Annual Report 2009 - Istituto di Ricerche Farmacologiche Mario Negri

Transcription

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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.............................................................................
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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123
155
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273
NEGRI BERGAMO LABORATORIES
DEPARTMENTS
Department of Molecular Medicine ……….……………………………………….………… 279
Department of Biomedical Engineering……….……………………………………………… 399
Laboratory of Biology and Therapy of Metastasis…………………………………….. 315
ALDO and CELE DACCO’ CENTER
DEPARTMENT
Department of Renal Medicine…………….…………………………………………………… 319
LABORATORIES AND CENTERS
Rare Diseases Documentation and Research..................................................…..… 343
International Relations Office of rare Diseases........................................................ 353
T he Transplant Research Center…………….………………………………………………… 357
EDUCATION ACTIVITIES
359
STAFF
361
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 2010
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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 – 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 Therapy of Metastasis
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.
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. From 1997 he is the Preclinical Coordinator of the Southern Europe New Drug Organization
(SENDO) and since 2006 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). He is on the editorial board of many international cancer-related scientific journals and since
September 2000 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
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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 2009 E-pub.
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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).
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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).
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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.
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Salvati E., Leonetti C., Rizzo A., Scarsella M., Mottolese M., Galati R., Sperduti I., Stevens M., D’Incalci M., Blasco
M., Chiorino G., Horard B., Gilson E., Zupi G., Biroccio A. Telomere damage promotes antitumoral activity of the Gquadruplex ligand RHPS4. J. Clin. Invest., 2007; 117:3236-3247.
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Tavecchio M., Natoli C., Ubezio P., Erba E., D’Incalci M. Dynamics of cell cycle phase perturbations by Trabectedin
(ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematical
simulation approach. Cell proliferation, 2007; 40: 885-904.
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) and listed as National Expert at the European
Agency for the Evaluation of Medicinal products (EMEA) in London (UK). 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;
• Education and health promotion research and programs.
He is author or co-author of more than 270 publications, mostòy 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.
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Corli O, Apolone G, Pizzuto M, Cesaris L et al. Illness awareness in terminal cancer patients: an Italian study. Palliative
Medicine, 23: 354-9, 2009
Riva E, Tettamanti M, Mosconi M, Apolone, G et al. Association of Mild Anemia with Hospitalization and Mortality
in the Elderly The “Health and Anemia” Population-Based Study. Haematologica, 94 (1): 22-28, 2009
Apolone G, Corli O, Negri E, Mangano S, Montanari M, Greco MT. Effects of transdermal buprenorphine on patientsreported outcomes in cancer patients. Results from the Cancer Pain Outcome Research (CPOR) Study Group.
Clinical J Of Pain, 25:671-682, 2009
Apolone G, Corli O, et al. Pattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome
Research Study Group (CPOR SG). Br J Cancer, 100:1566-74, 2009.
Apolone G, on behalf of the 2008 Erice Group. The 2008 Erice Statement toward a more humanistic oncology. J Amb
care Manage 32:252-258,2009.
De Andrea S, Corli O, Moschetti I, Apolone G. Managing severe cancer pain. The role of TDS buprenorphine: a
systematic review. Therapeutics and Clinical Risk management, 5:1-12, 2009.
Gallus S, Tramacere I, La Vecchia C, Colombo P, Zuccaro P, Paleari L, Cesario A, Russo P, Apolone G. Use of
pharmacotherapy for smoking cessation in Italy. Arch Intern Med 169: 1927-1928, 2009.
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.
Principali pubblicazioni
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Zangrossi S, Marabese M, Broggini M, Giordano R, D'Erasmo M, Montelatici E, Intini D, Neri A, Pesce M, Rebulla P,
Lazzari L. Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker. Stem Cells.
2007;25(7):1675-80.
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Marrazzo E, Marchini S, Previdi S, Broggini M. Questioning the oncogenic role of DeltaNp73alpha in different cell lines
expressing p53 or not. Cancer Biol Ther. 2006;5(7):794-803.
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Polato F, Codegoni A, Fruscio R, Perego P, Mangioni C, Saha S, Bardelli A, Broggini M. PRL-3 phosphatase is
implicated in ovarian cancer growth. Clin Cancer Res. 2005 11:6835-9.
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Maffucci T, Piccolo E, Cumashi A, Iezzi M, Riley AM, Saiardi A, Godage HY,Rossi C, Broggini M, Iacobelli S, Potter
BV, Innocenti P, Falasca M. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate
results in antiangiogenic and antitumor effects. Cancer Res. 2005;65:8339-49.
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Marabese M, Marchini S, Sabatino MA, Polato F, Vikhanskaya F, Marrazzo E, Riccardi E, Scanziani E, Broggini M.
Effects of inducible overexpression of DNp73alpha on cancer cell growth and response to treatment in vitro and in vivo.
Cell Death Differ. 2005;12:805-14.
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Sabatino MA, Colombo T, Geroni C, Marchini S, Broggini M. Enhancement of in vivo antitumor activity of classical
anticancer agents by combination with the new, glutathione-interacting DNA minor groove-binder, brostallicin. Clin
Cancer Res. 2003;9:5402-8.
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 also member as
bio-statistician of three Italian 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 diagnostic test evaluation.
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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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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, and 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 16 : 3431-3441
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
Garattini S, Torri V, Floriani I. Cetuximab for metastatic colorectal cancer. N Engl J Med 2009 361 : 96
Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E, Canestrari E,
Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A. PTEN expression
and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for
patients with metastatic colorectal cancer. J Clin Oncol 2009 27 : 2622-2629
Ferrari D, Fiore J, Codecà C, Di Maria G, Bozzoni S, Bordin V, Caldiera S, Luciani A, Zonato S, Floriani I, Foa P. A
phase II study of carboplatin and paclitaxel for recurrent or metastatic head and neck cancer. Anticancer Drugs 2009 20 :
185-190
Lissoni AA, Colombo N, Pellegrino A, Parma G, Zola P, Katsaros D, Chiari S, Buda A, Landoni F, Peiretti M, Dell'anna
T, Fruscio R, Signorelli M, Grassi R, Floriani I, Fossati R, Torri V, Rulli E. A phase II, randomized trial of neo-adjuvant
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. Ann Oncol 2009 20 : 660-665
Graziano F, Ruzzo A, Canestrari E, Loupakis F, Santini D, Rulli E, Humar B, Galluccio N, Bisonni R, Floriani I,
Maltese P, Falcone A, Tonini G, Catalano V, Fontana A, Giustini L, Masi G, Vincenzi B, Alessandroni P, Magnani
M.Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal
cancer. Pharmacogenomics J 2009 9 : 78-84
Mandalà M, Barni S, Floriani I, Isa L, Fornarini G, Marangolo M, Mosconi S, Corsi D, Rulli E, Frontini L, Cortesi E,
Zaniboni A, Aglietta M, Labianca R. Incidence and clinical implications of venous thromboembolism in advanced
colorectal cancer patients: The 'GISCAD-alternating schedule' study findings. Eur J Cancer 2009 45 : 65-73
Raffaella Giavazzi got her Biological Sciences degree (1979) at the University of Milan, and her Ph.D.
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
Tossicology-University of Siena, member of the Executive Committee at SENDO (South 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.
• 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.
• Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular disrupting activity of tubulin-binding
1,5-Diaryl-1H-imidazoles. Journal of Medical Chemistry, 52:7906-10, 2009.
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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.
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
Paola Mosconi got her Biological Science degree (Milan 1982) and the specialisation in Pharmacological
Research (Milan 1984). Her main areas of interest are:
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development of strategies to involve patients-consumer associations in the health debate, and
research projects;
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assessment of the quality of life, translation and cultural adaptation of questionnaires for quality of
life;
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studies to evaluate the type of information on diseases and treatments received by patients, mainly
cancer patients; set-up of websites targeted on consumers/patients www.partecipasalute.it,
www.paincare.it, www.fondazioneMattioli.it ;
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studies to evaluate the consumers’ level of satisfaction with the health services and care.
Paola Mosconi has participated as a 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.
• 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
• Donati S, Cotichini R, Mosconi P, Satolli R, Colombo C, Liberati A, Mele A Menopause: knowledge, attitude and
practice among Italian women.Maturitas 2009; 20; 63(3):246-52.
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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.
O’Connel D, Mosconi P. An active role for patients in clinical research? Drug Development Research 67 (3): 188-192,
2006.
• Mosconi P, Colombo Cinzia, La Bianca R, Apolone G. Oncologists' opinions about research ethics committees in Italy:
an update, 2004. Eur J Cancer Prev 2006; 15: 91-94
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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.
• 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
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
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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
post-surgical metastasis: a longitudinal study. Lancet Oncol. 2009; 10 (9): 877-84.
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.
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. 2008 Dec 1;14(23):7850-60.
Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M,Scambia G, Angioli R, Tateo S, Mangili G,
Katsaros D, Garozzo G, Campagnutta E,Donadello N, Greggi S, Melpignano M, Raspagliesi F, Ragni N, Cormio G,
Grassi R,
Franchi M, Giannarelli D, Fossati R, Torri V, Amoroso M, Crocè C, Mangioni C. Systematic pelvic lymphadenectomy
vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008 Dec
3;100(23):1707-16.
Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V,Elias D, O'Callaghan C, Langer B,
Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after
potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin
Oncol. 2008 Oct 20;26(30):4906-11.
Cascinu S, Labianca R, Barone C, Santoro A, Carnaghi C, Cassano A, Beretta GD, Catalano V, Bertetto O, Barni S,
Frontini L, Aitini E, Rota S, Torri V, FlorianiI; Italian Group for the Study of Digestive Tract Cancer, Adjuvant
treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and
epidoxorubicin in a randomised controlled trial. J Natl Cancer Inst. 2007;99(8):601-7.
Graziano F, Kawakami K, Ruzzo A, Watanabe G, Santini D, Pizzagalli F, Bisonni R, Mari D, Floriani I, Catalano V,
Silva R, Tonini G, Torri V, Giustini L, Magnani M Methylenetetrahydrofolate reductase 677C/T gene polymorphism,
gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population. Int J Cancer 2006 118 :
628-632
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 in 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).
At the MarioNegri Institute for Pharmacological Research she was a Fellow Research Scientist in the
Laboratory of Biology and Treatment of Metastasis, Bergamo from 1996 to 2002 and she became a Staff
Research Scientist in 2003. In April 2004 she became Head of the Molecular Cancer Therapeutics Unit.
She is the Scientific Manager of STROMA(since 2004) and ADAMANT(since2008), two Integrated
Projects within 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 molecular therapeutics. She is
co-author of 34 peer reviewed publications, 2 book chapters and 65 proceedings of which 15 selected for
oral presentation at international meetings.
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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.
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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. 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.
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• Vikhanskaya F.*, Bani M.R.*., Borsotti P., Ghilardi C., Ceruti R., Ghisleni G., Marabese M., Giavazzi R., Broggini M.
& Taraboletti G. p73 overexpression increases VEGF and reduces thrombospondin-1 production: implication for tumor
angiogenesis. Oncogene 20 : 7293-7300, 2001.
• 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.
Simone M, Erba E, Damia G, Vikhanskaya F, Di Francesco A M, Riccardi R, Baldeyrou B, Bailly C, Cuevas C, Sousa-Faro J M
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F, D'Incalci M. Variolin B and its derivate deoxy-variolin B: New marine natural compounds with cyclin-dependent kinase
inhibitor activity. Eur J Cancer 2005; 41: 2366-2377
Carrassa L, Broggini M, Erba E, Damia G. Chk1, but not Chk2, is involved in the cellular response to DNA damaging agents.
Differential activity in cells expressing or not p53. Cell Cycle 2004; 3: 1177-1181
Damia G, Broggini M. Improving the selectivity of cancer treatment by interfering with cell response pathways. Eur J Cancer
2004; 40: 2550-2559
Damia G, Broggini M. Cell cycle checkpoint proteins and cellular response to treatment by anticancer agents. Cell Cycle 2004;
3: 46-50
Carrassa L, Broggini M, Vikhanskaya F, Damia G. Characterization of the 5' flanking region of the human chk1 gene.
Identification of E2F1 functional sites. Cell Cycle 2003; 2: 604-609
Damia G, Sanchez Y, Erba E, Broggini M. DNA damage induces p53-dependent down-regulation of hCHK1. J Biol Chem 2001;
276: 10641-10645
Eugenio Erba has obtained his Biological and Biochemmistry 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.
• 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
• C. Valli, G. Paroni, A. Di Francesco, R. Riccardi, M. Tavecchio, E. Erba, A. Boldetti, M. Giannì, M. Fratelli, C. Pisano,
L. Merlini, A. Antoccia, C. Cenciarelli, M. Terao, E. Garattini. Atypical retinoids ST1926 and CD437 are S-phase
specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity. Mol.
Ca. Ther. 7(9),2941-54, 2008
• L. Roncoroni, L. Elli, E. Delfini, E. Erba, E. Dogliotti, C. Terrai, L. Doneda, MG. Grimoldi, MT. Bardella. Resveratrol
inhibits cell growth in a human cholangiocarcinoma cell line. Liver Int. 28(10),1426-36, 2008
• 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)
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• Tavecchio M., Natoli C., Ubezio P., Erba E., D’Incalci M. Dynamics of cell cycle perturbations by trabectedin
(ET-743) in nucleotide excision repair (NER) –deficient and NER-proficient cells, unravelled by a novel
mathematical simulation approach. Cell Prolif., 40:885-904 (2007)
• Tognon G., Bernasconi S., Celli N., Faircloth G.T. Cuevas C., Jimeno J., Erba E., D’Incalci M. Induction of
resistance to Aplidin® in a human ovarian cancer cell line related to MDR expression. Cancer Biology and
Therapy, 4(12): 1325-1330 (2005).
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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P. Benedetti Panici, A. Maggioni, N. Hacker, F. Landoni, S. Ackermann, E. Campagnutta, K. Tamussino, R. Winter, A.
Pellegrino, S. Greggi, R. Angioli, N. Manci, G. Scambia, T. Dell'Anna, R. Fossati, I. Floriani, R.S. Rossi, R. Grassi, G.
Favalli, F. Raspagliesi, D. Giannarelli, L. Martella, C. Mangioni. Systematic Aortic and Pelvic Lymphadenectomy versus
Resection of Bulky Nodes Only in Optimally Debulked Advanced Ovarian Cancer: A Randomized Clinical Trial J Natl
Cancer Inst 97:1-6;2005
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Buda A, Fossati R, Colombo N, Fei F, Floriani I, Gueli Alletti D, Katsaros D, Landoni F, Lissoni A, Calzoni C, Sartori E,
Scollo P, Torri V, Zola P, Mangioni C. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide,
and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell
cervical carcinoma: The SNAP01 (Studio Neo-Adjuvante Por. J Clin Oncol 2005; 23: 4137-4145.
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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.
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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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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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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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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
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.
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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.
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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.
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.
Taraboletti G. Micheletti G, Rieppi M, Poli M, Turatto M, Rossi C, Borsotti P, Roccabianca P, Scanziani E, Nicoletti MI,
Bombardelli E, Morazzoni P, Riva A, and Giavazzi R. Antiangiogenic and antitumor activity of IDN 5390, a new taxane
derivative. Clin Cancer Res. 8: 1182-1188, 2002
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.
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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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; 46: 505-516.
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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.
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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.
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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.
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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).
Rizzari C., Citterio M., Zucchetti M., Conter V., Chiesa R., Colombini A., Malguzzi S., D’Incalci M. Pharmacological
study on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic leukemia.
Hematologica, 91: 24-31 (2006).
ACTIVITIES
The Oncology Department comprises three preclinical experimental laboratories (Laboratory of
Cancer Pharmacology, Laboratory of Molecular Pharmacology and Laboratory of Biology and
Therapy of Metastasis) 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 (South
Europe New Drug Development Organization) and studies driven by the Laboratory of Cancer
Pharmacology, the Laboratory of Molecular Pharmacology and the Laboratory of Biology and
Therapy of Metastasis. 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. 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.
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Trabectedin modulates the transcription of genes involved in pro-inflammatory mechanisms that
are potentially relevant for tumor growth and progression.
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.
Overexpression of a truncated form of p73 (DNp73beta) in human cancer cells leads to growth
arrest and formation of tetraploid cells, suggesting a role of this isoform in mitosis.
A new mechanism of p73 activation mediated by the protease HtrA2 has been identified. After
apoptotic stimuli this protease cleaves p73 in the C-terminal region increasing its apoptotic
potential.
Inositol pentaphosphate analogues interfere with the PI3-kinase-induced phosphorylation of akt
and possess antitumor activity in vitro and in vivo, particularly when combined with other
anticancer agents.
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.
Inhibition of PLC gamma, through siRNA technology, reduces the in vivo growth of tumors and
reduces the formation of metastasis.
Identification of gene transcripts preferentially expressed by tumor associated endothelial cells.
Demonstration that the corresponding proteins localize within the tumor stroma.
VEGF released by cancer cells modulates the gene expression of the tumor microenvironment
(stroma). Identification of transcripts.
Soluble human VEGFC levels in serum and ascites correlate with tumor progression and
metastatic capability in human ovarian carcinoma models.
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A new antiangiogenic domain of thrombospondin-1 (an endogenous 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 designed as potential inhibitors of
angiogenesis.
New antineoplastic compounds directed against the tumor vasculature (vascular disrupting
agents) have been identified.
Proteins for which expression is selectively associated with liver metastasis have been identified
in preclinical models of advanced cancer.
The expression of protease-activated receptor-1 (PAR-1) correlates with the malignant
phenotype of human melanomas and is accountable for their motility and invasive features
The response to chemotherapy was a good surrogate endpoint of survival in patients with
locally advanced cervix carcinoma.
Adjuvant chemotherapy with the regimen vindesin, mitomycin C and cisplatin (MVP) did not
improve survival of non small cell lung cancer (NSCLC) patients compared with surgery alone.
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
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 patienst treated at home for cancer
pain with palliative care , only 58% were classified to be fully aware of ther 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 trial of patients with high risk (stage IcG3, IIG3 with myometrial invasion >50%,
and III) endometrial carcinoma showed the substantial equivalence between radiotherapy or
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chemotherapy as an adjuvant therapy after surgery. Although both radiotherapic and
chemotherapic approaches are still unsatisfactory, since the risk of progression or death remains
high, this encouraging evidence of clinical activity suggest a possible use of their concurrent or
sequential use in an adjuvant setting.
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
ASR, Agenzia Sanitaria Regionale, Bologna
AIFA, Agenzia Italiana del Farmaco (Roma)
Azienda Sanitaria Locale, Rimini
Assessorato Sanità, Regione Emilia Romagna
Azienda Sanitaria Unica Regionale, Regione Marche
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
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
Istituto Clinico Humanitas, Rozzano MI
Istituto Dermopatico dell'Immacolata, Roma
Istituto Ortopedico Galeazzi, Milano
Istituti Ortopedici Rizzoli, Bologna
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 Regina Elena, Roma
Istituto Superiore di Sanità
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Laboratorio Cell factory, Policlinico di Milano
Ospedale San Gerardo, Monza, Milano
Ospedale San Matteo, Pavia
Ospedale Santa Chiara, Trento
Rete Oncologica Lombarda (ROL), Milano
Università Cattolica del Sacro Cuore, Roma
Università di Bari
Università di Brescia
Università di Chieti
Università di L’Aquila
Università di Milano
Università di Modena e Reggio Emilia
Università di Monza
Università di Catania
Università di Padova
Università di Pisa
Università di Siena
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.
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)
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.
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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
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)
Current Cancer Therapy Reviews (Raffaella Giavazzi)
European Journal of Cancer (Maurizio D’Incalci, Giovanna Damia, Raffaella Giavazzi,
Massimo Broggini e Giulia Taraboletti)
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 Experimental Therapeutics and Oncology (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)
www.fondazionemattioli.it (Paola Mosconi)
PEER REVIEW ACTIVITIES
American Journal of Pathology, 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, ChemicoBiological Interactions, Clinical & Experimental Metastasis, Clinical Cancer Research,
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Cytometry, European Journal of Cancer, European Journal of Immunology, European Journal of
Neurology, 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 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 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 Preventive Medicine and Hygiene, Journal of the National Cancer Institute,
Leukemia, Molecular Cancer Therapeutics, Nature Biotechnology, Nature Reviews, Oncology
Research, PharmacoEconomics, Quality of Life Research, Science, The Patient: patientcentered 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
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)
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-CCI
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 Asociation 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
Il Comitato etico: luogo di partecipazione tra laici e tecnici?
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, January 13, 2009.
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Investigators’ Meeting “Cetuximab”, Istituto Ricerche Farmacologiche “Mario Negri ”, Milan
March 30, 2009.
International Clinical Trials’ Day.2009 Strategie di promozione della salute e delle malattie:
quale spazio per le evidenze degli studi clinici. Milan, May 20, 2009.
Meeting: Assessment of cancer pain in clinics and in research. Need for a common international
methodology? Istituto di Ricerche Faramacologiche Mario Negri, Milan, September 9-10, 2009.
Investigators’ Meeting “Head & Neck trial” Congresso AIOM, Milan, October 12, 2009.
Investigators’ Meeting “Tailor trial” Congresso AIOM, Milan, October 11, 2009.
Investigators’ Meeting “TOSCA” Congresso AIOM, Milan, October 11, 2009.
Investigators’ Meeting “COMETS” Congresso AIOM, Milan, October 11, 2009.
XXVII Conferenza Nazionale di Citometria, Centro Congressi Ferrara, October 14-17, 2009.
IV edizione percorso di formazione PartecipaSalute - “L’Accademia del Cittadino”. Milan,
Montecatini Terme, October 2009-March 2010.
CONFERENCE AND WORKSHOP CONTRIBUTIONS
Workshop: Chemoresistance - a major treatment failure in oncology . “Experimental bases”.
Milan (Italy), January 21, 2009.
Update sull’angiogenesi ad un anno dalla scomparsa di Judah Folkman. Rome (Italy), January
24, 2009. “Studi preclinici con inibitori dell’angiogenesi”.
Meeting: Trabectedin: Soft Tissue Sarcoma Treatment. New Horizons in Oncology. ”Drugs of
Marine Origin”. Antequera, Malaga (Spain), February 12, 2009.
Conference: Exploitation of research outcomes towards cancer patients’ expectations: European
perspectives. ”The importance of translational research for drug development: the example of
the marine natural product ET-743”. Bruxelles (Belgium), March 17, 2009.
Conference: IV Assemblea Plenaria, Conferenza Provinciale sulla Salute “La malattia che
impoverisce. La povertà che fa ammalare “Per discutere del valore del risultato dell’indagine
per l’introduzione di nuovi strumenti di misura nella pratica medica”, Turin (Italy), March 26,
2009.
CNIO Scientific Symposium: Molecular markers in cancer therapy: present use and future
perspectives. San Lorenzo de El Escorial, Madrid (Spain), March 26-27, 2009.
“Gene expression analysis of endothelial cells revealed novel markers of tumor vasculature”.
“Human Ovarian carcinoma xenografts equipped with different angiogenic phenotype differ in
the transcriptional profile profile of their stroma”.
Conference: XVII Conferenza Nazionale AIOM: Clinical pathways nel carcinoma del colon
retto: dalle linee guida alla pratica clinica. Florence (Italy), April 2-4, 2009.
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Conference: IV Giornata di Studio Novarese “Il Carcinoma Ovarico: conoscenze attuali e
prospettive future” La ricerca collaborativa del tumore ovarico: l’esperienza del MaNGO. Santa
Margherita Ligure (Italy), April 18, 2009.
Meeting: 100th AACR Annual Meeting. Denver (USA), April 18-22, 2009.
“PTX-008, a non-peptidic topomimetic of the antiangiogenic galectin-1-targeting anginex:
differential antiproliferative activity on cancer and endothelial cells”.
“Identification of novel markers of tumor-associated vasculature”.
XIII Riunione scientifica annuale, Italian Sarcoma Group. ”Meccanismo d’azione e selettività
per alcuni subset di pazienti”. Turin (Italy), April 20-21, 2009.
Meeting AGO-OVAR 12 VARGATEF, Frankfurt (Germany) April 28, 2009.
Course: Corso di perfezionamento “Formazione clinica, comunicazione e management in
Cardiologia": Novità nella ricerca farmacologica cardiovascolare. Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan (Italy), May 27, 2009.
Meeting: 45° Meeting ASCO, Orlando (USA) May 29 – June 2, 2009.
Conference: ESH Conference on Angiogenesis. Helsinki (Finlandia), June 5-8, 2009.
“Ovarian tumor models to study lymphatic spread”.
Assembly: VI Assemblea Gruppo Mango, Turin (Italy), June 12, 2009.
Symposium: 21th Pezcoller Symposium. Trento (Italy), June 11-13, 2009.
Novel “vascular markers” highly expressed by human tumor endothelial cells.
Meeting: Young Life Scientist 2009 - Networking Angiogenesis: bridging young researchers in
the vascular biology field. University of Chester (UK), July 14, 2009.
“The rational for combination treatments with vascular targeting therapy”.
Meeting: Assessment of cancer pain in clinics and in research. Need for a common international
methodology? Istituto di Ricerche Faramacologiche Mario Negri, Milan (Italy), September 910, 2009.
Course: Emerging Issues nei Sarcomi dei Tessuti Molli. “Trabectedina: meccanisco di azione e
aspetti farmacologici”. Brescia (Italy), September 28, 2009.
Congress: XI Congresso Nazionale SIPO “Professionalità ed Innovazione in Psico-Oncologia”
Dolore Oncologico: coinvolgere i pazienti nella valutazione e nel trattamento. Senigallia (AN,
Italy) October 1-3, 2009.
Congress: XI Congresso Nazionale dell’Associazione Italiana di Oncologia Medica (AIOM),
Simposio Satellite: Farmaci dal mare: realtà emergente. “Nuovi prodotti naturali marini: stato
dell’arte e prospettive”. Milan (Italy), October 10-13, 2009.
Meeting: XVI Meeting Internazionale della Società Europea di Ginecologia Oncologica,
Belgrado, October 11-14, 2009.
Conference: XXVII Conferenza Nazionale di Citometria, Centro Congressi Ferrara (Italy),
October 14-17, 2009.
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Conference: International Conference on Tumor Microenvironment: Progression, Therapy &
Prevention.Versailles (France), October 20-24, 2009.
“Interactions of Tumor Cells with Microenvironmental Cells & Molecules I”.
Congress: XVI Congresso Nazionale della Società Italiana di Cure Palliative. Studio di
Outcome Mario Negri: dati di confronto nel dolore da cancro. Lecce (Italy), October 27-30,
2009.
Congress: II° Convegno di Oncologia Interventistica: Tecniche innovative nel trattamento dei
tumori primitivi epatici. ”Importanza degli studi di farmacocinetica per ottimizzare le terapie
oncologiche”. Cervesina (PV, Italy), November 6-7, 2009.
Congress: II Congresso del Gruppo Oncologico Chirurgico Cooperativo Italiano: Terapie
Mediche Innovative in Oncologia. ”Progressi nella terapia medica dei sarcomi dei tessuti
molli”. Florence (Italy), November 6-7,2009.
Congress: VIII Convegno ACD SIAARTI 2009. Oppioidi a rapido onset nel breakthrough
cancer pain. Rome (Italy), November 11-13, 2009
Conference: AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics. Boston (USA),
November 15-19, 2009.
“Antiangiogenic proprieties of E-3810, a new dual inhibitor of VEGF and FGF receptors”.
51st Annual Meeting of the Italian Cancer Society (SIC). Sesto S. Giovanni (Milan, Italy)
November 23-26, 2009.
“Protease-activated receptor-1 (PAR-1) expression contributes to the metastatic capabilities of
primary melanoma lesions”.
“Renal carcinoma as model for anti-angiogenic therapy”.
“Antiangiogenic and antineoplastic activity of PTX-008, a nonpeptidic topomimetic of
Anginex”.
“Lymphatic spread: models of ovarian carcinoma xenografts”.
“The effect of vandetanib on tumor vasculature remodeling and paclitaxel uptake reflects the
antitumor activity in a xenograft model of human ovarian carcinoma”.
“Human Vascular Endothelial Growth Factor affects response to paclitaxel treatment in a model
of ovarian carcinoma”.
“Dual targeting of cancer and endothelial cells by gonadotropin-releasing hormone agonist to
reduce melanoma angiogenesis”.
“The isothiocyanate produced from glucomoringin inhibits NF-KB and reduces myeloma
growth in nude mice in vivo”.
“Molecular mechanisms of resistance to trabectedin of a myxoid liposarcoma cell line”.
“Studies on the ‘tumor initiating cell’ of ovarian cancer”.
“Generation-wise cell cycle analysis: a new insight into antiproliferative activity of anticancer
treatments”.
”From sea to bedside: trabectedin, a success story of translational research”.
Congress: V Congresso Nazionale “Approccio globale la paziente oncologico”, Forlì (Italy),
November 25-27, 2009.
Conference: Nuovi orizzonti nella gestione del paziente oncologico con BTcP: Valutazione
della frequenza e dell’impatto del BTcP in uno studio longitudinale. Rome (Italy), December 4,
2009.
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Congress: VII congresso COMU: Problematiche emergenti sull’uso dei nuovi farmaci in
oncologia. ”La Trabectedina”. Florence (Italy), December 17-18, 2009.
GRANTS AND CONTRACTS
AIFA Agenzia Italiana del Farmaco
Arcispedale Santa Maria Nuova di Reggio-Emilia
Azienda Sanitaria Locale - Rimini
Azienda Sanitaria Unica Regionale - MARCHE
AIFA Agenzia Italiana del Farmaco
Amgem SpA, Milano
AIRC Associazione Italiana per la Ricerca sul Cancro
ASL Padova
ASL Provincia di Lodi
Astra Zeneca SpA
Astra Zeneca UK
AVAPO (Associazione Volontari Assistenza Pazienti Oncologici)
Aventis Pharma
Azienda Ospedaliera Fatebenefratelli e Oftalmico- Milano
Azienda Sanitaria Locale, Rimini
Azienda Sanitaria Unica Regionale, Marche
Azienda Ospedaliera “Spedali Civili di Brescia”
Bracco Imaging SpA, Milan
Centro Cochrane Italiano
Chiesi Farmaceutici SpA
CIPOMO (Collegio Italiano dei Primari Oncologi Medici Ospedalieri)
CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, Milano
CNR Consiglio Nazionale delle Ricerche
CNR-MIUR Ministero Istruzione Università e Ricerca
Compagnia di San Paolo
Dompé
Eli Lilly Italia SpA
Elsevier Science Ltd.
EORTC-European Organization for Research and Treatment of Cancer
EOS SpA
European Commission - 7th Framework Programme (ADAMANT)
FIRB-MIUR Fondo per gli Investimenti della Ricerca di Base-Ministero Istruzione Università e
Ricerca
FIRC Fondazione Italiana per la Ricerca sul Cancro
Fondazione Cassa di Risparmio delle Province Lombarde
Fondazione SmithKline, Roma
Fondazione Lu.V.I.
Fondazione Nerina e Mario Mattioli Onlus
FSE Frontier Southern Europe
GISCAD(Gruppo Italiano Studi di Carcinomi Apparato Digerente)
GlaxoSmithKline, Verona
Grunenthal Italia, Milano
Indena SpA
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Institut de Recherche Pierre Fabre
Istituto Clinico Humanitas – Rozzano
Istituto Nazionale dei Tumori, Milano
Komen Italia Onlus
Lottomatica
Medac
Merck Sharp & Dome
Ministero della Salute
Nerviano Medical Science S.r.l.
Novartis
Novartis Farma SpA
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
Oncoethix
Optigenex Inc.
Pfizer Global Research and Development
Pfizer Italia
Pharma Mar, SA
Pharminox Ltd, UK
Policlinico di Padova / C.O.R.
Regione Emilia Romagna
Regione Lombardia
Regione Toscana
Regione Veneto
Sanofi-Aventis Pharma
Sara Bet, Roma
SENDO-Tech Srl
Sigma-Tau SpA
Università degli Studi di Padova
Università Federico II – Napoli (Dipartimento di Endocrinologia ed Oncologia molecolare e
clinica)
SCIENTIFIC PUBLICATIONS (2009)
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 2009 E-pub :
Cesca M, Frapolli R, Berndt A, Scarlato V, Richter P, Kosmehl H, D’Inclaci M, Ryan AJ, Giavazzi R
The effects of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human
ovarian carcinoma
Neoplasia 2009 11(11) : 1155-64
Ferketich A K, Gallus S, Colombo P, Apolone G, Rossi S, Zuccaro P, La Vecchia C
Use of pharmacotherapy while attempting cessation among Italian smokers
Eur J Cancer Prev 2009 18 : 90-92
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 13 : 1565-1576
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
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Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors
Mol Cancer Ther 2009 8 : 449-457
Corli O, Apolone G, Pizzuto M, Cesaris L, Cozzolino A, Orsi L, Enterri L
Illness awareness in terminal cancer patients: an Italian study
Palliat Med 2009 23 : 354-359
Lissoni A A, Colombo N, Pellegrino A, Parma G, Zola P, Katsaros D, Chiari S, Buda A, Landoni F,
Peiretti M, Dell'Anna T, Fruscio R, Signorelli M, Grassi R, Floriani I, Fossati R, Torri V, Rulli E
A phase II, randomized trial of neo-adjuvant 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 ce
Ann Oncol 2009 20 : 660-665
Marangon E, Citterio M, Sala F, Barisone E, Lippi A A, Rizzari C, Biondi A, D'Incalci M, Zucchetti M
Pharmacokinetic profile of imatinib mesylate and N-desmethyl-imatinib (CGP 74588) in children with newly
diagnosed Ph+ acute leukemias
Cancer Chemother Pharmacol 2009 63 : 563-566
Sessa C, Perotti A, Noberasco C, de Braud F, Gallerani E, Cresta S, Zucchetti M, Vigano' L, Locatelli A,
Jimeno J, Feilchenfeldt J W, D'Incalci M, Capri G, Ielmini N, Gianni L
Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast
cancer
Eur J Cancer 2009 45 : 1153-1161
Naldini A, Filippi I, Ardinghi C, Silini Antonietta, Giavazzi R, Carraro F
Identification of a functional role for the protease-activated receptor-1 in hypoxic breast cancer cells
Eur J Cancer 2009 45 : 454-460
Marrazzo E, Marchini S, Tavecchio M, Alberio T, Previdi S, Erba E, Rotter V, Broggini M
The expression of the ΔNp73β isoform of p73 leads to tetraploidy
Eur J Cancer 2009 45 : 443-453
Apolone G, Corli O, Caraceni A, Negri E, Deandrea S, Montanari M, Greco M T, CPOR SG
Investigators
Pattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome Research Study
Group
Br J Cancer 2009 100 : 1566-1574
Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi Gianluca, Graziano F, Cremolini C,
Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I,
Cascinu S, Falcone A
PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From
Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer
J Clin Oncol 2009 27 : 2622-2629
Mandalà M, Barni S, Floriani I, Isa L, Fornarini L, Marangolo M, Mosconi P, Corsi D, Rulli E, Frontini
L, Cortesi E, Zaniboni A, Aglietta M, Labianca R, GISCAD
Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: the
'GISCAD-alternating schedule' study findings
Eur J Cancer 2009 45 : 65-73
Riva E, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone M V, 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 Anemia population-based
study
Haematologica 2009 94 : 22-28
Graziano F, Ruzzo A, Canestrari E, Loupakis F, Santini D, Rulli E, Humar B, Galluccio N, Bisonni R,
Floriani I, Maltese P, Falcone A, Tonini G, Catalano V, Fontana A, Giustini L, Masi G, Vincenzi B,
Alessandroni P, Magnani M
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Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal
cancer Pharmacogenomics J 2009 9 : 78-84
Marano R, De Cobelli F, Floriani I, Becker C, Herzog C, Centonze M, Morana G, Gualdi G F, Ligabue
G, Pontone G, Catalano C, Chiappino D, Midiri M, Simonetti G, Marchisio F, Olivetti L, Fattori R,
Bonomo L, Del Maschio Alessandro, NIMISCAD Study Group
Italian multicenter, prospective study to evaluate the negative predictive value of 16- and 64-slice MDCT imaging in
patients scheduled for coronary angiography (NIMISCAD-Non Invasive Multicenter Italian Study for Coronary
Artery Disease)
Eur Radiol 2009 19 : 1114-1123
D'Incalci M
The potential impact of marine compounds in the era of targeting therapies
In :International Oncology Updates Permanyer Publications, Mallorca (Spain), 2009; 1-18
Corich L, Aranda A, Carrassa L, Bellarosa C, Ostrow J D, Tiribelli C
The cytotoxic effect of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells is modulated by the
expression level of MRP1 but not MDR1
Biochem J 2009 417 : 305-312
D'Incalci M
Adjuvant 5-FU based chemotherapy for colon cancer: match or miss the mismatch?
Eur J Cancer 2009 45 : 316-317
Mosconi P, Donati S, Colombo Cinzia, Mele A, Liberati A, Satolli R, Consensus Conference Working
Group
Informing women about hormone replacement therapy: the Consensus conference statemen
BMC Womens Health 2009 9 : 14
Apolone G, Corli O, Negri Emanuele, Mangano S, Montanari M, Greco M T, CPOR SG Investigators
Effect of transdermal buprenorphine on patients-reported outcomes in cancer patients. Results from the Cancer Pain
Outcome Research (CPOR) Study Group
Clin J Pain 2009 25 : 671-682
De Vargas Macciucca M, Casale A, Manganaro L, Floriani I, Fiore F, Marchetti L, Panzironi G
Rectal villous tumours: MR features and correlation with TRUS in the preoperative evaluation
Eur J Radiol 2009 E-pub :
Sessa C, Cresta S, Noberasco C, Capri G, Gallerani E, de Braud F, Zucchetti M, D'Incalci M, Locatelli A,
Marsoni S, Corradino I, Minoia C, Zintl P, Gianni L
Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours
Eur J Cancer 2009 45 : 2116-2122
Pace S, Capocasa F, Tallarico C, Frapolli R, Zucchetti M, Longo A
Determination of total and lactone form of a new camptothecin derivative gimatecan (ST1481) and its metabolite
ST1698 in human plasma by high-performance liquid chromatography with fluorimetric detection
J Pharm Biomed Anal 2009 50 : 507-514
Ferrari D, Fiore J, Codecà C, Di Maria G, Bozzoni S, Bordin V, Caldiera S, Luciani A, Zonato S,
Floriani I, Foa P
A phase II study of carboplatin and paclitaxel for recurrent or metastatic head and neck cancer
Anticancer Drugs 2009 20 : 185-190
Garattini S, Bertele' V, Floriani I, Torri V
Exenatide for type 2 diabetes
Lancet 2009 373 : 122
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Bardella M T, Elli L, De Matteis S, Floriani I, Torri V, Piodi L
Autoimmune disorders in patients affected by celiac sprue and inflammatory bowel disease
Ann Med 2009 41 : 139-143
Infante M, Lutman R F, Imparato S, Di Rocco M, Ceresoli G L, Torri V, Morenghi E, Minuti F, Cavuto
S, Bottoni E, Inzirillo F, Cariboni U, Errico V, Incarbone M, Ferraroli G, Brambilla G, Alloisio M,
Ravasi G
Differential diagnosis and management of focal ground-glass opacities
Eur Respir J 2009 33 : 821-827
Stacchiotti S, Collini P, Messina A, Morosi C, Barisella M, Bertulli R, Piovesan C, Dileo P, Torri V,
Gronchi A, Casali P G
High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic
and pathologic response by using RECIST and Choi criteria
Radiology 2009 251 : 447-456
Mazziotti G, Floriani I, Bonadonna S, Torri V, Chanson P, Giustina A
Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies
J Clin Endocrinol Metab 2009 94 : 1500-1508
Donati S, Cotichini R, Mosconi P, Satolli R, Colombo Cinzia, Liberati A, Mele A
Menopause: knowledge, attitude and practice among Italian women
Maturitas 2009 63 : 246-252
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 2009 52 : 7906-7910
Roesli C, Borgia B, Schliemann C, Gunthert M, Wunderli-Allenspach H, Giavazzi R, Neri D
Comparative analysis of the membrane proteome of closely related metastatic and non-metastatic tumor cells
Cancer Res 2009 69 : 5406-5414
Apolone G, Corli O, Mosconi P, et al, The 2008 Erice Group
The 2008 Erice statement toward a more humanistic oncology
J Ambul Care Manage 2009 32 : 252-258
Deandrea S, Corli O, Moschetti I, Apolone G
Managing severe cancer pain: the role of transdermal buprenorphine: a systematic review
Ther Clin Risk Manag 2009 5 : 707-718
Mosconi P, Donati S, Colombo C, Mele A, Liberati A, Satolli R, Consensus Conference Working Group
Informing women about hormone replacement therapy
Cancer Journal 2009 15 : 344
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 post-surgical metastasis:
a longitudinal study
Lancet Oncol 2009 10 : 877-884
Garattini S, Torri V, Floriani I
Cetuximab for metastatic colorectal cancer
N Engl J Med 2009 361 : 96
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
Taraboletti G, Bonezzi K
Inhibitors of angiogenesis based on thrombospondin-1
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In :Recent advances in angiogenesis and antiangiogenesis Bentham, United Arab Emirates, 2009; 112-126
Coltrini D, Ronca R, Belleri M, Zardi L, Indraccolo S, Scarlato V, Giavazzi R, Presta M
Impact of VEGF-dependent tumour micro-environment on EDB fibronectin expression by subcutaneous human
tumour xenografts in nude mice
J Pathol 2009 219 : 455-462
Marangon E, Falcioni C, Manzotti C, Fontana G, D'Incalci M, Zucchetti M
Development and validation of a LC–MS/MS method for the determination of the novel oral 1,14 substituted taxane
derivatives, IDN 5738 and IDN 5839, in mouse plasma and its application to the pharmacokinetic study
J Chromatogr B Analyt Technol Biomed Life Sci 2009 877 : 4147-4153
Sala F, Zucchetti M, Bagnati R, D'Incalci M, Pace S, Capocasa F, Marangon E
Development and validation of a HPLC-MS/MS method for the determination of ST1926, a novel oral antitumor
agent, adamantyl retinoid derivative, in human plasma of patients participating in a Phase I study
J Chromatogr B Biomed Appl 2009 877 : 3118-3126
Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E,
Rulli E, Floriani I, Bencardino K B, 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
Garassino M C, 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 : 2691-2701
Signorelli M, Lissoni A A, 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 16 : 3431-3441
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 2009 E-pub :
Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E
Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care
Cochrane Database Systematic Reviews 2009 CD000022
Ubezio P, Lupi M, Branduardi D, Cappella P, Cavallini E, Colombo V, Matera G, Natoli C, Tomasoni D,
D'Incalci M
Quantitative assessment of the complex dynamics of G1, S, and G2-M checkpoint activities
Cancer Res 2009 69 : 5234-5240
Damia G, D'Incalci M
Contemporary pre-clinical development of anticancer agents - What are the optimal preclinical models?
Eur J Cancer 2009 45 : 2768-2781
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 2009
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Cervellini I, Bello E, Frapolli R, Porretta-Serapiglia C, Oggioni N, Canta A, Lombardi R, Camozzi F,
Roglio I, Melcangi R C, D'Incalci M, Lauria G, Ghezzi P, Cavaletti G, Bianchi R
The neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction of
antitumor activity in 13762 adenocarcinoma-bearing rats
Neurotox Res 2009 E-pub :
LAY PRESS SELECTION (2009)
Candiani G, Colombo C, Daghini R, Magrini N, Mosconi P, Nonino F, Satolli R.
Manuale metodologico: come organizzare una conferenza di consenso
Istituto Superiore di Sanità, Sistema Nazionale Linee Guida SNLG, Roma, Novembre 2009
Mosconi P, Satolli R, Donati S, Colombo C, Liberati A, Mele A.
TOS: quale informazione alle donne? La conferenza di consenso di Torino
Dialogo sui Farmaci 6/2008 dossier:264-269
http://www.torinomedica.com/allegati/2009/All.%20a%20(23)%20Ferraro_PROCEDURE_Pre
venzione_01%20febbraio%202009.pdf
Mosconi P
Ancora a proposito di mammografia e buona informazione
http://www.partecipasalute.it/cms_2/node/1101 ; 23/2/2009
Braun C, Mosconi P
Il punto sulla pubblicità diretta ai consumatori
Ricerca & Pratica 2009 Numero 145 anno 25: 19-28
Mosconi P, Colombo C
I cittadini e l’innovazione. L’innovazione nell’assistenza e nuovi strumenti di valutazione
Il Pensiero Scientifico Editore, Suppl. 3 Politiche Sanitarie Vol 10 N°.1, 2009
Mosconi P, Satolli R, Liberati A, Donati S, Mele A et al.
Quale informazione per la donna in menopausa sulla terapia ormonale sostitutiva? Consensus
Conference Torino, 16-17 maggio 2008
Sistema Nazionale per le Linee Guida SNLG-ISS
http://www.pnlg.it/cms/files/CC_TOS.pdf giugno 2009: 1-48
Mosconi P
La tutela del cittadino nelle attività del comitato etico
Janus Numero 34, estate 2009, Zadig editore: 15-16
Mosconi P
Milano, capitale morale dell’impegno volontario
In: Milano capitale della salute, a cura di Roberto Satolli. Editrice Abitare Segesta, Milano,
2009
Giavazzi R. ADAMANT. In: The Parliament Magazine, issue 285, pag.50, 30 marzo 2009
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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 and inhibitors of telomerase.
Flow Cytometric analysis of the DNA content in human ovarian cancer:
clinical correlations
Conflicting results have been published on the prognostic significance of DNA aneuploidy on
advanced ovary carcinoma (stage III or IV). The Citometry unit has reported one of the largest
studies of the scientific literature indicating that the aneuploidy in the advanced ovary
carcinoma is not an independent prognostic factor. In a large number of cases of stage I and II
ovary tumors DNA content and the percentage of cells in S phase of the cell cycle, has been
measured with flow cytometry, demonstrating that in the early stages of the disease DNA
content is a prognostic factor important for ovary tumor.
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
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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.
Applying this procedure we demonstrated complex but biologically consistent patterns of time
and dose-dependence for each cell cycle effect descriptor, on a reference cell line of ovarian
carcinoma, following a short treatment with melphalan, doxorubicin, topotecan, cisplatin and
taxol. Within this project we produced a database containing the values associated to the new
effect descriptors, related to few compounds but rich of information about them, especially in
the dose and time dependence of the effects. This database will be used to compare the
treatment response of the most common drugs adopted in the ovarian carcinoma.
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 will apply the multidisciplinary approach,
exploiting cell cycle simulation tools, to the study of cell cycle perturbations induced by
erlotinib as a representative EGFR inhibitor. Studies of the time- and dose-dependence of
perturbations induced by treatments are ongoing for single erlotinib treatment or for erlotinib
combined with gemcitabine, irinotecan and oxaliplatin. The appreciation and the quantification
of these effects will provide an important contribution to the comprehension of the mode of
action of erlotinib alone or in combination. Such perspectives are vital if the events are to be
decoded and used in predictive models for the exploration of pharmacodynamic actions and in
understanding the origins of treatment failure.
Anticancer Drug Effects Decoded by Time-Lapse Imaging, Flow Cytometry
and Modeling
We aim to 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
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responses in term of the two major determinant 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).
The working hypothesis is that quantitative analysis of time-lapse microscopy data could be
integrated with the information provided by flow cytometry - allowing for the first time a joint
interpretation of both kind of experiments through a common mathematical model that simulate
the underlying phenomena. The final goal is to provide new levels of understanding and
simulation tools to the cancer research community.
Timing the changes of the cellular content of specific proteins inside G1,
in exponentially growing cells
We developed a method for measuring the content of immunocytochemically detected proteins
in individual cells progressing through G1 phase. The feasibility was demonstrated in the
analysis of cyclin E levels. The sequence of G1 events is tracked in unaltered cycling
conditions, in a cell line in the phase of balanced growth in vitro, to avoid the pitfalls of
synchronization.
The method is based on i) a bromodeoxyuridine (BrdUrd) pulse-and-chase experimental plan;
ii) triparametric flow cytometric detection of DNA, BrdUrd and cyclin E; iii) data analysis
supported by the basic mathematical theory of asynchronous growing populations with variable
cell cycle phase durations.
Pharmacokinetic of new taxane derivates
We have performed a study on a new taxane derivative, chemically and biologically different
from the conventional ones. For two of this compound, IDN6140, we evaluated the
pharmacokinetic profile applying analytical methods based on HPLC/MS/MS technique
developed in the Cancer Clinical Pharmacology Unit. It showed high ability to cross the blood
brain barrier, high distribution in brain and biological activity even in tumors with low
susceptibility to other taxanes (cerebral tumor), suggesting a potential clinical interest- for the
therapy of Central Nervous System tumors and metastasis.
Clinical pharmacology of CEP-18770 (a new proteasome inhibitor)
The study in collaboration with SENDO, was performed in 40 patients defining 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 espostion.
Pharmacokinetic/pharmacodynamic correlations showed in the patients studied a significative
inhibition of the proteasome activity.
Quality assurance program
During this last year we started a project aimed to achieve a quality system to bring the
Pharmacokinetic Unit inside the Laboratory of Cancer Pharmacology in compliance with Good
Laboratory Practice (GLP). On this purpose, as first step, we organized spaces and tools to
develop this process starting from the preparation of the standard operating procedures and
with the training of the personnel involved.
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.
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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.
Internal collaborations:
Department of Biochemistry and Molecular Pharmacology (ref.: Maddalena Fratelli, Mario
Salmona)
Department of Oncology (ref.: Sergio Marchini, Mariarosa Bani, Maurizio D'Incalci)
External collaborations:
Fondo Edo Tempia (ref.: Giovanna Chiorino)
Istituto Toscano Tumori (ref: Duccio Cavalieri)
Istituto Weizmann (ref. Eytan Domany)
Università di Birmingham (ref. Francesco Falciani)
Università di Aberdeen (ref. Tony Travis)
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 ET-743 working mechanism in human sarcoma, sensible
and resistant.
Related to the projects:
Department of Oncology (ref. Sergio Marchini, Maurizio D'Incalci, Massimo Broggini, Mirko
Marabese) –Agilent platform
‫ ־‬Metastasis/Relapses Project (phase III ovarian)
‫ ־‬LPS2 Project (cell lines, response to ET-743)
Department of Oncology (ref. Mariarosa Bani, Raffaella Giavazzi) –Affymetrics platform
‫ ־‬Stroma Project
‫ ־‬Parenchyma Project
Osp. S.Gerardo, Monza (ref. Robert Fruscio)
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
Internal collaborations:
Department of Oncology (ref.: Sergio Marchini, Mariarosa Bani, Raffaella Giavazzi, Maurizio
D'Incalci, Massimo Broggini, Mirko Marabese)
External collaborations;
Ospedale S.Gerardo, Monza (ref. Robert Fruscio)
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Implementation of the data management engine for the Italian Registry
Domiciliar Artificial Nutrition, in collaboration with the Scientific Society
SINPE (ref. Loris Pironi, S.Orsola, Bologna)
This activity involves all aspects of the data management, statistical analysis, help desk,
informatic infrastructures and software for handling an observational clinical study.
For this purpose a new ibrid online/offline database has been developed, compliant with the new
privacy related laws about the data protection issues.
Osp. S. Orsola, Bologna (ref. Loris Pironi)
Società Scientifica SINPE
Laboratory of Molecular Pharmacology
G2 checkpoint and cell cycle
The requirement of Chk1 for both S and G2/M checkpoints has been elucidated while only
few studies have connected Chk1 to the mitotic spindle checkpoint. This checkpoint ensures
proper chromosome segregation by delaying anaphase until chromosomes are aligned on the
spindle thus preventing chromosomal instability, aneuploidy and cancer predisposition. We
recently found that Chk1 depletion in U2OS human osteosarcoma cells inhibited cell
proliferation and raised the percentage of cells with a 4N DNA content, which correlated with
accumulation of giant polynucleated cells morphologically distinct from apoptotic cells,
while no increased number of cells in G2 or mitosis could be detected. Downregulation of
Chk1 also caused accumulation of cells in the last step of cytokinesis, and of tetraploid cells
in G1 phase, which coincided with activation of p53 and increased levels of p21. In addition,
Chk1 depleted U2OS cells failed to arrest in mitosis after spindle disruption by nocodazole and
showed decreased protein levels of Mad2 and BubR1, two mitotic checkpoint components.
These studies show that U2OS cells lacking Chk1 undergo abnormal mitosis and fail to activate
the spindle checkpoint, suggesting a role of Chk1 in this checkpoint. It will be now interesting
to further investigate the inter relationship existing among Chk1 and mitotic checkpoint
components.
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
from the crossing are at the normal Mendelian ratio, indicating that no specific genotypes
(p53;DRAGO) are favoured. The mice will be followed for tumor onset and survival and the
development of tumors in the double KO mice will be compared with p53 KO mice.
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 cancer. 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 the are microRNAs differentially expressed in the two
subgroups that, if confirmed in a larger sample size, could represent a potential therapeutic
target.
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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 cancer 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.
The encouraging study on the natural derivatives of inositol phosphates (IP5) had as a
consequence the synthesis of new derivatives which have been charcterised in vitro for their
activity. One of these derivatives, HYG9 (2-O-benzil-myo-inositol 1,3,4,5,6-pentakisphosphate)
has been further investigated because of its good pharmacological profile in vitro. In particular,
HYG9 showed activity also in cell lines resistant to IP5.
We have therefore evaluated the activity in vivo of HYG9 in a model of human prostate cancer,
PC3 were the drug showed a dose dependent inhibition of tumor growth. The pharmacodynamic
study prformed in parallel, showed that at the active doses, HYG9 was able to significantly
reduce in the tumor the phosphorylation of akt (indicative of an inhibition of the pathway).
From a mechanistic point of view, HYG9 has been shown to compete for the PH domain of akt
but also to directly inhibit PDK1, a kinase responsible for akt phosphorylation.
We have also studied other inhibitors, such as PIK-75 and PI-103 as isoform specific ad dual
PI3K mTOR inhibitors, respectively. Both drugs showed activity against human cancer cell
lines constitutively expressing activated akt and showed interesting results in combination
studies with drugs acting with a different mechanism of action.
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
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phospholipase C γ1 and new clones with inducible expression of phospholipase C γ1 have been
consequently generated. These models will will be extremely useful for better understanding the
role of this protein in the metastatic process.
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
We have identified a new mechanism through which cancer cells become resistant to the
anthracycline derivative, nemorubicin (methoxy morpholino doxorubicin). In resistant cells, in
fact, we have a a reduced DNA repair ability particularly they show defects in the nucleotide
excision repair (NER) due to the lack of expression of one of the NER genes, XPG.
The lack of XPG expressionin resistant cells is due to methylation of DNA in the regulatory
regions of the gene which blocks the transcription of the gene and consequently protein
formation. All the cells of different origin presenting resistance to nemorubicin show this
mechanism. This represent sthe first experimental evidence that a NERR gene can be
inactivated through methylation and offers new possibilties to revert the resistance mechanisms
by using demethylating and/or histone deacetylating inhibitors.
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
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.
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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
presentin 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. These data suggest
the possibility to act with molecules able to inhibit HGF or c-met as possible bone
antimetastatic agents.
Characterization of response of stem cells to damage
A number of studies have been conducted in our laboratory aimed at investigating the activation
of the DNA damage checkpoints after IR in hematopoietic stem cell obtained from umbilical
cord. Stem cells can be obtained from umbilical cord and expanded and partially differentiated
in vitro with a specific cytokine cocktails, having a system in which two different cell
population (staminal and more differentiated progenitors) can be studied. We could demonstrate
that the IR-DNA damage checkpoint is similar in hematopoietic stem cells and in the more
differentiated cells derived from them. We could also demonstrate that during this in vitro
expansion, the expression of the Chk1 protein (a master protein in the control of S and G2
checkpoints in cells) has a peculiar pattern of expression, being expressed only at the beginning
of the culture. Interfering with the activity of the protein with a specific inhibitors at the time
when the protein is expressed, induced a shift from myeloid to lymphoid differentiation,
unravelling a new role of chk1 in differentiation.
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 are
now performing a detailed phenotypical, molecular and pharmacological characterization.
Indeed all these studies will possibly lead to the identification of specific genes that could be
targeted in the opvarian tumor initiating cells with the final aim to improve the therapy of this
tumor.
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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
tumor types, 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.
Laboratory of Biology and Therapy of Metastasis
Physiologic regulation of angiogenesis
Angiogenesis, the formation of blood vessels from existing ones is a fundamental process in
tumor progression. A delicate balance between pro- and antiangiogenic factors finely tunes this
process. In the last years we have been interested in endogenous angiogenesis-regulatory
factors. During 2009 we have continued the study of trombospondin-1 (TSP-1), an endogenous
inhibitor of angiogenesis. TSP-1 directly binds to angiogenic factors, in particular FGF-2
(Fibroblast Growth Factor-2), inhibiting their bioavailability and activity. In a structure/function
relationship analysis of different active domains of TSP-1, we have identified the FGF-2
binding site of TSP-1. This sequence has beenused as a model to design new antiangiogenic
compounds based on the active sequence of TSP-1.
Lymphangiogenesis in ovarian carcinoma
Lymphatic spread in early ovarian cancer is a predictor of outcome with potential clinical value.
With the aim to clarify the molecular mechanisms involved in the process of lymphangiogenesis
in ovarian cancer, the expression of VEGFC, a factor that stimulates lymphangiogenesis, has
been measured in serum and ascites of mice bearing human ovarian carcinoma xenografts and
correlated with lymphonode infiltration by neoplastic cells.
To better represent the clinical features of ovarian neoplasia, an orthotopic model of human
ovarian carcinoma xenograft has been created by injecting ovarian tumor cells under the bursa
of the ovary. Infection of ovarian carcinoma cells with lentivirus vectors carrying the coding
sequence of VEGFC together with the firefly luciferease gene and fluorescent probes has been
performed; the invasive and metastatic potential of tumor cells producing VEGFC will be
evaluated using optical imaging techniques, in mice bearing tumor.
How the microenvironment affects endothelial cell gene expression
It is fundamental to understand qualitative and functional differences between tumor and normal
tissue endothelial cells (EC) and the molecular mechanisms that drive the angiogenic process.
This could lead to the identification of selective markers of the vascular endothelium associated
to pathologies and/or of target molecules for the development of novel therapeutic strategies. To
this purpose we analysed the gene expression profile of endothelial cells isolated from ovarian
carcinoma exposed or not to an “angiogenic/tumor” environment reconstituted in vitro. We have
found that:
i) the “angiogenic/tumor” environment is able to modulate EC gene expression
ii) a few genes are preferentially expressed by tumor associated endothelial cells.
Results suggest that those “genes” might be of interest as markers of tumor endothelium. Their
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expression is higher in endothelial cells from tumor specimens than from normal tissues. The
putative new tumor endothelial markers have been further validated by in situ hybridization
analysis of normal and tumor tissues (as mRNA transcript). Antibodies, directed against the
putative targets proteins, have indeed demonstrated the localization within the tumor stroma.
Preclinical models: role of Vascular Endothelial Growth Factor (VEGF) on
tumor growth, vascularization and response to therapy
To study the role of VEGF induced angiogenesis in the response of cancer to chemotherapy we
have generated a variant of the human ovarian carcinoma A2780/1A9 by stable transfection
with the VEGF121 isoform (1A9-VS1). In mice 1A9-VS1 xenografts show an angiogenic
phenotype associated to the high production of VEGF.
We have found that the response to chemotherapy (e.g. paclitaxel) differ in xenografts
producing different levels of VEGF. The blockade of VEGF, by the administration of
Avastin®, greatly improved the antitumor activity by paclitaxel treatment of 1A9-VS1.
Studies are ongoing to elucidate the mechanism, associated to modification of the tumor
microenvironment, that are responsible of these differences.
This model is therefore being used to study gene expression. Based on circulating VEGF levels
and morphological analysis of the tumor vasculature, tissue samples of the 1A9-VS1 were
microdissected (PALM Microlaser system, in collaboration with the Institute of Pathology at
Helios Klinikum, Germany) in order to isolate the stroma compartment to be evaluated by mean
of Affymetrix’s GeneChip® Arrays technology. The microarray hybridisation data were
analyzed with the aid of specialized software (i.e. GeneSpring and Rosetta Resolver) and
differentially expressed genes were identified. Specifically, we have discovered that in the
stroma of tumors 294 genes were up- and 162 were down-regulated in consequence of the
VEGF produced by the cancer cells. Gene Ontology (GO) enquiry, identified over-represented
categories of potentially biologically relevant genes in the stroma of 1A9VS1 (high VEGF)
tumors. Structural molecule activity, cell organization and biogenesis, and basement membrane
were among the up-regulated categories.
Preclinical evaluation of inhibitors of angiogenesis and vascular targeting
agents
Antineoplastic therapies directed against the tumor vascular system may be designed with two
different strategies. Antiangiogenic therapy prevents the formation of new vessels, while
vascular disrupting agents (VDA) aim to selectively destroy the already formed tumor vessels.
In 2009 we have investigated the activity of several inhibitors of angiogenesis and VDA.
We have investigated the antiangiogenic activity and mechanism of action of new molecules –
peptides or non-peptidic small molecules – which mimic endogenous inhibitors of angiogenesis,
including thrombospondin (TSP-1).
Among the VDA, we have studied the properties of novel tubulin binding agents (analogues of
colchicines and combretastatins), which cause microtubules depolymerization, selective damage
to tumor blood vessels and tumor necrosis in experimental models in vivo. In collaboration with
Prof. Bellina at the Department of Chemistry, University of Pisa , we have screened classes of
compounds with such properties. The lead compound/s will be further characterized for
pharmacological and vascular targeting/antineoplastic properties.
The challenge of the combinations
The optimization of biological therapies against selective targets in combinations with
chemotherapy is one of the interest of this laboratory. We are investigating small molecule
receptor tyrosine kinase inhibitors, that affects angiogenesis. We are studying vandetanib, an
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inhibitor of VEGFR, EGFR and Ret in combination with pacltaxel (PTX) on a model of human
ovarian carcinoma xenograft.
As expected we found vandetanib influences the tumor vasculature (decreased vascular volume
and increased maturation). This was associated to a decreased distribution of paclitaxel in the
tumor. Accordingly, a therapeutic advantage has been observed by the combination of
vandetanib administrated together with or after paclitaxel. These findings imply that the analysis
of vascular changes and chemotherapeutic drug uptake in vandetanib treated tumors may assist
to guide the schedule of this combination.
Identification of vascular markers of liver metastasis
Using mouse models of liver metastasis, vascular structure were biotinylated in vivo by terminal
perfusion methodology and biotinylated proteins analyzed by mass spectrometry (collaboration
with Dario Neri, ETH Zürich). A number of proteins selectively expressed at the level of the
metastatic nodules have been identified and confirmed by immunofluorescence analysis.
High PAR-1 expression is associated to a malignant phenotype
Protease-activated receptor-1 (PAR-1) over-expression has been associated to a variety of
human cancers, and increasing evidence implicates PAR-1 as a contributor to human melanoma
malignancy. We investigated melanoma cells, isolated from patient lesions representing various
stages of disease progression, for the expression of PAR-1 and evaluated their migratory and
metastatic capabilities. Cells from advanced stage melanomas expressed higher levels of PAR-1
than those from early stages. The metastatic capability showed by the melanoma cells which
overexpressed PAR-1 allowed these cells to colonize the lungs in 70-100% of the mice.
Accordingly, melanoma cells over-expressing PAR-1 had higher migrated (chemotaxis assay)
and invading (invasion assay-matrigel) cell counts than those expressing low PAR-1. Migration
and invasion were decreased by silencing PAR-1 (siRNA) and treating with SCH9797, a PAR-1
specific inhibitor.
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
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.
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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.
Since 2008 two phase II studies exploring the activity of sorafenib in patients with pancreatic
cancer and of Panitumubab in colorectal cancer 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
results about feasibility and tollerability will be published after the mid-2010. 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 molecular
features based on. In particular the epidermal growth factor (EGFR) is a promising target for
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anticancer therapy. A "tailored therapy" based on individual molecular features may result in
better responses and optimization of sources and costs. The study select specific patient
subgroups based on clinical and biological features. In this patients the target therapy may result
in better responses. In particular, the predictive value of PTEN mutations, EGFR protein
expression and 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), will enroll approximately 1500
patients in three years.
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.
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.
Breast cancer
TOP (Trastuzumab Optimisation trial) study is aimed at increasing the knowledge on the
efficacy of herceptin in the treatment of locally advanced or metastatic breast cancer patients. It
includes two randomised, open label, phase III clinical trials: the first addresses the impact of a
maintenace therapy with herceptin in patients previously treated with chemotherapy plus
herceptin, the second is focused on the efficacy in term of overall survival of a second-line of
chemotherapy plus herceptin versus chemotherapy alone in patients progressed to a first-line
containing herceptin. The results of TOP study will allow to evaluate the cost/benefit ratio of
herceptin treatment and to optimise the therapeutic effectiveness of such a drug, already
approved in Italy, but used without clear data supporting evidence of benefit in the considered
setting. This study is sponsored by Regione Lombardia and supported by the Agenzia Italiana
del Farmaco (AIFA).
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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 named 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.
Major activities in 2009:
• Publication of scientific articles on international journals: 4 published and 2
submitted
• Publication of the volume “Guida ragionata all’impiego dei farmaci oppioidi nel
dolore da cancro” (“The rational guide to use opioids in cancer pain”) written by
O.Corli and M.Pizzuto - CIC Editore;
• Educational activity: “2° Corso di Epidemiologia Clinica e Metodologia della
Ricerca” (“2nd Course of Clinical Epidemiology and Researching Methodology
” – Naples, feb. 2009;
• Organization of International Conference “Pain classification and assessment” Milan, sept. 2009;
• Participation in EAPC (European Association of Palliative Care) – Wien, May
2009 – and in EPIC Congress - Lisbon, Sept. 2009;
• Joining in the EuropeanPCR-network (Palliative Care Research Network);
• Initial planning and organization of new studies:
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‐
‐
‐
‐
A comparison RTC between strong opioids used in cancer pain treatment
(multicentric Italian/European study)
A validation research of an algorithm for chronic pain management in
general medicine
Planning of a HTA for a new opioid molecule: tapentadol
A systematic review on breakthrough cancer pain.
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. In 2009 the main results of CALYPSO study
were presented at ASCO meeting in Orlando. 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
2009 two randomized clinical trials in ovarian cancer with new antiangiogenic drugs (pazopanib
and vargatef) and internationally coordinated by the German onco-gynecologic group named
AGO were finalised and one started accrual 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 a randomized phase II trial aimed to
evaluate the efficacy of trabectedina in the treatment of patients with uterine leiomyosarcoma.
In 2009 the data collection for two observational studies was concluded: a retrospective study
describing the therapeutic approach to ovarian cancer relapsing after 6-12 months form a first
line platinum-based chemotherapy and a prospective study aimed at evaluating the reliability of
trans-vaginal echography to assess the depth of endometrial cancer miometrial invasion. During
2009 the data of the ILIADE III trial (chemo-radiotherapy compared with radiotherapy only in
high risk endometrial cancer patients ) were pooled with data coming form a similar Nordic
Society of Gynecologic Oncology (NSGO)’s trial
During 2008, MaNGO’s Technical-Scientific Committe met quarterly while MaNGO affiliates
were conveyed in one General Assembly.
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
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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 the final analyses will be finished and in 2010 results will be submitted to
an international peer reviewed journal.
Breast cancer
In the context of a multi-regional project sponsored by the Italian Ministery of Health (6°
Progetto Integrato Oncologia) LaTOR is coordinating 2 multi-center RCTs testing the efficacy
of different follw-up regimens in low and high riskpatienst with breast cancer.
Other research activities
LaTOR has continued on 2009 colklaboration with other laboratories of the Mario Negri
Institute. The most important collaboration are thos eeprtaining 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 beebn
extensivlely published on interbationala peweer-reviwed journals.
Laboratory of Medical Research and Consumer Involvement
This Laboratory promotes activities of research in the field of involvement of citizens and
patients and their associations in decision making in health and medical issues. The activities of
this laboratory include: researches on information conveyed to patients on illness and treatment,
implementation of web site on the topics of the health and the information
(www.partecipasalute.it; www.paincare.it; www.fondazionemattioli.it); strategy of involvement
of groups of patients for the publication of educational material; research on the evaluation of
the quality of the life and satisfaction with care through studies on ad hoc selected groups, and
implementation on validated ad hoc questionnaires.
PartecipaSalute (“Participate in Health Care”) - fostering a strategic
alliance between consumers’ associations and medical community
The project, started in 2003, has been extended over 2009 within a three years planning. It is
coordinated by Mario Negri Institute, with the collaboration of the Italian Cochrane Centre and
Zadig, an editorial and publishing company. It is supported by Compagnia di San Paolo, a non
profit private-law foundation. 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.
During 2009 the fourth edition of the training course for consumers and patients’ representatives
- called “Accademia del cittadino” - has been 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. The program is structured into three standard modules of the
Partecipasalute framework and two modules focused on the training goals of the Centro
Gestione Rischio Clinico. Participants are 33, coming mainly from Toscana. One of the future
aims of the project is to promote joint initiatives with national and regional institutions in order
to foster their collaborations and partnership with citizens and patients.
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During 2009, a training course dedicated to lay members of ethic committees in Lombardia has
been organized, together with the Rete Oncologica Lombarda and the Fondazione Istituto dei
Tumori di Milano. The main issues covered were the clinical relevance of research studies and
the critical aspects of information and informed consent for patients. The course was structured
into three modules of two days each and ended in a final congress.
The website of the project has been developed into the PartecipaSalute web 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.
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
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 on 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 2009 the project started, the persons in charge for the project in each local agency were
contacted and the information materials were draft. The booklet for women was also piloted
through three focus groups. Residential courses for the persons in charge of the project were
organized. The project lasts two years.
SNAP project - Smoke, Nutrition, Alcohol and Physical Activity
SNAP - Smoke, Nutrition, Alcohol and Physical Activity - is a campaign for the health
addressed to the whole population of the province of Como, 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 accessories
in Brianza, 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
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through a brochure. Data from the third questionnaire will be analyzed and compared with those
of the first two.
In 2009 a protocol for an intervention in secondary schools in Lombardia was written in
collaboration with FSE and IFOM.
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 on consumer involvement refers to the working group
focusing on information. It planned to evaluate 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.
The websites were collected through a research by key words on the search engine google. 72
websites were included in the sample. Each website was independently evaluated by two
reviewers, using the defined form. Discrepancies were settled by discussion between reviewers
and a third reviewer settled any remaining disagreement. Data collected were analyzed and
discussed by the Laboratory.
Each evaluation form was included in Cignoweb, a website developed within the project that
publishes a database collecting websites and information materials about cancer.
FSK project
The project "Inquire, know and participate to improve the quality of life. The case of asthma,
type 2 diabetes and breast cancer" is a study on the quality of information provided to citizens
and patients.
This project, sponsored by the Smith Kline Foundation, has been launched with the aim of
evaluating the quality of the brochures produced and distributed by the associations of patients
dealing with the three diseases and to produce a core of information on which associations can
draw evidence-based information to produce their brochures.
In February 2009, associations were contacted in Lombardy, Veneto, Tuscany, Emilia
Romagna, Puglia and Sardinia.
All the brochures, produced or distributed by the associations contacted, arrived at the Institute
and were evaluated twice. Analysis of data was carried out: most of the brochures are written in
a clear language, but only few raise awareness of the reader because the information does not
follow data reported in the literature. The core of information will be produced in collaboration
with representatives of patients’ associations contacted.
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
and in 2008 was discussed and developed the protocol and all related forms, including from the
point of fair and comprehensive information to patients who will be invited to participate in the
study.
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 moderate-
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low 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 will be operational from
2009.
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/qod. 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.
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.
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.
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.
4.
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.
5.
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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6.
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.
Principali pubblicazioni:
1.
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.
2.
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
3.
Fjororova N, Novich M, Vrachko M, Kharchevnichova N, Zholdakova Z, Sinitzyna O, Benfenati E, Regulatory
assessment of chemicals within OECD Member Countries, EU and in Russia, J Environ Sci Heal C 2008 26: 40-88
4.
Roncaglioni A, Benfenati E, In silico-aided prediction of biological properties of chemicals: oestrogen receptormediated effects, Chem Soc Rev 2008 37: 441-450
5.
Porcelli C, Boriani E, Roncaglioni A, Chana A, Benfenati E, Regulatory perspectives in the use and validation of
QSAR. A case study: DEMETRA model for daphnia toxicity, Environ Sci Technol 2008 42 : 491-496
6.
Benfenati E (Ed.), Quantitative Structure-Activity Relationships (QSAR) for Pesticide Regulatory Purposes,
Elsevier Science Ltd, Amsterdam, The Netherlands (2007), 1-510
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. Proteomics in oncology.
1.
Nephrol 2009 ; 20 : 123-130.
2.
Environ Health Perspect 2008; 116: 1027-1032.
3.
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.
4.
Castiglioni S, Zuccato E, Crisci E, Chiabrando C, Fanelli R, Bagnati R. Identification and measurement of illicit drugs and
their metabolites in urban wastewaters by liquid chromatography tandem mass spectrometry (HPLC-MS-MS). Anal Chem
2006;78: 8421-8429.
5.
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.
6.
Chiabrando C, Rivalta C, Bagnati R, Valagussa A, Durand T, Guy A, Villa P, Rossi JC, Fanelli R. Identification of
metabolites from type III F2-isoprostane diastereoisomers by mass spectrometry. J Lipid Res. 2002;43:495-509.
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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
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.
Selected Publications
1.
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.
2.
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.
3.
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.
4.
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
5.
Riservato M, Rolla A, Davoli E . An isotopic dilution approach for 1,3-butadiene tailpipe emissions and ambient air
monitoring. Rapid Commun Mass Spectrom 2004; 18: 399-404
6.
Davoli E, Gangai L, Morselli P, Tonelli D. Characterisation of Odorant emissions from Landfills by SPME and GC/MS.
Chemosphere 2003; 51: 357-368
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. Illicit drugs in the environment. Philos Transact A Math Phys Eng Sci 2009 ; 367 : 3965-3978.
2.
Environ Health Perspect 2008, 116: 1027-1032.
3.
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.
4.
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.
5.
their metabolites in urban wastewaters by liquid chromatography tandem mass spectrometry (HPLC-MS-MS). Anal Chem
2006, 78: 8421-8429.
6.
Zuccato E, Calamari D, Castiglioni S, Chiabrando C, Bagnati R, Fanelli R. Cocaine in surface water: a new evidence-based
tool to monitor community drug abuse. Environmental Health: A Global Access Science Source 2005, 4:14
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).
Selected Publications
1.
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.
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2.
3.
4.
5.
6.
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.
Analysis of phosphoinositides and their aqueous metabolites. Berrie CP, Iurisci C, Piccolo E, Bagnati R, Corda D. Methods
Enzymol. 2007;434:187-232.
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.
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.
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.
2.
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
3.
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.
4.
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.
5.
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.
6.
Fattore E, Fanelli R, Turrini A, Di Domenico A. Current dietary exposure to polychlorodibenzo-p-dioxins,
polychlorodibenzofurans, and dioxin-like polychlorobiphenyls in Italy. Mol Nutr Food Res 2006; 50: 915-921
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
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Roberta Pastorelli, Head of Protein and Gene Biomarkers Unit since 2004, Researcher 1992-2003,
Research fellow 1983-92 at the Mario Negri Institute.
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.
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.
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.
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.
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 new model for identification of endocrine disruptors using molecular docking.
A method aimed at characterizing environmental odors to identify odor sources in complex
environments.
Albumin can become a source of potentially antigenic peptides in proteinuric nephropaties.
Proteomic/bionformatic workflow for comparative secretome analysis to highlight perturbed
functional networks in cancer cell lines.
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.
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.
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ARPA Emilia Romagna
ARPA Veneto
ASL di Brescia
ASL di Como
ASL di Cagliari
ASL di Napoli
CNR - IRSA
Comune di Rosignano Marittimo (LI)
Comune di Sant’Urbano (PD)
CSRA-Asti
Federchimica
Fondazione 'S. Maugeri'
Fondazione ISI, Turin
Gruppo Collaborativo sulla Suscettibilità Genetica ai Cancerogeni Ambientali (GSEC), Milan,
Italia
INRAN-Istituto Nazionale di Ricerca sugli Alimenti e la Nutrizione
ISPO, Florence
Istituto Clinico Humanitas, Milan
I.Z.S.L.T - Istituto Zooprofilattico Sperimentale del Lazio e Toscana
Ministero dell'Ambiente
Politecnico di Milano
Politecnico di Torino
Provincia di Vercelli
Provincia Pordenone
Stazione Sperimentale dei Combustibili, Milan
Università degli Studi del Piemonte Orientale
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
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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 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
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
Symlog, Paris, France
Syngenta Crop Protection AG, Basel, Switzerland
TNO, Delft, Netherlands
University of Tartu, Tartu, Estonia
Journal of Environmental Science and Health, Part B (Emilio Benfenati), Journal of
ANNUAL REPORT
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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 and Bioanalytical Chemistry, Chemical Biology & Drug Design,
Chemical Research Toxicology, Chemometrics and Intelligent Laboratory Systems,
CHEMOLAB, Chemosphere, Clinical Biochemistry, , Environment International,
Environmental Pollution, Environmental Modeling & Software, Environmental Science &
Technology, Journal of Chemical Information and Modeling, International Journal of Molecular
Science, Journal Computer-Aided Molecular Design, Journal of Hazardous Materials, Lung
Cancer, Molecular Diversity, Proteomics, Royal Society's Philosophical Transactions,
Toxicology Letters, Waste Management, Water Research, International Journal of
Environmental Analytical Chemistry, Molecular Nutrition and Food Research, Journal of
Chromatography A, External review of the quality of the scientific outputs of the European
Food Safety Authority (EFSA).
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
Workshop of the CAESAR EC project on QSAR models for REACH, Istituto di Ricerche
Farmacologìche Mario Negri, Milan, Italy, 10-11 March 2009.
4th annual meeting of the ATHON EC project, Istituto di Ricerche Farmacologìche Mario
Negri, Milan, Italy, 24-26 March 2009.
OSIRIS Training Course on Integrated Testing Strategies (ITS), Istituto di Ricerche
Farmacologìche Mario Negri, Milan, Italy, 23-25 September 2009.
Workshop “Alta risoluzione, imaging, ion mobility: le sfide della spettrometria di massa
moderna”, Istituto di Ricerche Farmacologìche Mario Negri, Milan, Italy, 16 December 2009.
ANNUAL REPORT
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Workshop “Alta risoluzione, imaging, ion mobility: le sfide della spettrometria di massa
moderna”, Istituto di Ricerche Farmacologìche Mario Negri, Milan, Italy, 16 December 2009.
International Meeting on health and environment: challenges for the future. Istituto Superiore di
Sanità, Rome, Italy, 9-11 December 2009.
Milano Focus Salute. Seminari e Dibattiti sui temi della prevenzione e dei corretti stili di vita,
Milan, Italy, 25-27 November 2009.
Master di II livello anno accademico 2009 - 2010 “Management of chemicals: la normativa
REACH”, Teoria sui metodi di non testing e metodi in silico nel REACH, Genoa, Italy, 10
November 2009.
EPAA Annual Conference "Dissemination of 3Rs information", Brussels, Belgium, 6
November 2009.
3rd Meeting of the Extended OECD/IPCS Advisory Group on Molecular Screening and
Toxicogenomics, Paris, France, 26 October 2009.
XXXIII Congresso Nazionale dell’Associazione Italiana Studio Pancreas, Rozzano (Milan),
Italy, 15-17 October 2009.
34° Congresso Nazionale della Società Italiana di Farmacologia, Rimini, Italy, 14-17 October
2009.
Course “Philosophy of Risk in Health Risk Assessment”, Stockholm, Sweden, 12-16 October
2009.
Scuola di Alta Formazione - Università del Piemonte Orientale, Alessandria, Italy, 12 October
2009.
Sardinia 2010 International Symposium on Energy from Biomass and Waste. Cagliari, Italy, 5-8
October 2009.
National Congress of the Italian Society for Neuroscience (SINS), Milan, Italy, 2-5
October 2009.
WATERMED - Salone sulle Tecnologie dell'Acqua per il Mediterraneo, Rome, Italy, 1 October
2009.
ECNIS Workshop on Biomarkers and Cancer, Porto, Portugal, 21-23 September 2009.
International workshop “Illicit drug market” Università di Roma “la Sapienza”, Rome, Italy, 1617 September 2009.
ANNUAL REPORT
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VII World Congress on Alternatives & Animal Use in the Life Sciences, Rome, Italy, 30
August-3 September 2009.
10th International Conference on Environmental Mutagens, Florence, Italy, 20-25 August 2009.
EC Project Coordinators Meeting, Sintra, Portugal, 30-31 July 2009.
Hydrica - Salone Internazionale biennale Tecnologie per l’Acqua, Padua, Italy, 25 June 2009.
Italian Proteomics Association, 4th Annual National Conference, Milan, Italy, 22-25 June 2009.
57th American Society for Mass Spectrometry Conference, Philadelphia, PA, USA, 1-5 June
2009.
SETAC Europe 19th Annual Meeting, Gothenburg, Sweden, 31 May-4 June 2009.
Triple Quadrupole User Meeting, Florence, Italy, 22-23 May 2009.
International Society of Pharmacovigilance, Training Courses ‘Ecopharmacovigilance’, Verona,
Italy, 26-27 March 2009.
Workshop of the CAESAR EC project on QSAR models for REACH, Istituto di Ricerche
Farmacologìche Mario Negri, Milan, Italy, 10-11 March 2009.
13° Congreso de Investigacion en Salud Publica, Cuernavaca, Mexico, 3-6 March 2009.
A2A Brescia
ACEGAS S.p.A, Trieste
AIIPA (Associazione Italiana Industrie Prodotti Alimentari)
AMA, Roma
ASL Como
ASL Mantova
ASL Napoli 2
Associazione Italiana Ricerca sul Cancro
ASSOFOODTEC/UCIMAC (Costruttori Italiani Macchine per Caffè Espresso ed Attrezzature
per Bar)
Bluegreen Biotech
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)
ANNUAL REPORT
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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, Pavia
EnergyGreen S.r.l.
European Commission (ATHON, CASCADE, CAESAR, CHEMOMENTUM,
CHEMPREDICT, OSIRIS, ORCHESTRA)
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)
I.Z.S.L.T - Istituto Zooprofilattico Sperimentale del Lazio e Toscana
Lachifarma, Zollino (LE)
Lucart, Cartiera Lucchese S.p.A. Porcari, Lucca
Ministero della Salute, Italia
Ministero dell'Ambiente, Italia
Nufarm S.A.S., Francia
Oxon Italia S.p.A., Pero (MI)
Provincia di Pordenone
Provincia di Vercelli
SO.GE.NU.S. S.p.A
Tenacta Group
TM.E. S.p.A.
Veolia Servizi Ambientali S.p.A.
Vaissière T, Cuenin C, Paliwal A, Genair-EPIC Investigators, Hainaut P, Herceg Z. Quantitative analysis of DNA
methylation after whole bisulfitome amplification of a minute amount of DNA from body fluids. Epigenetics 2009 ;
4 : 221-230.
Carpi D, Korkalainen M, Airoldi L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R.
Dioxin-sensitive proteins in differentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci 2009 ; 108 :
330-343.
Airoldi L, Magagnotti C, Iannuzzi A R, 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 : 397-402.
Maggioni S, Benfenati E, Colosio C, Moretto A, Roots O, SAFEFOODNET Consortium. Food contamination control
in European new Member States and associated candidate countries: data collected within the SAFEFOODNET
project. J Environ Sci Health B 2009 44 : 407-414.
Toropov A A, Toropova A P, Benfenati E. QSAR modelling for mutagenic potency of heteroaromatic amines by
optimal SMILES-based descriptors. Chem Biol Drug Des 2009 ; 73 : 301-312.
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.
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Toropov A, Toropova A P, Benfenati E. Simplified molecular input line entry system-based optimal descriptors:
quantitative structure-activity relationship modeling mutagenicity of nitrated polycyclic aromatic hydrocarbons.
Chem Biol Drug Des 2009 ; 73 : 515-525.
Toropov A A, Toropova A P, Benfenati E. QSPR modeling bioconcentration factor (BCF) by balance of correlations.
Eur J Med Chem 2009 ; 44 : 2544-2551.
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.
Toropov A A, Toropova A P, Benfenati E, Manganaro A. QSPR modeling of enthalpies of formation for
organometallic compounds by SMART-based optimal descriptors. J Comput Chem 2009 ; 30 : 2576-2582.
Toropov A A, Toropova A P, Benfenati E. QSPR modeling of octanol water partition coefficient of platinum
complexes by InChI-based optimal descriptors. J Math Chem 2009 ; 46 : 1060-1073.
Bala P, Ostropytskyy V , Baldridge K, Rasch K, Benfenati E, Sild S, Casalegno M, Schone R, Maran U, Schuller B,
Miroslaw L, Williams N. UNICORE: A middleware for life sciences grids. In: Handbook of research on
computational grid technologies for life sciences, biomedicine, and healthcare. Vol. I, 2009; 615-643.
Roncaglioni A, Benfenati E. Computer-aided methodologies to predict endocrine-disrupting potency of chemicals. In:
Endocrine-disrupting chemicals in food. CRC Press, Boca Raton, 2009; 306-321.
Toropov A A, Toropova A P, Benfenati E, Leszczynska D, Leszczynksy J. Additive InChI-based optimal descriptors:
QSPR modeling of fullerene C60 solubility in organic solvents. J Math Chem 2009 ; 46 : 1232-1251.
Toropov A A, Toropova A P, Benfenati E. QSPR modelling of the octanol/water partition coefficient of
organometallic substances by optimal SMILES-based descriptors. Central European Journal Chemistry 2009 ; 7 :
846-856.
Toropov A A, Toropova A P, Benfenati E, Manganaro A. QSAR modelling of carcinogenicity by balance of
correlations. Mol Divers 2009 ; 13 : 367-373.
Toropov A A, Toropova A P, Benfenati E. Additive SMILES-based carcinogenicity models: probabilistic principles
in the search for robust predictions. Int J Mol Sci 2009 ; 10 : 3106-3127.
Toropov A A, Toropova A P, Benfenati E, Manganaro A. QSAR modelling of the toxicity to Tetrahymena pyriformis
by balance of correlations. Mol Divers 2009, DOI 10.1007/s11030-009-9186-0.
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.
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.
Zuccato E, Castiglioni S. Illicit drugs in the environment. Philos Transact A Math Phys Eng Sci 2009 ; 367 : 39653978.
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.
Sala F, Zucchetti M, Bagnati R, D'Incalci M, Pace S, Capocasa F, Marangon E. Development and validation of a
HPLC-MS/MS method for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative,
in human plasma of patients participating in a Phase I study. J Chromatogr B Biomed Appl 2009 ; 877 : 3118-3126
ANNUAL REPORT
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Zuccato E, Castiglioni S, Chiabrando C, Bagnati R, Fanelli R Valutazione dell'uso di droga nelle città. Residui nelle
acque di scarico e consumi nella popolazione. Ricerca & Pratica, 2009 145 : 3-11
Fattore E. Effetto accumulo attraverso la catena alimentare, occorre ridurre l'esposizione, ARPA 2009, n. 1: 32.
Fattore E. Esposizione acuta a pesticidi: e i bambini? Ricerca & Pratica, 2009 149 : 193-199
OTHER PUBLICATIONS (2009)
Brambilla G, Abate V, Davoli E, De Filippis S P, De Luca S, Dellatte E, Fanelli R, Fattore E, Fochi I, Fulgenzi A R,
Iacovella N, Iamiceli A L, Lucchetti D, Melotti P, Miniero R, Moret I, Pignata S, Roncarati A, Triboni P, Ubaldi A,
Zambon S, Di Domenico A. Occurrence of persistent organic pollutants in wild and farmed Italian fish in the
Mediterranean Sea. 29th International Symposium on Halogenated Persistent Organic Pollutants (Dioxin 2009)
August 23-28, 2009 Beijing. Organohalogen Compounds 2009, 71 : 1070-1074.
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
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
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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
chromatography, electrophoresis and mass spectrometry, for the identification and
characterization of proteins and peptides in biological samples. This activity is mainly aimed at
1) global characterization and comparison of secretomes from human cancer cell lines to
identify proteins that may be functionally relevant for tumor growth and spread; 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)
selectively isolating biologically relevant proteins by immunoaffinity-based micro-techniques.
Ongoing projects include the study of exogenous protein degradation in renal tubular cells in
relation to antigen presentation mechanisms, and the characterization of the secretome of cancer
cell lines in vitro to identify factors affecting immune cells.
Method development in proteomics
The laboratory works on the optimization of various analytical methodologies for proteomics,
i.e. various complementary techniques for protein isolation and identification by mass
spectrometry (MALDI-TOF-MS, LC-ESI-MS/MS).
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.
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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
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.
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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. PCBs were measured in food
items in different European countries, showing differences in PCBs exposure of European
consumers. 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. Ongoing
studies are focused to assess levels of PCBs and dioxins in samples of human milk collected
from mothers living in highly contaminated areas.
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, with the aim of better characterizing the contamination and assessing
related risks.
Human and environmental risks are evaluated by studying the toxic effects of pharmaceuticals
at environmental levels, on cultures of human and zebra fish cells. 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
abuse such as cannabis, opiates (heroin, morphine), and amphetamines (amphetamine,
methamphetamine, ecstasy). Consumption of these drugs have been subsequently estimated in
some European cities. 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.
Regulatory activities
On behalf of the Ministry of Health, we carried on the evaluation of the dossiers required for
pesticide registration within the European Union.
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.
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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
the emissions of pollutants from incinerators and landfills, including transfer of these
compounds into the food chain. During the 2009 a health impact assessment due to
concentrations of particulate matter, ozone, and nitrogen dioxide, in an highly industrialized
area, in northern Italy, and another study on the toxicological risk for consumers, due to the
release of heavy metals from the professional coffee machines have been completed.
Exposure to environmental pollutants
Research activities also include measurement of contaminants in environmental samples, and
assessment of human exposure. Specific research projects focuses 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 is 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.
Methods are developed mainly using solid phase extraction (SPE) followed by liquid
chromatography - mass spectrometry (LC-ESI-MS/MS) or gas chromatography - mass
spectrometry (GC-MS). Available instruments include mass spectrometers equipped with
different analyzers: magnetic fields, time of flight (TOF), quadrupoles (single and triple), ion
traps and high resolution orbitrap. The main ionization techniques are electron ionization (EI),
chemical ionization (CI), MALDI, ACPI and Electrospray (conventional and nanoSpray).
Substances of interest include proteins, peptides, hormones, pharmaceuticals, drugs of abuse,
pesticides, and other environmental contaminants (PCBs, hydroxy-PCBs, perfluorinated
compounds).
Work has been started for the development of imaging methods in biological tissues with the
MALDI-TOF technique.
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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.
Cell Death and Neuroprotection Unit
Head
Tiziana Borselllo, Biol.Sci.D.
Laboratory of Drug Metabolism
Head
Silvio CACCIA, Farm.D.
Laboratory of Experimental Neurology
Head
Annamaria VEZZANI, 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 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 170 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., Bertani, I. Calella, AM., Thaler, F.Invernizzi. R. Alpha-synuclein and Parkinson's disease selective
neurodegeneration effect of alpha synuclein fragment on dopaminergic neurons in vitro. Ann. Neurol. 47: 632-640
(2000)
•
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)
•
Pesaresi M, Lovati C, Bertora P, Mailland E, Galimberti D, Scarpini E, Quadri P, Forloni G, Mariani C. Plasma levels of
beta-amyloid (1-42) in Alzheimer's disease and mild cognitive impairment. Neurobiol Aging., 27:904-5 (2006)
•
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 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).
Ettore Beghi (EB) 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.
•
Leone, MA. Solari, A.,Beghi, E. for the FIRST Group. Treatment of the first tonic-clonic seizure does not affect longterm remission of epilepsy. Neurology 2006; 67: 2227-2229
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Millul, A., E. Beghi, G. Logroscino, A. Micheli, E. Vitelli, A. Zardi, for the “Registro Lombardo SLA”(SLALOM).
Survival of patients with amyotrophic lateral sclerosis in a population-based registry. Neuroepidemiology 2005; 25: 114119.
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Tonini, C., E. Beghi, A.T. Berg, G. Bogliun, L. Giordano, R.W. Newton, A. Tetto, E. Vitelli, D. Vitezic, S. Wiebe.
Predictors of epilepsy surgery outcome: a meta-analysis. Epilepsy Res 2004; 62: 75-87.
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Van den Broek, M., and Beghi E., for the RESt-1 Group. Morbidity in patients with epilepsy: type and complications. A
European Cohort Study. Epilepsia 2004; 45: 71-76.
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Van den Broek, M. and Beghi E. for the RESt-1 Group. Accidents in patients with epilepsy: type and complications. A
European Cohort Study. Epilepsia 2004; 45: 667-672.
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•
Musico, M., E. Beghi, A. Solari, F. Viani for the First Seizure Trial Group. Treatment of the first tonic-clonic seizure
does not improve the prognosis of epilepsy. Neurology 1997; 49: 991-998.
Caterina Bendotti, got her degree in Pharmacy at the University of Milano in 1984; In 1986 -1988 she was
post doc 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 is member of the Board of Directors 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.
•
Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M, Simeoni S, Crippa V, Onesto E, Palazzolo I,
Rusmini P, Bolzoni E, Bendotti C, Poletti A. Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet.
16(13):1604-18, 2007.
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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(3):719-25, 2007
•
Peviani M, Cheroni C, Troglio F, Quarto M, Pelicci G, Bendotti C. Lack of changes in the PI3K/AKT survival pathway
in the spinal cord motor neurons of a mouse model of familial amyotrophic lateral sclerosis.Mol Cell Neurosci. 34:592602, 2007
•
Carri MT, Grignaschi G, Bendotti C. Targets in ALS: designing multidrug therapies. Trends Pharmacol Sci. 27(5):26773, 2006
•
Cheroni C., Peviani M., Cascio P., Debiasi S., Monti C. and Bendotti C. Accumulation of human SOD1 and
ubiquitinated deposits in the spinal cord of SOD1G93A mice during motor neuron disease progression correlates with a
decrease of proteasome. Neurobiol. Disease. 18(3): 509-522, 2005
•
Bendotti C and MT Carri. Lessons from models of SOD1-linked familial ALS. Trends Mol Med. 10(8):393-400, 2004
•
Bendotti C., Tortarolo M., Suchak S.K., Calvaresi N., Carvelli L., Bastone A., Rizzi M., Rattray M. and Mennini T.
Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate
levels. J. Neurochem.,79, 737-746, 2001
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Migheli A., Atzori C., Piva R., Tortarolo M., Girelli M., Schiffer D. and Bendotti C. Lack of apoptosis in mice with
ALS. Nature Medicine: 5, 966-967, 1999.
Silvio Caccia. Laurea in Pharmacy at the University of Milan. Diploma in Industrial Chemistry at the L.
Cobianchi Technical Institute (Verbania, NO) and Diploma in Biochemical Research at the Istituto di
Ricerche Farmacologiche “Mario Negri” (Milan).
Research fellow, Laboratory of General Pharmacology at the Mario Negri Institute, 1970-1973;
Permanent Researcher, Laboratory of Neuropharmacology, 1975; Head of Pharmacokinetic Unit, 1983;
Head of Drug Metabolism Laboratory, 1988 to date, doing research in the field of pharmacology and
toxicology with particular focus on pharmacokinetic aspects, both at the pre-clinical and clinical level.
He has been member of the scientific assessment teams (acting as expert) for the evaluation of marketing
authorisation applications submitted to the European and Italian Agencies.He is author and co-author of
more than 200 articles, including reviews, monographs and book chapters.
•
Caccia S. N-dealkylation of arylpiperazine derivatives: disposition and metabolism of the 1-aryl-piperazines formed.
Curr Drug Metab 2007 ; 8 : 612-622.
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Caccia S. Main active components of St. John's Wort (Hypericum Perforatum) extracts: current analytical procedures for
pharmacokinetics and concentration-response studies. Curr Pharm Anal 2006; 2: 59-68.
•
Caccia S. Antidepressant-like components of Hypericum perforatum extracts: An overview of their pharmacokinetics
and metabolism. Curr Drug Metab 2005; 6: 531-543
•
Caccia S. Metabolism of the newest antidepressants: Comparisons with related predecessors IDrugs 2004; 7: 143-150.
•
Caccia S. Biotransformation of post-clozapine antipsychotics. Pharmacological implications. Clin Pharmacokinet
2000; 38: 39.
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Caccia S. Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic
implications. Clin Pharmacokinet 1998; 34: 281-302.
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.
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
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).
° 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)
° Chiesa R, Drisaldi B, Quaglio E, Migheli A, Piccardo P, Ghetti B, Harris DA Accumulation of protease-resistant prion
protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation. Proc Natl
Acad Sci U S A. 97:5574-9 (2000)
° Chiesa R, Harris DA.Prion diseases: what is the neurotoxic molecule? Neurobiol Dis. 8:743-63 (2001)
° 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)
Li A, Christensen HM, Stewart LR, Roth KA, Chiesa R, Harris DA.Neonatal lethality in transgenic mice expressing
prion protein with a deletion of residues 105-125. EMBO J. 26:548-58 (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. 2008, 60:598-609 (2008).
Chiesa R, Harris DA.Fishing for prion protein function. PLoS Biol. 2009 Mar 31;7(3):e75
Maria Grazia De Simoni got the Doctoral Degree in Biological Sciences in 1977 at the University of
Milano, Italy. 1981: Research Specialist in Pharmacology (PhD), Mario Negri Institute, Milan, Italy.
1981-1982: European Community fellowship for "Advanced Professional Training", INSERM U 171,
Universitè Claude Bernard, Lyon, France; 1984 Department of Histology, Karolinska Institute,
Stockholm. Working experience:1987-1997: Chief of the Neurochemistry Unit, Mario Negri Institute,
Milano; 1998-present: Chief of the Laboratory of Inflammation and Nervous System Diseases, Mario
Negri Institute. Scientific interests: pathogenesis of cerebral ischemia/reperfusion and traumatic brain
injury; inflammatory response and apoptotic mechanisms as targets of therapeutic strategies; animal
models and clinical studies. She is member of the board of “Master in Tecnologie Avanzate Applicate
alle Patologie Neurodegenerative", University of Milan and member of the board of “Associazione
Italiana per la Ricerca sull’Invecchiamento Cerebrale” (AIRIC).
Selected pubblications
•
De Simoni MG, Storini C, Barba M, Catapano L, Arabia AM, Rossi E, Bergamaschini L. Neuroprotection by
complement (C1)-inhibitor in mouse transient brain ischemia. J Cereb Blood Flow Metab, 23: 232-239, 2003.
•
De Simoni M G, Rossi E, Storini C, Pizzimenti S, Echart C, Bergamaschini L. The powerful neuroprotective action of
C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. Am J Pathol., 164: 1857-1863, 2004.
•
Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, De Luigi A, Vergani C and 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. 24: 4181-4186, 2004
•
Troglio F, Echart C, Gobbi A, Pawson T, Pelicci PG, De Simoni MG & Pelicci G. The neuron-specific Rai (Shc C)
adaptor regulates the PI3K-Akt pathway in vivo and protects against cerebral ischemia. Proc Natl Acad Sci U S A
101(43): 15476-15481, 2004.
•
Storini C, Bergamaschini L, Gesuete R, Rossi E, Maiocchi D, De Simoni MG. Selective inhibition of plasma kallikrein
protects brain from reperfusion injury. JPET 318: 849-854, 2006
•
Capone C, Fabrizi C, Piovesan P, Principato MC, Marzorati C, Ghirardi O, Fumagalli L, Carminati P and De Simoni
MG. 2-Aminotetraline derivative protects from ischemia/reperfusion brain injury with a broad therapeutic window,
Neuropsychopharmacology, 32: 1302-1311, 2007
•
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 2 e373, 2007.
•
Pastori C, Librizzi L, Breschi GL, Regondi C, Frassoni C, Panzica F, Frigerio S, Gelati M, Parati E, De Simoni MG, de
Curtis M.Arterially perfused neurosphere-derived cells distribute outside the ischemic core in a model of transient focal
ischemia and reperfusion in vitro.PLoS ONE. 3(7):e2754. 2008
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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•
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.
•
Guzzetti S, Calcagno E, Canetta A, Sacchetti G, Fracasso C, Caccia S, Cervo L, Invernizzi RW 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
•
Calcagno E, Carli M, Invernizzi RW The 5-HT1A receptor agonist 8-OH-DPAT prevents prefrontocortical glutamate
and serotonin release in response to blockade of cortical NMDA receptors J Neurochem 2006; 96: 853-860
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Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, Invernizzi
RWGenotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model
of depression J Neurosci 2005; 25: 8165-8172
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Greco B, Invernizzi RW, Carli M Phencyclidine-induced impairment in attention and response control depends on the
background genotype of mice: reversal by the mGLU2/3 receptor agonist, LY379268 Psychopharmacology (Berl) 2005;
179: 68-76
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).
•
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 Geriats Society 1993; 41: 45-49.
•
Lucca U, Tettamanti M, Forloni G, Spagnoli A. Nonsteroidal anti-inflammatory drug use in Alzheimer’s disease.
Biological Psychiatry 1994; 36: 854-856.
•
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.
•
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.
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Nobili A, Tettamanti M, Frattura L, et al. Drug use in the elderly in Italy. Ann Pharmacother 1997; 31:416-422.
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Nobili A, Gebru F, Rossetti A, et al. Doctorline a private toll-free telephone medical information service. Ann
Pharmacother 1998; 32:120-5.
•
Nobili A, Riva E, Tettamanti M, et al. The effect of a structured intervention on caregivers of patients with dementia and
problem behavior: a randomized controlled pilot study. Alzheimer Dis Assoc Disord 2004; 18: 75-82.
•
Lucca U, Nobili A, Riva E, Tettamanti M. Low level of B vitamins and the risk of cognitive and functional decline in the
very-old: results from the Monzino 80-Plus Study. Neurobiol Aging 2004; 25: 31.
•
Lucca U, Nobili A, Riva E, Tettamanti M Cholinesterase inhibitor use and age in the general population Arch Neurol
2006; 63: 154-155.
•
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).
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.
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-1 beta (2008) Brain, 131: 3256-65
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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
•
Dube’ C., Vezzani A., Behrens M., Bartfai T., Baram TZ. (2005) Interleukin-1beta contributes to the generation of
experimental febrile seizures. Ann Neurol, 57,152.
•
Richichi C, E-J. D. Lin, D. Stefanin, D. Colella, T. Ravizza,G. Grignaschi, G. Sperk, M. J. During and A. Vezzani “
Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in
the rat hippocampus” (2004) J Neurosci, 24,3051
•
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
•
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. (2000) "Powerful anticonvulsant action of IL-1 receptor antagonist upon
intracerebral injection and astrocytic overexpression in mice" Proc. Natl. Acad. Sci. USA, 97, 11534.
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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. (2000) "Powerful anticonvulsant action of IL-1 receptor antagonist upon
intracerebral injection and astrocytic overexpression in mice" Proc. Natl. Acad. Sci. USA, 97, 11534.
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
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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
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Repici M, Centeno C, Tomasi S, Forloni G, Bonny C, Vercelli A, Borsello T.Activation After Cerebral Ischemia And
Effect Of D-Jnki1 On C-Jun And Caspase-3 Activation. Neuroscience. 2007, 150: 40-9
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Borsello T., Centeno C., Riederer IM, Haeflinger JA and Riedere BM. Phosphorylation-dependent dimerization and
subcellular localization of islet-brain 1/c-Jun N-terminal kinase-interacting protein 1. J Neurosci Res. 2007, 85:3632-41.
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Borsello T Ed “Neuroprotection: Methods In Molecular Biology” Published By Humana Press, Usa Humana Press,
USA, Methods in Molecular Biology, June 2007
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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.
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Borsello T and Forloni G. JNK signalling: a possible target to prevent neurodegeneration. Current Pharmaceutical
Design 2007, 13, 1875-1886
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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.
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Borsello T. and Bonny C.Use of cell-permeable peptides to prevent neuronal degeneration. Trend in Mol. Med. 2004, 10:
239-44
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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
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.
•
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
•
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
•
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
•
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
•
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
consumers to evaluation of services, and acknowledgment of the value of the consumers’ point of view
about psychiatric treatments and services.
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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, D'Avanzo B. Efficacy of couple therapy as a treatment for depression: a meta-analysis. Psychiatr Q. 2008,
79:121-32.
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.
•
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)
•
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
•
Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch Neurol
2006;63:154-155
•
Nobili A, Riva E, Tettamanti M, Lucca U, Liscio MR, Petrucci B, Salvini Porro G. The effect of a structured intervention
on caregivers of patients with dementia. Results of a Randomized Controlled Study. Alzheimer Dis and Associated
Disorders 2004;18:75-82
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Il malato terminale oncologico. Esperienze dall’hospice. Ed. Emma Riva. Il Pensiero Scientifico, 2001
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Riva E, Tettamanti M, Gallini C. Il ruolo del medico di medicina generale nella gestione dei malati terminali oncologici.
Indagine svolta tra i medici di medicina generale in Friuli Venezia Giulia. Ricerca & Pratica 2001
•
Riva E, Nobili A, Trecate F. Per un impiego "ragionato" dei neurolettici, per la gestione dei disturbi del comportamento
in corso di Malattia di Alzheimer. Rec Prog Med 1998;89:598-603
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.
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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.
•
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
•
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).
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
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. Pharmacokinetics studies,
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
In a cellular model it has been shown that the peptide of D-JNK-1-TAT inhibiting the JNK
phosphorylation activity mediated by the enzyme JNK, exerts a control on β amyloid
production, these data indicate possible therapeutic perspectives in Alzheimer’s disease
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
monomeric form of fibrils species.
The exposure of cultured hippocampal cells to β amyloid 1-42 in oligomeric form induces an
alteration of dendritic spines.
The resveratrol, a well-known antioxidant induces its neuroprotective effect through the
activation of SIRT.1
ANNUAL REPORT
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2009
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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.
Polymorphisms in gene encoded for serotonin transporter protein influenced the risk to develop
Parkinson’s disease
In a prospective population-based study in the very old (Monzino 80-plus Study), behavioral
disturbances are uncommon prior to clinical dementia onset. After dementia diagnosis,
behavioral disturbances affect a large proportion of subjects, increasing with disease severity
while decreasing in the oldest-olds.
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.
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.
An intervention of common mental health disorders prevention in schools have produced no
change in information, attitudes and help seeking behaviour in students, partly because of the
high baseline levels.
In the period 2000-2007, antidepressant prescription doubled. In 2000 it concerned 5.5% of the
aging population, 11.4% seven years after. This increase is connected with SSRI, whose
prescription rose from 2.5% to 8.6%. No proportional decrease in the prescription of trycliclics
or the so-called atipical antidepressants was observed.
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..
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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).
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 averagely 11 days. At hospital discharge there was an increase in the rate
of patient with polypharamacy (+13%) and with multiple disease (+16%).
The long-term prognosis of epilepsy is the same in patients treated at the first seizure and those
treated at the recurrence. These findings suggest that treatment should be started at the first
seizure only on a case-by-case basis. The use of a third drug in children refractory to two
anticonvulsants does not affect the chance of seizure remission, suggesting that drug resistance
in epilepsy can be identified at the time of failure of two drugs.
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 low. Cerebral hemorrhage is the only independent predictor of acute
symptomatic seizures.
Psychiatric comorbidity is different when comparing patients with migraine to patients with
tension-type headache. This can be explained the severity of the disease and the underlying
pathophysiologic mechanisms. Patients with epilepsy-headache comorbidity differ from patients
with epilepsy or headache alone in terms of family history and severity of the clinical picture.
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.
Recombinant complement inhibitor (rhC1-INH) has a powerful neuroprotective action and a
wide therapeutic window in brain ischemia/reperfusion injury
ANNUAL REPORT
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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
A dysfunction of proteasome is found in the motor neurons of SOD1 mutant mice, which might
contribute to the accumulation of intracellular protein aggregates. This discovery open a route
for a possible therapeutic strategy based on the application of substance that may increase the
activity of proteasome
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.
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.
ANNUAL REPORT
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2009
IRFMN
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
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
ANNUAL REPORT
87
2009
IRFMN
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)
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 Superiore di Sanità, Roma
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
ANNUAL REPORT
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2009
IRFMN
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
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
ANNUAL REPORT
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IRFMN
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, Francia
Ohio State Univ, Columbus, Ohio, USA
Robarts Research Institute, London, Ontario, Canada
Royal Manchester Children's Hospital, Manchester, UK
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, Ungary
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)
ANNUAL REPORT
90
2009
IRFMN
Clinical Drug Investigation (Beghi)
Clinical Neurology and Neurosurgery (Beghi)
Cochrane Collaboration, Epilepsy (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)
International Journal of Molecular Epidemiology and Genetics (Forloni, senior, Albani
associate)
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 Scandinavica
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
Behavioural Brain Research
Behavioural Neuroscience
Biochimica et Biophysica Acta
Biochemical Journal
Biochemistry
BioMed Central Neurology
Biological Psychiatry
Brain Research
Brain Research Bulletin
Brain Research Review
Clinical Drug Investigation
Clinical Neurology and Neurosurgery
ANNUAL REPORT
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2009
IRFMN
Clinical Pharmacokinetics
Clin Pharm Therapy
CNS Drugs
Dialogo sui farmaci
Drugs
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 Alzheimer’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
ANNUAL REPORT
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2009
IRFMN
Nature Neuroscience
Neuroepidemiology
Neurology
Neurological Sciences
Neurobiology 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
Synapse
Trends Molecular Medicine
Agenzia Europea di Valutazione dei Medicinali (EMEA)
Agenzia Italiana per il Farmaco (AIFA)
Associazione Italiana di Neuroepidemiologia (Presidente Uscente)
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 Appicate alle Patologie
Neurodegenerative", Università di Milano
Committee for Proprietary Medicinal Products (CPMP) presso L’EMEA
Consiglio Direttivo AIRIC
Consiglio Direttivo della Società Italiana di Neuroscienze (SINS)
Coordination Group IMI-PharmaCog project
Direttivo della Lega Italiana contro l’Epilessia (LICE)
Editorial Committee, Guidelines of community based rehabilitation, World Health
Organization.
National Expert, recognized by AIFA (Agenzia Italiana del Farmaco), per l’EMEA (The Expert
for the 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)
ANNUAL REPORT
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2009
IRFMN
Medical Research Council Strategic Grant Application, UK
Mental Health Working Party, work group created by the Directorate General for health and
Consumer Protection (DG-SANCO), Bruxelles.
Coordination Group Neuroprion NoE, EU
International Committee on “Epilepsy and the Law”
International Organizing Committee and Secretariat coordinator for the Global Forum for
Community Mental Health, managed by the Department of Mental Health of the World Health
Organization.
International Subcommittee of the American Academy of Neurology
International Steering Committee of the ’European Network on mental health promotion and
mental disorder prevention (EMHPA).
International Subcommittee of the 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 (Exiting Chair)
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, France
Working Group on Epilepsy of the World Health Organization (WHO)
EVENT ORGANIZATION
7a Giornata di studio sulla malattia di Alzheimer
Problemi etici nella cura della persona affetta da demenza
March 14 2009, Ateneo Veneto, Venezia
Workshop
La società della paura
May 22nd, 2009, Istituto di Ricerche Farmacologiche Mario Negri, Milano
Corso sull’epidemiolgia e metodologia della ricerca.
“Medicina basata sull’evidenza in neuropsichiatria dello sviluppo: la diagnosi come strumento
di codifica per una banca-dati. Istituto Scientifico Stella Maris, Calabrone (Pisa) June 7-9,
2009.
Secondo Investigators’ Meeting Studio GiSAS
June 9, 2009, Istituto di Ricerche Farmacologiche Mario Negri, Milano
Corso per medici e operatori sanitari:
Associazione Nazionale Dentisti Italiani (ANDI)
Il supporto farmacologico per una terapia di successo
- Meccanismi delle interazioni tra farmaci
- Valutazione e significato clinico delle interazioni
May 4-11, 2009 - Milano.
ASL Provincia di Lecco, Lecco
ANNUAL REPORT
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IRFMN
Trattamento delle infezioni delle vie urinarie nell’anziano istituzionalizzato: tra evidenze e
incertezze
May 16, 2009 - Lecco.
Serate di aggiornamento in Patologia e Medicina Orale
Università degli Studi di Milano
Interazioni tra farmaci: una valutazione della rilevanza clinica
May 19, 2009 - Milano.
ASL Provincia di Bergamo, Bergamo
Reazioni avverse e interazioni tra farmaci: valutazione della rilevanza clinica.
September 19, 2009 – ASL Bergamo (BG)
Medical Evidence, Arese
Le interazioni tra farmaci
December 11, 2009, Arese
GFCMH Meeting regionale
June, 10-11 2009, Entebbe, Uganda
Workshop “Identification of molecular targets for next-generation treatments of Motor Neuron
Disease”4th ESN Conference on Advances in Molecular Mechanisms of Neurological
Disorders Leipzig, Germany; July 11-19, 2009
Workshop “Il ruolo degli utenti nella tutela della salute mentale”
10° Congresso Mondiale della WAPR
November, 14th 2009, Bangalore, India
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
CURE
EISAI
Epilepsy
Dipartimento di Salute Mentale, Azienda Ospedaliera Niguarda Ca’ Granda, Milano
Dana Foundation
Evidentia Medica, Grottaferrata (Roma)
Fondazione Cariplo, Milano
Fondazione Mariani, Milano
Fondazione Italo Monzino, Milano
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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
IMPHA II, DG-SANCO, Public Health and Consumers' Protection (Directorate General
Istituto Comprensivo Statale "G.D. Romagnosi", Carate Brianza (MI)
Istituto per la Ricerca e l’Educazione Regionale (Regione Lombardia)
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
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
Albani, D., Prato, F., Tettamanti, M., Lovati, C., Galimberti, D., Mariani, C., Lucca, U., Quadri,
PL., Scarpini, E., Forloni, G. The Serotonin Transporter Promoter Polymorphic Region is not a
Risk Factor for Alzheimer Disease Related Psychological J Alzheimers Dis 18:125-30 (2009)
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 (142) peptide. J Neurochem. 2009;110:1445-56
Albani D, Vittori A, Batelli S, Polito L, De Mauro S, Galimberti D, Scarpini E, Lovati C,
Mariani C, Forloni G.Serotonin transporter gene polymorphic element 5-HTTLPR increases the
risk of sporadic Parkinson's disease in Italy.
Eur Neurol. 2009; 62:120-3
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Albani D, Batelli S, Polito L, Prato F, Pesaresi M, Gajo GB, De Angeli S, Zanardo A,
Galimberti D, Scarpini E, Gallucci M, Forloni G. Interleukin-6 plasma level increases with age
in an Italian elderly population ("The Treviso Longeva"-Trelong-study) with a sex-specific
contribution of rs1800795 polymorphism.
Age (Dordr). 2009, 31:155-6
Antoniou X, Sclip A, Ploia C, Colombo A, Moroy G, Borsello T. JNK Contributes to Hif1alpha Regulation in Hypoxic Neurons. Molecules. 2009; 15:114-27.
Balosso S, Ravizza T, Pierucci M, Calcagno E, Invernizzi R, 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
Barbato A, Aresu A, Battino RN, Troisi E, Tettamanti M, Parabiaghi A. Uno strumento per la
ricerca transculturale in psichiatria: studio pilota sull’adattamento del Chinese Health
Questionnaire a 12 item (CHQ-12) per i cinesi residenti in Italia. Rivista di Psichiatria 2009; 44:
1-9.
Barbato A, D’Avanzo B. Efficacy of couple therapy as a treatment for depression, in Directions
in Psychiatry, ed. by Frederic Flach, Heatherleigh Press, New York, 2009.
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. 2009 Dec 2;4(12):e8130.
Beghi, M., R. Savica, E. Beghi, A. Nobili, L. Garattini. Utilization and costs of antiepileptic
drugs in the elderly. Drugs Aging 2009; 26: 157-168.
Beghi. E. Accidents and injuries in patients with epilepsy. Expert Rev. Neurother. 2009;
9(2):291-298.
Beghi. E., The concept of the epilepsy syndrome: How useful is it in clinical practice? Epilepsia
2009; 50 (Suppl.5): 4-10.
Beghi, E. Pupillo, S. Zoccolella, On behalf of the European Amyotrophic Lateral Sclerosis
Consortium (EURALS). 148th ENMC international workshop on the scientific contributions of
the EURALS consortium on amyotrophic lateral sclerosis. Neuromuscular Disorders 2009; 19:
379-381.
Bendotti C, Carrì MT. Amyotrophic lateral sclerosis: mechanisms and countermeasures.
Antioxid Redox Signal. 2009; 11:1519-22.
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
Colombo, A., Bastone, A., Ploia, C., Sclip, A., Salmona, M. Forloni, G. Borsello, TJNK
regulates APP cleavage and degradation in a model of Alzheimer's disease Neurobiol Dis 33:
518-25. (2009)
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Caccia S, Garattini S, Pasina S, and Nobili A. Predicting the clinical relevance of drug interactions
from pre-approval studies. Drug Safety 2009; 32: 1017-1039.
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
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
Cheroni C, Marino M, Tortarolo M, Veglianese P, De Biasi S, Fontana E, Vitellaro Zuccarello
L, 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. 2009; 18:82-96
A.Chiò, G. Logroscino, O. Hardiman, R. Swingler, D. Mitchell, E. Beghi, B.G. Traynor, on
behalf of the EURALS Consortium. Prognostic factors in ALS: a critical review. Amyotroph
Lateral Scler 2009; 10(5-6): 310-323.
Chiesa R. and Harris D.A. (2009) Fishing for prion protein function. PloS Biol., 7(3):e1000075.
Citterio,A., E. Beghi, A. Millul, A Evoli, R. Mantegazza, C. Antozzi, et al. Risk factors for
tumor occurrence in patients with myasthenia gravis. J. Neurol 2009; 256: 1221-1227
Colombo L, Piovesan P, Ghirardi O, Salmona M, Forloni G.
ST1859 reduces prion infectivity and increase survival in experimental scrapie.
Arch Virol. 2009; 154:1539-44..
Di Lazzaro, V., F. Pilato, P. Profice, F. Ranieri, G. Musumeci, L. Florio, E. Beghi, et al. Motor
cortex stimulation for ALS: a double blind placebo-controlled study. Neuroscience Letters
2009; 464: 18-21.
Feigin, AV. , J.F. Kurtzke, A. Korczyn, E. Beghi, A. Brown. Bridging the gap between
experimental and nonexperimental neuroepidemiology, and ultimately-between
neuroepidemiological research and practice: round table discussion at the First International
Congress on Clinical Neurology and Epidemiology. Neuroepidemiology 2009; 33: 296-304.
Forloni G, Salmona M, Marcon G, Tagliavini F.Tetracyclines and prion infectivity.
Infect Disord Drug Targets. 2009; 9: 23-30.
Fumagalli F, Franchi C, Caffino L, Racagni G, Riva MA, Cervo L.
Single session of cocaine intravenous self-administration shapes goal-oriented behaviours and
up-regulates Arc mRNA levels in rat medial prefrontal cortex.
Int J Neuropsychopharmacol. 2009; 12:423-9
Gesuete R., Storini C. Fantin A., Stravalaci M., Zanier E.R., Orsini F, Vietsch H., Mannesse M.
L. M., Ziere B., Gobbi M. and De Simoni M.G. “Recombinant C1-inhibitor in Brain Ischemic
Injury” Annals of Neurology, 66:332-342, 2009
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Giordano C, Albani D, Gloria A, Tunesi M, Batelli S, Russo T, Forloni G, Ambrosio L, Cigada
A.
Multidisciplinary perspectives for Alzheimer's and Parkinson's diseases: hydrogels for protein
delivery and cell-based drug delivery as therapeutic strategies.
Int J Artif Organs. 2009; 32:836-50.
Guerini, F.R., E. Beghi, G. Riboldazzi, et al. BDNF Val66Met polymorphism is associated with
cognitive impairment in Italian patients with Parkinson’s disease. Eur J Neurol 2009; 16:12401245.
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, 37:659-665, 2009
Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, Bendotti C, Mora G.
Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing
neuroinflammatory process. J Neuroimmunol. 2009; 210:73-9.
Marcon J, Gagliardi B, Balosso S, Maroso M, Noé F, Morin M, Lerner-Natoli M, Vezzani A,
Ravizza T. Age-dependent vascular changes induced by status epilepticus in rat forebrain:
implications for epileptogenesis (2009) Neurobiol Dis, 34:121
Mennini, T., L.Giordano, M. Mengozzi, P.Ghezzi, R. Tonelli, R. Mantegazza, V. Silani,
M.Corbo, C. Lunetta, E. Beghi. Increased IL-8 levels in the cerebrospinal fluid of patients with
amyotrophic lateral sclerosis. European Journal of Inflammation 2009;7:39-44.
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. 2009; 11:1559-67.
Nobili A, Pasina L, Trevisan S, Riva E, Lucca U, Tettamanti M, Matucci M, Tarantola M. Use
and misuse of antipsychotic drugs in patients with dementia in Alzheimer special care units.
International Clinical Psychopharmacology 2009; 24: 97-104.
Nobili A, Pasina L, Tettamanti M, Lucca U, Riva E, Marzona I, Monesi L, Cucchiani R,
Bortolotti A, Fortino I, Merlino L, Locatelli GW, Giuliani G. Potentially severe drug
interactions in elderly outpatients: results of an observational study of an administrative
prescription database. Journal Clinical Pharmacy Therapeutics 2009; 34: 1-10.
Noé F, Frasca A, Balducci C, Carli M, Sperk G, Ferraguti F, Pitkänen A, Bland R, Fitzsimons
H, During M, Vezzani A. Neuropeptide Y overexpression using recombinant adeno-associated
viral vectors
Neurotherapeutics. 2009; 6:300-6.
Ortolano F, Colombo A, Zanier E R, Sclip A, Longhi L, Perego C, Stocchetti N, Borsello T, De
Simoni M G.Human and experimental cerebral contusion: relevance of JNK pathway activation. J
Neuropathol Exp Neurol, 68:964-971, 2009
Papantonio, A.M., E. Beghi, D. Fogli, M. Zarrelli, G. Logroscino, A. Bentivoglio, P. Simone,
P. Tonali, L.M. Specchio. Prevalence of primary focal or segmental dystonia in adults in the
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district of Foggia, Southern Italy: A service-based study. Neuroepidemiology 2009; 33: 117123.
Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, Carri MT, Bendotti C. Treatment with
lithium carbonate does not improve disease progression in two different strains of SOD1 mutant
mice.Amyotroph Lateral Scler. Amyotroph Lateral Scler. 2009; 10:221-8.
Relja B, Schwestka B, Lee VS, Henrich D, Czerny C, Borsello T, Marzi I, Lehnert M.Inhibition
of c-Jun N-terminal kinase after hemorrhage but before resuscitation mitigates hepatic damage
and inflammatory response in male rats.Shock. 2009; 32:509-16.
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 Anemia Population-Based
Study. Haematologica 2009; 94: 22-3
Serretti A, Olgiati P, Politis A, Malitas P, Albani D, Dusi S, Polito L, De Mauro S, Zisaki A,
Piperi C, Liappas I, Stamouli E, Mailis A, Atti AR, Morri M, Ujkaj M, Batelli S, Forloni G,
Soldatos CR, Papadimitriou GN, De Ronchi D, Kalofoutis A.Lack of association between
interleukin-1 alpha rs1800587 polymorphism and Alzheimer's disease in two Independent
European samples. J Alzheimers Dis. 2009;16:181-7.
Striano,S., Beghii, E.,Epilepsy Syndromes in Development. Introduction. Epilepsia 2009; 50
(Suppl. 5): 1-3.
Valerio A, Dossena M, Bertolotti P, Boroni F, Sarnico I, Delbalba A, Faraco G, Chiarugi A,
Giordano A, Frontini A, Tonello C, Liou H C, De Simoni M G, Spano P F, Carruba M O, Pizzi
M, Nisoli E Leptin protects against cerebral ischemia through inhibition of glycogen synthase
kinase-3Beta and activation of NF-kB/c-Rel-dependent transcription. Stroke, 40: 610-617, 2009
Zoccolella S, Bendotti C, Beghi E, Logroscino G. Homocysteine levels and amyotrophic lateral
sclerosis: A possible link. Amyotroph Lateral Scler. 2009 Jun 23:1-8
Nobili A, Pasina L, Garattini S. Il paziente oncologico in trattamento con i farmaci inibitori
delle chinasi. Aggiornamento Medico 2009 ; 33 : 28-32.
Nobili A, Pasina L, Garattini S. Il paziente affetto da artrite reumatoide. Aggiornamento Medico
2009 ; 33 : 104-114.
Nobili A, Pasina L, Garattini S. Il paracetamolo. Aggiornamento Medico 2009 ; 33 : 173-175.
Camporese M, Frau S, Zimol R, Zermiani G, Nobili A, Conforti A, Giustetto G, Converso F,
Lombardo G, Del Zotti F, Font M, Mezzalira L. L'informazione sui farmaci nei software di
gestione delle cartelle cliniche. Dialogo sui Farmaci 2009; n. 3 : 108-112.
Nobili A, Pasina L, Garattini S. Il paziente con impotenza. Aggiornamento Medico 2009 ; 33 :
232-236.
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Nobili A, Pasina L, Garattini S. Farmaci antidemenza. Aggiornamento Medico 2009 ; 33 : 290293.
Marcucci M, Iorio A, Agnelli G, Nobili A, Salerno F, Corrao S, Mannucci PM, a nome del
partecipanti al Progetto Registro Politerapie SIMI. Somministrazione di FANS in pazienti in
trattamento anticoagulante orale ed eventi emorragici correlati in una coorte di anziani ricoverati
in reparti di medicina interna. Intern Emerg Med 2009; 4: S11.
Salerno F, Pasina L, Gobbo G, Cazzaniga M, Nobili A, Tettamanti M, Corrao S, Bonazzi J,
Vicidomini R, Mannucci PM, a nome del partecipanti al Progetto Registro Politerapie SIMI.
Utilizzo cronico di farmaci anti-ulcera peptica/reflusso gastroesofageo e infezione batterica
come causa di ricovero in soggetti anziani ricoverati in reparti di medicina interna. Intern Emerg
Med 2009; 4: S12.
Nobili A, Tettamanti M, Salerno F, Corrao S, Pasina L, Spirito V, Bonazzi J, Noce D, Mannucci
PM, a nome del partecipanti al Progetto Registro Politerapie SIMI. Studio sulla prevalenza di
polipatologie e politerapie nei reparti di medicina interna. Intern Emerg Med 2009; 4: S13.
Nobili A, Tettamanti M, Salerno F, Corrao S, Pasina L, Spirito V, Bonazzi J, Noce D, Mannucci
PM, a nome del partecipanti al Progetto Registro Politerapie SIMI. Analisi dei predittori di
mortalità e durata della degenza in anziani ricoverati in reparti di medicina interna. Intern
Emerg Med 2009; 4: S124-S125.
Iorio A, Marcucci M, Agnelli G, Nobili A, Salerno F, Corrao S, Mannucci PM, a nome del
partecipanti al Progetto Registro Politerapie SIMI. Terapia antitrombotica combinata e correlati
eventi emorragici in una coorte di anziani ricoverati in reparti di medicina interna. Intern Emerg
Med 2009; 4: S14.
Iorio A, Mannucci PM, Pasina L, Marcucci M, Bonazzi J, Agnelli G, Salerno F, Corrao S,
Nobili A, a nome del partecipanti al Progetto Registro Politerapie SIMI. La profilassi
antitrombotica in pazienti con fibrillazione o flutter atriale (FFA) preesistente ricoverati in
reparti di medicina interna. Intern Emerg Med 2009; 4: S26.
Pasina L, Nobili A, Tettamanti M, Salerno F, Corrao S, Bonazzi J, Vicidomini R, Mannucci
PM, a nome del partecipanti al Progetto Registro Politerapie SIMI. Utilizzo e appropriatezza
d’uso dei farmaci anti-ulcera peptica/reflusso gastroesofageo in una coorte di anziani ricoverati
in reparti di medicina interna. Intern Emerg Med 2009; 4: S69.
Marengoni A, Bonometti F, Mannucci PM, Salerno F, Corrao S, Nobili A, Tettamanti M, a
nome del partecipanti al Progetto Registro Politerapie SIMI. Politerapioa, eventi avversi durante
il ricovero e out come alla dimissione in relazione a diversi clusters di malattie. Intern Emerg
Med 2009; 4: S124.
RESEARCH ACTIVITIES
Laboratory of Biology of Neurodegenerative Disorders
Alzheimer's disease: genetic studies and clinical investigations
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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 started also the collection of blood samples from
subjects with front-temporal dementia. The genetic studies are aimed to the identification of
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
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.
The role of oligomers in the Alzheimer pathogenesis
Recent data have shown the essential role plays 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 an 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.
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).
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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
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).
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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 style of life,
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.
Prion's disease: in vitro studies
Immunopurification of pathological PrP aggregates
A great deal of effort has been devoted to developing protocols for purifying the abnormal PrP
isoform for structural studies, and testing its biological properties. Most procedures rely on
protease digestion, allowing efficient purification of PrP27-30, the protease-resistant core of
misfolded PrP. However, protease treatment cannot be used to isolate abnormal forms of PrP
lacking conventional protease resistance, such as those found in several genetic and atypical
sporadic cases. We developed a method for purifying pathological PrP molecules based on
sequential centrifugation and immunoprecipitation with a monoclonal antibody selective for
aggregated PrP. With this procedure we purified pathological PrP aggregates at electrophoretic
homogeneity and demonstrated that they retain their native biological activity. These
preparations may be useful for investigating the structural and chemico-physical properties of
infectious and neurotoxic PrP aggregates.
Development of a novel drug-based, 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.
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Prion's disease: in vivo studies
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 2D gel-based 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 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. These 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.
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
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 event extremely rare, only three mutations
identified until now, the parkin mutations are numerous ether 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 indicate 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 develop of cellular models to investigate
the pathogenesis of the disease. In past we showed the potential neurotoxic activity of alphasinuclein using the synthetic peptide homologous to the fibrillogenic fragment 61-95 (NAC) of
the protein. Successively with 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 alphasinuclein 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
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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 alpha-synuclein,
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..
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
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. Other studies are ongoing under the coordination of the Laboratory of
Neurological Disorders: 1. A case-control study on trauma and risk of ALS (in collaboration
with the Italian registries); 2. A case-control study on ALS, physical exercise and sport (in
collaboration with the EURALS Consortium). 3. A survey of the prevalence of cognitive
impairment and extrapyramidal signs in patients with newly diagnosed ALS (Italian registries);
4. 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.
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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 started to assess the prevalence 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. Anxiety, depression and
epilepsy are the commonest clinical conditions. On this background, two observational studies
have been completed to assess the correlation between headache, anxiety and depression and,
respectively, between headache and epilepsy. The aim of the first study was to assess the
prevalence and characteristics of anxiety and depressive disorders in cohorts of patients with
migraine (with or without aura), tension-type headache (episodic or chronic) or both. The
sample included 158 patients with migraine and 216 patients with tension-type headache with or
without migraine. Psychiatric disorders were different in the two groups. The greatest
differences were observed for panic and obsessive-compulsive disorders (predominating in
patients with migraine). The second study aimed at showing 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 a preliminary analysis of 583 patients, the incidence of
acute symptomatic seizures (5.7%) and the independent predictors of seizures (cerebral
hemorrhage).
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Therapeutic trials in neurological disorders
During the year 2009 six therapeutic trials sponsored by the Italian Drug Agency (AIFA) and a
therapeutic trial sponsored by the Italian Ministry of Health were started or continued. 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 Erythropoietine to Metyl-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
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.
Laboratory of Drug Metabolism
1-Aryl-piperazine as active metabolites of centrally acting drug
Starting from the previously reported 5-HT7 receptor compounds with N-(1,2,3,4tetrahydronaphthalen-1-yl)-4-aryl-1-piperazineexanamide structure (Leopoldo et al., J. Med. Chem.,
2007, 50, 4214), a new series of 1-(2-methythiophenyl)-, 1-(2-biphenyl)-, 1-(2-isopropylphenyl)- and
1-(2-methoxyphenyl)-piperazine derivatives were designed with the aim to obtain new potent
derivatives endowed with suitable physicochemical properties for rapid and extensive penetration into
the brain. The newly synthesized compounds underwent radioligand binding assays to assess their
affinities for 5-HT7, 5-HT1A, and D2 receptors. The intrinsic activities at 5-HT7 receptor as well as
those for serotonin 5-HT1A and dopamine D2 of the most potent compounds were determined
(Leopoldo et al., J. Med. Chem., 2008; 51: 5813).
The proposed structural modifications on the tetrahydronaphthalenyl ring of the original compounds
were, in most cases, detrimental for 5-HT7 receptor, whereas had limited impact on the affinity for 5HT1A and D2 receptors. Nonetheless, the pursued strategy led to the identification of the 1-(2-biphenyl)
piperazine derivatives which retained nanomolar affinity at 5-HT7 receptor, still showing lipophilicity
within the target range. Among these, the N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1piperazinehexanamide derivative also demonstrated high selectivity over 5-HT1A and D2 receptors
(324- and 245-fold, respectively) and showed full competitive agonism at 5-HT7 receptor in an
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isolated guinea-pig ileum assay. It rapidly reached the systemic circulation and entered the brain,
achieving concentrations in the low micromolar range after intraperitoneal doses in mice. Its brain
concentration-time profile paralleled that in plasma, indicating that it rapidly and freely distributes
across the blood-brain barrier. Similar studies were performed on the most potent and selective 5-HT7
agonist derivative of the previous series - which had lipophilicity comparable to the new derivative which, however, was cleared more rapidly from mouse plasma. Moreover, the potential formation of
the 1-aryl-piperazine metabolite and its brain-to-plasma concentration ratio were also examinated,
because arylpiperazine derivatives generally undergo CYP3A-mediated N-dealkylation of the aliphatic
chain attached to the piperazine nitrogen. While the plasma concentrations of the metabolites were
always below the detection limit of the analytical procedure, their brain concentrations exceeded that
of their parent compound, by about 1.6 and 4 times for the new and original derivative, respectively.
This was not surprising as previous studies have shown that 1-arylpiperazines concentrate in brain
tissue. Future studies will focus on characterization of the neuropharmacological profile of the 1-arylpiperazine metabolite compared with its parent compound.
Pharmacological role of the constituents of Hypericum perforatum
extracts
The chemical composition of extracts of hypericum perforatum L. (St. John’s wort) is essentially
known but is still not clear which constituent(s) account, wholly or in part, for the antidepressant
activity of the extracts, and through what neurochemical mechanism(s). The phloroglucinol hyperforin
shares most of the in vitro and in vivo pharmacological properties of the extracts, and is possibly a
main “antidepressant” component, but there is also evidence for other pharmacologically active
components. However, identifying the roles of the various derivatives and the mechanism(s) of their
activity is complicated by the scarcity of information about their ability to cross the blood-brain
barrier and the concentrations reached in brain after administration of the extracts. This is also true for
the biflavone biapigenin and particularly its I3’,II8 analog amentoflavone which, although present in
smaller amounts in extracts, shows a multitude of pharmacological actions in vitro and in vivo in
animal models. The lack of pharmacokinetic data in man and animals and questions about the brain
uptake of amentoflavone and biapigenin prompted us to examine their brain uptake and concentrations
and the relationships with plasma concentrations after pharmacologically effective doses in mice.
After doses of Hypericum perforatum extracts the brain concentrations of biapigenin and
amentoflavone were below the limit of quantification. The same was true for amentoflavone after a
biflavone-enriched extract of Ginkgo biloba. Levels were consistently detected only after
intraperitoneal biapigenin or amentoflavone but were low and mostly related to the residual biflavone
in the circulation. Poor brain-to-blood permeability is common to other polar components of
Hypericum perforatum, resulting in brain concentrations generally too low for any direct interaction
with neurotransmitter transporters and receptors which are obviously important for the action of
conventional antidepressants. Likewise, the in vitro interactions of biapigenin and amentoflavone with
known central mechanisms are apparently not relevant for the in vivo effects of the extracts because
they occur at biflavone concentrations far exceeding those found in the brain after pharmacologically
effective doses. However, this does not exclude that tissues other than brain may concentrate
biapigenin or amentoflavone sufficiently to exert beneficial effects after daily intake of the extracts.
Resistence to antidepressant drugs: studies in animal models
The selective serotonin reuptake inhibitors are the drugs of choice in the treatment of depression.
However, they are not or only partially effective in a fraction of depressed patients. The reasons are
substantially unknown, though pharmacogenetic studies have linked the response to serotonin reuptake
inhibitors to polymorphisms in various genes coding for serotonin mechanisms, particularly the
promoter of the serotonin transporter molecule. These studies are therefore aimed to investigate the
neurobiological mechanism(s) of resistance to antidepressant drugs in strains of mice carrying
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different isoforms of tryptophan hydroxylase-2, the enzyme responsible for the synthesis of brain
serotonin.
These studies are conducted in collaboration with the laboratory of Experimental Psycopharmacology
(L. Cervo) and the laboratory of Neurochemistry and Behaviour (R.W. Invernizzi), who will provide a
brief description of recent results with the potent serotonin reuptake inhibitors citalopram and
paroxetine.
Laboratory of Experimental Neurology
Role of inflammatory molecules in ictogenesis and epileptogenesis
We are studying the role of IL-1beta, TNF-alpha 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
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 drugresistant epileptic patients. This possibility is encouraged by the clinical use of some of these
molecules in chronic inflammatory and autoimmune diseases in humans (e.g. anakinra, the IL1R antagonist). We are studying pharmacological approaches to block IL-1beta- and HMGB1signaling 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 postnatal
development in rodents, we study 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
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.
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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.
Effects of anemia in the elderly
A previous large survey in old resident of Biella (65-84 years old) has been conducted in
collaboration with the Local Health Authority of Biella (ASL 12) to determine the
prevalence of anemia. We have now extended the investigation to the oldest old residents
(about 1500 85 years or older individuals) in order to estimate the prevalence and impact
of mild anemia also in this segment of the elderly population.
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.
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.
Quality of care of terminally ill oncological subjects
In 1999 we started a collaborative program with the hospice “via di Natale Franco
Gallini” in Aviano (PN). The aim of the research project was to assess the quality of care
given in hospice to terminally ill oncological patients at the end of life. Present aim of the
collaboration is the assessment of the hospice activities after its opening and to provide
nurses with continuous training on use of databank.
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 250 patients. Thirty
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services are currently participating and 150 patients already entered the study, among whom 74
completed one-year follow-up
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 reviewed the scientific literature on the prevalence and determinants of the psychosocial
assessment of cases of self-harm and suicide attempts in the emergencies, and enlarged the
network of services where the Schedule 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. More areas have been involved in discussion
of the schedule and Ethical Committees contacted. 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 schedule will
be further introduced and family practitioners will be trained about depression identification and
suicide risk detection.
European
Network
of
Bipolar
Research
Export
Centres
ENBREC is designed to build an EU-wide network of expert centres specialising 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
interventions for bipolar disorders in routine clinical practice. On the basis of the above
mentioned research review the implementation of psychoeducation groups for bipolar patients is
in progress in the Department of Mental Health of San Carlo Hospital.
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
meaningful contribution of users and distributed by them. Various focus groups were held
involving 12 users. A sample of 250 patients with severe mental illnesses and intensively cared
were described and the questionnaire was administered by a group of trained patients.
Evaluation of an intervention of common psychiatric disorders prevention
in schools
The intervention delivered by an association for mental health through psychiatrists to students
of various school types aged 16 years was modified in order to include components suggested
by the available literature as evidence based (videos and testimonial). Its efficacy in terms of
information, attitudes and help seeking behaviour was tested at end of treatment and after three
months.
Prevalence and incidence of antidepressant prescribing in an aging
population
The study investigates prevalence and incidence of antidepressant use and changes in the
patterns of antidepressant prescribing from 2000 to 2007 in the elderly population of a large
area in Lombardy by using a population-based prescription dataset.
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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 eight 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.
Michel’s game: a table game for group cognitive-behavioural therapy of
psychotic symptoms.
Cognitive therapies of psychotic symptoms (CBT) have shown a certain efficacy in the
treatment of psychoses. Their spreading within naturalistic settings is, however, limited.
“Michael’s Game”, a training module for hypothetical reasoning, which comes 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 three centers in Italy to a multi-center international
non-profit clinical trial evaluating the effectiveness of “Michael’s Game” program (training to
reason with hypotheses) on adult patients who show residual psychotic symptoms.
Laboratory of Inflammation and Nervous System Diseases
Inhibition of selected aspects of the inflammatory response powerfully
reduces ischemia/reperfusion injury
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, markedly improves neurological
deficits and reduces infarct volume in mice with focal transient as well as permanent ischemia
induced by middle cerebral artery occlusion. We have further extended this finding defining its
effectivness on different strains of mice (displaying different levels of complement expression),
the time-window and the dose-response curves. Since C1-INH may act on different substrates,
we have evaluated the specific involvement of the different complement pathways and of the
other inflammatory systems, ie kinin and coagulation systems. To explore the mechanisms of
C1-INH neuroprotection, we have also investigated the expression (protein and mRNA) of
inflammatory cytokines, adhesion molecules, NO synthase isoforms, apoptosis markers.
In sum the results obtained show that: i) C1-INH effectively and markedly reduces brain
ischemia/reperfusion injury, inducing a decrease of the 90% of the ischemic lesion; ii) C1-INH
actions lead to inhibition of cell recruitment, inflammation and apoptosis; iii) a major target of
C1-INH neuroprotection is mannose-binding lectin (MBL), a key protein in the complement
lectin pathway; iv) C1-INH protective effects can be observed also in traumatic brain injury
models.
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 (De Simoni et al. 2003; De Simoni et al. 2004; Storini et al. 2005; Storini et
al. 2006, Longhi et al. 2008, Gesuete et al, 2009). Ongoing studies are focussed on MBL as a
novel target for stroke and traumatic brain injury.
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Stem cells as a therapeutic approach in stroke and traumatic brain injury
In the past years we have demontrated a beneficial effect of neural stem cells after transient
brain ischemia (Capone et al. 2007, Pastori et al. 2008). However, 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, in collaboration with Cell Factory, Ospedale
Maggiore Policlinico di Milano) in reducing the ischemic and traumatic brain injury 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 evaluated: distribution and phenotype of injected cells, neurodegeneration,
behavioral deficits, cytokine and trophic factor gene expression, microglia activation. In our
traumatic brain injury (TBI) model the results obtained show that CB-MSC: 1) migrate towards
the contused tissue and survive in the injured brain up to 4 weeks postinjury 2) effectively
decrease anatomical damge and induce an early and persistent attenuation of functional
impairments related to sensory/motor activity and cognitive functions up to 6 weeks post-TBI.
In our focal ischemia model the results obtained 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 CBMSC and of the reciprocal interaction between CB-MSC and injured environment with specific
analysis of the protective/toxic role of microglia (Capone et al, 2007); 2) definition of the
mechanisms of homing of stem cells in the injured brain; 3) evaluation of the ability of CBMSC to differentiate into functional neural progeny 3 months after transplantation.
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 mechanims 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 insight of these dynamic events.
In collaboration with the Centre For Biophotonics at the Strathclyde University of Glasgow, 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 focus on the blood flow dynamics following focal brain ischemia and on the
tracking of lymphocytes infiltrated in the ischemic territory. We obtained high 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 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.
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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 occur hours or days before a severe ischemic
insult. This phenomenon is known as Ischemic PreConditioning (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 the underlying endogenous protective cellular receptor/signaling cascades, with the
long-term goal to allow therapeutic augmentation of the endogenous protective mechanisms in
cerebral ischemia.
Although most attention has focussed on the neuronal effects of IPC, recent studies have shown
that IPC reduces ischemia-induced cerebrovascular damage. The major goal of the research is to
identify the underlying endogenous protective cellular receptor/signaling cascades, by
addressing the specific 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. We are specifically addressing the following aspects: 1)
elucidation of BBB involvement in cerebral ischemia and preconditioning in in vivo and in vitro
mouse models; 2) identification of mediators and/or pathways involved in activation and
maintenance of ischemic tolerance in the cerebrovascular unit; 3) characterization of the effects
and identification of the mechanisms involved in preconditioning induced by different stimuli in
BBB models; 4) identification of new pathways and molecular targets useful for a potential
therapeutical stroke treatment.
Blood-brain barrier and ischemic preconditioning
The endothelial cells belonging to the cerebral microvasculature are the main component of the
Blood-Brain Barrier (BBB). These cells are attached to each other by intercellular Tight
Junctions and are closely associated with the endfeet of astrocytes, with pericytes and with
microglia, resulting in a complex network of cellular interactions. The integrity of this structure
is essential for the maintenance of the ischemic environment. We have recently established a
bidimensional BBB model by means of co-cultures of mouse brain endothelial cells and mixed
glial cells. These coltures retain the BBB typical features, namely they express thight junctions,
they present typical transendothelial electrical resistence (TEER), and paracellular and
transcellular permeability values. To mimic the ischemic insult, the BBB coltures are exposed to
oxygen-glucose deprivation (ODG) protocols. The ongoing project is aimed at studying the
involvement of BBB in ischemic preconditiong (IPC, see previous research topic). Albeit IPC
has been reported to reduce edema formation and thus BBB disruption following ischemia, no
information about a direct role of BBB cells in IPC is presently available. The major goal of the
research has been to assess if BBB cells may be preconditioned. To this purpose a brief OGD
stimulus was delivered before a severe OGD exposure. The results obtained have shown that a
mild OGD stimulus may actually dampen the effects of a subsequent severe OGD exposure
showing that BBB cells can be effectively preconditioned. Ongoing studies are presently aimed
at identifying mediators and/or pathways involved in activation and maintenance of IPC in the
cerebrovascular unit with the final aim of selecting new pathways and molecular targets useful
for a therapeutic stroke strategies.
Laboratory of Molecular Neurobiology
Study on pathogenic mechanisms of Amyotrophic Lateral Sclerosis
Role of protein aggregation
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A pathological feature of ALS is the accumulation of protein aggregates in the perykaria and
axons of motor neurons. Our hypothesis is that this may be due to an impairment of the
ubiquitin/proteasome system (UPS). To functionally investigate the UPS in ALS motor neurons
in vivo, we crossed SOD1G93A mice with transgenic mice that express a fluorescently-tagged
reporter substrate of the UPS (UbG76V-GFP, from now on indicated as GFP mice). In double
transgenic GFP/SOD1G93A mice an increase in UbG76V-GFP reporter, indicative of UPS
impairment, was detectable in a few spinal motor neurons and not in reactive astrocytes or
microglia, at symptomatic stage but not before symptom onset. These data suggest that UPS
impairment occurs in motor neurons of mutant SOD1-linked ALS mice and may play a role in
the disease progression.
Another major route for intracellular protein degradation is the autophagy−lysosomal pathway.
The rat microtubule-associated protein 1 light chain 3 (LC3), plays a critical role in the
formation of autophagosomes and its conversion from LC3I into LC3II is accepted as a simple
method for monitoring authophagy. Recently, we have observed that levels of LC3II which is
known to be correlated with the extent of autophagosome formation, was increased in
SOD1G93A mice with at an advanced stage of disease compared with non transgenic mice.
This indicates that the activation of autophagy may be an alternative mechanism of cell
defense to eliminate the proteins misfolded when the proteasome is partially inhibited as
demonstrated above. We are now examining the autophagy at earlier times of the pathology.
In collaboration with the Molecular Biochemistry and Pharmacology department we carried out
a proteomic analysis of the protein composition of the Triton-insoluble fraction (TIF), as a
model of protein aggregates, from the SOD1G93A mice at different disease stages. We
identified several proteins enriched in TIF of ALS mice already at preclinical stage, including
intermediate filaments, chaperones and mitochondrial proteins. Some of them, HSP90,
aconitase, HSC70 and cyclophilin A, were also analyzed in TIF of spinal cord of ALS patients
and found significantly enriched. Interestingly, the majority of proteins in mice and at least
HSP90 in patients were tyrosine nitrated. We therefore investigated the role of nitrative stress in
aggregate formation in a cellular model of ALS. We could demonstrate that by inhibiting nitric
oxide synthesis it is possible to substantially reduce the amount of insoluble proteins and in
particular of aconitase, HSC70, cyclophilin A and SOD1. In conclusion, the analysis of the
insoluble fractions from cellular/mouse models and human tissues could reveal novel aggregateprone proteins in ALS and suggest that nitrative stress may contribute to protein aggregate
formation. These results are in a manuscript submitted to Brain.
Role of glutamate AMPA receptors in the pathogenesis of ALS
To further study the role of glutamate AMPA receptors in the susceptibility of motor neurons
we have examined the expression and distribution of GluR2 subunit in motor neurons still
maintaining a functional connection with muscle fibers. We found a significant decrease of
Glur2 suggesting that this is a very early event that may play an important role in the
pathogenesis of the disease. The analysis of all these data are under completion.
In vitro studies on neuron-glia interaction
To investigate further the role of inflammatory mechanisms, we have set up an in vitro coculture of spinal neurons and astrocytes derived from SOD1G93A mice embryos. We are
verifying in this model the alterations observed in vivo such as the activation of TNFalphap38MAPK pathway. This model, hopefully, will allow to examine more rapidly the protective
effect of various strategies interfering with this pathway and will provide a model to test new
pathogenic mechanisms.
Altered axonuclear communication in motor neurons of a mouse model of
familial amyotrophic lateral sclerosis (European collaborative project FP6
program EU-NES AXON SUPPORT))
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Impairment in the maintenance of axon-nuclear communication, and viceversa, due to motor
proteins defects may play a primary role in the ALS.
To assess this hypothesis we examined the expression and the distribution of different
components of the nucleocytoplasmic-transport system, such as importins and vimentin, in the
ventral horn spinal cord and in the peripheral nerves of transgenic mice and rats carrying human
SOD1G93A. We found reduction of importin beta and slight increase of vimentin protein levels
in homogenates from ventral horn spinal cord concomitantly with the appearance of first
symptoms of the pathology. Using confocal miscroscopy, we detected abnormal accumulation
of vimentin in the perikaria of motor neurons at the presymptomatic stage; moreover we
observed a reduction of importin beta staining in the cytoplasm of motor neurons showing
accumulation of phosphorylated neurofilaments, a hallmark of neuronal damage, and defects in
retrograde transport. Based on these evidences we suggest that alterations of nucleocytoplasmic
transport-related proteins are linked with the degenerative process of motor neurons and may
play a role in ALS pathology.
Therapeutical interventions in mouse model of ALS
Development of target genes-based therapies for the protection of motor
neurons
It is emerging evidence that in the motoneurons of patients with sporadic ALS and in
animal models of the disease, there is a remarkable activation of pro-degenerative
pathways (like p38 MAP-Kinase). On the other side, the mechanisms involved in the
modulation of cell survival (like PI3K/Akt pathway) are not activated, thus suggesting
an impairment in the induction of neuroprotective responses.These pathways may be
considered as potential therapeutic targets. Based on these evidences, with this project
we propose: 1) to develop gene-targeted strategies aimed at counteracting p38 prodegenerative pathway and activating Akt pro-survival cascade inside motorneurons of
spinal cord; 2) to evaluate efficacy and safety of these potential therapeutic
interventions in an animal model of ALS. We have developed lentiviral vectors
expressing candidate p38-targeted shRNA sequences. These shRNAs were tested in
primary mouse astrocyte-motoneuronal cell co-cultures or in cultures of rat cortical
neurons. They were able to prevent activation of p38 and its downstream targets after
TNFalpha stimulation, and to reduce neuronal loss after toxic stimuli. In parallel, we
have developed constructs that express constitutively active forms of Akt1 and Akt3
(caAkt1 and caAkt3). Preliminary experiments in cell lines showed that either caAkt1 or
caAkt3 efficiently phosphorylates and inhibits downstream pro-apoptotic targets, such
as GSK3beta. Current studies aim to selectively drive the expression of p38-shRNA and
Akt1 to motor neurons and to increase the efficiency of their cellular expression.
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 a project in collaboration with Dr. A. Michael-Titus del Queen Mary University
of London supported by MND Association) Based on the observations by Dr. A.
Michael-Titus that a diet enriched of omega 3 is neuroprotective in a model of spinal
cord trauma in rat we decided to investigate if such treatment could have a beneficial
effect on SOD1G93A mice. The study is in progress.
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Treatment with lithium carbonate does not improve disease progression in two
different strains of SOD1 mutant mice
Female SOD1G93A mice on different genetic background and different phenotype of
disease severity were treated daily with Li2CO3 37mg/kg (1 mEq /kg) i.p. starting from
age 75 days until death. We observed a significant anticipation of the onset and reduced
survival in 129Sv/G93A and no effect in C57G93A mice treated with lithium as
compared to vehicle treated mice. Moreover, lithium neither exerted neuroprotective
effects not increased the expression of LCII and the activity of mitochondrial complex
IV in the spinal cord. The present study does not identify any therapeutic or
neuroprotective effect of lithium in SOD1G93A female mice. This study is in press in
Amyotrophic Lateral Sclerosis.
Studies aimed to identify biomarkers for the diagnosis and progression of
the disease in ALS patients
In collaboration with the department of Neurology of the Fondazione Salvatore Maugeri,
IRCCS, of Pavia, we have started a series of studies aimed to investigate the immune
system and the oxidative stress products in the PBMC of sporadic ALS patients in
comparison to healthy age matched controls. The results show that sporadic ALS
patients exhibit immunological alterations in their blood, in respect to healthy controls.
This study strengthens the hypothesis of an involvement of the adaptive immune system
associated with a neuroinflammatory process in the pathobiology of ALS. The
manuscript describing these data is under revision for the J. of Neuroimmunology.
In parallel, we are examining the levels and the characterisation of the nitrated protein
in the PBMC of ALS patients compared to healthy controls. We also evaluated the
PBMC of SOD1G93A transgenic rats. The protein nitration on tyrosine is an oxidative
mechanism that alters the function of proteins inducing their inactivation or a gain of
toxic functions. Using a proteomic approach we have observed that a series of proteins
are overnitrated in ALS patients and in SOD1G93A rats in respect to controls. Some
proteins are the same in rat and patients suggesting that they could be a reliable
biomarkers for the diagnosis and prognosis of the disease. These data are in a
manuscript under revision for the Antioxidant and Redox Signalling.
Another approach to identify potential specific diagnostic and prognostic markers of
the disease has been set up in collaboration with the department of neurology of the
Istituto Auxologico , IRCCS of Milano. In particular, we have used genomic and
proteomic analyses to identify and characterize genes and proteins specifically modified
in the muscles of ALS transgenic mouse models, at the onset of disease, in respect to
control mice. We have completed the examinations and the data are now under analysis.
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.)
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cocaine self-administration session. Animals self-administering cocaine did more active
lever-presses than yoked-cocaine (YC) and yoked-vehicle (YV) animals. This goaloriented behavior 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 behavior towards goal-directed
behaviors 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 self-administration, 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 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.
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 behavioral and
biochemical characterization of an experimental model of resistance to the
antidepressant drugs.
Using an animal model 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
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since DBA/2J and BALB/c carring a single nucleotide polymorphism (C1473G mice) in
the gene for the brain-specific 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 Neurochemistry and Behavior
“Resistance” to antidepressant drugs
In collaboration with the Laboratories of “Experimental Psychopharmacology” and
“Drug Metabolism” we set up a murine model of resistance to antidepressant drugs
based on the comparison between mice strains in the forced swimming test (FST), a
behavioural procedure widely used to screen potential antidepressant compounds We
showed that mice carrying a genetic mutation of the brain-specific isoform of
tryptophan hydroxylase-2, the rate-limiting enzyme in the synthesis of serotonin, did not
respond to antidepressants inhibiting selectively the reuptake of serotonin (SSRI). In
2009 we found that in “non-responder” mice serotonergic autoregulatory feedback
mechanisms are defective. Particularly, we found that 5-HT2C receptors are overactive.
Blockade of 5-HT2C receptors with a selective antagonist restored the effects of SSRI.
These results suggest that overactive feedback control suppresses the effects of SSRI
and identify pharmacological strategies that may enhance the response in treatmentresistant 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.
Antipsychotics possess a complex pharmacology across the biogenic amine receptor
families as shown by affinity constants derived from radioligand-binding techniques.
The ability to antagonise the DA D2 receptor function is shared by the conventional and
by the atypical antipsychotics. However, atypical antipsychotics show a high affinity
also for serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors. Our studies compared the
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effects of conventional and atypical antipsychotics in this model of cognitive deficit of
schizophrenia. The results show that antipsychotics may be differentiated by a selective
effect of typical antipsychotics on compulsive perseveration, and atypical antipsychotics
on impulsivity. Biochemical studies show that attentional deficits induced by NMDA
receptor antagonists are associated with excessive glutamate in the medial prefrontal
cortex of the rat and activation of the transcription factor CREB 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
•
Chiodini B, Franzosi MG, Barlera S, Signorini S, Lewis CM, D'Orazio A, Mocarelli P, Nicolis E, Marchioli R, Tognoni
G, on behalf of the GISSI Investigators, SIBioC-GISSI Prevenzione Group. Apolipoprotein E polymorphisms influence
effect of pravastatin on survival after myocardial infarction in a Mediterranean population: the GISSI-Prevenzione study.
Eur Heart J 2007 ; 28: 1977-1983
•
Anand SS, Islam S, Rosengren A, Franzosi MG, Steyn K, Yusufali AH, Keltai M, Diaz R, Rangarajan S, Yusuf S, on
behalf of the INTERHEART Investigators. Risk factors for myocardial infarction in women and men: insights from the
INTERHEART study. Eur Heart J 2008 29 : 932-940
•
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,
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•
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
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
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360: 1606-1617
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Malarstig A, Buil A , Souto JC, Clarke R, Blanco-Vaca F , Fontcuberta J, Peden J, Andersen M, Silveira A, Barlera S,
Seedorf U, Watkins H, Almasy L, Hamsten A, Soria JM ,on behalf of the Genetic Analysis of Idiopathic Thrombophilia
(GAIT) and Precocious Coronary Artery Disease (PROCARDIS) consortia. Identification of ZNF366 and PTPRD as
novel determinants of plasma homocysteine in a family-based genome-wide association study. Blood 2009; 114: 14171422
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
1981-1983
Merck Sharp & Dohme International Fellow in Clinical Pharmacology
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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
•
Latini R, Masson S, Anand I S, Missov E, Carlson M, Vago T, Angelici L, Barlera S, Parrinello G, Maggioni A P,
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
•
Salio M, Chimenti S, De Angelis N, Molla F, Maina V, Nebuloni M, Pasqualini F, Latini R, Garlanda C, Mantovani A.
Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction. Circulation 2008; 117: 1055-1064
•
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
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
•
Roncaglioni MC, Avanzini F, Roccatagliata D, Monesi L, Tamayo-Benitez D, Tombesi M, Caimi V, Longoni P, Lauri
D, Barlera S, Tognoni G, Collaborative Group Risk Prevention Study. How general practitioners perceive and grade the
cardiovascular risk of their patients Eur J Cardiovasc Prev Rehabil 2004; 11: 233-238
•
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, Roncaglioni MC. 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
Gianni Tognoni got his Medical Doctor 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
• Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, Marilus R, Villegas A, Tognoni G, Barbui T.
Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J. Clin. Oncol. 2005; 23: 2224-2232
• Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, 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 Jan
18;295(3):306-13. Erratum in: JAMA. 2006 May 3;295(17):2002
• Strippoli GF, Tognoni G, Navaneethan SD, Nicolucci A, Craig JC. Haemoglobin targets: we were wrong, time to move
on. Lancet 2007;369:346-350
• GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,
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360: 1606-1617
Maggioni AP, Fabbri G, Lucci D, Marchioli R, Franzosi MG, Latini R, Nicolosi GL, Porcu M, Cosmi F, Stefanelli S,
Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators. Effects of rosuvastatin on atrial fibrillation occurrence:
ancillary results of the GISSI-HF trial. Eur Heart J 2009; 30: 2327-2336
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
•
Toscani F, Di Giulio P, Campi R, Pellerin I, De Luca A, Casale G, on behalf of the End of Life Observatory Research
Group. Off-label prescriptions in Italian hospices: a national survey. J Pain Symptom Manage 2009; 38: 365-371
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, Chimenti S, Staszewsky L, Bai A, Carlo E, Cuccovillo I, Doni M, Mengozzi M, Tonelli R, Ghezzi P,
Coleman T, Brines M, Cerami A, Latini R. A non-erythropoietic derivative of EPO effectively ameliorates experimental
cardiac ischemia with reperfusion. Proc Natl Acad Sci USA 2005; 102: 2046-2051
•
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
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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
•
Masson S, Latini R, Anand I S, Barlera S, Judd D, Salio M, Perticone F, Perini G, Tognoni G, Cohn JN, on behalf of the
Val-HeFT Investigators. The prognostic value of Big endothelin-1 in more than 2,300 patients with heart failure enrolled
the Valsartan in Heart Failure Trial (Val-HeFT). J Card Fail 2006; 12: 375-380.
•
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, Vago T, Angelici L, Barlera S, Missov ED, Clerico A, Tognoni G, Cohn JN, on behalf of
the Val-HeFT Investigators. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a
large population of patients with chronic and symptomatic heart failure. The Valsartan Heart Failure (Val-HeFT) data.
Clin Chem 2006; 52: 1528-1538.
•
Staszewsky L, Wong M, Masson S, Barlera S, Carretta E, Maggioni AP, Anand IS, Cohn JN, Tognoni G, Latini R,
Valsartan Heart Failure Trial Investigators. Clinical, neurohormonal, and inflammatory markers and overall prognostic
role of chronic obstructive pulmonary disease in patients with heart failure: data from the Val-HeFT Heart Failure Trial.
J Card Fail 2007; 13: 797-804.
•
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
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.
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 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.
MAIN FINDINGS
GISSI-AF, a randomized, prospective, parallel group, placebo-controlled, multicenter study on
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the use of valsartan, an angiotensin II AT1-receptor blocker (ARBs) in the prevention of Atrial
Fibrillation (AF) recurrence, has recruited and treated for 12 months 1400 patients with a
history of recent AF associated with cardiovascular diseases/comorbidities. In GISSI-AF, the
largest trial ever conducted with ARBs in pts with AF, Valsartan did not reduce AF recurrence.
The ongoing analyses on echocardiographic and biohumoral data of 382 pts from GISSI-AF led
to the identification of some predictors of recurrence of AF such as natriuretic peptides, highsensitive troponin T and atrial volumes measured by echocardiography.
The GISSI-HF Study, a randomized multicenter trial conducted in nearby 7000 patients from
357 cardiology sites in Italy, showed that a simple, safe, one-a-day capsule of n-3
polyunsaturated fatty acids (PUFA) can reduce mortality (9%) and admission to hospital for
cardiovascular reasons (8%) in patients with heart failure. Patients received either n-3 PUFA in
a capsule once daily (3494 patients) or placebo (3481). 955 patients in the PUFA group (27%)
died, compared with 1014 (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 (2053/59%) died or
were admitted to hospital for cardiovascular reasons than in the PUFA group (1981/57%) a
relative reduction of 8% in the PUFA group. In absolute terms, 56 patients needed to be treated
with PUFA for four years to avoid one death, or 44 patients to avoid one event of either death or
admission to hospital for cardiovascular causes. Statin treatment with rosuvastatin does not
affect clinical outcomes in patients with chronic heart failure.
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 (CAD). 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, rs2891168 and
rs10811661, that are independently associated with CAD and with type 2 diabetes (T2D)
respectively.
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.
Angiogenesis and Tumor Targeting Research Unit & Telethon Institute for Gene Therapy,
Ospedale San Raffaele, Milano
AMD (Associazione Medici Diabetologi) - Lombardia
ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri)
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
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Sofferenza IRCCS, San Giovanni Rotondo
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)
IEO (Istituto Europeo di Oncologia), Milano
IFOM-FIRC, Milano
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
Laboratorio di Endocrinologia, Ospedale Luigi Sacco, Milano
Regione Lombardia
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
Unità di Cardiologia, IEO, Milano
Università degli Studi di Milano, Dipartimento di Medicina Interna
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, New Zealand
CTSU (Clinical Trial Service Unit) /ISIS (International Studies on Infarct Survival), Oxford,
UK
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)
JW Goethe University, Department of Cardiology, Frankfurt, Germany
Karolinska Institutet, Stockholm, Sweden
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, Norway
University Medical Center, Groningen, The Netherlands
Wellcome Trust Centre for Human Genetics, University of Oxford, UK
WONCA (World Organization of Family Doctors)
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Circulation, International Journal of Health Services, European Heart Journal (Gianni Tognoni)
Journal of Cardiac Failure, Journal of Cardiovascular Medicine (Roberto Latini)
Assistenza Infermieristica e Ricerca, European Journal of Cancer Care, European Journal of
Oncology Nursing, International Nursing Perspectives (Paola Di Giulio)
American Heart Journal, American Journal of Cardiology, American Journal of Medicine,
Archives of Medical Research, Atherosclerosis Thrombosis and Vascular Biology,
Cardiovascular Drugs and Therapy, Cardiovascular Research, Circulation, Circulation Research,
Clinical Pharmacology and Therapeutics, 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 Vessels, International
Journal of Cardiology, International Journal of Obesity, 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, Life Sciences, The
Lancet, PharmacoEconomics, Pharmacological Research, Redox Report, Value in Health.
Ethical Committee of the ASL of Milan
Ethical Committee of Lombardy Region
Ethical Committee of the Provincia of Verona
Ethical Committee of the A.O. Fatebenefratelli e Oftalmico of Milan
Agenzia Italiana del Farmaco, Direzione Generale Farmaci e Dispositivi Medici
EVENT ORGANIZATION
PROCARDIS Annual Meeting
21-22/04/09, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Investigator's Meeting – Riunione di avvio dello studio GLICINE SPIDER
27/04/09, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Seminar - Fabio Di Lisa: Mitochondrial ROS formation and cardiac diseases
Seminar - Michel Ovize: Cyclosporine A to prevent ischemia/reperfusion injury
Seminar – Salim Yusuf: Risk factors, management challenges, and new data on treatment
options for patients with Atrial Fibrillation
Investigator's Meeting – Riunione degli Sperimentatori dello studio GLICINE SPIDER
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01/10/09, sala ARIES – Polo Fieristico Rho-Pero, Milano
Investigator's Meeting – Stato di avanzamento dello studio "NeuroMorfeo"
Master di I° Livello in Ricerca Clinica dell’Università degli Studi di Milano, Facoltà di
Medicina e Chirurgia, Dipartimento di Medicina Interna (Anno Accademico 2009-2010)
03/11/09 Introduzione al corso
La ricerca clinica oggi: profit e no-profit
Corso di introduzione alla statistica
04/11/09 La variabilità dei fnomeni biologici
Elementi di statistica descrittiva
05/11/09 Test diagnostici
Esercitazione di statistica descrittiva
06/11/09 Legislazione sulla sperimentazione clinica e ruolo dei Comitati Etici
09/11/09 Il disegno dello studio in epidemiologia
Il disegno degli studi clinici
10/11/09 Misure di rischio in epidemiologia
11/11/09 Monitoraggio degli studi clinici no-proft
Report delle Reazioni avverse negli studi clinici no-profit
12/11/09 Studi di fase 2: Obiettivi, disegno e stima del campione in oncologia
16/11/09 Analisi della sopravvivenza
Inferenza statistica
17/11/09 Farmacovigilanza
Esercitazione di Inferenza Statistica
18/11/09 Ricerca clinica nel campo dell'epilessia
Ricerca clinica nell'ictus
Internet e le nuove tecnologie per l'aggiornamento medico-scientifico
23/11/09 Studi di fase 3: Obiettivi, disegno e indicatori in oncologia
Revisioni sistematiche e metaanalisi
24/11/09 Monitoraggio degli studi clinici profit
Report delle Reazioni Avverse
La ricerca bibliografica oggi
Le interazioni tra farmaci
25/11/09 Ricerca in medicina generale
30/11/09 Ricerca Traslazionale
Outcome Research
Dalla preclinica alla clinica: sviluppo di nuovi farmaci cardiovascolari
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Seminar – Domenico Corradi: Basi anatomopatologiche della fibrillazione atriale
Dipartimento di Genetica Biologia e Biochimica-Centro di Biotecnologie Molecolari,
Università di Torino. I Cardionetwork meeting, 5-6/03/09, Torino, Italy
- Translational approaches to myocardial infarction: pentraxins and stem cells
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SMART-Organizing and Scientific Committee. 20° SMART – Simposio Mostra Anestesia,
Rianimazione e Terapia Intensiva, 6-8/05/09, Milano, Italy
- Troponina e proBNP come marker di disfunzione cardiaca
Università degli studi di Padova - Fondazione Livia e Vitttorio Tonolli. Formazione clinica,
comunicazione, management in cardiologia. Corso di perfezionamento post laurea – Modulo 16,
27/05/09, Milano, Italy
- L’impiego delle cellule staminali: dai modelli animali all’applicazione nell’uomo nelle
lesioni del miocardio
- Gli studi clinici nello scompenso cardiaco
- Novità vere e apparenti in cardiologia
European Society of Cardiology. Heart Failure 2009, 30/05-02/06/09, Nice, France
- Emerging targets from basis mechanisms. Pentraxins
Associazione Nazionale Medici Cardiologi Ospedalieri. 40° Congresso Nazionale di
Cardiologia, 04-07/06/09, Firenze, Italy
- Valore prognostico della variabilità della frequenza cardiaca nello studio GISSI-HF
- La concentrazione plasmatica di pentraxina-3 predice la mortalità in pazienti con
insufficienza cardiaca cronica. Dati dallo studio GISSI-HF
- Acidi grassi plasmatici e mortalità in pazienti con insufficienza cardiaca cronica. Dati dallo
studio GISSI-HF
- Prevalenza di disfunzione sistolica asintomatica su popolazione: risultati preliminari dello
studio PREDICTOR (valutazione della prevalenza di disfunzione cardiaca asintomatica e di
scompenso cardiaco conclamato in un campione di popolazione di età ≥ 65 anni nel Lazio)
- Prevalenza di disfunzione sistolica asintomatica su popolazione anziana: risultati preliminari
dello studio PREDICTOR
- Profilo di sicurezza e tollerabilità di Aliskiren quando aggiunto alla terapia ottimizzata di
pazienti con scompenso cardiaco e disfunzione renale
- Valutazione della prevalenza di disfunzione cardiaca asintomatica e di scompenso cardiaco
su popolazione di età ≥ 65 anni nel Lazio: risultati preliminari dello studio PREDICTOR
- Efficacia e tollerabilità di Aliskiren aggiunto alla terapia ottimizzata di pazienti con diabete
mellito e scompenso cardiaco
- Vi sono differenze tra la popolazione di un trial e quella arruolata da un singolo centro?
Un’analisi all’interno del GISSI-HF
- Concentrazioni di NT-proBNP in 537 soggetti anziani nel Lazio: risultati preliminari dello
studio edidemiologico PREDICTOR
European Society of Cardiology. ESC Congress 2009, 29/08-02/09/09, Barcellona, Spain
- Aldosterone escape is associated with insulin resistance in patients with heart failure –
findings in the ALiskiren Observation of heart Failure Treatment trial (ALOFT)
- Plasma renin activity retains a strong prognostic value in patients with chronic HF,
independent of ACE inhibitor or beta-blocker therapy. Data from the Valsartan Heart Failure
(Val-HeFT)
- Time course analysis of the effect of n-3 PUFA on fatal and non fatal arrhythmias in heart
failure: secondary results of the GISSI-HF trial
- Safety and tolerability profile of aliskiren added to optimized therapy in elderly and very
elderly patients with heart failure
- Prevalence of heart failure in the community: preliminary results of an epidemiological
survey in the elderly population in Italy. The PREDICTOR Study
- Effect of n-3 PUFA in heart failure patients with different dietary habits: preliminary results
of the GISSI-Heart Failure trial
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- Predictive role of QRS duration in patients with chronic heart failure. Data from the GISSIHF trial
- Prognostic ability of a Mediterranean dietary score in heart failure: preliminary analysis of
the GISSI-Heart Failure trial
- Antiarrhythmic effects of n-3 PUFA in patients with heart failure and an implantable
cardioverter defibrillator in the GISSI-HF trial
- Epidemiology and prognosis of diabetes in acute and chronic heart failure
- Erythropoieting as a cardioprotectant with clinical potential
- Predictors of change of dietary habits in cohort of 12,513 patients at high risk of
cardiovascular risk followed by 860 Italian general Practitioners: preliminary analysis of the
Risk & Prevention trial
- Prognostic ability of a simple dietary score in cohort of 12,513 patients at high risk of
cardiovascular risk followed by 860 Italian GPs: preliminary analysis of the Risk & Prevention
trial
IEO European Institute of Oncology. Cardioncology 2009. 25-26/09/09, Milano, Italy
- Markers of inflammation in heart diseases
Dipartimento Cardiovascolare “A. De Gasperis” – Azienda Ospedaliera Ospedale Niguarda Ca’
Granda. 43° Convegno Cardiologia 2009, 28/09-02/10/09, Centro Congressi Stella Polare.
Porta Sud, Nuovo Polo della Fiera di Milano, Pero-Rho, Italy
- La fragilità sociale e la compliance farmacologica
Heart Care Foundation. Integriamo l’evidence based medicine con le cure “su misura”. Il ruolo
della clinica nella pratica e nella ricerca cardiovascolare, 22-23/10/09, Grand Hotel Dino,
Baveno, Italy
- Il “rinascimento” dell’osservazione clinica – parte 2. Risposta neuro umonale
SIGU Società Italiana di Genetica Umana. XII Congresso Nazionale SIGU, 8-10/11/09,
Lingotto, Torino, Italy
- Common genetic variants on chromosome 9p21 are associated with myocardial infarction
and type 2 diabetes in an Italian population
American Heart Association. AHA Scientific Session 2009, 14-18/11/09, Orlando, Florida,
USA
- Significant association between atrial and ventricular echocardiographic findings and cardiac
circulatin biomarkers in patients with a history of atrial fibrillation. Data from the GISSI-AF
Trial
- Transthoracic echocardiographic parameters as predictors of atrial fibrillation recurrence.
Data from the GISSI-AF Echocardiographic Study
- Prognostic value and serial changes of plasma adiponectin concentration in patients with
chronic heart failure. Data from GISSI-HF Trial
Cardiologia Prof. M Viecca - Ospedale Luigi Sacco, ARCA, AIMEF. I° Convegno - Breaking
news in interventistica cardiovascolare e nuove frontiere terapeutiche nel trattamento delle
patologie cardiovascolari, 21/11/09, Milano. Italy
- Terapia farmacologica non antiaritmica della fibrillazione atriale: quale ruolo per i Sanitari e
gli ACE-inibitori?
Società Italiana di Gerontologia e Geriatria. 54° Congresso Nazionale, Salute e benessere
dell’anziano: la nostra missione, 2-5/12/09, Palazzo dei Congressi, Firenze Italy
- Indice di complessità assistenziale (ICA): studio di validazione
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AIFA (Agenzia Italiana del Farmaco), AstraZeneca, Azienda Ospedaliera San Gerardo Monza,
Chiesi Farmaceutici, Boehringer Ingelheim Italia SpA, BRAHAMS AG, Centro Cardiologico
Monzino IRCCS Milano, Cambridge University, CONGENIA, Fondazione Don Gnocchi
Milano, Fondazione San Raffaele Milano, Heart Care Foundation, International Biomedical
System SpA, Istituto Auxologico di Milano, Istituto Dermopatico dell’Immacolata di Roma,
LACHIFARMA, Ministero della Salute, NOEMALIFE GmbH, Novartis Pharma, Ospedale
Casa Sollievo della Sofferenza IRCCS San Giovanni Rotondo, Oxford University, Population
Health Research Institute-Mc Master University, Pfizer Italia, Regione Lombardia, SanofiAventis, Sigma Tau, SPA Società Prodotti Antibiotici S.p.A., Takeda Italia S.p.A., Università
degli Studi Torino
ACTIVE Investigators
Effect of clopidogrel added to aspirin in patients with atrial fibrillation
N Engl J Med 2009; 360: 2066-2078
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
Avanzini F, Marelli G, Donzelli W, Sorbara L, Palazzo E, Bellato L, Colombo EL, Roncaglioni MC, Riva E, De
Martini M, on behalf of the DDD study group
Hyperglycemia during acute coronary syndrome: A nurse-managed insulin infusion protocol for stricter and safer
control
Eur J Cardiovasc Nurs 2009; 8: 182-189
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: 747-755
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; 119: 524-530
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, on behalf of 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
Citerio G, Franzosi MG, Latini R, Masson S, Barlera S, Guzzetti S, Pesenti A
Anaesthesiological strategies in elective craniotomy: randomized, equivalence, open trial - The NeuroMorfeo trial
Trials 2009; 10: 19
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
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone
J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener H-C, Joyner CD, Wallentin L, the RELY Steering Committee and Investigators.
Dabigatran versus Warfarin in patients with atrial fibrillation
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N Engl J Med 2009; 361: 1139-1151
Freel EM, Tsorlalis IK, Lewsey JD, Latini R, Maggioni AP, Solomon S, Pitt B, Connell JMC, McMurray JJV
Aldosterone status associated with insulin resistance in patients with heart failure - data from the ALOFT study
Heart 2009; 95: 1920-1924
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
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
Heymans S, Hirsch E, Anker SD, Aukrust P, Balligand J-L, Cohen-Tervaert JW, Drexler H, Filippatos G, Felix SB,
Gullestad L, Hilfiker-Kleiner D, Janssens S, Latini R, Neubauer G, Paulus WJ, Pieske B, Ponikowski P, Schroen B,
Schultheiss H-P, Tschöpe C, Van Bilsen M, Zannad F, McMurray J, Shah AM
Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research
Committee of the Heart Failure Association of the European Society of Cardiology
Eur J Heart Fail 2009; 11: 119-129
Joyner CD, Peters RJG, Afzal R, Chrolavicius S, Mehta SR, Fox KAA, Granger CB, Franzosi MG, Flather M, Budaj
A, Bassand JP, Yusuf S
Fondaparinux compared to enoxaparin in patients with acute coronary syndromes without ST-segment elevation:
outcomes and treatment effect across different levels of risk
Am Heart J 2009; 157: 502-508
Latini L, Masson S
Biomarkers of myocyte injury in heart failure
Heart Fail Clin 2009; 5: 529-536
Maggioni AP, Fabbri G, Lucci D, Marchioli R, Franzosi MG, Latini R, Nicolosi GL, Porcu M, Cosmi F, Stefanelli S,
Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators
Effects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trial
Eur Heart J 2009; 30: 2327-2336
Maggioni AP, Franzosi MG, Latini R
Beta-adrenoceptor antagonists and antianginal drugs
In: Side effects of drugs, Annual 31
Elsevier, Amsterdam, 2009; 339-343
Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo E
Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature
in transgenic mouse models
J Clin Invest 2009; 119: 3356-3372
Malarstig A, Buil A , Souto JC, Clarke R, Blanco-Vaca F , Fontcuberta J, Peden J, Andersen M, Silveira A, Barlera
S, Seedorf U, Watkins H, Almasy L, Hamsten A, Soria JM ,on behalf of the Genetic Analysis of Idiopathic
Thrombophilia (GAIT) and Precocious Coronary Artery Disease (PROCARDIS) consortia
Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide
association study
Blood 2009; 114: 1417-1422
Marchioli R, Levantesi G, Silletta MG, Barlera S, Carbonieri E, Cosmi F, Franzosi MG, Latini R, Lucci D, Maggioni
AP, Moretti L, Nicolosi GL, Porcu M, Rossi MG, Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators
Effect of n-3 polyunsaturated fatty acids and rosuvastatin in patients with heart failure: results of the GISSI-HF trial
Expert Rev Cardiovasc Ther 2009; 7: 735-748
Nobili A, Pasina L, Tettamanti M, Lucca U, Riva E, Marzona I, Monesi L, Cucchiani R, Bortolotti A, Fortino I,
Merlino L, Locatelli GW, Giuliani G
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Potentially severe drug interactions in elderly outpatients: results of an observational study of an administrative
prescription database
J Clin Pharm Ther 2009; 34: 377-386
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
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
Toscani F, Di Giulio P, Campi R, Pellerin I, De Luca A, Casale G, on behalf of the End of Life Observatory Research
Group
Off-label prescriptions in Italian hospices: a national survey
J Pain Symptom Manage 2009; 38: 365-371
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
Franzosi MG
Il modello GISSI e la scoperta della cura per l’infarto
In: Milano capitale della salute. Editrice Abitare Segesta, Milano, 2009; 176
Nobili A, Latini R
Interazioni pericolose in cardiologia
In: Cardiologia 2009. Atti del 43° convegno internazionale del dipartimento cardiologico A. De Gasperis. 28
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Oliva F, Macera F, Verde A, Vittori C, Cipriani M, Masciocco G, Garascia A, Foti G, Turazza F, Frigerio M
Valore scientifico e limiti epidemiologici dei registri di patologia come fonte di informazione: l’esempio dello
scompenso cardiaco
In: Cardiologia 2009. Atti del 43° convegno internazionale del dipartimento cardiologico A. De Gasperis. 28
settembre-2 ottobre 2009, Milano. Fond. Centro Cardiologia e Cardiochirurgia A. De Gasperis, Milano, 2009; 6-9
Tognoni G
QDF: Qualità di vita, Depressione, Funzioni cognitive. Un progetto di ricerca cardiologica che può essere lettura
obbligatoria e strumento di lavoro di interesse generale
Assistenza Infermieristica e Ricerca 2009; 28: 2-4
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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. The same model of coronary
ligation in immunodeficient mice is being used for testing in vivo the angiogenic potential of
other 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.
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 main injurious mechanism of AP is the chemical insult due to the low pH of gastric
secretions, which causes a chemical burn of the airway tree and of the alveolar structures. 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 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.
Conditional transgenic model of cardiac HGF expression to promote
neovascularization and to recruit stem cells in the myocardial infarction
Growth factors such as hepatocyte growth factor (HGF) through angiogenic and anti-apoptotic
effects may promote cardiac repair after myocardial infarction and in heart failure. The cardiacspecific α-Myosin Heavy Chain (MHC-α) transactivator was used to direct expression of HGF
to cardiomyocytes: by this way the effects of HGF can be tested under cardiac ischemia and
reperfusion, without the need for administration of exogenous HGF. In the first half of 2010 it is
expected the conclusion of the experiments aimed at verifying the ability of HGF in vivo to
promote neovascularisation, to protect cardiomyocytes from apoptosis, to recruit and activate
endogenous or transplanted stem cells and to sustain their cellular replication and differentiation
into cardiomyocytes after ischemia followed by reperfusion.
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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 deposition occurs and neonagiogenesis, 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.
Effects of dipeptidyl peptidase-4 (DPP-4) inhibition on endothelial
progenitor cells and hypoxic injury in type 2 diabetes
Diabetic patients have a two- to threefold greater risk of developing congestive heart failure
after myocardial infarction. Decreased microvascular density, one of major vascular
complications in diabetes, is accompanied by increased susceptibility to myocardial ischemia
and by progressive left ventricular dysfunction. Circulating Endothelial Progenitor Cells (EPCs)
are incorporated into new vessels and promoted neo-vascularization. Insufficient numbers of
endothelial progenitor cells (EPCs) are reported in both type 1 and type 2 diabetic patients.
The present study aims 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), mediator of progenitor cell
mobilization increases EPC circulating levels, which, in turn, may contribute to the
regeneration of blood vessels and reducing myocardial ischemic stress induced by strenuous
exercise.
Effects of propionyl-L-carnitine on vascular damage and cardiovascular
oxidative stress in type 2 diabetic mouse
Experimental and clinical evidence suggest that the generation of reactive oxygen species
(ROS) is increased in both types of diabetes and that the onset of diabetes and diabetic cardiac
complications are closely associated with oxidative stress which is exacerbated during strenuous
exercise.
Oxidative stress represents a primary cause of the microvascular and macrovascular
complications in diabetes. Among these complications, reduced neovascularization in diabetes
is not solely the result of reduced proliferation of local endothelial cells but is also due to a
decrease of the number of circulating Endothelial Progenitor Cells (EPCs) observed in both type
I and type 2 diabetic patients. The mechanism involved in the impairment of the function of
these cells in diabetic patients might be related to eNOS-mediated superoxide anion production.
L-Carnitine is essential for the transfer of long-chain fatty acids from cytosol into the
mitochondrial matrix where β-oxidation and production of cellular energy occur. An
abnormality in myocardial energy metabolism is a reported factor in the development of
diabetes-induced heart dysfunction. L-Carnitine is present in both plasma and tissue as either
free carnitine or bound to fatty acids as acyl-carnitine derivatives, such as propionyl-L-carnitine
which has a higher affinity for the muscular carnitine transferase and is readily converted into
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propionyl-coenzyme A and free carnitine, increasing the intracellular pool of L-carnitine and
free fatty acid oxidation in carnitine-deficient-states.
Propionyl-L-carnitine has been shown to act as an intracellular superoxide scavenger, improving
mitochondrial function and reducing DNA damage and these properties might in part account
for the functional improvement of diabetic heart. Similarly, the antioxidant activity of
propionyl-L-carnitine has been reported to determine an improvement in the aortic endothelial
dysfunction based on the evidences that the enhanced production of superoxide anions in
vascular endothelium is responsible for endothelial dysfunction, due to NO inactivation.
The present study aims at evaluating whether the propionyl-L-carnitine treatment for 8 weeks in
obese/diabetic ob/ob mice improves mobilization/homing of endogenous progenitor cells (so
called EPCs) and diminishes the vascular damage in myocardium and aorta by reducing
superoxide anion production at cellular levels and consequently increasing NO availability in a
model of swimming exercise-induce oxidative stress.
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 recently been published (Lancet 2008; 372: 1223-1230 e Lancet 2008; 372: 1231-1239).
The biomarker substudy aims at exploring the pathophysiology of heart failure and mechanisms
of action of the treatments in study. Overall, 1237 patients have been enrolled in the substudy.
Blood samples were collected at enrolment and after three months to measure plasma PUFA,
and markers of ventricular myocyte stress (brain natriuretic peptides, BNP and N-terminal
proBNP, MR-proANP), myocardial damage (cardiac troponin T, measured with the standard
assay or with a newly developed high sensitive method) and inflammation (C-reactive protein,
CRP, pentraxin-3, PTX3). Baseline fraction of n-3 PUFA averages 3.4 and increases by about
50% over 3 months. Baseline BNP concentration in 1223 patients is 141 pg/mL (median) and
correlates with the severity of heart failure. The number of circulating endothelial progenitor has
been measured in a smaller group of 68 patients, in collaboration with the laboratory of E.
Dejana (IFOM). Number of endothelial progenitor cells in patients with heart failure is 30-50%
lower than in healthy volunteers was inversely correlated to morbidity/mortality in a population
of patients from 5 Italian centers and a Cardiology center in Frankfurt (collaboration with
Andreas Zeiher). 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. Novel and more stable
circulating biomarkers have been successively assayed. They belong to the family of natriuretic
peptides (mid-regional pro-atrial natriuretici peptide, MR-proANP), endothelin (C-terminal proendothelin-1, CT-proET-1), vasopressin (C-terminal pro-vasopressin, CT-proAVP) and
adrenomedullin (mid-regional pro-adrenomedullin, MR-proADM). Other markers related to
infection and innate immunity are currently measured (chromogranin A, mannose-binding
lectin, osteoprotegerin, and alpha-defensin). We are currently performing studies on the
relationship between circulating levels of adiponectin, single nucleotide polymorphisms of the
gene encoding this peculiar cytokine (in collaboration with the Laboratory of Clinical Drug
Evaluation of the Department), and outcome.
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. 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
Alberto 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 more than
3500 patients.
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, have been prepared and are currently
under evaluation.
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 487 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. Main statistical
analyses have been performed and a paper is being drafted.
Trial Prone/Supine 2: effects of prolonged prone position on survival in
severe acute respiratory distress syndrome (ARDS)
After the publication of the results of the trial, a collaborative meta-analysis has been conducted
and published of all published studies on postural changes in adult ARDS. The meta-analysis
showed that prone position for several hours each day improves survival of patients with severe
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ARDS.
DyDa: left ventricular dysfunction in diabetes. Prevalence and incidence
of left ventricular dysfunction in diabetics patients without clinical cardiac
disease
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 drafted and are
currently evaluated. In a subgroup of patients from the study, levels of circulating progenitor
cells and their angiogenic potential in vitro will be measured to assess whether they are
associated to risk of developing cardiovascular disorders in diabetics.
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. 704 patients have been randomized by the end of 2009, and blood samples
collected in at least 350 of them.
Clinical, biochemical and instrumental predictors of outcome in
rehabilitation after cardiac surgery (MIUR)
Due to the short length of hospital recovery in patients with cardiac disease, the period of
rehabilitation becomes crucial and is indicated for almost all the cardiomyopathies, including
myocardial revascularization and surgery of cardiac valves. The objective of this study is to
evaluate the prognostic role of circulating biomarkers in 250 patients enrolled in 5 Centers for
rehabilitation after cardiac surgery. A plasma bank will be collected under the responsibility of
the Laboratory of Cardiovascular Clinical Pharmacology from the Mario Negri Institute to assay
potential markers of interest. The project is coordinated by the Fondazione Don Gnocchi in
Milan. About 500 samples of blood and urine have been collected. Assays of high sensitivity
cardiac troponin T and microalbuminuria are concluded and statistical analyses under way.
Evaluation of different anesthesiological strategies for supratentorial
neurosurgery. The NeuroMorfeo Study (AIFA)
The aim of the study is to evaluate whether an anesthesia with volatile anesthetics is equivalent
to endovenous anesthetics for elective supratentorial surgery. This is a multicenter, randomized,
controlled and opened study, based on a design of equivalence for comparison of different
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anesthesiological strategies (see Laboratory of Clinical Drug Evaluation for details). The
biohumoral response to surgical stress will be measured as an indicator of homeostasis and
neurovegetative status. The urinary excretion of catecholamines and cortisol and the plasma
concentration of cortisol will be measured in a central laboratory. Plasma concentrations of
cortisol and urine excretion of cortisol, adrenaline and noradrenaline have been measured, in
collaboration with the Laboratory of Pharmacokinetics and Clinical Chemistry from the Istituto
Mario Negri at Ranica. Statistical analyses and drafting of manuscripts are ongoing.
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
severity of heart failure. By the end of 2009, almost 2000 subjects have been enrolled, a figure
close to the final objective of this study.
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, the Mario Negri Institute with the support of the GISSI group, Oxagen, a
biotechnology company, and AstraZeneca. 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, by typing anonymous highly
informative markers spaced throughout the genome, to identify chromosomal regions which are
linked to the susceptibility to early-onset CAD. The study design is based on family
ascertainment, to allow non-parametric linkage analyses (in ASPs). The PROCARDIS collected
2,036 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; one of the linked regions (Chromosome 17) was confined to families with
multiple cases of myocardial infarction and was replicated in a second independent series of
families. In addition the linkage scan confirmed a previously identified locus on Chromosome 2.
Additionally, the program has collected nuclear families (e.g. parent-offspring trios) for
transmission-based tests of association for fine mapping by linkage disequilibrium analysis and
testing of positional candidate genes. 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
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candidate genes. The results are replicated in different populations. The collaboration has been
extended to include complementary expertise, as proteomics, bioinformatics, functional
analysis.
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, rs2891168 and
rs10811661, 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, with an odds ratio of 1.70 (95% CI 1.491.95) 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.
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 2200 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.
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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).
Association studies in the same population on the adiponectin gene variants, the CRP (Creactive protein) gene variants, some genetic variants on Chromosome 9p21 are in progress. 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.
GISSI-AF. Clinical trial testing the efficacy of an angiotensin II AT1receptor blocker in Atrial Fibrillation
The GISSI-AF is a randomized, prospective, parallel group, placebo-controlled, multicenter
study on the use of valsartan, an angiotensin II AT1-receptor blocker in the prevention of Atrial
Fibrillation (AF) recurrence.
Atrial fibrillation is the most frequent form of arrhythmia in clinical practice, affecting 6% of
people over 65 years old. The traditional therapies are often able to restore the sinus rhythm but
are subject to a very high percentage of relapses, above all when the AF has been present for a
long time and when there are structural changes at both atrial and ventricular level. The reninangiotensin-aldosterone system (RAAS) plays a key role in the “remodelling” phenomenon,
which makes increasingly irreversible the electrical, mechanical and structural properties of the
atrial tissue. Existing experimental and clinical data do not allow any definite conclusion
regarding the efficacy of an angiotensin II AT1-receptor blocker in the prevention of AF. The
GISSI group decided to conduct a specific trial of adequate size versus placebo aimed to assess
if the addition of valsartan on top of established therapies can reduce the recurrence of atrial
fibrillation in patients with a history of recent AF associated with cardiovascular
diseases/comorbidities. The study has recruited and treated for 12 months 1400patients with a
history of recent AF associated with cardiovascular diseases/comorbidities. In GISSI-AF, the
largest trial ever conducted with ARBs in pts with AF, Valsartan did not reduce AF recurrence.
A trend favouring valsartan was observed only in the small group of pts with heart failure
and/or left ventricular dysfunction.
The project was conducted in collaboration with the Laboratory of Cardiovascular Clinical
Pharmacology.
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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.
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).
ACTIVE study (Atrial Fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events)
The aims of the study were to evaluate whether clopidogrel plus acetylsalicylic acid (ASA) is
superior to ASA alone (A study) and non-inferior to standard oral anticoagulant therapy (W
study) in preventing vascular events in patients with atrial fibrillation and to evaluate whether
blood pressure lowering with irbesartan is superior to placebo in preventing vascular events in
patients with atrial fibrillation (I study). The primary efficacy outcome is the first occurrence of
stroke, myocardial infarction, vascular death over the duration of follow-up, (a minimum of 2
and maximum of 4 years approximately). A sample size of 14000 patients was planned, 6500 in
the W study (testing the efficacy of warfarin vs ASA + clopidogrel) and 7500 in the A study
(testing the efficacy of ASA + clopidogrel vs ASA alone). The W study was stopped early by
the Data and Safety Monitoring Board in September 2005 after an interim analysis showing a
significant difference in favour of warfarin over the combination of ASA + clopidogrel. The
details of the ACTIVE W have been published (Lancet 2006; 367:1903-1912). The A and the I
studies have been now completed: the ACTIVE A showed that the addition of clopidogrel to
aspirin reduces the risk of major cardiovascular events and cardiovascular deaths by 11% with
respect to a treatment with aspirin alone. In the ACTIVE I the irbesartan treatment did not affect
the primary endpoint (a composite of stroke, MI and vascular death); however, the secondary
endpoint of the study (hospitalization for cardiac failure) was reduced.
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
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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. Dabigatran given at a dose of 110 mg was associated with
rates of stroke and systemic embolism that were 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.
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
of a new anticoagulant that directly addresses this important unmet need. Patients with AF
(n=5600) not suitable for VKA, for one or more of the reasons given above, are randomized to
receive a new oral anticoagulant, Apixaban, or aspirin. Apixaban is simple to use, convenient,
does not require laboratory monitoring, does not interact with foods, and has very few drug
interactions. Successful completion of the AVERROES trial will potentially establish Apixaban
as 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 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
FUTURA is the eighth in the series of Organization to Assess Strategies in Acute Ischemic
Syndromes (OASIS) trials.
FUTURA builds upon the MICHELANGELO: OASIS 5 & 6 trials to determine the optimal
dose of adjunctive UFH during PCI in patients with unstable angina or myocardial infarction
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without ST-segment elevation on a background of fondaparinux. While the existing safety
experience from OASIS 5 and OASIS 6 supports the use of UFH during PCI in patients initially
treated with fondaparinux, it is based on relatively
limited patient numbers and on retrospective analyses.
The FUTURA study will expand the safety experience in UA/NSTEMI patients initially treated
with fondaparinux who undergo PCI with adjunctive UFH, while also addressing the question
of the optimal dosing strategy with adjunctive UFH during the procedure. The study design will
consist 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.
In addition, subjects with multi-vessel disease will be further randomised in a partial 2x2
factorial sub-study, assessing culprit vessel only revascularization or complete
revascularization.
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).
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.
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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 2007.
• 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 the result of 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
the incidence of mortality and cardiovascular complications occurred during the
hospitalization according to diagnosis and blood glucose level
It was estimated a sample of about 1300 patients. The study is currently ongoing.
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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%
• 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 two main fields: controlled
clinical trials 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.
Actually, GISSI trials focus on GISSI-HF and GISSI-AF clinical trials, concerning heart failure
and atrial fibrillation and a large trial concerning primary prevention, Risk and Prevention
study (Rischio & Prevenzione). Statistical methodology applied to clinical studies has a leading
and developing role as far as methods are concerned (for instance: missing data management;
development of prognostic risk markers, development of forecasting models for biomarkers
based on ROC and Reclassification techniques, 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).
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
analysis techniques concerning cardiovascular genetics have been developed in the last five
years.
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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.
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.
Laboratory of Clinical Pharmacology
Quality of Life, Depression and Cognitive problems in heart failure
patients (QDF-GISSI-HF)
The 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.
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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,
Synaptic Transmission Unit
Head
Marco GOBBI, Pharm.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 Receptor Pharmacology
Head
Tiziana MENNINI, 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.
•
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.[Epub ahead of print], 2009
•
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 323: 1473-1477, 2009
•
Saracino GA, Villa A, Moro G, Cosentino U, Salmona M.
Spontaneous beta-helical fold in prion protein: The case of PrP(82-146)
Proteins 75: 964-76, 2009
•
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 3(3):e1888, 2008
•
Cosentino U, Pitea D, Moro G, Saracino GA, Caria P, Varì RM, Colombo L, Forloni G, Tagliavini F, Salmona M.
The anti-fibrillogenic activity of tetracyclines on PrP 106-126: a 3D-QSAR study.
J Mol Model. 14: 987-94, 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, Salmona M.
Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.
J Biol Chem 281: 843-9, 2006
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
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•
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
•
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 26 publications from 1994 to 2007, in peer-reviewed journals. Among
them she is first author in 11 and last author in 4. She is also author of 2 reviews. 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 [Epub ahead of print], 2009
•
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
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•
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.
•
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
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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
Blood 100: 3719-3730, 2002
Tiziana Mennini got her degree in Pharmacy at the University of Milano (1975). In
the same year she obtained a fellowship from the European Molecular Biology
Organization, to learn sub-cellular fractionation techniques and synaptosomes
utilization in neurochemistry, at the laboratory of Prof. VP Whittaker ( Stockholm,
Sweden). In 1882 she spent a further period in Prof. Whittaker’s laboratories (MaxPlank-Institut fur Biophysikalische Chemie, Abteilung Neurochemie Am Fassberg,
Gottingen, Germany). She spent all her scientific career at the Mario Negri Institute:
1967- 1975 Research Assistant in the Laboratory of Drug Metabolism
1975-1987 Chief of the Unit of Neurochemical Transmission,
1988 to date Chief of the Laboratory of Receptor Pharmacology
Speaker, chairman and organizer at many congresses and courses, author of more than
200 articles published in international journals in the area of receptor pharmacology and
neuropharmacology.
•
Bastone A, Fumagalli E, Bigini P, Perini P, Bernardinello D, Cagnotto A, Mereghetti I, Curti D, Salmona M, Mennini T
Proteomic profiling of cervical and lumbar spinal cord reveals potential protective mechanisms in the wobbler
mouse, a model of motor neuron degeneration
J Proteome Res 8: 5229-40, 2009
•
Beghi E, Bendotti C, Mennini T.
Merits of a new drug trial for ALS?
Science 308:632-633, 2005
•
Gobbi M, Mennini T.
Is St John's wort a 'Prozac-like' herbal antidepressant?
Trends Pharmacol Sci 22:557-559, 2001
•
The Italian ALSSG.
Ceftriaxone in amyotrophic lateral sclerosis
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•
•
Eur J Neurol 3:295-298, 1996
Mennini T, Mocaer E, Garattini S.
Tianeptine, a selective enhancer of serotonin uptake in rat brain.
Naunyn-Schmiedebergs Arch Pharmacol 336:478-482, 1987
Mennini T, Garattini S.
Benzodiazepines receptor binding in vivo: pharmacokinetic and pharmacological
Significante
Advances Biochemical Psychopharmacol 38:189-199,1983
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
•
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
•
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
Marco Gobbi got his degree in Pharmacy at the University of Milan, Italy, in 1989.
His main fields of interest are: 1) neuropharmacology, in particular with studies on the
interaction of drugs and neurotransmitters with receptors and transporters; 2)
neurodegenerative diseases associated to misfolding and aggregation of
peptides/proteins, such as beta-amyloid and prions; 3) biomolecular interactions,
studied using Surface Plasmon Resonance (SPR). Dr. Gobbi is now the responsible for
the SPR apparatus present at Mario Negri Institute.
1981-1989 Researcher, Laboratory of Neuropharmacology and, from 1988, in the
Laboratory of Receptor Pharmacology, Mario Negri Institute
1989 to date Head, Unit of Synaptic Transmission, Mario Negri Institute
ANNUAL REPORT
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Co-author in more than 90 scientific publications on peer-reviewed international
journals. First or last author in more than 40 of them. Reviewer for international
scientific journals operating in the Neuroscience/Neuropharmacology fields.
•
Colleoni S, Jensen AA, Fumagalli E, Conti P, De Amici M, Pellegrini-Giampietro DE, De Micheli C, Mennini T, Gobbi
M
Neuroprotective effects of the novel glutamate transporter inhibitor (-)-HIP-A which acts on reverse transport (glutamate
release) more than on glutamate reuptake
J. Pharmacol. Exp. Ther. 326: 646:656, 2008
•
Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantù L, Kirschner D A, Ceci P,
Ubezio P, Manzoni C, Forloni G, Tagliavini F, Salmona M. Gerstmann-Straussler-Scheinker disease amyloid protein
polymerizes according to the "dock-and-lock" model
J Biol Chem 281: 843-9, 2006
•
Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T.
p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from
neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro
J Neurochem 82:1435-1443, 2002
•
Gobbi M, Mennini T.
Is St John's wort a 'Prozac-like' herbal antidepressant?
Trends Pharmacol Sci 22:557-559, 2001
•
Gobbi M, Gariboldi M, Piwko C, Hoyer D, Sperk G, Vezzani A.
Distinct changes in peptide YY binding to, and mRNA levels of, Y1 and Y2 receptors in the rat hippocampus
associated with kindling epileptogenesis.
J Neurochem 70:1615-1622, 1998
•
Crespi D, Mennini T, Gobbi M.
Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine
Br J Pharmacol 121:1735-1743, 1997
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
•
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
ANNUAL REPORT
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•
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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
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.
Characterization of the role of Junctional Adhesion Molecule-A (JAM-A) in the control
of
cell
motility.
Characterization of the effect of inflammatory cytokines on JAM-A function.
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.
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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.
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
New conformationally constrained aspartate and glutamate analogues dissociate
glutamate uptake inhibition and reverse transport-mediated release.
Dimethyl sulfoxide, a solvent commonly utilized to dissolve hydrophobic compound
for in vitro experiments, interferes with the 5-HT6 agonists activity when the
scintillation proximity assay is used for evaluating 35S-GTP-γ-S binding; but does not
interfere with the europium labelled GTP binding determined by “time-resolved
fluorescence” .
Evidence that the glutamate release mediated by excitatory amino acid transporters
(EAAT) (reverse transport) might be dissociated from the EAAT-mediated glutamate
reuptake. Identification of novel glutamate transporter inhibitors, with neuroprotective
properties, which preferentially inhibits glutamate release compared to glutamate
reuptake.
Evidence that the monoamine release induced by amphetamine derivatives is mainly
calcium-dependent. Neurotoxic amphetamine derivatives, such as
methylendioxymethamphetamine (MDMA, ecstasy), differ from non-neurotoxic ones in
their interaction with presynaptic nerve endings.
Studies on the mechanism of action underlying the antidepressant effects of Hypericum
perforatum extracts and its main putative active principle Hyperforin: no interaction
with central monoamine transporters (as classic antidepressants) but possible action at a
peripheral level by modulation of IL6 release.
ANNUAL REPORT
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Cellular localization of neuropeptide Y (NPY) receptor subtypes Y1 and Y2, and their
adaptive changes following epileptic seizures.
Recombinant C1-inhibitor binds with high affinity with Mannose Binding Lectins, an
interaction possibly underlying its superior anti-ischemic properties in animal models.
Advanced Biology Center, Genoa
Centro Clinico Nemo, Ospedale Niguarda, Milan
Dip. Anatomia, Farmacologia, Medicina Legale, University of Turin
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
Dip. Farmaco-Chimico, Università degli Studi, Messina
Dip. Farmaco-Chimico-Tecnologico, University of Siena
Dip. Farmacologia Medica, Università degli Studi, Milan
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 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
ANNUAL REPORT
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Newron Pharmaceuticals, Milan
Ospedale Maggiore Policlinico, Milan
Ospedale Pediatrico Bambino Gesu', Rome
Ospedale Pediatrico "Gaslini", Genoa
Ospedale S. Gerardo, Monza, Milan
Sigma-Tau, Pomezia, Rome
Zambon, Milan
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
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
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
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
ANNUAL REPORT
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University of Glasgow, UK
University of Gottingen, Germany
University of Muenster, Germany
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.
Course: “Nanoparticles in Medicine”, “Pharmacokinetics and bioavailability of
Nanoparticles based drug delivery system”, 11-13 March, Milan, Italy
Meeting: “XIII Riunione del GSSNP”, "Hyperglycemia and nerve functional parameters
are normalized by syngenically transplanted microcapsulated rat pancreatic islets in rats
with streptozotocin-induced diabetes”, “The neuroprotective effect of erythropoietin
(EPO) in docetaxel (DOCE)-induced peripheral neuropathy (PN) in exerted with no
ANNUAL REPORT
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reduction of antitumor activity in 13762 breast carcinoma bearing rats” 14 May,
Otranto, Italy
Meeting: “4th Meeting, Molecular Mechanisms of Neurodegeneration”, “Mutant prion
protein expression causes impairment of voltage-gated calcium channels in a transgenic
mouse model”, “The expression of the steroidogenic acute regulatory protein (STAR) is
increased in degenerating trait of spinal cord of wobbler mice”, “Role of the axonalSMN (a-SMN) protein in axon growth and spinal muscular atrophy (SMA)
pathogenesis”, “Good gene, bad gene: new APP variant may be both”, “Protein toxicity
in Alzheimer and Parkinson Disease”, “Nitroproteomics of peripheral blood
mononuclear cells from patients and rat model of ALS”, “Mutant prion protein
expression is associated to an alteration of the RAB GDP disassociation inhibitor
alpha(GDI)RAB11 pathway”, “Characterization of detergent-insoluble proteins in ALS
models and patients indicates a possible causal link between nitrative stress and
aggregation in pathogenesis”, 8-10 May, Milan, Italy
Meeting: “EuroNanoForum 2009”, “The NAD project: Nanoparticles for therapy and
diagnosis of Alzheimer’s disease. Preliminary results with nanoliposomes”, 2-5 June,
Prague, Czech Republic
Meeting: “Joint Meeting on Medicinal Chemistry”, “New benzoxazole and
benzothiazole derivatives as potential 5-HT7 receptor ligands”, 25 June, Budapest,
Hungary
Meeting “PNS Meeting”, “ Evaluation of the continuous buprenorphine delivery
analgesic effect in an experimental rat model of painful diabetic neuropathy”,
“Functional recovery with syngenically transplanted microcapsulated pancreatic islets in
streptozotocin-induced diabetic rats”, 9 July, Wurzburg, Germany
Conference: “ICAD 2009 - Alzheimer’s Associations International Conference on
Alzheimer’s Disease”, “A novel approach to control Abeta peptide aging during storage
and handling”, “Membrane protein and Abeta peptide toxicity”, 10 July, Wien, Austria
Course: “First training course 2009 for NAD - Nanoparticles for therapy and diagnosis
of Alzheimer disease”, 5-10 September, Patras, Greece
Conference: “VI International Conference on Proteoglycan”, “Re-appraisal of the role
of NG2-expressing olygodendrocyte subsets in the pathogenesis of Multiple Sclerosis”,
13 September, Aix-les-Bains, France
Congress: “2nd European Congress of Immunology”, “PTX3 acts as a regulator of
leukocyte rolling and extravasation via P-selectin binding”, 13-16 September, Berlin,
Germany
Meeting: “Tetracycline Day”, “Caenorhabditis elegans come modello di malattia di
Alzheimer e di altre amiloidosi per lo sviluppo di nuove strategie terapeutiche”, 15
September, Pavia, Italy
ANNUAL REPORT
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Conference: “2nd National Nanomedicine Conference”, “The NAD project:
Nanoparticles for therapy and diagnosis of Alzheimer’s disease. Preliminary results
with nanoliposomes”, 21 September, Pavia, Italy
Conference: “Prion 2009”, “Characterization of the molecular heterogeneity of mutant
prion proteins”, 23-25 September, Chalkidiki, Greece
Congress: “XIII National Congress of the Italian Society for Neuroscience”,
“Cholesterol in PrP and Aβ amyloid formation”, “C-jun N-terminal kinase regulates
synaptic dysfunction”, “Artificial chaperone, ciclodextrin, decreases accumulation of
misfolded proteins in intracellular inclusions in motoneuron diseases”, 2-5 October,
Milan, Italy
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
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
Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni Claudia, 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 αsynuclein or amyloid-β (1-42) peptide
J Neurochem 2009 110 : 1445-1456
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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. 2009, [Epub ahead of print]
Basso M, Samengo G, Nardo G, Massignan T, D'Alessandro G, Tartari S, Cantoni L, Marino M, Cheroni C, De
Biasi S, Giordana M T, Strong M J, Estevez A G, Salmona M, Bendotti C, Bonetto V
Characterization of detergent-insoluble proteins in ALS models indicates a causal link between nitrative stress
and aggregation in pathogenesis
PLoS One 2009 4: e8140
Bastone A, Fumagalli E, Bigini P, Perini P, Bernardinello D, Cagnotto A, Mereghetti I, Curti D, Salmona M,
Mennini T
Proteomic profiling of cervical and lumbar spinal cord reveals potential protective mechanisms in the wobbler
mouse, a model of motor neuron degeneration
J Proteome Res 2009 8: 5229-5240
Bate C, Tayebi M, Diomede L, Salmona M, Williams A
Glimepiride reduces the expression of PrPc, prevents PrPSc formation and protects against prion mediated
neurotoxicity in cell lines
PLoS One 2009 4 : e8221
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
Biasini E, Tapella L, Mantovani S, Stravalaci M, Gobbi M, Harris D A, Chiesa R
Immunopurification of pathological prion protein aggregates
PLoS One 2009 4 : e7816
Bonanno G, Fumagalli E, Milanese M, Zappettini S, Mennini T
Release of [3H]D-aspartate induced by K+-stimulation is increased in the cervical spinal cord of the wobbler
mouse: a model of motor neuron disease
Neurochem Int 2009 55 : 302-306
Butini S, Budriesi R, Hamon M, Morelli E, Gemma S, Brindisi M, Borrelli G, Novellino E, Fiorini I, Ioan P,
Chiarini A, Cagnotto A, Mennini T, Fracasso C, Caccia S, Campiani G
Novel, potent and selective quinoxaline-based 5-HT3 receptor ligands. 1. Further structure-activity relationships
and pharmacological characterization
J Med Chem 2009 52 : 6946-6950
Butini S, Gemma S, Campiani G, Franceschini S, Trotta F, Borriello M, Ceres N, Ros S, Sanna Coccone S,
Bernetti M, De Angelis M, Brindisi M, Nacci V, Fiorini I, Novellino E, Cagnotto A, Mennini T, SandagerNielsen K, Andreasen J T, Scheel-Kruger J, Mikkelsen J D, Fattorusso C
Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and
serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavio
J Med Chem 2009 52 : 151-169
Caccia S, Gobbi M
St. John's wort components and the brain: Uptake, concentrations reached and the mechanisms underlying
pharmacological effects
Curr Drug Metab 2009 10: 1055-1065
Calabro' M L, Raneri D, Ficarra P, Mennini T, Colleoni S, Grazioso G, Micale N, Zappala' M, Grasso S
Synthesis, chiral resolution and pharmacological evaluation of a 2,3-benzodiazepine-derived noncompetitive
AMPA receptor antagonist
ChemMedChem 2009 4 : 415-420
Cervellini I, Bello E, Frapolli R, Porretta-Serapiglia C, Oggioni N, Canta A, Lombardi R, Camozzi F, Roglio I,
Melcangi R C, D'Incalci M, Lauria G, Ghezzi P, Cavaletti G, Bianchi R
The neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction of
antitumor activity in 13762 adenocarcinoma-bearing rats
Neurotox Res 2009 [Epub ahead of print]
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Chiorazzi A, Nicolini G, Canta A, Oggioni N, Rigolio R, Cossa G, Lombardi R, Roglio I, Cervellini I, Lauria G,
Melcangi R C, Bianchi R, Crippa D, Cavaletti G
Experimental epothilone B neurotoxicity: results of in vitro and in vivo studies
Neurobiol Dis 2009 35 : 270-277
Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, Borsello T
JNK regulates APP cleavage and degradation in a model of Alzheimer's disease
Neurobiol Dis 2009 33 : 518-525
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 2009, in press
Colombo L, Piovesan P, Ghirardi O, Salmona M, Forloni G
ST1859 reduces prion infectivity and increase survival in experimental scrapie
J Virol 2009 154: 1539-1544
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
Ferry C, Giannì M, Lalevée S, Bruck N, Plassat J - L, Raska I Jr, Garattini E, Rochette-Egly C
SUG-1 plays proteolytic and non-proteolytic roles in the control of retinoic acid target genes via its interaction
with SRC-3
J Biol Chem 2009 284 : 8127-8135
Forloni G, Salmona M, Marcon G, Tagliavini F
Tetracyclines and prion infectivity
Infect Disord Drug Targets 2009 9 : 23-30
Garattini E, Fratelli M, Terao M.
The mammalian aldehyde oxidase gene family
Hum Genomics. 2009 4: 119-30
Gesuete R, Storini C, Fantin A, Stravalaci M, Vitsch H, Mannesse M L M, Ziere B, Gobbi M and De Simoni MG
Recombinant C1-inhibitor in Brain Ischemic Injury
Annals of Neurology 2009 66: 332-342
Gianazza E, Eberini I, Ghezzi P
Detection of protein glutathionylation
Methods Mol Biol 2009 519 : 397-415
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-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to
retinoic acid via stabilization of RARα and PML-RARα
Cancer Res 2009 69 : 1016-1026
Manzoni Claudia, Colombo L, Messa M, Cagnotto A, Cantu' L, Del Favero E, Salmona M
Overcoming Aβ peptides aging: a new approach to an age-old problem
Amyloid 2009 16 : 71-80
Massignan T, Biasini E, Veglianese P, 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 2009 [Epub ahead of print]
Massignan T, Stewart R S, Biasini E, Solomon I H, Bonetto V, Chiesa R, Harris D A
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A novel, drug-based, cellular assay for the activity of neurotoxic mutants of the prion protein
J Biol Chem 2009 [Epub ahead of print]
Ma Y J, Doni A, Hummelshøj T, Bastone A, Mantovani A, Thielens N M, Garred P
Synergy between Ficolin-2 and PTX3 boost innate immune recognition and complement deposition
J Biol Chem 2009 284 : 28263-28275
Mennini T, Giordano L, Mengozzi M, Ghezzi P, Tonelli R, Mantegazza R, Silani V, Corbo M, Lunetta C, Beghi
E
Increased IL-8 levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis
Amyotroph Lateral Scler 2009 7 : 39-44
Mennini T, Testa R
Are descending control pathways of the lower urinary tract and pain overlapping systems?
Central Nervous System Agents Medicinal Chemistry 2009, in press
Morelli E, Gemma S, Budriesi R, Campiani G, Novellino E, Fattorusso C, Catalanotti B, Sanna Coccone S, Ros
S, Borrelli G, Kumar V, Persico M, Fiorini I, Nacci V, Ioan P, Chiarini A, Hamon M, Cagnotto A, Mennini T,
Fracasso C, Colovic M, Caccia S, Butini S
Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structureactivity relationships
J Med Chem 2009 52 : 3548-3562
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. 2009 11: 1559-1567
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 2009, in press
Paris L, Bononi E, Bazzoni G
Network analysis of cell adhesion: Adhesomes as context-defined subnetworks
Communicative & Integrative Biology 2009 2 : 20-22
Pera M, Martinez-Otero A, Colombo L, Salmona M, Ruiz-Molina D, Badia A, Clos M V
Acetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation process
Mol Cell Neurosci 2009 40 : 217-224
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
Repici M, Mare L, Colombo Alessio, Ploia C, Sclip A, Bonny C, Nicod P, Salmona M, Borsello T
c-Jun N-terminal kinase binding domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4
and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase and
extracellular signal-regulated kinase
J Neurochem 2009 159 : 94-103
Roglio I, Bianchi R, Camozzi F, Carozzi V, Cervellini I, Crippa D, Lauria G, Cavaletti G, Melcangi R C
Docetaxel-induced peripheral neuropathy: protective effects of dihydroprogesterone and progesterone in an
experimental model
J Peripher Nerv Syst 2009 14 : 36-44
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 75: 964-976
Schumann S, Terao M, Garattini E, Saggu M, Lendzian F, Hildebrandt F, Leimkuhler S
Site directed mutagenesis of amino acid residues at the active site of mouse aldehyde oxidase AOX1
PLoS One 2009 4 : e5348
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Tartari S, D'Alessandro G, Babetto E, Rizzardini M, Conforti L, Cantoni L
Adaptation to G93Asuperoxide dismutase 1 in motor neuron cell line model of amyotrophic lateral sclerosis. The
role of glutathione.
FEBS J 2009 276: 2861-2874
Tamborini L, Conti P, Pinto A, Colleoni S, Gobbi M, De Micheli C
Synthesis of new β- and γ-benzyloxy-S-glutamic acid derivatives and evaluation of their activity as inhibitors of
excitatory amino acid transporters
Tetrahedron 2009 65: 6083-6089
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
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
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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.
In cooperation with the Laboratory of Biology of Neurodegenerative Disease, molecules
that are potentially active are evaluated in different experimental models of central and
peripheral amyloidosis. We have reported that tetracyclines are new candidates as antiamyloidogenesis 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.
Another therapeutic strategy is based on the development of molecules which inhibit
PrP formation by interacting with the lipid metabolism or by destabilizing particular
cellular membrane domains. In collaboration with the Department of Pathology and
Infective Disease of the Royal Veterinary School (Hawkshead, UK) we have shown
that statins, able to inhibit the cellular cholesterol synthesis and levels, reduced the in
vitro prion protein production. On the other hands, other molecules known for their
activity in decreasing cholesterol levels, such as polyunsaturated fatty acids, increased
PrP production. Our studies are aimed to the comprehension of the relationship
between the cholesterol cellular membrane distribution, the stability of lipid domains
and the conversion of the prion protein from the cellular to the pathological form.
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.
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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
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.
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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.
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
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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
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.
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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
from retinoid-based treatment or associations between retinoids and inhibitors of HER2
receptor tyrosine kinase activity.
Laboratory of Receptor Pharmacology
Studies on the role of dysfunction of the endoplasmic reticulum (ER) or
the Golgi apparatus (GA) in neurodegenerative disease
The secretory pathway starts at the endoplasmic reticulum (ER) where proteins are
synthesized and folded and chaperone–mediated quality control prevents misfolded
proteins to reach their destination and interfere with normal metabolism. Protein
transport by mean of vesicles continues through the Golgi Apparatus (GA), that is most
abundant in neurons, and finishes in the plasma membrane, secretory vesicles or
lysosomes. The endocytic pathway enables internalized macromolecules to be delivered
via endosomes to lysosomes where they are enzymatically digested.
In mammalian cells, the Golgi-associated retrograde protein (GARP) complex is
involved in retrograde transport of endosomes to the trans GA network. Defective
intracellular membrane trafficking is common to several neurodegenerative diseases.
Among the neuronal population, motor neurons, due the their high energy requirement
and long axons are, together with retinal cells, the most sensitive ones.
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The Laboratory of Receptor Pharmacology utilizes two mouse models of
neurodegeneration related to cellular transport disruption, carrying mutation in proteins
resident in the ER (the mnd mouse) or in the GARP complex (the wobbler mouse),
models, respectively, of EPMR, a form of neuronal ceroid lipofuscinosis, and
Amyotrophic Lateral Sclerosis.
We have found that mnd mice are more sensitive to convulsions induced by intrahippocampal kainic acid or i.p. pentylenetetrazole. New non-invasive approaches, like
Optical Imaging , MRI, MicroCT and Confocal Angiography are in progress, in order
to allow a better translation of the results to the human disease.
In the wobbler mice we have tested two different approaches of cell therapy.
Undifferentiated adult neural stem cells (in collaboration with Dr. Parati, Istituto Besta)
produced a weak and transient protective effect in clinical progression but significantly
reduced motor neuron loss occurring in the wobbler mouse. Transplantation of
mononucleate cells from human cord blood (in collaboration with Dott. Lazzari,
Policlinico), although did not replace degenerating motor neurons, produced a marked
neuroprotective effect by slowing the clinical progression and reducing motor neuron
loss, biceps atrophy and neuroinflammation (reactive gliosis). Finally, we have tracked
by MRI cells obtained from human amniotic fluid or chorioid villi labelled with
paramagnetic nanoparticles (SPIO), and found that they can be detected for two months
after transplantation.
Neuropharmacology of serotonergic transporter
We have ongoing collaborative studies with Dr. Gobbi (Lab. biochemistry and protein
chemistry, IRFMN), Lundbeck and Vanderbilt University to characterize the role of the
allosteric site at the serotonin transporter on the mechanism of action of SSRI (selective
serotonin reuptake inhibitors) antidepressant, like escitalopram.
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).
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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
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
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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
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, in Pavia and Milan 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 already were measured at a
presymptomatic stage. Among them, actin, ATP synthase, and vinculin overlap between
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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.
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
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
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organizing principles of the junctional complex, thus confirming the usefulness of
network analysis for studying the components and the interactions of the cell.
Novel regulators of cell motility
Cell motility plays a central role in several biological processes, under both normal (e.g.
embryonic development) and pathological conditions (e.g. tumor cell dissemination).
Thus, it is important to identify the molecular mechanisms that regulate cell motility. In
recent years, we have characterized Junctional Adhesion Molecule-A (JAM-A), a
membrane molecule that localizes to the intercellular tight junctions and binds PDZtype intracellular proteins. In the course of these studies, we have discovered that JAMA expression reduces cell motility. In addition, we have found that JAM-A enhances
microtubule stability and focal adhesion formation, which are the adhesive points of
contact between cells and extracellular matrix. All these functional changes require
amino acid residues that mediate binding to PDZ-type intracellular proteins. These
findings have highlighted a novel mechanism of motility inhibition that requires the
interaction between a membrane protein and PDZ-type intracellular proteins.
Effect of inflammatory cytokines on Junctional Adhesion Molecule-A
(JAM-A)
In the course of inflammatory responses, JAM-A contributes to the leakage of plasma
proteins and the transmigration of circulating leukocytes. Although it has been reported
that the inflammatory cytokine Tumor Necrosis Factor (TNF) causes the disassembly of
JAM-A from the intercellular junctions, the mechanism has not been elucidated fully.
Recently, we found that TNF enhances the solubility of JAM-A in non-ionic detergents
and increases the amount of detergent-soluble JAM-A at the cell surface. In addition,
we found that, upon cell treatment with TNF, higher levels of JAM-A become
detectable at the cell surface (by FACS analysis). As these higher levels of JAM-A
derive from the intercellular junctions (and not from intracellular stores), we propose
that TNF causes not only the disassembly of JAM-A from the junctions and its
subsequent redistribution to the cell surface, but also its dispersal in such a way that
JAM-A becomes more easily accessible to the antibodies used for FACS analysis.
These findings are important to highlight potential mechanisms of permeability
regulation during inflammation that might be modulated by inflammatory interventions.
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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 holds a Doctor of Medicine from the University of Milan, a Master of Science in
Clinical Medicine (epidemiology) from Oxford University and a Diploma from the Post-Graduate School
of Pharmacological Research at the “Mario Negri” Institute for Pharmacological Research in Milan.
Work experiences: He is Head of the Department of Epidemiology at the Mario Negri Institute for
Pharmacological Research in Milan, Italy. He is also Associate Professor of Epidemiology at the
University of Milan, Adjunct Professor of Epidemiology, University of Lausanne, Switzerland (since
2002) and Adjunct Professor of Medicine, School of Medicine, Vanderbilt University, Nashville, TN
(2002-2009).
Dr. La Vecchia is a temporary advisor at the International Agency for Research on Cancer IARC/WHO in
Lyon and at the WHO in Geneva, and a registered journalist in Milan. He was an Honorary Senior
Lecturer in Oral Medicine at the Eastman Dental Institute at the University College of London (19962003) and Adjunct Associate Professor of Epidemiology at the Harvard School of Public Health (19962001).
He is Associate Editor to: European Journal of Cancer Prevention and Annals of Oncology, and serves on
the editorial boards of the Jornals: Alimentazione e Prevenzione; Archives of Medical Science; Asian
Pacific Journal of Cancer Prevention; Current Cancer Therapy Reviews; Dermatology Research and
Practice; Digestive and Liver Disease; Economia Politica del Farmaco; European Journal of Nutrition; In
Scope Oncology & Haematology; Maturitas; Nutrition and Cancer; Oncology; Open Cancer Journal; Oral
Oncology; Revisiones en Ginecologia y Obstetricia; Revista Española de Nutrición Comunitaria; Revue
d'Epidémiologie et de Santé Publique;Tumori. In 1993, he received the Glaxo Prize for medical
publication.
He has authored or co-authored over 2000 publications in peer reviewed journals (1500 included in
Pubmed), with a mean Impact Factor of 3.8 and a total Impact Factor over 5000 (1995-2006). He has over
62.000 citations, and 380 publications quoted more than 30 times (H-index 81).
Eva Negri got a degree in Mathematics in 1985 at the University of Milan, School of Mathematics.
Awards: EEC scholarship for postgraduate training in Epidemiology (1988).
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.
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.
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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
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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
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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
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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
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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
of Chronic Diseases of the Department of Epidemiology, “Mario Negri” Institute for Pharmacological
Research.
Awards: "Rafaelsen Scholar Award" from the Collegium Internationale Neuro-Psychopharmacologicum
(CINP), 16th Meeting, Munich (F.R.G.), 1988.
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.
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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
Tavani A, Bravi F, Dal Maso L, Zucchetto A, Bosetti C, Pelucchi C, Montella M, Franceschi S, La Vecchia C. Physical
activity and risk of endometrial cancer: an Italian case-control study. Eur J Cancer Prev 2009; 18: 303-306
Tavani A, Pelucchi C, Parpinel M T, Negri E, Franceschi S, Levi F, La Vecchia C. n-3 Polyunsaturated fatty acid intake
and cancer risk in Italy and Switzerland. Int J Cancer 2003; 105: 113-116
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
Tavani A, Pelucchi C, Negri E, Bertuzzi M, La Vecchia C. n-3 polyunsaturated fatty acids, fish, and nonfatal acute
myocardial infarction. Circulation 2001; 104: 2269-2272
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, 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 180 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,
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care, and education in health”. Il Pensiero Scientifco Editore, Roma 2009.
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Santoro E., Tinazzi A.“Clinical Trials Data Management”. In “Clinical Trials Handbook” (Wiley 2009, Edited by Gad
S.C.).
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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
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
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.
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.
She is author/coauthor of more than 130 publications on these issues on peer-reviewed scientific journals.
Work experiences: Visiting scientist at the”Life style and cancer group” of the International Agency for
Research on Cancer (IARC), Lyon, France (Oct 2009); Unit Head, Unit of Cancer Epidemiology,
Department of Epidemiology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan (since Sept.
2005); Collaboration with the “International Epidemiology Institute”, Rockville, MD, USA (since 2002); Visiting scientist at the Unit of “Field and intervention studies”, IARC, Lyon, France (sett-2000-giu.
2001); Visiting scientist at the Department of Epidemiology, Harvard School of Public Health, Boston,
MA (sett-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). She has over 200 publications on peerreviewed scientific Journals cited in PubMed/MEDLINE. Mean I.F.: 3.68. H-index: 30 (on Google
Scholar or SCOPUS).
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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. 2009 Oct 7. [Epub ahead of print]
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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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Bosetti C, Micelotta S, Dal Maso L, Talamini R, Montella M, Negri E, et al. Food groups and risk of prostate cancer in
Italy. Int J Cancer 2004; 110: 424-428.
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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).
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).
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.
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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
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.
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.
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.
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).
Since 2008, Dr Gallus is Associate Editor of the journal BMC Public Health, and is member of the
editorial board of The Open Obesity Journal (since 2009) and the World Journal of Gastrointestinal
Oncology (since 2009).
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Gallus S, Tramacere I, La Vecchia C, Colombo P, Zuccaro P, Paleari L, Cesario A, Russo P, Apolone G. Use of
pharmacotherapy for smoking cessation in Italy. Arch Intern Med. 2009;169:1927-8.
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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
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to various substances and the development of various forms of cancers and cardiovascular
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; epidemiological and clinical studies in dermatology in collaboration with the
“Gruppo Italiano per gli Studi Epidemiologici in Dermatologia” (GISED); 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. 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
Inverse associations between dietary vitamin D intake and the risk of
oesophageal/oral/pharyngeal cancers were found.
Gastric cancer was inversely associated with intake of vitamin E, alpha-carotene and betacarotene, and positively associated with sodium intake in our study conducted in Milan.
Besides micronutrients, we evaluated the association between macronutrients and gastric cancer,
and found a protective effect of selected vegetable fats, which are common in the Mediterranean
diet.
High glycemic index and load increase the risk of gastric cancer. The risk is particularly when
high levels of glycemic load are combined to low intake of fruit and vegetables.
In the same study of gastric cancer, we found a protective effect of total fiber intake. With
reference to the source of fiber intake, vegetable and fruit fiber, but not grain fiber, decreased
gastric cancer risk.
In a case-control study from China, we found an inverse relation between green tea drinking and
gastric cancer risk limited to the intake of cold tea.
We found a protective effect against gastric cancer risk of dietary patterns rich in fruits and
vegetables, and a positive association of dietary patterns rich in meats and animal fats and
starchy foods.
Subjects in the highest decile of vitamin D intake had an about 30% decreased risk of colon
cancer. Rectal cancer was unrelated to vitamin D intake in the investigated population.
Inverse associations between proanthocyanidins and the risk of colorectal cancer may explain
the protective effect of vegetables and fruit on colorectal cancer.
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A diet with a high glycemic load was directly associated with the risk of hepatocellular
carcinoma in two studies from Italy and Greece.
Obesity and diabetes increase HCC risk, and that these factors may explain a relevant
proportion of cases among subjects without markers of HBV/HCV infection.
Besides colon cancer, very high levels of vitamin D intake might have a protective effect against
breast cancer, too.
Our study did not lend support to the hypothesis that alcohol or wine consumption improves the
survival of women with breast cancer.
We found a direct association between consumption of red meat and endometrial cancer, and a
moderate increase in risk for consumption of sweets and poultry. A high consumption of cereals
and vegetables decreased the risk of endometrial cancer by 44% and 41%, respectively.
Our study confirmed the results of previous reports that a family history of endometrial, uterine
and colorectal cancer increases the risk of endometrial cancer.
The study of endometrial cancer confirmed the importance of multiparity, years of
menstruation, and oral contraceptives use in endometrial cancer aetiology, thus contributing to
identify women at elevated risk of such neoplasm.
The cluster of subjects mainly consuming bread and pasta was unfavourable for breast and
ovarian cancers. The group including subjects mainly consuming fruits and vegetables was
protective against ovarian cancer.
We found direct relations between dietary levels of glycemic index and load and renal cell
cancer risk. This positive association can be related to mechanisms related to insulin resistance
and sensitivity.
Regular use of aspirin for at least six months was not related with risk of renal cell cancer.
The data on renal cell carcinoma provided evidence that a diet rich in beta-carotene and
lutein/zeaxanthin may play a role in renal cell cancer prevention.
Tobacco smoking and alcohol drinking are two independent risk factors for pancreatic cancer
which may be responsible for approximately one third of these cancers in Italy.
There is a positive association between pancreatic cancer risk and the intake of animal protein,
and a negative one with sugars.
A diet rich in meat, sugar and potatoes has an unfavourable role on pancreatic cancer. Noncitrus fruit, cooked vegetables and pulses have a protective effect on this cancer.
A varied diet has a beneficial effect on laryngeal cancer. Diversity within vegetables and fruit
has also a protective effect.
Citrus fruit showed a protective effect against cancers of the digestive and respiratory tract,
whereas no association was found with breast, endometrial, ovarian, prostate and renal cell
cancer.
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Several aspects of the Mediterranean diet might be favourable not only on cardiovascular
disease, but also on cancer risk. This hypothesis was supported by findings from our network of
case-control studies.
There is no evidence of an adverse effect of low-calorie sweetener (including aspartame)
consumption on the risk of common neoplasms in the Italian population.
In a review of epidemiological studies on selected aspects of diet and oral and pharyngeal
cancer risk, we confirmed and quantified the protective role of vegetable and fruit consumption.
Given the absence of apparent effect of moderate alcohol drinking and pancreatic cancer risk,
and the moderate association observed with heavy drinking, alcohol would be responsible for a
small fraction of all pancreatic cancer.
In a meta-analysis on oral contraceptives use and colorectal cancer we observed that oral
contraceptive users have a reduced risk of colorectal cancer, with a greater protection for recent
users.
In a meta-analysis of published studies on coffee and hepatocellular carcinoma, we observed a
decreased risk of 31% for moderate coffee drinkers, and of 56% for heavy coffee drinkers, as
compared to non-drinkers.
Recent studies conducted in different areas of North America and Europe showed a 5-10%
decline in the incidence of breast cancer, that might be explained by an effect of reduced
hormone therapy use. However, the reasons of the falls in incidence of breast cancer remain
open to discussion.
Epidemiological data on coffee and alcohol drinking and bladder cancer are suggestive of no
association.
We reviewed epidemiological evidence on risk factors for thyroid cancer. At present, the only
recognized measures for reducing thyroid cancer risk is to avoid ionizing radiation and iodine
deficiency, particularly in childhood and young women, and to increase vegetable consumption.
Aspirin has emerged as the most likely NSAID for use in chemoprevention of colorectal and
other selected neoplasms because of its known cardiovascular benefit and available safety and
efficacy data.
In 2008, smoking prevalence was the lowest observed over the last 50 years, in Italy. Subjects
with less privileged socio-economic characteristics should be considered target populations for
tobacco control.
In Italy, in 2007, the highest prevalence of hardcore smoking that has been reported in the
literature to date has been observed.
Analyzing data from 7 tobacco surveys conducted between 2002 and 2008, we observed that
further methods to increase the use of pharmacotherapy for smoking cessation are needed in
Italy.
Using data from 4 surveys conducted annually between 2005 and 2008, we showed that in Italy
cigarette smuggling now contributes only a small proportion of total tobacco sales and that
internet is not yet used as source for cigarette sales.
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In Italy, 3 years after the law came into force, the smoke-free legislation remains respected and
appears to have favourably affected the business of restaurants and bars.
An updated analysis of cancer mortality in Europe showed a persistent favourable trend over the
last years.
Updated trends for cancer mortality in Italy remained favourable for most cancer sites, mainly
for male tobacco-related cancers, and female cancers for which screening practices are more
widespread (uterus and female breast).
Mortality from childhood cancer continued to decline over more recent years in most European
countries. Some further improvement in childhood cancer mortality in Eastern and Southern
Europe is achievable through more widespread and better adoption of currently available
treatments.
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.
Steady downward trends persist in gastric cancer mortality worldwide even in middle aged
population, and hence further appreciable declines are likely in the near future.
Falling rates for biliary tract cancer mortality were recorded throughout the Americas, Europe
and Asia, there are however some high risk areas, mainly in South America and India where
access to gall-bladder surgery remains inadequate
There are persistent declines in HL mortality in western European countries, and favourable
patterns over more recent calendar years in central/eastern ones, where rates, however, are still
at levels observed in western Europe in the early 1990s.
Though mortality from cardio- and cerebrovascular diseases continued to decline in several
areas of the world, unfavourable trends were still observed in the Russian Federation and other
countries of the former Soviet Union, whose recent rates remain exceedingly high.
The most reliable estimate of incident kidney cancer cases in Italy over the period 2007-2012 is
likely to range between 7000 and 9000. Of these, between 6000 and 8000 are renal cell cancer
cases.
The most reliable estimate of hepatocellular carcinoma incident cases in Italy in 2007 is
between 5500 and 6000, and this figure is likely to decline to 5000-5500 in 2012.
In a meta-analysis of studies on interventions for the prevention of falls in elderly people,
intervention based on exercise alone resulted more effective as compared to multifactorial
interventions.
Our investigation on gastric cancer provided convincing evidence that coffee and tea
consumption are unlikely to be strongly associated with this neoplasm.
Results from our case-control study ruled out a strong relation between physical activity and
endometrial cancer risk.
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We provided further evidence that coffee, decaffeinated coffee and tea consumption is not
related to renal cell cancer risk.
A diet rich in onion, and not in garlic, may have a favourable effect on the risk of acute
myocardial infarction.
A meta-analysis of case-control studies provided quantitative evidence of an inverse relation
between coffee drinking and colorectal (mainly colon) cancer risk.
In another meta-analysis of two cohort and seven case-control studies, an inverse relation
between coffee drinking and endometrial cancer risk emerged.
Agenzia giornalismo scientifico Zadig, Milano
Associazione Nazionale dei Medici Cardiologi Ospedalieri (ANMCO)
Associazioni Sguazzi Onlus
Associazione Chirurghi Ospedalieri Italiani (ACOI),
Centro di Riferimento Oncologico, Servizio di Epidemiologia, Aviano (PN)
Comune di Milano, Direzione centrale salute, Settore politiche per la salute
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 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
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
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 Società Italiana Attività Regolatorie
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Università Bocconi di Milano, Dipartimento di Analisi Istituzionale e Management Pubblico
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, Istituto di Statistica Medica e Biometria “G.A. Maccacaro”, 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, Varsavia, 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
Faculty of Medical Sciences, University of Córdoba, Argentina
Harvard School of Public Health, Department of Epidemiology, Boston, USA
Hellenic Health Foundation
Hôpital Necker - Enfants Malades, Centre of the Association Claude Bernard on Auto-immunes
diseases, Parigi, 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
TobaccoFree Research Institut, Dublin, Ireland
eUNDP/UNFPA/WHO/WORLD Bank special programme of research development and
research training in human reproduction, Ginevra, Switzerland
Universitat Pompeu Fabra, Department of Experimental and Health Sciences, Barcellona, Spain
University of Athens Medical School, Department of Hygiene and Epidemiology, Atene,
Greece
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, USA
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Advances in Therapy (Eva Negri)
Alimentazione e Prevenzione (Carlo La Vecchia)
Annals of Oncology (Carlo La Vecchia)
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)
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
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
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Medical Internet Research , Journal of the National Cancer Institute, Lancet Oncology,
Maturitas, Melanoma Research, Nicotine & Tobacco Research, Nutrition and Cancer, Obstetric
and Gynecology, Oncology, 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.
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
IARC/OMS di Lione e OMS di Ginevra
Ministero della Salute, Sottocomitato fumo.
Ministero della Salute, Commissione Oncologica Nazionale.
Scientific Review Committee del UND/WHO/World Bank Human Reproduction Programme
Società Italiana della Riproduzione
EVENT ORGANIZATION
Corso “Clinical Trials, HTA reports, practice guidelines. Where and how to search”,
organizzato dal personale del dipartimento nel corso dell’European Association for Health
Information and Libraries Workshop, Dublino 2-5 giugno 2009.
III° edizione del corso ECM “"La ricerca bibliografica su database biomedici", Istituto di
Ricerche Farmacologiche “Mario Negri”, Milano, 8 giugno 2009
III° edizione del corso ECM "Internet e l’aggiornamento professionale in ambito medico",
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 9 giugno 2009
III° 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 giugno 2009
IV° edizione del corso ECM “"La ricerca bibliografica su database biomedici", Istituto di
Ricerche Farmacologiche “Mario Negri”, Milano, 10 novembre 2009
IV° edizione del corso ECM "Internet e l’aggiornamento professionale in ambito medico",
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 11 novembre 2009
IV° edizione del corso ECM "Il web 2.0 al servizio della formazione e dell’aggiornamento del
medico", Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, 12 novembre 2009
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Workwhop on Environment and Health: Evaluating European air quality research and
translating priorities into actions. CONCAWE. Brusselles, Belgio 19-20 January 2009
Pancreatic Cancer case-control (PANC4) consortium. “PANC4 plans and potential
collaboration with Cohort studies”. Rockville, MD, 26 February 2009.
PPACTE Kickoff Meeting. Dublino, Irlanda, 26-27 February 2009.
Seminario “ Internet e giovani: potenzialità e pericoli”, promosso dal Laboratorio Salute Sociale
e Comune di Milano. Titolo relazione “Internet e salute: come evitare i pericoli”. Milano,
February 18 2009.
Lo stress ossidativo: dal laboratorio alla pratica. “Componenti antiossidanti di frutta e verdura e
rischio di tumore.” Bologna, 21 March 2009.
6th Annual INHANCE Meeting. “Principal components analysis for diet”. Paris, France, 24-25
March 2009
International experts workshop on the risk of hepatocellular carcinoma caused by exposure to
vinyl chloride monomer. Leuven, Belgium., 21 April 2009
Workshop on Nutrition and Cancer: from epidemiology to molecular mechanisms. “Diet and
Cancer Prevention: Italian data”. Padova, 30 April 2009
Tavola rotonda “Prevenzione nei media: responsabilità o business”, promossa nell’ambito del
Festival Internazionale del Giornalismo, Perugia, April, 1-5.
Corso “Internet e l’aggiornamento professionale in ambito medico”, promosso dal servizio
formazione del personale medico della Provincia Autonoma di Bolzano, Bolzano, April 16 2009
La metodologia della ricerca clinica. “Gli studi osservazionali”. Università degli Studi di
Milano, Ospedale Niguarda. Milano, 6 May 2009.
Partecipation to a special expert panel meeting to evalute the proposals in the January 2009 call.
Helsinki, Finlandia 11-12 May 2009
2nd International Congress on Nutrition and Cancer. “Overweight, adiponectin and
ginecological cancer”, “Diet and cancer in Mediterranean countries: carbohydrates, fats and
flavonoids”, “Sun exposure, vitamin D and lymphohaemopoietic cancers”. Antalya, Turchia,
18-22 May 2009
Sweden Research Council for Working Life and Social Research. Allocation of resources to
national and international research infrastructures within the framework of the strategic research
areas. Evaluation form Strategic research areas 2009. Stockholm, Sweden, 24-25 May 2009
XI Convegno Nazionale tabagismo e Servizio sanitario nazionale. “Dimezzare i morti e i tumori
da fumo”. Roma, 29 May 2009
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Convegno “Crisi ed editoria: vecchi problemi e nuove soluzioni, XXVI convegno GIDIF, RBM
(Gruppo Italiano Documentalisti dell’Industria Farmaceutica e degli Istituti di Ricerca
Biomedica). Titolo della relazione “I blog e le loro opportunità nel campo della editoria medicoscientifica”, Monza, May 26 2009.
Corso “Internet e l’uso dei nuovi strumenti del web 2.0 in ambito medico: potenzialità e
applicazioni”, Istituto Nazionale dei Tumori, Milano, May 7 2009
Corso, “Medicina basata sulle prove di efficacia” promosso dall’Azienda Unità Sanitaria Locale
n.1 di Sassari, Titolo della lezione “Siti e applicazioni Internet in ambito medico: tipologia di
informazione e modalità di reperimento”. Sassari, May 22 2009.
PSONET Steering Group Meeting. Roma, 4-5 June 2009
VII Congresso Nazionale SIB - Società Italiana di Biometria. “Confidence intervals for the
cost-effectiveness ratio: a new methodological proposal”. Ponte di Legno (BS), 10-12 June
2009,
Meeting. Caffè e rischio di cancro: il ruolo protettivo su alcune patologie tumorali. “Caffè e
rischio di tumore all’endometrio e altri tumori”. Milano, 16 June 2009.
Master Universitario di II livello in “Informatica medica”, Università di Udine, anno
accademico 2008-2009. Ruolo di docenza nel modulo “Internet, web 2.0 e sanità; strumenti e
applicazioni al servizio del medico e del cittadino”, Udine, June 18, 19 2009.
Seminario “Cartella clinica informatizzata”, promosso dall’Associazione Nazionale Medici
Cardiologi Ospedalieri nel corso del congresso ANMCO 2009. Titolo relazione “Utilità
dell’informatizzazione per la riduzione del rischio clinico”, Firenze, June 5 2009.
Expert Meeting. Rischio cardiovascolare e valutazione del paziente HIV. “Il punto di vista
dell’epidemiologo-analisi dati”. Milano 1 July 2009.
Meeting HiWATE. Dublino, Irlanda. 25 August 2009
Gordon conference. “Colorectal cancer and disinfection by-products. Exposure measurement in
an on-going case-control study in Spain and Italy. Dublino, August 2009
Meeting. Bone fractures after menopause. “Chairman Session 3” and“Frequency of falls and
prevalence of fractures in postmenopausal women”. Capri, 30-31 August 2009
Workshop on the enhancement of the scientific process and transparency of observational
epidemiology studies. ECETOC. Londra, UK 24-25 September 2009
Convegno. Le diossine Taranto tra ambiente e salute. Le diossine a Taranto tra ambiente e
salute. Taranto, 26 September 2009
Convegno. Alcohol & collutori. “Review studi epidemiologici su rischio cancro orale e utilizzo
collutori a base di alcohol”. Milano, 29 September 2009
Corso, “Medicina basata sulle prove di efficacia. Corso avanzato” promosso dall’Azienda Unità
Sanitaria Locale n.1 di Sassari. Titolo della lezione “Siti e applicazioni web 2.0 in ambito
medico: tipologia di informazioni e metodologia d’uso”. Sassari, September 10,11 2009.
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Corso, “Siti, strumenti ed applicazioni web 2.0 in ambito medico” promosso dalla Biblioteca
Medica della AIL Biella-Fondazione Clelio Angelino onlus, Biella, September 8 2009.
Congresso. Integrazione di un nuovo farmaco antifumo nei programmi di diagnosi precoce nei
forti fumatori. “Tavola rotonda: l’esperienza del MILD”. Milano, 9 October 2009
Il carcinoma epatocellulare. Opera editoriale Prof. Massimo Colombo. Milano, 11 October 2009
XXXIII Congresso nazionale della Associazione Italiana di Epidemiologia (AIE). “Acceptance
of HPV vaccination among parents and adolescents in Italy”. Modena, 22-24 October 2009.
XI Congresso Nazionale della Associazione Italiana Oncologi Medici (AIOM). Titolo relazione:
“RSS technology and podcasts in oncology: a new way to deliver scientific information”.
Milano, October 10-13 2009.
Corso “Accesso, distribuzione e valutazione dell’informazione medica e il ruolo degli strumenti
web 2.0”, promosso dall’Arcispedale Santa Maria Nuova, Azienda Ospedaliera di Reggio
Emilia, Reggio Emilia, October 2 2009.
Seminario “Il ruolo degli strumenti del web 2.0 nell’aggiornamento professionale del medico e
del ricercatore”, Istituto Superiore di Sanità, Roma, October 9 2009
Convegno “Web 2.0 per guadagnare salute”, promosso dall'Associazione Italiana della
Comunicazione Pubblica e Istituzionale nell’ambito di COM.Lab 2009. Bologna, October 15
2009
Seminario “Siti, strumenti e applicazioni web 2.0 in ambito medico”, Biblioteca Ospedale
Bellaria, Bologna, October 26 2009
XIII Weekend clinico. Tumori Ginecologici e della Mammella: stile di vita, ormoni e
riproduzione. “Soprappeso Adiponectina e Tumori Ginecologici”. Castrocaro Terme, 6-7
November 2009
Milano Focus Salute. “Epidemiologia del fumo e dell’alcool”, “Asbesto e mesotelioma pleurico:
rischi attuali e futuri”. Milano, 26-27 November 2009
Conferenza AIRC. “I tumori: cause e prevenzione”. Bellinzago, 26 November 2009
Master Universitario di I° livello in Ricerca Clinica, Università di Milano, anno accademico
2009-2010. Ruolo di docenze nel modulo “Internet e le nuove tecnologie per l’aggiornamento
medico-scientifico”, Milano, November 18 2009
Tavola rotonda “Internet e le nuove tecnologie del web: applicazioni e ricadute in chirurgia”,
congresso di videochirurgia della Associazione Chirurghi Ospedalieri Italiani (ACOI),
Conegliano, November 24 2009
70° Congresso Nazionale della Società Italiana di Cardiologia. Titolo relazioni: “L’uso della
tecnologia RSS in cardiologia: un nuovo modo di distribuire l’informazione scientifica” e
“Twitter, il web 2.0 e loro applicazioni in ambito cardiovascolare”. Roma, December 12 – 15
2009
ANNUAL REPORT
198
2009
IRFMN
XXXIV Congresso Nazionale SINU. Nutrizione, la pietra d’angolo. Fabbisogni nutrizionali e
salute nell’epoca del genoma. “Alcool e tumori”. Firenze, 11-12 December 2009
AIFA
Associazioni Sguazzi Onlus
Associazione Italiana per la Ricerca sul Cancro
Comune di Milano
Lega Italiana Lotta contro i Tumori
European Commission (FP7)
European Research Council (ERC)
Fondazione Politecnico di Milano
GISED
Regione Lombardia
Weber Shandwich
Consorzio Assomela
ISA
Perfetti Van Melle
Gallus S, Tramacere I, Tavani A, Bosetti C, Bertuccio P, Negri E, La Vecchia C
Coffee, black tea and risk of gastric cancer.
Cancer Causes Control, 20: 1303-1308 (2009).
Montella M, Tramacere I, Tavani A, Gallus S, Crispo A, Talamini R, Dal Maso L, Ramazzotti
V, Galeone C., Franceschi S, La Vecchia C.
Coffee, decaffeinated coffee, tea intake and risk of renal cell cancer.
Nutr. Cancer, 61: 76-80 (2009).
Gallus S, Tavani A, La Vecchia C.
Response to Chocolate, well-being and health among elderly men: chocolate and acute
myocardial infarction in a case-control study from Italy.
Eur. J. Clin. Nutr., 63: 588-589 (2009).
Lucenteforte E, Talamini R, Montella M, Dal Maso L, Pelucchi C, Franceschi S, La Vecchia C,
Negri E.
Family history of cancer and the risk of endometrial cancer.
Eur. J. Cancer Prev., 18: 95-99 (2009).
Bravi F, Scotti L, Bosetti C, Zucchetto A, Talamini R, Montella M, Greggi S, Pelucchi C, Negri
E, Franceschi S, La Vecchia C.
Food groups and endometrial cancer risk: a case-control study from Italy.
Am. J. Obstet. Gynecol, 200: 293.e1-293.7 (2009).
ANNUAL REPORT
199
2009
IRFMN
Tavani A, Bravi F, Dal Maso L, Zucchetto A, Bosetti C, Pelucchi C, Montella M, Franceschi S,
La Vecchia C.
Physical activity and risk of endometrial cancer: an Italian case-control study.
Eur. J. Cancer Prev., 18: 303-306 (2009).
Ferketich AK, Gallus S, Colombo C, Pacifici R, Zuccaro P, La Vecchia C.
Hardcore smoking among Italian men and women.
Eur. J. Cancer Prev., 18: 100-105 (2009).
Negri E, Boffetta P, Berthiller J, Castellsague X, Curado MP, Dal Maso L, Daudt AW,
Fabianova E, Fernandez L, Wünsch-Filho V, Franceschi S, Hayes RB, Herrero R, Koifman S,
Lazarus P, Lence JJ, Levi F, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Olshan AF,
Rudnai P, Shangina O, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM,
Zaridze D, Lissowska J, Zhang ZF, Ferro G, Brennan P, La Vecchia C, Hashibe M.
Family history of cancer: Pooled analysis in the International Head and Neck
Cancer Epidemiology Consortium.
Int. J. Cancer, 124: 394-401 (2009).
Hashibe M, Brennan P, Chuang S-, Boccia S, Castellsague X, Chen C, Curado MP, Dal Maso
L, Daudt AW, Fabianova E, Fernandez L, Wünsch-Filho V, Franceschi S, Hayes RB, Herrero
R, Kelsey K, Koifman S, La Vecchia C, Lazarus P, Levi F, Lence JJ, Mates D, Matos E,
Menezes E, McClean MD, Muscat J, Eluf-Neto J, Olshan AF, Pudue A, Rudnai P, Schwartz
SM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, Shangina
O, Pilarska A, Zhang Z-, Ferro G, Berthiller J, Boffetta P.
Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled
analysis in the International Head and neck Cancer Epidemiology Consortium.
CEBP, 18: 541-550 (2009).
Bosetti C, Bianchi C, Negri E, La Vecchia C.
Estimates of the incidence and prevalence of renal cell carcinoma in Italy in 2002 and
projections for the years 2007 and 2012.
Tumori, 95: 142-145 (2009).
Bosetti C, Bianchi C, Negri E, La Vecchia C.
Estimates of the incidence and prevalence of hepatocellular carcinoma in Italy in 2002 and
projections for the years 2007 and 2012.
Tumori, 95:23-27 (2009).
Pelucchi C, La Vecchia C
Alcohol, coffee, and bladder cancer risk: a review of epidemiological studies.
Eur. J. Cancer Prev. 18: 62-68 (2009).
Rossi M, McLaughlin JK, Lagiou P, Bosetti C, Talamini R, Lipworth L, Giacosa A,
Montella M, Franceschi S, Negri E, La Vecchia C.
Vitamin D intake and breast cancer risk: a case-control study in Italy.
Ann. Oncol., 20: 374-378, 2009.
Bosetti C, Pelucchi P, La Vecchia C.
Diet and cancer in Mediterranean countries: carbohydrates and fats.
Publ. Health Nutr., 12 (9A): 1595-1600 (2009).
Ferketich AK, Gallus S, Colombo C, Apolone G, Rossi S, Zuccaro P, La Vecchia C.
ANNUAL REPORT
200
2009
IRFMN
Use of pharmacotherapy while attempting cessation among Italian smokers.
Eur. J. Cancer Prev., 18: 90-92 (2009).
Garavello W, Lucenteforte E, Bosetti C, Talamini R, Levi F, Tavani A, Franceschi S, Negri E,
La Vecchia C.
Diet diversity and the risk of laryngeal cancer: a case-control study from Italy and Switzerland.
Oral Oncol., 45: 85-89 (2009).
Lipworth L, Bender TJ, Rossi M, Bosetti C, Negri E, Talamini R, Giacosa A, Franceschi S,
McLaughlin JK, La Vecchia C.
Dietary vitamin D intake and cancers of the colon and rectum: a case-control study in Italy.
Nutr. Cancer, 61: 70-75 (2009).
Purdue MP, , Hashibe M, Berthiller J, La Vecchia C, Dal Maso L, Herrero R, Franceschi S,
Castellsague X, Wei Q, Sturgis EM, Morgenstern H, Zhang Z-F, Levi F, Talamini R, Smith E,
Muscat J, Lazarus P, Schwartz SM, Chen C, Eluf Neto J, Wünsch-Filho V, Zaridze D, Koifman
S, Curado MP, Benhamou S, Matos E, Szeszenia-Dabrowska N, Olshan AF, Lence J, Menezes
A, Daudt AW, Mates IN, Pilarska A, Fabianova E, Rudnai P, Winn D, Ferro G, Brennan P,
Boffetta P, Hayes RB.
Type of alcoholic beverage and risk of head and neck cancer - A pooled analysis within the
INHANCE consortium.
Am. J. Epidemiol., 169: 132-142 (2009).
Lucenteforte E, Bosetti C, Gallus S, Bertuccio P, Pelucchi C, Tavani A, La Vecchia C, Negri E.
Macronutrients, fatty acids and cholesterol intake and stomach cancer risk.
Ann. Oncol., 20: 1434-1438 (2009).
Maconi G, Sainaghi M, Molteni M, Bosani M, Gallus S, Ricci G, Alvisi V, Bianchi Porro G
Predictors of long-term outcome of functional dyspepsia and duodenal ulcer after successful
Helicobacter pylori eradication - a 7-year follow-up study
Eur. J. Gastroenterol. Hepatol., 21: 387-393 (2009).
Naldi L, Parazzini F, Gallus S, and GISED study centres.
Prevalence of atopic dermatitis in Italian schoolchildren: factors affecting its variations
Acta Derm.Venereol., 89: 122-123 (2009).
Bravi F, Scotti L, Bosetti C, Bertuccio P, Negri E, La Vecchia C.
Dietary fiber and stomach cancer risk: a case-control study from Italy.
Levi F., Randimbison L., Te VC, Maspoli Conconi M., La Vecchia C.
RE: Risk of prostate, breast and colorectal cancer after skin cancer diagnosis.
Int. J. Cancer, 123: 2899-2901 (2009).
Bosetti C., Levi F., Ferlay J., Lucchini F., Negri E., La Vecchia C.
The recent decline in mortality from Hodgkin lymphomas in Central and eastern Europe.
Ann. Oncol., 20: 767-774 (2009).
Gallus S, Tramacere I, Zuccaro P, Colombo P, La Vecchia C.
Tobacco sales to minors in Italy.
Tumori, 95:283-285 (2009).
ANNUAL REPORT
201
2009
IRFMN
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, 46: 546-551 (2009).
Polesel J, Zucchetto A, Montella M, Dal Maso L, Crispo A, La Vecchia C, Serraino D,
Franceschi S, Talamini R.
The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma.
Ann. Oncol., 20: 353-357 (2009).
Galeone C, Pelucchi C, Dal Maso L, Negri E, Talamini R, Montella M, Ramazzotti V, Bellocco
R, Franceschi S, La Vecchia C.
Glycemic index, glycemic load and renal cell carcinoma risk.
Ann. Oncol., 20: 1881-1885 (2009)
Pira E, Manzari M, Gallus S, Negri E, Bosetti C, Romano C,
McLaughlin JK, Boffetta P, La Vecchia C.
Cancer mortality in a cohort of continuous glass filament workers.
J. Occup. Environ. Med. J. Occup Environ. Med., 51:239-242 (2009)
La Vecchia C, Negri E, International Collaboration of Epidemiological Studies of Cervical
cancer.
Cervical carcinoma and sexual behaviour: collaborative reanalysis of individual data
on 15,461 women with cervical carcinoma and 29,164 women without cervical
carcinoma from 21 epidemiological studies.
Cancer Epidemiol. Biomarkers Prev., 18: 1060-1069 (2009).
Galeone C, Tavani A., Pelucchi C, Negri E, La Vecchia C:
Allium vegetable intake and risk of acute myocardial infarction in Italy.
Eur. J. Nutr., 48: 120-123 (2009).
Pelucchi C, Tramacere I, Bertuccio P, Tavani A, Negri E, La Vecchia C.
Dietary intake of selected micronutrients and gastric cancer risk: an Italian case-control study.
Ann. Oncol., 20: 160-165 (2009).
Randi G, Malvezzi M, Levi F, Ferlay J, Negri E, Franceschi S, La Vecchia C.
Epidemiology of biliary tract cancers: an update.
Ann. Oncol., 20: 146-159 (2009).
Dal Maso L, Bosetti C, La Vecchia C, Franceschi S.
Risk factors for thyroid cancer: an epidemiological review focused on nutritional.
Bravi F, Scotti L, Bosetti C, Gallus S, Negri E, La Vecchia C, Tavani A.
Coffee drinking and endometrial cancer risk: a meta-analysis of observational studies.
Am. J. Obstet. Gynecol., 200: 130-134 (2009).
Edefonti V, Randi G, Decarli A, La Vecchia C, Bosetti C, Franceschi S, Dal Maso L, Ferraroni
M.
Clustering dietary habits and the risk of breast and ovarian cancers.
Ann. Oncol., 20: 581-590 (2009).
ANNUAL REPORT
202
2009
IRFMN
Bertuccio P, Praud D, Chatenoud L, Lucenteforte E, Bosetti C, Pelucchi C, Rossi M, Negri E,
La Vecchia C.
Dietary glycemic load and gastric cancer risk in Italy.
Br. J. Cancer, 100: 558-561 (2009).
Vajdic CM, Falster MO, de Sanjose S, Martinez-Maza O, Becker N, Bracci PM, Melbye M,
Smedby KE, Engels EA, Turner J, Vineis P, Seniori Constantini A, Holly EA, Kane E, Spinelli
JJ, La Vecchia C, Zheng T, Chiu BCH, Dal Maso L, Cocco P, Maynadié M, Foretova L, Staines
A, Brennan P, Davis S, Severson R, Cerhan JR, Breen EC, Birmann B, Cozen W, Grulich AE.
Atopic disease and risk of non-Hodgkin lymphoma: an InterLymph pooled analysis.
Cancer Res., 69: 6482-6489 (2009).
Esposito S, Pelucchi C, Tel F, Chiarelli F, Sabatini C, Semino M, Marseglia GL, De Mattia D,
Principi N.
Factors conditioning effectiveness of a remainder/recall system to improve influenza
vaccination in asthmatic children.
Vaccine., 27: 633-635 (2009).
Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E, Malvezzi M, La Vecchia C.
Recent patterns in gastric cancer: a global overview.
Int. J. Cancer, 125: 666-673 (2009).
Gallus S., Naldi L.
Longitudinal studies of melanocytic nevi in children. A clue to improve understanding of
melanoma in adults.
Arch. Dermatol., 145: 191-193 (2009).
Levi F, Chatenoud L, Bertuccio P, Lucchini F, Negri E, La Vecchia C.
Mortality from cardiovascular and cerebrovascular diseases in Europe and other areas of the
world: an update.
Eur. J. Cardiovasc. Prev. Rehabil., 16: 333-350 (2009).
Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, Jankowski J, La Vecchia C,
Meyskens F, Senn HJ, Thun M.
Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: An international
consensus statement.
Lancet Oncol., 10: 501-507 (2009).
Levi F, Randimbison L, Blanc-Moya R, La Vecchia C.
Second neoplasms following invasive and borderline ovarian cancer.
Eur. J. Cancer Prev., 18:216-219 (2009).
Lucenteforte E, Garavello W, Bosetti C, La Vecchia C.
Dietary factors and oral and pharyngeal cancer risk.
Oral Oncol. 2009;45:461-7 (2009)
Tramacere I, Gallus S, Zuccaro P, Colombo P, Rossi S, Boffetta P, La Vecchia C.
Socio-demographic variation in smoking habits. Italy 2008.
Prev. Med., 48: 213-217 (2009).
Lipworth L, Rossi M, McLaughlin JK, Negri E, Talamini R, Levi F, Franceschi S, La Vecchia
C.
ANNUAL REPORT
203
2009
IRFMN
Dietary vitamin D and cancers of the oral cavity and esophagus.
Ann. Oncol., 20: 1576-1581 (2009).
Lagiou P, Rossi M, Tzonou A, Georgila C, Trichopoulos D, La Vecchia C.
Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatitits
infection.
Ann. Oncol., 20: 1741-1745 (2009).
Gallus S, Tramacere I, Zuccaro, Colombo P, La Vecchia C
Cigarette smuggling in Italy, 2005-8.
Tobacco Control,18: 159-160 (2009).
del Pilar Diaz M, Osella AR, Aballay LR, Munoz SE, Lantieri MJ, Butinof M, Meyer Paz R,
Pou S, Eynard AR, La Vecchia C.
Cancer incidence pattern in Cordoba, Argentina.
Eur. J. Cancer Prev., 18: 259-266 (2009).
Zucchetto A, Serraino D, Polesel J, Negri E, De Paoli A, Dal Maso L, Montella M, La Vecchia
C, Franceschi S, Talamini R.
Hormone-related factors and gynecological conditions in relation to endometrial cancer risk.
Eur. J. Cancer Prev., 18: 316-321 (2009).
Lubin JH, Purdue M, 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 A, Mates IN, Lissowska J, Levi F, Lazarus P, La Vecchia C, Koifman S,
Herrero R, Franceschi S, Wunsch-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.
Total exposure and exposure rate effects for alcohol and smoking and risk of head and neck
cancer: a pooled analysis of case-control studies.
Am. J. Epidemiol., 170: 937-947 (2009).
Rossi M, Lipworth L, Dal Maso L, Talamini R, Montella M, Polesel J, McLaughlin JK,
Parpinel M, Franceschi S, Lagiou P, La Vecchia C.
Dietary glycemic load and hepatocellular carcinoma with or without chronic hepatitis infection.
Ann. Oncol., 20: 1736-1740 (2009).
Tramacere I, Gallus S, Fernandez E, Zuccaro P, Colombo P, La Vecchia C.
Medium-term effects of the Italian smoke-free legislation: findings from 4 annual population
based surveys.
J Epidemiol Community Health, 63: 559-562 (2009).
Paleari L, Negri E, Catassi A, Cilli M, Servent D, D’Angelillo R, Cesario A, Russo P, Fini M.
Inhibition of nonneuronal α7-nicotinic receptor for lung cancer treatment.
Am. J. Respir. Crit. Care Med., 179: 1142-1150 (2009).
Polesel J, Serraino D, Zucchetto A, Lucenteforte E, Dal Maso L, Levi F, Negri E, Montella M,
Franceschi S, Talamini R, La Vecchia C.
Cigarette smoking and endometrial cancer risk: the modifying effect of obesity.
Eur. J. Cancer Prev., 18: 476-481 (2009).
Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ.
ANNUAL REPORT
204
2009
IRFMN
A further plea for adherence to the principles underlying science in general and the
epidemiologic enterprise in particular. (Authors’response)
Int. J. Epidemiol., 38: 678-679 (2009).
Sverzellati N, Calabrò E, Randi G, La Vecchia C, Marchianò A, Kuhnigk J-M, Zompatori M,
Spagnolo P, Pastorino U.
Sex differences in emphysema phenotype in smokers without airflow obstruction.
Eur. Resp. J., 33: 1320-1328 (2009).
Lam TK, Cross AJ, Consonni D, Randi G, Bagnardi V, Bertazzi PA, Caporaso NE, Sinha R,
Subar AF, Landi MT.
Intakes of red meat, processed meat, and meat mutagens increase lung cancer risk.
Cancer Res., 69: 932-939 (2009).
Bosetti C, Gallus S, Talamini R. Montella M, Franceschi S, Negri E, La Vecchia C.
Artificial sweeteners and the risk of gastric, pancreatic and endometrial cancers in Italy.
CEBP, 18: 2235-2238 (2009)
La Vecchia C.
Mouthwash and oral cancer risk: An update.
Oral Oncol., 45: 198-200 (2009).
Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ.
Response: Re: False-positive results in cancer epidemiology: A plea for epistemological
modesty.
JNCI,101: 213-214 (2009).
Conway DI, Hashibe M, Wunsch-Filho V, Muscat J, La Vecchia C, Winn D, Boffetta P, on
behalf of the INHANCE consortium.
Enhancing epidemiologic research on head and neck cancer: INHANCE – the international head
and neck cancer epidemiology consortium.
Oral Oncol., 45: 743-746 (2009).
Bosetti C, Gallus S, La Vecchia C.
Aspirin and cancer risk: a summary review to 2007.
Recent Results Cancer Res. 181: 231-251 (2009).
Petracci E, Farella M, Galeone C, Albano A, Ferraroni M, Decarli A.
Survival analysis with clustered observations of orthodontic brackets.
Stat. Med., 28: 3483-3491 (2009).
Nieuwenhujisen MJ, Smith R., Golfinopoulos S, Best N, Bennett J, Aggazzotti G, Righi E,
Fantuzzi G, Buchini L, Cordier S, Villanueva CM, Moreno V, La Vecchia C, Bosetti C,
Vartiainen T, Rautiu R, Toledano M, Iszatt N, Grazuleviciene R, Kogevinas M.
Health impacts of long-term exposure to disinfection by-products in drinking water in Europe:
HIWATE.
J. Water Health, 7: 185-207 (2009).
Naldi L, Chatenoud L.
Registry research in dermatology.
Dermatol. Clin., 27: 185-191, vii (2009).
ANNUAL REPORT
205
2009
IRFMN
Franceschi S, Dal Maso L, Zucchetto A, Talamini R, Bidoli E, Lise M, Polesel J, Serraino D,
Bosetti C, Galeone C, Gallus S, La Vecchia C, Negri E, Pelucchi C, Zanier L, de Dottori M,
Stocco CF, Zambon P, Puppo A, Vercelli M, Falcini F, Ravaiolo A, Prospective Analysis of
Case-control studies on Environmental factors and health (PACE) study group.
Alcohol consumption and survival after breast cancer.
Cancer Epidemiol. Biomarkers Prev., 17: 1988-1996 (2009).
Edefonti V, Randi G, La Vecchia C, Ferraroni M, Decarli A.
Dietary patterns and breast cancer: a review with focus on methodological issues.
Nutr. Rev., 67: 297-314 (2009).
Hu J, La Vecchia C, Negri E, DesMeules M, Mery L, The Canadian Cancer Registries
Epidemiology Research Group.
Dietary vitamin C, E, and carotenoid intake and risk of renal cell carcinoma.
Gallus S, Tramacere I, La Vecchia C, Colombo P, Zuccaro P, Paleari L, Cesario A, Russo P,
Ferketich A, Apolone G.
Use of pharmacotherapy for smoking cessation in Italy.
Arch. Int. Med., 169: 1927-1928 (2009)
Boccardi D, Menni S, La Vecchia C, Nobile M, Decarli A, Volpi G, Ferraroni M.
Overweight and childhood psoriasis. Letter.
Br. J. Dermatol.,161: 484-486 (2009).
Garavello W, Lucenteforte E, Bosetti C, La Vecchia C.
The role of foods and nutrients on oral and pharyngeal cancer risk.
Minerva Stomatol., 58: 25-34 (2009).
La Vecchia C.
Association between Mediterranean dietary patterns and cancer risk.
Nutr. Rev., 67 (suppl.1): S126-S129. (2009)
Bertuccio P, Edefonti V, Bravi F, Ferraroni M, Pelucchi C, Negri E, Decarli A, La Vecchia C.
Nutrient dietary patterns and gastric cancer risk in Italy.
CEBP, 18: 2882-2886 (2009)
Bravi F, Bosetti C, Tavani A, La vecchia C.
Coffee drinking and hepatocellular carcinoma: an update.
Hepatology, 50: 1317-1318 (2009).
Boffetta P, La Vecchia C.
Neoplasms.
In: “Oxford Texbook of Public Health”, vol. 3, V edition “The Practice of Public Health”,
Detels R, Beaglehole R, Lansang MA, Gulliford M , New York: Oxford Univ. Press,
Chapter 9.3, pp. 997-1020 (2009).
La Vecchia C, Bosetti C.
Oral contraceptives and neoplasms other than breast and female genital tract.
Eur. J. Cancer Prev., 18: 407-411 (2009).
Petridou E Th, Manti EG, Ntinapogias AG, Negri E, Szczerbinska K.
ANNUAL REPORT
206
2009
IRFMN
What works better for community-dwelling older people at risk to fall? A meta-analysis of
multifactorial versus physical exercise-alone interventions.
J. Aging Health, 21: 713-729 (2009).
Santoro E, Tinazzi A.
Clinical trials data management.
In: Clinical Trials Handbook, Gad S.C. ed.
Wiley & Sons, Inc., Hoboken, New Jersey, 2009, Ch. 8, pp.203-225.
Lipworth L, La Vecchia C, Bosetti C, McLaughlin JK.
Occupational exposure to rock wool and glass wool and risk of cancers of the lung and the head
and neck: a systematic review and meta-analysis.
J. Occup. Environ. Med., 51: 1075-1087 (2009).
Bosetti C, Bravi F, Negri E, La Vecchia C.
Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis.
Human Repr. Update, 15: 489-498 (2009).
Pelucchi C, Bosetti C, Rossi M, Negri E, La Vecchia C.
Selected aspects of Mediterranean diet and cancer risk.
Nutr. Cancer, 61: 756-766 (2009)
Parente F, Molteni M, Marino B, Colli A, Ardizzone S, Greco S, Sampietro G, Gallus S.
Bowel ultrasound and mucosal healing in ulcerative colitis.
Dig. Dis., 27: 285-290 (2009).
Chuang S-C, La Vecchia C, Boffetta P.
Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection.
Cancer Letters, 286: 9-14 (2009).
Pelucchi C, Negri E, Gallus S, Boffetta P, Tramacere I, La Vecchia C.
Long-term particulate matter exposure and mortality: a review of European epidemiological
studies.
BMC Publ. Health, 9:453 (2009).
Levi F, Randimbison L, Te VC, Maspoli Conconi M, La Vecchia C.
Re: Risk of prostate, breast, and colorectal cancer after skin cancer diagnosis.
Int. J. Cancer, 124: 1743-1744 (2009).
Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C.
Re: Misleading figures on trends in mortality from hepatocellular carcinoma in Europe.
Hepatology, 49: 336 (2009).
Santoro E. RSS technology and podcasts in oncology: a new way to deliver scientific
information. Annals of Oncology 2009; 20 (Supplement 8):viii43.
ANNUAL REPORT
207
2009
IRFMN
Gallus S, Apolone G.
Tumore al polmone: prevenzione primaria e secondaria.
In: “La Salute del Respiro. Fattori di rischio, epidemiologia, costi e impatto sociale delle
malattie respiratorie nella realtà sanitaria italiana”, a cura di Testi R. et al.,
Milano, Franco Angeli, 2009, pp. 267-298.
Gallus S, La Vecchia C
Fumo e malattie dell’apparato respiratorio.
malattie respiratorie nella realtà sanitaria italiana”, a cura di Testi R. et al., Milano,
Franco Angeli, 2009, pt. II “Fattori di rischio per le malattie polmonari croniche”,
Cap. 1, pp. 31-46.
Testi R, Rizzini P, Bosetti C, La Vecchia C, Bettoncelli G, Dal Negro RW.
Terapie farmacologiche per asma e BCPO in Italia: farmaco utilizzazione e stima delle
necessità terapeutiche.
malattie respiratorie nella realtà sanitaria italiana”, a cura di Testi R. et al., Milano,
Franco Angeli, 2009, pt. IV “Prevenzione, programmazione e cura delle patologie respiratorie”,
Cap. 2, pp. 267-298.
Tavani A
Caffè e tumori
2009; Weber Shandwick Italia, Milano
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Una città che invecchia e si ripopola.
In: Milano capitale della salute
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un'indagine
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Partecipasalute 2009; http://www.partecipasalute.it/cms_2/node/1243
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4-5
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65-67
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l’informazione scientifica”. Giornale Italiano di Cardiologia 2009; 10 (Suppl 1):252.
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di Cardiologia 2009; 10 (Suppl 1):252.
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RESEARCH ACTIVITIES
Laboratory of General Epidemiology
CASE-CONTROL STUDIES ON CANCER
Digestive tract neoplasms
Dietary vitamin D and cancers of the oral cavity and esophagus
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Data on the association between vitamin D and upper digestive tract neoplasms are limited. We
examined the relation between dietary vitamin D intake and risk of oesophageal and
oral/pharyngeal cancers in two case-control studies conducted in Italy between 1992 and 2005.
Using data on 304 incident cases of oesophageal cancer and 804 cases of oral/pharyngeal cancer
with corresponding 743 and 2,080 hospital controls, respectively. We reported inverse
associations between dietary vitamin D intake and risk of oesophageal cancer and, perhaps,
oral/pharyngeal cancer, which were most pronounced among heavy current smokers and heavy
consumers of alcohol.
Micronutrients and gastric cancer
No specific constituent of plant foods has been consistently identified to explain the inverse
association between non-starchy vegetables and fruit and gastric cancer. In our study, we
estimated micronutrient intake using information from a validated and reproducible food
frequency questionnaire, through an Italian food composition database. We found decreased
odds ratios (ORs) for the highest vs. lowest quartile of vitamin E (OR = 0.50), alpha-carotene
(OR = 0.52) and beta-carotene (OR = 0.42) intake. Gastric cancer was directly associated with
sodium, with ORs of 2.22 for the second, 2.56 for the third and 2.46 for the fourth quartile of
intake. No significant relation emerged with iron, calcium, potassium, zinc, vitamin C, thiamin,
riboflavin, niacin, vitamin B6, folate, vitamin D, retinol, beta-cryptoxanthin, lycopene and
lutein plus zeaxanthin.
Macronutrients, fatty acids and cholesterol intake and gastric cancer
Besides micronutrients, we also evaluated the association between specific macronutrients
(including total energy, various macronutrients and fatty acids) and stomach cancer risk. The
multivariate ORs were 1.79 (95% confidence interval, CI, 1.16-2.76) in the highest versus
lowest tertile of total energy intake, 0.65 (95% CI, 0.43-0.98) for vegetable fats, and 0.66 (95%
CI, 0.44-0.97) for polyunsaturated fatty acids. No significant association was found for proteins,
sugars, starch, total and animal fats, saturated and monounsaturated fatty acids and cholesterol.
Our study thus indicated that selected vegetable fats, which are common in the Mediterranean
diet, have a potential for prevention through dietary changes in stomach cancer.
Glycemic index and load and gastric cancer
We further investigated gastric cancer risk in relation to dietary glycemic index (GI) and
glycemic load (GL). We found that adjusted ORs in the highest versus the lowest quintile were
1.9 (95% CI, 1.0–3.3) for GI and 2.5 (95% CI, 1.3–4.9) for GL. Compared with participants
reporting low GL and high fruit/vegetables intake, the OR rose across strata of high GL and low
fruit/vegetables, to reach 5.0 (95% CI, 2.2–11.5) for those reporting low fruit/vegetables intake
and high GL.
Dietary fiber and gastric cancer
Fiber intake has been inversely related to stomach cancer risk in some studies, although this
issue is still controversial. In our study, the multivariate OR for total fiber was 0.47 (95% CI,
0.28-0.79 for the highest quintile of intake as compared to the lowest). With reference to the
sources of dietary fiber, an inverse association was found for fiber from vegetable (OR=0.42,
95% CI, 0.24-0.72) and to a lesser extent from fruit (OR=0.65, 95% CI, 0.38-1.10), but not for
fiber from grain (OR=1.25, 95% CI, 0.77-2.03).
Green tea intake and the risk gastric cancer risk in China
We considered the relationship between green tea and gastric cancer risk in Harbin,
Heilongjiang province, northeast China, an area with high baseline risk of stomach cancer. We
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used data from a case-control study conducted from 1987 to 1989 among 266 incident cases of
stomach cancer and 533 controls admitted to the same hospitals as cases. No association
emerged when tea consumption alone was considered: the OR for green tea consumption was
0.87 (95% CI: 0.60-1.25) for green tea intake ≥750 g/year versus no intake and 0.99 (95% CI:
0.97-1.02) for an increment of 500 g of tea per year. When tea consumption was further
classified according to the temperature, however, the OR was 0.19 (95% CI: 0.07-0.48) for cold
tea intake ≥750 g/year and 1.27 (95% CI: 0.85-1.90) for hot tea intake (p value for interaction
<0.001) as compared to non drinkers. The corresponding ORs for an increment of 500 g of tea
per year were 0.61 (95% CI: 0.45-0.82) and 1.03 (95% CI: 0.99-1.07) for cold and hot tea,
respectively (p value for interaction<0.001). In conclusion, this study suggests that temperature
is an effect modifier of the relation between green tea and stomach cancer.
Nutrient dietary patterns and gastric cancer
In a case-control study conducted in Northern Italy, we identified four major nutrient dietary
patterns in relation to gastric cancer risk. We observed a positive association between gastric
cancer risk and the “animal products” (OR=2.13, 95% CI, 1.34-3.40, for the highest versus the
lowest score quartile) and the “starch-rich” (OR, 1.67, 95% CI, 1.01-2.77) patterns. The
“vitamins and fiber” pattern was inversely associated with gastric cancer (OR=0.60, 95% CI,
0.37-0.99), whereas no significant association emerged with the “vegetable unsaturated fatty
acids” pattern (OR=0.89, 95% CI, 0.56-1.42).
Vitamin D and colorectal cancer
Epidemiologic evidence indicates that vitamin D is inversely associated with risk of colon or
rectal cancer or both. In our analyses on 1953 cases and 4154 controls, we found that adjusted
ORs for colon cancer decreased after the fifth decile of vitamin D intake, reaching 0.69 for the
ninth and tenth deciles. The inverse association appeared to be somewhat more pronounced for
the proximal than the distal colon, and was similar among strata of geographic region and
calcium intake. Rectal cancer was unrelated to vitamin D intake in this population.
Proanthocyanidins and colorectal cancer
In vitro and animal studies suggest that proanthocyanidins decrease cancer risk, particularly
colorectal cancer. We used data from an Italian case-control study including 1953 colorectal
cancer and 4154 controls in order to investigate whether proanthocyanidins are related to
colorectal cancer risk. Through multiple logistic regression, we found a decreasing risk with
increasing intake of proanthocyandins with a significant trend for all classes except monomers.
The OR for the highest versus the lowest quintile of intake was 0.88 for monomers, 0.75 for
dimers, 0.84 for trimers, 0.80 for 4-6 mers, 0.79 for 7-10 mers, and 0.69 for polymers more than
10 mers. The associations were apparently stronger for rectal than for colon cancer. These
results may explain the protective effect of vegetables and fruit on colorectal cancer.
Glycemic load and hepatocellular carcinoma according to chronic
hepatitis infection
The association of diabetes mellitus and obesity with hepatocellular carcinoma (HCC) raises the
possibility that dietary GL may interact with chronic hepatitis infection in the causation of HCC.
We examined the issue using data from two Italian and Greek HCC studies. In the Italian study,
we observed a positive association between GL and HCC overall, with an OR of 3.02 (95% CI,
1.49-6.12) for the highest quintile of GL compared with the lowest, and a significant trend in
risk. The OR among HCC cases with evidence of chronic infection with hepatitis B and/or C
viruses was 3.25 (95% CI, 1.46-7.22), while the OR among those with no evidence of infection
was 2.45 (95% CI, 0.69-8.64), with no significant trend. The association was not explained by
the presence of cirrhosis or diabetes. In the Greek study, we found a non-significant positive
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association between GL and HCC, which was exclusively accounted for by a positive
association between GL and HCC cases with chronic infection with hepatitis B and/or C. For
the latter group of patients, the OR at the highest compared to the lowest GL quintile was 1.95
(95% CI, 1.09-3.48). The association was strengthened after exclusion of subjects with diabetes.
Diabetes and hepatocellular carcinoma
We also considered the impact of obesity and diabetes mellitus (DM) on the risk of HCC in
Italy, providing further evidence that obesity and DM increase HCC risk and that these factors
may explain a relevant proportion of cases (over a trend) among subjects without markers of
HBV/HCV infection.
Female breast and genital neoplasms
Vitamin D and breast cancer risk
We investigated whether vitamin D was associated with risk of breast cancer in our study
including 2569 cases of breast cancer and 2588 hospital controls. After allowance for major risk
factors for breast cancer and dietary covariates, including calcium and energy intake, there was
no association up to the seventh decile between vitamin D intake and breast cancer. Thereafter,
the OR declined, so that the overall trend was statistically significantly inverse. The OR for
subjects in the three highest deciles of consumption of vitamin D compared with those in the
lowest ones combined was 0.79 (95% CI, 0.70-0.90). Only intake of vitamin D over 3.57 μg or
143 IU appeared to have a protective effect against breast cancer.
Alcohol and survival after breast cancer
A recent study from the United Kingdom reported that alcohol consumption may improve breast
cancer survival. To provide information on this issue, we used follow-up information (median,
12.6 years) from 1,453 women with incident invasive breast cancer, diagnosed between 1991
and 1994 and interviewed in our case-control study. We observed 503 deaths, and estimated
hazard ratios (HR) for all-cause mortality using Cox proportional hazard models, adjusted for
major tumor characteristics (tumor, node, and metastasis stage, and estrogen and progesterone
receptor status) and potential lifestyle factors associated with survival. The HR in the fully
adjusted model were 0.98 (95% CI, 0.79-1.22) for all drinkers and 1.17 (95% CI, 0.85-1.61) for
≥21 drinks/wk, compared with nondrinkers. The corresponding figures for wine consumption,
which accounted for 79% of all alcohol consumption in our study, were 0.94 (95% CI, 0.761.16) and 1.11 (95% CI, 0.71-1.73). In no category of alcohol consumption did drinkers survive
any longer than nondrinkers. Our study did not lend support to the possibility that alcohol or
wine consumption improves the survival of women with breast cancer.
Diet and endometrial cancer
We analyzed data from a case-control study on endometrial cancer, conducted during 19922006 in three areas of Italy, including 454 cases and 908 controls, to investigate the relationship
between various aspects of diet and risk of endometrial cancer. With reference to main food
groups, we found a significant direct association with consumption of red meat, and a moderate
increase in risk for consumption of sweets and poultry. On the other hand, a high consumption
of cereals and vegetables decreased the risk of endometrial cancer by 44% and 41%,
respectively, while other food groups investigated were not associated with the risk of this
cancer. Another study considered the role of allium vegetables, which were found to be
inversely related with risk of various other cancers in an earlier Italian study. For endometrial
cancer too, we found significant inverse associations with consumption of both onions (OR =
0.40 for the highest vs. lowest level of consumption) and garlic (OR = 0.62).
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Family history of cancer and endometrial cancer risk
With reference to family history of cancer, our questionnaires had detailed information on
history of all cancers in first-degree relatives and thus allowed a thoroughly investigation of the
relation with endometrial cancer risk. The OR of endometrial cancer for women with at least
one first-degree relative diagnosed the same neoplasm was 2.13, while those who had relatives
with a diagnosis of uterine and colorectal cancer had OR of endometrial cancer of 1.76 and
1.62, respectively. Risks were also increased in women younger than 55 years at diagnosis (OR
= 2.60 for family history of uterine cancer, OR = 2.79 for family history of colorectal cancer).
We found direct associations with some other cancer sites, while there was no association with
the family history of breast cancer. Thus, our study confirmed that a family history of
endometrial, uterine and colorectal cancer increases the risk of endometrial cancer.
Hormone-related factors, gynecological conditions and endometrial
cancer risk
The objectives of this study were to investigate the effect of menstrual and reproductive
variables, breastfeeding, exogenous hormones, and gynaecological conditions on endometrial
cancer risk. Endometrial cancer risk was inversely associated with parity (OR=0.5, 95% CI 0.40.8, for ≥3 deliveries vs. none) and age at menarche (OR=0.7, 95% CI 0.5-1.0, for ≥14 vs. <12
years), and directly with age at menopause (OR=1.8, 95% CI 1.1-2.7, for ≥55 vs. <50 years) and
years of menstruation (OR=2.4, 95% CI 1.7-3.4, for highest vs. lowest tertile). Oral
contraceptives use conferred a 40% reduced risk (95% CI 0.4-1.0), irrespective of time since
cessation. Conversely, women with a history of treated infertility (OR=2.7, 95% CI 1.1-6.4) or
endometriosis (OR=4.0, 95% CI 1.0-15.5) were at increased risks. No significant associations
with endometrial cancer risk emerged for age at first/last birth, breastfeeding, menopausal
status, hormone replacement therapy, and history of uterine fibromyomas or polycystic ovary.
In conclusion, this study confirmed the importance of multiparity, years of menstruation, and
oral contraceptives use in endometrial cancer aetiology, thus contributing to identify women at
elevated risk of such neoplasm.
Dietary pattern and breast and ovarian cancer risk
We considered the relationship between diet, breast and ovarian cancer in terms not only of
specific foods and/or nutrients, but also of complex dietary patterns. In our dataset we identified
five groups of subjects. The cluster including subjects mainly consuming bread and pasta was
unfavourable for both cancers. The group including subjects mainly consuming fruits and
vegetables was protective against ovarian cancer. We also reviewed papers published to date
that have identified dietary patterns according to all the existing approaches and have assessed
their association with breast cancer. Nineteen articles published since 1995 were identified
based on studies conducted in various populations across many countries. Six studies did not
find associations between any of the identified dietary patterns and breast cancer. Nine studies
identified one dietary pattern significantly associated with breast cancer, and the remaining four
identified two to four dietary patterns related to breast cancer.
Glycemic index and glycemic load and renal cell cancer
The risk of renal cell cancer (RCC) has been related to refined cereals and starchy foods, but the
association has not been studied in terms of GI and GL. We found direct relations between
dietary levels of GI and GL and RCC risk. In fact, compared to the lowest quintile, the ORs for
the highest quintile were 1.43 (95% CI, 1.05-1.95) for GI and 2.56 (95% CI, 1.78-3.70) for GL,
with significant trends in risk. Compared with the lowest quintile, the risk of RCC for all
subsequent levels of GL was higher in never than in ever drinkers. This direct association can be
related to mechanisms related to insulin resistance and sensitivity.
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Aspirin use and renal cell cancer
Aspirin and non-steroideal anti-inflammatory drugs (NSAIDs) have been related to decreased
risk of several cancers, but studies on the relation with the risk of RCC are inconsistent. We
have analyzed data of our case-control study conducted in Italy in 1992-2004, based on 755
cases and 1,297 controls. 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.
Micronutrients and renal cell cancer
We contributed to the analysis of a nationwide multi-site population-based case-control study
based on cancer registration in Canada. The data on RCC provide evidence that a diet rich in
beta-carotene and lutein/zeaxanthin may play a role in RCC prevention.
Other neoplasms
Diet diversity and the risk of laryngeal cancer
Diet diversity (defined as the number of different foods consumed) has been considered an
indicator of a healthy diet, and favorably related to the risk of several digestive tract cancers.
We analyzed the relation between diet diversity and the risk of laryngeal cancer using data from
a case-control study carried out between 1992 and 2000 in Italy and Switzerland. The subjects
of the study were 527 patients with histologically confirmed incident cancers of the larynx and
1297 patients admitted for acute, non-neoplastic diseases, unrelated to tobacco or alcohol
consumption. Total diversity was computed as the number of different foods (overall and within
four food groups, i.e., vegetables, fruit, meat, and cereals) consumed at least once per week. A
significant inverse association was observed for vegetable diversity (OR=0.41, 95% CI: 0.280.59, for the highest versus the lowest quartile) and fruit diversity (OR=0.40, 95% CI: 0.270.59). Conversely, a direct association was found for meat diversity (OR=1.67, 95% CI: 1.112.50), while no meaningful association was found for total diet and cereal diversity.
Tobacco, alcohol and pancreatic cancer risk
Tobacco smoking is the major established risk factor for pancreatic cancer, whereas the role of
alcohol consumption is still open to debate. Between 1991 and 2008, we conducted a hospitalbased case-control study in northern Italy on 326 cases with pancreatic cancer, and 652 controls.
Pancreatic cancer was associated to current smoking (OR=1.68; 95% CI, 1.13-2.48), and the
risk rose with increasing number of cigarettes/day (OR=2.04; 95% CI, 1.14-3.66 for 20
cigarettes/day). No association emerged for former smokers (OR=0.98; 95% CI, 0.66-1.45).
Alcohol consumption was associated to increased pancreatic cancer risk, but ORs were
significant only among heavy drinkers (ORs = 2.03 and 3.42 for 21-34 and ≥35 drinks/week,
respectively). Pancreatic cancer risk was 4.3-fold higher in heavy smokers (≥20 cigarettes/day)
and heavy drinkers (≥21 drinks/week) in comparison with never smokers who drunk <7
drinks/week.
Citrus fruit consumption and risk of selected cancers
Citrus fruit has shown a favourable effect against various cancers. We considered their role on
cancer risk, using data from Italian and Swiss case-control studies, including a total of 955
patients with oral and pharyngeal cancer, 395 with oesophageal, 999 with stomach, 3634 with
large bowel, 527 with laryngeal, 2900 with breast, 454 with endometrial, 1031 with ovarian,
1294 with prostate, and 767 with RCC. After adjustment for major identified confounding
factors for each cancer site and energy intake, the ORs for the highest versus lowest category of
citrus fruit consumption were 0.47 (95% CI, 0.36-0.61) for oral and pharyngeal, 0.42 (95% CI,
0.25-0.70) for oesophageal, 0.69 (95% CI, 0.52-0.92) for stomach, 0.82 (95% CI, 0.72-0.93) for
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colorectal, and 0.55 (95% CI, 0.37-0.83) for laryngeal cancer. No consistent association was
found with breast, endometrial, ovarian, prostate and RCC. Thus, our findings indicated that
citrus fruit has a protective role against cancers of the digestive and upper respiratory tract.
Selected aspects of Mediterranean diet and cancer risk
Several aspects of the Mediterranean diet are considered favourable not only on cardiovascular
disease, but also on cancer risk. We reviewed the role of various aspects of the Mediterranean
diet on cancer risk in our series of case-control studies conducted between 1991 and 2007. For
most epithelial cancers, the risk decreased with increasing vegetable consumption, with ORs
between 0.3 and 0.8 for the highest versus the lowest level. Allium vegetables were also
favourably related to cancer risk. The risk of a few cancer sites, mainly of digestive tract and
larynx, was inversely associated with fruit intake. For digestive tract cancers, the population
attributable risks for low intake of vegetables and fruit ranged between 15 and 40%. Fish, and
consequently a diet rich in n-3 polyunsaturated fatty acids, was another favourable diet
indicator, while red meat intake was directly related to some common neoplasms. Olive oil and
unsaturated fats, which are also typical aspects of the Mediterranean diet, were inversely related
to the risk of several cancer sites, particularly of the upper aerodigestive tract. Whole grain food
(and hence possibly fiber) intake was also related to reduced risk of upper aerodigestive tract
and various other cancers. In contrast, refined grain intake and, consequently, glycemic load and
glycemic index were associated to increased risk for several cancer sites. A number of
antioxidants and other micronutrients and food components (including folate, flavonoids and
carotenoids) showed an inverse relation with cancer risk, but the main component(s) responsible
for the favourable effect of a diet rich in vegetables and fruit remain undefined.
Artificial sweeteners and the risk of gastric, pancreatic, and endometrial
cancers
The role of sweeteners on cancer risk has been widely debated over the last few decades. We
provided additional information on saccharin and other artificial or low-calorie sweeteners
(mainly aspartame), using data from a network of case-control studies conducted in Italy
between 1991 and 2004 including data on 230 cancers of the stomach, 326 of the pancreas, and
454 of the endometrium. After allowance for various confounding factors, ORs for ever users of
sweeteners versus nonusers were 0.80 (95% CI, 0.45-1.43) for gastric cancer, 0.62 (95% CI,
0.37-1.04) for pancreatic cancer, and 0.96 (95% CI, 0.67-1.40) for endometrial cancer.
Corresponding ORs for saccharin were 0.65, 0.19, and 0.71, and for other sweeteners were 0.86,
1.16, and 1.07, respectively, for the three cancer sites.
META-ANALYSES AND REVIEW PAPERS
Dietary factors and oral and pharyngeal cancer
We reviewed data from six cohort studies and approximately 30 case-control studies on the
relation between selected aspects of diet and the risk of oral and pharyngeal cancer. The pooled
relative risk (RR) for high vegetable consumption were 0.65 from three cohort studies on
UADT cancer, and 0.52 from 18 case-control studies of oral and pharyngeal cancer.
Corresponding RRs for fruit consumption were 0.78, and 0.55.
Oral contraceptives and colorectal cancer risk
In order to quantify the association between oral contraceptive (OC) use and colorectal cancer
risk, we performed a systematic review and meta-analysis of studies on this issue. We identified
all relevant studies published, in English, as original articles up to December 2008 through a
search of the literature using PubMed and EMBASE, and by reviewing the references from the
retrieved articles.The summary relative risk of colorectal cancer for ever versus never OC use
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was 0.82 (95% confidence interval, CI, 0.69-0.97) from 11 case-control studies, 0.81 (95% CI,
0.75-0.89) from seven cohort studies, and 0.81 (95% CI, 0.72-0.92) from all studies combined.
The results were similar for colon and rectal cancer. No difference was evident according to
duration of OC use both for colon and rectal cancer, although there is an indication that the
protection is stronger for more recent use (OR = 0.70, 95% CI, 0.53-0.90, on the basis of four
studies).
Alcohol drinking and pancreatic cancer risk
We performed a meta-analysis of relevant dose-risk results on the association between alcohol
consumption and pancreatic cancer risk. We conducted a PubMed search of all case-control
(N=21) and cohort (N=11) studies published up to March 2009. The pooled RR was 0.92 (95%
CI, 0.86-0.97) for <3 drinks/day and 1.22 (95% CI, 1.12-1.34) 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. This meta-analysis
provides strong evidence for the absence of a role of moderate drinking in pancreatic
carcinogenesis, coupled to an increased risk for heavy alcohol drinking. 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.
The rise and fall in 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. Disentangling the effects of HT use
and screening is difficult, as women who stop using HT might also undergo mammography
screening less frequently. Thus, the reasons of the falls in incidence of breast cancer remain
open to discussion.
Coffee, alcohol and bladder cancer risk
We reviewed the epidemiological literature to evaluate the association between consumption of
coffee and alcohol and urinary bladder cancer. Results allow to exclude a strong association
between coffee and bladder cancer. Several studies reported a moderate increase in risk in
coffee drinkers as compared to non drinkers, but no trend with dose has been established.
Epidemiological data on alcohol drinking and bladder cancer are suggestive of no association,
though findings were not always consistent. For both habits, an explanation of the moderate
increase in risk observed in some investigations might be attributed to residual confounding by
smoking, or to an association between alcohol, coffee and yet unidentified risk factors for
bladder cancer.
Risk factors for thyroid cancer
We reviewed epidemiological evidence on risk factors for thyroid cancer (TC), including in
particular nutritional factors. Exposure to ionizing radiation, particularly during childhood, is
the best-established risk factor for TC. There is also a strong association with history of benign
nodules/adenoma or goiter. Iodine deficiency may induce an increasing incidence of benign
thyroid conditions, but very high iodine intake also affects thyroid function and, possibly, TC
risk. Among dietary factors, fish - the major natural source of iodine in human diet - is not
consistently related to TC risk. High intake of cruciferous vegetables shows a weak inverse
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association with TC. Among other food groups, vegetables other than cruciferous are the only
food group showing a favourable effect on TC, with an approximate 20% reduction in risk for
subjects with the highest consumption. No effect on TC risk of alcohol, coffee, or other food
groups/nutrients emerged. Height and weight at diagnosis show a moderate positive association
with TC risk. At present, the only recognized measures for reducing TC risk is to avoid ionizing
radiation and iodine deficiency, particularly in childhood and young women, and to increase
vegetable consumption.
Aspirin and cancer risk
In two papers, we reviewed aspirin and cancer risk. Aspirin has emerged as the most likely
NSAID for use in chemoprevention of colorectal and other selected neoplasms because of its
known cardiovascular benefit and available safety and efficacy data. Other traditional NSAIDs,
particularly sulindac, and selective COX-2 inhibitors are now given to patients at high risk of
colorectal cancer, although these drugs do not provide cardioprotection.
TOBACCO CONTROL
Smoking prevalence in 2008
We provided updated information on smoking prevalence in Italy, with a focus on demographic
and socio-economic characteristics, using a representative survey conducted in 2008 on a
sample of 3035 Italian individuals (1459 men and 1576 women) aged 15 years or over. Overall,
22.0% of Italians described themselves as current cigarette smokers (26.4% of men, 17.9% of
women); ex-smokers were 18.4% (24.1% of men, 13.2% of women). Smoking prevalence in the
young (15-24 years) was around 30% in males, and almost 20% in females. For both sexes,
current smoking was less prevalent in higher (22.9% of men, 20.1% of women) than in lower
educated participants (34.8% of men, 22.1% of women), and in northern (22.5% of men, 16.1%
of women) than southern Italy (31.8% of men, 18.4% of women).
Hardcore smoking among Italian women and men
Hardcore smokers are described as heavy smokers who have not attempted to quit and have no
future intentions to quit. In 2007, we collected data from 3057 Italians aged 15 years and older,
who were randomly selected to be representative of the population. The smoking prevalence
overall was 23.5% (27.9% among males and 19.3% among females). An estimated 7.8% of
individuals were hardcore smokers (9.7% among males and 6% among females), which
translates into 33.1% of all smokers in Italy. Age at smoking initiation, occupation (among
males), home smoking rules, and perceived stress (among females) distinguished hardcore from
non hardcore smokers.
Tobacco sales to minors
One of the strategies to control tobacco is to limit purchase of cigarettes to minors. To
understand the attitudes of Italian adults towards regulations to prevent minors from purchasing
tobacco products, we considered data from a representative tobacco survey on 3057 subjects,
conducted in 2007. Overall, 78% of Italians believed that a restriction of the current tobacco
sales-to-minors law could be moderately to extremely effective as a strategy to decrease
smoking prevalence and consumption. More than 90% of Italians reported that they had never
seen in their lifetime a retailer refusing to sell cigarettes to an adolescent or requesting the
minor's identification or age.
Use of pharmacotherapy for smoking cessation
We examined the use of pharmacotherapy while attempting smoking cessation among current
smokers and also the prevalence of use among former smokers in Italy, using data from six
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representative surveys conducted between 2002 and 2007 on a total of 19,459 Italians aged 15
years and older. Among 1854 smokers who had made at least one quit attempt in the past, 9.4%
reported using pharmacotherapy during at least one attempt. Use of pharmacotherapy was
related to smoking intensity, education level, and age. Among former smokers,
pharmacotherapy use for cessation ranged between 0 and 4.9%. Analyzing data from a
subsequent survey conducted in 2008 we found similar results. Therefore, methods to increase
the use of pharmacotherapy for smoking cessation need to be enhanced in Italy because these
products are not reaching a large majority of smokers. One possible solution is to add
pharmacotherapy to the list of medications covered by the National Health Service.
Cigarette smuggling
We updated information on cigarette smuggling in Italy, using data from 4 surveys annually
conducted between 2005 and 2008. Of the total of cigarettes smoked, 90.9% had been bought
from tobacco shops, 6.9% from vending machines, 0.7% from smugglers, 0.0% from the
internet, and 1.5% from peers. The proportion of smuggled tobacco consumption appeared to be
greater in heavy smokers, while no significant difference was found according to sex, age
group, geographic area, education and survey. Among 2893 current smokers, only 46 subjects
(1.6%) bought their cigarettes through illicit trade. Of these, 11 (0.4%) bought cigarettes
exclusively from smugglers. Only 2 subjects, both in 2008, reported purchasing cigarettes from
the internet.
Medium-term effects of the Italian smoke-free legislation
In order to quantify, 3 years after the law came into force, the effects of the smoking ban in
terms of observance of the legislation and change of habits, we considered data from four
representative surveys on smoking, conducted between 2005 and 2008 on a total of 12,245
individuals (5906 men and 6339 women) aged 15 years or over. In 2008, more than 80% of
Italians (more than 90% in northern Italy) had the perception that the smoking ban was
respected in bars/cafes and restaurants, despite a slight reduction since 2005. In all the surveys
combined, 75% of the Italian population reported that the smoking ban was respected in
workplaces. Overall, approximately 10% of Italians reported that, after the implementation of
the tobacco regulation, they went to bars/cafes and restaurants more frequently, and
approximately 7% less frequently, than before. Our study shows that in Italy the smoke-free
legislation did not affect the business of restaurants and bars, and remains widely respected 3
years after the law came into force.
Lung diseases in smokers
We are involved in the conduction and analysis of the MILD study of CT scan in heavy
smokers. In this investigation, bronchial diverticula are a frequent finding in the major airways
of smokers, and they are associated with other markers of smoking-related damage.
In the same study, compared with males, females exhibited an emphysema phenotype less
extensive in each pulmonary lobe. However, in females, the increase of emphysema with age
was more pronounced and displayed a more significant relationship with FEV(1)% decline.
Males and females responded differently to the type and location of lung damage due to tobacco
exposure. In smokers, sex influences the relationship between emphysema and clinical features.
Likewise, lung function production lung cancer risk in smokers.
OTHER PROJECTS
HI-WATE project on colorectal cancer and drinking water by-products
There appears to be very good epidemiological evidence for a relationship between chlorination
by-products, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but
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the evidence for other cancers, including colorectal cancer appears to be inconclusive and
inconsistent. There appears to be some evidence for a relationship between chlorination byproducts, as measured by THMs, and small for gestational age (SGA)/intrauterine growth
retardation (IUGR) and preterm delivery, but evidence for other outcomes such as low birth
weight (LBW), stillbirth, congenital anomalies and semen quality appears to be inconclusive
and inconsistent.The overall aim of the HIWATE study (supported by th EU FP-6) is to
investigate potential human health risks (e.g. bladder and colorectal cancer, premature births,
SGA, semen quality, stillbirth, congenital anomalies) associated with long-term exposure to low
levels of disinfectants (such as chlorine) and DBPs occurring in water for human consumption
and use in the food industry. The study will comprise risk-benefit analyses including
quantitative assessments of risk associated with microbial contamination of drinking water
versus chemical risk and will compare alternative treatment options. The outcome will be
improved risk assessment and better information for risk management. The work is divided into
different topics (exposure assessment, epidemiology, risk assessment and management) and
studies.
In 2008, the Department started the collection of data for a case-control study on colorectal
cancer within the HI-Wate project. The study is conducted in the greater Milan area and in the
Provinces of Pordenone and Udine, and includes incident, histologically confirmed cases
enrolled in the major general and teaching hospital of the study area, and frequency-matched
controls, admitted to the same hospital as cases for acute, nonneoplastic conditions. Cases and
controls are interviewed using an extensive questionnaire. Detailed information on water use
and water-related habits for etiologically relevant time periods is collected, including not only
water consumption, but also water related activities, such as showering, bathing and swimming,
that may influence exposure assessment. Moreover, in order to assess the subjects’ exposure to
DBPs and THMs in water, current and historical THM levels, water source and year of starting
chlorination in the study area will be collected from local companies, authorities and
municipalities. About 250 colorectal cancer cases and 250 corresponding controls have been
collected, i.e., about half of the total number of cases and controls which should be enrolled at
the end of the study. Giving the large number of people exposed to chlorinated drinking-water
and its DBPs, the study has potentially important implications in terms of public health. Even
modest excess risk in relation to DBP exposure may in fact have a relevant impact on a
population level, and may be responsible of a considerable number of colorectal cancer cases.
Mortality from cancer and other causes in a cohort of chrysotile asbestos
miners
We updated the analyses from the cohort of Balangero mine workers, including 1056 males and
a total of 34,432 man-years of observation, using follow-up data to the end of 2003. Aim of the
study was to investigate mortality from cancer and other causes among chrysotile asbestos
miners several years after stopping exposure. We obtained employment data from personnel
records at the factory, and ascertained vital status and causes of death through population
registers and death certificates from municipal registration offices. We found a significant
excess mortality from pleural and peritoneal cancers combined (5 deaths, standardized mortality
ratio, SMR=3.16). All pleural and peritoneal cancer deaths occurred 30 or more years after first
exposure. The SMRs were 1.27 for lung cancer (45 deaths), 1.82 for laryngeal cancer (8 deaths)
and 1.12 for all cancers (142 deaths). There were 57 deaths from cirrhosis (SMR=2.94) and 54
from accidents and violence (SMR=1.88). Overall, we observed a total of 590 deaths as
compared to 412.9 expected (SMR=1.43). This updated analysis, with almost 60% of workers
of the cohort who had died, confirmed the excess mortality from pleural and peritoneal cancers
and from several alcohol-related causes.
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INHANCE study
We were actively involved in the International Head and Neck Cancer (HNC) Epidemiology
(INHANCE) consortium, which includes data from 33 HNC studies worldwide, and a total of
about 25,000 cases of 33,000 controls. During 2009, we published a paper summarizing scope,
aims, design and motivation of the study, and a number of pages on selected topics. These
include family history, since family history of HNC in first-degree relatives increased the risk of
HNC (OR=1.7, 95% CI, 1.2-2.3). The risk was higher when the affected relative was a sibling
rather than a parent and for more distal HNC anatomic sites (hypopharynx and larynx). The risk
was also higher, or limited to, in subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.59.5) among subjects with family history, who were alcohol and tobacco users.
With reference to type of alcoholic beverage there were similar associations with ethanolstandardized consumption frequency for beer-only drinkers and liquor-only drinkers. Among
wine-only drinkers, the ORs for moderate levels of consumption approached the unity, whereas
those for higher consumption levels were comparable to those of drinkers of other beverage
types. These study findings suggest that the RRs of HNC for beer and liquor are comparable. A
greater than multiplicative effect between ever tobacco and alcohol use was observed for head
and neck cancer risk. The population attributable risk for tobacco or alcohol was 72% for HNC,
of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to
tobacco and alcohol combined Quitting tobacco smoking resulted in a HNC risk reduction in the
short-term (OR 0.70, CI 0.61-0.81 after 1-4 years compared with current smoking). For alcohol
use, a beneficial effect on the risk of head and neck cancer was only observed after ≥20 years of
quitting. We also modeled the excess OR (EOR) for total exposure to alcohol and tobacco.
Above 15 cigarettes/day, the EOR/pack-year decreased with increasing cigarettes/day,
suggesting that greater cigarettes/day for a shorter duration was less deleterious than fewer
cigarettes/day for a longer duration. EOR/drink-year estimates increased through 10 drinks/day,
suggesting that greater drinks/day for a shorter duration was more deleterious than fewer
drinks/day for a longer duration.
InterLymph study
We also participated to another consortium study of non-Hodgkin lymphoma (NHL) worldwide.
A study on allergy and NHL showed evidence of a modest but consistent reduction in the risk of
B-cell NHL associated with atopy.
DERMATO EPIDEMIOLOGY
Frequency of atopic dermatitis in Italian children
The frequency of atopic dermatitis in Italian children and its relationship with selected
variables were analysed in a large survey of skin health conducted in Italy on more than
3,000 schoolchildren. A diagnosis of atopic dermatitis was reported in 224 cases
(7.0%). The frequency of reported atopic dermatitis was significantly higher in children
with asthma. The lifetime prevalence of a diagnosis of atopic dermatitis was higher
among schoolchildren reporting a diagnosis of psoriasis and vitiligo.
Longitudinal studies of melanocytic nevi in children
In an editorial, we revised the literature on longitudinal studies of melanocytic nevi in
children. The number of nevi represents the strongest independent risk factor for
cutaneous malignant melanoma, and risk factors for the number of melanocytic nevi
parallel those for cutaneous malignant melanoma, including intensive sun exposure,
high propensity to sunburn, and pale skin. Nevi usually develop during childhood and
adolescence, and their body site distribution is influenced by sun exposure. Thus,
monitoring the evolution of nevi in children from different geographic areas with
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varying sun exposure patterns and behavioural norms might offer additional clues to
understanding melanoma development. Further data are also needed from geographic
areas other than the United States and Australia, particularly Europe, where the lack of
longitudinal studies is of concern.
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 IN EUROPE
Cancer mortality in Europe, 2000-2004
We updated the pattern of cancer mortality in 34 European countries during 2000-2004, with an
overview of trends in 1975-2004, using data from the WHO. From 1990-1994 to 2000-2004,
overall cancer mortality in the European Union (EU) declined from 185.2 to 168.0/100 000
(world standard, -9%) in men and from 104.8 to 96.9 (-8%) in women, with larger falls in
middle age. Total cancer mortality trends were favourable, though to a variable degree, in all
major European countries, including Russia, but not in Romania. The major determinants of
these favourable trends were the decline of lung (-16%) 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.
Cancer mortality in Italy, 2003
Italian Cancer mortality was updated with data for 2003, with a change of classification from 9th
edition to the 10th edition of the International Classification of Diseases (ICD). The total number
of cancer deaths was 167,144 (96,127 men and 71,017 women), the age standardised death rates
were 160.63 and 89.32/100,000 for men and women respectively for all cancers. Most tobaccorelated cancers confirmed their declining trends in men, but not in women. Male lung cancer
mortality was 43.72/100,000. Cancers of the uterus and female breast also confirmed their
favourable trends with rates of 17.11 and 3.71/100,000 respectively. Falls in mortality were also
recorded for stomach and testis cancers. Some cancers such as prostate and multiple myeloma
appeared to rise, but this is mainly due to the change in ICD and the stricter age standardisation
adopted.
Childhood cancer mortality in Europe, 1970-2007
We updated trends in childhood cancer mortality in 30 European countries up to 2007, using
data from the WHO for all childhood neoplasms, bone and kidney cancers, NHL and
leukaemias. 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
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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.
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 levelled 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.
Gastric cancer mortality: a global overview
We analyzed gastric cancer mortality in Europe and other areas of the world from 1980 to 2005
using joinpoint regression analysis, and provided updated site-specific incidence rates from 51
selected registries. Over the last decade, the APC in mortality rate was around -3, -4% for the
major European countries. The APC were similar for the Republic of Korea (APC=-4.3%),
Australia (-3.7%), the USA (-3.6%), Japan (-3.5%), Ukraine (-3%) and the Russian Federation
(-2.8%). In Latin America, the decline was less marked, but constant with APC around -1.6% in
Chile and Brazil, -2.3% in Argentina and Mexico and -2.6% in Colombia. Cancers in the fundus
and pylorus are more common in high incidence and mortality areas and have been declining
more than cardia gastric cancer.
Biliary tract cancer mortality
Biliary tract cancer mortality and incidence data were updated, and analysed using joinpoint
regression analysis. Biliary tract cancer mortality is characterised by a wide geographical
variation and a female to male mortality ratio greater than unity in most countries. In Europe
and North America it is a rare cancer, while it has a high incidence in some areas Latin America
and Asia. Decreasing biliary tract cancer mortality rates were observed since the 1980s in
Australia, Hong Kong, New Zealand, Israel, Canada, the United States and the EU as a whole,
as well as high risk countries such as Japan and Venezuela, with joinpoint regression indicating
that the decreasing trends are more favourable in more recent calendar periods. However, high
mortality rates were still observed, particularly in women, in some central and eastern European
countries and Japan (4-5/100,000 female mortality rate) and Chile (16.6/100,000 female
mortality rate). The study of incidence rates identified other high-risk areas in India
(8.5/100,000 women), Korea (5.6/100,000 women) and Shanghai in China (5.2/100,000
women). The observed decreases in biliary tract cancer mortality are a consequence of the more
widespread adoption of cholecystectomy, since the main risk factor for this cancer is gallstones.
However in some high-risk areas of South America and India, access to gall-bladder surgery
remains inadequate.
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The recent decline in mortality from Hodgkin lymphomas in central and
eastern Europe
Hodgkin lymphoma (HL) is a largely curable disease and its mortality had steadily declined in
Western Europe since the late 1960s. Only modest declines were, however, observed in
central/eastern Europe. We updated trends in mortality from HL in various European areas up to
2004 and analyzed patterns in incidence for selected European countries providing national
data. In most western European countries, HL mortality continued to steadily decline up to the
mid 2000s. More recent reductions were also observed in eastern European countries. Overall,
mortality from HL declined from 1.17/100,000 (age-standardized, world population) in 19801989 to 1.42/100,000 in 2000-2004 in men from the 15 member states of the EU from western
and northern Europe. In the EU 10 accession countries of central and eastern Europe, male
mortality from HL was 1.42/100,000 in 1980-1984, 1.32 in 1990-1994, and declined to 0.76 in
2000-2004. Similar trends were observed in women. No consistent patterns were found for HL
incidence.
Mortality from coronary heart diseases and cerebrovascular diseases
We updated trends in mortality from coronary heart diseases (CHD) and cerebrovascular
diseases (CVD) over the period 1981 to 2004 in Europe, the USA, Latin America, Japan and
other selected areas of the world. Though mortality from CHD and CVD continue to decline in
several areas of the world including most countries of Europe and of the Americas providing
data, and Australia, unfavourable trends were still observed in the Russian Federation and other
countries of the former Soviet Union, whose recent rates remain exceedingly high.
Estimates of the incidence and prevalence of renal cell carcinoma in Italy
We provided estimates of the number of incident and prevalent cases of kidney and RCC in
Italy overall and in various regions in 2002 and gave projections for the years 2007 and 2012. In
2002, there were about 8000 incident cases and 26,800 prevalent cases of kidney cancer in Italy.
Of these, approximately 6800 and 22,750 were incident and prevalent cases of RCC,
respectively. The most reliable estimate of incident kidney cancer cases in Italy over the period
2007-2012 is likely to range between 7000 and 9000. Of these, between 6000 and 8000 are
RCC cases. The best estimate of prevalence of kidney cancer is between 20,000 and 34,000
cases and that of RCC between 17,000 and 29,000 cases. Incidence and prevalence of RCC are
likely to remain approximately stable between 2002 and 2007. Increased diagnostic attention
due to widespread use of echography and other diagnostic techniques may, however, lead to
earlier detection of kidney neoplasms and consequently to an apparent increase in the incidence
of RCC.
Estimates of the incidence and prevalence of hepatocellular carcinoma in
Italy
Using the same methodology adopted for RCC, we provided estimates of the number of incident
and prevalent cases for HCC in Italy overall and in various regions in 2002 and gave projections
for the years 2007 and 2012. In 2002, there were about 5800 incident cases and 4300 prevalent
cases of HCC in Italy. The most reliable estimate of HCC incident cases in Italy in 2007 is
between 5500 and 6000, and this figure is likely to decline to 5000-5500 in 2012. The best
estimate of prevalence is about 4000 cases in 2007, which is likely to decline to 3700 in 2012.
Incidence and prevalence of HCC are likely to remain approximately stable between 2002 and
2007 and slightly decrease in the subsequent quinquennia. These projections are, however,
subject to large uncertainties because of the problems in diagnosis and death certification for
this neoplasm, particularly for the elderly.
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OTHER PROJECTS
Strategies and best practices for the reduction of injuries
Since 2006, our Department is involved in the Apollo project, a European project aiming at
identifying strategies and best practices for the reduction of injuries. Within this project, our
Department is coordinator of the Workpackage 4 on the development and implementation of
recommendations for the prevention of falls among elderly people in the EU.
The majority of falls in elderly people are due to a combination of several interacting factors.
Many studies have investigated the role several factors on the risk of falling. Thus we conducted
a systematic review and a quantitative meta-analysis of risk factors for falls in communitydwelling elderly people, including relevant studies published up to 2006. Fifty-nine studies were
included and 28 risk factors were analyzed, including socio-demographic characteristics,
mobility, sensory, psychological and medical factors, and medication use. The strongest
associations were found for history of falls, vertigo, gait problems, use of walking aids, and use
of antiepileptics.
Moreover, we investigated the amount of information on the participation rates reported from
studies investigating the effectiveness of selected intervention for the prevention of falls among
community-dwelling elderly people. We identified 32 studies implementing interventions based
on an exercise program, an exercise program in combination with other measures, or other types
of interventions. Fourteen studies did not report information on the refusal rate; most studies
reporting the information had a refusal rate between 25 and 50%. We also conducted a survey to
investigate the attitudes of elderly people towards selected intervention for the prevention of
falls. The study was conducted in Italy, Poland, Greece, Hungary, and Slovenia, countries for
which limited data is available on this issue. A total of 1497 subjects aged 65 to 89 years were
interviewed to evaluate their beliefs and attitudes towards two evidence-based interventions, i.e.
a social activity aimed at improving muscle strength and balance (such as exercise class or
dancing), and a home safety assessment and modification program. Among the respondents
about 47% would accept to participate to a social activity, and about 38% would accept a
program of home hazard assessment and modification. However, we found marked differences
between countries in the acceptability of the two proposed interventions.
Finally, we conducted a meta-analysis of studies for the prevention of falls in elderly people. A
computerized search in several medical databases allowed to identify 52 published studies,
including 10 studies complying with the inclusion criteria (absence of comorbidity, noninstitutionalized subjects, previous history of falls). These studies included interventions based
on exercise only and multifactorial interventions, and showed a reduction in the risk of falling,
with an overall estimate of 0.67 (95% CI: 0.52-0.85). Considering 5 studies based on physical
exercise, the overall estimate was 0.45 (95% CI: 0.28-0.71), while considering 5 studies based
on multifactorial interventions the estimate was 0.90 (95% CI: 0.82-1.00).
Record-linkage for cohort analyses
The main aim of this project is to collect follow-up information to the end of 2008 on vital
status and, when needed, cause of death for each subject included in the case-control studies, in
order to obtain a prospective study from retrospectively collected data. During recent years, we
included in a single large database the data of the case-control surveillance collected in the
greater Milan area during the last 25 years. We made uniform the information coming from
different generations of structured and validated questionnaires, and assigned a single
identification number to each subject interviewed. In 2009, we added further data for studies on
cancers of the oral cavity, pharynx, stomach, pancreas and endometrium, that have been
recently finalized. This added to the unique database of subjects about 1500 further cancer cases
and 1500 controls, so that the total number of subjects now exceed 29,000. We organized the
strategy to obtain and manage information on vital status and death certificates of the subjects
included in our database, by contacting the competent institutional sources (Municipalities,
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Local Health Units, General Registry Offices) and through the use of an ad hoc developed
software.
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.
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.
Coffee, black tea and gastric cancer
To provide further information on the association between coffee, tea and gastric cancer risk, we
pooled data from 2 hospital-based case-control studies from northern Italy, on a total of 999
cases with gastric cancer and 2,628 controls. As compared to non coffee drinkers, the
multivariate OR was 0.94 for drinkers of 1 cup of coffee per day, 1.03 for 2, 1.07 for 3, and 1.24
for 4 or more cups per day. No association was found with reference to duration of coffee
consumption, nor to consumption of decaffeinated coffee. As compared to non tea drinkers, the
OR was 0.89 for 2 or more cups of black tea per day. Our investigation provided convincing
evidence that coffee and tea consumption are unlikely to be strongly associated to gastric cancer
risk.
Physical activity and endometrial cancer
In the case-control study of endometrial cancer, we investigated the relation with physical
activity at different ages. Taking into account various potential confounding factors, including
age, body mass index, diabetes, hormonal/reproductive factors and energy intake, the OR of
endometrial cancer in women at high level of occupational physical activity, as compared with
those at the lowest level, were 1.69 at 12 years of age, 1.33 between 15 and 19 years, 1.17
between 30 and 39 years and 0.82 between 50 and 59 years. No significant trend in risk with
level of occupational physical activity was found at any age. Similarly, no significant
association was detected with recreational physical activity in different periods of life, since the
OR for the highest vs. lowest level of physical activity were 0.82 at 12 years of age, 0.78
between 15 and 19 years, 1.12 between 30 and 39 years and 0.97 between 50 and 59 years.
Therefore, our results ruled out a strong relation between physical activity and endometrial
cancer.
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Coffee, decaffeinated coffee, tea intake and risk of renal cell cancer
The relation between coffee, decaffeinated coffee and tea intake and RCC risk was analyzed in
our case-control study on 767 cases with RCC and 1534 controls. Coffee intake (mostly
espresso and mocha) was not associated with RCC (OR = 1.02 in drinkers of 4 or more
cups/day compared with drinkers of less than 1 cup/day). No relation was observed with
decaffeinated coffee and tea intake, the ORs being 1.38 and 0.78 for drinkers compared with
nondrinkers respectively, although these two estimates were based on a low number of drinkers.
This study, based on a large dataset, provided further evidence that coffee, decaffeinated coffee
and tea consumption is not related to RCC risk.
Allium vegetables and the risk of acute myocardial infarction
Only two previous epidemiological studies considered the relation between dietary intake of
allium vegetables and cardiovascular diseases. To provide further information we analysed the
relationship between onion and garlic intake and acute myocardial infarction (AMI). We used
data from a case-control study of 760 patients with a first episode of non-fatal AMI and 682
controls admitted to the same hospitals. Compared with nonusers, the ORs of AMI for
subsequent categories of onion intake were 0.90 (95% CI, 0.68-1.22) for <1 portion of onion per
week and 0.77 (95% CI, 0.56-0.98) for ≥1 portion per week. For garlic, the ORs for subsequent
categories of intake were 0.84 (95% CI, 0.65-1.09) for intermediate and 0.93 (95% CI, 0.671.31) for high use, compared with none or low use. The current study suggested that a diet rich
in onion, but not in garlic, may have a favourable effect on the risk of AMI.
META-ANALYSIS
Coffee consumption and risk of colorectal cancer
We conducted a meta-analysis of case-control studies on coffee consumption and the risk of
colon cancer. We included 24 studies published before April 2009, for a total of 14,846 cases of
colon cancer, colon or rectum. Compared with non/occasional coffee drinkers, the ORs for
drinkers were 0.86 (95% CI, 0.77-0.97) for colorectal cancer, 0.96 (95% CI, 0.84-1.10) for
colon and 0.97 (95% CI, 0.84-1.12) for rectum, with heterogeneity between the studies. The
corresponding ORs for the highest coffee consumption were 0.69 (95% CI, 0.60-0.80), 0.80
(95% CI, 0.65-0.99) and 0.89 (95% CI, 0.78-1.01). The ORs were similar in strata of types of
controls (population or hospital) and geographic area. The results of this meta-analysis indicated
that coffee consumption is inversely associated with risk of colon cancer.
Coffee consumption and endometrial cancer
Some studies found an inverse relation between coffee consumption and endometrial cancer
risk. We conducted a meta-analysis of published studies on this issue, including 2 cohort (201
cases) and 7 case-control studies (2409 cases). We observed a summary RR of 0.80 (95% CI,
0.68-0.94) for coffee drinkers as compared to nondrinkers. Compared to nondrinkers, the
summary RRs were 0.87 (95% CI, 0.78-0.97) for low-to-moderate coffee drinkers and 0.64
(95% CI, 0.48-0.86) for heavy drinkers.
OTHER PROJECTS
Definition and management of a cohort of subjects living at Asti for
cardiovascular risk assessment
This study is conducted in collaboration with the ALMA association and the “Ordine dei Medici
di Asti” and includes data collection and first analyses of follow-up.
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Laboratory of Medical Informatics
“A library for the Hospital of Man” project
The project is based on a collaboration between the “Associazione Sguazzi Onlus” of Bergamo,
the association ACIM of Man (Côte d'Ivoire – Ivory Coast), and the Sistema Bibliotecario
Biomedico Lombardo (SBBL) of the Regione Lombardia. It’s aim is to provide the Hospital of
Man (Côte d'Ivoire) with a modern and efficient medical (e)library where people can access to
medical information (journal publications, grey literature, etc.) and use e-learning, distance
learning and telemedicine tools. The Mario Negri Institute is a partner of the project with the
European Space Agency (ESA), the Università of Bergamo, and the Ospedali Riuniti of
Bergamo. During 2009, the Laboratory of Medical Informatics has been involved in training
courses that were provided through e-learning and audio/video conferences tools (more than 50
people in Côte d'Ivoire have been trained remotely). The use of medical databases (such as
PubMed-Medline) and the Internet tools to locate medical information on the Web were some
of the issues covered in the lessons.
The equipment for the video-conferences and the distance learning sessions has been provided
and programmed by the Mario Negri Institute.
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 2009, 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
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
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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 2009, 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 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"Mario Negri" Institute for Pharmacology Research.
•
Bonati M, Campi R. What Can We Do to Improve Child Health in Southern Italy? PLos Medicine 2005;2(9):e250.
•
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.
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.
• 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
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comparative analysis. Health Policy (online from November 2009).
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.
•
Simini B, Bertolini G. Should same anaesthetist do preoperative anaesthetic visit and give subsequent anaeshetic?
Questionnaire survey of anaesthetists. BMJ 2003;327:79-80.
•
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;102:2717-2723.
•
Vanoli M, Daina E, Salvarani C, Sabbadini MG, Rossi C, Bacchiani G, Schieppati A, Baldissera E, Bertolini G.
Takayasu's arteritis: A study of 104 Italian patients. Arthritis Rheum 2005;53:100-107.
•
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.
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.
•
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
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2009, he is the head of the Unit of Computer Methods and Programs for Clinical Research of the
•
•
•
•
•
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).
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 use the available knowledge and resources at their best; to play a role in the growth
of useful knowledge for clinical practice. The Laboratory operates particularly 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.
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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).
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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 Bicocca, Dipartimento di Informatica Sistemistica
Comunicazione.
Medicina Interna e Geriatria, Università Cattolica del Sacro Cuore, Roma
e
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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
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−
−
−
−
−
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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Centre for Intensive Care Medicines, Bloomsbury Institute, London, UK
Clinic of Anesthesiology and Intensive Therapy, Jena, Germany
Department of Anesthesiology and Intensive Cares, University of Toronto, Canada
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
Intensive Medicine, Regional Hospital of Lugano, Switzerland
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−
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−
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Intensive Medicine, Regional Hospital Beata Vergine, Mendrisio - Ticino, Switzerland
Institute of Anesthesia and Intensive Cares, Semmelweis University, Budapest,
Hungary
Laboratory of Experimental Physiopathology, Academic Unity of Sciences of the
Health, University of the Studies Extremo Sul Catarinense, Criciúma, SC, Brasil
Machine Intelligence Group, University di Aalborg, Denmark
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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; Paediatric & Perinatal Drug Therapy; 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:
Archives of Diseases Childhood; BMC Health Services Research; BMC Psychiatry; BMC
Public Health; British Medical Journal; European Child & Adolescent Psychiatry; European
Journal of Clinical Pharmacology; Human Psychopharmacology; Clinical and Experimental;
Journal of Child and Adolescent Psycopharmacology; Pharmacoepidemiology and Drug Safety;
Prescrire; Trials Journal.
NATIONAL:
Assistenza Infermieristica e Ricerca; Dialogo sui Farmaci; Giornale Italiano di Farmacia
Clinica; Medico e Bambino; Quaderni ACP.
−
Comitato di Bioetica, Provincia Autonoma di Trento
− 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
− Ethical committee A.O. "Ospedale Maggiore" of Crema
− ADHD Scientific committee, Superior Institute of Health (ISS)
− Technical-scientific Commission for the planning and verification of
vaccinations, Lombardy Region
− Technical Commission for the management, update, and elaboration of the
Regional Therapeutic Formulary, Valle d'Aosta Autonomous Region
− Breastfeeding Promotion Work Group, Lombardy Region
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− Expert Group, EMA
− Scientific Advisory Board (PRIOMEDCHILD)
EVENT ORGANIZATION
Congress: Convegno Nazionale di Farmacoeconomia: “Economia del farmaco: fra soluzioni
tecniche e decisioni politiche”, June 9-10, Ranica (BG)
Congress: Convegno Regionale di Farmacoeconomia: “Politiche vaccinali regionali: esperienze
a confronto”, October 6, Milan.
Congress, GiViTI Annual Meeting, October 28-30, Pesaro.
Workshop, Meeting Compact, June 15, Milan.
Seminary “Children’s medicines: a global problem”. 11 November, Milan.
Meeting of the ADHD referral centres: “ADHD: registro e stateìo dell'arte in Lombardia” 20
March, Milan.
March
Congress: “HIV Summit Italia 2009-Diagnosi precoce, qualità della vita”. “Prevenzione e
accesso alle cure nell’era del federalismo”; Rome.
August
Workshop: “Depression workgroup” (expert panel); Milan.
October
Congress: “La farmacovigilanza in pediatria” (round table); Milan.
November
Congress: “La valutazione economica delle nuove tecnologie in sanità- Modelli e
applicazioni”. “Lo stato dell’arte dell’HTA in Italia tra Stato e Regioni”; Verona.
December
Congress: “Respiratory Advisory Board” (tavola rotonda); London.
ANNUAL REPORT
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2009
IRFMN
Course: “Approfondimenti in tema di farmacoeconomia e HTA”. “Impiego dei costi indiretti
nelle valutazioni economiche”. “Evoluzione dell’organizzazione del SSN e degli SSR”.
“Analisi della gestione della spesa farmaceutica ospedaliera regionale”; Rome.
February
Congress, Trauma e Subintensive, Bologna
Congress, "Riusciremo a morire in pace?", Milano
Congress, Emorragia intracerebrale (ICH): quale paziente si giova di un trattamento intensivo
in ambiente neurochirurgico? Torino
Course, Statistica di Base, Torino
March
Congress, Fine Vita, Padova
Course, Excel e MargheritaDue: applicazione pratica, Torino
Congress, GiViTI Bergamo, Zingogna (BG)
Congress, La sorveglianza delle infezioni in TI, Zingonia
April
Congress, Le infezioni in TI: Presentazione dei dati regionali del gruppo GiViTI, Bologna
Course, Margherita Due (Course, avanzato), Torino
May
Congress, Analgesia, anestesia, terapia intensiva in ostetricia, Torino
Workshop, Perfezionamento e aggiornamento in medicina intensiva , Mendrisio
Congress, Appropriatezza dei ricoveri in terapia intensiva, Torino
June
Congress, Valutazione della qualità della Assistenza sulla base degli indicatori di gravità del
paziente, Avezzano
September
Congress, ESPEN Congress, Firenze
Congress, Sepsi nel trauma - Trauma Update, Roma
Course, MargheritaTre: stato dell'arte e pianificazione dei lavori, Ivrea
October
Congress, Incontri GiViTI-Piemonte, Torino
Course, Migliorare la compilazione di Margherita Due ed imparare a leggere il report, Torino
Course, Migliorare la compilazione di Margherita Due ed imparare a leggere il report, Torino
Workshop, Accademia della cura, Rho (MI)
Congress, Meeting GiViTI, Pesaro
November
Congress, Trauma Update, Cesena
Course, Margherita Tre: presentazione dei nuovi moduli, Torino
December
Workshop, PNS: Euronetwork Sindromi Paraneoplastiche, Treviso
Congress, Sorveglianza delle infezioni in ti con margherita due: Presentazione dei dati 2007,
Torino
ANNUAL REPORT
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IRFMN
January
Course. Università degli Studi di Milano, Facoltà di Farmacia; Milan.
Congress: “Scegliere per la propria salute prima dei 18 anni: troppo giovane per dire la mia”.
Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, U.O.N.P.I.A. (Child
and Adolescent, Neuropsychiatry Unit); Milan.
II ACP Regional Congress: “Etica della responsabilità in pediatria”. Pediatricians’ Cultiral
Association, Campania Region, CEINGE biotecnologie avanzate; Naples.
February
XVIII Tabiano Congress: “A volte ritornano”. Pediatricians’ Cultiral Association (ACP);
Tabiano (PR).
March
Course: “Migrazione e salute mentale dall’età evolutiva all’età adulta: un progetto per
Milano”. Milan Province, Lombardy Region, Municipality of Milan, Asl of Milan, Maggiore
Policlinico Mangiagalli e Regina Elena Hospital; Milan.
Congress: “Autismo e sindromi correlate: la realtà dei servizi e della ricerca in Italia”. ISS
(Istituto Superiore di Sanità), ANGSA (Autismo Italia, Società Italiana di Pediatria,
Federazione Italiana Medici Pediatri); Rome.
Meeting of the ADHD Register’s Referral Centres. ISS (Istituto Superiore di Sanità); Rome.
III Annual Seminary of the Corporate Therapeutic Commission: “L’uso dei farmaci dalla parte
dei bambini”. Azienda Provinciale per i servizi Sanitari, Provincia Autonoma di Trento; Trent.
Congress: “Incontro su farmaci e neonato. Luci, ombre e ... prospettive”. SIN (Società Italiana
di Neonatologia); Rome.
Meeting: “Artemisia and fight against malaria”. ICEI (Ist. Cooperazione Economica
Internazionale); Rome.
April
Meeting: ENBe Study (Efficacia del Beclometasone versus placebo nella profilassi del
wheezing virale in età prescolare). Meeting between local coordinators and the Research
Monitoring Committee; Rome.
Round Table: il conflitto di interessi e il ruolo dell’Università e della ricerca nello sviluppo dei
farmaci per le malattie dimenticate. C.S.I. (Centro Salute Internazionale) Università di
Bologna, Gruppo Prometeo; Bologna.
May
Meeting: Uso e abuso degli psicofarmaci nella ricerca e nell’assistenza ai minori e agli adulti.
Trattamenti psicofarmacologici in gravidanza. ADHD: registro e stato dell’arte. Nuove
frontiere psicofarmacologiche nell’infanzia nell’adolescenza e nell’adulto dalle sinapsi alla
terapia integrata. Farmaci e allattamento cosa chiedono le madri. Progetto formativo/Evento
residenziale “Nuove frontiere psicofarmacologiche nell’Infanzia nell’adolescenza e
nell’adulto”. Regione Piemonte ASL TO5; Moncaglieri (TO).
Course: pharmacovigilance SEFAP (Servizio di Epidemiologia e Farmacologia Preventiva);
Milan.
26° National Congress S.I.O.P. (Società Italiana di Oftalmologia Pediatrica); Milan.
June
Congress: “GENITORI PIU’: Stato dell’Arte. Un rilancio per il futuro? Genitoripiù, Ministero
del Lavoro della Salute e delle Politiche Sociali, Regione Veneto, Azienda ULSS 20 Verona;
Verona
12th ESDPPP Biannual Congress. European Society for Developmental Perinatal & Paediatric
Pharmacology; Chamonix, France.
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IRFMN
Meeting: "Tubercolosi: omissione di soccorso - L'impegno per gli investimenti italiani nella
ricerca e lo sviluppo di nuove terapie contro una malattia globale". Medecins Sans Frontieres,
Rome.
July
9th Congress of the EACPT. European Association of Clinical Pharmacology & Therapeutics
(EACPT); Edimburgh, Scotland.
September
1° National Congress: “Con ragione e Sentimento”. Società Italiana di Neonatologia (Gruppo
di studio sulla Care - Gruppo di studio QCN); Turin.
Meeting APCP (Associazione per la Promozione della Cultura Pediatrica); Verona.
3° International Congress: "La Vita dei Farmaci: Prospettive scientifiche e analisi
interdisciplinare di un prodotto in trasformazione". Medecins Sans Frontieres, Milan.
October
XXX National SIFO Congress: “L’assistenza come occasione di ricerca”. Società Italiana di
Farmacia Ospedaliera (SIFO); Ascoli Piceno.
XXI National ACP Congress: “I bambini e il dottore”. Associazione Culturali Pediatri (ACP),
Servizio Sanitario Regionale Emilia-Romagna; Cesenatico (FC).
Meeting. Città di Garbagnate Milanese Assessorato alle Politiche Culturali; Garbagnate
Milanese (MI).
Congress: “La farmacovigilanza in pediatria”. Università di Milano - Ospedale Luigi Sacco;
Milano.
Meeting. Comune di Capiago Intimiano, Assessorato ai Servizi Sociali; Capiago Intimiano
(CO).
Course: “L’Accademia del cittadino: valutare la qualità e la sicurezza dei servizi sanitari per
fare scelte consapevoli e partecipare al miglioramento”. Regione Toscana Settore Equità e
Accesso, Regione Toscana Gestione Rischio Clinico Sicurezza del Paziente, Partecipasalute;
Milan.
Meeting: “Un metodo vincente per riconoscere ed ostacolare il disagio infantile”. Per la
Famiglia, Centro di Consulenza e Formazione; Orzinuovi (BS).
Course: Farmacologia pediatrica. Scuola di Specializzazione in Pediatria. Università degli
Studi Milano-Bicocca, Facoltà di Medicina e Chirurgia; Monza (MB).
November
89° National Congress: Società oftalmologica Italiana “Simposio ROP - Gruppo di studio per
la ROP. Attualità in tema di ROP ELBW”. Milan.
Congress: “I percorsi di cura e di inclusione sociale della salute mentale nella regione Friuli
Venezia Giulia”. Regione Autonoma Friuli Venezia Giulia, Centro Regionale di Formazione
per l’Area delle Cure Primarie (ARS); Udine.
Meeting: Ospedale-Territorio. Struttura Complessa di Pediatria, Azienda Ospedaliera
Ospedale di Circolo di Melegnano; Melegnano (MI).
Course on corporate training. ASL Salerno 1. Nocera Inferiore (SA).
Course: “Le incertezze in medicina e i conflitti di interesse”. Regione Toscana Settore Equità
e Accesso, Regione Toscana Gestione Rischio Clinico Sicurezza del Paziente, Partecipasalute;
Milan.
65° Congress SIP “Nuove frontiere della moderna pediatria”. Società Italiana di Pediatria
(SIP); Padua.
Course: Principi di terapia in età pediatrica. Scuola di Specializzazione in Pediatria. Università
degli Studi Milano-Bicocca, Facoltà di Medicina e Chirurgia; Monza (MB).
December
Course for the pharmacy degree “Attività di preparazione in farmacia”. Università degli
Studi; Milan.
Meeting: Me lo dici in … bambinese. Presentazione del libro in oggetto. Edizioni Paoline;
Milan.
ANNUAL REPORT
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IRFMN
Symposium: AIPO - Medecins Sans Frontieres "Tubercolosi:omissione di soccorso". Medici
senza Frontiere, Milan.
−
−
−
−
−
−
−
−
Abbott
AIFA
Grunenthal-Prodotti Formenti
Merck Serono
Sanofi Aventis
Sanofi Pasteur MSD
Schering Plough
Vivisol
−
−
−
−
−
−
−
−
−
−
−
−
ARESS Piemonte
ASL TO-2 Piemonte
AstraZeneca
Azienda ULSS 16, Padova – Italia
Bellco SpA
Draeger Italia
Regione Lombardia
Regione Toscana
Commissione Europea DG SANCO
Hill-Rom
Brahms
Astellas
−
−
−
−
−
−
−
Boehringer Ingelheim
European Union
Hospital of Bergamo “Ospedali Riuniti”
Italian Drug Agency, (AIFA)
Provinve of Milan
Regional Health Ministry - Lombardy Region
Regional Health Ministry - Valle d’Aosta Region
ANNUAL REPORT
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2009
IRFMN
Koleva D, De Compadri P, Virgili G, Nobili A, Garattini L. A critical review of the full economic evaluations of
pharmacological treatments for glaucoma. JME 2008 [published in 2009];11(4):719-741.
Beghi M, Savica R, Beghi E, Nobili A, Garattini L. Utilization and Costs of Antiepilectic Drugs in the Elderly. Drugs &
Aging 2009;26(2):157-168.
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, Casadei G. Letter to the Editor. Vaccine 2009;27(38):5171.
Garattini L, Gritti S, De Compadri P, Casadei G. Continuing Medical Education in six European countries: A comparative
analysis. Health Policy 2009 [online from November 2009].
Garattini L, Casadei G. Letter to the Editor. (2nd) Vaccine 2009 [online].
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.
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. 2009 Lancet.
Poole D, Bertolini G. Outcome-based benchmarking in the ICU Part II: Use and limitations of severity scores in critical care.
Patient Safety and Quality of Care in Intensive Care Medicine 2009;151-159
Poole D, Bertolini G. Outcome-based benchmarking in the ICU Part I: Statistical tools for the creation and validation of
severity scores. Patient Safety and Quality of Care in Intensive Care Medicine 2009;141-149.
Foltran F, Baldi I, Bertolini G, Merletti F, Gregori D. Monitoring the performance of intensive care units using the variable
life-adjusted display: a simulation study to explore its applicability and efficiency. J Eval Clin Prac 2009;15: 506–51.
G. Bertolini, M. Langer, D. Poole. The project Margherita for assessing italian ICU performance. ICU-management
2008/2009;8;(4):42-43.
Angermayr B, Luca A, König F, Bertolini G, Ploner M, Gridelli B, Ulbrich G, Reiberger T, Bosch J, Peck-Radosavljevic M.
Aetiology of cirrhosis of the liver has an impact on survival presicted by the Model of End-stage Liver Disease score.
European Journal of Clinical Investigation 2009;39(1):65-71.
Poole D, Guido B, Silvio G. Errors in the approval process and post-marketing evaluation of drotrecogin alfa (activated) for
the treatment of severe sepsis. The Lancet Infectious Diseases 2009;9(1):67-72.
Bianchi M, Clavenna A, Labate L, Bortolotti A, Fortino I, Merlino L, Locatelli WG, Giuliani G, Bonati M. Antiasthmatic drug prescriptions to an Italian paedriatic population. Pediatric Allergy Immunology 2009;20:585-591.
Bonati M. Once again, children are the main victims of fake drugs. Arch Dis Child 2009;94:468.
Bonati M, Garattini S. Controlling Cervical Cancer. PharmacoEconomics 2009;27:91-93.
Campi R, Barbato A, D’Avanzo B, Guaiana G, Bonati M. Suicide in Italian children and adolescents. Journal of
Affective Disorders 2009;113:291-295.
ANNUAL REPORT
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2009
IRFMN
Clavenna A, Berti A, Gualandi L, Rossi E, De Rosa M, Bonati M. Drug utilisation profile in the Italian paediatric
population. Eur J Pediatr 2009;168:173-180.
Clavenna A, Bonati M. Adverse drug reactions in childhood: a review of prospective studies and safety alerts. Arch
Dis Child 2009;94:724-728.
Clavenna A, Bonati M. Drug prescriptions to outpatient children: a review of the literature. Eur J Clin Pharmacol
2009;65:749-755.
Clavenna A, Sequi M, Bortolotti A, Merlino L, Fortino I, Bonati M. Determinants of the drug utilisation profile in the
paediatric population in Italy’s Lombardy Region. Br J Clin Pharmacol 2009;67:565-571.
Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfeeding: a review of the evidence.
Pediatrics 2009;124:e547-e556.
Pandolfini C, Bonati M. Children’s presence in research. A review of online registers. Eur J Clin Pharmacol
2009;65:873-880.
Pandolfini C, Bonati M, Sammons HM. Registration of trials in children. Update of current international initiatives.
Arch Dis Child 2009;94:717-719.
Pandolfini C, Clavenna A, Bonati M. Quality of cystic fibrosis information on Italian websites. Informatics Health
Social Care 2009;34:10-17.
Toscani F, Di Giulio P, Campi R, Pellerin I, De Luca A, Casale G, on behalf of the end of life observatory Research
Group. Off-label prescriptions in Italian hospices: a national survey. Journal of Pain and Symptom Management
2009;34:10-17.
Garattini L. Extra sconti generici: una proposta nella giusta direzione? [Editorial] Quaderni di Farmaco Economia 2009;8:56.
De Compadri P, Koleva D, Garattini L. Revisione critica della valutazioni economiche sull’estensione del vaccino
antinfluenzale alla fascia di età 50-64 anni. Quaderni di Farmaco Economia 2009;8:7-15.
Casadei G, Gritti S, Garattini L. La gestione dei vaccini nelle ASL lombarde: un’indagine in nove province. Quaderni di
Farmaco Economia 2009;8:17-25.
De Compadri P, Koleva D, Garattini L. Analisi costo-beneficio del vaccino anti-influenzale per soggetti di età compresa tra
50 e 64 anni: un tentativo di stima a livello nazionale. Quaderni di Farmaco Economia 2009;9:9-18.
Casadei G, De Compadri P, Gritti S, Garattini L. ASL e controllo della spesa farmaceutica: un’indagine conoscitiva.
Quaderni di Farmaco Economia 2009;9:19-24.
Casadei G, Garattini L. Costi di distribuzione, ma quando mai una seria riforma strutturale? Quaderni di Farmaco Economia
2009;9:27-31.
Casadei G, Garattini L. Questioni di interesse [Editorial] Quaderni di Farmaco Economia 2009;10:5-6.
De Compadri P, Koleva D, Mangia A, Motterlini N, Garattini L. Analisi costo minimizzazione della terapia di durata 12 o 24
settimane di peginterferone alfa-2b e di ribavirina nell’infezione da virus dell’epatite C. Quaderni di Farmaco Economia
2009;10:7-16.
Garattini L. Extrasconti generici-Una proposta nella giusta direzione? Dialogo sui farmaci 2009;1:29-30.
Garattini L. Via le alternative per la bolla “extrasconto. Sanità del Sole 24 Ore 7-13 Aprile 2009:12.
ANNUAL REPORT
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2009
IRFMN
Casadei G, Garattini L. Spesa farmaceutica territoriale e costi di distribuzione- E’ tempo di pensare ad una riforma
strutturale? Ricerca & Pratica 2009;25(3):91-99.
Garattini L. ECM, nessuna sanzione vera per chi non la fa. Sanità del Sole 24Ore 13-19 October 2009:18-19.
Casadei G, Garattini L. Farmaci, trasparenza all’innovatività. Sanità del Sole 24Ore 3-9 November 2009:16.
Bertolini G. Imparare dall’errore. Appunti per una riflessione in medicina. R&P 2009; 25: 127-130
Bertolini G, Luciani D, Tavola M, Livigni S, Bertoni C, Tetamo, Radrizzani D, Biolo G, GiViTI. PROMISED:
protocollo di ricerca GiViTI per studiare il profilo metabolico del glucosio nel paziente critico e nel paziente
diabetico. EsaDia 2009;11: 42-48
Bertolini G. L'articolo 32. R&P 2009;146:82
Bonaccorsi A. Marketing farmaceutico in Internet. R&P 2009;25:104-117.
Bonaccorsi A. Universities Allied For Essential Medicines (UAEM). GIFC 2009;23:118-19.
Bonati M. La guerra dei bambini. R&P 2009;25:1-2.
Bonati M, Panei P. Il registro dell’ADHD:lo stato dell’arte. Medico e Bambino 2009;8:279-281.
Clavenna A. Tra nuova influenza e vecchie questioni irrisolte. Ricerca&Pratica 2009;25:133-135.
Clavenna A, Andretta M, Pilati P, Dusi M, Gangemi M, Gattoni M B, Lombardo G, Zoccante L, Mezzalira L, Bonati
M. I percorsi diagnostico-terapeutici e assistenziali di bambini e adolescenti con disturbi psichiatrici nell'Azienda
ULSS 20 di Verona. R&P 2009;149:179-189.
Clavenna A, Bonati M. Profilo epidemiologico delle ADR in pediatria. Medico e Bambino 2009;28:503-504.
Clavenna A, Fortinguerra F. Aumentano le evidenze contro la profilassi antibiotica delle infezioni delle vie urinarie.
Quaderni acp 2009;16:33.
Clavenna A, Fortinguerra F. Una formulazione adatta ai bambini per la cura della malaria. Quaderni acp 2009;16:82.
Clavenna A, Fortinguerra F. Uso degli antivirali nei bambini: il punto della situazione. Quaderni acp 2009;16:269.
Clavenna A, Fortinguerra F. Aumentano le segnalazioni di reazioni avverse: solo una su dieci dai pediatri di famiglia.
Quaderni acp 2009;16:132.
Clavenna A, Fortinguerra F. Novità sugli psicofarmaci per uso pediatrico, ma con molte perplessità. Quaderni acp
2009;16:184.
Clavenna A, Fortinguerra F. Gli psicostimolanti aumentano il rischio di morte improvvisa. Quaderni acp
2009;16:219.
Fortinguerra F, Bianchi M, Clavenna A, Bonati M. Il destino dei medicinali dopo la prescrizione medica. R&P
2009;25:47-56.
Garattini S, Bonati M. La ricerca in Italia contro una malattia globale. In: Tubercolosi: omissioni di soccorso. Medici
Senza Frontiere 2009;3.
ANNUAL REPORT
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2009
IRFMN
Garattini L “Aspetti economici: analisi dei gap di conoscenza” in chapter “Prevenzione e accesso alle cure nell’era
del federalismo” in “HIV Summit Italia 2009- Diagnosi precoce, qualità della vita” [conference documentation].
Roma: Weber Shandwick;2009 (pag. 66).
Rossi C, Pezzi A, Bertolini G. Progetto Margherita - Promuovere la ricerca e la valutazione in Terapia Intensiva
RAPPORTO 2008. Bergamo: Edizioni Sestante, 2009
Bonati M. Cuba. In: Global health and Development Assistance. Rights, Ideologies and Deceit. Edizioni ETS, Pisa.
2009;267-275. [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]
Bianchi M, Clavenna A, Bonati M. Anti-asthmatic prescription and prevalence rate in the outpatient paediatric
population. Analysis of studies published during 2000-2008. In: ESDPPP Chamonix Congress. June 17th to 20th
2009. [abstract]
Bonati M. Current issues in paediatric prescribing. In:Basic & Clinical Pharmacology & Toxicology. Abstarcts of the
9th Congress of the European Association for Clinical Pharmacology and Therapeutics; 12-15 July 2009, Edimburgo,
UK. 2009;105:18. [abstract]
Clavenna A, Fortinguerra F, Bonati M, Study Working Group. Diagnostic and therapeutic approaches in children and
adolescents with neuropsychiatric disorders. In: ESDPPP Chamonix Congress. June 17th to 20th 2009. [abstract]
Clavenna A, Sequi M, Bonati M. Children taking antiepileptic drugs have an increased risk of death. In: ESDPPP
Chamonix Congress. June 17th to 20th 2009. [abstract]
Didoni A, Costantino A, Panei P, Clavenna A, Bonati M. Pharmacological treatment ADHD children of Lombardy
Region (Italy). In: ESDPPP Chamonix Congress. June 17th to 20th 2009. [abstract]
Per un uso razionale dei farmaci. Controparte: Assessorato alla Sanità, Regione Lombardia. [report]
Registro Nazionale ADHD. Controparte : AIFA. [report]
Analisi delle richieste riguardanti pazienti pediatrici giunte al Centro Antiveleni di Bergamo nel corso dell’anno
2007. (Progetto REAPEDINPS) Controparte: Regione Lombardia. [report]
Formazione farmaco epidemiologia pediatrica. Controparte: Boehringer Ingelheim S.p.A. [report]
During 2009 the laboratory’s activities were covered by the national media 91 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.
ANNUAL REPORT
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IRFMN
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).
Additionally, in the current year, a software based on a probabilistic model (bayesian
network) covering a large set of clinical variables, has been further implemented. Such an
activity, lead by the Unit of Clinical Knowledge Engineering, and also involving the
Machine Intelligence Group of the University of Aalborg (Denmark), pursues the realization
of tools for the retrospective evaluation of specific treatments in ICU. By means of this
model, it is meant to overcome the current limits of an overall evaluation of ICU, likewise it
happens when the traditional models for mortality prediction are adopted. Within this
activity, a bayesian system to monitor the Standardised Mortality Ratio of the single ICU.
This system, which resembles the bayesian pharmacovigilance system currently in use at the
WHO and FDA, will identify periods during which some problems occurred, allowing the
physicians of the Center to promptly and efficacy react.
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 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
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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, and the correspondence between the generalized alarm on this phenomenon and what
really took place in Italian ICUs.
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.
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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
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.
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.
In this regard, the prescriptions dispensed during 2005 by 1107 family paediatricians to
486,406 children <14 years old (corresponding to 53% of the children they cared for) were
analysed with the aim to identify the drugs for which a high degree of concordance exists
between paediatricians.
A total of 634 different drugs were prescribed by more than one paediatrician (52% of those
prescribed during 2005 to the Lombardy’s population covering all ages).
The median number of drugs prescribed by each paediatrician was 60 (range 19-189;
interquartile range 51-71). The median number of antibiotics prescribed by each
paediatrician was 16 (range 9-32; interquartile range 15-18); in particular, each paediatrician
prescribed a median number of 7 cephalosporins.
The number of drugs prescribed by the paediatrician increased with the number of children
in charge. On the contrary, the number of drugs did not differ between male and female
paediatricians.
42 drugs, belonging to 13 therapeutic classes, were prescribed by at least 50% of family
paediatricians. Six drugs were prescribed by all the family paediatricians
(amoxicillin+clavulanic acid, amoxicillin, beclometasone, clarithromycin, salbutamol, and
cefaclor), while 22 were prescribed by more than 75% of the family paediatricians.
During 2005, a total of 1015 out of 1107 family paediatricians (92%) prescribed all four
inhaled steroids marketed in Italy, while 95% prescribed the four leading cephalosporins
(cefaclor, cefixime, ceftibuten and cefpodoxime).
Findings from this study confirm that a plethora of me too drugs was prescribed in Italy,
since only 42 out of 634 drugs were prescribed by at least half of the paediatricians.
Moreover, the essential list developed on the basis of the prescribing pattern is redundant. In
fact, 15 antibiotics, 7 of which were cephalosporins, 8 anti-asthmatics and 6 anti-histamines
were included.
The use of a wide range of me-too drugs and the lack of compliance with therapeutic
guidelines underline the need for continuous audit and educational programmes in paediatric
general practice in Italy.
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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 inan
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.
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 Children and Adolescents in Italy (CRC).
This year the 2nd supplementary report was published, which ends the first cycle of
monitoring carried out by the CRC group that began following the observations of the
United Nations Committee to Italy in 2003.
During this period the CRC Group developed and published an annual update report to
monitor the progress and problems found implementation of the rights guaranteed by the
CRC in Italy.
As part of this course the number issues has widened progressively while ensuring a timely
update on issues already addressed.
Efficacy of Nebulised Beclometasone versus placebo in preventing viral
wheezing in pre-school children. (ENBe)
Viral wheezing (intermittent episodes of wheezing induced by viral infection of the upper
respiratory tract) is a common condition in pre-school children. A prospective study
performed by a group of Italian paediatricians reported that 19% of children under 18
months had had at least one episode of wheezing associated with an upper respiratory tract
infection. The efficacy of drug treatments in the prevention and/or treatment of viral
wheezing is controversial, but, despite the scant evidence, nebulised steroids in particular
beclometasone, are widely prescribed in Italy as prophylaxis or treatment for viral wheezing.
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Beclometasone is the second most prescribed drug in Italian children among the medications
reimbursed by the National Health Service, with a prevalence estimated around 15% (9-22%
depending on the setting), and the fourth drug in order of expenditure. No changes were
observed in beclometasone prevalence rate in the 2000-2006 period. In such a context, a
rigorous evaluation of current practice is fundamental. A randomised controlled trial was
therefore planned with the aim to evaluate the safety and effectiveness of beclometasone in
preventing wheezing in respiratory tract infection.
The study will be performed in the primary care setting and will involve 36 family
paediatricians in 9 Italian local health units representative of geographical distribution and
setting.
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 expected results are: to evaluate the efficacy of a widespread practice; to assess viral
wheezing incidence and the disease's natural history; to assess therapeutic approaches used
by the paediatricians; to collect useful evidence to plan interventions for improving rational
drug use in 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 centres.
The Lombardy Region, with 272 patients, is second only to the Veneto Region in number of
patients monitored by the register.
There are 181 patients with a first methylphenidate or atomoxetine prescription (86%),
reported by 14 of 21 referral centres (70%) indicated by the Lombardy Region (4-40; median
7,5). Of these patients: 57 were present in 2007, 82 in 2008, and 42 in 2009. In all, 86% of
patients are male, aged between 5 and 16 years (median 10 years, mode 8). For 118 patients
(65%) at least one familiarity was found: 6 with ADHD, 12 with ADHD and learning
disabilities, 8 with ADHD, learning disabilities, and other positive familiarities, 12 with
learning disabilities.
In agreement with the protocol’s indications, 53 patients were evaluated with a
multidimensional approach (29% of the total, with K-SADS, CPRS, CTRS e WISC). The
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most common diagnosis was complex ADHD (80%) compared to the disorder characterised
prevalently by attention deficit (16%) or hyperactivity (4%). In 42 cases (23% of the total)
no comorbidities were found, while in 95 cases one was found and in 1case five were found.
The most common comorbidities were learning disorders (44%) and oppositional defiant
disorder (35%). Both were diagnosed in 25 patients (15% of total). In all, 129 patients began
treatment with atomoxetine (71%) and 52 with methylphenidate. Adverse effects were found
in 65 patients (36% of total). A total of 22 adverse events were found during
pharmacological treatment in 14 patients (8%, 5 of whom had more than one adverse effect).
The Laboratory set up ADHDNews, a newsletter aimed at providing interested health care
operators a monthly bibliographic update of the recent scientific literature via email. This
initiative is part of the Italian Drug 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, identifying 1010 scientific articles. 277 people have
registered to receive the update (125 psychiatrists and neuropsychiatrists; 48 MD; 36
psychologists and speech therapist; 32 pediatricians; 7 pharmacists; 7 operating scholastic;
22 other). The newsletter is also viewable on the Mario Negri’s website under the section
“The Mario Negri Institute for the physician” (L’Istituto Mario Negri per il Medico):
http://www.marionegri.it/mn/it/index.html
Migration and psychological difficulties in growth and adulthood
The primary goal of the project is the creation of shared, coordinated practices that are
integrated among the different services available, for an appropriate management of the
mental health needs of migrant children and adolescents.
The project involves the Childhood and Adolescence Neuropsychiatry Units (7 UONPIAs), a
mental health service of one of Milan’s local health units, and 11 third-sector organisations.
The Laboratory is a member of the Scientific and Technical Committee and is involved in
the project’s epidemiological analyses and in the development of its information system.
TINN – Treat Infections in NeoNates
Ciprofloxacin and Fluconazole are two anti-infectious drugs included in the European
Medicines Agency’s (EMEA) priority list of therapeutic areas that need specific drug
evaluation in preterm and term neonates. More specifically, ciprofloxacin is an antibiotic
used in newborns with sepsis caused by multiple resistant organisms and fluconazole is an
antimicotic used to prevent or treat invasive candidiasis. These two drugs are prescribed offlabel to treat infections that can make babies seriously ill or even kill them. To improve the
situation, the Tinn project will conduct two clinical trials to evaluate the utility and safety of
Ciprofloxacin and Fluconazole, administered as formulations adapted to preterm and term
neonates.
The project will coordinate and integrate the experience of numerous European countries in
carrying out research in neonates in order to produce detailed evidence on the safety and
efficacy of these two drugs in infants. One of the final goals of the project is to apply for a
Peadiatric-Use Marketing Authorization (PUMA).
Analysis of the requests of information concerning paediatric patients
collected by the Poisons Information Centre in Bergamo during 2007.
As part of a pharmacovigilance project funded by the Lombardy region and a long lasting
collaboration, 1,579 phone calls received during 2007 by the Unità di Tossicologia Clinica,
Ospedali Riuniti di Bergamo (a poisons information centre) concerning 1,591 children and
adolescents < 18 years old with a suspect intoxication, were analysed.
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Drugs were the most commonly involved substances (36% of the cases), followed by home
products (19%). 65% of the queries regarding drugs were due to accidental ingestions, 25%
to therapeutic errors and 5% to intentional ingestion and to adverse drug reactions (ADRs).
In all, the 141 queries related to therapeutic errors concerned a total of 75 drugs. An error in
the dosage was the most frequent cause of therapeutic error (67% of the queries). Antibiotics
and analgesics were the therapeutic class most commonly involved. Paracetamol (20 cases)
and cetirizine (9 cases) were the drugs with the greatest number of queries.
In 10 out of 19 cases of suspect ADR the call was made by a physician and in 9 cases by a
parent. In 7 cases the child was hospitalized; and when child was at home, parents were
advised to consult a physician. 20 drugs were associated to the ADRs: antibiotics (8 out 19
cases) and prokinetics (4 cases) were the drugs most commonly suspected as the cause of the
ADR. Symptoms most frequently reported regarded the central nervous system and skin (5
cases each). These findings are consistent with the results of retrospective and prospective
studies that monitored ADR incidence in the paediatric population.
Mechanical ventilation in children
The Laboratory for Mother and Child Health takes part, in collaboration with the Department
of Anesthesiology and Intensive Care Medicine, San Giovanni Battista-Molinette Hospital,
in the first national study of home mechanical ventilation of children < 18 years old.
The main purpose was to identify the number of children who need long-term home
ventilation and clinical variables associated with primary care after hospital discharge.
Information was collected on 378 patients discharged from 30 hospitals.
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 e the Balkans, continues.
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LABORATORY OF REGULATORY
POLICIES
STAFF
Head
Vittorio BERTELE’, M.D.
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CURRICULA
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" Institute5-10.
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. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E
in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89-95
5. Garattini S, Bertele’ V. Adjusting regulatory rules to public health needs. Lancet 2001; 358: 6467
6. Garattini S, Bertele' V. Efficacy, safety, and cost of new anticancer drugs. BMJ 2002; 325: 269271
7. Garattini S, Bertele’ V, Li Bassi L. How can research ethics committees protect patients better?
BMJ 2003; 326:1199–201
8. Joppi R, Bertele' V, Garattini S. Disappointing biotech. BMJ 2005; 331: 895-897
9. Garattini S, Bertele' V. Non-inferiority trials are unethical because they disregard patients'
interests. Lancet 2007; 370 : 1875-1877
10. Garattini S, Bertele' V. Homoeopathy: not a matter for drug-regulatory authorities. Lancet 2009;
374 : 1578-1580
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)
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
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Evaluation of marketing authorization applications submitted to the European or the Italian
regulatory agency (respectively, EMA and AIFA) and of subsequent variations
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
Recommendations for Pan-European pricing policies for generics as well as interchangeable
brands in a class once generics are available
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.
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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)
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
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
Technical Scientific Committee at the Italian Drug Agency (AIFA)
European Clinical Research Infrastructure Network (ECRIN) Scientific Board, Secretariat
Scientific Committee of the Italian Horizon Scanning Project
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•
Comma A, Zara C, Godman B, Augusti A, Diogene E, Wettermark B, Haycox A. Policies to enhance
the efficiency of prescribing in the Spanish Catalan Region: impact and future direction. Exp Review
of Pharmacoeconomics and Outcomes Research 2009; 9: 569-581
•
Garattini S, Bertele' V. Homoeopathy: not a matter for drug-regulatory authorities. Lancet 2009; 374
: 1578-1580
•
Garattini S, Bertele' V. Ethics in clinical research. J Hepatol 2009; 51 : 792-797
•
Garattini S, Bertele' V, Floriani I, Torri V. Exenatide for type 2 diabetes. Lancet 2009; 373 : 122
•
Godman B, Wettermark B, Vlahovic-Palcevski V, Schwabe U, Gulbinovic J, Laius O, Diogene E,
Paterson K, Martikainen J, Bennet K, Gustafsson LL. Impact of reforms to enhance the quality and
efficiency of statin prescribing across 20 European countries. Basic & Clin Pharm & Toxicology
2009; 105 (Suppl 1):35
•
Godman B, Vlahovic-Palcevski V, Laius O, Bennet K et al. Trends in consumption and expenditure
of proton pump inhibitors (PPIs) in 20 European countries. Basic & Clin Pharm & Toxicology 2009;
105 (Suppl 1):37
•
Godman B., Burkhardt T, Bucsics A et al. Impact of recent reforms in Austria on utilisation and
expenditure of PPIs and lipid lowering drugs; implications for the future. Expert Rev
Pharmacoeconomics Outcomes Research 2009; 9:475-484
•
Godman B, Schwabe U, Selke G, Wettermark B. Update of recent reforms in Germany to enhance
the quality and efficiency of prescribing of proton pump inhibitors and lipid lowering drugs.
Pharmacoeconomics 2009; 27: 435-438
•
Godman B, Wettermark B, Hoffman M, Andersson K, Haycox A, Gustafsson LL. Multifaceted
national and regional drug reforms and initiatives in ambulatory care in Sweden; global relevance.
Expert Rev Pharmacoeconomcis Outcomes Research 2009; 9:65-83
•
Joppi R, Bertele' V, Garattini S. Orphan drug development is not taking off. Br J Clin Pharmacol 2009; 67 : 494502
•
Joppi R, Demattè L, Menti AM, Pase D, Poggiani C, Mezzalira L, on behalf of the Italian Horizon
Scanning Project Group. The Italian Horizon Scanning Project. Eur J Clin Pharmacol 2009; 65:775–
781
•
Ottolenghi L, Bertele' V, Garattini S. Limits of add-on trials: antirheumatic drugs. Eur J Clin
Pharmacol 2009 65 : 33-41
•
Vitry A, Bertele' V, Garattini S. Drug regulation and the need for greater transparency. RAJ Pharma
2009 March; 1-4
•
Wettermark B, Godman B, Jacobsson B, Haaijer-Ruskamp F. Soft regulations in pharmaceutical
policymaking - an overview of current approaches and their consequences. Appl. Health Econ Health
Policy 2009; 7: 1-11
•
Wettermark B, Pehrsson A, Juhasz-Haverinen M, Veg A, Edlert M, Törnwall-Bergendahl G,
Almkvist H, Godman B, Granath F, and Bergman U. Financial incentives linked to self-assessment
of prescribing patterns – a new approach for quality improvement of drug prescribing in primary
care. Quality in Primary Care 2009;17:179–89
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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 ‘five Es’,
namely: evaluation; economics; enforcement; education and engineering to further fund
increased volumes and new valuable innovative drugs
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
Assessment of drug dossiers for regulatory approvals
Expert support to the Rapporteurship for marketing authorisation applications and variations to
the conditions of marketing authorisation
Activities for the Technical Scientific Committee at the AIFA
Consultative activities for the Italian Drug Agency regarding regulatory duties with respect to
drug quality, safety, efficacy, and cost
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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:
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 multimedial divulgation
Davide Bazzi graduated in Informatics with specialization in ABACUS at Istituto Tecnico Industriale
Statale of Corsico. He has been working with the Institute of Mario Negri since 1997.
Main areas of interest:
1. Planning, realization and management of communication Network and Data Center
2. Definition and management of quality levels in ICT services distribution
3. Planning and realization of technological innovation for ICT systems
4. Definition and application of organization’s methodologies and processes for the informatics security
management
ACTIVITIES
In order to fulfil 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 e of Clinical Trials’ gathering forms (E-CRF)
−
Lab. Clinical Trials
o GLAUCOMA PEDIATRICO
o Amendment of Trial TAILOR
o Trial HEAD & NECK
−
Lab. New Drug Development Strategies (Dep. Oncology)
o Trial MUCOSITIS
o Trial TRIAC
−
Lab. Neurological Disorders (Dep. Neuroscience):
o Trial ANTIEPILETTICI
o Trial ADONE
o Trial EDU-COM
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Maintenance and management of data gathering forms for the following
clinical trials
−
Lab. Neurological Disorders (Dep. Neuroscience):
•
Estensione Registro Europeo SLA
•
Trial L-ACETYLCARNITINE
•
Trial ANTIEPILETTICI
•
Trial EPILESSIA E STROKE
•
Trial EPO VS MP IN SPINAL SHOCK
•
Trial VALPROATO
•
Trial THEOREM
−
Lab. Clinical Trials (Dep. Oncology)
o Trial FOLFOX
o Trial TOP
o Trial COMETS
o Trial TAILOR
o Trial HEAD & NECK
−
Lab. New Drug Development Strategies (Dep. Oncology)
•
Trial MAPS
•
Trial STARPAN
−
Dep. Epidemiology
− Trial CADASIL
−
Lab. Quality Assessment of Geriatric Therapies and Services (Dep. Neuroscience)
− Trial GISAS
− Patients registry for Polipathologies and Politherapies – SIMI web
Web based applications connected to the projects
-
Utility system for the current trials gathering data program (realized)
Redesign of the database concerning hospitalizations, recipes and medical
visitation provided from Regione Lombardia for covenant data analysis
Support to data processing in recipes analysis for Regione Lombardia
Creation of a feedback system for TINN study
Analysis software for interaction between drugs and integrations between
interaction database and drugs reference book (in collaboration with Lab.
Quality Assessment of Geriatric Therapies and Services).
Other projects
Web based application for in-plant automation
•
New database for the Institute Orders
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•
•
•
•
•
New database for the Institute Distributed Publications
Management of the database and credits of ECM
New clinical trial Register for the Institute
Creation of a management system for the entrance exams of the Regione
Lombardia school
Creation of a management system for the entrance exams for PhD
Multimedial communication
-
Management of multimedia contents for the Institute website
DVD video editing and realization for presentations
Creation of promotional videos for the “5xmille” annual campaign
Websites
−
−
−
Management of the Institute website
Management of the related websites
Restyling of "Fondazione Mattioli" website
Informatics infrastructures
-
Realization of the virtualization platform of the Institute server systems
Planning and realization of the accesses and management and supporting
processes control system
Migration to the new e-mail system
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ITALIAN COCHRANE CENTRE
STAFF
Head
Alessandro LIBERATI, M.D.
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CURRICULA
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, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to reduce respiratory tract
infections and mortality in adults receiving intensive care. Cochrane Database Syst Rev. 2009
•
Donati S., Cotichini R., Mosconi P., Satolli R., Colombo C., Liberati A., Mele A. Menopause: knowledge, attitude and
practice among Italian women Maturitas 2009;63:246-252
•
Mosconi P., Donati S., Colombo C., Mele A., Liberati A., Satolli R., Consensus Conference Working Group. Informing
women about hormone replacement therapy: the Consensus Conference statement. BMC Women’s Health 2009;9:14
•
Mosconi P., Donati S., Colombo C., Mele A., Liberati A., Satolli R., Consensus Conference Working Group. Informing
women about hormone replacement therapy. Cancer Journal 2009;15:344
•
Moher D., Liberati A., Tetzlaff J., Altman D.A. Preferred reporting items for systematic reviews and metanalysis: the
PRISMA Statement. Ann Intern Med 2009;151:264-269
•
Banzi R., Moja L., Liberati A., Gensini G.F., Gusinu R., Conti A.A. Measuring the impact of evidence: the Cochrane
systematic review of organized stroke care. Intern Emerg Med 2009;4:507-510
•
Liberati A., Altman D.A., Tetzlaff J., et al. The PRISMA Statement for reporting systematic reviews and metanalyses of
studies that evaluate health care interventions: explanation and elaboration. Annals of Internal Medicine 2009;151:w1w30
•
Moja L., Moschetti I., Nurbhai M., Compagnoni A., Liberati A. et al. Compliance of clinical trial registries with the
World Health Organization minimum data set: a survey. Trials 2009;10:56
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
quarterly 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 contribute to the adoption and dissemination of Evidence-based Medicine in Italy.
d) to collaborate with NHS to improve the quality of clinical and epidemiological research.
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MAIN FINDINGS
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.
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
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.
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EVENT ORGANIZATION
I° Edition Master in “Promozione e governo della ricerca nelle aziende sanitarie”
February - December 2009 - Modena
Course EBM - I.R.C.C.S. Istituto Ortopedico Galeazzi, Febbraio – March 2009 - Milan
Corso di perfezionamento avanzato in “Revisioni sistematiche e meta-analisi – metodologia
Cochrane” –
November 2009- March 2010
Workshop: November 20-21, 2009 - Perugia
- Quando i comitati etici possono interferire nella valutazione del disegno e del
significato di uno studio clinico
- La medicina non convenzionale: il ruolo delle revisioni sistematiche
XIV Annual Meeting of the Italian Cochrane Network “Le priorità della ricerca nei sistemi
sanitari” –
November 20-2, 2009- Perugia
II° Edition “Corso di epidemiologia clinica e metodologia della ricerca: il dolore nel paziente
con cancro”
20-21 February 2009, Napoli
Meeting “Evidence-based veterinary medicine” March 14 ,2009 - Bologna
Master in “Ricerca Organizzativa nelle strutture sanitarie” May 22-23 2009, Università degli
Studi di Ferrara
Master in Scienze Mediche di II livello “Metodologia della Ricerca”, February 2009,
Università degli Studi di Parma
“Evidence-based clinical practice workshop: architecture of prognostic and diagnostic studies” 2
October 2009, Gargnano
2009 Mid-Year Steering Group and Centre Directors’ Meeting April 20-25, 2009 - Copenhagen
Annual Continental European Cochrane Entities Meeting (CECEM), June 10-12, 2009 Maastricht
First Annual Croatian Cochrane Symposium, June 26-27- Spalato
XVI Cochrane Colloquium, October 11-14, 2009 - Singapore
Worskhop del Centre for Evidence based Medicine di Oxford (CEBM) per la revisione della
“CEBM Level of Evidence classification”; Oxford (UK) December 17, 2009
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Trenta Anni del Dipartimento di Epidemiologia della Regione Lazio, December 18,2009 Rome
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
All publications of the Italian Cochrane Center are available on web site www.cochrane.it.
Virgili G, Conti AA, Moja L, Gensini GF, Gusinu R. Heterogeneity and meta-analyses: do
study results truly differ? Internal and Emergency Medicine 2009;4:423-427
Sirtori V, Corbetta D, Moja L, Gatti R. Constraint-induced movement therapy for upper
extremities in stroke patients. Cochrane Database of Systematic Reviews 2009, Issue 4. Art.
No.: CD004433
Amato B, Moja L, Panico S, Persico G, Rispoli C, Rocco N, Moschetti I. Shouldice technique
versus other open techniques for inguinal hernia repair. Cochrane Database of Systematic
Reviews 2009, Issue 4. Art. No.: CD001543
Banzi R, Moja L, Liberati A, Gensini GF, Gusinu R, Conti AA. Measuring the impact of
evidence: the Cochrane systematic review of organised stroke care. Internal and Emergency
Medicine 2009;4:507-510
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche P, et al. The Prisma Group. The
PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate
health care interventions: explanation and elaboration. PLoS Med 2009;6
Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to
reduce respiratory tract infections and mortality in adults receveing intensive care. Cochrane
Database of Systematic Review, 2009 (4)
Moher D, Liberati A, Tetzlaff J, Altman DG, The Prisma Group. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med
2009;18:151(4):264-9
Li LC, Moja L, Romero A, Sayre EC, Grimshaw JM. Nonrandomized quality improvement
trials might overstate the strenght of causal inference of their findings. Journal of clinical
epidemiology 2009;62(9):959-66
Banzi R, Moschetti I, Moja L. Internet-based education for health professionals. JAMA
2009;301(6):599-600
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Squizzato A, Moja L, Gensini GF, Gusinu R, Conti AA. Is thrombolysis for intermediate-risk
pulmonary embolism beneficial? The case of Emeritus Professor Crow. Internal and Emergency
Medicine 2009;4:339-41
Moja L, Moschetti I, Nuebhai M, Compagnoni A, Liberati A; Grimsha JM, Chan AW,
Dickersin K, Krleza-Jeric K, Moher D, Sim I, Volmink J. Compliance of clinical trial registries
with the World Health Organitation minimum data set: a survey. Trials 2009; 22 :10-56
Deandrea S, Corli O, Moschetti I, Apolone G Managing severe cancer pain: the role of
transdermal buprenorphine: a systematic review. Therapeutics and clinical risk management
2009; 5: 707-18.
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
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”.
The ICC offered individual training and support to reviewers involved in specific research
projects aimed at producing Cochrane systematic reviews (see scientific publication section).
The ICC researchers collaborate with the Social and Health Regional Agency of Emilia
Romagna to produce clinical recommendations in oncology.
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). In 2009 54 press releases were cited by relevant Italian newspapers
and radio programs.
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.
- Users’ guide on discordant systematic reviews: to investigate the scientific validity and
reliability of systematic review’s results. The project final output will be a critical tool
deal with discordant systematic reviews in order to inform clinical and policy decision
making.
- ICEKUBE: randomized controlled trial to evaluate the effectiveness of the distant
learning project ECCE, based on the Clinical Evidence contents, to improve clinician
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-
knowledge. In 2009 the trial was concluded and the preliminary results are now
available.
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.
AFO (progetto Appropriatezza Farmaci Oncologici): methodological support to the
Social and Health Regional Agency of Emilia Romagna to produce clinical
recommendations in oncology.
In 2009 the ICC continued its collaboration with the PartecipaSalute ("Participate in Health
Care") project to foster a strategic alliance between patients’ groups and professional societies
with the common goal of promoting better health and shared decision-making. The project’s
main aims are:
- to increase patients’ associations’ involvement in healthcare assistance and in decision
making processes;
- to promote a partnership between patients’ associations and medical societies soliciting
medical societies’ attention to patients’ need and perspectives
- to develop a partnership between citizens, patients and healthcare system.
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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.
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Negri Bergamo Laboratories
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REPORT 2009
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DEPARTMENT OF MOLECULAR
MEDICINE
STAFF
Head
Ariela BENIGNI, Biol.Sci.D., Ph.D.
Unit of Gene Therapy
Head
Susanna TOMASONI, 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.
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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.
− Schiffmann R, Waldek S, Benigni A, Auray-Blais C. Biomarkers of Fabry Disease Nephropathy. Clin J Am Soc Nephrol.
2009 Nov 5. [Epub ahead of print].
− Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C, Mazzinghi B,
Ronconi E, Becherucci F, Benigni A, Steenbergen E, Lasagni L, Remuzzi G, Wetzels J, Romagnani P. Renal progenitor cells
contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol. 2009
Dec;20(12):2593-603.
− 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 Ther. 2009 Nov;16(11):13739.
− Gagliardini E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti L, Remuzzi A, Remuzzi G,
Benigni A. Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental
diabetes. Am J Physiol Renal Physiol. 2009 Nov;297(5):F1448-56.
− 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.
− Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E, Noris M, Buelli S, Zoja C, Corna D, Mele C, Fanelli
Nephrol. 2009 Jan;20(1):123-30. Epub 2008 Dec 17.
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: 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);
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; cell therapy and tissue regeneration: Capability of adult stem cells to
differentiate and to regenerate renal tissue in acute and chronic experimental models of renal disease.
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Murine embryonic stem cell therapy to correct the genetic defect characteristic of Fabry disease in an
experimental mouse model.
- 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.
- 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):10509. Epub 2009 Feb 25.
- 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.
- 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
Nov;18(11):2921-8. Epub 2007 Oct 17.
- Geelen J Valsecchi F, van der Velden T, van den Heuvel L, Monnens L, Morigi M. Shiga-toxin-induced firm adhesion of
human leukocytes to endothelium is in part mediated by heparan sul fate. Nephrol Dial Transplant. 2008 Oct;23(10):3091-5.
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.
•
Noris M, Remuzzi G. Atypical Hemolytic Uremic Syndrome N Engl J Med. 2009 Oct 22;361(17):1676-87.
•
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 Oct
1;183(7):4249-60.
•
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.
•
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.
•
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.
•
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.
•
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.
•
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.
ANNUAL REPORT
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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 20042007 member Editorial Board, Journal of the American Society of Nephrology.
− 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;
76:960-7.
− Zanchi C, Zoja C, Morigi M, Valsecchi F, Liu XY, Rottoli D, Locatelli M, Buelli S, Pezzotta A, Mapelli P, Geelen J,
Remuzzi G, Hawiger J. Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. J
Immunol. 2008; 181:1460-9.
− 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; 19:1158-67.
− Zoja C, Casiraghi F, Conti S, Corna D, Rottoli D, Cavinato RA, Remuzzi G, Benigni A. Cyclin-Dependent kinase
inhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus. Arthr.Rheumatism 2007; 56;
1629-37.
− Donadelli R, Zanchi C, Morigi M, Buelli S, Batani C, Tomasoni S, Corna D, Rottoli D, Benigni A, Abbate M, Remuzzi
G, Zoja C. Protein overload induces fractalkine upregulation in proximal tubular cells through NF-kB and p38 MAPK
dependent pathways. J Am Soc Nephrol. 2003;14:2436-46.
− Zoja C, Corna D, Camozzi D, Cattaneo D, Rottoli D, Batani C, Zanchi C, Abbate M, Remuzzi G. How to fully protect
the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol. 2002;13:2898-908.
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.
ANNUAL REPORT
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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).
Employment: 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.
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:
− 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.
ANNUAL REPORT
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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.
Cavinato RA, Casiraghi F, Azzollini N, Cassis P, Cugini D, Mister M, Pezzotta A, Aiello S, Remuzzi G, Noris M.
Pretransplant donor peripheral blood mononuclear cells infusion induces transplantation tolerance by generating
regulatory T cells. Transplantation. 2005;79(9):1034-9.
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.
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, IRFMN, Bergamo, Italy; from 2000 Head, Unit of Gene Therapy,
IRFMN, Bergamo, Italy
•
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.
•
Tomasoni S, Remuzzi G, Benigni A. Allograft rejection: acute and chronic studies. Contrib Nephrol. 2008; 159:122-34.
Review.
•
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.
•
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.
ANNUAL REPORT
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2009
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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.
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.
ACTIVITIES
The Department of Molecular Medicine was established in 1999 at the Negri Bergamo
laboratories to coordinate the work of three laboratories and three 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;
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.
MAIN FINDINGS
Knocking out angiotensin II type 1 receptor prolongs survival of mice.
A new drug association to slow the progression of chronic renal disease.
Thrombomodulin modulates complement activation on the surface of endothelial cells: a novel
link between complement and coagulation systems.
ANNUAL REPORT
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Cord blood mesenchymal stem cells are more effective than bone marrow mesenchymal stem
cells in repairing acute renal injury and in prolonging survival of mice.
A new approach to improve mesenchymal stem cells tissue regeneration capability in acute
renal failure.
Gene therapy restores ADAMTS13 deficiency: new hope for gene therapy for Thrombotic
Thrombocytopenic Purpura.
TIR8 modulates innate immune response against kidney transplantation.
Genetic abnormalities in thrombomodulin – a coagulation protein -predispose to atypical
Heamolitic Uremic Syndrome (aHUS).
Complement factors mutations in atypical HUS (aHUS) cause massive complement system
activation responsible for endothelial cells injury.
Laboratorio di Terapia genica e cellulare, G. Lanzani, Divisione di Ematologia, Ospedali Riuniti
di Bergamo
Laboratorio di Tecnologie riproduttive, Istituto Sperimentale Lazzaro Spallanzani, 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 Istologia Microbiologia e Biotecnologie Mediche, Università di Padova
Dipartimento di Biotecnologie, Università di Verona
International Centre for Genetic Engineering and Biotechnology, Molecular Medicine Group,
Trieste
U.O. di Ostetricia e Ginecologia, Ospedale San Gerardo di Monza
U.O. di Ostetricia e Ginecologia, Azienda Ospedaliera Ospedali Riuniti di Bergamo
U.O. di Ostetricia e Ginecologia, Azienda Ospedaliera Spedali Civili di Brescia
I.R.C.C.S. Policlinico San Matteo, Pavia
Consorzio per la Ricerca sul Trapianto di Organi, Tessuti, Cellule e Medicina Rigenerativa
CORIT, Padova
Academisch Ziekenhuis Maastricht, Interne Geneeskunde, Maastricht, The Netherlands
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA
Charitè Campus Virchov Klinikum, Berlin, Germany
Children's Hospital and Regional Medical Center, University of Washington, Seattle, USA
Departements 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, The Netherlands
Hans-Knoll Institute for Natural Products Research, Jena, Germany
INSERM, Paris, France
Klinikum der Ludwig Maximillians Universitat Munchen, Germany
ANNUAL REPORT
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Max Delbruck Center for Molecular Medicine, Berlin, Germany
Max-Plank Gesellschaft zur Forderung der Wissenshaften, Hpi of experimental endocrinology,
Hannover, Germany
Necker Hospital, Paris, France
Renal Transplant Unit, Hospital de Bellvitge, Barcelona, Spain
Rosalind Franklin University of Medicine and Science, Chicago, USA
Universitaet Hamburg, Institut fur Molekulare Neuropathobiologie, Hamburg, Germany
University of Aarhus, Denmark
University of British Columbia, Vancouver, Canada
University of Colorado Cardiovascular Institute, Denver, USA
University of Groningen, The Netherlands
University of Liverpool, School of Biological Sciences, UK
University of Oulu, Denmark
University of Pittsburgh School of Medicine, Pittsburgh, USA
University of Zurich, Switzerland
Weizmann Institute of Science, Rehovot, Israel
World Health Organization, Geneva, Switzerland
Journal of American Society of Nephrology
International Journal of Artificial Organs
Cell Proliferation
Diabetologia
Hypertension
Immunology
Kidney International
Journal of Clinical Investigation
Journal of the Renin Angiotensin Aldosterone System
Journal of the American Society of Nephrology
Journal of Thrombosis and Haemostasis
Nature Medicine
Nephrology, Dialysis and Transplantation
Nephron Clinical Practice
New England Journal of Medicine
Pediatric Nephrology
Plos Medicine
The American Journal of Pathology
The Canadian Journal of Physiology and Pharmacology
The Journal of Experimental Medicine
The Lancet
The Open Urology & Nephrology Journal
Transplant Immunology
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Trends in molecular medicine
33° Congresso Nazionale Società Italiana Trapianto d’Organo, Milano, 13-15 December 2009
Grandangolo 2009 in nefrologia, dialisi e trapianto, Bologna, 17 December2009
Stem cell-based therapies: background and practice, Università degli Studi di Milano, 3
December 2009
XVI Symposium of the “Reina Sofia”, Madrid, 19-20 November 2009
XII Corso Educazionale SISET: Microangiopatie trombotiche e coagulopatie da consumo,
Bosco Marengo, 6-7 November 2009
Meeting American Society of Nephrology, San Diego, 29 October -2 November 2009
The Cord meeting , Policlinico Mangiagalli, Cell Factory, Milano, 19 October 2009
Joint Meeting IPITA-IXA 2009, Venezia, 12-16 October 2009
Focus on cell therapy: Transplantation and tissue repair, Bergamo, 8-10 October 2009
50° Congresso Nazionale Società Italiana di Nefrologia (SIN), Bologna, 7-10 October2009
4th International Workshop on Thrombotic Microangiopathies, Weimar, 1-3 October2009
Meeting per progetto GENECURE, FP6, Stoccolma, 16-17 September 2009
Congresso Europeo di Immunologia, Berlino, September13-16, 2009
ET-11, 11° International Conference on Endothelin, Montreal, 9-12 September 2009
12th European Meeting on Complement in Human Disease, Visegrad, 5-8 September 2009
FRR-E Society for Free Radicals Research Europe Meeting 2009, Roma, 27-28 August 2009
University of Florence Workshops Series “Systemic Sclerosis and its vascular complications:
state of the art in diagnosis and therapy”, Firenze, 22 June 2009
KIDSTEM International Conference, Edinburgh, 29-31 July 2009
American Transplant Congress, Boston, 30 Maggio-3 June 2009
WCN 2009 World Congress of Nephrology, Milano, 22-29 May 2009
Serono Symposia International Foundation, Progress in stem cell biology and medical
applications’, Stresa, 14-16 Maggio 2009
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Conference on “HUS- Current diagnosis and therapy of haemolytic uremic syndrome”,
Innsbruck, 18-20 May 2009
EuReGene Meeting, FP6, Berlino, 14-16 May 2009
EuroKup European Kidney and Urine Proteomics, European Science Foundation, Nafplio, 2930 March 2009
21st Annual Meeting of the European Renal Cell Study Group ERCSG, Delphi, 26-28 March
2009
KIDSTEM meeting Vienna, 26-27 March 2009
Cellule staminali e medicina rigenerativa 2009, attualità e prospettive, Pavia, 16-20 March 2009
Atrasentam (M10-815) Protocol Advisory meeting, 6-7 March 2009, Atlanta,
12° Convegno Patologia Immune e malattie orfane 2009, Torino, 22-24 January
Star-T Rek kick off Meeting, Siena, 14-15 January 2009
Comitato Telethon Fondazione ONLUS
European Commission FP6 and FP7
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
Ablynx NV
ACRAF (Aziende Chimiche Riunite Angelini Francesco Spa)
Alexion Pharmaceuticals
Evolva AG
Genzyme Corporation
LFB Biotechnologies
Taligen Therpeutics
Schiffmann R, Waldek S, Benigni A, Auray-Blais C. Biomarkers of Fabry Disease Nephropathy. Clin J
Am Soc Nephrol. 2009 Nov 5. [Epub ahead of print].
Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C,
Mazzinghi B, Ronconi E, Becherucci F, Benigni A, Steenbergen E, Lasagni L, Remuzzi G, Wetzels J,
Romagnani P. Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic
glomerulonephritis. J Am Soc Nephrol. 2009 Dec;20(12):2593-603.
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Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Oct 22;361(17):167687. Review.
Cassis P, Conti S, Remuzzi G, Benigni A. Angiotensin receptors as determinants of life span. Pflugers
Arch. 2009 Sep 11. [Epub ahead of print].
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.
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 Oct 1;183(7):4249-60.
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 Ther. 2009 Nov;16(11):1373-9.
Gagliardini E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti L,
Remuzzi A, Remuzzi G, Benigni A. Unlike each drug alone, lisinopril if combined with avosentan
promotes regression of renal lesions in experimental diabetes. Am J Physiol Renal Physiol. 2009
Nov;297(5):F1448-56.
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):960-7.
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 hemolyticuremic syndrome. N Engl J Med. 2009 Jul 23;361(4):345-57.
Goumenos DS, Kawar B, El Nahas M, Conti S, Wagner B, Spyropoulos C, Vlachojannis JG, Benigni A,
Kalfarentzos F. Early histological changes in the kidney of people with morbid obesity. Nephrol Dial
Transplant. 2009 Dec;24(12):3732-8.
Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, Remuzzi A, Benigni A. Bone marrowderived mesenchymal stem cells improve islet graft function in diabetic rats. Transplant Proc. 2009
Jun;41(5):1797-800.
Benigni A, Remuzzi G. Treatment of chronic proteinuric kidney disease: what next? Hypertension. 2009
Jul;54(1):29-31.
Longaretti L, Benigni A. Endothelin receptor selectivity in chronic renal failure. Eur J Clin Invest. 2009
Jun;39 Suppl 2:32-7. Review. Erratum in: Eur J Clin Invest. 2009 Jul;39(7):630.
Noris M, Remuzzi G. Thrombotic microangiopathy: what not to learn from a meta-analysis. Nat Rev
Nephrol. 2009 Apr;5(4):186-8.
Zoja C, Garcia PB, Remuzzi G. The role of chemokines in progressive renal disease. Front Biosci. 2009
Jan 1;14:1815-22. Review. PubMed PMID: 19273165.
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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.
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.
Galbusera M, Noris M, Remuzzi G. Inherited thrombotic thrombocytopenic purpura. Haematologica.
2009 Feb;94(2):166-70. Review.
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 Jan;20(1):123-30.
Vlahou A, Charonis A, Benigni A. Report on the first combined working group and management
committee meeting of EuroKUP (Urine and Kidney Proteomics cost action). J Proteomics. 2009 Jan
30;71(6):682-4.
RESEARCH ACTIVITIES
Laboratory of Cell Biology and Xenotransplantation
Human amniotic fluid stem cells accelerate recovery of acute kidney
injury and prolong survival in mice
Transplantation of bone marrow or cord blood-derived mesenchymal stem cells (MSCs) has
been indicated as a new approach for the cure of acute kidney injury (AKI). However, bone
marrow collection is associated with considerable patient’s discomfort and isolation of MSCs
from cord blood is not invariably successful. By contrast, various progenitors have been easily
obtained from amniotic fluid. Here we investigated the potential of human amniotic fluidderived stem (hAFS) cells to prevent AKI induced by cisplatin and prolong survival in
immunodeficient mouse model. Human AFS cells were obtained by amniotic fluid taken
between 14-18 weeks of gestation from amniocentesis. Cells were immunoselected for CD117
positivity. Results showed that infusion of human AFS cells significantly protected cisplatinmice from renal function deterioration as documented by low levels of serum blood urea
nitrogen in respect to mice given saline at 4 days. In parallel, human AFS cell injection
markedly reduced tubular damage in terms of less number of luminal casts and necrotic tubuli.
Improvement of function and preservation of tubular structures resulted in a significant
prolongation (p<0.005) of animal survival. Transplanted hAFS cells, labelled with PKH26,
engrafted the injured kidney and localized in the peritubular areas and within tubular epithelium
at 4 days. These findings indicate that hAFS cells are renotropic, help to repair the renal tissue
and improve survival of mice with AKI. The mechanisms underlying renal recovery by AFS
cells need to be clarified before a possible application to human AKI.
Metanephros transplantation for the treatment of chronic renal failure
In collaboration with the Laboratory of Experimental Models of Kidney Diseases
Strategies to support and improve renal function in patients with chronic renal failure are greatly
demanded. The use of xenogeneic embryonic kidney tissues has been suggested and might be
considered as a possible interesting option. In this context, we proposed to study, firstly in a
syngeneic setting, the developmental capacity and the pro-regenerative potential of metanephroi
(MET) isolated from rat embryos of 15 days, which spontaneously develop chronic renal
disease. The nephrogenic site was identified under a stereomicroscope and MET were isolated.
In order to study their capacity to develop and to regenerate renal tissues, MET have been
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transplanted under the kidney capsule of 25 weeks-old rats exhibiting proteinuria and
histological changes. At sacrifice, 6 weeks later, macroscopic views revealed that MET had
developed into large structures, some of them with cysts containing fluid with a concentration of
creatinine much higher as compared to the serum suggesting a filtering action of MET to form
diluted urine. Histological analysis of grafted MET showed the presence of glomeruli and
tubuli. Blood vessels within grafts exhibited intraluminal FITC-albumin upon intravenous
injection of the tracer, indicating vascular connection to the host. FITC-BSA in the tubular cells
of the graft suggested a basic absorptive capacity. Our data provide evidence that, in the context
of chronic renal disease, MET can mature into new nephrons. Whether these neo-kidneys are
able of creating pro-regenerative environment is presently matter of investigation.
Atypical Haemolytic Uremic Syndrome (aHUS)-associated genetic
complement abnormalities cause C3 deposition on endothelial cells.
In collaboration with the Laboratory of Immunology and Genetic of Rare Diseases and
Organ Transplantation
aHUS is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia
and renal dysfunction due to endothelial cell damage and thrombus formation in renal
microcirculation. Genetic abnormalities of complement regulators and of the components of the
alternative pathway C3 convertase, CFB and C3, have been reported in aHUS. To investigate
whether these mutations cause C3 deposition on endothelial cells and whether complement
inhibitors prevent C3 accumulation, we selected 25 aHUS patients carrying mutations in CFH,
CFI, C3 and mutations or the risk R32W polymorphism in CFB. Human microvascular
endothelial cells (HMEC-1) pre-activated with ADP were incubated with serum from patients or
healthy controls, C3 deposits were visualized by immunofluorescence and the area measured.
HMEC-1 exposed to patient serum showed intense deposition of C3 on cell surface. Indeed, the
area covered by C3 was significantly higher on cells exposed to aHUS serum than on cells
exposed to control serum. Soluble complement receptor1 (sCR1) -an inhibitor of all the three
pathways (classical, alternative and lectin) of complement activation- markedly inhibited C3
deposits. No appreciable C4 or IgG staining was observed on cells exposed to the same aHUS
sera, indicating a selective activation of the alternative pathway of complement. We then
evaluated whether two specific inhibitors of the alternative pathway of complement, an antiCFB antibody (TA106) and the C3d-targeted complement inhibitor CR2-FH (TT30) were able
to inhibit aHUS-serum induced C3 deposition on HMEC-1. Addition of either TT30 or TA106
to patients’ serum (with CFH mutations) lead to a significant reduction of area covered by C3 as
compared to untreated serum. In conclusion, we documented that aHUS-associated mutations in
complement components cause alternative pathway-mediated complement hyperactivation and
impair the natural resistance of endothelial cells to complement attack. These findings offer the
rationale for the development of new mechanism-based complement inhibitors to cure this lifethreatening disease.
Laboratory of Experimental Models of Kidney Diseases
Disruption of the Ang II type 1 receptor promotes longevity in mice
The renin-angiotensin system plays a role in the etiology of hypertension and the
pathophysiology of cardiac and renal diseases in humans. Ang II is the central product of this
system and is involved in regulating immune responses, inflammation, cell growth, and
proliferation by acting through Ang II type 1 receptors (AT1). Our recent study shows that
targeted disruption of the Agtr1a gene that encodes AT1A results in marked prolongation of life
span in mice. Agtr1a–/– mice developed less cardiac and vascular injury, and heart, aorta and
kidney from these mice displayed less oxidative damage than wild-type mice. The longevity
phenotype was associated with an increased number of mitochondria and upregulation of the
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prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the
kidney. In cultured tubular epithelial cells, Ang II downregulated Sirt3 mRNA, and this effect
was inhibited by an AT1 antagonist. These results demonstrated that disruption of AT1 promotes
longevity in mice, possibly through the attenuation of oxidative stress and overexpression of
prosurvival genes. AT1 receptor antagonists have been proven safe and are used as a key
component of the modern therapy for hypertension and cardiac failure. Whether the results
obtained in mice were confirmed in humans, AT1 receptor antagonists could represent a possible
therapeutic strategy for diseases of aging and to extend life span. Further studies are necessary
to deepen the role of AT1 receptor in humans and to understand whether its function is similar to
that found in animals.
Combined treatment of angiotensin converting enzyme inhibitor with
endothelin receptor antagonist induces a complete renoprotection in
experimental diabetes
In collaboration with the Department of Biomedical Engineering
Proteinuria is one of the major risk factors for renal disease progression in patients with chronic
nephropathies. The hyperfiltration of proteins through the glomerular barrier is associated with
alterations in structure and function of visceral epithelial cells, the podocytes, with the
consequent increased dimension of pores perforating the glomerular capillary. The increased
glomerular filtration of plasma proteins leads to damage of tubuli, which try to recover the
exaggerated amount of proteins escaped from the glomerular filter with the consequent
accumulation of inflammatory cells in the interstitium. Angiotensin converting enzyme
inhibitors (ACEi) represent the current gold standard for renoprotection. However, an imperfect
protection was observed when these drugs were given in the advanced phase of the disease.
From previous studies, a role for endothelin-1 in proteinuric chronic renal diseases has been
suggested, thus providing the rationale for novel therapeutic approaches with endothelin
receptor antagonists (ETRA). In experimental diabetes we recently observed a complete
renoprotection with the combined treatment of ACEi with ETRA. Renoprotection resulted in a
normalization of proteinuria and regression of glomerular lesions in terms of reduced
accumulation of extracellular matrix. The effect of the drug combination of fully protecting
animals from renal injury is the result of two diverse mechanisms acting synergistically. The
ACEi preserved the glomerular permselective properties restoring the pore dimension of the
glomerular barrier and improving the integrity and function of podocytes with the consequent
reduction of proteinuria. ETRA improved the architecture of peritubular capillaries and,
therefore, renal interstitial blood perfusion, and preserved tubulointerstitial structure which
would possibly lead to amelioration of tubular function and protein reabsorption. In conclusion,
combined administration of ACEi and ETRA could provide a novel opportunity to treat patients
with diabetes and overt nephropathy who have incomplete benefit from ACE inhibitor alone.
Renal progenitor cells contribute to hyperplastic lesion of different human
diseases
A wide variety of renal diseases, including collapsing glomerulopathy, focal segmental
glomerulosclerosis and extracapillary glomerulonephritis, is characterized by glomerular
lesions. In the early stage of the injury, an excessive proliferation of glomerular epithelial cells
leads to obliteration of the space between Bowman’s capsule and capillary tuft. This generates
pathological bridges connecting these different glomerular districts, and subsequent hyperplastic
lesions called crescents. Progression of glomerular injury toward glomerulosclerosis is
characterized by the evolution from an early hyperplastic lesion to a fibrous lesion, related to a
gradual accumulation of extracellular matrix (ECM). Theories explaining the origin of crescents
are controversial, and which cells contribute to the formation of these lesions is still unknown.
A previous study described along the Bowman’s capsule of healthy human glomeruli the
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presence of three subsets of cell populations: immature renal progenitors, visceral epithelial
cells or podocytes, and transitional cells which co-express markers of both the other cell
populations. Progenitor cells were able to replace injured podocytes. In a recent study we
characterized the phenotype of the cell populations of hyperplastic lesions of patients suffering
from different types of glomerulopathies. We have observed that most of the cells within
crescents display features of immature progenitors and transitional cells sometimes
proliferating, but a high percentage of differentiated podocytes, which can even represent 50%
of total cells in the lesions, are present. Through in vitro study we have observed that these
cells, and in particular progenitors, when exposed to transforming growth factor-b (TGFb), are
able to produce type IV collagen, fibronectin and laminin, which are the main constituents of
ECM. Taken together, these results suggest that, while in the early phase of the disease renal
progenitors of the Bowman’s capsule differentiate into podocytes thus replacing injured cells, in
presence of a severe glomerular damage, they excessively proliferate leading to formation of
hyperplastic lesions.
V1/V2 vasopressin receptor antagonism potentiates the renoprotection of
renin-angiotensin system inhibition in a rat model of proteinuric chronic
nephropathy.
In collaboration with the Department of Renal Medicine
The current therapy for chronic proteinuric nephropathy is based on blockade of the reninangiotensin system (RAS) which slows, but may not halt, the progression of disease particularly
when pharmacologic intervention is started late. Besides RAS, vasopressin has been suggested
to play a role in the progression of renal disease by increasing intraglomerular capillary pressure
and stimulation of mesangial cells proliferation. Vasopressin exerts its biological effects by the
interaction with a specific subtype of receptors, including vascular V1 and renal V2 receptors.
Thus, V1 and/or V2 receptor antagonists could be included in a multimodal strategy to
implement renoprotection obtained by blockade of RAS. We studied the effect of a dual V1 and
V2 vasopressin receptor antagonist (RWJ-676070) alone or combined with ACE inhibitor on
proteinuria and renal disease progression in rats with 5/6 nephrectomy starting during overt
nephropathy. This model is characterized by severe hypertension, proteinuria,
glomerulosclerosis, tubulointerstitial damage and progressive renal function deterioration. Our
results demonstrate that RWJ-676070 afforded a partial antiproteinuric effect, which was
enhanced by the addition of ACE inhibitor. Renal function impairment, and glomerular and
tubular changes were partially ameliorated by RWJ-676070. These parameters were
significantly improved by ACE inhibitor and to a greater extent by the combined therapy. The
present findings suggest that vasopressin receptor antagonists combined with ACE inhibitor
could be considered a valid therapeutic approach for those patients who do not completely
benefit by ACE inhibiton.
Laboratory of Immunology and Genetic of Rare Diseases and
Organ Transplantation
The Toll-Interleukin-1 Receptor member Tir8/SIGIRR negatively regulates
adaptive immunity against kidney grafts
Members of the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily mediate
ischemia/reperfusion injury and initiate immune response in transplanted organs. Here we tested
the hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed in
the kidney, modulates immune cell activation underlying kidney rejection. In a mouse model of
fully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraft Tir8 expression was enhanced compared to naïve kidneys. Targeted deletion of Tir8 in the
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graft exerted a powerful anti-tolerogenic action leading to acute rejection. Despite similar levels
of TLR4, IL-1R and their ligands, post-transplant ischemia/reperfusion-induced inflammatory
response was more severe in Tir8-/- than in Tir8+/+ grafts and was followed by expansion and
maturation of resident dendritic cell (DC) precursors. In vitro, Tir8-/- DC precursors acquired
higher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand and
TNF-alpha than Tir8+/+ cells, which may explain the increased frequency of anti-donor
reactive T cells and the block of regulatory T cell formation we found in vivo in recipients of a
Tir8-/- kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in the
kidney. Tir8 expression and/or signalling in donor tissue are envisaged as a novel target for
control of innate immunity and amelioration of graft survival.
Toward MSC in solid organ transplantation: 2008 position paper of the
MISOT study group.
Mesenchymal Stem Cells (MSC) have emerged as a promising cell population for
immunomodulatory therapy. A variety of promising results have been reported in vitro and in
animal models of (auto-) immunity. Notwithstanding these early promising results with MSC
therapy, moving this concept forward clinical application in solid organ transplantation should
be critically assessed by experts in the field. Our initiative focuses on the application of MSC to
solid organ transplantation for the purpose of inducing operational immunologic tolerance or at
least enabling the reduction of pharmacological immunosuppression. For this purpose, we have
formed a study group, MISOT (Mesenchymal Stem Cells in Solid Organ Transplantation,
www.misot.de) to discuss our current base of knowledge and to consider if, and how, to proceed
with ethical clinical trial using MSC. This is the position paper summarizes the
recommendations for early clinical trials and ongoing basic research in the field of
mesenchymal stem cell-induced solid organ graft acceptance--agreed upon on the first meeting
of the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late
2008.
Atypical haemolytic-uremic syndrome
The haemolytic–uremic syndrome is characterized by non immune haemolytic anemia,
thrombocytopenia, and renal impairment. The disorder occurs most frequently in children under
the age of 5 years, with an annual incidence of 6.1 cases per 100,000 children under 5 years, as
compared with an overall incidence of 1 to 2 cases per 100,000. The presentation is generally
heralded by diarrhea, which is often bloody. Most cases (including more than 90% of those in
children) are secondary to infection with Escherichia coli serotypes O157:H7, O111:H8,
O103:H2, O123, O26, or others, which produce Shiga-like toxin (Stx), and several other
bacteria, such as Streptococcus pneumoniae. Approximately 10% of cases of the haemolytic–
uremic syndrome are classified as atypical, since they are not caused by either Stx-producing
bacteria or streptococci. Atypical hemolytic–uremic syndrome has a poor prognosis, with death
rates as high as 25% and progression to end-stage renal disease in half the patients. Research
has linked atypical haemolytic–uremic syndrome to uncontrolled activation of the complement
system. This article reviews current concepts about the pathobiology of this syndrome and its
diagnosis and management.
Thrombomodulin mutations in atypical hemolytic-uremic syndrome
The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia,
thrombocytopenia, and renal failure. The common form of the syndrome is triggered by
infection with Shiga toxin-producing bacteria and has a favourable outcome. The less common
form of the syndrome, called atypical haemolytic-uremic syndrome, accounts for about 10% of
cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of
the patients with atypical haemolytic-uremic syndrome have mutations in genes that regulate the
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complement system. Genetic factors in the remaining cases are unknown. We studied the role of
thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and
cytoprotective properties, in atypical haemolytic-uremic syndrome. We sequenced the entire
thrombomodulin gene (THBD) in 152 patients with atypical haemolytic-uremic syndrome and
in 380 controls. Using purified proteins and cell-expression systems, we investigated whether
thrombomodulin regulates the complement system, and we characterized the mechanisms. We
evaluated the effects of thrombomodulin missense mutations associated with atypical
haemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants
in cultured cells. Of 152 patients with atypical haemolytic-uremic syndrome, 7 unrelated
patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin
binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor Imediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By
promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates
the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin
variants associated with atypical hemolytic-uremic syndrome had diminished capacity to
inactivate C3b and to activate procarboxypeptidase B and were thus less protected from
activated complement. Mutations that impair the function of thrombomodulin occur in about 5%
of patients with atypical haemolytic-uremic syndrome.
Unit of Gene Therapy
Gene therapy to correct Thrombotic Thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura is a thrombotic microangiopathy characterized by
anemia and thrombocytopenia caused by erythrocytes fragmentation in the microcirculation and
by the formation of intravascular thrombi, respectively. The disease manifests prevalent, but not
exclusive, neurologic symptoms and renal dysfunction. TTP patients show deposition of
ultralarge multimers of von Willebrand (vWF) factor due to the deficiency of ADAMTS13
protease, a plasma protein able to cleave VWF secreted from endothelial cells. ADAMTS13
deficiency may be constitutive due to mutations in the corresponding gene, or acquired, due to
the presence of circulating autoantibodies. Plasma infusion is the treatment of choice for
patients with familial TTP, however, it exposes patients to high risk of infections, fluid volume
overload and allergies. These main limitations prompted us to look for an alternative therapy.
One of the project research of the Department is to evaluate if a gene therapy approach is able to
restore ADAMTS13 production in Adamts13-/- knockout mice. We first generated a recombinant
adenoviral vector encoding for human ADAMTS13 and tested its efficacy in vitro. In vivo
experiments on Adamts13-/- mice were subsequently performed. A systemic injection of
adenoviral vector induced transgene expression in liver, kidney, heart, lung, and spleen one
week after injection with concomitant release into the plasma of large amounts of functionally
active ADAMTS13 protein. ADAMTS13 protein persisted in plasma for at least 12 weeks.
Moreover, by mean of an ex vivo thrombogenesis test, we demonstrated that the protein secreted
in the blood of treated mice reduced the area covered by thrombi in respect to blood from
control mice. The use of an adenoviral vector as a gene transfer tool, however, causes the
production of antibodies against both the adenovirus and the transgene that may be responsible
for the reduction in the expression and activity of the recombinant protein in the long term. In
order to reduce the activation of the immune system, we are now evaluating alternative gene
delivery strategies. Moreover, since ADAMTS13 deficiency in mice does not cause TTP , we
are trying to obtain a mouse TTP model to test if gene therapy approach is able to cure the
disease.
Mechanism of cell-to-cell communication between MSc and tubular cells
injury
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In collaboration with the Laboratory of Cell Biology and Xenotransplantation
Recent studies demonstrated that exogenous bone marrow mesenchymal stem cells (MSCs) may
contribute to the recovery of tissue injury in several organs. We demonstrated that
administration of mouse primary bone marrow-derived MSC in a mouse model of cisplatininduced 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.
Further studies of the Department will be performed to characterize the signaling mediators
involved in the mechanism of cell-to-cell communication between MSCs and damage tubular
cells (growth factors, antiinflammatory cytokines and exosomes).
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 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.
Induction of pluripotent stem cells from somatic cells
In collaboration with the Laboratory of Renal Biophysics (Department of Bioengineering)
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 the more safe, because it can avoid the
integration into the house genome. On the basis of these evidences, our group cloned the four
transcription factors in a single plasmid vector that assures the same expression levels for the
four factors in the differentiated cells. In particular, we have chosen to reprogram human adult
dermal fibroblast cells because they are easy to obtain from patients. The final goal of our
research will be to obtain iPS cells from patients affected from rare genetics diseases in order to
correct their pathology.
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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.
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
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 Biophisics, Department of
Biomedical Engineering; 1994-2000 Head, Unit of Inflammatory Mediator of Leucocyte Origin; 1989- 94
Scientist, 1985-89 post-doctoral fellow Mario Negri Institute for Pharmacological Research, Bergamo,
Italy; 1982-83 fellow Laboratory of the Division of Nefrology e Dialysis, Ospedali Riuniti di Bergamo,
Bergamo, Italy
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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 Pathos 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 a MSc in Mechanical Engineering in 1990 at the Oil & Gas Institute in
Ploiesti (Romania). In 1992 he joined the Bioengineering Laboratory at NegriBERGAMO Laboratories.
Main interests: renal research (hemodynamics and remodeling of arteriovenous fistula for vascular access,
morfometrical analysis of glomerular capillaries) and controlled clinical trials (data management and data
analysis); clinical research informatics (local and web-based application development), coordination of IT
activity in the Clinical Research Center for Rare Diseases ‘Aldo e Cele Daccò’, applied clinical
informatics (development and maintenance of Electronic Health Records - EHR).
Roles: since January 2000 is head of the Biomedical Technologies Laboratory, Department of Biomedical
Engineering.
• 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.
• Remuzzi A and Ene-Iordache B. Capillary network structure does not affect theoretical analysis
of glomerular size selectivity. Am J Physiol 268: F972-F979, 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.
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: 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.
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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.
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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.
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):2653-2661.
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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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.
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.
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ACTIVITIES
The Department of Bioengineering conducts research and development in biomedicine, both at
experimental and clinical level. Physiopathological processes are studied through the use of
engineering techniques and to develop innovative treatment strategies. Several lines of research
in basic, applied research and clinical are currently active within the Department . The main
instruments 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; technologies for archiving and processing of
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 hemodynamics in the
development of vascular diseases; 3) development of laboratory techniques for tissue
engineering, 4 ) developement of information systems to manage clinical data and images
generated in the context of controlled clinical trials and in routine clinical practice.
MAIN FINDINGS
We produced evidence demonstrating a possible relationship between the geometry of the
cerebral arterial vessels, hemodynamic conditions and location of cerebral aneurysms. These
findings are opening new perspectives in the understanding of the mechanisms responsible for
this disease.
Demonstration of a significant relationship between morphometric parameters of the renal
parenchyma, quantified through elaboration 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 the proliferation of parietal cells of
Bowman capsule and their migration on the glomerular capillary loops.
Implementation of a web-based system for the management, in compliance with GCP, of
clinical data generated in controlled clinical trials.
Set up a new network of specialists in Nephrology for data collection aimed at monitoring the
quality of treatment of chronic progressive nephropathy in current clinical practice.
Dipartimento di Bioingegneria, Politecnico di Milano, Milano.
Fidia Advanced Biopolymers, Abano Terme, Padova.
Unità di Diabetologia, Ospedali Riuniti, Bergamo.
STMicroelectronics , Agrate Brianza, Milano
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
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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 Lubjana, Ljubljana, Slovenia.
The University of Sheffield, Sheffield, United Kingdom.
International Journal of Artificial Organs, (Andrea Remuzzi)
Annals of Biomedical Engineering
ASME Journal of Biomechanical Engineering
Journal of Vascular Research
Magnetic Resonance in Medicine
Stroke
Journal of the American Society of Nephrology
American Journal of Kidney Diseases
Medical & Biological Engineering & Computing
New England Journal of Medicine
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
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EVENT ORGANIZATION
Seminar: “High resolution micro-CT in biological and biomedical applications", Dr. Jeroen
Hostess, SkyScan (http://www.skyscan.be/home.htm) (seminario organizzato in collaborazione
con Assing S.p.A. - Roma) September, Sala Conferenze Centro Daccò, Ranica, Bergamo.
Seminar: "Uno strumento web-base per la randomizzazione negli studi clinici controllati.
Presentazione del nouvo portale degli studi clinici del centro Daccò" Simone Manini,
September, Sala Conferenze Centro Daccò, Ranica, Bergamo.
Seminar: "Developing regulatory-compliant eletronic case report forms for clinical trials: the
DEMAN rats." Journal of the American Medical Informatics Association, Bogdan EneIordache, May, Sala Conferenze Centro Daccò, Ranica, Bergamo.
Mini Course: Utilizzo del programma per analisi di immagini "ImageJ", Dipartimento
Bioingegneria Luca Antiga, Aprile, Sala conferenze Centro Daccò, Ranica Bergamo.
Seminar: “The Pathobiology of the Saccular Cerebral Artery Aneurysm Rupture and Repair”,
Juhana Frösén, Department of Neurosurgery, Helsinki University Central Hospital, February,
Sala Conferenze Centro Daccò, Ranica, Bergamo.
Course for nephrologists and diabetologists: “La Remission Clinic nella pratica clinica: nuove
prospettive di prevenzione e trattamento per le nefropatie croniche progressive”.
Dicember, Sala Conferenze Centro Daccò, Ranica, Bergamo.
1st Open Clinica European Summit, April 2009, Brussels; Presentations were given by
individuals involved in both industry and academic clinical trials.
Vascular Access Society 6th Congress, April 2009, Roma; Hemodynamics of vascular access:
technical aspects.
The 15th ERCIM Environmental Modelling Group Workshop took place on 27 May 2009
during the ERCIM Spring Days Meeting & 20th Anniversary Celebration, Les Jardins du
Marais Hotel, Paris, France.
2nd ICT Coordinators Day on Project Management in FP7, June 2009, Brussels.
VPH IM2IM Meeting, July 2009, Berlin. 7th Annual HealthGrid International Conference
“Cardiovascular flow, function e tissue Mechanics”, International society for Magnetic
resonance in Medicine ISMRM, September 2009, Sintra Portugal.
ASN 42st Annual Renal Week 2009, November 2009, San Diego, CA.
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Open Information Day – IMI Joint Undertaking, November 2009, Brussels
IPITA-IXA Joint Meeting Venice Italy, October 2009.International pancreas and islet transplant
association.Poster: Regression of diabetic complications by singenically transplanted rat
pancreatic islets.
DEMAND 30th Annual Meeting of the Society for Clinical Trials – Atlanta USA, May 2009
ATTD 2nd International Conference on Advance Technologies & Treatments for Diabetes,
February 2009, Athens, Greece.
WC2009 World Congress Medical on Medical Physics and Biomedical Engineering, September
2009, Munich.
XXVIII Scuola Annuale di Bioingegneria, Bioingegneria per le neuroscienze cognitive,
Università degli studi di Padova, Bressanone Settembre 2009.
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.
Progetto di ricerca - FP6 UE-STEPS "A system approach to tissue engineering products and
processes" FP6-500465
Progetto di ricerca - 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.
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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.
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. 2009; 174(3): 797-807.
Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G, Remuzzi A.
the DEMAND trial. J Am Med Inform Assoc. 2009 16(3):404-408.
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.
Transplantation Proceedings 2009 41, 1797-1800.
Morbelli S, Piccardo A, Villavecchia G, Dessi B, Brugnolo A, Piccini A, Caroli A, Frisoni G,
Ridriguez G, Nobili F. Mapping brain morphological and functional conversion patterns in
amnestic MCI: a voxel-based MRI and FDG-PET study. Eur J Nucl Med Mol Imaging 2009;
37(1): 36-45.
Piccinelli M, Veneziani A, Steinman DA, Remuzzi A, Antiga L. Framework for geometric
analysis of vascular structures: application to cerebral aneurysms. IEEE Trans Med Imaging
2009; 28(8): 1141-55.
Cornolti R, Figliuzzi M, Remuzzi A. Effect of micro-and macroencapsulation on oxygen
consumption by pancreatic islets. Cell Transplant. 2009; 18(2): 195-201.
Casagrande G, Lanzarone E, Miglietta F, Remuzzi A, Fumero R, Costantino ML. Determination
of Cardiovascular Mechanics Evolution in the Presence of the Arteriovenous Fistula. ASAIO J.
2009; 55(5): 484-93.
Gagliardini E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti
L, Remuzzi A, Remuzzi G, Benigni A. Unlike each drug alone, lisinopril if combined with
avosentan promotes regression of renal lesions in experimental diabetes. Am J Physiol Renal
Physiol. 2009; 297(5): F1448-56.
Lee SW, Antiga L, Steinman DA. Correlations among indicators of disturbed flow at the normal
carotid bifurcation. J Biomech Eng. 2009; 131: 061013.
Antiga L, Steinman DA. Rethinking turbolence in blood. Biorheology 2009; 46(2): 77-81.
Caroli A, Frisoni GB. Quantitative evaluation of Alzheimer's disease.
Expert Rev Med Devices 2009; 6(5): 569-588.
Frisoni GB, Lorenzi M, Caroli A, Kemppainen N, Någren K, Rinne JO. In vivo mapping of
amyloid toxicity in Alzheimer disease. Neurology. 2009 Apr 28;72(17):1504-11.
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Nobili F, De Carli F, Frisoni GB, Portet F, Verhey F, Rodriguez G, Caroli A, Touchon J,
Morbelli S, Guerra UP, Dessi B, Brugnolo A, Visser PJ. SPECT Predictors of Cognitive
Decline and Alzheimer's Disease in Mild Cognitive Impairment. J A Dis. 2009;
Duchesne S, Caroli A, Geroldi C, Collins DL, Frisoni GB. Relating one-year cognitive change
in mild cognitive impairment to baseline MRI features. Neuroimage. 2009 Oct 1;47(4):1363-70.
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.
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; 11(12):805-11.
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. To quantify 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 we are developing
three dimensional (3D) reconstruction of tissues by several approaches: one of them is the
vascular corrosion casting technique, using a polyurethane resin, that allows to obtain casts of
the vascular architecture of the glomerular capillary to be analyzed by scanning electron
microscopy. We are also setting up a new technique to study the morphology of the glomerular
capillary and its wall by electron microscopy, based on a combination of an electron beam with
an ionic one, in order to achieve sectioning of samples and acquisition of serial images for 3D
reconstruction of the ultrastructure by mathematical algorithms.
Study of the role of the AcSDKP peptide in the regression of renal damage
induced by angiotensin II blockade
Clinical and experimental studies have documented that lowering proteinuria by
pharmacological interventions retards renal disease progression and even induces
remission. We have recently shown in MWF rats, a genetic model of spontaneous
glomerular damage, that the ACE inhibitor, lisinopril, induces regression of proteinuria
and of existing glomerulosclerosis, ameliorates interstitial damage and stabilizes renal
function even when given in advanced stages of nephropathy. Given the key role of
angiotensin II (Ang II) in renal disease progression, the renoprotective effect of ACE
inhibition has been attributed to the suppression of Ang II formation. However, the
possibility that other substrates that are processed by ACE may contribute to the
therapeutic benefits of ACE inhibition cannot be ruled out.
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Somatic ACE in vertebrate is a zinc metallo peptidyl–dipeptidase that displays activity toward a
broad range of substrates and has two homologous N- and C-terminal active domains. Both
domains contribute to Ang II formation by hydrolysis of angiotensin I and to the inactivation of
bradykinin. Very recently, experiments of gene targeting revealed that the ACE C-terminal
catalytic domain is the main site of angiotensin I cleavage in vivo. N-terminal active domain of
ACE specifically cleaves its natural substrate N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) a
tetrapeptide that reduces inflammation, fibrosis and target organ damage induced by
hypertension. Moreover, the peptide likely induces regeneration of myocardial endothelial cells.
Ac-SDKP is rapidly cleared from plasma by two different mechanisms: enzymatic cleavage of
the Asp-Lys peptide bound by ACE and by glomerular filtration. Basing on the above evidence
we have pursued a study aimed at evaluating whether the ACE inhibitor protects from advanced
nephropathy also through the regulation of endogenous Ac-SDKP. The peptide levels will be
measured in the plasma, urine, and kidney by EIA assay and correlated with the extent of
collagen deposition and inflammation.
Application of confocal microscopy to the study of cells and tissues
Fluorescent probes to investigate the distribution and co-localization of proteins and other
specific antigens in cell monolayers and tissue specimens are commonly used in the majority of
experimental applications. Bidimensional images are not of high resolution to provide correct
information, thus the use of 3D reconstruction of fluorescent signal becomes mandatory. These
problems can not be solved by the classic fluorescent microscopy that has some limitations. For
these reasons we have optimized the laser confocal microscopy by using the LSM510 META
microscope from Zeiss (Germany). The microscope is equipped with four laser lines that excite
the sample within the whole visible spectrum plus the characteristic “META scan head” that
allow to analyze the emission spectrum of different fluorophores to optimally separate them.
The instrument is characterized by and used for its high specificity and for the excellence of the
revealed and elaborated signal.
Laboratory of Biomedical Technologies
Remission Clinic Network
Many forms of chronic kidney diseases progress with a constant rate of glomerular filtration
rate towards the end stage renal disease (ESRD). Often, even when the responsible cause for the
onset of the disease is removed or disappears, we are witnessing the progressive loss of renal
function. 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 treatment of hypertension by using drugs that
reduce the urinary excretion of proteins (ACE-inhibitors), are effective in reducing the rate of
decline of glomerular filtration rate (GFR) and even in obtaining stabilization or recovery of
GFR. These kind of treatments allow to delay the start of dialysis or need of kidney transplant in
subjects with CKD. It is therefore essential to assess to what extent the results obtained in
controlled clinical trials may actually be achieved also in clinical practice. With this purpose, in
collaboration with the Renal Department, we started a quality control and monitoring
programme of patients affected by proteinuric nephropathies (Remision Clinic protocol) aimed
at verifying that 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
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patients with chronic kidney diseases treated according to the guidelines of Remission Clinic
protocol. In addition, our tool allows report analyses and quality controls of this clinical activity
to assess in what extent adherence to the protocol factors, may itself affect the progression of
nephropathy in time.
KDDC – a coordinating 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 problems about 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 center, allow us to have a
general overview on the health of population under study. The prevention program is underway
and we have already collected data from participating centres from Nepal, Mongolia, India,
China, Moldova, Bosnia-Herzegovina, Bolivia, Panama and Mozambique. Initial results on
screening on several thousands of subjects, confirm the need to proceed with prevention
programs in theses countries. Through the activity of KDDC it is possible to monitor the course
of the prevention programs and to tailor them to fit the needs of each participating country.
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 with respect to the GCP (Good Clinical
Practice) guidelines and require high quality of data. 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. REIN, BENEDICT MYSS REIN2, DKG are just
few of the trials concluded successfully and published in prestigious medical journals. This
accomplishment is, in part, due to the contribution of our Lab. For the DEMAND study we have
developed an innovative electronic CRFs based on laptop computers. We are implementing 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-tools 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 centers, rare diseases archive, associations of patients 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) was developed by LI in
collaboration with our group. SMR application is using web-based technology and can be used
jointly with the health patient card. It is actually in use in almost all centres dedicated for rare
diseases in Lombardy. Our laboratory is involved in the maintenance of SMR, statistical
analyses of registry data and creation of a minimal set of data that are shared at national level by
the Istituto Superiore di Sanità (ISS).
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. Two
typical examples of such relationship are atherosclerosis and intracranial aneurysm disease. In
atherosclerosis, a pathology leading to lipid-rich and fibrotic plaque formation in artery walls,
lesions tend to form mainly in correspondence to bifurcations (e.g. carotid bifurcation) and great
curvature tracts (e.g. coronary arteries). In intracranial aneurysm disease, characterized by the
formation of one (or more) artery wall protrusions in the cerebral arterial circulation, cerebral
aneurysms tend to locate at the distal wall of main bifurcations and at the exteral wall of
segments characterized by large curvature.
Besides being involved in pathogenesis, hemodynamics also plays a role at a mechanical level
for the determination of atherosclerotic plaque rupture, responsible for heart attacks and stroke,
or cerebral aneurysm rupture with consequent intracranial hemorrhage.
It has been experimentally shown that endothelial cells (lining vessel walls) and smooth muscle
cells (the vasoactive component of the wall) exposed to flow exhibit changes in gene
expression, cytoskeleton reorganization and permeability according to the characteristics of the
imposed flow (e.g. laminar vs turbulent).
In spite of this data supporting the hypothesis of a close relationship between hemodynamics
and vascular pathology, the nature of such relationship is still under scrutiny, mainly due to the
difficulty of measuring in-vivo hemodynamics-related quantities.
Thanks to innovative technologies developed during the last few years in the medical imaging
and mathematical modelling 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
Union within the Seventh Framework Programme, starting from 2008, aimed at improving the
functionality of vascular access in hemodialysis patients, for which the Department is the
coordinator centre.
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Theoretical and experimental study of filtration of 'albumin in the kidney
The Department is studying the mechanisms responsible for glomerular filtration of albumin.
Recently we have been dedicated to the experimental measurement and theoretical modelling of
filtration of albumin and its concentration at the renal tubule. In an experimental model of
nephropathy, we studied the variations in the concentration of albumin in the tubules and
studied the effect of treatment with an ACE inhibitor. The combination of the experimental
approach with the theoretical modelling allowed to elucidate an aspect of renal pathophysiology
still not highlighted.
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 is involved
in three clinical trials one of which funded by the Polycystic Kidney Foundation, aimed at
reducing the overall kidney cyst volume with the use of novel therapies. In this context, CT
image quantification has recently led to the discovery of a high correlation between a specific
portion of polycystic kidney tissue and renal function, 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.
Development of biomedical image analysis and computational modelling
tools
The employment of quantitative imaging and mathematical modelling 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 Modelling 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.
Development of devices for the transplantation of immunoisolated islets
The project’s main objective is to develop an immunisolation device for pancreatic
islets that can be implanted in diabetic patients permitting allo-islet transplantation
without the use of pharmacological immunosuppression and avoiding allosensitization
of the patient. The study started from the design and characterization of the semipermeable membrane used for the device construction. 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 tubular membranes of polyvinyl alcohol. The aims of our
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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 rats with chemically induced diabetes. For
this study, we used three groups of rats: healthy controls, diabetics and diabetics with
transplanted islet two months after induction of diabetes. At this time, the behavioural tests for
determination of thermal and mechanical nociceptive threshold and the measurement of nerve
conduction velocity in the nerves of the tail (NCV) show a significant neuropathic damage. At
the end of the experiment a morphometrical analysis of the number of myocytes in the heart was
carried out. 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
observed in diabetic rats return to values similar to the control in transplanted rats. The loss of
myocytes and their hypertrophy is reduced after islet transplantation. In conclusion, the
transplantation of pancreatic islets not only normalizes blood glycemia levels in diabetic
animals, but also stop the neuropathy getting worse and improves cardiovascular complications.
(In collaboration with the Department of Biochemistry and Molecular Pharmacology and the
Department of Cardiovascular Research).
Mesenchymal stem cells improve vascolarization in pancreatic islet
transplantation
Pancreatic islet transplantation represents a cure for type I diabetes but there are still big
limitations including the lack of metabolic capacity of transplanted islets in the long-run. This
phenomenon must be mainly attributed to delayed and insufficient islet revascularization that
can deprive newly transplanted islets of oxygen, resulting in permanent cell death. Promotion of
islet revascularization through locally increased expression of growth factors, such as vascular
endothelial growth factor (VEGF), could improve the efficiency of islet transplantation. On this
basis, we elected to investigate whether rat MSCs co-transplanted with pancreatic islets may
serve as cell therapy to promote therapeutic angiogenesis ultimately leading to an effective
metabolic activity of islet grafts. 2,000 syngenic islets alone or in combination with MSCs were
transplanted under the kidney capsules of diabetic Lewis rats. Animals transplanted with islets
alone never reached normoglycemia. In contrast, in rats transplanted with islets and MSCs,
glycemia gradually fell after transplantation and normoglycemia was maintained for a long
time. In transplanted animals, islet vascularization was quantified by morphometrical analysis.
Mean capillary density was significantly increased in islet co-transplanted with MSCs indicating
that co-transplantation of MSCs with pancreatic islets improves islet graft function by
promoting graft vascularization. (In collaboration with Laboratory of Cellular Biology and
Xenotransplantation).
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
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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 d 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, The structures were implanted into the subcutaneous
tissue of rat and retrieved 15 days after transplantation for morphological evaluation of tissue.
The analysis by light microscopy showed that fibroin tissue was completely enveloped in a very
thick fibrous capsule, with cells infiltrating into the fibers of fibroin. These data confirmed the
biocompatibility of fibroin. The vascular prosthesis will be implanted in small animals (rats) to
replace abdominal aorta and, therefore, to evaluate the functionality of the prosthesis.
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
maintenance 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)
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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 Pharmacology and Pharmacogenetics
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, 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, EneIordache 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.
• 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.
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•
•
•
•
•
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, 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): 960-7.
• 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
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•
•
•
•
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, 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.
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
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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
cyclosporine-related 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).
•
Rigotti P, Ekser B, Furian L, Baldan N, Valente ML, Boschiero L, Motterlini N, Perna A, Remuzzi G, Ruggenenti P.
Outcome of renal transplantation from very old donors, N Engl J Med, 2009; 360 (14): 1464-5.
•
Vegter S, Perna A, Hiddema W, Ruggenenti P, Remuzzi G, Navis G, Postma MJ. Cost-effectiveness of ACE inhibitor
therapy to prevent dialysis in nondiabetic nephropathy: influence of the ACE insertion/deletion polymorphism.
Pharmacogenet Genomics, 2009. 19(9): 695-703.
•
Cravedi P, Perna A, Ruggenenti P, Remuzzi G. Mycophenolate Mofetil Versus Azathioprine in Organ Transplantation.
Am J Transplant, 2009; 9 (12): 2856-7.
•
De Cosmo S, Motterlini N, Prudente S, Pellegrini F, Trevisan R, Bossi A, Remuzzi G, Trischitta V, Ruggenenti P;
BENEDICT Study Group. Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on newonset microalbuminuria in type 2 diabetes: evidence from BENEDICT. Diabetes, 2009 Dec; 58 (12): 2920-9.
•
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.
•
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
cyclosporine-related adverse events and kidney allograft outcome. J Am Soc Nephrol, 2009 Jun; 20 (6): 1404-15.
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.
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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 insulin), 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, 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): 162934.
• 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.
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.
•
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.
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•
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.
ACTIVITIES
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 six
Laboratories and three 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:
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
Molecular 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.
MAIN FINDINGS
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
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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.
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.
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.
Lombardia
- AO Bolognini Seriate, Ospedale Bolognini, Seriate (BG)
- AO Bolognini Seriate, Ospedale Briolini, Gazzaniga (BG)
- AO Bolognini Seriate, Ospedale M. O. A. Locatelli, Piario (BG)
- AO Bolognini Seriate, Ospedale Pesenti Fenaroli, Alzano Lombardo (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
- 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 Istituti Ospedalieri, Cremona
- AO Lecco, Presidio Ospedaliero Alessandro Manzoni, Lecco
- AO Ospedale di Lecco, Presidio di Merate Leopoldo Mandic, Merate (LC)
- AO Desio e Vimercate, Ospedale di Desio (MI)
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-
AO Melegnano, Presidio Ospedaliero di Vizzolo Predabissi (MI)
AO e Polo Universitario, Ospedale Luigi Sacco, Milano
AO Ospedale Civile di Legnano, Ospedale Cesare Cantù, Abbiategrasso (MI)
AO Guido Salvini, Ospedale Caduti Bollatesi, Bollate (MI)
AO Ospedale Fatebenefratelli e Oftalmico, Milano
AO Ospedale Niguarda Cà Granda, Milano
AO Ospedale San Carlo Borromeo, Milano
AO San Gerardo, Ospedale Bassini, Cinisello Balsamo (MI)
AO San Gerardo, Ospedale San Gerardo, Monza (MI)
ASL Provincia di Milano 2, Ospedale A. Uboldo, Cernusco sul Naviglio (MI)
Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Clinica
Pediatrica Giuditta e Demetrio De Marchi, Milano
Gruppo Ospedaliero San Donato, Istituti Clinici Zucchi, Monza (MI)
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)
IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano
AO Desio e Vimercate, Ospedale di Vimercate (MB)
AO Ospedale Carlo Poma, Ospedale Civile di Asola, Asola (MN)
AO Pavia, Ospedale Civile di Voghera, Voghera (PV)
Università degli Studi di Pavia, Dipartimento di Medicina Interna e Terapia Medica, Pavia
AO Valtellina e Valchiavenna, Ospedale di Sondrio, Sondrio
AO Universitaria, Ospedale di Circolo e Fondazione Macchi, Varese
Piemonte
- ASO Santa Croce e Carli, Cuneo
- AO Universitaria Maggiore della Carità, Novara
- AO Ospedale Infantile Regina Margherita-Sant’Anna di Torino, Ospedale Infantile Regina
Margherita, Torino
- AO Ordine Mauriziano, Ospedale Mauriziano Umberto I, Torino
- AO Universitaria, Ospedale San Giovanni Battista, Torino
- ASL TO1, Presidio Ospedaliero Martini, Torino
- ASL TO4, Ospedale di Ivrea, Ivrea (TO)
- Ospedale Luigi Einaudi, Torino
Veneto, Trentino Alto-Adige e Friuli Venezia Giulia
- AO Padova, Ospedale Civile, Padova
- AO Padova, Ospedale Giustinianeo, Padova
- AULSS 17 Este, Ospedale di Monselice, Monselice (PD)
- Policlinico Abano Terme, Presidio Ospedaliero Regione Veneto, Abano Terme (PD)
- Università degli Studi di Padova, Istituto di Anatomia Patologica, Padova
- AULSS 4 Alto-Vicentino, Ospedale San Camillo de Lellis, Schio (VI)
- AULSS 8 Asolo, Ospedale San Giacomo Apostolo, Castelfranco Veneto, Treviso
- AULSS 9 di Treviso, Ospedale Regionale Santa Maria dei Battuti, Treviso
- AULSS 9 di Treviso, Ospedale Santa Maria di Ca' Foncello, Treviso
- AULSS 12 Veneziana, Ospedale Civile Umberto I, Mestre (VE)
- AULSS 12 Veneziana, Ospedale Civile Maggiore-Borgo Trento, Verona
- AULSS 12 Veneziana, Ospedale Policlinico Gianbattista Rossi-Borgo Roma, Verona
- AULSS 6 di Vicenza, Ospedale San Bortolo, Vicenza
- AO Universistaria degli Ospedali Riuniti di Trieste, Ospedale di Cattinara, Trieste
- IRCCS materno-infantile Burlo Garofalo, Trieste
- ASS 4 Medio Frìuli, Ospedale di San Daniele, San Daniele del Frìuli (UD)
ANNUAL REPORT
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2009
IRFMN
-
Università degli Studi di Udine, Centro Trapianti Fegato-Rene-Pancreas, Udine
AULSS 1, Ospedale Civile di Belluno, Belluno
APSS, Presidio Ospedaliero Santa Chiara, Trento
Liguria, Emilia Romagna e Toscana
- AO Universitaria San Martino, Genova
- IRCCS Pediatrico Istituto Giannina Gaslini, Genova
- AO Universitaria di Bologna, Policlinico Sant’Orsola-Malpighi, Bologna
- AUSL Bologna, Ospedale Maggiore, Bologna
- AUSL Imola, Ospedale Civile, Imola (BO)
- AO Universitaria di Ferrara, Arcispedale Sant’Anna, Ferrara
- AUSL Forlì, Ospedale G. B. Morgagni - L. Pierantoni, Forlì
- AO Universitaria di Modena, Policlinico, Modena
- AO Universitaria di Parma, Ospedale di Parma, Parma
- AUSL Ravenna, Ospedale Santa Maria delle Croci, Ravenna
- AUSL Ravenna, Ospedale di Ravenna, Ravenna
- AO Reggio Emilia, Arcispedale Santa Maria Nuova, Reggio Emilia
- AUSL Rimini, Ospedale Infermi, Rimini
- AS Firenze, Ospedale Nuovo San Giovanni di Dio, Firenze
- AS Firenze, Ospedale Santa Maria Annunziata, Bagno a Ripoli (FI)
- AO Universitaria Careggi, Firenze
- AO Universitaria, Ospedale Pediatrico Meyer, Firenze
- AUSL 11 Empoli, Ospedale degli Infermi San Miniato, San Miniato (FI)
- AUSL 2 Lucca, Ospedale Campo di Marte, Lucca
- AO Universitaria Pisana, Stabilimento Ospedaliero di Cisanello, Cisanello (PI)
- AO Universitaria Pisana, Ospedale Santa Chiara, Pisa
- AUSL 3 Pistoia, Ospedale del Ceppo, Pistoia
Marche
- AO Universitaria Ospedali Riuniti, Ospedale Umberto I - G.M. Lancisi - G. Salesi, Ancona
- IRCCS Istituto Nazionale di Ricovero e Cura per Anziani, Ancona
- ASUR Zona Territoriale 13, Ospedale Mazzoni, Ascoli Piceno
- AO San Salvatore, Pesaro
Lazio, Basilicata e Campania
- AO San Camillo-Forlanini, Ospedale San Camillo, Roma
- ASL Roma H, Ospedale di Anzio, Anzio (RM)
- IRCCS Pediatrico Bambino Gesù, Roma
- Ospedale Policlinico Umberto I, Roma
- Ospedale San Giovanni Calibita Fatebenefratelli, Roma
- Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli, Roma
- Università La Sapienza, Dipartimento di Biopatologia Umana, Roma
- AUSL Latina, Presidio di Formia, Latina
- AUSL Rieti, Rieti
- AUSL Viterbo, Ospedale Grande degli Infermi, Viterbo
- ASL Matera, Ospedale Riuniti, Matera
- AO Ospedale San Giuseppe Moscati, Avellino
- AO Cardarelli, Napoli
- AO Ospedale Monaldi, Napoli
- AO Sant’Anna e San Sebastiano, Ospedale Civile, Caserta (NA)
- Università Azienda Ospedaliera Universitaria Federico II, Napoli
- Università Azienda Ospedaliera Universitaria Federico II, Policlinico Nuovo, Napoli
ANNUAL REPORT
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-
AO Universitaria di Salerno, Ospedali Riuniti San Giovanni di Dio e Ruggi d’Aragona,
Salerno
Abruzzo
- Ospedale Civile San Massimo, Penne (PE)
- ASL Chieti, Ospedale G. Bernabeo, Ortona (CH)
- ASL Teramo, Presidio Ospedaliero Giuseppe Mazzini, Teramo
Puglia, Calabria, Sicilia e Sardegna
- AO Pugliese Ciaccio, Ospedale Pugliese Ciaccio, Catanzaro
- AO Cosenza, Ospedale Civile dell'Annunziata, Cosenza
- AS 3 Rossano, Ospedale Civile Nicola Giannettasio, Rossano (CS)
- AO Bianchi-Melacrino-Morelli, Reggio Calabria
- CNR Reggio Calabria, Reggio Calabria
- 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 Ospedali Riuniti Villa Sofia-Cervello, Ospedale Vincenzo Cervello, Palermo
- AO Universitaria Policlinico Paolo Giaccone, Università degli Studi, Palermo
- Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IsMeTT), Palermo
- ASP 7 Ragusa, Ospedale Maggiore, Modica (RG)
- Azienda Ospedaliera, Ospedale Umberto I, Siracusa
- AO Universitaria Consorziale Policlinico di Bari, Ospedale Giovanni XXIII, Bari
- Ospedale Generale Regionale Francesco Miulli, Acquaviva delle Fonti (BA)
- Policlinico di Bari, Ospedale Pediatrico Giovanni XXIII, Bari
- AO Universitaria di Foggia, Ospedali Riuniti, Foggia
- IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG)
- AUSL Le/1, Ospedale Vito Fazzi, Lecce
- ASL Taranto, Ospedale di Martina Franca, Martina Franca (TA)
- AO Brotzu, Ospedale San Michele, Cagliari
- Università degli Studi di Cagliari, Istituto di Clinica e Biologia dell’Età Evolutiva, 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
- ASL Sassari, Ospedale Antonio Segni, Ozieri (SS)
- ASL Sassari, Ospedale Civle SS. Annunziata, Sassari
- Policlinico Sassarese, Sassari
Umbria
- AO Perugia, Perugia
-
University Medical Center, Ljubljana Slovenia
-
University Hospital Ziekenhuius, Edegem Antwerpen, Belgium
Clinique de Nephrologie-Dialyse Chu Brugmann, Bruxelles, Belgium
University Ziekenhuius Gent, Gent, Belgium
ANNUAL REPORT
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2009
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U.Z. Gasthuisberg, Leuven, Belgium
General Hospital Maria Middelares, Sint Niklaas, Belgium
-
University of Groningen, AV Groningen, The Netherlands
Academisch Ziekenhuis, Maastricht, The Netherlands
-
Thracian University, Stara Zagora, Bulgaria
-
The Birmingham Children's Hospital, Birmingham, UK
Guy’s Hospital, London, UK
Manchester Children's Hospital, Manchester, UK
Nottingham City Hospital, Nottingham, UK
-
Aalborg Hospital, Aalborg, Denmark
Nephrological Department, University of Copenaghen, Copenaghen, Denmark
Steno Diabetes Center, Gentofte, Denmark
Department of Nephrology, Odense University Hospital, Odense, Denmark
-
Department of Nephrology, Sahlgrenska University Hospital, Goteborg, Sweden
-
Ospedale San Giovanni, Bellinzona, Switzerland
-
Carl Thiem Klinikum, Cottbus, Germany
Klinikum der Johann Wolfgang, Frankfurt am Main, Germany
Arbeitsgruppe fyr Biomolekulare Medizin, Hamburg, Germany
Univeristatklinik Heidelberg, Heidelberg, Germany
Medizinische Klinik, Mannheim, Germany
Luitpold Krankenhaus Med. Universitatklinik/Dialyse, Wurzburg, Germany
-
Fundacion Jimenez Diaz, Madrid, Spain
Hospital 12 de Octubre, Madrid, Spain
Hospital Clinico Martin Logas, Madrid, Spain
Hospital Gregorio Maranon, Madrid, Spain
Hospital La Paz, Madrid, Spain
Hospital Ntra Sra. de Sonsoles, Avila, Spain
Hospital Puerta de Hierro, Madrid, Spain
Hospital Ramon y Cajal, Madrid, Spain
Hospital Severo Ochoa, Leganes, Madrid, Spain
Hospital Universitario de Canarias, Tenerife, Spain
Hospital Universitario de Tarragona Joan XXIII, Tarragona, Spain
Hospitalet de Llobregat, Institut Català de la Salut, Barcellona, Spain
-
Hospital Garcia de Orta, Almada, Portugal
-
Department of Pharmacy, Unit of PharmacoEpidemiology & PharmacoEconomics,
University Medical Center Groningen, Groningen, The Netherlands
GENomic stratEgies for treatment and prevention of Cardiovascular death in Uraemia and
end-stage REnal disease (GENECURE) University Medical Center Groningen, Groningen,
The Netherlands
-
Department of Nephrology, University of Wien, Wien, Austria
ANNUAL REPORT
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Moscow State University of Medicine and Dentistry, Mosca, Russian Federation
-
Chişinău Hospital, Chişinău, Moldavia
-
Damanhour Medical National Institute, Damanhour, Beheira, Egypt
-
Health Sciences University, Ulaanbaator, Mongolia
-
BP Kerala Institute of Health, Dharan, Nepal
-
Brigham & Women's Hospital, Boston, USA
CKD Prognosis Consortium, Department of Epidemiology, Johns Hopkins Bloomberg
School of Public Health, Baltimore, MD, USA
Hennepin County Medical Center, Minneapolis, USA
SIU School of Medicine, Springfield, USA
-
Complejo Hosp Metropolitano de la Caja de Seguro Social, Panama City, Panama
-
The Toronto Hospital, Toronto, Canada
-
INCUCAI, Buenos Aires, Argentina
Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
-
Hospital Juan XXIII, La Paz, Bolivia
-
Hospital Regional de Valdivia, Valdivia, Cile
Istituto de Medicina – Universidad Austral de Chile, Valdivia, Cile
-
Soroka Medical Center, Beer Sheva, Israel
EDITORAIL BOARD MEMBERSHIP
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 Pharmacologica Sinica
American Journal of Kidney Diseases
American Journal of Transplantation
American Transplant Journal
Archives of Medical Science
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IRFMN
Clinical Journal of the American Society of Nephrology (CJASN)
International Journal of Clinical Practice
Journal of the American Society of Nephrology (JASN)
Lancet
Nephrology Dialysis and Transplantation
Nephron Clinical Practice
Transplantation
Transplant International
”Trapianto di pancreas o solo delle isole?”. In “Bergamo, i trapianti e Giuseppe
Locatelli”. Bergamo, Italy. March 14th, 2009.
“Studio randomizzato, prospettico, multicentrico, double-blinded per valutare l’efficacia
e la sicurezza della Propionill-carnitina nella prevenzione della disfunzione posttrapianto del graft in riceventi di trapianto renale ad alto rischio di ritardata ripresa
funzionale“. In the 2nd Meeting “Scientific Clubs Fair & Exhibition della Società
Italiana di Nefrologia”. Roma, Italy. March 23 th-24 th, 2009.
“Prevention and treatment of diabetic nephropathy”. In “XXV Congreso Internacional
de Medicina ITESM”. Monterrey, Mexico. April 16 th-18 th. 2009.
“La modulazione del continuum cardiorenale, microalbuminuria e rischio cardiovascolare”. In “Congresso Nazionale Associazioni Regionali Cardiologi Ambulatoriali
(A.R.C.A.)”. Sorrento, Italy. May 13th-16th, 2009.
“Transplantation”. In “CNE Course of World Congress of Nephrology”. Milano, Italy.
May 25th, 2009.
“Clinical and therapeutic aspects on cystic diseases”. In “5th international course on
genetics and renal diseases”. Genova, Italy. May 29th, 2009.
“Immunosuppressive drugs in renal transplantation”. In “Scuola di Specializzazione in
Nefrologia dell’Università degli Studi di Firenze”. Firenze, Italy. June 9th, 2009.
“Trials clinici con terapie innovative”. Colli del Tronto (Ascoli Piceno), Italy. June 13 th,
2009.
”Diabetic Glomerulopathy: Pathogenesis, Mechanisms of Progression and
Management”. In the 15th “Nantes/Actualités/Transplantation (N.A.T.)”. Nantes,
France. June 18th-19th, 2009.
“The protection of the kidney with reduced mass”. In “12th International Symposium on
Perinatal Nephrology”. Brescia, Italy. June 26th-27th, 2009.
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“Albuminuria/proteinuria as risk factors fo CKD progression”. In “1st International
Course in Nephrology, prevention and management of CKD”. La Paz, Bolivia. August
20th, 2009.
“The ISN COMGAN prevention programs for emerging countries”. In “1st
International Course in Nephrology, prevention and management of CKD”. La Paz,
Bolivia. August 20th, 2009.
“Remission and regression of proteinuric nephropathies”. In “1st International Course in
Nephrology, prevention and management of CKD”. La Paz, Bolivia. August 21st, 2009.
“Therapeutic perspectives in polycystic kidney disease”. In “Advances in therapy in
nephrology dialysis and Transplantation Congress”. Lucca, Italy. September 12th, 2009.
“Regression of chronic renal disease and the case of kidney self repairing” and “TTP
and HUS: are they separate diseases? Vitamina D e proteinuria”. In “XXVII Congress
& XLIII Annual Meeting”. México City, Mexico. September 12th-14th, 2009.
“Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference”. London,
England. October 4th-6th, 2009.
“Terapia della malattia policistica del rene autosomica dominante”. In the “50th Congresso
Nazionale della Società Italiana di Nefrologia”. Bologna, Italy. October 8th, 2009.
“Vitamina D e proteinuria”. In “Corso Residenziale Vitamina D e Analoghi”. Torino,
Italy. October 20th-21st, 2009.
“Immunosuppression minimization: less side effects, more prolonged graft survival?”.
In “WWVI Congreso conjunto Sociedades Chilenas de Nefrología Hipertensíon y
Transplantes”. Puerto Vara, Chile. November 5th, 2009.
“Remission/regression of chronic proteinuric nephropathies”. In “WWVI Congreso
conjunto Sociedades Chilenas de Nefrología Hipertensíon y Transplantes”. Puerto Vara,
Chile. November 5th, 2009.
“Inducing transplant tolerance: progress and challenges”. In “WWVI Congreso conjunto
Sociedades Chilenas de Nefrología Hipertensíon y Transplantes”. Puerto Vara, Chile.
November 5th, 2009.
“L’attività di farmacovigilanza per i promotori no-profit. L’esperienza del Centro di Ricerche
Cliniche Aldo e Cele Daccò.” In “Master di I° livello in Ricerca Clinica” dell’Università degli
Studi di Milano. Milano, Italy. November 11th, 2009.
“Remission/regression of chronic proteinuric nephropathies”. In “ISN COMGAN
Course”. Dharan, Nepal. DEcember, 2009.
“Hemolytic uremic syndrome” al “ISN COMGAN Course”. Dharan, Nepal. DEcember,
2009.
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“Immunosuppressive regimens for kidney transplantation affordable for emerging
countries”. In “ISN COMGAN Course”. Dharan, Nepal. DEcember, 2009.
“Quali dati per disegnare uno studio clinico”. In “Corso Sperimentazione Clinica e
Monitoraggio”.Torino, Italy. Dicember 10th, 2009.
“L’estensione del network: la Remission Clinic internazionale”. In “La Remission Clinic nella
pratica clinica: nuove prospettive di prevenzione e trattamento per le nefropatie croniche
progressive”. Ranica (Bergamo), Italy. DEcember 12th, 2009.
AIFA (Agenzia Italiana del Farmaco)
International Society of Nephrology (ISN)
Istituto Superiore di Sanità (ISS)
Regione Puglia
Università degli Studi di Firenze / Regione Toscana
Abbott GmbH & Co.
AstraZeneca SpA
ACRAF Spa (Aziende Chimiche Riunite Angelini Francesco)
Baxter SpA
Boheringer Ingelheim Italia SpA
Genzyme Europe BV
Sanofi-Aventis SpA
Sigma-Tau Industrie Farmaceutiche Riunite SpA
Solvay Pharmaceuticals
Cravedi P, Perna A, Ruggenenti P, Remuzzi G. Mycophenolate mofetil versus azathioprine in
organ transplantation. Am J Transplant. 2009 Dec; 9 (12): 2856-7.
De Cosmo S, Motterlini N, Prudente S, Pellegrini F, Trevisan R, Bossi A, Remuzzi G, Trischitta
V, Ruggenenti P; BENEDICT Study Group. Impact of the PPAR-gamma2 Pro12Ala
polymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 diabetes:
evidence from BENEDICT. Diabetes. 2009 Dec; 58 (12): 2920-9.
Vegter S, Perna A, Hiddema W, Ruggenenti P, Remuzzi G, Navis G, Postma MJ. Costeffectiveness of ACE inhibitor therapy to prevent dialysis in nondiabetic nephropathy: influence
of the ACE insertion/deletion polymorphism. Pharmacogenet Genomics. 2009 Sep; 19 (9): 695703.
Ruggenenti P, Remuzzi G. Proteinuria: Is the ONTARGET renal substudy actually off target?
Nat Rev Nephrol. 2009 Aug; 5 (8): 436-7.
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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.
Ruggenenti P, Cravedi P, Remuzzi G. Proteinuria: Increased angiotensin-receptor blocking is not
the first option. Nat Rev Nephrol. 2009 Jul; 5 (7): 367-8.
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 cyclosporine-related adverse events and
kidney allograft outcome. J Am Soc Nephrol. 2009 Jun; 20 (6): 1404-15.
Cravedi P, Ruggenenti P, Remuzzi G. Sirolimus to replace calcineurin inhibitors? Too early yet.
Lancet. 2009 Apr 11; 373 (9671): 1235-6.
Rigotti P, Ekser B, Furian L, Baldan N, Valente ML, Boschiero L, Motterlini N, Perna A,
Remuzzi G, Ruggenenti P. Outcome of renal transplantation from very old donors. N Engl J
Med. 2009 Apr 2; 360 (14): 1464-5.
Cravedi P, Ruggenenti P, Remuzzi G. Intensified inhibition of renin-angiotensin system: a way
to improve renal protection? Curr Hypertens Rep. 2009 Apr; 11 (2): 118-24.
Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G, Remuzzi A.
the demand trial. J Am Med Inform Assoc. 2009 May-Jun; 16 (3): 404-8.
Cravedi P, Ruggenenti P, Mingardi G, Sghirlanzoni MC, Remuzzi G. Thrice-weekly in-center
nocturnal hemodialysis: an effective strategy to optimize chronic dialysis therapy. Int J Artif
Organs. 2009 Jan; 32 (1): 12-9.
Saland JM, Ruggenenti P, Remuzzi G; Consensus Study Group. Liver-kidney transplantation to
cure atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2009 May; 20 (5): 940-9.
Ruggenenti P, Cravedi P, Remuzzi G. Rituximab for membranous nephropathy and immune
disease: less might be enough. Nat Clin Pract Nephrol. 2009 Feb; 5 (2): 76-7.
Warnock DG, Remuzzi G, Brenner BM, Levin A, Wanner C. Introduction to Focus on Fabry
Nephropathy: Biomarkers, Progression, and Disease Severity. Clin J Am Soc Nephrol. 2009 Dec
17.
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.
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.
Remuzzi G, Chiaramonte S, Perico N, Ronco C. Humoral immunity in kidney transplantation:
what clinicians need to know. Preface. Contrib Nephrol. 2009; 162: vii-ix.
Cortinovis M, Perico N, Cattaneo D, Remuzzi G. Aldosterone and progression of kidney disease.
Ther Adv Cardiovasc Dis. 2009 Apr; 3 (2): 133-43.
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Perico N, Cattaneo D, Bikbov B, Remuzzi G. Hepatitis C infection and chronic renal diseases.
Clin J Am Soc Nephrol. 2009 Jan; 4 (1): 207-20.
Perico N, Cattaneo D, Remuzzi G. Kidney injury molecule 1: in search of biomarkers of chronic
tubulointerstitial damage and disease progression. Am J Kidney Dis. 2009 Jan; 53 (1): 1-4.
Saland JM, Ruggenenti P, Remuzzi G; Consensus Study Group. Liver-kidney transplantation to
cure atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2009 May; 20 (5): 940-9.
Saland JM, Shneider BL, Bromberg JS, Shi PA, Ward SC, Magid MS, Benchimol C, Seikaly
MG, Emre SH, Bresin E, Remuzzi G. Successful split liver-kidney transplant for factor H
associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009 Jan; 4 (1): 201-6.
RESEARCH ACTIVITIES
Laboratory of Biostatistics
DElapril and MAnidipine for Nephroprotection in Diabetes (DEMAND)
clinical trial: final analyses
The DEMAND study is a multicenter, double-blind, placebo-controlled, randomized trial
assessing whether angiotensin-converting-enzyme inhibitors and third-generation
dihydropyridine calcium-channel-blockers ameliorate chronic complications in hypertensive
type 2 diabetic patients without nephropathy. Three-hundred-eighty patients were randomized to
at least three-year treatment with manidipine (10 mg/day) plus delapril (30 mg/day), delapril (30
mg/day), or placebo. Target blood pressure was 120/80 mmHg. Primary comparison was
between combined therapy and placebo. During 2009 we performed statistical analysis of final
data.
DElapril and MAnidipine for Nephroprotection in Diabetes (DEMAND) –
Neuropathy substudy: final analyses
A total of 243 subjects were included in the DEMAND – Neuropathy substudy. Peripheral
nerve involvement at inclusion and 3 years was centrally graded by examiners blinded to study
data by means of the Total Neuropathy Score (TNS) scale. TNS combines symptoms (sensory,
motor, and autonomic), signs (pin and vibration sensibility, strength, and tendon reflexes),
vibratory threshold measured by the quantitative sensory testing, and nerve conduction study
(sural and peroneal amplitude) findings. Neuropathy was defined with score greater than 2.
Quantitative sensory testing was performed at the first metatarsal phalanx of the big toe using
the Computed-Assisted Sensory Examinator (CASE IV) device (W.R. Medical Electronics Co.,
Stillwater, MN). Data were referred to the normative ranges provided by the software. Nerve
conduction studies were performed in a warm room with temperature between 25 and 28°C and
controlled skin temperature using a Keypoint (Medtronic, Copenhagen, Denmark). Peroneal
nerve compound motor action potential amplitude (normal >4 mV) and antidromic sural nerve
action potential amplitude (peak-to-peak value; normal >6 μV) were recorded in the dominant
leg using surface stimulating and recording electrodes with standard placement. During the
2009 we performed statistical analysis of final data.
DElapril and MAnidipine for Nephroprotection in Diabetes (DEMAND) –
Retinopathy substudy: final analyses
A total of 258 subjects were included in the DEMAND – Retinopathy substudy. All subjects
consenting to funduscopy evaluation were centrally assessed at the Unit of Ophtalmology of the
Azienda Ospedaliera of Ospedali Riuniti (Bergamo, Italy) by ophthalmologists blinded to study
ANNUAL REPORT
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data. Indirect binocular ophthalmoscopy was performed by a L-0185 slit-lamp biomicroscope
(magnification 10x and 16x) and hand-held lens (magnification 90x) (27). Photographs of four
standard 30° fields of each eye were taken through dilated pupils in stereo pairs (lateral to
macula, macula, disc, and nasal) with Canon CF 60 UV fundus camera (Tokio, Japan). Retinal
involvement was graded from no apparent retinopathy to mild, moderate or severe preproliferative retinopathy and to proliferative retinopathy. The eye with the higher grade was
considered for statistical analysis. New onset retinopathy was diagnosed when any grade of
retinopathy was observed in two consecutive evaluations in eyes with no retinopathy at
baseline. During the 2009 we performed statistical analysis of final data.
BErgamo NEphrologic DIabetes Complications Trial (BENEDICT) – Follow
up Extension
The main objective of the follow up extension of the BENEDICT study was to evaluate the
effect of low albuminuria levels (among the normoalbuminuric range) on cardiovascular disease
(CVD) in the long term in type 2 diabetic patients. The BENEDICT phase A core study was a
randomized, double blind clinical trial that evaluated diverse therapeutic strategies to prevent
microalbuminuria in 1209 patients. A post-hoc follow-up evaluation was undertaken in order to
analyse the long-term impact of albuminuria in CVD. The follow-up evaluation consisted in the
following: a.- scheduled visits offered to all eligible participants at the end of the trial (n= 1194)
which were accepted by 645 (54%) and ii.- an evaluation of clinical charts in the whole group of
patients. Through this approach, extended follow-up data was obtained in 993 patients (83.16
%). For the remaining group of 201 patients, information was obtained by telephone calls in 62.
So, from the initial cohort of 1209 patients, complete follow-up information was available in
1055 patients (87%) and 139 (11%) only had follow-up data during the core study. Several
multivariable models were developed to evaluate the independent impact of low and even very
low levels of albuminuria in cardiovascular disease. During the 2009 we performed statistical
analysis of preliminary data.
Laboratory of Coordination and Conduction of Controlled Clinical
Trials
The main aim of the Laboratory is to implement and coordinate all the activities needed to fulfil
the trials planned by the Renal Medicine Department, according to the study protocols and the
Good Clinical Practice (GCP).
To Laboratory staff collaborates with all the Laboratories/Unit of the Mario Negri Institute
involving in the clinical studies coordinated by the Renal Medicine Department taking care of:
to guarantee the flow of the information between the Laboratories/Units of the Renal Medicine
Department and to guarantee a continuous updating of the trial status; to develop the case report
form of studies; to develop the database of studies; to implement and update a centralized
system of data management easily enjoyable by researchers of the Renal Medicine Department;
to promote training activities for young investigators; to implement and update the SOPs needed
for the trial protocols.
Moreover part of the Laboratory staff is specifically devoted to the clinical study monitoring
which purposes are to verify that: the rights and well-being of human subjects are protected; the
reported trial data are accurate, complete, and verifiable from source documents; and the
conduct of the trial is in compliance with the currently approved protocol/ amendments, with
GCP, and with applicable regulatory requirements.
Clinical monitors acting as the main line of communication between the sponsor and the
investigator; verifying that the investigator has adequate qualifications and resources and these
remain adequate throughout the trial period, and that the staff and facilities, including
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laboratories and equipment, are adequate to safely and properly conduct the trial and these
remain adequate throughout the trial period; verifying that the investigator follows the approved
protocol and all approved amendments; discussing with the investigator any protocol deviation;
verifying that each adverse event is well-documented and timely notified to Authorities as
required by GCP; verifying the subjects recruitment rate and discussing with Sponsor and
investigator new strategies to implement the enrolment. For the investigational medicinal
product (IMP), verifying: that storage times and conditions are acceptable, and that supplies are
sufficient throughout the trial; that the IMP are supplied only to subjects who are eligible to
receive it and at the protocol specified doses; that subjects are provided with necessary
instruction on properly using, handling, storing, and returning the IMP; that the receipt, use, and
return of the IMP at the trial sites are controlled and documented adequately; that the disposition
of unused IMP the trial sites complies with applicable regulatory requirements and is in
accordance with the sponsor’s authorized procedures.
In 2009 the Laboratory coordinated and monitored 20 clinical studies performed in
collaboration with 84 Italian Hospital where 250 monitoring visits have been done.
Laboratory of Pharmacokinetics and Clinical Chemistry
Hyperfiltration and renal function decline in patients with type 2 diabetes
Type 2 diabetes mellitus is a public health concern. According to the World Health
Organization (WHO), diabetes affects more than 170 million people worldwide, and this
number will rise to 370 million by 2030. One third of diabetic patients will eventually develop
diabetic nephropathy, a syndrome of macroalbuminuria, declining glomerular filtration rate
(GFR) and increased cardiovascular mortality. Untreated, these patients progress to end stage
renal disease (ESRD) requiring renal replacement therapy in about ten years. Early GFR
elevation, commonly referred to as hyperfiltration (GFR > 120 mL/min/1.73m2), has been
consistently found to play a central role in the pathogenesis and progression of renal disease in
experimental models of both type 1 and type 2 diabetes. Some studies found an accelerated
renal function loss in hyperfiltering patients compared to those with normal or reduced GFR,
but these findings were not confirmed in other studies. To address this issue we examined an
homogeneous cohort of 600 normo- and microalbuminuric patients with type 2 diabetes
included in the BENEDICT and DEMAND studies and allocated to ACE inhibitors therapy or
not who had their GFR prospectively monitored with serial measurements of at least 4 iohexol
plasma clearance. In addition we estimated the renal function of the patients and its decline over
time by means of 14 prediction equations developed to provide an estimate of GFR from serum
creatinine and demographic characteristics. Overall, we performed 4593 GFR measurements by
iohexol plasma clearance over a median follow-up of 4.3 ± 1.4 years and each patient had up to
18 GFR determinations. Of these patients, 449 (74.8%) had at least four GFR measurements on
follow up available for renal function decline analyses. The total GFR slope was of -3.37
mL/min/1.73m2 per year. Hyperfiltering patients showed a significantly faster total GFR slope: 4.39 mL/min/1.73m2/y than non-hyperfiltering -3.23 mL/min/1.73m2/y. Conversely, no
differences in total GFR slope were observed in patients with micro- or normoalbuminuria and
in those receiving ACE inhibitors or not. However, an in depth analysis of the data, showed that
hyperfiltering patients had a non linear GFR decline characterized by an acute followed by a
slower decrease. The acute GFR change from baseline to 6 months was significantly deeper in
hyperfiltering patients: -13.64±19.04 mL/min/1.73m2 when compared to non-hyperfiltering: 1.18±13.65. The chronic GFR slope, calculated from month 6, was not different between
hyperfiltering (-2.49 mL/min/1.73m2/y) and non-hyperfiltering patients (-3.38
mL/min/1.73m2/y) or when comparing micro- and normoalbuminuric patients or in those
allocated to ACE inhibitors or not.
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In the studied patients as a whole, all prediction equations, with the single exception of the
Ibrahim model, significantly underestimated baseline GFR. GFR underestimation ranged from
1.48 to 29.72 mL/min/1.73m2 and the percentage of estimates with less than 10% deviation
from measured GFR ranged from 8.3% to 48.2%. The largest deviations from measured GFR
were observed in the subgroup of hyperfiltering patients where all formulas significantly
underestimated the GFR and the proportion of hyperfiltering subjects correctly identified ranged
from 0 to 27%. In addition, none of the 14 GFR models reliably predicted GFR decline in
diabetics with micro- or normoalbuminuria. Underestimation of the decline ranged from 2.09
mL/min/1.73m2/y to 3.11 mL/min/1.73m2/y and similar trends were observed in hyperfiltering
and non-hyperfiltering patients considered separately. Acute GFR decrease was underestimated
by all tested formulas and in particular in hyperfiltering patients where the underestimation
ranged from 11.54 to 13.16 mL/min/1.73m2. Chronic GFR slope was also markedly
underestimated in the whole population, (from 2.03 to 3.02 mL/min/1.73m2/y) as well as in
hyperfiltering subjects (2.21 to 3.59 mL/min/1.73m2/y) and in non-hyperfiltering patients (2.00
to 3.00 mL/min/1.73m2/y).
These findings showed that in hyperfilterng and non-hyperfiltering patients measured GFR
chronic decline was similar and all considered prediction formulas underestimated GFR and
GFR decline to a substantial extent. This is true particularly in patients with hyperfiltration, but
formulas were imprecise also in subjects with normal or decreased GFR with large deviations
from actual values.
Sirolimus therapy to halt the progression of Autosomal Dominant
Polycystic Kidney Disease
Activation of mammalian target of rapamycin (mTOR) pathways may contribute to
uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant
polycystic kidney disease (ADPKD). We planned to assess the effects of mTOR inhibition on
disease progression, in a prospective, randomized, cross-over study comparing by computed
tomography the effects of six-month treatment with sirolimus or conventional therapy alone on
the growth of kidney volume and its compartments in 21 patients with ADPKD and a
glomerular filtration rate (GFR) >40 mL/min/1.73m2. Total kidney volume increased less on
sirolimus than on conventional therapy, but the difference between the two treatments did not
reach statistical significance; cyst volume was stable on sirolimus and increased by on
conventional therapy, whereas parenchyma volume increased on sirolimus and was stable on
conventional therapy. Percent changes in cyst and parenchyma volumes were significantly
different between the two treatment periods. Sirolimus had no appreciable effects on
intermediate volume and GFR. Sirolimus halted cyst growth and increased parenchyma volume
in patients with ADPKD, and was well tolerated. These findings provide the rationale for
adequately powered trials aimed to assess whether and to which extent chronic sirolimus
therapy may improve clinical outcomes of ADPKD patients in the long run.
Laboratory of Advanced Development of Drug
Omega-3 polyunsaturated fatty acids affect sirolimus exposure in kidney
transplant recipients on calcineurin inhibitor-free regimen
Sirolimus (SRL) is an immunosuppressive drug extensively metabolized by the cytochrome
P450 (CYP3A4) system. Therefore, its pharmacokinetics is influenced by drugs that interfere
with CYP3A4 activity, such as cyclosporine. Patients on SRL therapy frequently require
omega-3 polyunsaturated fatty acids (PUFA) to control hypertriglyceridemia, a common side
effect of chronic treatment with mammalian target of rapamycin inhibitors. Although
experimental studies have shown that PUFA inhibit CYP3A4 activity, the impact of these lipid-
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lowering agents on SRL exposure in kidney transplant recipients has not been investigated so
far.
To address this issue, we performed a retrospective analysis of a pharmacokinetic data set of
two groups of patients: one with and one without PUFA treatment. 445 SRL trough levels and
55 daily pharmacokinetic profiles were collected from 22 kidney transplant recipients given
low-dose SRL and low-dose MMF as maintenance immunosuppressive regimen up to 36
months post-transplant. Nine out of 22 patients started PUFA administration at different timepoints after surgery to control hypertriglyceridemia. We found that from month 4 posttransplant dose-normalized SRL trough levels were higher in patients given PUFA in
comparison to those not receiving the lipid-lowering agents. The difference became statistically
significant from month 7 after surgery and it remained significant throughout the study.
Moreover, when we compared mean dose-adjusted SRL trough levels in the same patients
before and after starting PUFA administration, we found that the treatment resulted in a
significant increase of dose-adjusted SRL concentrations. Pharmacokinetic studies demonstrated
that concomitant PUFA administration also increased dose-adjusted SRL AUC0-24 values
compared with those observed in untreated patients. Interestingly, the major differences in the
pharmacokinetic profiles were observed from 240 to 480 minutes after SRL administration,
namely during the phase of drug metabolism. Nearly 25% reduction in the SRL dose was
required in patients given PUFA to reach trough concentrations and AUC0-24 comparable with
those found in patients not receiving the lipid-lowering agents. Altogether, these clinical data
suggest that daily SRL exposure was significantly increased by concomitant administration of
PUFA and extend previous in vivo experimental observation showing the inhibitory effect of
PUFA on the activity of CYP3A4 , the main enzyme involved in SRL metabolism. These
findings might be helpful to better individualize SRL therapy in kidney transplant recipients.
The results of this study have been published in Transplantation (2010; 89:126-127).
Limiting sampling strategies for the estimation of daily sirolimus
exposure in kidney transplant recipients on a calcineurin inhibitor-free
regimen
Sirolimus (SRL) in an immunosuppressive drug characterized by a narrow therapeutic index.
Monitoring of SRL blood concentrations is mandatory to optimize drug dosing. The area under
the concentration-time curve (AUC) is generally accepted as the best surrogate marker of SRL
exposure. Assessment of full SRL AUC, however, requires the collection of multiple blood
samples, imposing both time and cost constrains. Limiting sample strategies (LSS) may be of
clinical relevance to improve the therapeutic drug monitoring of SRL. In this study different
LSS equations have been identified based on 2 or 3 sample points collected within the first 6
hours after drug intake. Most of the proposed algorithms are associated with good correlations
with the measured AUC and acceptable bias and imprecision. In particular, two equations, based
on two time points collected within the first 4 hours after dosing, have been identified that
reliably predict SRL exposure in routine clinical practice compared with traditional C0-based
approach. These tools provide additional information to optimize SRL therapeutic drug
monitoring in renal transplant recipients.
The results of this study have been published in The Journal of Clinical Pharmacology (2009;
49: 773-781).
ABCB1 genotypes predict cyclosporine-related adverse events and kidney
allograft outcome
Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the
ABCB1 gene. Previous studies have shown that, compared with carriers of wild-type gene,
carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and,
secondarily, increased intracellular CsA concentrations. Therefore, at comparable CsA
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exposure, carriers of T allelic variants might be at increased risk for CsA-related adverse events.
To test this hypothesis, we evaluated the association between ABCB1 genotype (in exons 12, 21
and 26) and clinical outcomes in 147 kidney transplant recipients who were receiving CsAbased immunosuppression regimen and were included in the Mycophenolate Steroids Sparing
study. During a median follow-up of 65.5 mo, carriers of T allelic variants in exons 21 or 26 had
a three-fold higher risk for delayed graft function (DGF), a trend to slower recovery of renal
function and lower glomerular filtration rate at study end, significantly higher incidences of
new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type
genotype. In particular, T variants in both exons 21 and 26 were independently associated with
3.8- and 3.5-fold higher risk for DGF, respectively (p = 0.022 and p = 0.034). The incidence of
acute rejection episodes, mean CsA dose and blood levels were comparable in genotype groups.
In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at
increased risk for CsA-related adverse events. Pre-transplant genetic evaluation may help to
identify patients at increased risk of side effects and to modulate CsA therapy in order to
optimize graft and patient outcomes. The results of this study have been published in J Am Soc
Nephrol (2009; 20:1404-15).
Mesenchymal stem cells in living-related kidney transplant recipients
Currently available immunosuppressive drugs are associated with long-term complications
including premature cardiovascular disease, metabolic disorders, infections and malignancy.
Moreover, although these drugs have reduced the incidence of acute rejections and one-year
graft survival rate, they failed to increase long-term renal allograft survival. Thus, the ultimately
goal of kidney transplantation is to find strategies to induce allograft “tolerance”, a condition in
which the transplanted organ is accepted without long-term maintenance immunosuppressive
treatment. In this context, mesenchymal stem cells (MSC) have attracted attention because they
avoid recognition by the immune system and they also exert immunomodulatory functions. One
of our experimental studies published in Journal of Immunology (2008; 181: 3933-3946) has
evaluated the effect of MSC infusion on the incidence of acute rejection episodes in a
semiallogenic heart transplant mouse model. We found that either single (day -7) or a double
(day -7 and day -1) pretransplant infusion of donor-derived MSC induced a profound T cell
hyporesponsiveness and prolonged cardiac allograft survival. MSC-induced tolerance was
associated with CD4+CD25+FOXP3+ T cells (Treg) expansion. MSC-induced Treg were donorspecific since adoptive transfer of splenocytes from tolerant mice prevented rejection of donorspecific secondary allografts but not of third-party grafts. Based on these results a pilot,
exploratory study has started to define the safety and biological/mechanistic effects of the
systemic infusion of autologous ex-vivo expanded human MSC in living-related kidney
transplant recipients. The condition of donor-specific immune tolerance that might be achieved
through MSC infusion might allow tapering and discontinuation of maintenance
immunosuppressive drugs.
Laboratory of Clinical Pathophysiology of Renal Disease and
Transplantation
Main objective of the Laboratory of Clinical Pathophysiology of Renal Disease and
Transplantation is the study of pathophysiological mechanisms underlying the progression of
chronic kidney disease and the identification of new therapeutic strategies for diabetic kidney
disease and nondiabetic proteinuric nephropathies and chronic rejection. The multidisciplinary
nature of these lines of research necessarily requires a close integration between various skills of
clinical physiology and clinical pharmacology, and of molecular biology. For this reason, the
laboratory includes not only researchers from the Department of Renal Medicine, which touch
on the laboratory, but also the Department of Public-Private Medical Specialist and Transplants.
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From an operational standpoint, the laboratory interacts closely with the Laboratory for the
coordination and conduct of controlled clinical trials which finalizes the protocols designed for
clinical research within the Department of Renal Medicine.
Laboratory of Regulatory Affairs for Clinical Studies
Since 1999, the Department of Renal Medicine, in collaboration with other Departments of the
Institute and with the Hospital of Bergamo, within the framework of activities of the PublicPrivate Department of Specialist and Transplant Medicine, designs, promotes and coordinates
projects of clinical research. These are mainly independent research projects; some of them are
carried out exclusively in the Daccò Centre, but most of them are multi-centre trials, in
collaboration with Hospitals, Research Centres and Universities, both Italian and foreign.
The Laboratory of Regulatory Affairs for Clinical Studies has been created in relation to this
activity, to verify that the studies are conducted in compliance with patient’s safety and rights
and according to the legislation in force.
In the execution of its activities, the Laboratory, interacts with several interlocutors, among
them the Ministry of Health, the Italian Agency for Drugs (AIFA), the Local Ethic Committees,
the ASL and the Pharmaceutical companies.
The Laboratory, supported by a secretariat, participates in all the phases of planning, organizing,
conducting and managing the clinical studies.
During the preparatory phase, preceding the onset of the study, the Laboratory collaborates with
the researchers in order to establish the protocol and the study’s documents in accordance with
the principles of Good Clinical Practice. In addition it verifies the adherence of these documents
to regulatory and ethical aspects. Once the protocol has been established, the Laboratory
proceeds to the input of the trial in the National Monitoring Centre on Clinical Research with
Medicines (OsSC) and subsequently submits all the documents to the competent authorities, in
order to obtain the ethical and administrative approvals and manages all the bureaucratic
procedures.
During the course of the study, the Laboratory is responsible for complying with the legal
obligations to keep AIFA and the Ethic committees constantly updated on the progress of the
experimentation. Moreover, it occupies with the collection and maintenance of all essential
documents for the conduction of clinical studies.
Since 2005, according to the rules set by the International Committee of Medical Journal
Editors, the Laboratory ensures that all the clinical studies promoted by the Centre Daccò are
registered to the NIH international registry, “clinicaltrials.gov”.
The Laboratory develops its activities within a research frame that promotes primarily academic
studies, therefore, particular attention is paid to the creation of networks of Italian and foreign
researchers, who are interested in collaborating with the institute on specific topics. The
researchers are involved in collaborative studies and are supported in the beginning and during
the conduction of the studies and constantly updated through workshops and investigator
meetings.
Finally, it falls into the responsibilities of the Laboratory Head, to be constantly updated on the
national and international norms and procedures that regulate the clinical studies.
In respect to the recent sanitary accreditation of Daccò Centre, the Laboratory interfaces with
ASL and other competent authorities, in order to comply with the legal and administrative
requirements.
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RARE DISEASES DOCUMENTATION
AND RESEARCH
STAFF
Head
Erica DAINA, M.D.
Genetics for Clinical Research
Head
Elena BRESIN, M.D.
Network Development for Rare Diseases
Head
Sara GAMBA, Research Nurse
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CURRICULA
Erica Daina got her degree in Medicine at the University of Milan in 1987 and the specialisation in
Medical Nephrology in 1990 at the same University.
She performed her training at the II° Medical Division - San Raffaele Hospital - Milan, and at the
Division of Nephrology and Dialysis - Riuniti Hospital - Bergamo.
In March 1988 she started her collaboration with the Mario Negri Institute and since June 1993 she works
as full-time clinical researcher at the Clinical Research Center for Rare Diseases Aldo e Cele Daccò.
1996 – 2009: Chief, Information Center for Rare Diseases
June 2009: Chief, Laboratory of Rare Diseases Documentation and Research
Areas of interest: Rare diseases, Takayasu’s Arteritis, Hemolytic Uremic Syndrome/Thrombotic
Thrombocytopenic Purpura, genetic kidney diseases.
1.
2.
3.
4.
5.
Warnock DG, Daina E, Remuzzi G, West M. Enzyme Replacement Therapy and Fabry Nephropathy. Clin J Am Soc
Nephrol. Epub 2009 Dec. 10. 2010 feb; 5(2):371-8
Bresin E, Gastoldi S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G,
Galbusera M. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of
anti-ADAMTS13 autoantibodies. Thromb Haemost 2009; 101(2):233-8
Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet. 2008
Jun 14;371(9629):2039-41.
Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship T H J, Remuzzi G, International Registry
Recurrent Familial HUS/TTP. Outcome of renal transplantation in patients with non-Shiga toxin-associated Hemolytic
Uremic Syndrome: Prognostic significance of genetic background. Clinical Journal American Society Nephrology 2006;
1: 88-99
Daina E, Schieppati A, Remuzzi G. Mycophenolate mofetil for the treatment of Takayasu arteritis: report of three cases.
Ann Intern Med. 1999 Mar 2;130(5):422-6.
Elena Bresin got her degree in Medicine at the University of Padua in 1994 and the specialisation in
Medical Genetics at the University of Verona in 2000.
She performed her training at the Department of Pediatrics of the University Policlinic of Padua, then at
the Department of Biology and Genetics of the University Policlinic of Verona and since 2000 at t the
Clinical Research Center for Rare Diseases Aldo e Cele Daccò.
Since January 2001 she works as full-time clinical researcher at the Clinical Research Center for Rare
Diseases Aldo e Cele Daccò and since June 2009 she is Unit Head of Genetics for Clinical Research.
Areas of interest: thrombotic microangiopathies, membranoproliferative glomerulonephritis, familial
focal segmental glomerulosclerosis.
1.
2.
3.
4.
5.
Bresin E, Gastoldi S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G,
Galbusera M. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of
anti-ADAMTS13 autoantibodies. Thromb Haemost 2009; 101(2):233-8
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 Feb 19;105(7):2538-43
Monteferrante G, Brioschi S, Caprioli J, Pianetti G, Bettinaglio P, Bresin E, Remuzzi G, Noris M Genetic analysis of the
complement factor H related 5 gene in haemolytic uraemic syndrome. Mol Immunol 2007; 44:1704-1708
impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood
2006;108(4):1267-79
Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship T H J, Remuzzi G, International Registry
Recurrent Familial HUS/TTP. Outcome of renal transplantation in patients with non-Shiga toxin-associated Hemolytic
Uremic Syndrome: Prognostic significance of genetic background. Clinical Journal American Society Nephrology 2006;
1: 88-99
Sara Gamba got her Nurse Diploma on 1994 at Bolognini Hospital Nurses School, Seriate (Bergamo).
Educational training: Clinical Research Nurse Diploma on 1996 at IRFMN – Daccò Center.
First Level Master on Clinical Research at Milan University on 2008.
ANNUAL REPORT
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IRFMN
Areas of interest: rare diseases studied by the Laboratory staff. She is involved with the Italian rare
diseases patients’ Associations and she coordinates the documentation service addressed to the patient
with rare conditions, their relatives and the health care professionals.
Employment: In 1997-2003 she was involved as co-organizing, speaker, co-speaker and tutor for the
Clinical Research Course for Nurses at IRFMN – Daccò Center.
Since 2009 she is Chief of the Unit Network Development for Rare Diseases.
1.
2.
3.
4.
5.
impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood
2006;108(4):1267-79
Krulichova I, Gamba S, Ricci E, Garattini L on behalf of the Italian Takayasu Arteritis Study Group. Direct medical
costs of monitoring and treating patients with Takayasu arteritis in Italy. Eur J Health Econ Vol. 49, August 2004
Noris M, Brioschi S, Caprioli J, Todeschini M, Porrati F, Gamba S, Remuzzi G for the International Registry of
Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation. The Lancet, Vol. 362,
November 8, 2003
Gamba S, Cicci L, Stefanov R. Qualità della vita in pazienti con malattie rare:l’esperienza degli infermieri del Centro di
Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò. Assistenza Infermieristica e Ricerca, Vol. 22, N. 3, JulySeptember 2003.
Remuzzi G, Ga

Annual Report 2009 - Istituto di Ricerche Farmacologiche Mario Negri

Transcription

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