging Research Laboratories, Robarts Research
Institute, London, Ontario.
Areas of interest: acquisition and image processing for medical and microscopy applications, numerical
modeling of transport phenomena.
Roles: from 2000 to 2002 Doctoral Student at the Laboratory of Biomedical Technology, Department of
Bioengineering, from 2002 to 2003 visiting scientist Robarts Institute for medical Imaging, London,
Ontario, Canada, from 2004 to 2006 resercher at the Laboratory of Biomedical Technology, Department
of Bioengineering, from 2007 Head Unit of Medical Imaging, Department of Bioengineering.
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Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, Ondei P, Rubis N, Diadei O, Gherardi G, Prandini
S, Panozo A, Bravo RF, Carminati S, De Leon FR, Gaspari F, Cortinovis M, Motterlini N, Ene-Iordache B, Remuzzi A
and Remuzzi G. Sirolimus therapy to halt the progression of Autosomal Dominant Polycystic Kidney Disease:
The SIRENA study. JASN, 21(6):1031-1040, 2010.
Caroli A, Antiga L, Cafaro M, Fasolini G, Remuzzi A, Remuzzi G and Ruggenenti P. Reducing polycystic liver volume
in ADPKD: effects of the extended release somatostatin analogue octreotide. CJASN, 5(5): 783-789, 2010.
Botti L, Piccinelli M, Ene-Iordache B, Remuzzi A and Antiga L. An adaptive mesh refinement solver for largescale simulation of biological flows. Communications in Numerical Methods in Engineering, 26(1): 86-100, 2010.
Antiga L, and Steinman DA. Rethinking turbulence in blood. Biorheology, 46(2): 77-81, 2009.
Piccinelli M, Veneziani A, Steinman DA, Remuzzi A and Antiga L. A framework for geometric analysis of vascular
structures: application to cerebral aneurysms. IEEE Transactions on Medical Imaging, 28(8): 1141-55, 2009.
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Botti L, Piccinelli M, Ene-Iordache B, Remuzzi A and Antiga L. An adaptive mesh refinement solver for large-scale
simulation of biological flows. Communications in Numerical Methods in Engineering, 26(1): 86-100, 2010.
Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G, Remuzzi A. Developing regulatorycompliant electronic case report forms for clinical trials: the DEMAND trial. JAMIA, 16(3): 404-408, May-Jun 2009.
Lee SW, Antiga L and Steinman DA. Correlations among indicators of disturbed flow at the normal carotid bifurcation.
Journal of Biomechanical Engineering, 131(6): , Jun 2009.
Antiga L, Piccinelli M, Botti L, Ene-Iordache B, Remuzzi A and Steinman DA. An image-based modeling framework for
patient-specific computational hemodynamics. Medical and Biological Engineering and Computing, 46: 1097-1112, Nov
2008.
Antiga L, Wasserman B, Steinman D. On the overestimation of early wall thickening at the carotid bulb by black blood
MRI, with implications for coronary and vulnerable plaque imaging. Magnetic Resonance in Medicine, 60(5): 10201028, Nov 2008.
Antiga L, Piccinelli M, Fasolini G, Ene-Iordache B, Ondei P, Ruggenenti P, Remuzzi G and Remuzzi A. Computed
tomography evaluation of ADPKD progression: a progress report. Clinical Journal of the American Society of
Nephrology (CJASN), 1(4): 754-760, Jul 2006.
Thomas JB, Antiga L, Che S, Milner JS, Hangan Steinman DA, Spence JD, Rutt BK and Steinman DA. Variation in the
carotid bifurcation geometry of young vs. older adults: Implications for "geometric risk" of atherosclerosis. Stroke,
36(11): 2450-2456, Nov 2005.
Antiga L, Steinman DA. Robust and objective decomposition and mapping of bifurcating vessels. IEEE Transactions on
Medical Imaging, 23(6): 704-713, June 2004.
Antiga L, Ene-Iordache B and Remuzzi A. Computational geometry for patient-specific reconstruction and meshing of
blood vessels from MR and CT angiography. IEEE Transactions on Medical Imaging, 22(5): 674-684, May 2003.
Antiga L, Ene-Iordache B, Remuzzi G and Remuzzi A. Automatic generation of glomerular capillary topological
organization. Microvascular Research, 62: 346-354, June 2001.
The Department of Bioengineering conducts research activities in biomedicine, both at
experimental and clinical level. Physiopathological processes are studied using engineering
techniques with the aim to develop innovative treatment strategies. Several lines of research in
basic, applied clinical research are currently active within the Department. The main tools used
for this research consist of theoretical models, diagnostic imaging, histological measures,
physical and chemical parameters in both experimental and clinical studies, cell culture
techniques, biomaterials, computational technologies for archiving and processing clinical data.
The ongoing studies relate to four main areas: 1) study of the mechanisms involved in the
progression of chronic nephropathy; 2) studies on the role of hemodynamics in the development
of vascular diseases; 3) development of laboratory techniques for tissue engineering; 4)
development of information systems to manage clinical data and digital images generated in the
context of controlled clinical trials and in routine clinical practice.
We produced evidence demonstrating a possible relationship between the geometry of the
cerebral arterial vessels, location of cerebral aneurysms. These findings are opening new
perspectives in the understanding of the role of hemodynamic conditions as responsible for this
disease.
Demonstration of a significant relationship between morphometric parameters of the renal
parenchyma, quantified through numerical analysis of CT images, and the loss of renal function
in patients with polycystic kidney disease.
Demonstration that the mechanism responsible for regeneration of the glomerular capillary,
induced by drugs that inhibit the angiotensin II, depends on proliferation of parietal cells of the
Bowman’s capsule and their subsequent migration on to the glomerular capillary loops.
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Implementation of a paper less web-based system for the management, of clinical data
generated in controlled clinical trials, in compliance with GCP.
Set up a new network of specialists in Nephrology for long-term data collection aimed at
monitoring the quality of treatment of chronic progressive nephropathy in current clinical
practice.
Dipartimento di Bioingegneria, Politecnico di Milano, Milano.
Unità di Diabetologia, Ospedali Riuniti, Bergamo.
STMicroelectronics, Agrate Brianza, Milano
Matematici, Università di Bergamo
Dipartimento di scienze Neurologiche e della visione, Università di Verona.
Dipartimento di Ingegneria Industriale e Dipartimento di Ingegneria dell’informazione e metodi
Matematici
Facoltà di Medicina e Chirurgia, Università degli studi di Milano
Massachussetts Institute of Technology, Cambridge MA, USA.
National Alliance for Medical Imaging Computing, USA.
Harvard Medical School, Cambridge MA, USA.
Department of Mathematics and Computer Science, Emory University, Atlanta, Georgia, US.
Simula Laboratories, Oslo, Norway
Academisch Medisch Centrum, Amsterdam, the Netherlands
University of Toronto, Ontario, Canada.
Ghent University, Ghent, Belgium.
Technical University, Eindhoven, The Netherlands.
University Hospital, Maastricht, The Netherlands.
Universzitetni Klinikni Center Ljubjana, Ljubljana, Slovenia.
The University of Sheffield, Sheffield, United Kingdom.
ESAOTE, Maastricht, The Nederland.
International Journal of Artificial Organs, (Andrea Remuzzi)
Annals of Biomedical Engineering
ASME Journal of Biomechanical Engineering
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Journal of Vascular Research
Magnetic Resonance in Medicine
Stroke
Journal of the American Society of Nephrology
Medical & Biological Engineering & Computing
IEEE Transactions on Medical Imaging
IEEE Transactions on Biomedical Engineering
Medical Physics
Journal of Biomechanics
Medical Engineering and Physics
Artificial Organs
International Journal of Artificial Organs
Biomaterials
Contemporary Clinical Trials
Journal of Endocrinological Investigation
Pediatric Nephrology
Nephrology Dialysis
Translantation
Acta Diabetologica
EVENT ORGANIZATION
Seminar: "Sviluppo di un sistema per l'elaborazione di immagini digitali al microscopio per la
quantificazione di componenti cellulari in tre dimensioni”, Benedetta Nodari (Università degli
studi di Bergamo, Facoltà di Ingegneria Informatica), Sala Riunioni Centro Anna Maria Astori
Km Rosso Bergamo.
Seminar: "Hemodynamic factors in cardiovascular disease: Bridging the gap between
Engineering and Medicine" Prof. David Steinman (Professor of Mechanical and Biomedical
Engineering at the University of Toronto), October, Sala Conferenze Centro Anna Maria Astori
Km Rosso - Bergamo.
Seminar: " Biomedical Engineering: from basic research to clinical application. The Maastricht
University Medical Center Experience", Dr. Frans Van de Vosse (Prof. of Cardiovascular
Biomechanics, Eindhoven University of Technology, Netherlands), 10 Anni del Dipartimento di
BIOINGEGNERIA, November, Sala Consiliare - Ospedali Riuniti di Bergamo.
Seminar: "Evaluation of different DW-MRI Protocols on ex vivo mouse spinal cord", Jeire
Steinbuch (Eindhoven University of Technology, Medical Engineering - The Netherlands), July,
Sala Conferenze Centro Daccò – Bergamo.
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Seminar: "Computational modelling and CFD models for hemodynamic behaviour in AVF",
Raf Van Hoof (Eindhoven University of Technology, Biomedical technology - The
Netherlands), July, Sala Conferenze Centro Daccò – Bergamo.
Seminar: "Sviluppo e testing di software web-based per il progetto COMGAN", Lorenzo
Fugazza (Università degli Studi di Bergamo, Facoltà di Ingegneria), July, Sala Conferenze
Centro Daccò – Bergamo.
Seminar: "Ingegneria del tessuto renale progetto e sperimentazione di un sistema per la
decellularizzazione del rene", Paola Cucchetti (Dipartimento di Bioingegneria, Politecnico di
Milano POLIMI), July, Sala Conferenze Centro Daccò – Bergamo.
Seminar: "Studio spettroscopico e morfologico della interazioni tra sistemi biologici e materiali
organici ed inorganici", Prof. Loredana Latterini (Dipartimento di Chimica, Università di
Perugia), March, Sala Conferenze Centro Daccò – Bergamo.
Seminar: "Studio numerico dell'emodinamica nelle fistole artero-venose di tipo end-to-side
utilizzate come accesso vascolare nell'emodialisi", Cristina Semperboni, February, Sala
Conferenze Centro Daccò – Bergamo.
PARTICIPATION IN EVENTS IN WHICH THE DEPARTMENT WAS
INVOLVED
VPH NoE WP2/WP3/VPH-I Meeting, 4th-5th February 2010, Laboratory of Anatomy,
Biomechanics, Organogenesis, Universite Libre de Bruxelles (ULB) – Erasme Campus,
Bruxelles(The VPH ToolKit – A Focus on Sustainability and Cooperation).
14th European Vascular Course(EVC2010), February 25-27, 2010 Maastricht, The Netherlands.
CO.R.TE 2010: Conferenza Italiana per lo Studio e la Ricerca sulle Ulcere, Piaghe, Ferite e la
Riparazione Tessutale. 4-6 Marzo 2010, Roma Cavalieri, Via Cadlolo, 101, Roma
(www.romecavalieri.it)
46th Annual Meeting of the European Association for the Study of Diabetes (EASD),
Stoccolma, Sweden
Secondo Congresso Nazionale di Bioingegneria, GNB2010, 5-7 Luglio 2010, Torino
ESB2010, 17th Congress of the European Society of Biomechanics, 5 - 8 July 2010, University
of Edinburgh, UK.
Call for an VPH FET Flagship All Hands meeting, Barcelona July 22nd, 2010.
Meeting VPH FET Flagship All Hands, Zurigo 10 September 2010.
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VPH Conference 2010, Virtual Physiological Human Network of Excellence, 29-01 September
2010, Brussels.
SIAPAV - XXXII Congresso Nazionale, Società Italiana di Angiologia e Patologia Vascolare,
Padova, 17-20 Novembre 2010 - Sheraton Hotel.
Renal Master Class Mario Negri Institute, October 7-9 2010
"La Remission Clinic nella pratica clinica: nuove prospettive di prevenzione e trattamento per le
nefropatie croniche progressive". Villa Camozzi, Bergamo, sabato18 December 2010.
Corso Teorico-Pratico avanzato di eco color Doppler carotideo e vertebrale, Milano 11-13
February 2010.
Research grants AIFA - trial clinici controllati (VARIETY, VALID, ATHENA, ARCADIA,
NEMO).
Research grant PKD foundation - ALADIN trial “Effect of long-acting somatostatin on disease
progression in ADPKD: a long-term three year follow-up study”.
Research grant Baxter – ASAP trial “Acute Start Access Programme”.
Research grant ISN per il Kidney Disease Data Center (KDDC ) del COMGAN.
Contributo Regione Lombardia per data management del Centro di Coordinamento della Rete
Regionale per le Malattie Rare.
Project - FP7 UE - ARCH "Patient specific image-based computational modelling for
improvement of acute and long-term outcomes of vascular access for hemodialysis”
FP7-224390 - Project Coordination.
VASCOSILK, Fondazione Cariplo - N.536/5314 - Protesi vascolari in fibroina elettrofilata per
la rigenerazione in vivo di arterie di piccolo calibro.
LIGASILK, Regione Lombardia - N.534/5287 - Bioingegnerizzazione di tendini e legamenti:
impiego combinato di supporti tessili in seta e cellule staminali adulte.
1. A. Caroli, M. Lorenzi, C. Geroldi, F. Nobili, B. Paghera, M. Bonetti, M. Cotelli, G.B. Frisoni.
Metabolic Compensation and Depression in Alzheimer’s Disease. Dement Geriatr Cogn Disord
2010;29:37–45.
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2. Botti L, Piccinelli M, Ene-Iordache B, Remuzzi A, Antiga L. An adaptive mesh refinement
solver for large-scale simulation of biological flows. Communications in Numerical Methods in
Engineering 2010; 26(1): 86-100.
3. Caroli A, Antiga L, Cafaro M, Fasolini G, Remuzzi A, Ruggenenti P. Reducing polycystic
liver in ADPKD: effects of somatostatin analogue octreotide. Clin J Am Nephrol. 2010 Feb 25.
4. Macconi D. Targeting the renin angiotensin system for remission/regression of chronic
Kidney disease. Histol Histopathol. 2010 May;25(5):655-68.
5. Steinman DA, Antiga L, Wasserman BA. Overestimation of cerebral aneurysm wall
thickness by black blood MRI? Magn Reson Imaging. 2010 Mar;31(3):766.
6. Boccardi M, Almici M, Bresciani L, Caroli A, Bonetti M, Monchieri S, Gennarelli M, Frisoni
GB. Clinical and medial temporal features in a family with mood disorders. Neurosci Lett. 2010
Jan 4; 468(2): 93-97.
7. Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, Ondei P, Rubis N, Diadei
O, Gherardi G, Prandini S, Panozo A, Bravo RF, Carminati S, De Leon FR, Gaspari F,
Cortinovis M, Motterlini N, Ene-Iordache B, Remuzzi A, Remuzzi G. Sirolimus therapy to halt
the progression of ADPKD. J Am Soc Nephrol. 2010 Jun;21(6):1031-40.
8. Caroli A, Frisoni GB. The dynamics of Alzheimer's disease biomarkers in the Alzheimer's
Disease Neuroimaging Initiative cohort. Neurobiol Aging. 2010 Jun 8.
9. Ruggenenti P, Iliev I, Filipponi M, Tadini S, Perna A, Ganeva M, Ene-Iordache B, Cravedi P,
Trevisan R, Bossi A and Remuzzi G. Effect of trandolapril on regression of retinopathy in
hypertensive patients with type 2 diabetes: a prespecified analysis of the BENEDICT Trial. J
Ophthalmology, 2010.
10. Ruggenenti P, Cattaneo D, Rota S, Iliev I, Parvanova A, Perna A, Diadei O, Ene-Iordache
B, Ferrari S, Bossi A, Trevisan R, Belviso A and Remuzzi G. Effects of combined ezetimibe
and simvastatin therapy as compared to simvastatin alone in patients with type 2 diabetes: a
prospective, randomized, double-blind clinical trial. Diabetes Care, 2010.
11. Ruggenenti P, Perna A, Tonelli M, Loriga G, Motterlini N, Rubis N, Ledda F, Rota S, Satta
A, Granata A, Battaglia G, Cambareri F, David S, Gaspari f, Stucchi N, Carminati S, EneIordache B, Cravedi P and Remuzzi G. Effects of add-on fluvastatin therapy in patients with
chronic proteinuric nephropathy on dual RAS blockade: the ESPLANADE trial. Clin J Am Soc
Nephrol, 2010.
12. Cravedi P, Remuzzi A and Remuzzi G. Comment on: Robertson (2010) Islet
Transplantation a Decade Later and Strategies for Filling a Half-Full Glass. Diabetes;59:12851291. Diabetes. 2010 Sep;59(9):e13.
13. Figliuzzi M, Bonandrini B, Cattaneo I, Remuzzi G and Remuzzi A. Effect of inborn
pancreatic islet deficit in the Munich Wistar Fromter rat. Islets 2010.
14. Piccinelli M, Bacigaluppi S, Boccardi E, Ene-Iordache B, Remuzzi A, Veneziani A, Antiga
L. Geometry of the ICA and recurrent patterns in location, orientation and rupture status of
lateral aneurysms: an image-based computational study. Neurosurgery, 2010.
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15. Sharma KS, Hequn Z, Togtokh A, Ene-Iordache B, Carminati S, Remuzzi A, Wiebe N,
Ayyalasomayajula B, Perico N, Remuzzi G and Tonelli M. Burden of CKD, proteinuria, and
cardiovascular risk among Chinese, Mongolian, and Nepalese participants in the International
Society of Nephrology screening programs. Am J Kidney Dis, 2010.
16. Morbiducci U, Gallo D, Ponzini R, Massai D, Antiga L, Montevecchi FM, Redaelli A.
Quantitative Analysis of Bulk Flow in Image-Based Hemodynamic Models of the Carotid
Bifurcation: The Influence of Outflow Conditions as Test Case. Annals of Biomedical
Engineering, 2010.
17. Morbiducci U, Gallo D, Massai D, Consolo F, Ponzini R, Antiga L, Bignardi C, Deriu MA,
Redaelli A. Outflow Conditions for Image-Based Hemodynamic Models of the Carotid
Bifurcation: Implications for Indicators of Abnormal Flow. Journal of Biomechanical
Engineering 2010 Sep;132(9):091005.
18. Gagliardini E, Conti S, Benigni A, Remuzzi G, Remuzzi A.
Imaging of the Porous ultrastructure of the glomerular epithelial filtration Slit. Journal
American Society Nephrology 21: 2081-2089, 2010.
RESEARCH ACTIVITIES
Laboratory of Renal Biophysics
Three dimensional reconstruction of the glomerular capillary network
We have recently documented that angiotensin II blockade not only retards the progression of
renal diseases, but also induces regression of the glomerular lesions. Quantification of the extent
of the regression of sclerotic lesions and the potential regeneration of the glomerular capillary,
induced by a therapy with angiotensin converting enzyme (ACE) inhibitors, can be achieved by
a technology based on three dimensional (3D) reconstruction of tissues. A new approach is the
vascular corrosion casting that produces replicas of normal and abnormal vasculature and
microvasculature of various tissues and organs that can be viewed at the ultrastructural level.
We applied this technique to the kidney that, after exanguination, is perfused with a rapidlyhardening polyurethane resin. Once hardening of the resin is complete, the kidney is excised and
placed in an alkaline solution for maceration of the soft tissue leaving an intact cast of the renal
vasculature to be analyzed by scanning electron microscopy. This allows the morphological
analysis of the vascular architecture of the glomerular capillary and the estimation, by
morphometry, of the geometrical parameters of the capillary network. Another electron
microscopy technique, based on a combination of an electron beam with an ionic one, allows
sectioning and acquisition of serial images of the whole glomerulus for 3D reconstruction of the
glomerular capillary ultrastructure by mathematical algorithms.
Identification of immunogenic albumin peptides in the kidney of rats with
proteinuric nephropathy
(In collaboration with the Department of Molecular Medicine and with the Protein
Chemistry/Proteomics Unit, Institute of Biomedicine, Biomedicum, Helsinki, Finland)
In proteinuric nephropathies abnormal filtration of proteins, mainly albumin, across the
glomerular membrane, causes distress of the proximal tubular cell inducing the release into the
interstitium of chemokines responsible for the recruitment and activation of inflammatory cells.
The interstitial infiltrates are commonly characterized by immune-competent cells including
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dendritic cells (DCs) and CD8+ T cells that accumulate within renal parenchyma even in the
absence of an immune insult. Within the kidney, DCs are in close contact with the tubular
epithelium and work as immune sentinels to probe renal interstitium in search for foreign
antigens. Upon injury, inflammatory stimuli released from the tubular cell enable DC to become
immunogenic towards normally ignored self-antigens. We have recently documented that
albumin is processed, through the concerted action of proximal tubular cells and DCs, in
immunogenic peptides, thus triggering an immune response (JASN 20:223,2009). Proximal
tubular cells in culture exposed to excess autologous albumin, as in case of proteinuric
conditions, cleave albumin in the N terminal fragments the most abundant being the 24aminoacid peptide (Alb1-24). This peptide is taken up by DCs and digested, by a proteasomedependent pathway, to antigenic peptides that bear binding motifs for MHC class I and activate
syngeneic CD8+ T cells. The functional role of Alb1-24 processing in inducing immune
response was further confirmed in a rat model of proteinuria secondary to renal mass reduction
(RMR) by 5/6 nephrectomy. Four weeks after surgery, DCs decreased in the kidney and
increased in the renal lymph node, suggesting migration of DCs from the renal interstitium.
CD8+ T cells isolated from renal lymph nodes from RMR rats were already activated at the first
encounter, when incubated with Alb1-24 pulsed DC, suggesting that they were primed by
albumin peptide in vivo during the course of the disease. By contrast, in vivo treatment with the
proteasome inhibitor bortezomib prevented T cell activation. As follow-up of the study, we
sought to evaluate the presence of Alb1-24 in the kidney of rats with overt proteinuria using a
new technique, the imaging mass spectrometry that allows simultaneous analysis in the tissue of
hundreds of different molecules including peptides/proteins. To this end, we started a
collaboration with the Protein Chemistry/Proteomics Unit, Institute of Biomedicine,
Biomedicum in Helsinki within the EUROKup (Urine and Kidney Proteomics), a multidisciplinary network from 26 European countries, who is focused on facilitating translational
proteomic research in kidney diseases, by promoting interactions between basic scientists and
clinicians. Kidney sections from RMR rats analyzed by MALDI (matrix-assisted laser
desorption/ionization) imaging mass spectrometry showed the presence of a peptide with an
average monoisotopic molecular mass corresponding with the predicted mass of Alb1-24 within
and in proximity of the tubular epithelium.
Laboratory of Biomedical Technologies
Remission Clinic Network
Many forms of chronic kidney diseases progress with a constant rate of renal function loss
towards the end stage renal disease (ESRD). These forms of kidney disease are frequently
associated with arterial hypertension and urine proteins, known as aggravating factors in the
progression of the disease. Controlled clinical trials have demonstrated that specific treatments
of hypertension with drugs that reduce the urinary excretion of proteins (ACE-inhibitors) are
effective in reducing the rate of decline of GFR and even in obtaining stabilization or recovery
of renal function allowing to delay the start of dialysis or the need of kidney transplant in
subjects with chronic kidney disease.
In collaboration with the Renal Department we have started a quality control and monitoring
programme of patients affected by proteinuric nephropathies (Remission Clinic protocol) aimed
at verifying whether GFR improvement might be obtained in routine clinical practice as well.
Our laboratory developed a web-based application and established a network of specialists
involved in the treatment of chronic progressive nephropathies distributed nationally
(http://clinicalweb.marionegri.it/remission). Our tool offers computer support to medical
specialists from all participating centers to gather, extract and analyze real time clinical data for
patients with chronic kidney diseases treated according to the guidelines of Remission Clinic
protocol. In addition, our tool allows real time analyses and quality controls of this clinical
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activity to assess in what extent adherence to the protocol may itself slow the progression of
nephropathy in time.
KDDC – a centre for data collection and surveillance of prevention
programs on non-communicable chronic diseases in emerging countries
Chronic kidney diseases are emerging as a global threat to human health. Prevalence and
incidence of renal diseases in developing countries are not known, and this is an obstacle to the
adoption of preventive measures. Prevention is the only hope for these countries where
treatment options for end stage renal failure are simply not available to the vast majority of the
population because of their costs.
The International Society of Nephrology (ISN), through the Commission for Global
Advancement of Nephrology (COMGAN), has established a research committee in order to face
the problem of prevention of kidney diseases in developing countries. The coordination of the
team and intervention programs was committed to the Mario Negri Institute for
Pharmacological Research at the Clinical Research Centre “Aldo e Cele Daccò”. The general
aim of the project is to define programs in developing countries to identify those subjects who
are at risk of developing a renal disease later in life, in order to design a prevention strategy on
national basis by means of interventions of the local ministries of health to governmental and
financial level. The Kidney Disease Data Centre (KDDC) established in our Laboratory, is
dedicated to data management for the prevention programs underway in emerging countries. We
have set up an a tool to collect clinical data from different centres located world-wide
(http://comgan.marionegri.it). Data are stored in a dedicated server in our Laboratory. Results of
our epidemiological analyses, shared also with medical staff of the centre, allow us to have a
general overview on the health of population under study. The prevention programme has
started in 2006 and today KDDC owns more than 45,000 records of subjects from 15 countries
located all over the world. Recently we have published the results of a screening on over 10.000
subjects from Nepal, India and Mongolia showing the burden of chronic diseases in these
countries and demonstrating the feasibility of the ISN prevention programme. Through the
activity of KDDC it is thus possible to monitor the course of the actual screening projects, to
tailor them to the specific needs of each participating country, and even more important to
commence follow-up programs in low income countries.
Development of computerized systems for controlled clinical trials
Numerous clinical trials are conducted in the Clinical Research Center for Rare Diseases “Aldo
e Celè Daccò”. These studies must be carried out in accordance with all regulatory requirements
(GCP, EMEA, FDA). Every clinical study requires a paper case report form (CRF) for
collection of patients’ clinical observations. These data must be verified for inconsistency by
dedicated monitoring staff, and then recorded electronically. In our Lab we have developed
applications tailored for data management of clinical studies using relational databases systems
(RDBMS) and specific programs aimed to data elaboration, validation and extraction for
subsequent statistic analyses. For the DEMAND study we have developed an innovative
electronic CRF based on laptop computers. We have implemented also a web-based framework
for electronic data capture and clinical data management for clinical trials. Thus, recently we
have set-up a dedicated portal (http://clintrials.marionegri.it) as a show-case for the clinical
trials conducted at the Clinical Research Center “Aldo e Cele Daccò” and a platform for the new
web-based e-CRFs developed in our Lab.
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Data Management for the Registry for Rare Disease - Lombardy
Our laboratory contributes to the management of the Regional Network for Rare Diseases of
Lombardy. We are directly involved for the development and maintenance of the web site of the
centre and management of a regional Registry for Rare Diseases. We have set-up the databases
and developed related web-pages for centres, rare diseases archive, patient associations and
congenital rare diseases. These are published on the homepage of the web-site
(http://malattierare.marionegri.it/).
The Registry for Rare Diseases was born in 2007 as a collaboration between Mario Negri
Institute, Lombardia Informatica (LI) and Regione Lombardia. The aim was to create a regional
registry for rare diseases where all medical staff from Lombardy could register information
regarding rare diseases. The application (Sistema Malattie Rare - SMR) is actually in use in
almost all centres dedicated for rare diseases in Lombardy and can be used jointly with the
patient health card.
Hemodynamics and vascular pathology
During the last ten years the presence of a close relationship between hemodynamics and
vascular pathology has been pointed out both in the biological and in the clinical field. Typical
fields of application are the investigation of the formation of atherosclerotic lesions in the
arterial circulation, of intracranial and abdominal aneurysm disease, and of the effect of surgical
and endovascular procedures. Thanks to innovative technologies developed during the last few
years in the medical imaging and mathematical modeling fields, also within the Biomedical
Engineering Department, it is now possible to accurately reproduce patient-specific
hemodynamic force distribution from computed tomography (CT) or magnetic resonance (MR)
acquisitions. Within the Department of Biomedical Engineering such technologies have three
main applications: atherosclerosis (carotid bifurcation and renal artery level), intracranial
aneurysm disease and complications of vascular access in hemodialysis. In particular, the
Department is currently involved in an international collaborative project (ARCH) funded by
the European Commission within the Seventh Framework Programme, aimed at improving the
functionality of vascular access in hemodialysis patients, for which the Department is the
coordinator centre. Within this project, computational tools for predicting post-operative from
pre-operative scenario, aimed to help clinicians to plan for each patient the most suitable
vascular access, are under development and validation.
Theoretical and experimental study of filtration of 'albumin in the kidney
Since years the Department have been studied the mechanisms responsible for glomerular
filtration of proteins, and in particular, albumin. Recently, we have been dedicated to the
theoretical modelling of filtration of albumin and of its concentration in the renal tubule by
combining the experimental approach to the theoretical modelling. In an experimental model of
nephropathy, we studied the selective properties of the glomerular membrane through infusion
of specific fluorescent tracers and changes in albumin concentration in the glomerular filtration.
Applying some mathematical models we evaluated the effect of the administration of an ACE
inhibitor on the distribution of the membrane pores and the reabsorption of albumin in the
tubules.
The combination of the experimental approach with the theoretical modelling allowed us to
elucidate an aspect of the renal pathophysiology which is still not highlighted such as the
quantification of albumin concentration along the nephron either in normal and in pathological
conditions.
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Imaging of glomerular filtration slit ultrastructure
In collaboration with the Department of Molecular Medicine. The glomerular capillary wall
allows an important filtration of pleasure water but efficiently retains circulating proteins and
macromolecules. This selective function is mainly due to the specific ultrastructure of the
intercellular junction of the visceral epithelial cells, the podocytes, that allow water passage but
retain macromolecules with radius greater than 4nm. The study on the morphology of this
cellular junction are based essentially on very few observations of TEM done in the ‘70s, who
suggested a zipper-like structure of the filtration slits, with openings smaller than 4nm. The
inconsistency of these observations and the use of a new setup of a scanning electron
microscope (SEM) allowed us to study in detail the ultrastructure of the filtration slits in
physiological and in pathological conditions. The results are interesting since they disclosed a
completely new ultrastructure of the pores of the epithelial filtration slits, and their dimensions.
Imaging and quantification in renal physiopathology
The use of imaging techniques such as CT, MR, and echography, and the application of
advanced image processing tools make it possible to perform non-invasive in-vivo quantitative
analysis of biological phenomena. Within the Department of Biomedical Engineering, this
approach is applied to the investigation of renal physiopathology. Through CT and MR imagebased quantification, new therapies for autosomal dominant polycystic kidney disease
(ADPKD) are currently being evaluated. To this purpose, the Medical Imaging Unit has been
involved in several clinical trials, some of which still ongoing, one funded by the Polycystic
Kidney Foundation, aimed at reducing the overall kidney cyst volume with the use of novel
therapies. Using specific automatic algorithms, it has been possible to quantify on contrastenhanced CT images the volume of individual tissue components (cysts and residual
parenchyma), beyond total kidney volume only. Moreover, CT image quantification has
recently led to the discovery of a fibrotic tissue component (named intermediate volume),
highly correlated with both renal function and disease progression rate, showing for the first
time a likely direct relationship between structure and function, thus opening the way to new
therapeutic targets.
Beyond ADPKD studies, new methodologies for noninvasive characterization of renal
functionality from diffusion-weighted MR images are currently under study. Preliminary studies
on normal control subjects showed high resolution of the images and high reproducibility of the
measures, indicative of both renal perfusion and diffusion mechanisms, pointing out the
potential of DWI for the investigation of renal physiopathology.
Development of biomedical image analysis and computational modelling
tools
The employment of quantitative imaging and mathematical modeling techniques aimed at the
study of physiopathological processes is directly linked to medical image management and
processing methodologies. Within the Department, research activity related to the development
of new image processing algorithms and mathematical models for the numerical simulation of
biological phenomena, both theoretical and in terms of software development, is actively
performed. The department contributes to the development of three main open-source projects
in the biomedical imaging field: Vascular Modeling Toolkit (www.vmtk.org), as main
developer, Insight Toolkit (www.itk.org), a state-of-the-art library for medical image analysis,
and Slicer 3D (www.slicer.org), one of the main medical imaging applications. The Department
is directly involved in the development activities carried out within the National Alliance for
Medical Image Computing, an inter-university consortium gathering the main academic
institutions of the United States.
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Development of devices for the transplantation of immunoisolated islets
The project’s main objective is to develop an immunisolation device for pancreatic islets or
insulin producing cells that can be implanted in diabetic rats and to test the efficacy and in vivo
resistance of the device. We have defined the most suitable geometry for an immunoisolation
device providing large surface area in a small volume. We have developed a device made using
parallel arrays of hollow fibers or a membrane device in the form of small coins. The device that
we are developing can be implanted with minimally invasive surgical procedures and easy to
retry. We have also developed a method for subcutaneous implantation as alternative site for
transplantation. We are tested different types of material to be used as polysulfone hollow fiber
or membranes of polyvinyl alcohol. The aims of our studies in the next months will be to
improve functionality using nanotechnologies for materials characterization. Moreover we will
develop new kinds of device and we will test new implantation sites.
Effect of pancreatic islet transplantation on diabetic complications
Diabetes type 1 is taking place as one of the most important worldwide public health problems
with a high morbidity and mortality. Diabetes is associated with increased risk of a number of
microvascular, neurologic and macrovascular complications due to poor glycemic control. The
aim of this project is to evaluate whether the transplantation of pancreatic islets can induce
regression of diabetic complications in a model of allotransplantation in rats with chemically
induced diabetes. For this study, we used four groups of rats: healthy controls, diabetics,
diabetics with transplanted islet four months after induction of diabetes and diabetics treated
with insulin to adjust glycemia under 200 mg/dl. Transplantation of islet induces a lowering of
blood glucose within a few days after transplantation, accompanied by an increase in body
weight. All the neurological parameters, such as the behavioral tests for determination of
thermal and mechanical nociceptive threshold and the measurement of nerve conduction
velocity in the nerves of the tail (NCV) observed in diabetic rats significantly ameliorate in
transplanted rats. Insulin treated rat group show similar improvement of the above described
parameters. In conclusion, the transplantation of pancreatic islets not only normalizes blood
glycemia levels in diabetic animals, but also reduce the neuropathy getting worse
Development of a protocol for kidney decellularization
Kidney tissue engineering applies the principles and methods of engineering to biological
sciences in an attempt to completely regenerate damaged renal tissues affected by chronic
nephropathy. This innovative strategy could solve problems related to dialysis therapies and
overcome toxicity of immunosuppressive drugs for organ transplantation. The aim of this
project is is to generate a biological and active support with the inherent ability to promote the
growth, the proliferation and the differentiation of multipotent embryonic stem cells into
glomerul, tubular and vascular renal cells. To this purpose we have developed a device includes
a roller pump, an hydraulic closed circuit and a perfusion cylindric chamber, and provides the
organ with constant physiological flows and pressures to obtain optimal cellular removal and to
maintain the 3D architecture of renal ECM matrix. It represents a helpful operative tool whose
features were experimented with success on rat kidneys. The proposed method consists in the
use of different solutions such as ionic and non-ionic detergents (SDS, Triton X-100), saline,
DNase and final washing with antibiotics and antimicrobials. Decellularization of kidney and
the presence of the extracellular matrix was confirmed by histological and histochemical
analysis. (In collaboration with the Department of Molecular Medicine).
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Vascular tissue engineering
The synthetic vascular grafts are studied for the replacement of large caliber vessels damaged by
pathological events. Currently available synthetic vascular grafts are limited to large internal
diameter grafts because of frequent thrombosis and occlusion. The alternative is represented
from the use of autologous vascular graft, but they are not always available in patients affected
from vascular pathology. Vascular tissue engineering has the objective to generate cellularized
vascular prosthesis made of biodegradable materials that can be colonized by endothelial cells.
For this purpose (in collaboration with Stazione Sperimentale della Seta in Milano and
Politecnico di Milano), we have studied an innovative strategy for the vascular prosthesis
realization using biodegradable material, the fibroin of the silk. Tubular structures were
produced through elettrospinning of the fibrin of the silk, and studies of biocompatibility and
biodegradation in vivo were performed. Tubular matrices (∅=1.8 mm) were implanted in situ in
the abdominal aorta of Lewis rats by end-to-end anastomosis in order to evaluate the
functionality of the graft. The histological analysis, performed on samples explanted after
subcutaneous implantation, showed a thin fibrotic membrane overgrowth around the implant
with cell infiltration in the construct. Immuno-fluorescence analysis demonstrated the presence
of a low number of macrophages and the absence of T lymphocytes. At 5 days after
implantation in abdominal aorta, histological analysis showed vascular tissue neoformation in
the luminal side. This tissue is characterized by the presence of smooth muscolar cells and
organized structures of neoformed elastin reach extracellular matrix. These data confirmed the
regeneration of vascular intima with the presence of smooth muscular cells and elastin,
resembling native arteries. These results indicate the great potential of this artificial structure to
allow the regeneration of the arterial wall intima, with characteristics of biocompatibility
requests to a surface in contact with blood.
The effect of flow on renal tubular cells
ADPKD (Autosomal Dominant Policystic Kidney Disease) is one of the major genetic renal
pathologies with an incidence of 1 in 1000 and it represents the main genetic cause of renal
insufficiency in adult. It is characterized by cysts growth in the tubular segment, which increase
in size and in number throughout an individual's lifetime, that leads to renal failure requiring
dialysis or transplant. This pathology is due to the mutation of two genes:PKD1 and PKD2. The
mutation of PKD1 gene is the most common, and is responsible of the 85% of cases, the gene
encoding for a protein, a membrane receptor, the polycystin 1, which is involved in the
mainteinace of cell/cell or cell/matrix interactions while the PKD2 gene product, polycystin 2,
is a ionic channel.Both the protein are localized in the cilia of renal tubular epithelial cells and
act as a mechanosensory organs. The bending of the cilium, caused by tubular flow, leads to the
activation of the polycystin 1 and to the generation of a peak of intracellular calcium
concentration. This increase in intracellular calcium activates signalling pathways that modify
cellular proliferation and other cellular functions. In pathologic conditions, polycystin
modification impairs the mechanosensitive function of cilia, altering tubular cellular functions.
The aim of this project is the in vitro study of renal tubular cells (MDCK2) in laminar flow
conditions, to investigate the role of mechanical stimulation in the pathology development.
Preliminary results showed that the application of a constant laminar flow to MDCK2 causes a
different tridimensional organization of the cellular layer, as compared to static control.
Furthermore, the inhibition of intracellular calcium increase impairs this reorganization when
flow is applied.
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LABORATORY OF BIOLOGY AND
THERAPY OF METASTASIS*
STAFF
Head
Raffaella GIAVAZZI, Biol.Sci.D., Ph.D.
Head
Giulia TARABOLETTI, Biol.Sci.D.
* Research activities of this Laboratory are listed in the Department of Oncology section (pag. 7)
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Aldo and Cele Daccò Center
Ranica (Bg)
ANNUAL
REPORT 2010
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DEPARTMENT OF RENAL MEDICINE
STAFF
Head
Piero RUGGENENTI, M.D.
Laboratory of Biostatistics
Head
Annalisa PERNA, Stat.Sci.D.
Laboratory of Coordination and Conduction of Controlled Clinical Trials
Head
Giulia GHERARDI, Res.N.
Unit of Drug Monitoring
Head
Nadia RUBIS, Res.N.
Laboratory of Pharmacokinetics and Clinical Chemistry
Head
Flavio GASPARI, Chem.D.
Laboratory of Advanced Development of Drugs
Head
Norberto PERICO, M.D.
Unit of Early Clinical Evaluation of Drugs
Head
Aneliya ILIEVA PARVANOVA, M.D.
Laboratory of Clinical Pathophysiology of Renal Disease and
Transplantation
Head
Paolo CRAVEDI, M.D., PhD.
Laboratory of Regulatory Affairs for Clinical Studies
Head
Paola BOCCARDO, Bio.Sci.D.
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CURRICULA
Piero Ruggenenti got his Medicine degree in 1983 at the University of Milan, Italy; he got his
specialization in Cardiology in 1985 and in Clinical Nephrology in 1989 at the same University; he
specialized in Pharmacological Research in 1988 at IRFMN.
Educational training: in 1980-1983 researcher at "Centro di Fisiologia Clinica e Ipertensione, Clinica
Medica IV", Università degli Studi di Milano; in 1984 Researcher at IRFMN, Bergamo, Italy in 19871988 Honorary Registrar of the Unit for Metabolic Medicine, Division of Medicine (University of
London) of Guy's and St. Thomas's Hospitals, London; in 1988-1989 Assistant Professor of the Division
of Nephrology and Dialysis of the Ospedali Riuniti di Bergamo.
Areas of interest: mechanisms of chronic renal disease progression, diabetes and diabetic complications,
clinical transplantation, thrombotic microangiopathies, cardiovascular complications of chronic renal
disease, clinical trials, clinical pharmacology.
Employment: from 1990 Assistant Professor of the Division of Nephrology and Dialysis of the
Ospedali Riuniti di Bergamo; in 1994-1999 Head, Unit of Advanced Development of Drugs, Daccò
Center, Ranica, Bergamo, Italy; since 2000 Head, Department of Renal Medicine, Daccò Center,
Bergamo, Italy.
• Ruggenenti P, Fassi A, Parvanova Ilieva A, Petrov Iliev I, Chiurchiu C, Rubis R, Gherardi G, Ene-Iordache B, Gaspari G,
Perna A, Cravedi P, Bossi A, Trevisan R, Motterlini N, Remuzzi G, for the BENEDICT-B Study Investigators. Effects of
verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B
randomized trial. J Hypert. In press.
• Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherardi G, Orisio S, Remuzzi G. Ameliorating hypertension
and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension, 2009
Sep; 54(3): 567-74.
• Remuzzi G, Cravedi P, Perna A, Dimitrov BD, Turturro M, Locatelli G, Rigotti P, Baldan N, Beatini M, Valente U,
Scalamogna M, Ruggenenti P Dual Kidney Transplant Group. Long-term outcome of renal transplantation from older
donors. N Engl J Med, 2006; 354: 343-352.
• Ruggenenti P, Fassi A, Parvanova A, Bruno S, Iliev I, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache
B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G for the Bergamo Nephrologic Diabetes Complications
Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med, 2004; 351: 1941-1951.
• Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, Gherardi G, Donati D, Salvadori M, Sandrini S,
Valente U, Segoloni G, Mourad G, Federico S, Rigotti P, Sparacino V, Bosmans JL, Perico N, Ruggenenti P. Mycophenolate
mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. Lancet,
2004 Aug 7-13; 364 (9433): 503-12.
• Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P. Rituximab for idiopathic membranous
nephropathy. Research Letter. Lancet, 2002; 360: 923-924.
• Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective
properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet ,1999; 354: 359-364.
Paola Boccardo got her classic High School Diploma in 1979 and the Biol. Sci. Degree at the University
of Pisa in 1985. In 1987 she passed the qualifying examination and got the license of Biologist.
Educational training: she performed her training first at Mutagenesis and Differentiation Institute, CNR,
of Pisa, and then at Mario Negri Institute for Pharmacological Research, where in 1990, got her diploma
of “Specialist in Pharmacological Research”. Since 1987 has been working as full-time researcher at
Mario Negri Institute, till 1995 at Molecular Medicine Department and then at Renal Medicine
Department.
Area of interest: since 1995 she is in charge of Regulatory Affairs and attends to the planning, organizing
and conducting of clinical studies in accordance with the principles of Good Clinical Practice and with
the laws in force.
Employment: since June 2006 to October 2009 Responsible of Clinical Trials Office; since November
2009 Head, Laboratory of Regulatory Affairs for Clinical Studies. Member of Internal Staff for Security,
since May 2008 she is Security Manager at Clinical Research Center for Rare Diseases Aldo e Cele
Daccò.
• Perico N, Delaini F, Lupini C, Benigni A, Galbusera M, Boccardo P, Remuzzi G. Blunted excretory response to atrial
natriuretic peptide in experimental nephrosis. Kidney Int, 1989; 36: 57-64.
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Benigni A, Perico N, Dadan J, Gabanelli M, Galbusera M, Boccardo P, Mennini T, Remuzzi G. Functional implications of
decreased renal cortical ANP binding in experimental diabetes. Circ Res, 1990; 66: 1453-60.
Benigni A, Boccardo P, Noris M, Remuzzi G, Siegler RL. Urinary excretion of platelet-activating factor in hemolytic uremic
syndrome. Lancet, 1992; 339: 835-6.
Noris M, Benigni A, Boccardo P, Aiello S, Gaspari F, Todeschini M, Figliuzzi M, Remuzzi G. Enhanced nitric oxide
synthesis in uremia: implications for platelet dysfunction and dialysis hypotension. Kidney Int, 1993; 44: 445-450.
Benigni A, Boccardo P, Galbusera M, Monteagudo J, De Marco L, Remuzzi G, Ruggeri ZM. Reversible activation defect of
the platelet glycoprotein IIb-IIIa complex in patients with uremia. Am J Kidney Dis, 1993; 22: 668-676.
Boccardo P, Noris M, Remuzzi G. Prevention and therapeutic management of bleeding in dialysis patients. In: Dialysis
Therapy, 3rd edition. Edited by Nissenson A.R., Fine R.N. Hanley & Belfus, Inc., Philadelphia 2001; 3: 190-194.
Remuzzi G, Galbusera M, Boccardo P. Disorders of hemostasis in dialysis patients. In: Heinrich, W.L. Ed. Principles and
Practice of Dialysis, 4th ed. Philadelphia, PA: Lippincot W & W, 2009.
Paolo Cravedi got his Medicine degree (cum laude) in 1999 at the University of Milan, Italy; he got his
specialization in Nephrology (cum laude) in 2004 at the University of Parma. In 2009 got a Ph.D. degree
from the Open University of London.
Educational training: in 2005 Master on Organ Transplant at the University of Milano Bicocca; in 2006
researcher at the Mario Negri Institute, Bergamo; since 2007 to 2008 Research Fellow at the Transplant
Branch of the National Institutes of Health (NIH) (Mentor Dr. Roslyn Mannon); since 2009 researcher at
the Mario Negri Institute, Bergamo.
Areas of interest: mechanisms of chronic renal disease progression, diabetes and diabetic complications,
clinical transplantation, membranous nephropathy, clinical pharmacology.
Employment: since 2010, Head Laboratory of Clinical Pathophysiology of Renal Disease and
Transplantation.
• Remuzzi G, Cravedi P, Perna A, Dimitrov BD, Turturro M, Locatelli G, Rigotti P, Baldan N, Beatini M, Valente U,
Scalamogna M, Ruggenenti P Dual Kidney Transplant Group. Long-term outcome of renal transplantation from older
donors. N Engl J Med, 2006; 354: 343-352.
• Cravedi P, Ruggenenti P, Remuzzi G. Sirolimus to replace calcineurin inhibitors? Too early yet. Lancet, 2009; 373:1235-6.
• Ruggenenti P, Cravedi P, Sghirlanzoni MC, Gagliardini E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G. Effects
of rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol, 2008; 3: 1652-9.
• Cravedi P, Ruggenenti P, Sghirlanzoni MC, Remuzzi G. Titrating rituximab to circulating B cells to optimize
lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol, 2007; 2: 932-7.
• Remuzzi G, Cravedi P, Costantini M, Lesti M, Ganeva M, Gherardi G, Ene-Iordache B, Gotti E, Donati D, Salvadori M,
Sandrini S, Segoloni G, Federico S, Rigotti P, Sparacino V, Ruggenenti P. Mycophenolate mofetil versus azathioprine for
prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical
trial. J Am Soc Nephrol, 2007; 18: 1973-85.
Flavio Gaspari got his Chemistry degree in 1977 at the University of Milano, Italy, and the
specialization in the same University in 1979.
Educational training: in 1981-1985 Fellow and Researcher at IRFMN, Milan; in 1985-1991 at IRFMN,
Bergamo, Italy.
Areas of interest: pharmacokinetics and the metabolism of xanthines in different animal species; drug
pharmacokinetics in uremic patients and in subjects with different degrees of renal function; analytical
methods to measure the most important immunosuppressive drugs to determine their pharmacokinetics in
kidney, heart, and liver transplant recipients; evaluation of the renal function by using different
approaches, in the study of renal disease progression, and in the comparison of different methods for
albuminuria determination.
Employement: he is Head of Laboratory of Pharmacokinetics and Clinical Chemistry since January 2000
and he was Head of this Unit since 1991.
• Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, Ondei P, Rubis N, Diadei O, Gherardi G, Prandini S,
Panozo A, Flores Bravo R, Carminati S, Rodriguez De Leon F, Gaspari F, Cortinovis M, Motterlini N, Ene-Iordache B,
Remuzzi A, Remuzzi G. Sirolimus therapy to halt the progression of ADPKD. JASN 2010; 21: 1031-1040.
• Gaspari F, Cravedi P, Mandalà M, Perico N, de Leon FR, Stucchi N, Ferrari S, Labianca, R, Remuzzi G, Ruggenenti P.
Predicting Cisplatin-Induced Acute Kidney Injury by Urinary Neutrophil Gelatinase-Associated Lipocalin Excretion: A Pilot
Prospective Case-Control Study. Nephron Clin Pract 2010;115:c154-c160.
• Ruggenenti P, Perna A, Tonelli M, Loriga G, Motterlini N, Rubis N, Ledda F, Rota S Jr, Satta A, Granata A, Battaglia G,
Cambareri F, David S, Gaspari F, Stucchi N, Carminati S, Ene-Iordache B, Cravedi P, Remuzzi G; for the ESPLANADE
Study Group. Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual ReninAngiotensin System Blockade: The ESPLANADE Trial. Clin J Am Soc Nephrol. 2010; 5:1928-38.
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Perico N, Zoja C, Corna D, Rottoli D, Gaspari F, Haskell L, Remuzzi G. V1/V2 Vasopressin receptor antagonism potentiates
the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction. Kidney Int, 2009 Nov; 76(9): 9607.
Ruggenenti P, Cravedi P, Sghirlanzoni MC, Gagliardini E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G. Effects of
rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol, 2008 Nov; 3(6):
1652-9.
Gotti E, Perico N, Gaspari F, Cattaneo D, Lesti MD, Ruggenenti P, Segoloni G, Salvadori M, Rigotti P, Valente U, Donati D,
Sandrini S, Federico S, Sparacino V, Mourad G, Bosmans JL, Dimitrov BD, Iordache BE, Remuzzi G. Blood cyclosporine
level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing
Trial. Transplant Proc, 2005 Jun; 37(5): 2037-40.
Perico N, Gaspari F, Remuzzi G. Assessing renal function by GFR prediction equations in kidney transplantation. Am J
Transplant, 2005 Jun; 5(6): 1175-6.
D. Cattaneo, F. Gaspari, S. Zanoni, S. Baldelli, E.Gotti, A. Perna, N. Perico, G. Remuzzi. Two-hour post-dose cyclosporine
monitoring does not fit all in kidney transplantation. Therapy, 2005; 2: 95-105.
Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache
B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabetes Complications Trial
(BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med, 2004 Nov 4; 351 (19): 1941-51.
Gaspari F, Ferrari S, Stucchi N, Centemeri E, Carrara F, Pellegrino M, Gherardi G, Gotti E, Segoloni G, Salvadori M, Rigotti
P, Valente U, Donati D, Sandrini S, Sparacino V, Remuzzi G, Perico N; MY.S.S. Study Investigators. Performance of
different prediction equations for estimating renal function in kidney transplantation. Am J Transplant, 2004 Nov; 4 (11):
1826-35.
Giulia Gherardi got her Scientific High School Diploma in 1989 at the Liceo Scientifico Marie Curie in
Zogno (Bergamo), the Nurse Diploma in 1995 at the Scuola per Infermieri Professionali, Ospedali
Riuniti, Bergamo and the 1st Level Master in Clinical Research in 2008 at the Medicine and Surgery
Faculty of the University in Milan.
Educational training: Clinical Research Nurse Diploma on 1997 at IRFMN –Daccò Center.
Areas of interest: statistical methodology of long-term randomised clinical trials in nephrology, and
diabetology; the coordination, conduction and monitoring of controlled clinical trials.
Employement: in 1997-2003 involved as co-organizing, speaker, co-speaker and tutor for the Clinical
Research Course for Nurse at IRFMN – Daccò Center (Ranica – Bergamo). Several training activities for
Nurses in Clinical Research area. In 1997-1999, Clinical Research Monitor at IRFMN – Daccò Center; in
2000-2008 Head of the Monitoring Drug Unit at IRFMN – Daccò Center. Since 2009 Head of the
Laboratory of Coordination and Conduction of Controlled Clinical Trials at IRFMN – Daccò Center.
• Ruggenenti P, Fassi A, Parvanova Ilieva A, Petrov Iliev I, Chiurchiu C, Rubis R, Gherardi G, Ene-Iordache B, Gaspari G,
• Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, Ondei P, Rubis N, Diadei O, Gherardi G, Prandini S,
Panozo A, Bravo RF, Carminati S, De Leon FR, Gaspari F, Cortinovis M, Motterlini N, Ene-Iordache B, Remuzzi A,
Remuzzi G. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol. 2010 Jun; 21(6): 1031-40.
• Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherardi G, Orisio S, Remuzzi G. Ameliorating hypertension
and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension, 2009
Sep; 54 (3): 567-74.
• Remuzzi G, Cravedi P, Costantini M, Lesti M, Ganeva M, Gherardi G, Ene-Iordache B, Gotti E, Donati D, Salvadori M,
Sandrini S, Segoloni G, Federico S, Rigotti P, Sparacino V, Ruggenenti P. Mycophenolate mofetil versus azathioprine for
prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial.
J Am Soc Nephrol, 2007 Jun; 18 (6): 1973-85.
• Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache
B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabetes Complications Trial
(BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med, 2004 Nov 4; 351 (19): 1941-51.
• Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, Gherardi G, Donati D, Salvadori M, Sandrini S,
Valente U, Segoloni G, Mourad G, Federico S, Rigotti P, Sparacino V, Bosmans JL, Perico N, Ruggenenti P. Mycophenolate
mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. Lancet,
2004 Aug 7-13; 364 (9433): 503-12.
• Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: outcomes and response to
treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis, 2000 Jun; 35 (6):
1155-65.
• Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective
properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet, 1999 Jul 31; 354 (9176):
359-64.
• Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for dialysis in chronic
nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia
(GISEN). Ramipril Efficacy in Nephropathy. Lancet, 1998 Oct 17; 352 (9136): 1252-6.
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Norberto Perico got his Medicine degree in 1983 at the University of Milano, Italy. He got his
specialization in Pharmacological Research in 1986 at IRFMN, Bergamo and in Clinical Nephrology in
1989 at the University of Verona, Italy.
Educational training: in 1982 Fellow, Department of Pharmacology, New York Medical College,
Valhalla, New York, USA; in 1984-1988 Post Doctoral Fellow, Laboratory of Kidney Diseases, IRFMN,
Bergamo, Italy; in 1988-1989 Researcher in the same laboratory.
Areas of interest: pathophysiology and pharmacology of cyclosporine nephrotoxicity; new
immunosuppressive strategies to prevent renal graft rejection; innovative approach to induce tolerance to
organ transplantation; mechanism(s) and management of progression of chronic renal diseases.
Employment: in 1990-1994 Head, Renal Physiology Unit, Laboratory of Kidney Diseases, IRFMN,
Bergamo, Italy; in 1990-2000 Assistant Professor, Division of Nephrology and Dialysis, Ospedali Riuniti
di Bergamo, Italy; in 1994 –1999 Head, Laboratory of Transplant Immunology, IRFMN, Bergamo, Italy;
from January 2000 Head, Laboratory of Drug Development, Department of Renal Medicine, IRFMN,
Bergamo, Italy; from September 2000 Health Director, Daccò Center, IRFMN, Bergamo, Italy. From
October 2002 he’s Member, ISN-COMGAN Research Committee of the International Society of
Nephrology.
• Dahlke MH, Hoogduijn M, Eggenhofer E, Popp FC, Renner P, Slowik P, Rosenauer A, Piso P, Geissler EK, Lange C,
Chabannes D, Mazzanti B, Bigenzahn S, Bertolino P, Kunter U, Introna M, Rambaldi A, Capelli C, Perico N, Casiraghi F,
Noris M, Gotti E, Seifert M, Saccardi R, Verspaget HW, van Hoek B, Bartholomew A, Wekerle T, Volk HD, Remuzzi G,
Deans R, Lazarus H, Schlitt HJ, Baan CC; MISOT Study Group. Toward MSC in solid organ transplantation: 2008 position
paper of the MISOT study group. Transplantation, 2009 Sep 15; 88 (5): 614-9.
• Cattaneo D, Cortinovis M, Baldelli S, Gotti E, Remuzzi G, Perico N. Limited sampling strategies for the estimation of
sirolimus daily exposure in kidney transplant recipients on a calcineurin inhibitor-free regimen. J Clin Pharmacol, 2009 Jul;
49 (7): 773-81.
• Cattaneo D, Ruggenenti P, Baldelli S, Motterlini N, Gotti E, Sandrini S, Salvadori M, Segoloni G, Rigotti P, Donati D, Perico
N, Remuzzi G; Mycophenolate Steroids Sparing (MYSS) Genetics Study Group. ABCB1 genotypes predict cyclosporinerelated adverse events and kidney allograft outcome. J Am Soc Nephrol, 2009 Jun; 20 (6): 1404-15.
• Perico N, Bravo RF, De Leon FR, Remuzzi G. Screening for chronic kidney disease in emerging countries: feasibility and
hurdles. Nephrol Dial Transplant, 2009 May; 24 (5): 1355-8.
• Perico N, Benigni A, Remuzzi G. Present and future drug treatments for chronic kidney diseases: evolving targets in
renoprotection. Nat Rev Drug Discov, 2008 Nov; 7 (11): 936-53.
• Ruggenenti P, Perico N, Gotti E, Cravedi P, D'Agati V, Gagliardini E, Abbate M, Gaspari F, Cattaneo D, Noris M, Casiraghi
F, Todeschini M, Cugini D, Conti S, Remuzzi G. Sirolimus versus cyclosporine therapy increases circulating regulatory T
cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury.
Transplantation, 2007 Oct 27; 84 (8): 956-64.
• Baldelli S, Merlini S, Perico N, Nicastri A, Cortinovis M, Gotti E, Remuzzi G, Cattaneo D. C-440T/T-331C polymorphisms
in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics, 2007
Sep; 8 (9): 1127-41.
Annalisa Perna got her Statistical Sciences degree in 1984 at the University of Bologna, Italy.
Educational training: She completed her research training at IRFMN, Bergamo Labs. and at the Daccò
Center.
Areas of interest: statistical methodology of long-term randomised clinical trials in nephrology, statistical
methods for calculating sample size and for meta-analytic techniques. She is also involved in performing
systematic reviews for the Cochrane Collaboration – Renal Review Group.
Employment: she is Head of the Laboratory of Biostatistics - Department of Renal Medicine at Daccò
Center, Ranica (Bergamo).
• Ruggenenti P, Iliev I, Filipponi M, Tadini S, Perna A, Ganeva M, Ene-Iordache B, Cravedi P, Trevisan R, Bossi, and
Remuzzi G. Effect of Trandolapril on Regression of Retinopathy in Hypertensive Patients with Type 2 Diabetes: A PreSpecified Analysis of the Benedict Trial, Journal of Ophthalmology, 2010; 2010:106384. Epub 2010 Jun 10.
• Ruggenenti P, Cattaneo D, Rota S, Iliev I, Parvanova A, Diadei O, Ene-Iordache B, Ferrari S, Bossi AC, Trevisan R, Belviso
A, Remuzzi G; for the Ezetimibe and Simvastatin in Dyslipidemia of Diabetes (ESD) Study Group. Effects of combined
ezetimibe and simvastatin therapy as compared with simvastatin alone in patients with type 2 diabetes: a prospective
randomized double-blind clinical trial. Diabetes Care. Sep;33(9):1954-6, 2010.
• Ruggenenti, P, Perna, A, Remuzzi, G. Effects of combined ezetimibe and simvastatin therapy as compared to simvastatin
alone in patients with type 2 diabetes: a prospective, randomized, double-blind, clinical trial. Diabetes Care: e133; 2010.
• Ruggenenti P, Perna A, Tonelli M, Loriga G, Motterlini N, Rubis N, Ledda F, Rota S Jr, Satta A, Granata A, Battaglia G,
Cambareri F, David S, Gaspari F, Stucchi N, Carminati S, Ene-Iordache B, Cravedi P, Remuzzi G; for the ESPLANADE
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•
•
Study Group. Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual ReninAngiotensin System Blockade: The ESPLANADE Trial. Clin J Am Soc Nephrol. Nov;5(11):1928-38, 2010.
Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, Ondei P, Rubis N, Diadei O, Gherardi G, Prandini S,
Panozo A, Bravo RF, Carminati S, De Leon FR, Gaspari F, Cortinovis M, Motterlini N, Ene-Iordache B, Remuzzi A,
Remuzzi G. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol. Jun;21(6):1031-40, 2010.
Ruggenenti P, Fassi A, Parvanova Ilieva A, Petrov Iliev I, Chiurchiu C, Rubis R, Gherardi G, Ene-Iordache B, Gaspari G,
Aneliya Parvanova Ilieva got her Medical Doctor degree at the Faculty of Medicine, Thracian
University (former Higher Medical Institute), Stara Zagora, Bulgaria in 1988, and the specialization in
Pharmacology in Department of Pharmacology, University of Medicine, Sofia in 1992. Her medical
degree is recognized in Italy in 2009.
Educational training: in 1989-1998 teaching of 3rd, 4th and 5th-year medical students and 2nd and 3rd-year
clinical nurses in a general pharmacology and clinical pharmacology, Thracian University, Stara Zagora,
Bulgaria; examiner of these students in theoretical and practical, oral and written exams and tests and
State examination. In 1993 Course on investigation of isolated organs – Bulgarian Academy of Sciences,
Sofia. In 1998 visiting scientist, IRFMN, Ranica, Bergamo, Italy. In 1998 proficiency in the methods for
insulin sensitivity evaluation (hyperinsulinemic euglicaemic clamp technique), in renal hemodynamic
measurements - glomerular filtration rate (plasma clearance of iohexol and inulin), in renal plasma flow
(plasma clearance of para-aminohippuric acid), glomerular size selectivity (plasma clearance of neutral
dextrans) and in twenty four-hour blood pressure monitoring.
Areas of interest: primary and secondary prevention of the chronic microvascular diabetic complications
(diabetic nephropathy, diabetic retinopathy and diabetic neuropathy); role of insulin resistance, arterial
hypertension, dyslipidemia and hyperhomocysteinemia in micro- and macrovascular diabetic
complications; possibilities for pharmacological treatment of these pathological conditions.
Employment: she participates as investigator in several clinical studies. She is Head of The Unit of Early
Clinical Evaluation of Drugs at IRFMN since 2000. She is a member of the Union of Bulgarian Doctors
(since 1989), of the Union of Pharmacologists in Bulgaria (since 1990), of the Union of Scientists in
Bulgaria (since 1991), and member of the Union of Medical Doctors and Dentists, Bergamo, Italy (since
05.03.2009).
• Ruggenenti P, Cattaneo D, Rota S, Iliev I, Parvanova A, Diadei O, Ene-Iordache B, Ferrari S, Bossi AC, Trevisan R, Belviso
A, Remuzzi G. Effects of combined ezetimibe and simvastatin therapy as compared with simvastatin alone in patients with
type 2 diabetes: a prospective randomized double-blind clinical trial. Diabetes Care 2010 Sep; 33(9): 1954-6. Epub 2010 Jun
21.
• Vogt L, Chiurchiu C, Chadha-Boreham H, Danaietash P, Dingemanse J, Hadjadj S, Krum H, Navis G, Neuhart E, Parvanova
AI, Ruggenenti P, Woittiez AJ, Zimlichman R, Remuzzi G, de Zeeuw; for the PROLONG (PROteinuria Lowering with
urOteNsin receptor antaGonists) Study Group. Effect of the Urotension Receptor Antagonist Palosuran in Hypertensive
patients with type 2 diabetic nephropathy. Hypertension 2010 May; 55(5): 1206-9. Epub 2010 Mar 15.
• Ruggenenti P, Iliev I, Costa GM, Parvanova A, Perna A, Giuliano GA, Motterlini N, Ene-Iordache B, Remuzzi G. Preventing
left ventricular hypertrophy by ACE inhibition in hypertensive patients with type 2 diabetes: a perspecified analysis of the
Bergamo Nephrologic Diabetes Complications Trial (BENEDICT). Diabetes Care, 2008 Aug; 31 (8): 1629-34.
• Parvanova A, Trevisan R, Iliev I, Dimitrov BD, Vedovato M, Tiengo A, Remuzzi G, Ruggenenti P. Insulin resistance and
microalbuminuria, A Cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary
albumin excretion. Diabetes, 2006; 55: 1456-1462.
• Parvanova A, Chiurchiu C, Ruggenenti P, Remuzzi G. Inhibition of the renin-angiotensin system and cardio-renal protection:
focus on losartan and angiotensin receptor blockade. Expert Opinion on Pharmacotherapy, 2005 Sep; 6 (11):1931-1942.
• Ruggenenti P, Fassi A, Parvanova A, Bruno S, Iliev I, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, EneIordache, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini A, Remuzzi G. Preventing Microalbuminuria in Type 2
Diabetes. NEJM, 2004;351 (19): 1941-51.
• Parvanova A, Iliev I, Filipponi M, Dimitrov BD, Vedovato M, Tiengo A, Trevisan R, Remuzzi G, Ruggenenti P. Insulin
resistance and proliferative retinopathy: a cross-sectional, case-control study in 115 patients with type 2 diabetes. J Clin
Endocrinol Metab, 2004 Sep; 89 (9): 4371-6.
• The BENEDICT Group. The Bergamo Nephrologic DIabetes Complications Trial (BENEDICT): design and baseline
characteristics. Controlled Clinical Trials, 2003; 24: 442-461.
• Parvanova A, Iliev I, Dimitrov BD, Arnoldi F, Zaletel J, Remuzzi G, Ruggenenti P. Hyperhomocysteinemia and increased
risk of retinopathy: a cross-sectional, case-control study in patients with type 2 diabetes. Diabetes Care, 2002; 25 (12): 2361.
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Nadia Rubis got her degree in licensed practical nurse in 1995 at the Nursing School of Azienda
Ospedaliera Ospedali Riuniti di Bergamo.
Education training: she completed her research training at IRFMN - Centro di Ricerche Cliniche per le
Malattie Rare Aldo e Cele Daccò – Bergamo, Clinical Research Nurse Course (1998).
Areas of interest: coordination of clinical studies, monitoring activities and data management,
pharmacovigilance.
Employment: in 1998-2003 involved as co-promoter and tutor for the Clinical Research Course for Nurse
at IRFMN - Centro Daccò. In 1998-2008 clinical monitor, Drug Monitoring Unit of Centro Daccò. Since
September 2008 Head of the Drug Monitoring Unit.
•
Piero Ruggenenti, Anna Fassi, Aneliya Parvanova Ilieva, Ilian Petrov Iliev, Carlos Chiurchiu, Nadia Rubis, Giulia Gherardi,
Bogdan Ene-Iordache, Flavio Gaspari, Annalisa Perna, Paolo Cravedi, Antonio Bossi, Roberto Trevisan, Nicola Motterlini,
Giuseppe Remuzzi, for the BENEDICT-B Study Investigators. Effects of verapamil added-on trandolapril therapy in
hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. J Hypertens 29:207-216,
2011. In Press.
•
Piero Ruggenenti, Annalisa Perna, Marcello Tonelli, Giacomina Loriga, Nicola Motterlini, Nadia Rubis, Franca Ledda,
Stefano Rota Jr., Andrea Satta, Antonio Granata, Giovanni Battaglia, Francesco Cambareri, Salvatore David, Flavio Gaspari,
Nadia Stucchi, Sergio Carminati, Bogdan Ene-Iordache, Paola Cravedi and Giuseppe Remuzzi for the ESPLANADE study
group. Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual Renin-Angiotensin
System Blockade: The ESPLANADE Trial. Clin J Am Nephrol 5: 1928-1938, 2010.
•
Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G and Remuzzi A. Developing regulatorycompliant electronic case report forms for clinical trials: experience with the demand trial. J Am Med Inform Assoc, 2009
May-Jun;16 (3): 404-8.
•
Fassi A, Rubis N, Parvanova A, Iliev I, Zamora J, Giuliano GA, Ene-Iordache B, Perna A, Anabaya A, Motterlini N,
Ruggenenti P, Remuzzi G for the BENEDICT Study Investigators. Randomized and non-randomized patients in the Bergamo
Nephrologic Diabetes Complications Trial (BENEDICT). Abstract. 29th Annual Meeting of the Society for Clinical Trials St
Louis, Missouri, May 18-21, 2008.
•
Ruggenenti P, Fassi A, Parvanova Ilieva A, Bruno S, Petro Iliev I, Brusegan V, Rubis N, Gherardi G, Arnoldi A, Ganeva M,
Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G, for the Bergamo Nephrologic Diabetes
Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med, 2004; 351:
1941-51.
•
Ruggenenti P, Perna A, Gherardi G, Benini R, Rubis N, Gritti D, Ciocca I, Stucchi N and Remuzzi G for the GISEN Group.
In chronic renal disease, hypertension and type 2 diabetes predict fast progression. Proteinuria < 2 g/24 hours, type 2 diabetes
and polycystic kidneys are associated with poor response to ACE inhibition. ASN, November 5-8, 1999.
The Department of Renal Medicine was established on 1999 at the Clinical Research Center for
Rare Diseases “Aldo e Cele Daccò” – Villa Camozzi, Ranica to coordinate the activities of 6
Laboratories and 2 Units.
The activities of the Department are mainly focused on the study of the mechanisms of
progression of chronic nephropathies, of new prevention and intervention strategies for diabetic
nephropathy, non diabetic chronic nephropathies, chronic allograft dysfunction, of
cardiovascular complications of diabetes, chronic renal disease, dialysis and transplantation and
of thrombotic microangiopathies.
The main aims of these activities are:
1. To identify screening and intervention strategies aimed to prevent the onset of nephropathy
and of other chronic complications of diabetes and/or hypertension.
2. To define intervention strategies to prevent or slow the progression of chronic nephropathies
and eventually obtain remission/regression of renal dysfunction.
3. To optimize immunosuppressive protocols in kidney transplantation and to define new donor
selection criteria in order to expand the pool of available organs.
These aims will be pursued through the following modalities:
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1. Pilot pathophysiology and clinical pharmacology studies fully finalized at the Clinical
Research Center to test new pathogenetic hypotheses and new treatment modalities.
2. National and international networks and multicenter trials aimed to verify the efficacy of
treatments of potential interest identified as described at point 1.
3. Meta-analyses and probabilistic models to test new risk factors and treatments in large
samples of patients and to transfer this information at individual level.
Many of these activities rest on the possibility of a tight cooperation with the Department of
Molecolar Medicine, the Department of Bioengineering and the Public-Private Department of
Specialist and Transplant Medicine. This cooperation allows to plan the research activities of
the Department on the basis of new information derived from basic research and of problems of
major clinical relevance emerging from routine clinical activities.
Definition and validation of specific treatments aimed to prevent the development and
progression of nephropathy and related micro and macrovascular complications in subjects with
type 2 diabetes.
Definition and validation of new integrated treatment protocols aimed to slow the progression
and/or to achieve remission/regression of diabetic and non-diabetic chronic nephropathies.
Institution of a standardized protocol “on line” (The “Remission Clinics”) finalized to achieve
regression/remission of chronic nephropathies and limit overall renal and radiovascular risk in
hospital practice in the setting of a multicenter Network.
Characterization of the antiproteinuric, nephroprotective and cardioprotective effect of
maximized and polypharmacologic renin-angiotensin system inhibition, intensified blood
pressure and lipid control and identification of novel treatments to reduce the blood pressure
and ameliorate insulin sensitivity in subjects at increased cardiovascular risk.
Identification of acquired or congenital risk factors for chronic complications of diabetes and
cardiovascular morbidity and mortality
Identification and validation of early markers of acute kidney failure and of methods for direct
and indirect measurements of kidney function and GFR decline.
Identification of safety and efficacy profile of new treatments for the Autosomal Polycistic
Kidney Disease (APKD).
Definition and validation of new, specific treatments for idiopathic membranous nephropathy
and for HUS forms associated with genetic defect of complement factors including the
standardization of combined liver and kidney transplantation to prevent post transplant
recurrence of genetic associated HUS.
Definition and validation of new laboratory procedures and predictive models to help
monitoring and optimizing immunosuppressive therapy in clinical transplantation with
particular focus on pharmacokynetic markers of drug exposure and genetic predictors of drug
tolerability and efficacy.
Definition and validation of selection and allocation criteria of kidneys from marginal and oldvery old donors to increase the donor pool and the transplant activity.
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Finalization and activation of multicenter clinical trials aimed to prevent onset and progression
of diabetic and non-diabetic chronic nephropathies, to achieve remission of the nephrotic
syndrome in primary glomerular diseases, minimize maintenance immunosuppression in kidney
transplantation and prevent cardiovascular morbidity and mortality in chronic hemodialysis.
Computerization of data acquisition and monitoring procedures for the conduction of controlled
clinical trials.
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AO Bolognini Seriate, Ospedale Bolognini, Seriate (BG)
AO Ospedali Riuniti, Bergamo
AO Treviglio, Ospedale di Treviglio, Treviglio (BG)
AO Treviglio, Ospedale SS. Trinità, Romano di Lombardia (BG)
AO Treviglio, Poliambulatorio extra-ospedaliero, Ponte San Pietro (BG)
ASL Bergamo, Bergamo
Istituto Humanitas Gavazzeni, Bergamo
AO Spedali Civili di Brescia, Presidio Ospedaliero di Montichiari, Montichiari (BS)
AO Spedali Civili, Spedali Civili, Brescia
AO Ospedale Sant’Anna, Presidio Ospedaliero Sant’Anna, Como
Azienda Ospedaliera Istituti Ospedalieri di Cremona, Cremona
AO Ospedale San Carlo Borromeo, Milano
AO San Gerardo, Ospedale Bassini, Cinisello Balsamo (MI)
AO San Gerardo, Ospedale San Gerardo, Monza (MI)
AO San Paolo – Polo Universitario, Milano
ASL Provincia di Milano 2, Ospedale A. Uboldo, Cernusco sul Naviglio (MI)
Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milano
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano
IRCCS Fondazione Centro San Raffaele del Monte Tabor, Milano
IRCCS Istituto Clinico Humanitas, Rozzano (MI)
IRCCS Multimedica di Sesto San Giovanni, Sesto San Giovanni (MI)
AO Pavia, Ospedale Civile di Voghera, Voghera (PV)
AO Valtellina e Valchiavenna, Ospedale di Sondrio, Sondrio
AO Universitaria, Ospedale di Circolo e Fondazione Macchi, Varese
AO Ospedale Infantile Regina Margherita-Sant’Anna di Torino, Ospedale Infantile Regina
Margherita, Torino
AO Ordine Mauriziano, Ospedale Mauriziano Umberto I, Torino
ASL TO2, Ospedale San Giovanni Bosco, Torino
AULSS 17 Este, Ospedale di Monselice, Monselice (PD)
AULSS 9 di Treviso, Ospedale Santa Maria di Ca' Foncello, Treviso
AO Universistaria degli Ospedali Riuniti di Trieste, Ospedale di Cattinara, Trieste
IRCCS Materno-Infantile Burlo Garofalo, Trieste
AO Universitaria di Bologna, Policlinico Sant’Orsola-Malpighi, Bologna
AUSL Forlì, Ospedale G. B. Morgagni - L. Pierantoni, Forlì
AO Universitaria di Parma, Ospedale di Parma, Parma
AUSL Ravenna, Ospedale Santa Maria delle Croci, Ravenna
AO Reggio Emilia, Arcispedale Santa Maria Nuova, Reggio Emilia
AUSL Rimini, Ospedale Infermi, Rimini
AO Universitaria Careggi, Firenze
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Università degli Studi, Firenze
AUSL 2 Lucca, Ospedale Campo di Marte, Lucca
AO Universitaria Pisana, Ospedale Santa Chiara, Pisa
ASUR Zona Territoriale 13, Ospedale Mazzoni, Ascoli Piceno
IRCCS Pediatrico Bambino Gesù, Roma
AUSL Latina, Presidio di Formia, Latina
AUSL Rieti, Rieti
AO Ospedale San Giuseppe Moscati, Avellino
AO Antonio Cardarelli, Napoli
AO Pediatrica Santobono-Pausilipon, Ospedale Santobono, Napoli
Università Azienda Ospedaliera Universitaria Federico II, Napoli
Università Azienda Ospedaliera Universitaria Federico II, Policlinico Nuovo, Napoli
ASL Salerno, Ospedale Maria SS. Addolorata, Eboli (SA)
ASL Teramo, Presidio Ospedaliero Giuseppe Mazzini, Teramo
Centro Nazionale Ricerche, Reggio Calabria
AS 3 Rossano, Ospedale Civile Nicola Giannettasio, Rossano (CS)
AO Ospedale Cannizzaro, Catania
AO Universitaria Policlinico-Vittorio Emanuele, Presidio Ospedaliero Vittorio Emanuele,
Catania
AUSL 3 Catania, Presidio Ospedaliero di Acireale, Acireale (CT)
ASP 5 Messina, Ospedale di Milazzo, Milazzo (ME)
AO Civico-Di Cristina-Benfratelli, Presidio Ospedaliero Civico e Benfratelli, Palermo
AO Universitaria Policlinico Paolo Giaccone, Università degli Studi, Palermo
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IsMeTT), Palermo
Fondazione Istituto San Raffaele – G. Giglio di Cefalù, Cefalù (PA)
Azienda Ospedaliera, Ospedale Umberto I, Siracusa
IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG)
AUSL Le/1, Ospedale Vito Fazzi, Lecce
ASL Taranto 1, Presidio Ospedaliero Valle D’Itria di Martina Franca, Martina Franca (TA)
AO Brotzu, Ospedale San Michele, Cagliari
ASL Sanluri, Presidio Ospedaliero Nostra Signora di Bonaria, San Gavino Monreale (VS)
ASL Olbia, Ospedale San Giovanni di Dio, Olbia (OT)
ASL Sassari, Azienda Ospedaliero-Universitaria di Sassari, Sassari
INTERNATIONAL COLLABORATION
- University Medical Center, Ljubljana (Slovenia)
- Service de Pharmacologie Clinique, Faculté de Médecine, Lyon (France)
- Hospital Universitario de Canarias, La Laguna, Tenerife (Spain)
-
Department of Primary Health Care , University of Oxford, Oxford (UK)
-
Department of Clinical Sciences/Diabetes & Endocrinology Lund University, Skåne
University Hospital, Malmö (Sweden)
-
University Medical Center Groningen, Groningen, (The Netherlands)
Department of Clinical Pharmacology, Groningen (The Netherlands)
Leiden University Medical Center, Leiden (The Netherlands)
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University Medical Center, Groningen (The Netherlands)
-
Mariinskaya Hospital, Saint-Petersburg (Russia)
Moscow State University of Medicine and Dentistry, Mosca (Russia)
-
Chişinău Hospital, Chişinău (Moldova)
-
Damanhour Medical National Institute, Damanhour, Beheira (Egypt)
-
Health Sciences University, Ulaanbaator (Mongolia)
-
BP Kerala Institute of Health, Dharan (Nepal)
-
Division of Cardiology, Brigham and Women's Hospital, Boston, MA (USA)
National Kidney Foundation, New York, NY (USA)
New England Medical Center, Boston, MA (USA)
-
Complejo Hosp Metropolitano de la Caja de Seguro Social, Panama City (Panama)
-
Hospital Juan XXIII, La Paz (Bolivia)
-
Hospital Maciel, Montevideo (Uruguay)
-
Cochrane Collaboration, Cochrane Renal Group, Centre for Kidney Research, NHMRC
Centre for Clinical Research Excellence in Renal Medicine, The Children's Hospital at
Westmead, Westmead, (Australia).
Current Diabetes Reviews (Piero Ruggenenti)
Clinical Journal of the American Society of Nephrology (Piero Ruggenenti)
Journal of Nephrology (Piero Ruggenenti)
Nephron (Norberto Perico)
The Open Hypertension Journal (Paolo Cravedi)
Acta Diabetologica
Acta Pharmacologica Sinica
American Journal of Hypertension
American Journal of Transplantation
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Archives of Medical Science
Bentham Science
Blood Purification
British Medical Journal (BMJ)
Circulation American Hearth Association (AHA)
Clinical Journal of the American Society of Nephrology (CJASN)
Clinical Nephrology
EMBO Molecular Medicine
Expert Opinion on Pharmacotherapy
Expert review of Clinical Immunology
Heart Failure Reviews
Indian Journal of Nephrology
Internal Urology and Nephrology
International Journal of Clinical Practice
Islets
Journal of the American Society of Nephrology (JASN)
Journal of Hypertension
Journal of Nephrology
Mediterranean Journal of Hematology And Infection Diseases
Nature Communications
Nature Reviews Nephrology
Nephrology Dialysis Transplantation
Nephron
The International Journal of Artificial Organs
The Lancet
Translational research
Transplant International
Transplantation
PARTICIPATION IN EVENTS
IN WHICH THE DEPARTMENT WAS INVOLVED
“Studi clinici controllati”. Presentation at the Specialization Course in Nephrology at the
University of Firenze. Firenze (Italy). March 2nd, 2010.
“Surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes
tools”. Malmo (Sweden)., March 10th-11th, 2010.
“Kidney Master Class”. Bergamo (Italy). March 17th, 2010.
“Il continuum cardiorenale ed i farmaci del sistema RAAS”. In the “Corso Diabete e Malattie
Cardiovascolari”. Perugia (Italy). March 19th-21st, 2010.
“Albuminuria nella nefropatia diabetica”. In the “Seminario Angelini”. Londra (UK). March
24th, 2010.
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“Nuove evidenze nel trattamento e prevenzione della CKD-MBD”. Firenze (Italy). April
2010.
8th
,
“ARCADIA Study: secondo investigator meeting”. Ranica, Bergamo (Italia). April 16th, 2010.
“ADPKD in Europe”. Bruxelles (Belgium), May 27th, 2010.
“ADPKD: nuove strategie terapeutiche”. In the “Giornate Cefaludesi di Nefrologia 2010”.
Cefalù (Italy). May 29th, 2010.
“ATHENA Study: secondo investigator meeting”.Bergamo (Italy), July 12th, 2010.
“New ways in treating membranous glomerulonephritis”. Goteborg (Sweden). September 22nd,
2010.
“Congresso di Oncologia”. Verona (Italy). September 24th, 2010.
“Il futuro è già tra noi? Il progetto ‛Remission Clinic’ è un progetto ambizioso, una sfida per il
futuro”. In the “2° Congresso Percorso Integrato Territoriale in Diabetologia”. Palermo (Italy).
October 1st-2nd, 2010.
“The third WHO meeting on a prioritized research agenda for prevention and control of
noncommunicable diseases”. Ginevra (Switzerland). October 20th-21st, 2010.
“Outcome trials and differential drug responses in CKD and diabetes”. In the Conference “How
can medical innovations reduce the cardiovascular disease burden?”. Bruxelles (Belgium).
November 4th-5th, 2010.
“Early detection and prevention of CKD in resource poor regione”. In the “43rd Annual Meeting
of the American Society of Nephrology”. Denver (USA). November 20th, 2010.
“ACEi+ARBs (kidney outcome)”. In the “2nd International Symposium on Albuminuria”.
Amsterdam (Nethe

Annual Report 2010 - Istituto di Ricerche Farmacologiche Mario Negri

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