Annual Report 2006 - Istituto di Ricerche Farmacologiche Mario Negri

Transcription

2006
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PREFACE
ANNUAL REPORT
MARIO NEGRI INSTITUTE, MILAN
www.marionegri.it
DEPARTMENTS
Department of Oncology ………………….………………………….………………………
7
Department of Environmental Health Sciences ……….………….……….……………… 49
Department of Neuroscience ………………….………………………….………………… 67
Department of Cardiovascular Research ………………….…………………….………… 109
Department of Molecular Biochemistry and Pharmacology .…….………….………… 139
LABORATORIES AND CENTERS
Laboratory of Regulatory Policies ……….………………………..……….………….……… 165
Laboratory for Mother and Child Health……….……………………….……………………… 171
Laboratory of General Epidemiology ……….…………….………………………….……… 187
Laboratory of Medical Informatics ……….……………………………………..….………… 211
Italian Cochrane Center …….….……………………………………………………………… 219
The Catullo and Daniela Borgomainerio Center…………………………………………… 225
Library ……….….…………………………………………………………….………….………… 227
NEGRI BERGAMO LABORATORIES
DEPARTMENTS
Department of Molecular Medicine ……….……………………………………….………… 233
Department of Biomedical Engineering……….……………………………………………… 251
ALDO and CELE DACCO’ CENTER
DEPARTMENT
Department of Renal Medicine…………….…………………………………………………… 267
LABORATORIES AND CENTERS
Laboratory of Clinical Epidemiology ……….…………………………………………………
Laboratory of Coordination of Diagnosis and Information on Rare Diseases …..…
A. and A. Valenti Health Economics Center, CESAV ……….…………………………
The Transplant Research Center…………….…………………………………………………
291
299
311
319
EDUCATION ACTIVITIES
321
STAFF
323
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 and Eugenio Santoro
in collaboration with the Laboratory of Medical Informatics
printed March 2007
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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.
Compared to previous years, our research programs are increasingly spreading out to involve
the collaboration among several laboratories within each department, and some are
interdepartmental. We have slimmed down the number of research topics in order to focus
more closely, to reach a “critical mass” of scientists and resources employed on each theme.
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 10.000 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) .
These are difficult years for research in Italy, and the Institute is most grateful to all those public
and private bodies, foundations and private citizens who generously support the work outlined
here, with their steady flow of contributions. Our sincere thanks to all of them.
Silvio Garattini
Director
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Mario Negri
INSTITUTE FOR
PHARMACOLOGICAL RESEARCH
Milan
ANNUAL
REPORT 2006
departments and laboratories
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DEPARTMENT OF ONCOLOGY
STAFF
Head
Maurizio D’INCALCI, M.D.
Oncological Studies Office and Documentation
Scientific Documentalist
Scientific Consultant
Stefania FILIPPESCHI, Chemist
Maria Grazia DONELLI, Biol.Sci.D.
Laboratory of Cancer Pharmacology
Head
Maurizio D’INCALCI, M.D.
Biophysics Unit
Head
Paolo UBEZIO, Phys.D.
Flow Citometry Unit
Head
Eugenio ERBA, Chemist
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
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, Biol. Sci.D,.Stat.Sci.D., Ph.D.
Laboratory of Transaltional and Outcome Research in Oncology
Head
Giovanni APOLONE, M.D.
Clinical Research Computing Unit
Head
Luca CLIVIO, Eng.D.
Gynecology Oncology Unit
Head
Roldano FOSSATI, M.D.
Laboratory of Medical Research and Consumer Involvement
Head
Paola MOSCONI, Biol.Sci.D.
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CURRICULA VITAE
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 Head of the Laboratory of Cancer Chemotherapy at the
Mario Negri Institute and since 1996 he has become Head 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).
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 400 papers on cancer chemotherapy published in peer reviewed
international journals, and of several chapters in books on cancer chemotherapy.
Selected publications
•
Biroccio A., Rizzo A., Elli R., Koering C., Belleville A., Benassi B., Leonetti C., Stevens M.F.G., D’Incalci M., Zupi G.,
Gilson E. TRF2 inhibition triggers apoptosis and reduces tumorigenicity of human melanoma cells. Eur. J. Cancer,
42:1881-1888 (2006).
•
Zongaro S., de Stanchina E., Colombo T., D’Incalci M., Giulotto E., Mondello C. Stepwise neoplastic transformation of
a telomerase immortalized fibroblast cell line. Cancer Research, 65:(24): 11411-11418 (2005).
•
Allavena P., Signorelli M., Chieppa M., Erba E., Bianchi G., Marchesi F., Garbi A., Lissoni A., de Braud F., Jimeno J.
and D’Incalci M. Anti-inflammatory properties of the novel antitumor agent Yondelis (Trabectedin): inhibition of
macrophage differentiation and cytokine production. Cancer REs., 65(7):2964-2971 (2005).
•
Lupi M., Matera G., Branduardi D., D’Incalci M., Ubezio P., Cytostatic and cytotoxic effects of topotecan decoded by a
novel mathematical simulation approach, Cancer Research, 64: 2825-2832 (2004).
•
Gambacorti-Passerini C., Zucchetti M., Russo D., Frapolli R., Verga M., Bungaro S., Tornaghi L., Rossi F., Pioltelli P.,
Pogliani E., Corneo G., Alberti D., D’Incalci M. Alpha 1 acid glycoprotein (AGP) binds to STI571 and substantially
alters its pharmacokinetics in chronic myeloid leukemia patients. Clin. Cancer Res., 9: 625-632 (2003).
•
Donald S., Veschoyle R.D., Greaves P., Gant T.W., Colombo T., Zaffaroni M., Frapolli R., Zucchetti M., D’Incalci M.,
Meco D., Riccardi R., Lopez-Lazaro L., Jimeno J., Gescher A.J. Complete protection by high-dose dexamethasone
against the hepatotoxicity of the novel antitumor drug Yondelis (ET-743) in the rat. Cancer Research 63: 5902-5908
(2003).
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
• 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 has authored or co-authored over 200 publications.
•
Apolone G, La Vecchia C, Garattini S. Targeted kinase inhibitors in lung cancer: from EGFR to patients Eur J of
Cancer, 42: 124-125, 2006
•
Apolone G & Grossi E. Effectiveness and Outcome Research studies: Current trends. Foreword. Drug Develop Res,
67(3):181-182, 2006
•
Apolone G, Joppi R, Bertelè V & Garattini S. Ten years of marketing approvals of anti-cancer drugs in Europe.
Regulatory policy and guidance documents need to find a balance between different pressures BJC 93: 504-509, 2005
•
Gallus S, Colombo P, Apolone G, Zuccaro P, La Vecchia C. A tax to prevent the epidemic of lung cancer. Lancet 366:
288, 2005
•
Mosconi P, Poli P, Giolo A, Apolone G. How Italian health consumers feel about clinical research. A questionnaire
survey. Eur J Public Health, 15: 372-379, 2005
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Mosconi P, Colombo C, La Bianca R, Apolone G. Oncologists' opinion about research Ethics Committees in Italy. An
up-date, 2004
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 for a period in the laboratory of Molecular Pharmacology of the National Cancer Institute of
Bethesda, Md, in 1986. From 1991 he is Head of the Molecular Pharmacology Unit of the Mario Negri
Institute and from 1999 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 proteins and genes altered in human cancer and the study of oncosuppressor genes. He is member of
the "Pharmacology and Molecular Mechanisms Group" of the European Organization 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
•
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.
•
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.
•
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.
•
Damia G, Broggini M. Cell cycle checkpoint proteins and cellular response to treatment by anticancer agents. Cell Cycle.
2004;3:46-50.
•
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.
•
Marabese M, Vikhanskaya F, Rainelli C, Sakai T, Broggini M. DNA damage induces transcriptional activation of p73 by
removing C-EBPalpha repression on E2F1. Nucleic Acids Res. 2003;31:6624-32.
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.
•
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., Giustizi L., Magnani M.
Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA
hypomethylation in an at-risk Italian population. International Journal of Cancer (2006); 118: 628-32
•
Buda A, Fossati R, Colombo N, Fei F, Floriani I, Gueli Alletti D, Katsaros D, Landoni F, Lissoni A, Malzoni 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 Portio) Italian Collaborative Study. J Clin Oncol.
2005 Jun 20;23(18):4137-45.
•
Panici P.B., Maggioni A., Hacker N., Landoni F., Ackermann S., Campagnutta E., Tamussino K., Winter R., Pellegrino
A., Greggi S., Angioli R., Manci N., Scambia G., Dell’Anna T., Fossati R., Floriani I., Rossi R., Grassi R., Favalli G.,
Raspagliesi F., Giannarelli D., Martella L., Mangioni C. Systematic aortic and pelvic lymphadenectomy versus resection
of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. Journal of the National
Cancer Institute 2005; 97: 560-566
•
ICON4 collaboration, Floriani I: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based
chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVAR-2. 2 Trial - Lancet 2003; 361: 20992106
•
ICON1 collaboration, Floriani I: International Collaborative Ovarian Neoplasm Trial 1: A randomized trial of adjuvant
chemotherapy in women with early-stage ovarian cancer - J Natl Cancer Inst 2003; 95: 125-132
•
Cantù M.G., Buda A., Parma G., Rossi R., Floriani I., Bonazzi C., Dell’Anna T., Torri V., Colombo N.
Randomised controlled trial of single agent paclitaxel against hree drugs combination of CAP (Cyclophosphamide,
Doxorubicin and Cisplatin) in recurrent ovarian cancer patients responding to first-line platinum-based regimens.
Journal of Clinical Oncology, 2002; 20: 1232-1237
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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 Tumor Institute, University of Texas System
Cancer Centre in Houston (TX).
Her research interests are in the field of tumor biology and pharmacology. Specifically, she is studying aspects
related to the metastatic process and angiogenesis. She is involved in the pre-clinical 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 beenHead of
the Laboratory of Biology and Treatment of Metastasis at Mario Negri Institute for Pharmacological Research
in Bergamo.
She was consulting scientist for the NCI-Drug Therapeutics Program, USA (1996-2006); she is member of the
decisional-network at SENDO (South Europe New Drug Development Organization) and adjutant Professor in
Oncology, Medical School, University of Pisa.
She is a member of the American Association for Cancer Research (AACR), International Metastases Research
Society (board of Directors), EORTC-Screening and Pharmacology Group. She is the President of the Italian
Cancer Society (2006-07). She is on the Editorial Board of the European Journal of Cancer, Journal of Clinical
Experimental Metastasis, Journal Exp. Therapeutic & Oncology and The International Journal of Biological
Markers.
She has published approximately 150 articles on “peer reviewed” journals.
•
Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccardi E., Scanziani E., Eccles S.A., Bani M.R., Giavazzi
R.: The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing
apoptosis of endothelial cells and inhibition of angiogenesis. Clin. Cancer Research 12(6):1839-49, 2006.
•
Bani M.R., Nicoletti M.I., Alkharouf N.W., Ghilardi C., Petersen D., Erba E., Sausville E.A., Liu E.T., Giavazzi R.: Gene
expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Molecular Cancer Therapeutics
3(2):111-121, 2004.
•
Belotti D., Paganoni P., Manenti L., Garofalo A., Marchini S., Taraboletti G., Giavazzi R.: Matrix Metalloproteinases
(MMP9 and MMP2) Induce the Release of Vascular Endothelial Growth Factor (VEGF) by Ovarian Carcinoma Cells:
Implications for Acites Formation. Cancer Res. 63:5224-5229, 2003.
•
Micheletti G., Poli M., Borsotti P., Martinelli M., Imberti B., Taraboletti G., Giavazzi R.: Vascular-targeting Activity of
ZD6126, a Novel Tubulin-binding Agent. Cancer Res. 63:1534-37, 2003.
•
Giavazzi R., Giuliani R., Coltrini D., Bani M.R., Ferri C., Sennino B., Molinari Tosatti M.P., Stoppacciaro A., Presta M.:
Modulation of tumor angiogenesis by conditional expression of fibroblast growth factor-2 affects early but not established
tumors. Cancer Res. 61:309-317, 2001.
•
Nicoletti M.I., Colombo T., Rossi C., Monardo C., Stura S., Zucchetti M., Riva A., Morazzoni P., Donati M.B.,
Bombardelli E., D’Incalci M., Giavazzi R.: IDN5190, a taxane with oral biovailability and potent antitumor activity.
Cancer Res. 60:842-846, 2000.
Paola Mosconi got his Biological Science degree (Milan 1982) and the specialization in Pharmacological
Research (Milan 1984). Her main areas of interest are:
• development of strategies to involve patients’ and consumers’ associations in health debate, and
research projects;
• assessment of quality of life, translation and cultural adaptation of questionnaires for quality of life;
• studies to evaluate the type of information on diseases and treatments received by patients, mainly
in cancer patients; set-up of websites targeted for consumers/patients www.partecipasalute.it,
www.paincare.it;
• studies to evaluate consumers’ level of satisfaction with health services and care.
Paola Mosconi participated as a teacher or coordinator, to the realization of training courses on
“Methodological aspects of clinical research” or “Evaluation of quality of life” for health care
professionals and representatives of voluntary associations.
•
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
•
Leone M A, Beghi E, Righini C, Apolone G, Mosconi P. Epilepsy and quality of life in adults: a review of instruments.
Epilepsy Research 66: 23-44, 2005.
•
Mosconi P, Poli P, Giolo A, Apolone G. How health consumers feel about clinical research: a questionnaire survey.
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•
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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.
Mosconi P, Apolone G. Fixed and dynamic health related quality of life measurements. J Headache Pain S31-S34, 2003.
Domenighetti G, D’Avanzo B, Egger M, Berrino F, Perneger T, Saracci R, Mosconi P. and M. Zwahlen.Women’s
perception of the benefits of mammography screening: population-based survey in four countries. Int J Epidem 32: 816821, 2003.
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.
•
Buda A, Fossati R, Colombo N, Fei F, Floriani I, Gueli Alletti D, Katsaros D, Landoni F, Lissoni A, Malzoni C, Sartori
squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study. J Clin Oncol.
2005 Jun 20;23(18):4137-45.
•
Labianca R, Fossati R, Zaniboni A, Torri V, Marsoni S, Nitti D, Boffi L, Scatizzi M, Tardio B, Mastrodonato
N, Banducci S, Consani G, Pancera G, ACOI/GIVIO/GISCAD Investigators. Randomized trial of intraportal and/or
systemic adjuvant chemotherapy in patients with colon carcinoma J Natl Cancer Inst 2004; 96: 750-758
•
ICON4 collaboration, Torri V: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based
chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVAR-2. 2 Trial - Lancet 2003; 361: 20992106
•
ICON1 collaboration, Torri V: International Collaborative Ovarian Neoplasm Trial 1: A randomized trial of adjuvant
chemotherapy in women with early-stage ovarian cancer - J Natl Cancer Inst 2003; 95: 125-132
•
Scagliotti G V, Fossati R, Torri V, Crinò L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M:
Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer - J
Natl Cancer Inst 2003; 95: 1453-1461
•
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) of the Open University (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.
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Since 2004 she is the Scientific Manager of STROMA, an integrated project within the 6th Framework
Program of the European Commission [FP6 LSHC-CT-2003- 503233, STROMA].
She is a member of the American Association for Cancer Research (AACR), Italian Cancer Society
(SIC) and European Association for Cancer Research (EACR).
Maria Rosa Bani research interests are in the field of cancer biology and molecular therapeutics.
•
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.
•
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.
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Alessandri G., Chirivi R.G.S., Fiorentini S., Dossi R., Bonardelli S., Giulini S.M., Zanetta G., Landoni F., Graziotti P.P.,
Turano A., Caruso A., Zardi L. Giavazzi R. & Bani M.R., Phenotypic and functional characteristics of tumor-derived
microvascular endothelial cells. Clinical & Experimental Metastasis 17 : 655-662, 1999.
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Bani M.R., Rak J., Adachi D., Wiltshire R., Trent J.M., Kerbel R.S. & Ben-David Y. Multiple features of advanced
melanoma recapitulated in tumorigenic variants of early stage (radial growth phase) human melanoma cell lines:
evidence for a dominant phenotype. Cancer Research 5 : 3075-3086, 1996.
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Bani M.R., Garofalo A., Scanziani E. & Giavazzi R. Interleukin-1 affects metastasis formation in different tumor
systems. Journal of the National Cancer Institute, 83 : 119-123, 1991.
Luca Clivio has received a degree in Electronic and Informatics Engineering at the Politecnico
University of Milan, Italy in 1996, he has collaborated with the Mario Negri Institute for Pharmacological
Research, Milan, Italy since 1996, and he is currently Head of the Clinical Research Computing Unit at
the Mario Negri Institute.
His main fields of interest are:
a) conceptualization and implementation of methods and software to be used in clinical research (phase II
and III clinical trials);
b) ideation, development and field test of a family of software, integrated in a free application, to enable
people with physical disabilities to carry out basic daily activities through the use of a computer, with
special emphasis on the following tasks: communication and interaction with other people and other
systems. Regarding a), Luca Clivio is currently involved in the following research projects in the context
of research activities carried out by the Department of Oncology at Mario Negri: web-based, online,
multicentric randomizer for clinical trials (Projects SNAP-02, EIT, GILDA, ILIADE, IELSG, ICON-5
and Bupropione*MMG); remote web-based, on line, GCP complaint data entry for clinical trials and gene
expression data (EIT, ICON-5, Bupropione*MMG, IGC3).
Regarding b), his major activities are related to the project MAIA (Multiple Access Input Assistant).
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Clivio L, Tinazzi A, Mangano S, Santoro E. The contribution of information technology: Towards a better clinical data
management. Drug Dev Res 2006; 67: 245-250.
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Clivio L, Mangano S, Tosato A, Rosas R, Taiana M. Il progetto MAIA, Ricerca & Pratica 2005; n. 121: 39-41.
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Clivio L, Mangano S. Progetto MAIA: l'impatto sugli utenti. Ricerca & Pratica 2005; n. 124: 151-156.
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Clivio L. Progetto MAIA: Affective Computing. Esprimere emozioni per comunicare con un computer. Ricerca &
Pratica 2005; n. 126: 241-243.
Giovanna Damia obtained her Medical Degree cum Laude from the University of Milan in 1985. After
specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of
Milan, she worked as a post-doctoral fellow in the Laboratory of Experimental Immunology of the
National Cancer Institute, Frederick, USA. She worked as a research fellow in the Laboratory of Cancer
Chemotherapy at the Mario Negri Institute and since April 2003 she has become chief of the DNA Repair
Unit at the Mario Negri Institute. From 1992 to1995 she has been consultant of the General Secretariat of
the Progetto Finalizzato CNR "Applicazioni Cliniche della Ricerca Oncologica". Since September 2005
she is Deputy Editor for Experimental Oncology of the European Journal of Cancer.
Her main fields of interest are: mechanism of action of anticancer drugs, cell cycle checkpoints
and natural compounds.
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Simone M, Erba E, Damia G, Vikhanskaya F, Di Francesco A M, Riccardi R, Baldeyrou B, Bailly C, Cuevas C, SousaFaro J M F, D'Incalci M. Variolin B and its derivate deoxy-variolin B: New marine natural compounds with cyclindependent kinase inhibitor activity. Eur J Cancer 2005; 41: 2366-2377
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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
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Damia G, Broggini M. Improving the selectivity of cancer treatment by interfering with cell response pathways. Eur J
Cancer 2004; 40: 2550-2559
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Damia G, Broggini M. Cell cycle checkpoint proteins and cellular response to treatment by anticancer agents. Cell Cycle
2004; 3: 46-50
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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
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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 degree in Industrial Chemistry in 1976. 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 Post-Graduate 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.
•
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).
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Minuzzo M., Ceribelli M., Pitarque-Martì M., Borrelli S., Erba E., di Silvio A., D’Incalci M., Mantovani R.
Selective effects of the anti-cancer drug Yondelis (ET-743) on cell-cycle promoters. Mol. Pharmacol., 68: 14961503 (2005).
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Simone M., Erba E., Damia G., Vikhanskaya F., Di Francesco A.M., Riccardi R., Bailly C., Cuevas C.,
Fernandez Sousa-Faro J.M., D’Incalci M. Variolin B and its derivate deoxy-Variolin B: new marine natural
compounds with a cyclin-dependent-kinase inhibitor activity. Eur. J. Cancer, 41: 2366-2377 (2005).
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Allavena P., Signorelli M., Chieppa M., Erba E., Bianchi G., Marchesi F., Garbi A., Lissoni A., de Braud F.,
Jimeno J. and D’Incalci M. Anti-inflammatory properties of the novel antitumor agent Yondelis (Trabectedin):
inhibition of macrophage differentiation and cytokine production. Cancer REs., 65(7):2964-2971 (2005).
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Tognon G., Frapolli G., Zaffaroni M., Erba E., Zucchetti M., Faircloth G.T., M. D’Incalci, Fetal bovine serum, but not
human serum inhibits the in vitro cytotoxicity of ET-743 (Yondelis TM; trabectedin). An example of potential problems
for extrapolation of active drug concentrations from in vitro studies. Cancer Chemother Pharmacol., 53(1): 89-90 (2004).
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Erba E., Cavallaro E., Damia G., Mantovani R., Di Silvio A, Di Francesco A.M., Riccardi R., Cuevas C.,
Faircloth G.T., D’Incalci M. The unique biological features of the marine product YondelisTM (ET-743,
Trabectedin) are shared by its analog ET-637, which lacks the C ring. Oncology Research, 14: 579-587 (2004).
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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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 randomized trial. Br J Cancer. 2006 Aug 7;95(3):266-71
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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
Buda A, Fossati R, Colombo N, Fei F, Floriani I, Gueli Alletti D, Katsaros D, Landoni F, Lissoni A, Calzoni C, Sartori
squamous cell cervical carcinoma: The SNAP01 (Studio Neo-Adjuvante Por. J Clin Oncol 2005; 23: 4137-4145.
F.E. Johnson, K.S. Virgo, R. Fossati. Follow-up for patients with colorectal cancer after curative-intent primary
treatment. J Clin Oncol 22:1363-65;2004
Roberto Labianca, Roldano Fossati , Alberto Zaniboni, Valter Torri , Silvia Marsoni, Donato Nitti, Lamberto Boffi,
Marco Scatizzi, Berardino Tardio, Nicola Mastrodonato, Stefano Banducci, Giampiero Consani, Gianfranco Pancera on
behalf of ACOI/GIVIO/GISCAD investigators. Randomized Trial of Intraportal and/or Systemic Adjuvant
Chemotherapy in Patients with Colon Carcinoma. J Natl Cancer Inst 96:750-8;2004
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 (thrombospondin1) and preclinical studies of antiangiogenic and vascular disrupting compounds, including tubulintargeting agents. She is member of Metatasis Research Society (MRS, Board of Directors), 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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Taraboletti G, Micheletti G, Dossi R, Borsotti P, Martinelli M, Fiordaliso F, Ryan AJ and Giavazzi R. Potential
antagonism of tubulin-binding anticancer agents in combination therapies. Clin Cancer Res, 11: 2720-2726, 2005.
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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.
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Taraboletti G, D’Ascenzo S, Borsotti P, Giavazzi R, Pavan R, and Dolo V Shedding of MMP-2, MMP-9 and MT1MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol,160: 673-680, 2002
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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
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Taraboletti G., Morbidelli L., Donnini S., Parenti A., Granger H.J., Giavazzi R., and Ziche M.The heparin binding 25
kDa fragment of thrombospondin-1 promotes angiogenesis and modulates gelatinase and TIMP-2 production in
endothelial cells. FASEB J., 14: 1674-1676, 2000.
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Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown P.D., and Giavazzi R. Inhibition of
angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J. Natl.
Cancer Inst. 87: 293-298, 1995
Paolo Ubezio got his B.Sc. degree in Physics at the University of Milan, in 1982, and the specialization
in Pharmacological Research Specialist" at the Mario Negri Institute for Pharmacological Research in
1986.
Main activities are: i) Study of cell-cycle mathematical models; ii) Development of flow cytometric
methods; iii) Optimization of anticancer drug scheduling.
Since 1991 is Head of the Unit of Biophysics at the Mario Negri Institute
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Spinelli, L., Torricelli, A., Ubezio, P., Basse, B. (2006) Modeling the balance between quiescence and cell death in
normal and tumor cell populations Math Biosciences 202: 349-370.
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Lupi, M., Matera, G., Branduardi, D., D'Incalci M. and Ubezio, P. (2004) Cytostatic and cytotoxic effects of topotecan
decoded by a novel mathematical simulation approach. Cancer Res. 64: 2825-2832.
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Matera, G., Lupi, M.,and Ubezio, P. (2004) Heterogeneous cell response to topotecan in a CFSE-based proliferation test.
Cytometry 62A:118-128.
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Ubezio, P. (2004) Unraveling the complexity of cell cycle effects of anticancer drugs in cell populations.Discrete and
Continuous Dynamical Systems-Series B 4:323-335.
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Tomasoni, D., Lupi, M., Bekkal Brikci, F. and Ubezio, P. (2003) Timing the changes of cyclin E cell content in G1 in
exponentially growing cells. Exp Cell Res.; 288: 158-167.
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Montalenti, F., Sena, G., Cappella, P., and Ubezio, P. (1998) Simulating cancer-cell kinetics after drug treatment:
Application to cisplatin on ovarian carcinoma. Phys. Rev. E, 57:5877-5887.
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Massimo Zucchetti obtained his Chem. Pharm. Degree from the University of Milan in 1982. After
specializing in Pharmacology at the Mario Negri Institute of Milan (1988), he worked in the Laboratory
of Clinical Pharmacology of Department of Oncology at San Giovanni Hospital, Bellinzona, Switzerland
(1988-1990). Since 1996 he has been chief of the Cancer Clinical Pharmacology Unit at the Mario Negri
Institute. He is member of the Pharmacology and Molecular Mechanisms Group of the European
Organization for Research and Treatment of Cancer (EORTC) from 1988 up to date. His main field of
interest are:
- Clinical pharmacology, phase I and Phase II studies
- Analysis of drugs, pharmacokinetic and pharmacodynamic studies in humans in GCP and GLP
conditions
- Pharmacokinetic and metabolic studies in animals
- Pharmacokinetic drug interaction
Dr Zucchetti is author of more than 70 papers on pre-clinical and clinical cancer chemotherapy published
in peer reviewed international journals.
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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).
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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).
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Fruscio R., Lissoni A.A., Frapolli R., Corso S., Mangioni C., D’Incalci M., Zucchetti M. Clindamycin-Paclitaxel
pharmacokinetic interaction in ovarian cancer patients. Cancer Chemother. Pharmacol., 58(3): 319-325 (2006).
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Gambacorti Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, Tornaghi L, Rossi F, Pioltelli P,
Pogliani E, Alberti D, Corneo G, D'Incalci M Alpha 1 acid glycoprotein binds to imatinib (STI571) and substantially
alters its pharmacokinetics in chronic myeloid leukemia patients Clin Cancer Res 2003; 9: 625-632
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Pratesi G, Laccabue D, Lanzi C, Cassinelli G, Supino R, Zucchetti M, Frapolli R, D'Incalci M, Bombardelli E,
Morazzoni P, Riva A, Zunino F IDN 5390: An oral taxane candidate for protracted treatment schedules Br J Cancer
2003; 88: 965-972
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Zaffaroni M, Frapolli R, Colombo T, Fruscio R, Bombardelli E, Morazzoni P, Riva A, D'Incalci M, Zucchetti M
High-performance liquid chromatographic assay for the determination of the novel C-Seco-taxane derivative (IDN 5390)
in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 780: 93-98
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INTRODUCTION TO THE DEPARTMENT'S 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). 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.
FINDINGS/MAIN RESULTS
At nanomolar concentrations, ET-743 affects the regulation mechanisms of the transcription.
Nucleotide excision repair deficient cells are less sensitive to ET-743 but are hypersensitive to
UV rays and to other DNA damaging drugs.
Use of mathematical models of tumor growth and anticancer treatment to interpret experimental
data and to manage the complexity of underlying biological phenomena.
The theoretical relationship between proliferation, quiescence and cell loss leading to growth
control of tumor cell populations was found.
Variolin and some of its derivatives induce rapid apoptosis in some tumor cell lines that have a
low sensitivity to other anticancer drugs.
By genetic expression analysis it is possible to identify those stage I ovarian canrcinoma
patients that show a high risk of relapse.
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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.
A new and efficient system to selectively downregulate CHK1 in vivo has been developed. The
system is suitable to test combinations of drugs in vivo and to study new checkpoints inhibitors.
An anthracycline derivative, Nemorubicin, has a peculiar mechanism of action and is active
against tumors resistant to drugs such as cisplatin. The combination of the two drugs is highly
synergic.
Embryo fibroblasts isolated from DRAGO KO mice show a reduced response to treatment with
different anticancer agents. DRAGO gene is particularly responsive to p73.
Inositol pentaphosphate analogues interfere with the PI3-kinase-induced phosphorylation of akt
and possess antitumor activity in vitro and in vivo.
Human humbilical 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 genes preferentially expressed on tumor associated endothelial cells.
Identification of several putative tumor-associated accessible antigens by the in vivo
biotinylation of mice bearing kidney cancer.
Membrane vesicles shed by tumor cells contain angiogenesis stimulatory factors, including
MMPs and VEGF.
VEGF produced by ovarian tumor cells stimulates host MMP9 expression.
A new antiangiogenic domain of thrombospondin-1 (an endogenous inhibitor of angiogenesis)
that binds the angiogenic factor FGF-2 has been identified and characterized.
New antineoplastic compounds directed against the tumor vasculature (vascular disrupting
agents) have been selected.
The sequence of drug administration determines the efficacy of combination treatments with
tubulin-binding vascular disrupting agents and cytotoxic drugs.
The expression of VEGF and FGF2 affects tumor angiogenesis and modulates the response to
chemotherapy.
SU6668, a tyrosin kinase inhibitor of VEGFR, PDGFR and FGFR, in combination with
paclitaxel sinergistically affect vascular cells in angiogenesis.
Histone deacetylase inhibitor SAHA potentiates the cytotoxic effect of paclitaxel in human
ovarian carcinoma cells resistant to paclitaxel. The effect is mediated by the acetylation of
tubulin.
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Protease-activated receptor-1 (PAR-1) expression correlates with the malignant phenotype in
human melanoma.
ICON4, a randomized trial of second-line chemotherapy in advanced ovarian cancer,
coordinated by the Mario Negri Institute and by MRC, showed for the first time a reduction in
mortality in favor of platinum and paclitaxel chemotherapy.
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 introduces and develops with
ad-hoc instruments the information transfer in an active way.
The LYMPHADENCTOMY trial in advanced ovarian cancer: “two decades of uncertainty
resolved” (editorial). This trial showed that systematic lymphadenctomy does not improve
overall survival and these results will spare many patients the unduly toxicity of this surgical
procedure.
Bupropion more than doubled the odds of continuous abstinence from smoking from week 4 to
7 and from week 4 to 12 months in a way similar to that observed in academic studies. The
adherence of GPs and participants to the protocol was excellent, making our findings robust and
easy to generalize to the context of primary care.
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
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.
The estimates of the prevalence and impact of cancer pain in a large and representative sample
of cancer patients (1800) recruited by several Italian centers (more than 120), with the
evaluation of the actual proportion of cases that received a substantial analgesic under-treatment
(about 25%), mainly attributable to a sub-optimal utilization of opioids.
An evaluation of the activity of the EMEA over the last 10 years, has documented that most of
the new anti-cancers drugs has actually received an approval on the basis of very preliminary
findings: in 48% of case the approval was based on studies using surrogate endpoints, and in
40% of cases the design of the study was non-comparative and non-randomized.
The activity of training and information 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.
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Development and validation of a new short questionnaire, the PGWBI-short version, to be used
in large sample of citizens or patients.
NATIONAL COLLABORATIONS
ASR, Agenzia Sanitaria Regionale, Bologna
AIFA, Agenzia Italiana del Farmaco (Roma)
Assessorato Sanità, Regione Emilia Romagna
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
EUROPA DONNA
Federazione Italiana Società Scientifiche
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
Istituti Ortopedici Rizzoli, Bologna
Istituto dei Tumori di Milano
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 Regina Elena, Roma
Laboratorio Cell factory, Policlinico di Milano
Ospedale San Gerardo, Monza, Milano
Ospedale San Matteo, Pavia
Unità di Tossicologia e Scienze Biomediche, ENEA Centro Ricerche, Roma
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
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INTERNATIONAL COLLABORATIONS
ARCAGY (Association de Recherche sur les Cancers Gynécologiques), France
Breakthrough Breast Cancer Center, Instutite of Cancer Reasearch, London, UK
Cancer Biomarkers and Prevention Group, University of Leicester, UK
Cancer Research UK, London, UK
Cancerdegradome Consortium, IP 6th FP, EC
EORTC, Bruxelles, Belgium
EUROPA DONNA
European Agency for the Evaluation of Medicinal Products (EMEA), London, UK
European Regulatory Issues on Quality of life Assessment (ERIQA), Paris, France
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
Helios Klinikum Erfurt GmbH, Institute of Pathology, Germany
Istituto Oncologico della Svizzera Italiana, Switzerland
Johns Hopkins University, USA
Ludwig Institute for Cancer Research, London, UK
National Cancer Center, Singapore
Stony Brook University, NY, USA
Massachusetts General Hospital and Harvard Medical School, USA
MD Anderson Cancer Center, Houston, Texas, USA
Metastasis Research Lab, University of Liegi, Belgium
MRC, London, UK
National Cancer Institute (NCI), Bethesda and Frederick, MD, USA
Ospedale San Giovanni, Bellinzona, Switzerland
Paterson Institute for Cancer Research, Manchester, UK
Southern Europe New Drug Organization (SENDO), Milan, Italy
Stroma Consortium, IP 6th FP, EC
Swiss Federal Institute of Technology, Zurigo, Switzerland
The Sackler Institute, University College London, UK
Tumor Biology and Metastasis Institute of Cancer Research, Sutton, UK
University College, London UK
University of Cincinnati, USA
University of Crete Medical School, Greece
University of Newcastle, UK
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)
ANNUAL REPORT
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2006
IRFMN
European Journal of Cancer (Maurizio D’Incalci, Raffaella Giavazzi, Massimo Broggini and
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 Experimental Therapeutics and Oncology (Raffaella Giavazzi)
Journal of Medicine and the Person (Giovanni Apolone)
Journal of Preventive Medicine and Hygiene (Giovanni Apolone)
Molecular Cancer Therapeutics (Maurizio D’Incalci)
Oncology Research (Maurizio D’Incalci)
Tumori (Maurizio D’Incalci, Raffaella Giavazzi)
www.senology.it (Paola Mosconi)
www.PartecipaSalute.it (Paola Mosconi)
PEER REVIEW ACTIVITIES
American Journal of Pathology, Annals of Oncology, Anticancer Drug Design, Anti-cancer
Drugs, Biochemical Pharmacology, British Journal of Cancer, British Journal of Pharmacology,
British Medical Journal, Cancer Chemotherapy and Pharmacology, Cancer Detection and
Prevention, Cancer Letters, Cancer Research, Carcinogenesis, Chemico-Biological Interactions,
Clinical & Experimental Metastasis, Clinical Cancer Research, Cytometry, European Journal of
Cancer, European Journal of Immunology, Gynecologic Oncology, Health and Quality of Life
Outcomes, 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 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, Leukaemia, Molecular Cancer Therapeutics, Nature Reviews, PharmacoEconomics,
Quality of Life Research, Science, Tumori
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
AACR-Pezcoller International Award for Cancer Research
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
ANNUAL REPORT
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IRFMN
Ethical Committee, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
Scientific Committee, Associazione Italiana Ematologia e Oncologia Pediatrica, Monza, Milan,
Italy
Technical-Scientific Commitee, Associazione Italiana per la Ricerca sul Cancro, Milan, Italy
Board of Directors, Metastasis Research Society (MRS)
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
NHS R&D National Coordinating Centre for Health Technology Assessment, UK
Quinquennial Review Committee, Cancer Research UK
Scientific Committee, Swiss Cancer League
University Medical School of Siena, Italy
EVENT ORGANIZATION
Meeting: Percorso di formazione alle scelte su ricerca clinica e salute pubblica per membri di
associazioni di cittadini e pazienti, 1° Edition, 2005-2006.
Meeting: III Annual Scientific Meeting FP6-STROMA 503233, Paris (France), January 25-27,
2006.
Workshop: Progetto " Sostenibilità economico-finanziaria dei servizi sanitari, equità e qualità
della cura", CNP DS-Regione Lombardia - Villa Cagnola, Gazzada VA (Italy), February 10-11,
2006.
Meeting: “Costruire un ruolo per i pazienti nella ricerca e nel percorso di cura”, Milan (Italy),
March 30, 2006.
Meeting: “International Clinical Trials’ Day”- 1° giornata della ricerca clinica. Centro
Congressi Fondazione Cariplo, Milan (Italy), May 20, 2006.
Seminar: “La Diagnosi in medicina dai bisogni all’uso eccessivo” – IEO, Milan (Italy), October
9, 2006.
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2006
IRFMN
PARTICIPATION IN EVENTS IN WHICH THE DEPARTMENT WAS
INVOLVED
Meeting: Biomedical Optics Topical Meeting “Fluorescent imaging of vascular shutdown in
vivo.” Fort Lauderdale (USA), March 19-23, 2006.
Conference: 4th Conference on experimental and translational oncology. “Tumor VEGF
modulates host proteolytic activity during ovarian cancer progression”. Kranjska Gora
(Slovenia), March 22-26, 2006.
Meeting: 97th Annual Meeting AACR “Location of the FGF-2 binding site of thrombospondin1 in the C-terminal cassette”. Washington DC (USA), April 1-5, 2006.
Meeting: 97th Annual Meeting AACR “Involvement of tubulin acetylation in the antimotility
activity of the taxanes paclitaxel and IDN5390”. Washington DC (USA), April 1-5, 2006.
Meeting: 97th Annual Meeting AACR “Down-regulation of angiogenic growth factor
expression affects vascularization without impairing tumor response to chemotherapy”.
Washington DC (USA), April 1-5, 2006.
Meeting: 97th Annual Meeting AACR “Expression of Gonadotropin-Releasing Hormone
receptors in human malignant melanomas and regulation of gene expression associated with
their antitumor activity”. Washington DC (USA), April 1-5, 2006.
Meeting: 97th Annual Meeting AACR “Nemorubicin: a doxorubicin-like structure with a novel
mechanism of action different from anthracyclines”. Washington DC (USA), April 1-5, 2006.
Meeting: 97th Annual Meeting AACR “Antitumor activity of a new synthetic camptothecin
with the open lacton ring”. Washington DC (USA), April 1-5, 2006.
Congress: XIII Congresso Nazionale Società di Cure Palliative “Internet come strumento di
ricerca e informazione sul dolore cronico nel paziente con cancro”. Bologna (Italy), April 26-29,
2006.
Conference: Sixth ESH Euroconference on Angiogenesis “Protease-activated receptor-1 (PAR1) expression correlates with a malignant phenotype in human melanoma”. Mandelieu (France),
May 13-16, 2006.
Workshop: 5th European Workshop on Cell Death “Role of Dnp73alpha on cancer cell growth
and response to anticancer treatment in vitro and in vivo”. Rolduc (The Netherlands), May 28 –
June 2, 2006.
Meeting: 42nd Annual Meeting of the American Society of Clinical Oncology “Randomized
trial of Systematic Lymphadenectomy (LY) vs Nodal Sampling (SA) at Second Look Surgery
(SLS) in Ovarian Cancer Patients: Final Results”. Atlanta, GA (USA), June 2-6, 2006.
Meeting: 42nd Annual Meeting of the American Society of Clinical Oncology “Factors influencing
the switch from Tamoxifen (TAM) to Aromatase Inhibitors (AIs) as adjuvant therapy in early breast
cancer (EBC) patients (pts). Results from the NORA study”. Atlanta, GA (USA), June 2-6, 2006.
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IRFMN
Symposium: 18th Pezcoller Symposium “Identification of new markers expressed by tumor
endothelial cells”. Trento (Italy), June 27-29, 2006.
Congress: 8th World Congress on Gastrointestinal Cancer “How do I follow my patients with
colon and rectal cancer after curative resection?” Barcelona (Spain), June 28 –July 1, 2006.
Meeting: 19th Meeting of the European Association for Cancer Research “Histone deacetylase
inhibitor SAHA enhances paclitaxel cytotoxic effect in paclitaxel resistant human ovarian
cancer cells”. Budapest (Hungary), July 1-4, 2006.
Meeting: 19th Meeting of the European Association for Cancer Research. “VEGF released by
ovarian cancer cells stimulates host proteolytic activity within the tumor and in distant organs”.
Budapest (Hungary), July 1-4, 2006.
Congress: Wonca Europe 2006 Congress “The PartecipaSalute Project”. Florence (Italy),
August 27-30, 2006.
Congress: 11th International Congress of Metastasis Research Society “Increased host MMP9
expression in tumors and ovaries of mice bearing ovarian carcinoma cells overexpressing
VEGF”. Tokushima (Japan), September 3-6, 2006.
Congress: 11th International Congress of Metastasis Research Society. “Thrombospondin-1/
FGF-2 interaction in angiogenesis and tumor progression. Tokushima (Japan), September 3-6,
2006.
Workshop: EMBO – Stemness: the bright and the dark side. “Investigation of the DNA damage
response and checkpoints activation in stem cells derived from umbilical cord blood”.
Catanzaro (Italy), September 19-22 2006.
Congress: 31st ESMO Congress “ERCC1 and RRM1 mRNA expression in resected patients with
non- small- cell lung cancer (NSCLC). (a study of the Perugia multidisciplinary team for thoracic
tumors) “Research project AIRC“”. Istanbul (Turkey), September 29 -October 3, 2006.
Congress: 31st ESMO Congress “Analysis of treatment and prognosis in PT4 early breast cancer
patients in the Italian NORA study: outcome research”. Istanbul (Turkey), September 29 -October
3, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “VEGF and Matrix
Metalloproteinases in ovarian cancer xenografts: cross-talk between tumor and stroma cells”.
Bari (Italy), October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Vascular targeting activity of
new tubulin-binding imidazole derivatives”. Bari (Italy), October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Identification of novel markers of
tumor endothelium.”. Bari (Italy), October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “EDB/Fibronectin expression in
human tumor xenografts: modulation by microenvironment.”. Bari (Italy), October 1-4, 2006.
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2006
IRFMN
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Gonadotropin releasing hormone
receptors in human malignant melanomas: gene expression profile associated with their
inhibitory activity on cell migration/invasion”. Bari (Italy), October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Quantitative real time PCR
analysis of p63 and p73 isoforms expression in human ovarian cancer biopsies.”. Bari (Italy),
October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Questioning the oncogenic role
of Δnp73α in different cell lines expressing p53 or not”. Bari (Italy), October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Molecular mechanisms
regulating the G2 checkpoint focusing on CHK1.” Bari (Italy), October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Relationship between antitumor
activity of nemorubicin and DNA repair systems.” Bari (Italy), October 1-4, 2006.
Congress: 48° Congresso of the Italian Cancer Society (SIC). “Nemorubicin is a nonconventional anthracycline suitable for loco-regional treatment of hepatocellular carcinoma
(HCC).” Bari (Italy), October 1-4, 2006.
Workshop: Workshop on Molecular Targets for Cancer (EU) “Angiogenesis Inhibitors &
Vascular Disrupting Agents: Combination Therapies”. Luxembourg, October 6-7, 2006.
Congress: The 11th World Congress on Advances in Oncology and 9th International Symposium
on Molecular Medicine “Telomerase immortalized fibroblasts as a model system for neoplastic
transformation of human cells”. Hersonissos, Crete (Greece), October 12-14 2006.
Meeting: 14th Cochrane Colloquium “How Cochrane reviews can be used in a dissemination
project: preliminary findings from the “PartecipaSalute” project in Italy”. Dublin (Ireland),
October 23-26, 2006.
Meeting: 14th Cochrane Colloquium “Lay people empowerment: the “PartecipaSalute”
experience”. Dublin (Ireland), October 23-26, 2006.
Symposium: 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer
Therapeutics “Imidazole derivatives with vascular disrupting activity”. Prague (Czech
Republic), November 7-10, 2006.
Therapeutics “Antitumor activity of the new aureolic acid derivatives mithramycin SDK and SK
in human ovarian cancer xenografts”. Prague (Czech Republic), November 7-10, 2006.
Therapeutics “Investigating the role of Nucleotide Excision Repair (NER) in the antitumor
activity of Nemorubicin”. Prague (Czech Republic), November 7-10, 2006.
Therapeutics “Telomere damage promotes antitumoral activity of the G-quadruplex ligand
RHPS4”. Prague (Czech Republic), November 7-10, 2006.
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2006
IRFMN
Therapeutics “Pharmacokinetic of the novel oral camptothecin gimatecan in women with pretreated advanced breast cancer”. Prague (Czech Republic), November 7-10, 2006.
Therapeutics “The atypical retinoid ST1926 is synergistic with cisplatin in human
neuroblastoma xenografts”. Prague (Czech Republic), November 7-10, 2006.
Meeting: Milano New Drugs (IEO) – Angiogenesis, Environment and Stroma: Models,
Research and Care. “Vascular Targeting”. Milan (Italy), November 10-11, 2006.
Congress: 8th National Congress of Medical Oncology “Tumor characteristics, treatment
modalities and clinical outcome in breast cancer (BC) patients (pts) with 10 or more positive
nodes. Results from the NORA study”. Milan (Italy), November 18-21, 2006,
Congress: 8th National Congress of Medical Oncology “Evaluation of HER2 in serum and tissue:
correlation with clinicopathological parameters and outcome in early stage breast cancer patients”.
Milan (Italy), November 18-21, 2006.
Congress: 8th National Congress of Medical Oncology “Impact of recent legislative bills regarding
clinical research on ethics committees functioning in Italy”. Milan (Italy), November 18-21, 2006.
Congress: 8th National Congress of Medical Oncology “The clinical presentation of malignant
peritoneal mesothelioma: a multicentric study of 58 cases”. Milan (Italy), November 18-21, 2006.
Congress: 13th Congress of the European Society of Surgical Oncology “Young (≤45) and old
(≥65) early breast cancer (EBCc) patients (pts): two different populations for surgeons? Results
from the NORA study”. Venice (Italy), November 30-December 2, 2006.
Symposium: Annual San Antonio Breast Cancer Symposium “Prognostic value of serum HER2 in early stage breast cancer (BC) patients”. San Antonio, TX (USA), December 14-17, 2006.
GRANTS AND CONTRACTS
Agenzia Italiana del Farmaco
AIL Associazione Italiana contro le Leucemie, Padova
Amgem SpA, Milan
AIRC Associazione Italiana per la Ricerca sul Cancro
ASL Padova
ASL Provincia di Lodi
Astra Zeneca SpA
Astra Zeneca UK
Bracco Imaging SpA, Milan
Centro Cochrane Italiano
Chiesi Farmaceutici SpA
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, Torino
CTI Cell Therapeutics, Inc.
ANNUAL REPORT
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IRFMN
Cyclacel Ltd.
Dompé
Eli Lilly Italia SpA
Elsevier Science Ltd.
EORTC-European Organization for Research and Treatment of Cancer
EOS SpA
European Commission - 6th Framework Programme (Cancerdegradome, STROMA)
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 Lu.V.I.
Fondazione Nerina e Mario Mattioli Onlus
Fondo Edo Tempia
Grunenthal, Milano
GlaxoSmithKline, Verona
Indena SpA
Institut de Recherche Pierre Fabre
Istituto Superiore di Sanità
Italfarmaco
Komen Italia Onlus
Lottomatica
Madaus Srl
Medac
Merck Sharp & Dome
Ministero della Sanità
NCI –SAIC Frederick
Nerviano Medical Science S.r.l.
Novartis Farma SpA
Optigenex Inc.
Pfizer Global Research and Development
Pharma Mar, SA
Pharminox Ltd, UKPoliclinico di Padova / C.O.R.
PTC Pharma AG
Regione Emilia Romagna
Regione Veneto
Sara Bet, Roma
SENDO-Tech Srl
Sigma-Tau SpA
Università degli Studi di Padova
ANNUAL REPORT
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2006
IRFMN
SELECTION OF SCIENTIFIC PUBLICATIONS FROM 2006
Gallus S, Fernandez E, Pacifici R, Colombo P, Zuccaro P, Bosetti C, Apolone G, La Vecchia C. Channels of cigarette
distribution, price and tobacco consumption in Italy. Prev Med 2006; 42: 132-134.
Lupi M, Cappella P, Matera G, Natoli C, Ubezio P. Interpreting cell cycle effects of drugs: the case of melphalan.
Cancer Chemother Pharmacol 2006; 57: 443-457.
Gallus S, Pacifici R, Colombo P, Scarpino V, Zuccaro P, Bosetti C, Fernandez E, Apolone G, La Vecchia C.
Prevalence of smoking and attitude towards smoking regulation in Italy, 2004. Eur J Cancer Prev 2006; 15: 77-81.
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.
Gallus S, Colombo P, Scarpino V, Zuccaro P, Negri E, Apolone G, La Vecchia C. Overweight and obesity in Italian
adults 2004, and an overview of trends since 198360. Eur J Clin Nutr 2006; 60: 1174-1179.
Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantu' L, Kirschner D A,
Manzoni C, Beeg M, Ceci P, Ubezio P, Forloni G, Tagliavini F, Salmona M. Gerstmann-Straussler-Scheinker disease
amyloid protein polymerizes according to the "dock-and-lock" model. J Biol Chem 2006; 281: 843-849.
Rizzari C, Citterio M, Zucchetti M, Conter V, Chiesa R, Colombini A, Malguzzi S, Silvestri D, D'Incalci M. A
pharmacological study on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic
leucemia. Haematologica 2006; 91: 24-31.
Rizzardini M, Lupi M, Mangolini A, Babetto E, Ubezio P, Cantoni L. Neurodegeneration induced by complex I
inhibition in a cellular model of familial amyotrophic lateral sclerosis. Brain Res Bull 2006; 69: 465-474
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: 346-347.
Apolone G, La Vecchia C, Garattini S. Targeted kinase inhibitors in lung cancer: From EGFR to patients. Eur J
Cancer 2006; 42: 124-125.
Apolone G, Bertetto O, Caraceni A, Corli O, De Conno F, Labianca R, Maltoni M, Nicora M, Torri V, Zucco F,
Cancer Pain Outcome Research Study Group. Pain in cancer. An outcome research project to evaluate the
epidemiology, the quality and the effects of pain treatment in cancer patients. Health Qual Life Outcomes 2006,
http://www.hqlo.com/content/4/1/7.
Taraboletti G, D'Ascenzo S, Giusti I, Marchetti D, Borsotti P, Millimaggi D, Giavazzi R, Pavan A, Dolo V.
Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH. Neoplasia 2006; 8:
96-103.
Grosso F, Dileo P, Sanfilippo R, Stacchiotti S, Bertulli R, Piovesan C, Jimeno J, D'Incalci M, Gescher A, Casali P G.
Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma. Eur J
Cancer 2006; 42: 1484-1490.
Naumova E, Ubezio P, Garofalo A, Borsotti P, Cassis L, Riccardi E, Scanziani E, Eccles S A, Bani M R, Giavazzi R.
The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing
apoptosis of endothelial cells and inhibition of angiogenesis. Clin Cancer Res 2006; 12: 1839-1849.
Spinelli L, Torricelli A, Ubezio P, Basse B. Modelling the balance between quiescence and cell death in normal and
tumour cell populations. Math Biosci 2006; 202: 349-370.
Fruscio R, Lissoni A A, Frapolli R, Corso S, Mangioni C, D'Incalci M, Zucchetti M. Clindamycin-paclitaxel
pharmacokinetic interaction in ovarian cancer patients. Cancer Chemother Pharmacol 2006; 58: 319-325.
ANNUAL REPORT
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2006
IRFMN
Colucci S, Taraboletti G, Primo L, Viale A, Roca C, Valdembri D, Geuna M, Pagano M, Grano M, Pogrel A M,
Harris A L, Athanasou N N, Mantovani A, Zallone A, Bussolino F. Gorham-Stout syndrome: A monocyte-mediated
cytokine propelled disease. Journal Bone Mineral Research 2006; 21: 207-218.
Mondello C, Zongaro S, D'Incalci M. Telomerase expression in somatic cells: fountain of youth or Damocles' sword?
Cell Cycle 2006; 5: 465-466.
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.
Apolone G, Grossi E. Effectiveness and outcome research studies: current trends. Drug Dev Res 2006; 67: 181-182.
Floriani I, Torri V. Methodology of clinical research: an overview. Drug Dev Res 2006; 67: 183-187.
O'Connell D, Mosconi P. An active role for patients in clinical research? Drug Dev Res 2006; 67: 188-192.
Cavuto S, Bravi F, Grassi M C, Apolone G. Propensity score for the analysis of observational data. An introduction
and an illustrative example. Drug Dev Res 2006; 67: 208-216.
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.
Grossi E, Groth N, Mosconi P, Cerutti R, Pace F, Compare A, Apolone G. Development and validation of the short
version of the Psychological General Well-Being Index (PGWB-S)
Health Qual Life Outcomes 2006, http://www.hqlo.com/content/4/1/88.
Apolone G, Mangano S, Compagnoni A, Negri Emanuele, Mosconi P, Mannino S, Villa M, Zuccaro P, Cancer Pain
Outcome Research Study Group. A multidisciplinary project to improve the quality of cancer pain management in
Italy. Background, methods and preliminary results. J Ambul Care Manage 2006; 29: 332-341.
Corica F, Corsonello A, Apolone G, Lucchetti M, Melchionda N, Marchesini G, QUOVADIS Study Group.
Construct validity of the Short-Form-36 Health Survey and its relationship with BMI in obese outpatients. Obesity
2006; 14: 1429-1437.
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; 95: 266-271.
Maggioni A, Benedetti Panici P, Dell'Anna T, Landoni F, Lissoni A, Pellegrino A, Rossi R S, 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; 95: 699-704.
Cazzaniga M E, Mustacchi G, Pronzato P, De Matteis A, Di Costanzo F, Floriani I, Rulli E, Porcu L, NORA Study
Group. Adjuvant systemic treatment of early breast cancer: the NORA study. Ann Oncol 2006; 17: 1386-1392.
Regge D, Campanella D, Anselmetti G C, Cirillo S, Gallo T M, Muratore A, Capussotti L, Galatola G, Floriani I,
Aglietta M. Diagnostic accuracy of portal-phase CT and MRI with mangafodipir trisodium in detecting liver
metastases from colorectal carcinoma. Clin Radiol 2006; 61: 338-347.
Mandala M, Falanga A, Cremonesi M, Zaccanelli M, Floriani I, Vigano M G, Rosti A, Cazzaniga M E, Ferretti G,
Cabiddu M, Barni S. The extension of disease is associated to an increased risk of venous thromboembolism (VTE)
in patients with gastrointestinal (GI) carcinoma. Thromb Haemost 2006; 95: 752-754.
Parrella E, Gianni M, Fratelli M, Barzago M M, Raska I Jr, Diomede L, Kurosaki M, Pisano C, Carminati P, Merlini
L, Dallavalle S, Tavecchio M, Rochette-Egly C, Terao M, Garattini E. Antitumor activity of the retinoid-related
molecules (E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid (ST1926) and 6-[3-(1-adamantyl)-4hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) in F9 teratocarcinoma: Role of retinoic acid receptor gamm.
Mol Pharmacol 2006; 70: 909-924.
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D'Incalci M. Correlation of ErbB2 gene status, mRNA and protein expression. Onkologie 2006; 29: 246-247.
Sironi M, Conti A, Bernasconi S, Fra A M, Pasqualini F, Nebuloni M, Lauri E, De Bortoli M, Mantovani A, Dejana
E, Vecchi A. Generation and characterization of a mouse lymphatic endothelial cell line. Cell Tissue Res 2006; 325:
91-100.
Frapolli R, Marangon E, Zaffaroni M, Colombo T, Falcioni C, Bagnati R, Simone M, D'Incalci M, Manzotti C,
Fontana Gabriele, Morazzoni P, Zucchetti M. Pharmacokinetics and metabolism in mice of IDN 5390 (13-(N-Boc-3i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III) a new oral C-seco-taxane derivative with antiangiogenic
property effective on paclitaxel-resistant tumors. Drug Metab Dispos 2006; 34: 2028-2035.
Beretta G L, Petrangolini G, De Cesare M, Pratesi G, Perego P, Tinelli S, Tortoreto M, Zucchetti M, Frapolli R, Bello
E, Manzotti C, Fontana Gabriele, Bombardelli E, Battaglia A, Samori' C, Zunino F. Biological properties of
IDN5174, a new synthetic camptothecin with the open lactone ring. Cancer Res 2006; 66: 10976-10982.
Moreno M, Sani M, Raos G, Meille S V, Belotti D, Giavazzi R, Bellosta S, Volonterio A, Zanda M. Stereochemically
pure alfa-trifluoromethyl-malic hydroxamates: synthesis and evaluation as inhibitors of matrix metalloproteinases.
Tetrahedron 2006; 62: 10171-10181.
Kruczynski A, Poli M, Dossi R, Chazottes E, Berrichon G, Ricome C, Giavazzi R, Hill B T, Taraboletti G. Antiangiogenic, vascular-disrupting and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical
development. Eur J Cancer 2006; 42: 2821-2832.
Marrazzo E, Marchini S, Previdi S, Broggini M. Questioning the oncogenic role of
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Sessa C, Cresta S, Cerny T, Baselga J, Caremoli E, Malossi A, Hess D, Trigo J, Zucchetti M, D’Incalci M, Zaniboni
A, Capri G, Gatti B, Carminati P, Zanna C, Marsoni S, Gianni L. Concerted escalation of dose and dosing duration in
a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors. Ann Oncol
2006; Dec. 5, Epub ahead of print.
Verschoyle RD, Greaves P, Cai H, Borkhardt A, Broggini M, D’Incalci M, Riccio E, Doppalapudi R, Kapetanovic
IM, Steward WP, Gescher AJ. Preliminare safety evaluation of the putative cancer chemopreventive agent tricin, a
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Floriani I, Torri V
Come sopravvivere alle curve di sopravvivenza II – Ovvero come si confrontano le curve di KaplanMedical Oncology Progress & Perspectives, Update 2006; 24: 9-10
Floriani I, Torri V
Sopravvivere alle curve di sopravvivenza
Medical Oncology Progress & Perspectives, Update 2006; 22: 21-25
Floriani I, Rulli E, Compagnoni A, Torri V
I criteri decisionali: dal valore soglia alla predizione. In:PSA. Antigene Prostatico Specifico. CIC Edizioni
Internazionali 2006; 87-96
Floriani I., Torri V.
Endpoints surrogati: non è tutto oro quello che luccica
Medical Oncology Progress & Perspectives, Update 2006; 21:21-25
Velo G, Bassi M, Apolone G, Rossi M, Buscone N, Scarpino V, Rizzini P.
Informazione scientifica sul farmaco: risultati di un'indagine pilota su un campione di Medici di Medicina Generale
Economia e Politica del Farmaco 2006; 7: 13-19
Colombo Cinzia, Mosconi P, Nonis A, Apolone G.
Aspetti etici della ricerca clinica in oncologia. In: Fondamenti di oncologia clinica.
Elsevier, Amsterdam 2006; 101-113
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Nonis A, Apolone G.
La regolamentazione della ricerca clinica in oncologia. In: Fondamenti di oncologia clinica. Elsevier, Amsterdam
2006; 789-804
Apolone G, Garattini S.
Il trasferimento dell'innovazione nella clinica e nella organizzazione: sintesi, commenti e riflessioni
In: Rapporto Sanità 2006. Il trasferimento dell'innovazione nella clinica e nell'organizzazione sanitaria. Il Mulino,
Bologna 2006; 159-167
Apolone G, Rizzini P.
L'innovazione a braccetto di clinica e organizzazione
Sole 24 Ore 2006; 8: 20-21
Rodriguez T, Gallus S, Chatenoud L, Zuccaro P G, Colombo P, Apolone G, Pacifici R, Garattini S, La Vecchia C.
Efecto de la nueva regulaciòn antitabaco en italia.
Salud Publica Mex 2006; 48 suppl 1: S137-S139
Clivio L
Progetto MAIA: dispositivi e strategie
Ricerca & Pratica 2006; 22: 86-88
Clivio L
Progetto MAIA: dispositivi e strategie
Ricerca & Pratica 2006; n.128: 86-88
Clivio L
Progetto MAIA. Una sperimentazione formale di strategie di comunicazione alternativa per disabili motori: analogie
con la sperimentazione di farmaci
Ricerca & Pratica 2006; n.129: 126-129
Mosconi P, Apolone G
Cosa sono i Comitati Etici e che ruolo hanno le associazioni
MOVI Movimento Volontariato in Italia 2006; 6
Colombo C, Mosconi P, Nonis A, Apolone G
Aspetti etici della ricerca clinica in oncologia.
In: Fondamenti di oncologia clinica. Elsevier, Amsterdam; 2006 : 101-113
Mosconi P, Patrucco V, Colombo C
Il coinvolgimento dei cittadini in sanità
Salute e Territorio 2006; 27: 120-125
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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 surprisingly 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.
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.
Mode of action of Variolins
These compounds rapidly induce apoptosis in different cell types but their mechanism of action
is still not known. They cause perturbations of the cell cycle with a cell block in G1 and G2
probably due to inhibition of CDKs. It is interesting to note that these drugs are also active on
cells resistant to other natural products, eg cells that overexpress Pgp, responsible for
“Multidrug resistance”.
Studies performed by using confocal microscopy analysis, to identify the variolin’s cellular
localization suggest that Variolin is localized mostly in the nucleous. We have obtained two
human ovarian cancer cell lines resistant to Variolin and studies are in progress to characterize
the mechanism of resistance.
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.
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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
populations. Several computing tools have been produced, to simulate the cell proliferation at
different levels (from molecular interactions to in vivo growth of solid tumors) 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
The project addresses the issue of establishing a connection between the intracellular drug
interactions and the resulting cell cycle perturbations. It starts from the single-cell 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, following a short treatment with
melphalan on a reference cell line of ovarian carcinoma. These results add to the previously
reported studies on topotecan, cisplatin and taxol. Eventually, this project will produce 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.
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
synchronisation.
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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.
Establishing a CFSE-based method for quantitative measuring cytostatic
effects of drugs on tumor cell populations
Carboxyfluorescein diacetate succinimidyl ester (CFSE) is currently used to investigate
migration and proliferation of hematopoietic cells. Several technical problems had precluded
until now its use in the studies on the antiproliferative activity of anticancer drugs. We analysed
several critical steps of the procedure, providing the way to overcome potential pitfalls. The
project was eventually successful and the previous limitations were overcome. The outcome
was a new standardized procedure of cytometry and data-analysis allowing a measure of the
dynamics of cell cycle blockades after drug treatment. The new method was applied in the study
of the drug topotecan, measuring the variability of response to treatment in terms of percentage
of cells immediately blocked, divided once or more times and then blocked or unaffected by the
treatment.
Pharmacokinetic of new taxane derivates
Preclinical studies have been done on new taxane derivatives, chemically and biologically
different from the conventional ones. For three of these compounds we evaluated the
bioavailability after oral administration and the kinetic and metabolic profile has been entirely
characterized by applying analytical methods based on HPLC/MS/MS technique developed in
the Cancer Clinical Pharmacology Unit. They showed biological activity even in tumors with
low susceptibility to other taxanes (cerebral tumor), suggesting a potential clinical interest.
According to the hypothesis that these drugs act through an antiangiogenic mechanism, put
forward by the Laboratory of the Biology and Therapy of Metastasis, it would be important to
investigate prolonged chronic treatments and therefore we are investigating the pharmacokinetic
properties after oral administration and after prolonged daily treatment.
Clinical pharmacokinetics of gimatecan
A study in collaboration with SENDO has shown the clinical pharmacokinetics of a new
derivative of camptothecin (Gimatecan) in patients with breast cancer and in patients with
sarcoma under phase II investigation. Studies still in progress show that this compound is
rapidly absorbed after oral administration and has a long half life, with consequent long
exposure to the drug.
Pharmacokinetic parameters will be correlated to the clinical data, i.e. toxicity and tumor
activity, to characterize the properties of this new drug.
Other relevant clinical studies
Imatinib mesylate. The clinical pharmacokinetic of imatinib is under investigation in adults and
children with Philadelphia Chromosome positive (Ph+) leukemias. In particular we studied the
bioavailability of the drug and its metabolism in young children providing for the first time data
on the main plasma metabolite of imatinib (N-Desmethyl-imatinib), showing that its formation
and disposition is similar to those found in adult patients. In addition, we found that children
with high plasma levels of alpha1-acid glycoprotein (AAG) had highest Cmax and AUC of
drug. Our data, even if preliminary, suggest that the plasma levels of AAG influence imatinib
pharmacokinetics and that drug protein binding had to be considered in children.
Gemcitabine. To exert the pharmacological activity, gemcitabine (dFdC) is a pro-drug that have
to be converted at intracellular level to the active metabolite dFdCTP. Previous studies
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demonstrated that the achievement of a threshold value of plasma concentration of gemcitabine
superior to 15 µM is essential to obtain the best intracellular accumulation of dFdCTP.
In our study, we wanted to verify, if administering the drug as fixed dose rate of 10 mg/m2/min
(total dose range 600-1200 mg/m2) the target level of 15 µM could be achieved. Starting from
January 2006, the study was conducted in 8 patients enrolled in the protocol for the treatment of
the advanced non-small-cell lung cancer at the Department of Oncology of Santa Chiara
Hospital, Trento. The pharmacokinetic results obtained showed that the steady state target
plasma concentration of 15 µM was successfully achieved in all courses of the patients treated
with 600 mg/m2 (range D1: 20.2-25.8 µM; D8: 16.9-28.2 µM) and in 14/16 of those treated with
1200 mg/m2 (range D1: 17.1-64.2 µM; D8: 15-39.8 µM). In only two occasions were achieved
concentrations of 12.5 and 12.6 µM. In conclusion our results suggest that the critical
concentration of 15µM was achieved both at 600 or at 1200 mg/m2 and, as expected, it was
maintained longer with the infusion of 120 min
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 and
combinations is being investigated using rodent tumors and human tumor xenografts.
Antitumoral activity of compounds with known chemopreventive activity
The mechanism of action and the antitumor activity of Indole-3 carbinole, its derivatives and
some isothiocianates of natural origin are being investigated in several experimental systems.
Laboratory of Molecular Pharmacology
G2 checkpoint and cell cycle
A new system able to specifically inhibit CHK1 expression in vivo in nude mice transplanted
with human tumors has been developed. The system has been proved to be able to reduce the
expression only in cancer cells. This plasmid allows the expression of the siRNA only after
induction with tetracycline and is therefore a unique tool to determine the effect of CHK1
inhibition in human tumors growing in nude mice following treatment with anticancer agents.
Characterization of new potential oncosuppressor genes
The DRAGO gene, identified and cloned in our laboratory is one of the most interesting
projects of the group. The characterisation of the response of KO mice for DRAGO to ionising
radiation is similar to normal mice. The characterisation of the transcriptional regulation of
DRAGO indicated that the gene is not only a p53-responsive gene, but, inside the p53 family,
p73 has a strong ability to induce the transcription. Drago therefore, represents a new p73
responsive gene.
Molecular characterization of ovarian carcinoma
The molecular characterization of stage I ovarian carcinomas has been further studied.
The gene expression profile analysis has showed interesting results:
It is possible to identify genes able to discriminate in ovarian cancer the different histotypes,
suggesting that specific biological and molecular characteristics are responsible for the
differences in morphology and clinical behavior. These studies can help in identifying new
specific molecular targets for the different subclasses of ovarian cancer that have a different
clinical outcome.
It is possible to identify patients with higher probability of relapse because there are genes able
to differentiate these two classes of genes.
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We have demonstrated that stage I borderline patients have a gene expression profile similar to
that of grade 1 patients, while they are well distinguishable from grade 2 and grade 3 patients.
This can have important clinical implications for the treatment of this particular subgroup of
patients.
Expression of p63 in ovarian tumors
P63 belongs to the family ofp53 and its role is particularly relevant in embryo development. Its
role as tumor suppressor has not been clarified yet. The gene encoding for p63 has a complex
organisation which generates, among the others, a truncated isoform (DNp63), lacking the
transactivation domain, which could act as a dominant negative for either p63 or p53. We have
analysed the expression of the entire form (TAp63) and of DNp63 in approximately 90 ovarian
cancer patients at stage I (early) and 90 at stage III (advanced tumor). The levels of TAp63 are
similar in the two groups of patients, while the levels of DNp63 were higher in stage III tumors
than in stage I tumors. The ratios between DNp63 and TAp63 increased consequently with the
increase in malignancy. As a result, patients with higher ratio between DNp63 and TAp63 have
a worst probability to survive. This has been observed not only in the whole population, but the
tendency has been observed also analysing separately the two groups of patients. Altogether
these results suggest that DNp63 can be considered as a new target to inhibit in this malignancy.
Inhibition of the signal mediated by PI3K/akt
In ovarian carcinoma cells PI3K gene is often overexpressed or mutated and this kinase is then
constitutively activated. The consequence is the presence of proteins involved in cell survival,
like akt, constitutively phosphorylated and then active. This project evaluated the capacity of
tetra and pentaphosphate inositols and of some analogues to inhibit akt recruitment to the
membrane and its further phosphorylation. IP5 and some new synthetic molecules, were shown
to induce a reduction of the phosphorylation of akt and therefore to reduce cell growth. The
activity of these molecules is not restricted to ovarian cancer, but has been shown also for other
tumors such as breast and prostate. The possibility to combine PI3K inhibitors and mTOR ( a
kinase downstream to PI3K and akt) inhibitors has been evaluated. It has in fact been shown
that some mTOR inhibitors induce an aberrant phosphorylation, and hence activation of akt, and
the combination of these inhibitors can block these undesired effects. The in vitro results show
that the combination has at least an additive effect and opens the way to find out new treatment
schedules tand verify whether the sequence of combination can be important for the
antiproliferative effects.
Oncosuppressors p53 and p73
The p53 analogue, p73 is present in different isoforms derived from alternative splicing of the cterminal. Among these isoforms there is one called DNp73 in which the transactivation domain
in the N-terminal of the protein is absent. This DN form of p73 is an antagonist of p53.
The DNp73 isoforms can be further processed through alternative splicing, to generate a number
of isoforms with a not yet clarified biological activity. We have previously shown that the alfa
form of DNp73 does not modify either the growth in vitro and in vivo of cancer cells or the
response to treatment with anticancer agents.
We have therefore generated clones derived from the human lung cancer derived cell line
H1299 which express DNp73 beta following induction. These clones show, upon induction,
interesting effects on cell growth suggesting that the presence of high levels of this isoform can
have unpredicted effects. Since from the data generated on the expression of p73 isoforms in
cancer patients indicate that the beta isoform of DNp73 is indeed present in human cancer, the
results obtained have a particular relevance and will be further analysed to verify which are the
effects linked to the overexpression of this isoform.
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Mechanisms of action of new antitumor drugs
The mechanism of action of a new anthracycline derivative, nemorubicin (methoxy morpholino
doxorubicin) has been characterised. Nemorubicin presents a pattern of antitumor activity in
vitro and in vivo different from that of doxorubicin.
We have found that cell lines with defects in DNA repair mechanisms, and particularly in the
nucleotide excision repair (NER), are resistant to the treatment with this molecule. It is
interesting to note that the majority of the drugs interacting with DNA, like cisplatin, show
exactly the opposite: defects in NER are associated with high sensitivity. Moreover, a possible
resistance mechanism for these drugs, is associated with an increased activity of NER in some
tumors.
Nemorubicin resistant cells have instead a reduced NER activity and show a collateral
sensitivity to cisplatin. These results represent the molecular rational for the combined treatment
between cisplatin and nemorubicin and /or for the treatment of cisplatin resistant tumors with
nemorubicin.
Characterisation of response of stem cells to damage
The therapeutic use of stem cells is continuously increasing. This project aims to investigate the
ability of stem cells isolated from umbilical cord to respond to stress induction with particular
emphasis on their ability to activate checkpoint proteins. Stem cells isolated and maintained in
vitro with specific cytokine cocktails able to induce partial differentiation, have shown a
peculiar expression of proteins controlling the cell cycle. In particular, there is a specific time
point in the differentiation process in which cell cycle checkpoints proteins are present in high
levels. This could imply that this represents the time point in which these cells are more
susceptible and must be “protected” from external damages. The characterisation of these
important molecular aspects will be further studied.
Identification of cancer stem cells form ovarian cancer
This project is aimed at isolating and characterising 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
characterise the cancer stem cell would theoretically open the way to the selection of new
generation molecules able to preferentially kill these cells. Cancer stem cells have been already
identified in different human tumors including breast and hematopoietic tumors. We will focus
our attention on human ovarian cancer by the use of antibodies directed against surface marker
proteins to identify such potentially relevant cancer sub populations.
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 2006 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 particular, we are
studying the structure/function relationship of the different active domains of TSP-1, with the
main aim to identify the FGF-2 binding site.
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We are studying the involvement of matrix metalloproteinases (MMPs) in angiogenesis and
tumor progression. In particular in 2006, we studied the cross-talk between MMPs and Vascular
EndothelialGrowth Factor (VEGF), a factor that stimulates angiogenesis and vessel
permeability, during ovarian carcinoma progression. We are analyzing modifications in
metastasis/invasion-related gene expression profile in stroma cells induced by tumor VEGF.
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 new drugs. To this purpose we
analysed the gene expression profile of endothelial cells isolated from ovarian carcinoma and
adrenal glands exposed or not to an “angiogenic/tumor” environment reconstituted in vitro. We
have found that
i) the “angiogenic/tumor” environment is indeed able to modulate EC gene expression;
ii) few genes are preferentially expressed by tumor associated endothelial cells.
Preliminary results suggest that few of the genes might be of interest as markers of tumor
endothelium. Their expression is higher in endothelial cells from tumor specimens than from
normal tissues and they are not expressed by tumor cells.
The putative new tumor endothelial markers identified has been further validated as anti-cancer
/ vascular targets by in situ hybridisation analysis of several normal and tumor tissues.
The putative targets (identified as mRNA transcript) are being produced as a recombinant
protein (either intact/full antigens or globular domains), with the aim to isolate antibodies,
directed against the recombinant proteins, suitable for immunohistochemical analyses.
In collaboration with ETH-Zurich we have refined orthotopic metastatic models (colon
carcinomas metastatic to the liver) for the in vivo biotinylation studies. The terminal perfusion
of mice with a reactive ester derivative of biotin that enables the covalent modification of
proteins readily accessible from the bloodstream has been performed. The comparative
proteomic analysis (performed by ETH-Zurich) will allow to find both quantitative and
qualitative differences in biotinylated proteins in metastatic organs.
Preclinical models: role of FGF2 and VEGF on tumor growth and
vascularization and response to therapy
Tumor angiogenesis is controlled by multiple factors produced by the tumor and host. Human
endometrial carcinoma cells (HEC-1-B) have been generated that differ for the expression of
FGF-2 and/or VEGF) (studies performed in collaboration with the University of
Brescia). We have shown the tumor growth and vascularization are tight regulated by the
simultaneous expression of these growth factors. We have found that tumors (xenografts
trasplanted in nude mice) in which FGF2/VEGF are down expressed are still highly sensitive to
chemotherapy (e.g. to paclitaxel, doxorubicin). We are now studying the influence of the stroma
composition, modified by the expression of the different growth factors, to the kinetic of the
drug distribution and ultimately to the drug response.
The role of VEGF in the ovarian carcinoma has been studied in the A2780/1A9 transfected with
VEGF121 (VS1 variant) or its antisense (VAS-3 variant). In nude mice, VS1 shows an
angiogenic phenotype and produce high plasma VEGF.
We have found that the response to chemotherapy (e.g. paclitaxel) might differ in xenografts
producing different levels of VEGF. Studies are ongoing to elucidate the mechanism
responsible of these differences.
This model is being used to study gene expression in the stroma of tumors producing angiogenic
growth factor.
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Based on circulating VEGF levels and morphological analysis of the vasculature, samples were
chosen to undergo the gene expression study. In collaboration with the Institute of Pathology at Helios
Klinikum (Germany) tissue slices of the 1A9-VS1 and 1A9-VAS3 tumors were cut, stained with
hematoxylin and eosin, and microdissected (PALM Microlaser system) in order to isolate the
stroma compartment to be evaluated by mean of Affymetrix’s GeneChip® Arrays technology.
The microarray hybridisation data are currently being analyzed with the aid of specialized
softwares (i.e. GeneSpring and Rosetta Resolver). Initial analysis suggest that 183 transcripts
are preferentially expressed by the stroma of tumors showing a pronounced angiogenic
phenotype.
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 treatment aims to selectively destroy the already formed tumor vessels. In
2005 we have continued the study of antiangiogenic compounds, with particular interest for the
mechanism the anti-angiogenic activity of taxanes.
Among the anti-vascular compounds, we have studied the properties of 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 the Department of Chemistry at the University of Pisa, we have screened
classes of compounds with such properties. The lead compound/s will be further characterized
for pharmacological and anti-vascular/antineoplastic properties.
Antineoplastic combination Therapies
The optimization of biological therapies against selective targets in combinations with
chemotherapy is one of the interest of this laboratory. The main class of compounds under study
are the angiogenesis inhibitors that are thought to achieve optimal therapeutic efficacy when
combined with conventional therapies. We have previously shown that paclitaxel added to
SU6668, a tyrosin kinase inhibitor of VEGFR2, FGFR1 and PDGFR receptors, potentiated the
antineoplastic activity on human ovarian carcinoma xenograft models. We have now shown that
SU6668 and paclitaxel act sinergistically on vascular cells, inhibiting their proliferation, causing
increased apoptosis and inhibiting angiogenesis response in vivo.
We have shown that in combination treatments, the vascular disupring activity of the tubulin
binding ZD6126 is blocked by pretreatment with paclitaxel, a tubulin binding drug with
opposite mechanism of action. An optimized schedule of administration of the two agents not
only avoids the interference among drugs, but greatly improves the antineoplastic efficacy of the
combination in experimental models. Studies are undergoing to further otpimize schedules of
treatment on the basis of the mechanism of action of the drugs given in combination.
There is clear evidence that histone deacetylase inhibitors are a new potential class of anticancer
agents; recent reports indicate a greater antitumor effect of these compounds combined with
radiation and chemotherapy. To evaluate whether the inhibition of histone deacetylase (HDAC)
activity could enhance sensitivity to paclitaxel we investigated the effect of suberoylanilide
hydroxamic acid (SAHA) on the paclitaxel-sensitive 1A9 and -resistant 1A9PTX22 cells.
SAHA induced a comparable growth inhibition at micromolar concentrations and in a dosedependent manner in both 1A9 and 1A9PTX22 cells. Inhibition of cell proliferation, evaluated
by combining doses of SAHA and paclitaxel ranging from IC30 to IC0, produced a synergistic
effect. These findings show that SAHA has an antitumor activity in ovarian cancer cells with
different sensitivity to paclitaxel. Furthermore, SAHA seems to be capable to partially restore
sensitivity to paclitaxel in the 1A9PTX22 resistant cells. The effect is not due to a cell cycle
blokade or augmented apoptosis, but is instead associated to enhanced tubulin acetylation.
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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 human melanoma cells, isolated from lesions representing various
stages of disease progression, for the expression of PAR-1 (in collaboration with the University
of Siena) and evaluated their migratory and metastatic capabilities. Cells from advanced stage
melanomas expressed higher levels of PAR-1 than those from early stages. Melanoma cells
over-expressing PAR-1 had higher migrated (chemotaxis assay) and invading (invasion assaymatrigel) cell counts than those expressing low PAR-1. The metastatic capability, examined
after intravenous injection in nude mice, shows the melanoma cells which overexpressed PAR-1
were able to colonize the lungs in 70-100% of the mice.
Laboratory for the development of new pharmacological
strategies
This recently instituted 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.
The acquisition of know how and the development and application of new designs for clinical
activity studies, including the use of randomization, the introduction 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 move biomarkers evaluation already to 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 of those therapies aimed at specific molecular targets,
as well as the identification of factors predictive of therapeutic response.
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Laboratory of Clinical Trials
The Laboratory of Clinical Trials is involved in the planning, coordination and analysis of
randomised clinical trials in oncological field, conducted in cooperation with a network of
medical oncologists. Main covered research areas are gastric, colo-rectal, breast and lung
cancer.
Gastric cancer
ITACAS ”Intergruppo Nazionale Adiuvante Gastrico” study is a randomised, open-label,
multicentric, 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. Started in February 2005, at present the study has recruited more than 500
out of the expected 1100 patients.
Lung cancer
The epidermal growth factor (EGFR) is overexpressed in many solid tumors including nonsmall
cell lung cancer (NSCLC) and is associated with disease progression and poor prognosis. EGFR
is therefore a promising target for anticancer therapy. Compounds that block ligand induced
EGFR activation have been developed. Gefitinib is an active quinazoline derivative that
selectively inhibits EGFR- tyrosine kinase, thereby blocking signal transduction pathways
implicated in proliferation and survival of cancer cells. There is now considerable evidence that
EGFR is overexpressed in an extensive range of human cancers including NSCLC. Importantly,
this has been correlated in many cases with poor prognostic features. According to this
rationale, a randomised clinical trial has been launched in Europe sponsored by EORTC and, in
Italy, by the Mario Negri Institute. Aims are to demonstrate in a prospective way a benefit in
terms of overall survival and progression-free survival of Gefitinib compared to placebo in
patients with advanced non small cell lung cancer (NSCLC), who are not progressing on first
line palliative induction chemotherapy: Patient accrual started in 2005 is still ongoing.
Colon cancer
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 regiomen (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.
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
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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.
Laboratory of Translational and Outcome Research in Oncology
The Laboratory is mainly aimed at documenting, by using either 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). In order to facilitate the research activities and optimize the outputs, the
Laboratory hosts the Coordination Centers of two multi-disciplinary Groups (MANGO: Mario
Negri Gynecologic&Oncology and the CP-OR: Cancer Pain Outcome Research Study Groups),
and an Informatics Unit that develops and implements informatics tools to facilitate the
conduction of multi-center clinical studies, such as eCRF and web-based remote data entry.
Colo-rectal cancer
The assessment of efficacy of screening for relapses of colorectal carcinoma has been debated
for a long time, with controversial results. GILDA is an open label, international, randomised
study comparing two different strategies of post surgical surveillance in colorectal cancer
(Dukes B2-C stage): minimalist versus intensive. Primary endpoints of this trial are disease free
survival (which is used to assess diagnostic anticipation of metastases), overall survival, health
related quality of life, direct and indirect costs evaluation. At present, GILDA trial is the largest
randomised study evaluating the efficacy of two follow-ups in colorectal carcinoma. The trial
was closed to patient entry in September 2006 when a total of 1200 patients had been enrolled.
Follow up of patients is ongoing and preliminary results in terms of diagnostic anticipation and
pattern of relapses are expected in 2008.
Smoking cessation
Bupropion is an antidepressant with dopaminergic and noradrenergic activity and has shown
clinical efficacy for smoking cessation in specialized clinics when combined with high levels of
psychosocial support. The aim of this trial is to confirm the efficacy of bupropion in the setting
of family medical practice, within a simplified strategy of counseling not provided by trained
counselors. The research design is the double blind, placebo controlled, randomised clinical
trial. Eligible for inclusion are subjects who have smoked an average of 10 cigarettes or more
per day for the past year. The length of treatment is 7 weeks with three clinic visits scheduled
over this period. Clinic visits for follow up assessments will occur at 26 and 52 weeks. Primary
outcome measures are continuous abstinence and point prevalence rate of abstinence (self report
of abstinence during the seven days preceding assessment); changes in weight, blood pressure,
heart rate and the incidence of adverse events will be recorded and analysed. The study has
reached the required number of patients and has been closed. A network of 71 Italian general
practitioners (GPs) enrolled 593 participants between April 2004 and May 2005. Forty-one
percent of the group given bupropion were continuously abstinent from week 4 to 7 as
compared with 22% of the placebo group (OR, 2.37; 95% CI, 1.60 to 3.53). The continuous
abstinence rates from week 4 to 12 months were 25% in the bupropion group and 14% in the
placebo group (OR, 2.13; 95% CI, 1.33 to 3.41). The adherence of GPs and participants to the
protocol was excellent, making our findings robust and easy to generalize to the context of
primary care. This study, moreover, highlighted the great research potential of Primary Care
setting which, in Italy, has been overlooked for a long time because of legislative vacuum.
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Lymphoangiogenesis in epithelial ovarian cancer: clinical aspects and
experimental studies
Epithelial ovarian carcinoma is the leading cause of death from gynecologic malignancies in the
developed world. Lymphatic spread in early ovarian cancer is a predictor of outcome with
potential clinical value. In fact, the presence of node metastases upstages the patients with
ovarian cancer apparently limited to the pelvis to FIGO stage IIIc disease and these patients are
appropriate candidates for postoperative chemotherapic treatments. Even in advanced phases of
the disease the metastatic involvement of aortic and pelvic nodes is still a predictor of survival.
This project is aimed at providing further insight into the lymphatic spread of ovarian cancer.
Two approaches will be followed to study this pathogenetic aspect of ovarian cancer: a clinical
approach where the lymphoangiogenetic activity of primary ovarian cancer will be quantified
and correlated with the nodal status of women who underwent systematic lymphadenectomy
(task 1) and an experimental approach where a model of human ovarian cancer xenograft
overexpressing VEGFC will be set up and used to study the mechanisms of lymphatic spread
and possible therapeutic approaches (task 2).
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. In fact, 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 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), a true International Forum that circulates the scientific proposals
from fifteen collaborative groups through ten countries. Currently, two randomized clinical
trials in ovarian cancer have already started recruitment, one sponsored by a French group
(CALYPSO study) and the other sponsored by EORTC. Other collaborations with Dutch and
German collaborative groups will soon be activated to conduct randomized clinical trials in
endometrial cancer.
Pain in cancer. Outcome research study
Between 60% and 80% of patients with advanced cancer will need pain treatment in their life.
In spite of availability of effective pain treatment, several studies document under-treatment of
pain, mostly in Italy, where multiple barriers do exist limiting the use of opioid drugs. In order
to increase the quality and effectiveness of pain management in cancer patients, in 2004 a multistep outcome research project was designed and launched. Two areas were identified as relevant
and important: information and education activities and prospective data collection to document
patterns of care and outcomes. Operationally, under the supervision of a Board of experts some
working groups met several times during 2004, identified a selected sample of about 100 centers
treating cancer patients with advanced/metastatic disease and pain that could be potentially
eligible for a prospective study and planned 3 lines of activities to be implemented during the
following 3 years (2005-2007): a) information and education: a prototype of educational course
for professionals (physicians and nurses) has been assembled and tested in 2005 on a sample of
participants (through a residential course approved by the Italian Committee for Medical
Continuing Education with 26 and 33 credits for physicians and nurses, respectively); the course
will be replicated in 2006 on a larger sample of participants; b) a critical appraisal of
information available on the web (Internet) was also done with the preparation and publication
of a meta-site that facilitates the use of selected resources for people interested and/or involved
in issues related to cancer pain (http://www.paincare.it); b) drug utilization and appropriateness:
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an evaluation of the volume and quality (appropriateness) of prescription of analgesic drugs in a
large administrative data base in collaboration with a local Italian Health Authority (ASL
Cremona, Italy) has been successfully carried out in 2005 to test the feasibility of the approach,
and then an application in a wider context (Le Marche, Italy) will be also implemented in 2006;
c) a prospective, multicenter, nationwide effectiveness study to test the effect of different and
alternative analgesic strategies (such as oral morphine, fentanyl and buprenorphine patches, etc)
on patient-reported-outcome. In 2005 a pilot study to test the study methods and feasibility has
been successfully carried out by 130 centers, recruiting more than 250 cases. In 2006 the
Outcome Research Study was started, involving about 130 centers that recruited about 1800
cases. An interim analysis carried out after 6 months on the first 1100 cases has documented
that. a) this kind of prospective and longitudinal study is feasible in Italy; b) the tools and
methods used have a good performance (for the first time in this setting data collection was
carried out using an electronic, web-based CRF); c) the quality of analgesic treatment is
questionable, as 25% patients at baseline they received a non-appropriate level of analgesic
care. The study will be completed by June 2007. Details about the study and preliminary results
are available at http://crc.marionegri.it/cancerpain/
A population based evaluation of an intervention to improve cancer pain
management
The purpose of the project, designed in 2005 on the basis of preliminary results of the activities
carried out in the context of the Outcome Research project above summarized (see the part b:
evaluation of the volume and quality – appropriateness - of prescription of analgesic drugs in a
large administrative data base ) is to evaluate the effect of a community-oriented multimodal
intervention to change the quantity and quality of analgesic drugs for the treatment of cancer
pain. The project, after the pilot phase carried out in a smaller geographic area (Cremona:
350,000 citizens) will be carried out in an Italian Region (Le Marche:1.500.000 citizens). The
project , sponsored by he Italian Agency for Drug evaluation (AIFA), was started in 2006 with
the creation of the integrated system (data-bases) that will be used to monitor the effect of the
intervention using pre-defined indicators of opioids prescriptions, and the -assembling of
relevant panels and working groups of experts (methodologists, clinicians, general
practitioners, health care managers, representative of citizens and patients, etc). The educational
and information intervention will be implemented in 2007. Results are expected by the end of
2008.
GCPBASE
GCPBASE is a general data entry engine for clinical trials developed by the Clinical Research
Computing Unit of the Laboratory in order to centralize the remote data collection and handling
processes. Two main aspects have been considered in developing this tool: the full compliance
with the requirements of current laws concerning ethical and regulatory issues, and the use of
the tool with or without an Internet connection (i.e. on-line and off-line). In addition the design
of a new study as well as every step of the study conduction or monitoring would have been
accessible by non technical staff.
Every transaction is logged in the database in order to keep track of each data modification and
the details about who, when, and why these changes have been made. These details may be
accessible only by the database administrator for debugging purposes and by external auditors
for monitoring reasons.
A set of metadata including notes for Investigator’s or Data-Manager’s comments and field
status (e.g. “valid data”, “to be checked”, “never available”), is automatically assigned to each
item collected in the database. They may only be filled by authorized users for monitoring
purposes. The GCPBASE provides the users with general commands to search the database, add
new cases, confirm changes, eliminate changes, and delete cases.
In order to reduce the amount of memory needed to store the data, an extension of Entity-
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Attribute-Value (EAV) model has been used to design the database.
The user is required to design the CRF pages using a html editor and to specify the items to be
collected. These items are used to properly design the database and the user’s interface. For this
task we have decided to leave the user free to use commercial software such as MS Front Page
or Dreamweaver as well as free software such as NVU (http://www.nvu.com). The GCPBASE
system has been developed as free software (GNU-GPL licensed, see
http://www.fsf.org/licensing/licenses/gpl.html for details) in Java and JavaScript.
Other research activities
During 2006, other activities on patient-oriented clinical translational research in oncology were
carried out. The focus was on the improvement of transferring information from the pre-clinical
to clinical and research setting, and from clinical research to clinical practice. Most of this work
involves data-entry, storage and other computerized applications for the management of large
and complex databases of biological and clinical data. In addition to the methodological and
bio-informatics issues that are relevant in this area, particular attention was also given to issues
related to the ethical and legal issues pertaining the collection, storage and utilization of
biological samples from patients and citizens.
Such activities are carried out in strict collaboration with other Laboratories of the Department
of Oncology, the Epidemiology Department at the Mario Negri Institute, the Policy Regulations
Laboratory at the Mario Negri Institute, the Cancer Pharmacogenomic Lab at the Fondo Edo
Tempia, in Biella, and SENDO (Southern Europe New Drug Organization), in Milan.
Finally, the Laboratory of Translational and Outcome Research has a major collaborative role in
the following research projects (described by others in the current report): the PRI-ER Project,
coordinated by the Regione Emilia-Romagna (in collaboration with the Laboratory for Medical
Research and Consumers Involvement), the GILDA RCT (in collaboration with the Laboratory
of Medical Research and Consumer involvement), and the Project on “Anemia&Salute” (in
collaboration with the Geriatric Neuropsychiatric Laboratory).
Laboratory of Medical Research and Consumer Involvement
This Laboratory promotes activities of research in the field of the involvement of citizens and
patients and their associations in decision making in health and medical issues. Moreover the
activities of this laboratory include: researches on information conveyed to patients on illness
and treatment, implementation of web site on the topics of health and information
(www.partecipasalute.it; www.paincare.it); strategy of the 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 specific selected groups, and implementation on
validated ad hoc questionnaires.
Strategic alliance between consumers and the scientific community
The project “PartecipaSalute” is a multi step research program involving consumers and their
associations. The project - linking in a collaborative effort the Mario Negri Institute, the Italian
Cochrane Centre (www.cochrane.it), and the scientific editor Zadig (www.zadig.it) - aims to
increase the quality and quantity of evidence-based information for patients and citizens, as part
of an effort to increase the role and impact of citizens in clinical research and in clinical
decision-making. During 2006 the following activities have been carried out:
- Training advocacy course: 23 representatives of associations and lay members of Ethical
Committees have followed a training programme of six modules articulated in working groups,
frontal lessons, and debates. The group is today involved in the research activities through the
group GRAL (Group Representatives Associations and Lay people)
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- Development of the web site www.partecipasalute.it. In addition to the customary activity of
modernization of sections and columns, a new column has been presented “Cure utili, inutile,
non si sa” that represents the effort to translate in Italian the Cochrane reviews
- starting from the request of many representatives of associations, an ad hoc manual on the
topics of the methodology of clinical research and the doctor-scientific information has been
organized
- Organization and implementation the PARITA space “To participate to the research with the
associations”, the arena where it’s possible to discuss the grey areas of the research together
with patient associations and medical community.
Internet as research and formative tool on the chronic pain in cancer
patient
This researcj project was born in the framework of the project "Pain in the patient with cancer" .
Its aim is to make available for doctors, patients and families correct information about
therapies for cancer pain and to produce greater tests on the effectiveness of therapies based on
the use of analgesic drugs. This project is articulated in two main activities:
- Paincare, set-up a catalogue of selected web pages dedicated to the cancer pain and relative
periodical
update,
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.
During 2006 an ad hoc questionnaire from a multidisciplinary working group has been applied
to 133 websites included in the catalogue Paincare (www.paincare.it): 30 websites of scientific
and medical societies, 15 websites of associations of patients, 8 catalogues, 24 websites on pain
information, 10 websites of information for lay people, 33 websites of research institutes, 6
websites on drugs, 7 websites of guidelines. Areas considered in the questionnaire regard:
general description (authors, sponsor, advertising, address and mail, date of up-to-date, …),
contents (topics, presence of external link, presence of information for experts or patients,
citation of the sources, description of the drug, …), and the navigability. Fourteen reviewers: 4
lay patients, 4 researchers, 3 documentalists, 1 computer science, 1 psychologist, 1 oncologist,
have filled in a double questionnaire for websites. A third reviewer is checking all the material
arrived and cleaning data. Preliminary results have been presented to the working group.
Study on the appropriateness and appraisal of effectiveness in
oncological setting, follow-up
A timely oncological diagnosis and the appropriate surgical therapies remain the bench mark of
the primary therapy of many oncological diseases. Effective adjuvant therapies have allowed to
improve the survival of the patients, and have moreover supplied the base in order to set up
programs of surveillance (follow-up). In such programs, also in absence of good results on the
efficacy and effectiveness, the follow-up it is practiced with the assumption that the anticipated
discovery of one relapse allows the activation of effective therapies and therefore better the
prognosis, with benefits in terms of health, consumption of resources and costs. In some cases,
as an example in the breast and colon cancer, the follow-up it is pursued in the clinical practice,
also in presence of randomised clinical studies, meta-analyses, consensus conference, editorials
and statements of scientific associations and societies that suggest that obvious and great
benefits in leading many diagnostic examinations after the primary therapies do not exist. In
other cases (like in the case of the melanoma and some gynaecological tumours), because the
lack of valid information on follow-up, exist a wide variability of behaviors between centers,
doctors and patients.
This research, supported from the Emilia-Romagna Region, have been proposed to construct a
network of investigators, regional oncological centers and associations of patients who, after the
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review of the literature, share ideas and proposals to optimise follow-up. The activities regard
patients with breast, colon-rectum, ovarian cancer. During 2006 it has been organized a national
convention on the topic of follow-up and one local workshop in order to confront experiences
conduct abroad on the involvement of the general practitioner. On the basis of activities a
clinical follow-up protocol has been proposed. The present plan is currently under evaluation
from the Ministry of the Health.
Conference of Consent on the Substitutive Hormonal Therapy
At the end of 2006 a Conference of Consent on Hormonal Replacement Therapy has been
sponsorized by a bank foundation. The project will be articulated with multidiscliplinary
working groups and it will carry out to a consent document on a topic still extremely
controversial for public health, in particular regarding the information that is supplied to citizens
and patients.
Quality of life projects
No specific research projects have been carried out on quality of the life evaluation. However
are on going the activities of support and coordination of other groups using the instruments of
quality of life translated and validated by our research group, SF-36, SF-12, PGWBI. During the
year it has been periodically up-to-date the specific website http://crc.marionegri.it/qod. During
2006 two new instruments have been validated: the first one is the short version of questionnaire
PGWBI, the second is the version review and modernized of generic questionnaire SF-36
Version 2. Both questionnaires will be available to the public within the first semester of 2007.
Research projects in collaboration with other Mario Negri laboratories
This laboratory is actively involved in some plan of search in collaboration with other
laboratories of the Institute:
- GILDA Italian working group for early diagnosis (Gilda) in colo-rectal cancer: a randomised
multicentric clinical trial on the impact of different follow-up strategies on survival and quality
of life (Laboratory Giovanni Apolone);
- A population study on pain cancer treatment (Laboratory Giovanni Apolone), this laboratory
will be in charge of the informative interventions on different target population (people,
patients, associations, health professionals.
- Pain in cancer patients: a multicentric study on the information and treatment of the pain in the
patients with cancer (Laboratory Giovanni Apolone).
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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 VITAE
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:
•
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
•
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)
•
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
•
Zuccato E, Castiglioni S, Fanelli R. Identification of the pharmaceuticals for human use contaminating the Italian aquatic
environment. J Hazard Mater 2005; 122: 205-209
•
Airoldi L, Magagnotti C, Pastorelli R, Fanelli R. Enzyme polymorphisms influencing the metabolism of heterocyclic
aromatic amines. J Chromatogr B Analyt Technol Biomed. Life Sci 2004; 802: 175-181
•
Fattore E, Di Guardo A, Mariani G, Guzzi A, Benfenati E, Fanelli R. Polychlorinated dibenzo-p-dioxin and
dibenzofurans in the air of Seveso, Italy, 26 years after the explosion. Environmental Science Technology
2003; 37: 1503-1508
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; molecular
epidemiology focused on the identification and measurement of biomarkers of exposure to environmental
carcinogens and disease susceptibility; chemical carcinogenesis centered on the study of carcinogens’
mechanism of action.
•
•
Airoldi L, Vineis P, Colombi A, Olgiati L, Dell'Osta C, Fanelli R, et al. 4-Aminobiphenyl-hemoglobin adducts and risk
of smoking-related disease in never smokers and former smokers in the European Prospective Investigation into Cancer
and Nutrition Prospective study. Cancer Epidemiol Biomarkers Prev 2005; 14: 2118-2124
•
•
aromatic amines. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 802: 175-181
•
Magagnotti C, Pastorelli R, Pozzi S, Andreoni B, Fanelli R, Airoldi L. Genetic polymorphisms and modulation of 2amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes. Int J Cancer
2003; 107: 878-884
•
Airoldi L, Orsi F, Magagnotti C, Coda R, Randone D, Casetta G, Peluso M, Hautefeuille A, Malaveille C, Vineis P.
Determinants of 4-aminobyphenyl-DNA adducts in bladder cancer biopsies. Carcinogenesis 2002; 23: 861-866
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Emilio Benfenati, Head of the Laboratory of Environmental Chemistry and Toxicology since 1997, Unit
Head 1987-97, Researcher 1986-87, Research fellow 1981-86 at the Mario Negri Institute. Researcher at
Istituto Biochimico Italiano 1979-1981.
Doctoral Degree in Chemistry (University of Milan, 1979).
Member of Commissione Consultiva Prodotti Fitosanitari (Ministero Salute 1997-99), Certified Italian
Chemist.
Resarch 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.
•
Lo Piparo E, Koehler K, Chana A, Benfenati E, Virtual screening for aryl hydrocarbon receptor binding prediction, J
Med Chem 2006; 49: 5702-5709
•
Casalegno M, Sello G, Benfenati E, Top-priority fragment QSAR approach in predicting pesticide aquatic toxicity,
Chem Res Toxicol 2006; 19: 1533-1539
•
Lo Piparo E, Fratev F, Lemke F, Mazzatorta P, Smiesko M, Fritz J I, Benfenati E, QSAR models for Daphnia magna
toxicity prediction of benzoxazinone allelochemicals and their transformation products, J Agric Food Chem 2006; 54:
1111-1115
•
Mazzatorta P, Cronin M T D, Benfenati E, A QSAR study of avian oral toxicity using supprto vector machines and
genetic algorithms, QSAR Combinatorial Science 2006; 25: 616-628
•
Viganò L, Mandich A, Benfenati E, Bertolotti R, Bottero S, Porazzi E, Agradi E, Investigating the estrogenic risk along
the River Po and its intermediate section, Arch Environ Contam Toxicol 2006; 51: 641-651
•
Piclin N, Pintore M, Wechman C, Roncaglioni A, Benfenati E, Chretien J R, Ecotoxicity Prediction by Adaptive Fuzzy
Partioning. Comparing Descriptors Computed on 2D and 3D Structures. SAR QSAR Environ Res 2006; 17: 225-251
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 toxicology.
•
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.
•
identification of in vivo estrogen-regulated proteins in bone. Proteomics. 2005;5:4936.
•
evidence-based tool to monitor community drug abuse. Environ Health. 2005;4:14.
•
Chiabrando C, Avanzini F, Rivalta C, Colombo F, Fanelli R, Palumbo G, Roncaglioni MC; PPP Collaborative Group on
the antioxidant effect of vitamin E. Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at
cardiovascular risk: analysis of underlying factors. Curr Control Trials Cardiovasc Med. 2002;3:5.
•
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.
•
Chiabrando C, Valagussa A, Rivalta C, Durand T, Guy A, Zuccato E, Villa P, Rossi JC, Fanelli R. Identification and
measurement of endogenous beta-oxidation metabolites of 8-epi-Prostaglandin F2alpha.J Biol Chem. 1999 Jan
15;274:1313.
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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 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.
Research areas: Development of methodology, instrumentation and software for environmental research.
Studies of urban air pollution and characterization of environmental odor annoyance.
Selected Publications
•
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
•
Davoli, L. Cappellini, M. Moggi and R. Fanelli. Automated, high speed analysis of selected organic compounds in urban
air by on line isotopic dilution cryofocussing GC/MS. J. Am. Soc. Mass Spectrometry. 5: 1001-1007.1994
•
E. Davoli, L. Cappellini, M. Moggi S. Ferrari and R. Fanelli. On-Line Monitoring of Benzene Air Concentrations While
Driving in Traffic by Isotopic Dilution GC/MS. Int. Arch. Occup. Environ. Health 1996; 68: 262-267
•
E. Davoli, L. Cappellini, R. Fanelli, M. Bonsignore, M. Gavinelli. On-Site Analysis of World War II Cylinders and
Barrels with Unknown Contents. Field Anal. Chem. Technol. 2001; 5: 313-319
•
E. Davoli, L. Gangai, P. Morselli, D. Tonelli, Characterisation of Odorant emissions from Landfills by SPME and
GC/MS. Chemosphere 2003; 51: 357-368
•
E. Davoli, M. Giavini, S. Somaschini, L. Gangai, D. Tonelli, P. Morselli. A Mass Spectrometric Approach in Odour
Impact Assessment. (CD-ROM VERSION) in: Integrated Resources Management, 6TH World Congress EMPA,
Geneva, Switzerland, February 12-15. 2004
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.
•
and their metabolites in urban wastewaters by liquid chromatography tandem mass spectrometry (HPLC-MS-MS). Anal
Chem 2006, 78: 8421-8429.
•
Pomati F, Castiglioni S, Zuccato E, Fanelli R, Rossetti C and Calamari D. Effects of Environmental Contamination by
Therapeutic Drugs on Human Embryonic Cells. Environ. Sci. Technol. 2006, 40, 2442-2447.
•
Zuccato E, Calamari D, Castiglioni S, Chiabrando C, Bagnati R, Fanelli R. Cocaine in surface water: a new evidencebased tool to monitor community drug abuse. Environmental Health: A Global Access Science Source 2005, 4:14
•
Calamari D, Zuccato E, Castiglioni S, Bagnati R, Fanelli R. Strategic survey of therapeutic drugs in the rivers Po and
Lambro in northern Italy. Environ Sci Technol 2003; 37: 1241-1248
•
Zuccato E, Calamari D, Natangelo M, Fanelli R. Presence of therapeutic drugs in the environment. Lancet 2000; 355:
1789-1790
•
Zuccato E, Calvarese S, Mariani G, Mangiapan S, Grasso P, Guzzi A, Fanelli R. Level, sources and toxicity of
polychlorinated biphenyls in the Italian diet. Chemosphere 1999; 38 (12): 2753-2765.
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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).
•
and their metabolites in urban wastewater by liquid chromatography-tandem mass spectrometry. Anal Chem 2006; 78:
8421-8429.
•
Castiglioni S, Bagnati R, Fanelli R, Pomati F, Calamari D, Zuccato E. Removal of pharmaceuticals in sewage treatment
plants in Italy. Environmental Science Technology 2006; 40: 357-363.
•
evidence-based tool to monitor community drug abuse. Environ Health. 2005;4:14.
•
identification of in vivo estrogen-regulated proteins in bone. Proteomics 2005; 5: 4936-4945.
•
Bagnati R, Ramazza V, Zucchi M, Simonella A, Leone F, Bellini A, Fanelli R. Analysis of dexamethasone and
betamethasone in bovine urine by purification with an 'on-line' immunoaffinity chromatography-HPLC system and
determination by GC-MS. Anal Biochem 1996; 235: 119-126.
•
Davoli E, Fanelli R, Bagnati R. Purification and analysis of drug residues in urine samples by on-line immunoaffinity
chromatography/high-performance liquid chromatography/continuous-flow fast atom bombardment mass spectrometry.
Anal Chem 1993; 65: 2679-2685.
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 Group of Experts of the Italian Presidency of the Council of Ministers for the Surveillance
of Exposure to Endocrine Disrupters.
Research areas: Environmental chemistry, toxicology, assessment of human exposure and risk from
environmental pollutants with emphasis on dioxins and dioxin-like compounds.
•
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
•
Fattore E, and Fanelli R. Exposure Assessment to Dioxins of People Living in the Seveso (Italy) Area. In: Trends in
Agriculture and Soil Pollution Research. J.V. Livingston Ed., 2005, pp. 79-94.
•
Fattore E, Guardo A, Mariani G, Guzzi A, Benfenati E, Fanelli R. Polychlorinated Dibenzo-p-Dioxins and
Dibenzofurans in Air of Seveso, Italy, 26 years after the accident. Environ Sci Technol 2003; 37: 1503-1058
•
Fattore E, Fanelli R, La Vecchia C. Persistent organic pollutants in food: Public health and implications. J Epidemiol
Community Health 2002; 56: 831-832.
•
Fattore E, Trossvik C, Håkansson H. Relative potency values derived from hepatic vitamin A reduction in male and
female Sprague-Dawley rats following subchronic dietary exposure to individual polychlorinated dibenzo-p-dioxin and
dibenzofuran congeners, and a mixture thereof. Toxicol Appl Pharmacl 2000; 165: 184-194
•
Fattore E, Benfenati E, Mariani G, Fanelli R, Evers E H. Pattern and Sources of Polychlorinated dibenzo-p-dioxins and
Dibenzofurans in Sediment from Venice Lagoon. Environ Sci Technol 1997; 31: 1777-1784
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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.
•
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
•
Benfenati E, Mariani G, Lodi M, Reitano G, Fanelli R. Is bioexsiccation releasing dioxins? Organohalogen Compounds
2004; 66: 955-961
•
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 : 237240
•
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
•
Benfenati E, Pastorelli R, Castelli M G, Fanelli R, Carminati A, Farneti A, Lodi M. Studies on the tetrachlorodibenzo-pdioxins (TCDD) and tetrachlorodibenzofurans (TCDF) emitted from an urban incinerator. Chemosphere 1986; 15: 557561
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.
•
•
Pastorelli R, Carpi D, Airoldi L, Chiabrando C, Bagnati R, Fanelli R, Moverare S, Ohlsson C.Proteome analysis for the
•
aromatic amines. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 802: 175-181
•
Vineis P,V eglia F, Anttila S, Benhamou S, Clapper M L, Dolzan V, Ryberg D, Hirvonen A, Kremers P, Le Marchand L,
Pastorelli R, Rannug A, Romkes M, Schoket B, Strange R C, Garte S, Taioli E. CYP1A1, GSTM1 and GSTT1
polymorphisms and lung cancer: a pooled analysis of gene-gene interactions. Biomarkers 2004; 9: 298-305
•
Citerio G, Nobili A, Airoldi L, Pastorelli R, Patruno A. Severe intoxication after phenytoin infusion: A preventable
pharmacogenetic adverse reaction. Neurology 2003; 60: 1395-1396
•
Pastorelli R, Cerri A, Mezzetti M, Consonni E, Airoldi L. Effect of DNA repair gene polymorphisms on BPDE-DNA
adducts in human lymphocytes. Int J Cancer 2002; 100: 9-13
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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.
The lack of retinoic acid (knock-out mice for the retinal dehydrogenase 1 gene, RALDH1) modifies the
proteome profile of the bone,through changes in the expression of proteins involved in chondrogenesis
and osteoclastogenesis.
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.
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.
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
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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.
ARPA Veneto
ASL di Brescia
CESTEC , Regione Lombardia, Milano
CNR – IRSA
CSPO-Firenze
CSRA-Asti
Fondazione 'S. Maugeri'
Fondazione ISI, Torino
INRAN-Istituto Nazionale di Ricerca sugli Alimenti e la Nutrizione
Ministero dell'Ambiente
Politecnico di Milano
Politecnico di Torino
Provincia di Vercelli
Provincia Pordenone
Università degli Studi di Cagliari
Università degli Studi di Genova
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 Torino
Università dell’Insubria, Varese
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BASF Agricultural Centre, Limburgerhorf, Germany
Central Science Laboratory, York, UK
Danish Institute of Agricultural Sciences, Research Centre Foulum, Tjele, Denmark
Department of Analytical and Pharmaceutical Chemistry, The Royal Danish School of Pharmacy,
Denmark
Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland
Department of Analytical and Pharmaceutical Chemistry, The Royal Danish School of Pharmacy,
Denmark
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, United Kingdom
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, Spain
Division of Endocrinology, Department of Internal Medicine, Sahlgrenska University Hospital, Goteborg,
Sweden
Environmental Chemistry, IIQAB-CSIC, Barcelona, Spain
Environmental Hygiene and Chemistry Department, Institute of Environmental Medicine and Hospital
Epidemiology, University of Freiburg, Germany
Environmental Hygiene and Chemistry Department, Institute of Environmental Medicine and Hospital
Epidemiology, University of Freiburg, Germany
Faculté de Médicine et de Pharmacie, Université de Mons-Hainaut, Mons, Belgium
Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
Forschungzentrum Jülich Gmbh, Jülich, Germany
Gruppo Collaborativo sulla Suscettibilità Genetica ai Cancerogeni Ambientali (GSEC), Milano, Italia
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, Wien, 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
Lithuanian Institute of Agricultrure, Vilnius, Lithuania
Liverpool John Moores University, Liverpool, United Kingdom
National Institute of Chemistry, Kemijski Institut Ljubljana, Ljubljana, Slovenia
Natural Resources Research Institute, University of Minnesota, Duluth, MN
National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
Pesticide Safety Directorate, York, UK
Plant Protection Institute, Hungarian Academy of Sciences, Budapest, Hungary
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland
Syngenta Crop Protection AG, Basel, Switzerland
UFZ Leipzig, Germany
University of Tartu, Tartu, Estonia
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Journal of Environmental Science and Health, Part B (Emilio Benfenati), Journal of Environmental
Science and Health, Part C (Emilio Benfenati), International Journal of Computational Intelligence
(Emilio Benfenati), International Journal of Information Technology (Emilio Benfenati), International
Journal of Signal Processing (Emilio Benfenati), Chemistry Central Journal (Emilio Benfenati).
Analytical and Bio-analytical Chemistry, Atmospheric Environment, Chemosphere, Environmental
Science & Technology, Environmental Toxicology, Environmental Toxicology and Chemistry, European
Journal of Cancer, Expert Opinion on Drug Metabolism & Toxicology, International Journal of
Environmental Analytical Chemistry, Journal of Chemical Information and Modeling, Journal of
Agricultural Food Chemistry, Journal Chromatography A, Journal of Hazardous Materials, Journal of the
National Cancer Institute, Proteomics, QSAR & Combinatorial Science, Rapid Communications in Mass
Spectrometry, SAR and QSAR in Environmental Research, Science of the Total Environment, Water
Research, Waste Management.
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
IGQ - ETS Commission
EVENT ORGANIZATION
Workshop: “La sicurezza degli alimenti: nuove applicazioni per il controllo”, Istituto Mario Negri, Milan,
April 5, 2006.
54th American Society for Mass Spectrometry Conference. Afternoon Orals: New and Emerging
Contaminats. May 28-June 1, 2006, Seattle, WA. USA
Workshop of the DEMETRA project on QSAR for regulatory purposes, Como, June 6-7 2006.
6o Meeting of the BONETOX project (EU FP6), Milan, November 7-8, 2006.
Workshop of the RAINBOW project on integration between in vivo and in vitro data with computerbased modeling, Milan, December 11-13, 2006.
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INVOLVED
XIV Congresso Nazionale della Società Italiana di Tossicologia (SITOX), 6-9 February 2006, Istituto
Superiore di Sanità, Roma, Italy.
SETAC Europe 16th Annual Meeting, 7-11 May 2006, The Hague, The Netherlands.
QSAR2006, The 12th International Workshop on Quantitative Structure-Activity Relationships in
Environmental Toxicology, 8-12 May 2006, Lione, France.
Proteomix IX Incontro, 11-12 May 2006, Rimini, Italy.
Workshop: First European Inter-Laboratory on NSAIDs, 18-20 May 2006, Barcelona, Spain.
54th American Society for Mass Spectrometry Conference, May 28-June 1, 2006, Seattle, WA, USA
Workshop of the DEMETRA project on QSAR for regulatory purposes, Como, 6-7 June 2006.
Workshop: Ecopharmacology, 9-10 June 2006, Verona, Italy.
Giornata di studio: Farmaco Veterinario e Tutela della Salute Pubblica, 16 June 2006, Cuneo, Italy.
Convegno: Endocrine Disruptors, Farmaci e Prodotti ad Uso Personale nelle Acque Destinate al Consumo
Umano. 20 June 2006, Genova, Italy.
EuroQSAR2006, The 16th European Symposium on Quantitative Structure-Activity Relationships &
Molecular Modelling, 10-17 September 2006, Italy.
AGCHEM Forum, Amsterdam, 26-27 September 2006, The Netherlands.
Conference: Risk Assessment of Pharmaceuticals & Veterinary Medicines in The Environment, 26-27
September 2006, Amsterdam, The Netherlands.
EU Expert meeting on the EMCDDA key indicator Problem Drug Use 12-13 October 2006, Lisbon,
Portugal.
HUPO, Human Proteome Organization, 5th Annual World Congress, 28 October-2 November 2006, Long
Beach, CA, USA.
Proteomix, X Incontro, 30 November-1 December, 2006, Romano Canavese (TO), Italy.
Workshop of the RAINBOW project on integration between in vivo and in vitro data with computerbased modeling, 11-13 December 2006, Milano, Italy.
Workshop: Alcune considerazioni a 30 anni dall'incidente di Seveso, 18 December 2006, Istituto
Superiore di Sanità, Roma, Italy.
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ACEGAS S.p.A, Trieste
ASL Mantova
CSRA
Associazione Italiana Ricerca sul Cancro
Comune di Lomello
Consorzio Quadrifoglio S.p.A.
ECODECO, Pavia
European Commission (MEBFOOD; SAFEFOODNET; DEMETRA; EUFRAM; HERBICBIOREM;
BONETOX, ATHON, CASCADE, HAIR, CAESAR, RAINBOW, CHEMOMENTUM)
Ferrero, Alba (Cuneo)
FIAT Auto S.p.A.
Fondazione CARIPLO, Milano
Fondazione Italo Monzino, Milano
Ministero dell'Istruzione, dell'Università e della Ricerca, Italia
Ministero della Salute, Italia
Ministero dell'Ambiente, Italia
Provincia di Pordenone
Provincia di Vercelli
SOGEIVA S.p.A, Varese
SO.GE.NU.S. S.p.A
TM.E. S.p.A
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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.
Gormally E, Vineis P, Matullo G, Veglia F, Caboux E, Leroux E, Peluso M, Garte S, Guarrera S, Munnia A, Airoldi
L, Autrup H, Malaveille C, Dunning A, Overvad K, Tjonneland A, Lund E, Clavel-Chapelon F, Boeing H,
Trichopoulou A, Palli D, Krogh V, Tumino R, Panico S, Bueno-De-Mesquita H B, Peeters P H, Pera G, Martinez C,
Dorronsoro M, Barricarte A, Navarro C, Quiros J R, Hallmans G, Day N E, Key T J, Saracci R, Kaaks R, Riboli E,
Hainaut P. TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: A
prospective study. Cancer Res 2006; 66: 6871-6876
Matullo G, Dunning A M, Guarrera S, Baynes C, Polidoro S, Garte S, Autrup H, Malaveille C, Peluso M, Airoldi L,
Veglia F, Gormally E, Hoek G, Krzyzanowski M, 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, Lund E,
Pera G, Martinez C, Dorronsoro M, Barricarte A, Tormo M J, Quiros J R, Day N E, Key T J, Saracci R, Kaaks R,
Riboli E, Vineis P. DNA repair polymorphisms and cancer risk in non-smokers in a cohort study. Carcinogenesis
2006; 27: 997-1007.
Vineis P, Hoek G, Krzyzanowski M, Vigna-Taglianti F, Veglia F, Airoldi L, Autrup H, Dunning A, Garte S, Hainaut
P, Malaveille C, Matullo G, Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Linseisen J, Boeing H,
Trichopoulou A, Palli D, Peluso M, Krogh V, Tumino R, Panico S, Bueno-De-Mesquita H B, Peeters P H, Lund E E,
Gonzalez C A, Martinez C, Dorronsoro M, Barricarte A, Cirera L, Quiros J R, Berglund G, Forsberg B, Day N E,
Key T J, Saracci R, Kaaks R, Riboli E. Air pollution and risk of lung cancer in a prospective study in Europe. Int J
Cancer 2006; 119: 169-174.
Toropov A A, Benfenati E. Correlation weighting of valence shells in QSAR analysis of toxicity. Bioorg Med Chem
2006; 14: 3923-3928
Vigano L, Mandich A, Benfenati E, Bertolotti R, Bottero S, Porazzi E, Agradi E. Investigating the estrogenic risk
along the River Po and its intermediate section. Arch Environ Contam Toxicol 2006; 51: 641-651
Toropov A A, Benfenati E. QSAR models of quail dietary toxicity based on the graph of atomic orbitals. Bioorg Med
Chem 2006; 16: 1941-1943
Toropov A A, Benfenati E. QSAR models for Daphnia toxicity of pesticides based on combinations of topological
parameters of molecular structures. Bioorg Med Chem 2006; 14: 2779-2788
Lo Piparo E, Smiesko M, Mazzatorta P, Benfenati E, Idinger J, Bluemel S. Preliminary analysis of toxicity of
benzoxazinones and their metabolites for Folsomia candida. J Agric Food Chem 2006; 54: 1099-1104
Lo Piparo E, Fratev F, Lemke F, Mazzatorta P, Smiesko M, Fritz J I, Benfenati E. QSAR models for Daphnia magna
toxicity prediction of benzoxazinone allelochemicals and their transformation products. J Agric Food Chem 2006; 54:
1111-1115
Lemke F, Benfenati E, Muller J A. Data-driven modeling and prediction of acute toxicity of pesticide residues.
SIGKDD Explorations 2006; 8: 71-79
Duchowicz P R, Castro E A, Toropov A A, Benfenati E. Application of flexible molecular descriptors in the QSPRQSAR study of heterocyclic drugs. Topics Heterocyclic Chemistry 2006; 3: 1-38
Casalegno M, Sello G, Benfenati E. Top-priority fragment QSAR approach in predicting pesticide aquatic toxicity
Chem Res Toxicol 2006; 19: 1533-1539
Casalegno M, Benfenati E, Sello G. Application of a Fragment-based Model to the Prediction of the Genotoxicity of
Aromatic Amines. Internet Electron J Model Des 2006, 5: 431-446
Mazzatorta P, Cronin M T D, Benfenati E. A QSAR study of avian oral toxicity using support vector machines and
genetic algorithms. QSAR Combinatorial Science 2006; 25: 616-628
Lo Piparo E, Koehler K, Chana A, Benfenati E. Virtual screening for aryl hydrocarbon receptor binding prediction
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J Med Chem 2006; 49: 5702-5709
Piclin N, Pintore M, Wechman C, Roncaglioni A, Benfenati E, Chretien J R. Ecotoxicity Prediction by Adaptive
Fuzzy Partioning. Comparing Descriptors Computed on 2D and 3D Structures. SAR QSAR Environ Res 2006; 17:
225-251
LoPiparo E, Fratev F, Mazzatorta P, Smiesko M, Benfenati E. Toxicity in allelopathy: in silico approach. In:
Allelopathy: A physiological process with ecological implications, Reigosa M J, Pedrol N, Gonzalez L (eds.)
Springer-Verlag, Berlin; 2006 : 105-126
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-MSMS). Anal Chem 2006, 78: 8421-8429.
Pomati F, Castiglioni S, Zuccato E, Fanelli R, Rossetti C and Calamari D. Effects of Environmental Contamination
by Therapeutic Drugs on Human Embryonic Cells. Environ. Sci. Technol. 2006, 40, 2442-2447.
Castiglioni S, Bagnati R , Fanelli R, Pomati F, Calamari D, Zuccato E. Removal of pharmaceuticals in sewage
treatment plants in Italy. Environ Sci Technol. 2006, 40 : 357-363.
Zuccato E, Castiglioni S, Fanelli R, Reitano G, Bagnati R, Chiabrando C, Pomati F, Rossetti C, Calamari D.
Pharmaceuticals in the environment in Italy: Causes, occurrence, effects and control. Environ Sci Pollut Res Int 2006;
13: 15-21
Frapolli R, Marangon E, Zaffaroni M, Colombo T, Falcioni C, Bagnati R, Simone M, D'Incalci M, Manzotti C,
Fontana Gabriele, Morazzoni P, Zucchetti M. Pharmacokinetics and metabolism in mice of IDN 5390 (13-(N-Boc-3i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III) a new oral C-seco-taxane derivative with antiangiogenic
property effective on paclitaxel-resistant tumors. Drug Metab Dispos 2006; 34: 2028-2035
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.
Zuccato E. La sicurezza alimentare. http://www.treccani.it/site/Scuola/Zoom/ogm2/zuccato.htm 2006
Zuccato E, Chiabrando C, Castiglioni S, Calamari D, Bagnati R, Schiarea S, Fanelli R. Cocaina nelle acque di
superficie: un nuovo strumento evidence-based per monitorare l'abuso comunitario di sostanze. In: Cocaina. Manuale
di aggiornamento tecnico scientifico. Progetto Start, Verona; 2006 : 103-112
Bianchi G, Davoli E. I processi biologici nella gestione dei rifiuti urbani: il problema degli odori e delle emissioni
odorose. Nuova Gea- Quaderni Ambiente 2006; 3/2: 70-88
Fischietti M, Davoli E, Favoino E, Capelli L. Monitoraggio degli odori e comparazione di emissioni e immissioni
OTHER PRODUCTS PUBLISHED IN 2006
Sild S, Maran U, Romberg M, Schuller B, Benfenati E. OpenMolGRID: Using Automated Workflows in GRID
Computing Environment. Lecture Notes in Computer Science, Springer-Verlag GmbH, ISSN: 0302-9743, Volume
3470 / 2005 (Eds. P. M. A. Sloot, A. G. Hoekstra, T. Priol, et al., Advances in Grid Computing - EGC 2005:
European Grid Conference, Amsterdam, The Netherlands, February 14-16, 2005, Revised Selected Papers, ISBN: 3540-26918-5), 464
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RESEARCH ACTIVITIES
Laboratory of Molecular Toxicology
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. Qualitative and quantitative
proteome changes resulting from the exposure to environmental toxic compounds or in
pathological conditions are monitored also in humans and focused on plasma and urine.
Proteome analysis includes protein separation by two-dimensional gel electrophoresis and
protein 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.
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.
Pharmacogenetics
The study of the human genome has established that part of the observed individual variability
in the reaction to pharmacological therapies is due to genetic traits. The analysis of the genetic
polymorphism of drug metabolism and disposition allows optimizing the therapy according to
the individual genetic makeup. This provides useful information not only for a correct drug
dosage, but also for the prevention of adverse drug reactions.
Laboratory of Analytical Biochemistry
Identification and characterization of proteins by mass spectrometry
Our laboratory is developing different analytical and instrumental techniques for the
identification and characterization of proteins and peptides in biological samples. This activity
is mainly aimed at 1) characterizing different protein isoforms that are found significantly
altered in “differential proteomics” studies with two dimensional gel electrophoresis, 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 for subsequent identification by mass spectrometry, and characterization of
post-translational modifications by LC-MS/MS.
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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 of protein identification by mass spectrometry (MALDITOF-MS, LC-ESI-MS/MS), isolation and purification of proteins, and characterization of their
post-translational modifications.
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.
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Laboratory of Mass Spectrometry
Particulate air pollution
Epidemiological studies consistently show an association between an increasing number of
pathologies, both acute and chronic, and particulate air pollution. This has been shown not only
in respiratory, but in cardiovascular diseases as well. Airborne particulate sampling and analysis
strategies are developed to characterize both adsorbed compounds and exposition in different
activities.
Method development in environmental sciences
Methods, analytical methodologies, instrumentation and software for data acquisition and
reduction, are developed for environmental studies. High-sensitivity instrumentation, mainly
based on mass spectrometry, is developed for trace and ultra-trace analysis. Also, transportable
instrumentation is developed for field studies or continuous monitoring.
Characterization of environmental odor annoyance
Characterization of odors poses several analytical problems because they result from a complex
mixture of compounds (odorants) stimulating receptors in the nasal cavity. Most odorants are
volatile organic compounds (VOC) generated by bacterial degradation of organic matter. They
are often present at trace levels, while numerous sources can contribute to the total odor. Using
sampling techniques specifically developed for olfactometry, solid phase microextraction and
GC/MS analysis, we can detect traces (low ppb to high ppt) of a wide polarity/volatility range of
airborne VOC odorant compounds. With a chemometric approach, we can characterize the
sources of emissions, assess odor control methods, and identify emissions that contribute to
odors in ambient air.
Laboratory of Food Toxicology
Chemical contaminants in food
We are studying human exposure to dietary PCBs and dioxins. 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 food from an Italian
area at high risk of contamination. Ongoing studies are focused on other emerging food
contaminants.
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.
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Farming methods and emerging pollutants
A project has been outlined to set up new methods for the assessment of GMO safety in human
nutrition. This project is based on the use of new techniques to detect possible changes induced
in living organisms by GMO-derived foods.
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
Exposure to environmental pollutants
Research activities include both quantitative measurement of contaminants in environmental
samples, and assessment of exposure. Specific projects on dietary exposure of the general
Italian population include: an exposure assessment to PCBs thorough dietary farmed and wild
fish coming from Mediterranean sea; a study combining available data from food consumption
surveys in Italy with data on contamination by polychlorinated dibenzo-p-dioxins (PCDDs),
furans (PCDF), dioxin- and non-dioxin-like PCBs in European foodstuffs; an investigation of
the contamination level by PCDD, PCDF and PCB in different food coming from a suspected
polluted area.
A study on occupational exposure deals with measurements of PCBs and DDE in human blood
with the aim of assessing the correlation between exposure to these organochlorine compounds
and the bone mineral density of the population investigated.
Exposure assessment methodology development
New methods for exposure assessment are developed, employing probabilistic approaches and
more refined statistical models, starting from real cases of contamination. A current study deals
with the exposure of the Seveso population to dioxin from contaminated soil.
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). Substances of interest include proteins, peptides, hormones,
pharmaceuticals, drugs of abuse, pesticides, and other environmental contaminants (PCBs,
hydroxy-PCBs, perfluorinated compounds).
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DEPARTMENT OF NEUROSCIENCE
STAFF
Head
Gianluigi FORLONI, Biol.Sci.D.
Laboratory of Biology of Neurodegenerative Disorders
Head
Gianluigi FORLONI, Biol.Sci.D.
Laboratory of 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.
Quality Assessment of Geriatric Services Unit
Head
Alessandro NOBILI, M.D.
Laboratory of Inflammation and Nervous System Diseases
Head
Maria Grazia DE SIMONI, Biol.Sci.D.
Laboratory of Molecular Neurobiology
Head
Caterina BENDOTTI, Farm.D.
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Laboratory of Neurochemistry abd Behavior
Head
Roberto William INVERNIZZI, Biol. Sci D
Pharmacology of Cognitive Behaviour Unit
Head
Mirjana CARLI, Ph.D.
Laboratory of Neurological Disorders
Head
Ettore BEGHI, M.D.
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CURRICULA VITAE
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 and thematic leader on drugs development of European Network of Excellence
“Neuroprion”. 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 140 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)
•
Albani D., Peverelli, E., Zametta, R., Veschini, L. Negro, A. Forloni G. Protective effect of TAT-delivered alpha
synuclein: relevance of the C-terminal domain and involvement of HSP70. FASEB J. 18:1713-5 (2004)
•
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. 2006, 27:904-5.
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
•
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.
•
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.
•
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.
•
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.
•
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.
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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 2003-2004 has been member of the Italian Ministry of Health
Committees for the diagnosis, cure, care and assistance of patients with ALS (DM 10.4.2003, DM
10.09.2004). Scientific reviewer of 11 international scientific journals. She is author and co-author of
more than 100 articles 92 of which with peer-review. Rapporteur of many communications in national
and international meetings.
•
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.
280:16295-304, 2005
•
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: 509-522, 2005
•
C. Bendotti and MT Carri. Lessons from models of SOD1-linked familial ALS. Trends Mol Med. 10:393-400, 2004
•
C. Bendotti, C. Atzori, R. Piva, M. Tortarolo, M.J. Strong, S. DeBiasi and A. Migheli. Activated p38MAPK is a novel
component of the intracellular inclusions found in human amyotrophic lateral sclerosis and mutant SOD1 transgenic
mice. J. Neuropath Exp Neurol: 63 , 113–119, 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
•
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 got the Diploma in Industrial Chemistry at the L. Cobianchi Technical Institute (Verbania,
NO), the diploma in Tecnico di Ricerca Biochimica, Mario Negri Institute for Pharmacological
Researches (MI) and the degree in Pharmacy, University of Milan (1976). Research fellow, Laboratory
of General Pharmacology of the Mario Negri Institute, 1970-1973; Permanent Researcher, 1976. Head of
Pharmacokinetic Unit, 1983; Head of Drug Metabolism Laboratory, 1988. Current scientific interests are
in the field of pharmacology and toxicology of centrally acting drugs with particular focus on
pharmacokinetic and metabolic aspects, both at the pre-clinical and clinical level. Member of the
scientific assessment teams (acting as expert) for the evaluation of marketing authorisation applications
submitted to the European (EMEA) and Italian (AIFA) Agencies. Author and co-author of more than 200
articles, including reviews, monographs and book chapters.
•
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. New antipsychotic agents for schizophrenia: Pharmacokinetics and metabolism update. Curr Opin Invest
Drugs 2002; 3: 1073-1080
•
Caccia S. Biotransformation of post-clozapine antipsychotics. Pharmacological implications. Clin Pharmacokinet
2000; 38: 39
•
Caccia S. Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic
implications. Clin Pharmacokinet 1998; 34: 281-302
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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.
•
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
•
Cervo L, Cocco A, Carnovali F. Effects on cocaine and food self-administration of (+)-HA-966, a partial agonist at the
glycine/NMDA modulatory. Psychopharmacology (Berl) 2004; 173: 124-131
•
Grignaschi G, Burbassi S, Zennaro E, Bendotti C, Cervo L. A single high dose of cocaine induces behavioral
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, Burbassi S, Colovic M, Caccia S. Selective antagonist at D3 receptors, but not non-selective partial agonists,
influences the expression of cocaine-induced conditioned place preference in free-feeding rats. Pharmacol Biochem
Behav. 2005; 82(4):727-34.
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Cervo L, Cocco A, Putrella C, Heidbreder CA. Selective antagonism at dopamine D3 receptors attenuates cocaineseeking behavior in the rat. Int J Neuropsychopharmacol. 2006 Jan 23:1-15 [Epub ahead of print].
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
•
Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MG, Sperk G, Andell-Jonsson S,
Lundkvist J, Iverfeldt K and Bartfai T. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral
injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A, 97: 11534-11539, 2000.
•
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.
•
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 Nov 22;2006 (Epub ahead of print).
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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 group 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 team 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 of 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.
•
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 rats
Neuropsychopharmacology 2006; 31: 757-767
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Calcagno E, Carli M, Invernizzi R 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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Renoldi G, Invernizzi R Blockade of tachykinin NK1 receptors attenuates stress-induced rise of extracellular
noradrenaline and dopamine in the rat and gerbil medial prefrontal cortex J Neurosci Res 2006; 84: 961-968
•
Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, Invernizzi R
•
Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of
depression J Neurosci 2005; 25: 8165-8172
•
Greco B, Invernizzi R, 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
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Parini S, Renoldi G, Battaglia A, Invernizzi R Chronic reboxetine desensitizes terminal but not somatodendritic alfa2adrenoceptors controlling noradrenaline release in the rat dorsal hippocampus Neuropsychopharmacology 2005; 30:
1048-1055
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.
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Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer’s disease and Vascular Dementia. Am J Clinical Nutr 2004; 80: 114-122.
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Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. New England Journal of
Medicine 2006; 355: 1390.
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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, 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.
•
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.
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
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Carli M, Balducci C, Samanin R. Stimulation of 5-HT1A receptors in the dorsal raphe ameliorates the impairment of
spatial learning caused by intrahippocampal 7-chloro-kynurenic acid in naive and pretrained rats Psychopharmacology
(Berl) 2000; 158: 39-47
•
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
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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.
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. Marital therapy for depression. Cochrane Database Systematic Reviews 2006; Issue 2.
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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.
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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.
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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.
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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
Alessandro Nobili got his degree in Medicine (Milan, 1990). Master in Biotechonological Research,
Regione Lombardia, Milan 1988. International School of Pharmacology, 31° Course on: Drug
Epidemiology and Post-marketing Surveillance, Erice, September 1990. Course on: Methods in
Epidemiological Research, Milan, October 1990. Course: Long Term Clinical Trials, Cogne January
1991.
Main areas of interest Methodology of Randomized Clinical Trials; Pharmacoepidemiology and postmarketing surveillance research; Drug utilization studies; Quality assessment of geriatric services;
Qualitative studies on caregiver role in the care of patients with dementia; Methodological evaluation of
the Special Care Unit for Alzheimer Disease patients; Methodology of drug information. Employment
and research experience Chief of the Unit of Quality Assessment of Geriatric Services Chief of the Drug
Information Services for the Elderly, Laboratory of Geriatric Neuropsychiatry, Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan. Editorial Board of the MICROMEDEX Inc., Englewood,
Colorado 80111-4740 USA. National Expert accredited by Italian Ministry of Health for The Italian
(AIFA) and European Agency for the Evaluation of Medicinal Products (EMEA). Head of the
Laboratory of the Quality Assessment of Geriatric Services at the Mario Negri Institute since 2007.
•
Nobili A, Tettamanti M, Frattura L, et al. Drug use in the elderly in Italy. Ann Pharmacother 1997; 31:416-422.
•
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
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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: Cognitive
effects of anemia 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 “Hospice Via di Natale”, 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.
•
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
•
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.
•
Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, et al. Long-term acetyl-L-carnitine
treatment in Alzheimer's disease. Neurology 1991; 41:1726-1732.
•
Lucca U, Comelli M, Tettamanti M, Tiraboschi P, Spagnoli A. Rate of progression and prognostic factors in Alzheimer's
disease: A prospective study. J Am Geriatr Soc 1993; 41:45-49
•
Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004; 80: 114-122
•
Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch Neurol
2006; 63:154-155
•
Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. N Engl J Med 2006; 355:1390
•
Tettamanti M, Garri' M T, Nobili A, Riva E, Lucca U. Low folate and the risk of cognitive and functional deficits in the
very old: The Monzino 80-plus study. J Am Coll Nutr 2006; 25: 502-508
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The Department of Neuroscience is formed by nine 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
nervous system.
A new mutation on the gene encoding for PEN-2 was found in a subject with mild cognitive
impairment (MCI) belonging to a family with Alzheimer cases
In a large population of Alzheimer subjects it has been shown that the plasma levels of beta
amyloid 1-42 was not influenced by the polymorphisms of the PLAU_1 gene as previously
observed
In transgenic mice overexpressing mutated amyloid precursor protein (APP), used as Alzheimer
model, we found a cognitive deficit associated to the glutamatergic transmission alteration
independent from the beta amyloid deposits
Using synthetic peptides homologous to large portion of prion protein (PrP 82-146) it has been
shown a neurotoxic and a gliotrophic effect partially dependent from endogenous prion protein
expression
In human cell line, DJ-1, a protein associated to Parkinson's disease, might contribute to the
neuroprotective effect of alpha-synuclein,
In a cellular model it has been identified the biochemical pathway responsible of the
neuroprotective effect of D-JNK-1-TAT against excitotoxicity. This peptide was found active to
protect the brain from the ischemic damage.
About 60% of the initial unselected Alzheimer’s disease population was on donepezil after a 3year follow-up. After an initial improvement, patients tended to decline linearly on all outcome
measures. Donepezil showed a good safety profile.
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In a population-based study (Monzino 80-plus Study), anemia or hemoglobin concentration
were not cross-sectionally associated with dementia in the very old.
In the same population-based study in the very old (Monzino 80-plus Study), high serum total
cholesterol concentrations were not associated with a higher risk of dementia, while high HDL
cholesterol concentrations showed a protective effect.
A progressive worsening of explicit memory seems to characterize the very early changes in the
dementia course and to precede a more comprehensive cognitive deterioration. Free recall tasks
proved sensitive, though much less specific, measures in discriminating even minimally
cognitively impaired patients from normal elderly.
In a population-based study (Health and Anemia Study), anemia was found in about one out of
10 elderly residents in Biella (65-84 years old). Anemia was of a mild degree (85%) and
positively associated with older age and several pathological conditions. In the longitudinal part
of the study, anemia showed a relatively stable condition in the elderly and even though mild,
significantly affected mortality rate over two years.
In Alzheimer’s special care units (ASCU) 60% of patients with dementia were taking at least
one antipsychotic, 49% typical and 51% atypical.
From January to December 2003, in the Lecco Local Health Authority, 15.5% of elderly
patients were exposed to potential severe drug-drug interactions (60.8% were women).
Marked differences in the quality of acute care offered across various acute wards in Italy.
Serious inadequacies were reported in physical and process indicators in the private wards.
Whereas efficacy on crisis was evaluated as rather good, satisfaction of patients with care and
assistance received during the admission was modest.
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 quality of the epidemiological report on dystonia depends on the background of the
investigators and the type of clinical condition.
The Natural Networks patients, followed according to a naturalistic design, showed significant
improvements in quality of life, needs satisfaction, and social functioning.
Compared to outpatient care, hospital admission is more effective in the management of
headache, as shown by the significant difference in the improvement of frequency, intensity and
duration of the attacks, as well as in the drug consumption and the satisfaction of relatives and
physicians. The success of hospitalization can be explained by a more careful management of
the underlying problems.
Motor neurons of SOD1 mutant mice are unable to activate the survival signaling mediated by
PI3K/Akt.
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A dysfunction of proteasome is found in the motor neurons of SOD1 mutant mice, which might
contribute to the accumulation of intracellular protein aggregates.
In SOD1 mutant mice, the transgenic SOD1 forms insoluble aggregates, which undergo
oligoubiquitination but not polyubiquitination. This might be the cause of their accumulation.
Carbamylated erythropoietin, like the human recombinant EPO, does not improve motor
dysfunction neither prolong the life span of SOD1 mutant mice.
Complement inhibitor (C1-INH) has powerful neuroprotective actions in brain
ischemia/reperfusion injury.
Peripheral treatment with enoxaparine, a low-molecular weight heparin, reduces plaques and
beta-amyloid accumulation in a mouse model of Alzheimer’s disease.
Microglia can explain protective actions in the ischemic environment.
Neural stem cell reduce ischemia/reperfusion injury by changing the ischemic environment.
Drugs with partial agonist and antagonist activity at dopamine D3 receptors selectively
modulate, in laboratory rodents, the drug seeking behavior induced by the environmental stimuli
predictive of cocaine availability.
DBA/2J and BALB/c mice are not respondent to serotonin selective uptake blockers in an
animal model predictive of the antidepressant activity and may represent an animal model of
resistance to SSRI.
Glutamate neurotransmission in the prefrontal cortex (PFC) is involved in attention and
executive control.
Genetic differences in serotonin synthesis contribute to the efficacy of SSRIs in mice.
The blockade of NMDA receptors of the rat prefrontal cortex induces an increase of glutamate
release and is deleterious for prefrontal cortex-dependent cognitive functions.
5-HT2A receptor antagonists and 5-HT1A receptor agonists prevent the increase of glutamate
release and attentional deficits caused by NMDA receptors blockade suggesting that these
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.
ANNUAL REPORT
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2006
IRFMN
Associazione Familiari Insonnia Familiare Fatale malattie da prioni, Treviso
Associazione per la Ricerca Neurogenetica, Lamezia Terme (CS) e ASL 6, Regione Calabria
Agenzia di Sanità Pubblica della Regione Lazio, Roma
Azienda Sanitaria Locale di Bergamo
Azienda Sanitaria Locale di Trento
Azienda Ospedaliera Ospedali Riuniti di Bergamo
CEND, Centro Eccellenza per le Malattie Neurodegenerative, Università di Milano
Centro Fatebenefratelli San Giovanni di Dio, Cernusco sul Naviglio (MI)
Centro Parkinson-Istituti Clinici di Perfezionamento
Centro Studi in Psichiatra, ASL 2, Torino
Clinica IRCSS S. Maria Nascente, Milano
Clinica Neurologica III Università di Milano, Azienda Ospedaliera S. Paolo, Milano
Consorzio Ricerche Luigi Amaducci, CRIC, Arcugnano (Vc)
Consorzio MIA, Milano
DIBIT, San Raffaele Scientific Insitute, Milano.
Dipartimento di Chimica Biologica, Università di Padova
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 Salute Pubblica, Sezione di Psichiatria e Psicologia Clinica,
Università di Verona
Dipartimento di Morfofisiologia, Scuola di Medicina Veterinaria, Università di Torino,
Grugliasco (TO).
Dipartimento Neurologia, 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. Oncologia Biologia and Genetica, Università of Genova
Dipartimento di Salute Mentale ASL 3 ”Genovese”, Genova
Dipartimento di Salute Mentale ASL 4, Torino
Dipartimento di Salute Mentale, Azienda Ospedaliera Carlo Poma di Mantova, Mantova
Dipartimento di Salute Mentale dell’Azienda Ospedaliera di Milano Niguarda
Dipartimento di Salute Mentale dell’Azienda Ospedaliera di Milano San Carlo
Dip. di Scienze Biomolecolari e Biotecnologie, Università di Milano
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 Neurologica, Università di Bologna
Federazione Alzheimer Italia, Milano
Franco Calori Cell Factory, Centro Trasfusionale e di Immunologia dei Trapianti, IRCCS
Ospedale Maggiore, Milano
Fondazione Clelio Angelino
Fondazione Floriani, Milano
Fondo Edo Tempia
Hospice “Via di Natale Franco Gallini”, Aviano (PN)
IRCSS "Casa Sollievo della Sofferenza", San Giovanni Rotondo
ANNUAL REPORT
79
2006
IRFMN
IRCCS Istituto Auxologico Italiano, Milano
IRCSS Neuromed, Pozzilli, Isernia
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 “G. Ronzoni”, Milano
Istituto Nazionale Neurologico “Carlo Besta”, Milano
Istituto Neurologico "Casimiro Mondino", Pavia
Istituto Scientifico Humanitas
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
Ospedale Regionale Cà Foncello, Treviso
Ospedale "Molinette", Torino
Polo Oncologico, ASL 12, Biella
Provincia Lombardo-Veneta Ordine Ospedaliero San Giovanni di Dio, Fatebenefratelli di
Cernusco sul Naviglio
Unione Nazionale delle Associazioni per la Salute Mentale (UNASAM), Milano
Unità di Geriatria, Ospedale Maggiore IRCCS, Università di Milano
Unità Operativa Neurologia, Clinica S. Maria, IRCCS, Castellanza (VA)
Unità Operativa di Psichiatria, Azienda Ospedaliera Luigi Sacco di Milano, Milano
Unità Operativa di Psichiatria, Azienda Ospedaliera San Gerardo di Monza, Monza
Unità Operativa di Psichiatria di Garbagnate, Azienda Ospedaliere Salvini di Garbagnate,
Garbagnate Milanese
Unità Operativa di Psichiatria, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli
e Regina Elena di Milano, Milano
Università degli Studi di Foggia
Università Cattolica del Sacro Cuore di Roma
Università del Piemonte Orientale, Novara
Università di Milano, IRCCS Ospedale Maggiore, Milano
Università Milano-Bicocca, Monza
Università La Sapienza, Roma
ANNUAL REPORT
80
2006
IRFMN
Albert Eistein College of Medicine, Bronx, NY, USA
Atomic Energy Commission, Service de Neurovirologie, Fontenay-aux-Roses, France
Beaumont Hospital, Dublin, Ireland
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
Chorley & South Ribble General Hospital, Chorley, UK
Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDAN), UK
Columbia Univ, Haverstraw, NY, USA
Department of Anatomy and Physiology, Laval University, Quebec
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 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
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
Institut de Génétique Humaine du CNRS, Montpellier, France
Jefferson Med Coll, Philadelphia, USA
Karolinska Institutet, Stockholm, Sweden
King’s College Hospital, London, UK
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
National Institute on Aging, NIH, Baltimore, USA
National Research and Development Centre for Welfare and Health (STAKES), Finland
Neuroprion, Network of Excellence, WP VI, EC
Neurological Department of the University of Tirana, Albania
Ninewells Hospital and Medical School, Dundee, Scotland UK
Northern Illinois University, DeKalb, IL, USA
Novartis Pharma, Basel, Switzerland
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, La Jolla, California, USA
University of Alberta, Canada
Univ of California at Irvine, Irvine, CA, USA
University of Cardiff, United Kingdom
Univ of Colorado, Denver, USA
University Hospital, London, ON, Canada
Univ of Innsbruck, Innsbruck, Austria
Univ of Maryland, Baltimore, USA
University of Maastricht, the Netherlands
ANNUAL REPORT
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2006
IRFMN
University of Rijeka Medical School, Rijeka, Croatia
Université Victor Segalen, Bordeaux, France
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)
Weill Cornell Medical College, New York, USA
World Mental Health, Department of Mental Health and Substance Abuse, Geneva,
Switzerland
Biochemical Journal ( Chiesa, Forloni)
Brain Aging (Forloni)
Clinical Drug Investigation (Beghi)
Clinical Neurology and Neurosurgery (Beghi)
Cochrane Collaboration, Epilessia (Beghi)
Drugs in the R&D (Beghi)
Epidemiologia e Prevenzione (Lucca)
Epilepsia (Beghi,Vezzani,Assistant editor)
Epilepsy Current (Vezzani)
Epilepsy Research (Vezzani)
Inpharma (Beghi)
International Journal of Mental Health (Barbato)
Journal of Neurochemistry (Bendotti)
Neurological Sciences (Beghi)
Neuroepidemiology (Beghi)
Neuroscience (Vezzani)
Psichiatria di Comunità (Barbato)
Ricerca & Pratica (Nobili)
Acta Neurologica Scandinavica
Acta Psychiatrica Scandinavica
Alzheimer Disease and Associated Disorders
American Journal of Human Genetics
American Journal of Pathology
American Journal of Physiology
Annals of Neurology
Annals of Pharmacotherapy
Behavioral Brain Research
Biochemical Journal
Biochemistry
Biological Psychiatry
Brain Research
Brain Research Review
Clinical Drug Investigation
Clinical Neurology and Neurosurgery
ANNUAL REPORT
82
2006
IRFMN
Clinical Pharmacokinetics
Clin Pharm Ther
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
Giornale di Neuropsichiatria dell’Età Evolutiva
Glia
International Journal of Neuropsychopharmacology
Journal of the American Board of Family Practice
Journal of Biological Chemistry
Journal of Cell. Biology
Journal of Chemical Neuroanatomy
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Science
Journal of Headache and Pain
Journal of Histochemistry and Cytochemistry
Journal of Immunology
Journal of Neurochemistry
Journal of Neuroimmunology
Journal of Neurology, Neurosurgery and Psychiatry
Journal of Neuroscience
Journal of Pharmacy and Pharmacology
Journal of Psychopharmacology
Journal of Psychosomatic Research
Journal of Structural Biology
Life Sciences
Lancet
Lancet Neurology
Molecular Brain Research
Molecular and Cellular Neuroscience
Neuroepidemiology
Neurology
Neurological Sciences
Nerobiology of Aging
Neurobiology of Diseases
Neuropharmacology
Neuropsychopharmacology
Neuroscience
Neuroscience Letters
N.S. Archives Pharmacology
ANNUAL REPORT
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2006
IRFMN
Parkinsonism & Related Disorders
Pharmacological Research
Pharmacoepidemiology and Drug Safety
Pharmacology Biochemistry & Behavior
Proc Natl Acad Sci, USA
Psychopharmacology
Synapse
Trends Molecular Medicine
Advisory Board of the Italian League Against Epilepsy
Board of "Master in Advanced Technologies for the Study of Neurodegenerative Diseases",
University of Milan
Commission on Health Care Policy of the International League Against Epilepsy (ILAE)
Commission of Italian Minister of Health for the study of the problems associated to diagnosis,
therapy and assistance ALS patients
Coordination Group of NoE Neuroprion EC
Council of AIRIC
Expert for European Agency for the Evaluation of Medicines (EMEA)
Expert reviewer for the Medical Research Council (MRC), UK
Expert of the Minister of Health to EMEA
Italian Association of Neuroepidemiology (Past President)
Italian Association on Brain Aging Research (AIRIC, President)
Italian Society of Neuroscience (Council)
International Committee on “Epilepsy and the Law”
International Subcommittee of the American Academy of Neurology
Medical Research Council Strategic Grant Application
Mental Health Working Party of DG-SANCO, Directorate General – Public Health and
Consumer Protection – of the European Union, Brussels, Belgium
National expert accredited by AIFA (Italian Medicines Agency) for the European Agency for
the Evaluation of Medicinal Products (EMEA)
Neurobiology Commission of the International League against Epilepsy
Research Advisory Panel, MND Association, UK
Scientific Advisory Board of Sheffield Institute Foundation for MND
“Standing committee of global forum for mental health”. Department of Mental Health and
Substance Abuse, WHO, Geneva, Switzerland
Study Group on Amyotrophic Lateral Sclerosis of the Italian Neurological Society
Study Group on Epilepsy of the Italian Neurological Society
Study Group on Quality of Life of the Italian Neurological Society
Task Force "Evidence-based psychosocial interventions in mental disorders" - WHO Working
Group on Epilepsy, Geneva, Switzerland
ANNUAL REPORT
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2006
IRFMN
EVENT ORGANIZATION
Course on the Epidemiology and research Methodology – January thru December 2006.
Calambrone (PI)
4th Giornata di studio sulla malattia di Alzheimer
Le cadute nel paziente demente. Fattori nutrizionali e deficit cognitivi nel paziente demente.
1 April 2006, Ateneo Veneto, Venezia
58th Annual Meeting of American Academy of Neurology – Breakfast Seminar – How to
manage a patient with a first epileptic seizure: An evidence-based approach - April 8, 2006, San
Diego, California.
Movimenti in Movimento. Salute mentale: la parola agli utenti 16-17 May 2006, Ospedale
Niguarda, Milano
Course on the Methodology of Biomedical Research. Fondazione Don Gnocchi, Milano May 15
& 22, June 12 & 26, July 3 2006.
Joint Meeting AIM-AINP-AIRIC, Workshop Tissue and Brain Banking, Roma 25 May 2006
Italian Neuroepidemiology Society – Introductory Course on Evidence Based Neurology.
Novara June 19-21 2006.
Prion 2006, The Third International Neuroprion Meeting, Turin, October 3-6, 2006
Behavioural disturbances in patients with dementia: from diagnosis to care. Continuing Medical
Education for physicians and nurses. October 21 and 28, 2006, Lecco
2nd Corso di formazione e aggiornamento per operatori socio-sanitari: Alzheimer's disease and
other dementias (10 days)17 October - 30 November 2006, IRE Venezia, Venezia
Abbott GmbH & Co. KG
Amgen, Milano
Bristol-Myers Squibb
Boehringer Ingelheim
CURE Epilepsy
Dipartimento di Salute Mentale, Azienda Ospedaliera Niguarda Ca’ Granda, Milano
Dana Foundation
Dyax
Federazione Alzheimer, Milano
Fondazione Cariplo
Fondazione Mariani, Milano
Fondazione Monzino, Milano
FP6, European Union
ANNUAL REPORT
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2006
IRFMN
Glaxo-SmithKline, Italy
Hospice "Via di Natale Franco Gallini", Aviano (PN)
Human Frontiers Science Programm
IMPHA II, DG-SANCO, Public Health and Consumers' Protection (Directorate General)
Istituto Comprensivo Statale "G.D. Romagnosi", Carate Brianza (MI)
I.R.I.S
Janssen-Cilag
H. Lundbeck A/S, Danimark
Ministero della Ricerca Scientifica
Ministero della Salute
Newron
Nikem Research
Ospedale “Casa Sollievo” di San Giovanni Rotondo
Ordine Ospedaliero Fatebefratelli San Giovanni di Dio
Pfizer Italia
Pharming
Regione Lombardia, Assessorato alla Famiglia e Solidarietà Sociale e Assessorato alla Sanità,
Milano
Rimoldi e Bergamini
Rottapharm
Sanofi-Aventis
SELECTA MEDICA, Pavia
Sigma-Tau
Telethon
Vertex
ANNUAL REPORT
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2006
IRFMN
Acutis, PL, A. Bossers, J. Priem, M.V. Riina, S. Peletto, M. Mazza, C. Casalone, G. Forloni, G. Ru, M. Caramelli.
Identification of prion protein gene polymorphisms in goats from Italia scrapie outbreaks J. Gen Virol., 2006,
87:1029-1038
Barbato A, D'Avanzo B. Marital therapy for depression. Cochrane Database Systematic Reviews 2006; Issue 2.
Barbato A. Psychosocial rehabilitation and severe mental disorders: A public health approach. World Psychiatry
2006; 5: 162-163.
Basso M, Massignan T, Samengo G, Cheroni C, De Biasi S, Salmona M, Bendotti C, Bonetto V. Insoluble mutant
SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J Biol Chem. 2006 281:33325-35.
Bauer, M., Langer, O., Dal-Bianco, P., Karch, R., Brunner, M., Abrahim1, A., Lanzenberger, R.,
Hofmann,A.,Joukhadar, C., Carminati, P., Ghirardi, O., Piovesan, P., Forloni, G., Corrado, ME., Lods, N., Dudczak,
R., Auff, E., Kletter, K., Müller, M. A PET microdosing study with a potential anti-amyloid drug in healthy
volunteers and Alzheimer’s disease patients Clin Pharmacol Ther. 2006, 80: 216-27.
Beghi, E. and Tonini.C Surgery for epilepsy: assessing evidence from observational studies. Epilepsy Research
2006: 70; 97-102
Beghi, M. Beghi, E. Cornaggia, CM., Gobbi.G. Idiopathic generalized epilepsies of adolescence. Epilepsia 2006; 47
(suppl.2): 107-110.
Beghi, M., Cornaggia, CM., Frigeni, L. Beghi, E. Learning disorders in epilepsy. Epilepsia 2006; 47 (suppl.2): 14-18.
Beghi,, E.,De Maria,G., Gobbi, G. Veneselli. E. Diagnosis and treatment of the first epileptic seizure: guidelines of
the Italian League Against Epilepsy. Epilepsia 2006; 47(Suppl. 5): 2-8.
Beghi, E., Logroscino, A. Chiò, O. Hardiman, D. Mitchell, R. Swingler, B.J. Tarynor on behalf of the EURALS
Consortium. The epidemiology of ALS and the role of population-based registries. Biochimica et Biophysica Acta
2006; 1762: 1150-1157.
Beghi E, Bendotti C, Mennini T. New ideas for therapy in ALS: critical considerations. Amyotroph Lateral Scler.
2006 7:126-7
Bendotti C., Toratrolo M., Borsello T. Targeting stress activated protein kinases, JNK and p38, as new therapeutic
approach for neurodegenerative disease Central Nervous System Agents in Medicinal Chemistry 2006, 6:109-117
Biasini, E., V. Rossi, Massignan T., Fioriti, L., Harris, D. Forloni, G. Bonetto, V. Chiesa, R. Proteomic analysis of a
transgenic mouse model of inherited prion disease reveals preclinical alteration of calcineurin activity. Proteomics.
2006, 6: 2823-34
Caccia S
Main active components of St. John's Wort (Hypericum Perforatum) extracts: current analytical procedures for
pharmacokinetics and concentration-response studies. Current Pharmaceutical Analysis 2006; 2: 59-68
Calcagno E., Carli M. and Invernizzi R. W. 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: 853860
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, Nov 2006 (epub ahead of print).
Caramelli, M. Acutis, G., Ru, G., Forloni, G. Prion Diseases: current understanding and research
CNS Drugs 2006, 20: 15-28.
Carloni S, Mazzoni E, Cimino M, De Simoni MG, Perego C, Scopa C and Balduini W. Simvastatin reduces caspase-3
activation and inflammatory markers induced by hypoxia-ischemia in the newborn rat. Neurobiol Dis, 2006, 21: 11926,
ANNUAL REPORT
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Carri MT, Grignaschi G, Bendotti C. Targets in ALS: designing multidrug therapies. Trends Pharmacol Sci. 2006,
27:267-73
Cervo L, Cocco A, Petrella C, Heidbreder CA. Selective antagonism at dopamine D3 receptors attenuates cocaineseeking behavior in the rat. Int J Neuropsychopharmacol. 2006 Jan 23:1-15 [Epub ahead of print]
Cervo L, Burbassi S, Colovic M, Caccia S.Selective antagonist at D3 receptors, but not non-selective partial agonists,
influences the expression of cocaine-induced conditioned place preference in free-feeding rats. Pharmacol Biochem
Behav. Epub 2006 Jan 6.
Colovic M, Campiani G, Butini S, Parabiaghi A, Caccia S. The 1-(2,3-dichlorophenyl)-piperazine-to-aripiprazole
ratio at steady state in rats and man Pharmacologyonline 2006; 2: 252-260.
Cornaggia, CM. Beghi, M. Moltrasio, L. Beghi, E. and the RESt-1 Group. Accidents at work among people with
epilepsy. Results of a European prospective cohort study. Seizure 2006; 15: 313-319.
Cornaggia, CM., Beghi, M. Provenzi, M., Beghi, E. Correlation between cognition and behavior in epilepsy.
Epilepsia 2006; 47(suppl.2): 34-39.
Carli M, Baviera M, Invernizzi R. W. and Balducci C. Dissociable contribution of 5-HT1A and 5-HT2A receptors in
the mPFC to different aspects of executive control such as impulsivity and compulsive perseveration in rats.
Neuropsychopharmacology 2006, 31:757-767
Colovic M, Campiani G, Butini S, Parabiaghi A, Caccia S The 1-(2,3-dichlorophenyl)-piperazine-to-aripiprazole ratio
at steady state in rats and man. Pharmacologyonline 2006; 2: 252-260
Elger B, Schneider H, Winter E, Carvelli L, Bonomi M, Fracasso C, Guiso G, Colovic M, Caccia S, Mennini T
Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of
neuronal ceroid lipofuscinosis. Chem Med Chem 2006; 1: 1142-1148.
Furlan R, Bergami A, Brambilla E, Butti E, De Simoni MG, Campagnoli M, Marconi P, Comi G, Martino G. HSV-1
mediated IL-1 receptor antagonist gene therapy ameliorates MOG35-55-induced experimental autoimmune
encephalomyelitis in C57BL/6 mice. 2006; Gene Ther 1-6,
Gobbi, M.Colombo L., Morbin, M., Mazzoleni, G., Accordo, E., Vanoni, M., Del Favero, E., Cantù L. . Kirschner,
DA., Canzoni, C., 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. 2006; 281: 843-9
Greco B, Carli M.Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to
anxiolytic-like phenotype. Behav Brain Res. 2006; 169:325-34.
Lanzi, S. D’Arrigo, C. Termine, C., Rossi, M., Ferrari Ginevra, O., Mongelli, A., Millul, A. Beghi, E. The
effectiveness of hospitalization in the treatment of pediatric idiopathic headache patients. Psychopathology 2006; 40:
1-7.
Leone, MA. Solari, A.,Beghi, E. for the FIRST Group. Treatment of the first tonic-clonic seizure does not affect
long-term remission of epilepsy. Neurology 2006; 67: 2227-2229
Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch.
Neurology 2006; 63:154-155.
Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. New Engl J Med 2006; 355:
1390.
Marchi N, Guiso G, Caccia S, Rizzi M, Gagliardi B, Noè F, Ravizza T, Bassanini S, Chimenti S, Battaglia G and
Vezzani A. Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical
development. Neurobiol Dis, 2006; 24: 429-42.
Noe’ F, Nissinene J, Pitkanen A, Gobbi M, Sperk G, During MJ, Vezzani A. Gene therapy in epilepsy: The focus on
NPY. Peptides. 2006 Dec 27; [Epub ahead of print)
Oby E, Caccia S, Vezzani A, Moeddel G, Hallene K, Guiso G, Said T, Bingaman W, Marchi N, Baumgartner C,
Pirker S, Czech T, Lo Russo G, Janigro D In vitro responsiveness of human-drug-resistant tissue to antiepileptic
drugs: Insights into the mechanisms of pharmacoresistance. Brain Res 2006; 1086: 201-213
ANNUAL REPORT
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Orsi, A., Fioriti, L., Chiesa, R. and Sitia, R. Conditions of Endoplasmic Reticulum Stress Favor the Accumulation of
Cytosolic Prion Protein J. Biol. Chem., 2006; 281: 30431 - 30438
Pappadà, G., Beghi, E.,Marina, R., Agostoni, E., Cesana, C., Legnani, F., Parolin, M., Petri, D., Sganzerla.EP.
Hemodynamic instability after extracranial carotid stenting. Acta Neurochir (Wien) 2006; 148: 639-645.
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 and mild cognitive impairment Neurobiol Aging 2006; 27: 904905
Pohlmann-Eden, B., Beghi, E., Camfield, C., Camfield. P. The first seizure and its management in adults and
children. BMJ 2006; 332: 339-342.
Poulet R, Gentile MT, Vecchione C, Distaso M, Aretini A, Russo G, Echart C, Maffei A, De Simoni MG, Lembo G.
Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab, 2006, 26: 253-262,
Raimondi A, Mangolini A, Rizzardini M, Tartari S, Massari S, Bendotti C, Francolini M, Borgese N, Cantoni L,
Pietrini G. Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial
ALS-linked G93ASOD1. Eur J Neurosci. 2006; 24:387-99.
Rastaldi, MP. Armelloni, S., Berra S., Calvaresi, N., Corbelli, A., Giardino LA., Li, m., Pesaresi, M. Wang, GQ.,
Fornasieri, A., Villa, A., Heikkila E., Soliymani, R., Boucherot, A., Cohen, CD., Kretzler, M., Nitsche, M., Koller,
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Ravizza T, Lucas S-M, Balosso S, Bernardino L, Ku G, Noé F, Malva J, Randle JC, Allan S, Vezzani A. Inactivation
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RESEARCH ACTIVITIES
Laboratory of Biology of Neurodegenerative Disorders
Alzheimer's disease: genetic studies
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. In 2005 we started also the collection of blood samples from subjects
with fronto-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 beta amyloid (Ab) 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 Ab in the pathogenesis of AD. Thus,
prevention the formation of Ab 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 Ab and the
enzymes influencing the metabolism of amyloid precursor protein. In the lab, we developed the
idea to interfere directly with the Ab 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. In collaboration with the Department of
Biochemistry and Molecular Pharmacology, in 2006 we tested new molecules that can bind the
amyloid aggregates to identify either anti-dementia drugs or potential diagnostic markers.
Furthermore, using in vitro and in vivo models, we are evaluating new approaches to reduce the
beta amyloid production either by affecting directly on beta secretase or by the modulation of
JNK pathway
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 considere the numerous other parameters
collected in our database.
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Prion's disease: in vitro studies
Prion’s diseases (TSE) are neurodegenerative disorders of sporadic inherited origin but also
transmissible, they have different clinic and neuropathological features but all are characterized
by the cerebral accumulation of an altered form of prion protein (PrPsc). TSE are rare diseases
but the transmission from bovine (BSE) to humans induced a public health alarm in UK and
successively in all Europe. PrPsc is involved in the pathogenesis of the disease and it is also an
essential component of the infective agent. In the lab numerous projects were developed to
understand the association between the presence of PrPsc and the neurodegenerative process.
The biological effects of peptides homologous to large fragment of PrP were investigated. In
particular PrP 82-146, synthesized in the Protein Chemistry and Biochemistry lab, homologous
to the fragment found in the cerebral deposits in TSE patients, is neurotoxic and spontaneously
structured in beta sheet conformation. The pathogenetic role of PrP was investigated not only
through the external application of peptides but also by the evaluation of intracellular
mechanisms potentially involved in the formation of PrP aggregates.
Prion’s diseases: studies in vivo
The lab has the facilities to study the experimental scrapie, mice and hamsters are inoculated
with infected brain homogenate. The hamsters after intracerebral inoculation develop the
disease in 60-70 days and died within a month. The histopathological analysis of the brain show
the presence of PrPsc deposits, neuronal damage, diffuse astrogliosis and the typical spongiosis
at cortical and thalamic level. The anti-amyloidogenic activity of tetracyclines has been
investigated also in this experimental contest. After the ex-vivo approach, where the
homogenate was treated before the inoculation, the curative effect of tetracyclines was tested in
collaboration with the lab of Chemistry and Biochemistry of Proteins by treatment the
experimental scrapie in hamsters with intramuscular doxycycline, the treatment prolonged the
survival of the animals. Other drugs are now under investigation to verify the curative effects in
TSE.
Other animal models of TSE are available in the lab, transgenic mouse developed by dr. Chiesa.
These mice express mutated forms of PrP associated to the familial TSE. The homozygotes
exhibit at different level of severity the symptoms reminiscent of the pathologies associated
with the mutations. From the neuropathological point of view some lines exhibit an
accumulation of PrP and clear neurodegeneration of the cerebellar granular cells, in the other
brain regions no evident alterations were found. In the brain tissue of the mice was found a PrP
with some of the characteristic of PrPsc, however the brain material is not infected. The
pathogenesis of TSE is investigated in these models through different approaches including the
proteomic approach and the electronic microscopy.
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 alpha-
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synuclein, parkin, DJ-1 and other factors potentially involved in PD.
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
recently again in collaboration with Dr. Negro, 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 eight provinces of Lombardy. 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. Three major scientific activities are in course: 1. A comparative study of the clinical
characteristics of patients with ALS enrolled in the registries as compared to those seen in
secondary and tertiary health care facilities; 2. A meta-analysis of the incidence of ALS,
performed by pooling data from the 1998-99 cohorts of patients enrolled in the populationbased registries; 3. A study on the validity and reliability of the El-Escorial diagnostic criteria
for ALS, done with the EURALS referent investigators; 4. An international protocol for the
implementation of a case-control study to assess the role of physical activity, trauma and
professional sports in ALS, done in collaboration of U.K. and Irish groups (leading populationbased registries). In addition, two studies have been completed, the first on the incidence of
ALS in Lombardy during the period 1998-2002 and a study on the progression of ALS (marked
by loss of ambulatiom, percutaneous gastrostomy and non-invasive assisted ventilation).
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Complications of epilepsy and its treatment
In the context of a European prospective cohort study on epilepsy and everyday life risks, a
subgroup analysis explored the risk of psychiatric disturbance in epilepsy. Enrolled were 951
children and adults with epilepsy and 909 age- and sex-matched controls. During a 1-2 year
follow-up, a total of 58 psychiatric events were recorded by 25 cases (88 events by 19 controls).
Housewives (9.3%) and unemployed persons (4.1%) were mostly affected. Most psychiatric
disturbances were mild, anxiety and depressive disturbances being largely predominant.
Innovative therapeutic strategies in patients with epilepsy
A cohort of patients with a first unprovoked seizure, randomised since 1988 by several Italian
centers to immediate treatment or to treatment only at the time of a seizure relapse, was
followed to verify the impact of the two therapeutic strategies on the long-term prognosis of
epilepsy, measured by the chance of achieving 5-year remission. To provide a pragmatic
definition of drug resistance in childhood epilepsy, children refractory to two antiepileptic drugs
(in sequence or in combination) were randomised to the use of a third drug or to the
optimization of the existing treatment and followed for up to three years. Therapeutic response
was measured by the achievement of a six-month period of remission. The study has been
conducted in collaboration with the IRCCS “Stella Maris” of Calambrone (PI).
Therapeutic strategies in children with chronic primary headache
A randomised pragmatic trial has been conducted in collaboration with the Child Neurology
Department of the University of Pavia to assess the benefits of a short hospital admission
compared to the outpatient management of children with chronic primary headache. The success
of the two therapeutic strategies has been measured by assessing their impact on the
characteristics of the headache attacks during follow-up and on other indicators of benefit (drug
consumption, family’s and physician’s satisfaction). Another randomised trial, promoted by the
Child Neurology Department of Pavia and conducted in collaboration with other Italian groups,
has been undertaken to verify the impact of psychological assessment compared to standard
management of attacks in children with chronic primary headache. The study is ongoing.
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). A study on the validation of the diagnostic criteria is in course.
Quality of life in children with neuromuscular disorders
With a financial support of the Telethon organization, a study is ongoing on the validation of a
questionnaire on the quality of life in children and adolescents with different neuromuscular
disorders. This is an Italian multicenter study coordinated to the Child Neurology Clinic of
Pavia.
Risk factors for tumors and co-morbidity in myasthenia gravis
A case-control study was undertaken in collaboration with the neurological clinic of the
university of Pavia in search of risk factors for tumors in patients with myasthenia gravis. The
study population included 2479 patients seen in tertiary centers in Italy and followed for an
average period of 9 years. One or more neoplasms were present in 221 cases (9%). Compared to
patients without neoplasms (controls), patients with neoplasms had more frequently a thymoma
and were more frequently exposed to immunoglobulins or less frequently exposed to
cyclophosphamide.
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The data from the case-control study were also examined to prepare study protocols aimed at
comparing these data with other data sets to verify whether mortality in patients with
myasthenia gravis and neoplasms and incidence of neoplasms in patients with myasthenia
gravis is higher than that of the general population. The principal predictors of mortality will be
also searched.
Diagnosis and prevalence of dystonia
As part of a collaboration with the institute “San Raffaele” of Milano, a study has been
completed on the prevalence of adult focal dystonia in the province of Foggia. Cases are
ascertained through different sources (hospital admissions, neurology, ENT, ophthalmology,
and ortopedics outpatient visits) in the two major local hospitals. To verify the quality of the
diagnosis of dystonia, a validation study was performed in the year 2002 involving four
neurologists and 14 residents in neurology who examined 29 video recordings referring to
patients with dystonia or related clinical conditions. Inter-rater agreement was poor in 26% of
pairs, was better between neurologists than between residents, and prevailed for blepharospasm,
cervical and upper limb dystonia, and spasmodic dysphonia.
Laboratory of Drug Metabolism
Mechanisms of multidrug resistance
These studies are conducted in collaboration with the Laboratory of Experimental Neurology (A.
Vezzani) and aim to investigate: A) the mechanism(s) of upregulation of the multidrug
transporter P-glycoprotein (the MDR1 gene product) in pathological tissues; B) whether Pglycoprotein overexpression accounts for reduced availability of anticonvulsant agents in the
brain, resulting in poor responsiveness to conventional anticonvulsant therapy and C) whether
this can be reversed by specific P-glycoprotein blockers.
We are also studying: A) whether MDR1 over-expression is intrinsic to cortical dysplasia or is
determined by seizures, or both; B blood-brain barrier permeability in dysplastic tissue with and
without seizures; (C) the role of P-glycoprotein and blood-brain barrier function in brain uptake
of substrates of this transmembrane pump. This is because MDR1 is over-expressed in
endothelium of the blood-brain barrier, in glia and in neurons in pharmacoresistant epilepsy
associated with malformations of cortical development, and many drugs are extruded from the
cells by membrane-bound glycoproteins, including P-glycoprotein.
Pharmacological role of the constituents of Hypericum perforatum
extracts
The chemical composition of the extracts of hypericum perforatum L. (St. John’s wort) is
essentially known but is still uncertain 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 evidence for other
pharmacologically active components has been reported. However, identifying the roles of the
various derivatives and mechanism(s) underlying their activity is complicated by the scant
information about their ability to cross the blood-brain barrier and the concentrations reached in
brain after 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 open question 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. As in vitro studies found amentoflavone was a substrate of P-glycoprotein, like other
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flavonoid derivatives, we are also studying how this efflux transporter influences their brain
availability.
1-Aryl-piperazine as active metabolites of centrally acting drugs
1-(2,3-Dichlorophenyl)-piperazine (2,3-ClPP) has been incorporated in the structure of centrally
acting compounds which, in analogy with related arylpiperazine derivatives, can form 2,3-ClPP
by CYP3A4-mediated cleavage of their side chain. However, there was no information on how
2,3-ClPP contributes to the pharmacological activity of its various parent compounds, including
the recently introduced antipsychotic aripiprazole. We therefore developed a reliable highperformance liquid chromatography-electrospray ionization mass spectrometric method for its
detection in body fluids and brain tissue. This enabled us to confirm that aripiprazole metabolism
includes N-dealkylation to 2,3-ClPP which, however, was present as a minor metabolite in
serum of schizophrenic outpatients (one male and seven females) taking the usual therapeutic
doses.
As phenylpiperazines concentrate in the brain causing a variety of serotonin receptor-related
pharmacological effects, we also examined the compounds’ concentrations in brain of rats given
aripiprazole dihydrochloride, and the metabolite-to-parent drug ratio at steady state. The
metabolite had higher brain uptake than aripiprazole, so the metabolite-to-parent drug ratio was
higher in brain than in blood. However, assuming that the compounds concentrate in human
brain to the same extent as in the rat, one can conclude that at the site of action the metabolite
accounts for only a small percentage of aripiprazole. It is therefore conceivable that 2,3-ClPP
contributes to the central effects of aripiprazole for the rats, but it should be of less clinical
significance for patients, although its pharmacological profile is still largely unknown and there
may be physiological and pathological factors that raise the metabolite-to-parent drug ratio at the
site of action.
Resistance to antidepressant drugs: studies in animal models
These studies investigate the neurobiological mechanism(s) of resistance to antidepressant drugs,
which is still an important question considering that a substantial proportion of patients show
only a partial or no response. The studies in animal models (mice carrying allelic differences in
tryptophan hydroxylase-2) are conducted in collaboration with the laboratory of Experimental
Psycopharmacology (L. Cervo), the laboratory of Neurochemistry and Behaviour (R.W.
Invernizzi), who will provide a brief description of recent results with selective serotonin
reuptake inhibitors, currently the mainstays in the treatment of depression.
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Laboratory of Experimental Neurology
Role of inflammatory molecules in ictogenesis and epileptogenesis
We are studying the role of IL-1beta and TNF-alpha 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 cytokines and related molecules involved in
inflammatory processes. IL-1beta has proconvulsant actions while its naturally occurring
antagonist (IL-1Ra) and TNF-alpha have anticonvulsant activities. We are now evaluating the
role of these molecules in seizure-associated neuronal damage in mature brain and during
postnatal development. We are studying pharmacological approaches to block IL-1betasignaling involved in the proconvulsant effects of this cytokine. Research activity 2:
Mechanisms of drug resistance in epilepsy: This study is aimed at investigating whether
multidrug resistance in epilepsy is dependent on the activity of membrane bound glycoproteins
able the extrude antiepiletic drugs from the brain tissue back into the blood stream. These
proteins (in particular those produced by the MDR or MPR genes) appear to have a significant
role in determining the resistance to some anticancer agents. Our studies indicate that the MDR
gene product, P-glycoprotein or P-gp, is increased in specific brain regions during epileptic
activity. The increase in protein determines a decreased brain concentration of phenytoin and
transgenic mice lacking this protein accumulate higher concentration of this antiepileptic drug in
their brain. Since an increased production of this protein occurs in the brain of human epileptics,
it is possible that it contributes to drug refractoriness by impairing the attainment of clinical
relevant concentrations of these drugs in the epileptic tissue.
We recently found that the inhibition of the activity of P-gp in experimental models of epilepsy
using specific blockers of its function, enhances the efficacy of anticonvulsant treatments. We
have also demonstrated a role P-gp in brain drug disposition in experimental models of focal
cortical dysplasia, a clinical condition associated with drug-refractory seizures.
Mechanisms of drug resistance in epilepsy
This study is aimed at investigating whether multidrug resistance in epilepsy is dependent on the
activity of membrane bound glycoproteins able the extrude antiepiletic drugs from the brain
tissue back into the blood stream. These proteins (in particular those produced by the MDR or
MPR genes) appear to have a significant role in determining the resistance to some anticancer
agents. Our studies indicate that the MDR gene product, P-glycoprotein or P-gp, is increased in
specific brain regions during epileptic activity. The increase in protein determines a decreased
brain concentration of phenytoin and transgenic mice lacking this protein accumulate higher
concentration of this antiepileptic drug in their brain. Since an increased production of this
protein occurs in the brain of human epileptics, it is possible that it contributes to drug
refractoriness by impairing the attainment of clinical relevant concentrations of these drugs in
the epileptic tissue.
We recently found that the inhibition of the activity of P-gp in experimental models of epilepsy
using specific blockers of its function, enhances the efficacy of anticonvulsant treatments. We
have also demonstrated a role P-gp in brain drug disposition in experimental models of focal
cortical dysplasia, a clinical condition associated with drug-refractory seizures.
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 vectors carrying the
human neuropeptide Y gene under the control of a neuronal promoter, significantly increase the
brain concentration of this peptide after intrahippocampal injection for a prolonged time (up to 3
months after a single intracerebral injection). The rats overexpressing this peptide are less
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susceptible to limbic seizures and to epileptogenesis. Future development of this study concerns
the optimization of the transgene transfer technology to inhibit spontaneously recurring seizures
and envisaging a possible clinical application.
Laboratory of Geriatric Neuropsychiatry
Clinical impact of donezepil in general AD population
Data collection in the longitudinal observational long-term study on the clinical impact of
donepezil use (oral dosage of 5 or 10 mg/die) came to an end. In collaboration with 52 Italian
neurologic and geriatric centers, 800 patients were followed up for a duration of three years
(also in the case, for whatever reason, of drug withdrawal). Clinical outcomes assessing the
various disease aspects as well as drug safety, caregiver stress and disease costs were
prospectively evaluated.
Survey on the health status of old people living in the rural community of
Moltrasio
95% of the 206 subjects potentially recruitable received a direct or indirect evaluation: this
response rate enables us to evaluate the health status of the population without bias. This
important result was achieved thanks to the great work of the general practitioners. From a
sociodemographic point of view more than 50% of the population was born within a radius of
10 km from present place of residence, thus giving rise to a relatively homogeneous group. First
analyses show that the most prevalent pathologies are those typical of this age range
(hypertension –70%-, arthrosis and related disorders –60%-), but disability is relatively
uncommon: only 1 subjects out of 20 has a major disability and 1 out of 3 a minor one.
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 two year follow-up of the population-based study Health and Anemia has been completed.
Mild anemia was shown to be a relatively stable condition in the elderly population studied.
Mild anemia in the elderly was found to be associated with clinical relevant outcomes such as
increased mortality rate.
Evaluating risk profiles in hospitalised elderly subjects
In collaboration with the Geriatric Division of the Beata Vergine Hospital, Mendrisio,
Switzerland, hospitalized and ambulatory patients are evaluated from a neuropsychological,
functional and mobility point of view in order to estimate the impact of these factors on heathrelated outcomes and disease progression.
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Longitudinal follow-up of individuals with mild cognitive impairment (MCI)
In collaboration with the Geriatric Unit of the Beata Vergine Hospital, Mendrisio, Switzerland,
follow-up study to estimate the rate of conversion to dementia of all Mild Cognitive Impairment
or Questionable Dementia (CDR 0.5) patients seen at the Memory Clinic of the Hospital.
Quality assessment of services on dementia
A study compared a sample of nursing homes (NH) with Special Care Units (SCU) for
Alzheimer’s Disease with a sample of nursing homes without a SCU to assess the effect of their
different organisations on patient outcomes. A sample of 600 patients with dementia was
enrolled and monitored for 18 months. Patients admitted at ASCU were younger, less
cognitively and functionally impaired, but had more behavioral disturbances than those
admitted to NH. At follow-up, patients admitted to ASCU had a lower risk of hospitalisation,
use of physical restraints, and a higher probability of withdrawing antipsychotics than patients
admitted to NH. No difference was reported on overall mortality and falls.
Antipsychotic use in a sample of Italian Alzheimer Special Care Units
An observational prospective study was set up to evaluate the frequency of antipsychotic use
and their association with BPSD in institutionalised patients with dementia in northern Italian
Alzheimer’s special care units (ASCU). Sixty percent of 319 patients were taking at least one
antipsychotic, 49% typical and 51% atypical. Forty five percent were exposed to one
antipsychotic, 14% two and 1% three. Risperidone was the most frequently prescribed
antipsychotic followed by promazine, olanzapine and haloperidol. In 40% of the cases, another
hypnotic or sedative drug was simultaneously administered. Antipsychotics were significantly
associated with female sex, older age and higher NPI score, but did not significantly influence
mortality, hospitalisation, falls or use of physical restraint at follow-up.
“Drug-drug interactions” project
An ad-hoc study in collaboration with Regione Lombardia was set up in the Lecco Local Health
Authority to evaluate the potential risk of drug-drug interaction. From January to December
2003, 9115 elderly (15.5%) were exposed to potentially severe drug-drug interactions and
60.8% were women. A total of 13.520 severe drug interactions were recognized, mainly
involving cardiovascular drugs (56.8% of the cases). Drug-drug interactions were significantly
related to increasing age and number of chronic drug used. The most common drugs involved in
potential drug interaction were digoxin, enalapril, the combination of
hydroclorotiazide+amiloride, furosemide, and acetylsalicylic acid.
Pharmacoepidemiology in the elderly project
In a study in collaboration with Regione Lombardia, an analysis of prescription data relative to
the Lecco Local Health Authority from January to December 2003, showed that 50,324 elderly
patients (65 years or older) received at least one prescription. On average each patient received
19.2 prescriptions. Cardiovascular drugs were the most frequently prescribed therapeutic group
(68.5%), followed by systemic antimicrobics (44.6%), musculoskeletal agents (42.8%),
gastrointestinal drugs (42.3%) and hematological medications (37.6%). Women received more
prescriptions than men.
Integrated intervention to rationalize the prescription of drugs by general
practitioners (GPs) of the Bergamo Local Health Authority
This study is aimed to rationalize the use of drugs by GPS of the Bergamo Local Health
Authority. The intervention is articulated in different educational events focused on critical
prescribing settings (antihypertensive agents, non-steroidal anti-inflammatory drugs, proton
pump inhibitors, and antibiotics). To critically assess the prescription data on the previously
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indicated therapeutical fields, and to review the most significant literature, four working groups
were created. Each group involved physicians, specialists, pharmacologists, and general
practitioners. At the end of revision each group will elaborate a “practical” document to
summarize the best evidence on each topic.
Drug information service for the elderly
A daily free of charge telephone service for drug and clinical information is available for
physicians and elderly. Nearly 600 questions are answered each year.
Quality of care of terminally ill oncological subjects
In 1999 we started a collaborative programme with the hospice “via di Natale Franco Gallini” in
Aviano (PN). The 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. Two studies have been planned, one
retrospective and one prospective. Present aim of the study is the assessment of the hospice
activities after its opening and to provide continuous training to nurses on use of databank..
GISAS (Italian Group for the Study of Second Generation Antipsychotics)
A new protocol has been defined, focusing on the medical consequences of first and second
generation antipsychotics used for many years (aloperidol and olanzapine) and the most recently
introduced into the Italian market new antipsychotic, aripiprazole. Tolerability, in particular risk
of metabolic syndrome onset, and effectiveness, pragmatically evaluated as rate of drug
retention at 12 months, are the primary outcomes. The scientific committee has been settled and
the coordinating centre defined. About 80 mental health centers will recruit 800 subjects into the
study in one year.
Suicides in Italy
Definition and submission for evaluation to the Ministry of Health of a research protocol on
definition of appropriateness and feasibility of suicide prevention initiatives and projects in the
Italian services and community, implementation of procedures and skills for a more complete
identification in the Emergency Units and referral to mental health services of suicide attempts,
monitoring of the contacts of referred subjects with the mental health services and efficacy of
staff training in prevention of suicide attempt recurrence in the subjects treated in the mental
health services.
Project resistance to depression treatment
Clinical study on the predictivity of genetic markers for the identification of subjects with
depression and resistant to SSRI treatment, and on the relationship between resistance to SSRI
treatment and serum levels of BDNF and serotonin transporter in a sample of patients treated for
depression in the mental health services of Lombardy. The network of participating centres was
extended to a new one, and the total number of centers active at present is six. Besides
continuing the recruitment of subjects according to the original protocol, based on a prospective
criterion for the definition of treatment resistant subjects, a retrospective recruitment was
started, which led to the inclusion of 27 new subjects and the respective blood sample.
The revolving door effect in psychiatric residential facilities: monitoring
the problem and identifying strategies
The third phase of the project aiming to investigate the revolving door effect in residential
facilities has been started. This phase addresses the outcomes on several endpoints related to
patients newly admitted to psychiatric residential facilities. Four mental health services, serving
a total of 500,000 inhabitants, and a large private centre have recruited, at present, 50 subjects.
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Besides clinical outcomes, quality of life, users' satisfaction with the residential service,
relevance of the therapeutic project and barriers to discharge are studied.
Empowerment Project
The Mental Health Department of the largest Health Trust of Milan has started a project aimed
at raising the awareness by mental health staff of users empowerment issues, the
implementation of forums and other possibilities for professional-user exchange and debate
about evaluation and organization of the services, and care. The same department has
implemented a project, the Natural Networks Project, which connects individuals with severe
mental health conditions to ordinary non-professional people willing, on a voluntary basis, to
help them in facing specific problems or to have with them a meaningful relationship. Both
projects, the second one in particular, require that specific methods for their evaluation are
addressed, which take into account the relevance of results which can not be evaluated as
clinical outcome only.
International working parties and committees
Participation in the Steering Committee of the European Network on Mental Health Promotion
and Mental Disorder Prevention and to the Mental Health Working Party of the Directorate
General for the Health and Consumer Protection of the European Union for the collection of the
documentation on initiatives, projects and programs of mental disorder prevention and mental
health promotion. Preparation of a European consensus conference.
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
effectiveness 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, i.e. 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.
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) C1-INH
neuroprotection is at least partially independent from the complement classical pathway and
inhibition of other complement pathways, of other inflammatory systems such as the
contact/kinin system, or of thrombotic events associated with ischemia-reperfusion injury may
be involved in its powerful protective action.
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
brain ischemia/reperfusion injury. Studies are presently going on to clarify the mechanism of
neuroprotection by C1-INH (De Simoni et al. 2003; De Simoni et al. 2004; Storini et al. 2005;
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Stem cells as a therapeutic approach in stroke The aim of the project is to verify the conditions for the effectiveness of microsphere-derived
stem cells (MSC) in reducing the ischemic injury and to investigate the mechanisms triggered
by their infusion in the ischemic brain. MSC, isolated from newborn mice (Lab Dr. Parati, Inst.
Neurologico C. Besta) are infused to syngenic mice in which transient ischemia is induced by
middle cerebral artery occlusion. At different time points, up to 14 days, several parameters are
evaluated: distribution and phenotype of injected cells, neurodegeneration, behavioral deficits,
cytokine and trophic factor gene expression, microglia activation. The results obtained show
that: i) MSC effectively counteract ischemia / reperfusion injury: they can decrease neuronal
loss and reverte functional impairments related to exploratory behavior and sensory/motor
activity; ii) they elicite an early response: 24 h after infusion, chemokines, angiogenic and
neurotrophic factor transcripts are activated; these factors are no more activated at longer times
or when cells are infused after 7 days; iii) the protective mechanism of MSC in this model of
mild ischemia seems to be mainly due to the induction of beneficial factors; iv) activation of
microglial cells is one of the aspects of changes in ischemic environment induced by MSC; v)
their presence in the brain tissue is enhanced by the ischemic injury. Thus the reciprocal
interaction between MSC and ischemic environment is crucial for stem cells protective actions.
Identification of ischemic tolerance mediators in cerebral ischemia
Recent studies indicate that cell death resulting from ischemic injury can be reduced when a
sublethal ischemic episode occurs hours or days before a severe ischemic insult. This
phenomenon is known as Ischemic PreConditioning (IPC) and the induced neuroprotection is
called Ischemic Tolerance (IT). Several models of induction and maintenance of tolerance have
been described, but the molecular mechanisms of the IPC-induced neuroprotection are not
identified yet and a clear view of the mechanisms responsible for ischemic preconditioning is
still lacking. Specific aims of the project are: i) to define the characteristics of IT induced by
small transient ischemic attack (TIA) in experimental models of cerebral ischemia; ii) to
elucidate the pathways and/or the mediators involved in ischemic tolerance; iii) to identify
endogenous protective molecules/pathways that may represent potential therapeutic targets for
stroke. The project plan includes the characterization of TIA model in mouse, the study of the
effect of TIA on subsequent ischemia and time window of ischemic tolerance, the identification
of mediators involved in IT by protein and mRNA assays, the study of direct effect of relevant
protective molecules in “in vitro” and “in vivo” ischemia models. Thus, ischemic
preconditioning provides an opportunity to identify the putative candidate that can confer
neuroprotection against stroke. 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.
Heparin and Alzheimer-s disease We have previously shown that heparin possess anti-inflammatory and neuroprotective actions
in vitro. We have now investigated the effect of long-term, peripheral treatment with
enoxaparin, a low-molecular-weight heparin, in transgenic mice overexpressing human APP751.
Enoxaparin intraperitoneal treatment for six months significantly lowered the number of cortical
beta-amyloid deposits, the area occupied by them and the total eta-amyloid cortical
concentration. Immunocytochemical analysis of glial-fibrillary-acid protein-positive cells
showed that enoxaparin markedly reduced the number of activated astrocytes surrounding betaamyloid deposits. In vitro the drug dose-dependently attenuated the toxic effect of beta–amyloid
on neuronal cells. Enoxaparin dose-dependently reduced the ability of beta-amyloidto activate
complement and contact system, two powerful effectors of inflammatory response in Alzheimer
brain. By reducing the beta-amyloid load, cytotoxicity and proinflammatory activity,
enoxaparin, an anticoagulant in common clinical use, offers promise as a tool for slowing the
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progression of Alzheimer's disease. Together with different scientists in our Department and in
collaboration with Policlinico di Milano (Dr Bergamaschini and Dr Scarpini), we have recently
started a “proof of concept” study in a selected group of AD patients to test the hypothesis that
the treatment with enoxaparin induces changes in beta-amyloid production in plasma and CSF
of these patients. (Bergamaschini et al, 2003; 2004).
Laboratory of Molecular Neurobiology
Study on pathogenic mechanisms of Amyotrophic Lateral Sclerosis
Role of protein aggregation
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). At present, we are investigating whether motor neurons of
SOD1 mutant mice may specifically display an impairment of the proteasome activity. To
address this issue we are using transgenic mice expressing in almost all cells a fusion protein
functioning as marker for the activity of the proteasome, the UbG76V-GFP mice (kindly
provided by Dr. Nico Dantuma of the Karolinska institute). These mice have been crossed with
the SOD1G93A mice and the progenies examined at different stages of the disease. The results
so far obtained show that in some motor neurons of symptomatic double transgenic mice,
showing neuropathological features such as the vacuolisation, there is an increase in the
immunoreactivity for GFP indicating a dysfunction of the proteasome. The study is ongoing for
a further characterisation of this phenomenon at different stages of the disease.
In addition, the purpose of our study in this context is to identify the proteins forming the
aggregates in order to characterise their role in the pathogenesis of the disease. In collaboration
with the Molecular Biochemistry and Pharmacology department we have completed the
proteomic analysis of the insoluble SOD1 in the spinal cord of transgenic SOD1G93A mice. We
observed that insoluble SOD1 aggregates are already present in the spinal cord of
presymptomatic mice. Subsequently they undergo oligoubiquitination, which could be
responsible for the progressive accumulation in the motor neurons. These data are published in
Journal Biological Chemistry.
In collaboration with the same group we are also completing the proteomic analysis of soluble
and insoluble proteins isolated from the spinal cord of SOD1G93A mice at different stages of
the disease.
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 proteins regulating the trafficking of the
AMPA receptor such as the proteins NSF, ABP, PICK1 in the spinal cord of SOD1G93A mice
at different stages of the disease. The results show that NSF, which is mainly involved in the
transport of the GluR2 subunit from the cytosol to the membrane, remarkably increased in the
motor neurons of mice at the presymptomatic stage. This could be an attempt of the motor
neurons to protect them from the excitotoxicity by increasing the calcium impermeable subunit
of AMPA receptor. In fact, we have recently demonstrated that the GluR2 subunit is remarkably
decreased in the motor neurons at an early stage of the disease probably inducing a massive
influx of calcium in the cell.
Study of inflammatory mechanisms
It is widely accepted that the degeneration of motor neurons in SOD1 mutant mice is not a cell –
autonomous phenomenon but it depends on the presence and activation of astrocytes and
microglia. These two cell populations are the main sources of pro-inflammatory molecules in
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the CNS. We have observed that in the motor neurons of SOD1G93A mice at a presymptomatic
stage the levels of TNFalpha receptors are increased and this occur in association with the
activation of the MAPK kinase cascade (ASK1, MKK3,4,6 and p38). The results are published
on Molecular Cellular Neuroscience. Interestingly, a similar response has been fund in the
motor neurons of patients affected by sporadic ALS. (Manuscript in preparation)
Moreover, we have examined in SOD1G93A mice the expression and localization of High
mobility group box protein 1 (HMGB1), an ubiquitous nuclear protein that exerts numerous
extranuclear and extracellular functions, including a proinflammatory activity, able to induce
cytokines expression and activate inflammatory cells. We observed that degenerating neurons
showed a reduction of HMGB1 immunoreactivity, which could reflect an extracellular release
of this protein. By contrast, in the reactive glial cells HMGB1 was remarkably expressed in the
nucleus, but not in the cytosol, likely contributing to the proliferation and/or hypertrophy of
these cells. These results are in press in Neurosci. Letters.
In the context of this project we have also investigated whether survival signals, such as the
PI3K/Akt pathway and its neuron-specific activator, Rai, susceptible to inflammatory and
oxidative stimuli, were modified in these mice. No substantial changes were found in the levels
of Rai, PI3K(p85) or phosphorylated Akt (P-Akt) in the ventral horn of spinal cord of
SOD1G93A mice during disease progression. P-Akt immunoreactivity was the same in
degenerating and healthy motor neurons. Thus, motor neurons in SOD1G93A mice do not lose
the pro-survival PI3K/Akt signal neither increase it in order to suppress the cell death
mechanisms. These results are in press in Molecular and Cellular Neuroscience.
Altogether, these studies indicate that the activation of TNF alpha receptors and its downstream
cascade of MAPK kinases may participate in the degenerative process of ALS. Studies using
mice lacking of TNF receptors or using strategies to inhibit selectively the MAPK cascade
(siRNA) are underway to verify this hypothesis.
In vitro studies on neuron-glia interaction
To investigate further the role of inflammatory mechanisms, we have set up an in vitro cocolture 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.
Therapeutical interventions in mouse model of ALS
After the demonstration that the human recombinant erytropoietin (rhuEPO) in SOD1G93a
mice remarkably increased the hematocrit levels, but showed no effect on the progression of the
disease, survival and motor neuron loss of these mice, we have investigated the effect of
carbamylated EPO (CEPO) which does not increase the hematocrit and showed neuroprotective
effect in models of stroke and spinal cord injury. As for the rhuEPO, we have observed no
effect on the progression of disease and survival.
Studies aimed to identify biomarkers for the diagnosis and progression of
the disease in ALS patients.
The diagnosis of ALS is based mainly on neurophysiological parameters associated to the
progression of the disease and requires about one year to be formulated with certainty. Such
interval is quite long considering that the prognosis of the disease is two-five years since the
onset of symptoms. This has a negative impact on the possibility to apply a prompt therapeutic
intervention. It is therefore urgent to identify specific biomolecular markers that can be detected
through diagnostic tests on blood or biopsy specimens easily obtained from the patients.
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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 so far obtained in 40 patients and 33 controls, show
significant alterations in the T-lymphocyte population profile as well as in the levels of
monocytes and their activation state between ALS and healthy controls. We are investigating on
the pathophysiological meaning of these alterations and whether they are correlated with the
progression of the disease.
In parallel, we are examining the levels and the characterisation of the nitrated protein in the
PBMC of ALS patients compared to healthy controls. 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 in respect to controls. Studies are underway to identify and
characterise these proteins.
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 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. The relevance and the specificity of
the results obtained from these analyses will be verified in muscular biopsies obtained from
ALS patients. The skeletal muscle, a target of ALS, unlike the nervous tissue, has the advantage
to be easily investigated by biopsies.
Laboratory of Experimental Psychopharmacology
Drug Abuse: Neural basis of drug self-administration, “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-associated cues, after a period of abstinence. It was found that
partial agonists and antagonists at dopaminergic D3 receptors selectively modulate rats’ seeking
behavior induced by cocaine-associated cues after a long period of abstinence and in the
absence of any further cocaine. Using a different animal paradigm such as conditioned place
preference it was confirmed that antagonists at D3 receptors reduce cocaine-induced place
conditioning. Ongoing studies are evaluating the role of several other neurochemical
mechanisms involved in the cocaine-seeking behavior. Opiates antagonists as well as agonists at
a particular sub type of serotonin receptor are some of the drugs under investigation.
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 since DBA/2J and
BALB/c carrying a single nucleotide polymorphism (C1473G mice) in the gene for the brain-
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specific isoform of tryptophan hydroxylase-2, the rate-limiting enzyme in the synthesis of
serotonin are characterized by a decreased serotonin synthesis.
Studies are ongoing to clarify whether 1) this lack in response is peculiar to citalopram or
generalized to other SSRI 2) whether DBA/2J and BALB/c are responder to SSRI effects other
than the anti-depressant-like 3) whether DBA/2J and BAB/c are responder to other class of
antidepressant drugs.
Laboratory of Neurochemistry and Behavior
“Resistance” to antidepressant drugs
The delay in the onset of antidepressant effect and the partial or no response in a considerable
portion of patients still limits the efficacy of the available drugs.
Ongoing studies in collaboration with the Laboratory of Experimental Psychopharmacology (L.
Cervo) are aimed at assessing the neurobiological mechanisms involved in the resistance to
antidepressant drugs. The gene for the brain-specific isoform of tryptophan hydroxylase-2, the
rate-limiting enzyme in the synthesis of serotonin, is mutated in DBA/2J and BALB/c mice, that
synthesize less serotonin than C57BL/6 mice (that carry the “wild type” form of TPH-2) and do
not respond to SSRI in the forced swimming test, a procedure used to screen compounds for
antidepressant effects. In addition, mutation of TPH-2 attenuated or abolished the ability of
SSRI on the synthesis of serotonin and the extracellular concentrations of the neurotransmitter
These results suggest that genetic differences in serotonin synthesis could contribute to the
efficacy of SSRI. Ongoing studies are aimed at assessing the role of the brain derived
neurotrophic factor in the response to SSRI in experimental and clinical settings (In
collaboration with the Psychiatry Unit)
New targets of the antidepressant action
The intracerebral microdialysis technique allows the monitoring of extracellular
neurotransmitters released by nerve endings. The technique has been established for the
measurement of monoamines release in the gerbil brain and used to study the effects of
Substance P, NK1 receptor antagonists, a new target for antidepressant action. We have shown
that blockade of NK1 receptors prevented the raise of extracellular noradrenaline and dopamine
in response to stress without affecting basal release.
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 modeled in rats, 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 prefrontal cortex (PFC)
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
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antipsychotics. However, atypical antipsychotics show a high affinity also for serotonin 5HT2A, 5-HT2C and 5-HT1A receptors. Our studies compared the 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.
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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.
Cardiovascular Endocrine Unit
Head
Serge MASSON, Ph.D.
Tissue Culture Unit
Head
Giovanna BALCONI, Univ.Dipl.
Laboratory of Clinical Drug Evaluation
Head
Maria Grazia FRANZOSI, Biol.Sci.D.
Bioinformatics Unit
Head
Enrico NICOLIS, Comp.Sci.Stud.
Laboratory of General Practice Research
Head
M.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.
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CURRICULA VITAE
Maria Grazia Franzosi got her Biological Science degree in 1972 at the University of Milan.
Education
1972
Doctoral degree in Biological Sciences, University of Milan, Italy
1978
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. Pharmacoeconomics. Drug Epidemiology and Post-Marketing
Surveillance.
Position
from 2002 Director of the Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
"Mario Negri", Milano, Italy
from 2004 Member of Steering Committee, Studio GISSI-AF Study, Milano, Italy
from 2001 Member of Steering Committee, Studio GISSI-HF Study, Milano, Italy
from 1998 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
from 1997 Member of “Antithrombotic Trialists’ Collaboration”, Oxford, UK
from 1996 Member of Steering Committee and National Coordinator for Italy of the Organization to Assess
Strategies for Ischemic Syndromes (OASIS-2, OASIS-5, OASIS 6, OASIS-7, CURE, INTERHEART studies), Canadian Cardiovascular Collaboration, McMaster University, Hamilton,
Canada and of ACTIVE and RELY studies, Canadian Cardiovascular Collaboration, McMaster
University, Hamilton, Canada
1994-1996 Director of European Coordinating Centre and Member of Steering Committee, Collaborative
Organization for RheothRx Evaluation (CORE), McMaster University, Hamilton, Canada
from 1993 Member of Steering Committee, Studio GISSI-Prevenzione, Milano, Italy
from 2002 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
1989-2001 Head of the Laboratory of Clinical Drug Evaluation, Istituto di Ricerche Farmacologiche "Mario
Negri"
1985-1988 Head of the Clinic Drug Evaluation Unit of the Laboratory of Clinical Pharmacology, Istituto di
Ricerche Farmacologiche "Mario Negri"
from 1984 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
1975-1984 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
•
Tognoni G, Franzosi M G, 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
•
Anand SS, Xie CC, Mehta S, Franzosi MG, Joyner C, Chrolavicius S, Fox KA, Yusuf S, CURE Investigators.
Differences in the management and prognosis of women and men who suffer from acute coronary syndromes. J Am Coll
Cardiol 2005, 46: 1845-1851
•
Yusuf S, Howken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L,
Tanomsup S, Wangai Jr P, Razak F, Shama AM, Anand SS, on behalf of the INTERHEART Study Investigators.
Obesity and the risk of myocardial infarction in 27000 participants from 52 countries: a case-control study. Lancet 2005,
336: 1640-1649
•
Levantesi G, Macchia A, Marfisi R M, Franzosi M G, Maggioni A P, Nicolosi G L, Schweiger C, Tavazzi L, Tognoni
G, Valagussa F, Marchioli R, on behalf of the GISSI-Prevenzione Investigators. Metabolic syndrome and risk of
cardiovascular events after myocardial infarction. J Am Coll Cardiol 2005; 46: 277-283
•
Franzosi MG. Should we continue to use BMI as a cardiovascular risk factor? Lancet 2006; 368: 624-625
•
Farrall M, Green FR, Peden JF, Olsson PG, Clarke R, Hellenius ML, Rust S, Lagercrantz J, Franzosi MG, Schulte H,
Carey A, Olsson G, Assman G, Tognoni G, Collins R, Hamsten A, Watkins H, on behalf of the PROCARDIS
Consortium. Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on
chromosome 17. PLoS Genet 2006 - http://genetics.plosjournals.org/archive/15537404/2/5/pdf/10.1371_journal.pgen.0020072-L.pdf
ANNUAL REPORT
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IRFMN
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
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
from 1999
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
•
Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, Salio M, Cerami A, Brines M. Recombinant human
erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl
Acad Sci USA 2003; 100: 4802-4806
•
Latini R, Maggioni A P, Peri G, Gonzini L, Lucci D, Mocarelli P, Vago L, Pasqualini F, Signorini S, Soldateschi D, Tarli
L, Schweiger C, Fresco C, Cecere R, Tognoni G, Mantovani A, LATIN Investigators. Prognostic significance of the long
pentraxin PTX3 in acute myocardial infarction. Circulation 2004; 110: 2349-2354
•
Corada M, Chimenti S, Cera M R, Vinci M, Salio M, Fiordaliso F, De Angelis N, Villa A, Bossi M, Staszewsky L,
Vecchi A, Parazzoli D, Motoike T, Latini R, Dejana E. Junctional adhesion molecule-A-deficient polymorphonuclear
cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury. Proc Natl Acad Sci USA 2005; 102:
10634-10639
•
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 nonerythropoietic derivative of erythropoietin protects the myocardium
from ischemia-reperfusion injury. Proc Natl Acad Sci USA 2005; 102: 2046-2051
•
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
•
Latini R, Masson S, Wong M, Barlera S, Carretta E, Staszewsky L, Vago T, Maggioni AP, Anand IS, Tan LB, Tognoni
G, Cohn JN, Val-HeFT Investigators. Incremental prognostic value of changes in B-type natriuretic peptide in heart
failure. Am J Med 2006; 119: 70.e23-70.e30
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IRFMN
Maria Carla Roncaglioni got her Biological Science degree in 1987 at the University of Milan.
Education
1987
Doctoral degree in Biological Sciences, University of Milan, Italy
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
Ricerche Farmacologiche "Mario Negri", Milano, Italy
•
Avanzini F, Palumbo G, Alli C, Roncaglioni MC, Ronchi E, Cristofari M, Capra A, Rossi S, Nosotti L, Costantini C,
Pietrofeso R, PPP Primary Prevention Project. Effects of low-dose aspirin on clinic and ambulatory blood pressure in
treated hypertensive patients. Am J Hypertens 2000; 13: 611-616
•
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
•
Monesi L, Avanzini F, Barlera S, Caimi V, Lauri D, Longoni P, Roccatagliata D, Tombesi M, Tognoni G, Roncaglioni
MC. Appropriate use of antiplatelets: is prescription in daily practice influenced by the global cardiovascular risk? Eur J
Clin Pharmacol 2005; 61: 595-601
•
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
ANNUAL REPORT
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2006
IRFMN
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
1987-1992
Degree in Political Science, area Statistics at the “Università degli Studi di Milano” in
Milano.
1997-1998
Master post-lauream 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
from Oct 2006 Head of the Laboratory of Medical Statistics, Department of Cardiovascular Research,
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
May 99-Sept 06 Head of the Medical Statistics Unit, Department of Cardiovascular Research, Istituto di
1998-1999
Visiting Scientist in the Department of Statistical Genetics, Wellcome Trust Centre for
Human Genetics, University of Oxford (UK).
1992-1997
Researcher in the Unit of Applied Statistics and Information Technology, Istituto di
•
Chiodini B, Barlera S, Franzosi M G, Labarta V, Introna M, Tognoni G.APO B gene polymorphisms with coronary
artery disease: A meta-analysis. Atherosclerosis 2003; 167: 355-366.
•
Wong M, Staszewsky L, Latini R, Barlera S, Glazer R, Aknay N, Hester A, Anand I, Cohn JN. Severity of left
ventricular remodeling defines outcomes and response to therapy in heart failure: Valsartan heart failure trial (Val-HeFT)
echocardiographic data. J Am Coll Cardiol 2004; 43: 2022-2027.
•
Latini R, Masson S, Anand I, Salio M, Hester A, Judd D, Barlera S, Maggioni AP, Tognoni G, Cohn J N, Val-HeFT
Investigatore. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure
enrolled in Val-HeFT. Eur Heart J 2004; 25: 292-299.
•
Roncaglioni M C, 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.
•
Maggioni AP, Latini R, Carson PE, Singh SN, Barlera S, Glazer R, Masson S, Cere` E, Rognoni G, Cohn JN. Valsartan
reduces the incidence of atrial fibrillation in patients with heart failure: Results from the Valsartan Heart Failure Trial
(Val-HeFT). Am Heart J 2005; 149: 1-10.
•
Masson S, Latini R, Anand IS, Vago T, Angelici L, Barlera S, Missov ED, Clerico A, Tognoni G, Cohn JN, 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.
ANNUAL REPORT
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2006
IRFMN
Gianni Tognoni got his Medical Doctor degree in 1970, University of Milan.
Education
1964
Philosophy Doctor, University of Rome
1970
Medical Doctor degree, University of Milan
Randomised Clinical Trials. Pharmacoepidemiology and pharmacoeconomics. Outcomes research
Genetic epidemiology. Technology transfer and drug policy in developing countries. Cardiocerebrovascular disorders; primary and secondary prevention; heart-failure; diabetes; aging; psychiatric
epidemiology. Health and human rights.
Position
from 1992 Coordinator, Department of Clinical Pharmacology and Epidemiology, Consorzio Mario
Negri Sud, S. Maria Imbaro, Chieti.
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 2001 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 1988 Coordinator of training and research programs in community medicine, clinical
epidemiology, pharmaco-epidemiology in Bolivia, Argentina, Chile, Brazil, Ecuador, Perù
from 1986 Founding member of the International Society of Drug Bulletins (ISDB)
Coordinator, Commission of Human Experimentation, Regione Lombardia
from 1983 Member of 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 (Costa Rica, Nicaragua, Bolivia, Perù) and Africa (Angola, Ethiopia, Burkina
Faso)
from 1976 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, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi M G, Geraci E, Levantesi
G, Maggioni A P, Mantini L, Marfisi R M, Mastrogiuseppe G, Mininni N, Nicolosi G L, Santini M, Schweiger
C, Tavazzi L, Tognoni G, Tucci C, Valagussa F, GISSI-Prevenzione. Early protection against sudden death by n-3
polynsaturated fatty acids after myocardial infarction. Time-course analysis of the results of the Gruppo Italiano per lo
Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002; 105: 1897-1903
•
Anand I S, Fisher L D, Chiang Y T, Latini R, Masson S, Maggioni A P, Glazer R D, Tognoni G, Cohn J N, Val-HeFT
Investigators. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the
Valsartan Heart Failure (Val-HeFT). Circulation 2003; 107: 1278-1283
•
Franzosi M G, Tognoni G, Gardinale E, INTERHEART Investigators. Association of psychosocial risk factors with risk
of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): casecontrol study. Lancet 2004; 364: 953-962
•
Franciosi M, Pellegrini F, De Berardis G, Belfiglio M, Di Nardo B, Greenfield S, Kaplan S H, Rossi M C E, Sacco
M, Tognoni G, Valentini M, Nicolucci A, QuED Study Group. Impact of physicians' beliefs and practices on cholesterol
levels in patients with type 2 diabetes: A longitudinal assessment. Am Heart J 2005; 149: 104-111
•
Maggioni A P, Latini R, Carson P, Singh S N, Barlera S, Glazer R, Masson S, Cere' E, Tognoni G, Cohn J N.Valsartan
reduces the incidence of atrial fibrillation in patients with heart failure: Results form the Valsartan Heart Failure Trial
(Val-HeFT). Am Heart J 2005; 149: 548-557
•
Monesi L, Avanzini F, Barlera S, Caimi V, Lauri D, Longoni P, Roccatagliata D, Tombesi M, Tognoni G, Roncaglioni
M C. Appropriate use of antiplatelets: is prescription in daily practice influenced by the global cardiovascular risk? Eur J
Clin Pharmacol 2005; 61: 595-601
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IRFMN
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.
“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
•
Condorelli G, Borello U, De Angelis L, Latronico M, Sirabella D, Coletta M, Galli R, Balconi G, Follenzi A, Frati G,
Cusella De Angelis M G, Gioglio L, Amuchastegui C S, Adorini L, Naldini L, Vescovi A, Dejana E, Cossu G
Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: Implications for myocardium
regeneration Proc Natl Acad Sci USA 2001; 98: 10733-10738
•
Balconi G, Spagnuolo R, Dejana E Development of endothelial cell lines from embryonic stem cells. A tool for studying
genetically manipulated endothelial cells in vitro Arterioscler Thromb Vasc Biol 2000; 20: 1443-1451
•
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 M G, 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
Paola Di Giulio got her Nursing Diploma in 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 studies in cardiology and palliative care.
Coordination of nursing networks.
Position
From 2001 Associated professor at the Turin university. Coordinator of the Editorial Board of Assistenza
Infermieristica e Ricerca since 1998.
Consultant of the Clinical Phrmacology Laboratory since 1989
Senior researcher of the Cardiovascular Research Department, since 1995
Responsible of the Nursing Research Unit since 1997
•
Gattinoni L, Tognoni G, Pesenti A, Taccone P, Mascheroni D, Labarta V, Malacrida R, Di Giulio P, Fumagalli R, Pelosi
P, Brazzi L, Latini R, Prone-Supine Study Group. Effect of prone positioning on the survival of patients with acute
respiratory failure. New Engl J Med 2001; 345: 568-73
•
Balestra E, Celani MG, Del Santo R, Di Giulio P et al. Variabilità delle pratiche assistenziali nelle stroke unit: analisi dei
protocolli. Assistenza Infermieristica e Ricerca 2002; 21: 6-13
•
Laquintana D, Di Giulio P: Per un ruolo infermieristico nella farmacovigilanza. Assistenza Infermieristica e ricerca
2002; 21: 198-210
•
Di Giulio P, Saiani L, Laquintana D, Palese A, Gruppo PARI-ETLD. Studio clinico randomizzato controllato in doppio
cieco sull’efficacia dei trattamenti delle lesioni da decubito. Assistenza Infermieristica e Ricerca 2004; 23: 201-218
•
Toscani F, Brunelli C, Miccinesi G, Costantini M, Gallucci M, Tamburini M, Paci E, Di Giulio P, Peruselli C and the
Italian Co-operative Research Group on Palliative Medicine Predicting survival in terminal cancer patients: clinical
observation or quality of life evaluations? Palliative Medicine 2005; 19: 220-227
•
Toscani F, Di Giulio P, Brunelli C, Miccinesi G. Laquintana D. How How people die in hospital general wards: a
descriptive study. J Pain Symptom Manage 2005; 30: 33-40
ANNUAL REPORT
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2006
IRFMN
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
•
Cohn JN, Anand IS, Latini R, Masson S, Chiang YT, Glazer R, for the Val-HeFT Investigators. Sustained reduction of
aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from
Val-HeFT. Circulation 2003;108: 1306-1309.
•
Latini R, Masson S, Anand IS, Salio M, Hester A, Judd D, Barlera S, Maggioni AP, Tognoni G, Cohn NJ, for the ValHeFT Investigators. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure
enrolled in Val-HeFT. Eur Heart J 2004; 25: 292-299.
•
Masson S, Staszewsky L, Annoni G, Carlo E, Arosio B, Bai A, Calabresi C, Martinoli E, Salio M, Fiordaliso F,
Scanziani E, Rudolph AE, Latini R. Eplerenone, a selective aldosterone blocker, improves diastolic function in aged rats
with myocardial infarction. J Cardiac Failure 2004; 10: 433-441.
•
Anand IS, Latini R, Florea VG, Kuskowski MA, Masson S, Signorini S, Mocarelli P, Hester A, Glazer R, Cohn JN, for
the Val-HeFT Investigators. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation
2005; 112: 1428-1434.
•
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.
•
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.
Enrico Bjørn Nicolis has attempted some 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
ANNUAL REPORT
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IRFMN
•
Nobili A, Gebru F, Rossetti A, Schettino F, Zahn R W, Nicolis E, Macario G, Celani L, Acik V O, Farina M L, 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
•
Santoro E, Nicolis E, Franzosi M G, Tognoni G. Internet for clinical trials: Past, present, and future. Control Clin
Trials 1999; 20: 194-201
•
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
•
GISSI-Avoidable Delay Study Group. Epidemiology of avoidable delay in the care of patients with acute myocardial
infarction in Italy. A GISSI-generated study. Arch Intern Med 1995; 155: 1481-1488
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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 myocardial infarction.
The activity in clinical research includes the clinical assessment of therapeutic strategies 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.
The analyses of plasma concentration of troponin T (TnT, a contractile protein) in 4053 patients
with stable chronic heart failure enrolled into Val-HeFT study have been completed.
A new pre-commercial assay has been used with a 10-fold higher sensitivity than the
commercial assay: with this improved assay, more than 80% of the patients with undetectable
TnT in plasma, had detectable levels. We show that TnT predicts the risk of these patients
equally or even better than the best available marker of risk in heart failure, the brain natriuretic
peptide (BNP). It can be hypothesized that the two markers reflect different pathophysiologic
processes: the stretch of cardiac myocytes increases the production of BNP whereas cardiac cell
(cardiac myocyte) death increases the release of TnT.
Coronary artery disease (CAD) is a leading cause of death world-wide, and most cases have a
complex, multifactorial aetiology that includes a substantial heritable component. Identification
of new genes involved in CAD may inform pathogenesis and provide new therapeutic targets.
The PROCARDIS study recruited 2,658 affected sibling pairs (ASPs) with onset of CAD before
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age 66 years from four European countries to map susceptibility loci for CAD. In a first study,
involving a genome-wide linkage screen, tentative loci were mapped to Chromosomes 3 and 11
with the CAD phenotype (1,464 ASPs), and to Chromosome 17 with the MI phenotype (739
ASPs). In a second study, these loci were examined with a dense panel of grid-tightening
markers in an independent set of families (1,194 CAD and 344 MI ASPs). This replication study
showed a significant result on Chromosome 17 (MI phenotype; p1/40.009 after adjustment
for three independent replication tests). This is the first genome-wide linkage analysis to map,
and replicate, a CAD locus. The region on Chromosome 17 provides a compelling target within
which to identify novel genes underlying CAD. Understanding the genetic aetiology of CAD
may lead to novel preventative and/or therapeutic strategies.
PROCARDIS data were analyzed with the goal to identify chromosomal regions associated to
the variability of quantitative phenotypes.
The serum concentration of lipoprotein Lp(a), known to be highly heritable and associated with
cardiovascular risk, was analyzed using a genome-wide linkage analysis. A highly significant
linkage was confirmed at LPA locus on chromosome 6q27, as well as another region of
significant linkage was detected on chromosome 13q22-31. These results have been published
on the European Journal Human Genetics 2007: 15, 221-227 and provide a basis for further
studies of candidate genes in these regions.
In patients with STEMI, particularly those not undergoing primary percutaneous coronary
intervention, fondaparinux significantly reduces mortality and reinfarction without increasing
bleeding and strokes. These are the results of the Michelangelo OASIS-6 study, a randomized,
double-blind, multinational clinical trial which aim was to evaluate the effect of fondaparinux, a
factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care. Among 12092
patients with STEMI from 447 hospitals in 41 countries, death or reinfarction at 30 days was
significantly reduced from 11.2% in the control group to 9.7% in the fondaparinux group. These
benefits were observed at 9 days. Mortality was significantly reduced throughout the study.
Significant benefits were observed in those receiving thrombolytic therapy and those not
receiving any reperfusion therapy, while there was no benefit in those patients undergoing
primary percutaneous coronary intervention. There was a tendency to fewer severe bleeds, with
significantly fewer cardiac tamponade with fondaparinux at 9 days.
ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri)
CINECA (Consorzio Interuniversitario per il Calcolo Automatico dell'Italia Nord-Orientale)
CSeRMEG (Centro Studi e Ricerche in Medicina Generale)
Gruppi organizzati di MMG (FIMMG, CoS, Ass.Cu.M.I., AMISI)
IEO (Istituto Europeo di Oncologia), Milano
IFOM-FIRC, Milano
Istituto di Ricerca in Cure palliative Lino Maestroni
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
Università degli Studi di Torino, Dipartimento di Sanità Pubblica e Microbiologia
Università di Verona, Istituto di Anatomia Umana
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Università di Torino, Dipartimento di Anatomia, Farmacologia e Medicina Forense
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
ECLA (Estudios Cardiologicos de Latino-America)
EVGN (European Vascular Genomics Network) VI Framework Program, Unione Europea
Hebrew-Hadassah Medical School, Jerusalem, Israel
JW Goethe University, Department of Cardiology, Frankfurt, Germany
Karolinska Institutet, Stockholm, Sweden
PHRI (Population Health Research Institute), McMaster University, Hamilton, Ontario, Canada
University of Minnesota, Minneapolis, USA
Wellcome Trust Centre for Human Genetics, University of Oxford, UK
WONCA (World Organization of Family Doctors), Europe
Circulation, International Journal of Health Services, Journal of Clinical Epidemiology (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 Managed Care, Atherosclerosis Thrombosis and
Vascular Biology, Cardiovascular Research, Circulation, Circulation Research, Clinical
Pharmacology and Therapeutics, European Heart Journal, European Journal of Cardiovascular
Nursing, Italian Journal of Cardiology, International Journal of Cardiology, Journal of Cardiac
Failure, PharmacoEconomics, Journal of Cardiovascular Medicine, Life Sciences, The Lancet.
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Ethical Committee of Lombardy Region
Ethical Committee of the Provincia of Verona
Agenzia Italiana del Farmaco, Direzione Generale Farmaci e Dispositivi Medici
EVENT ORGANIZATION
Corso di avvio dello studio Rischio & Prevenzione per i medici delle Aziende ASL di
Alessandria e ASL Verbano Cusio Ossola
14/01/06, Teatro Parvum, Alessandria
Corso sulla sperimentazione dei farmaci in medicina generale e sullo studio Rischio &
Prevenzione per i medici dell’Azienda USL di Reggio Emilia
25/03/06, Ospedale Nuovo, Reggio Emilia
Corso di avvio dello studio Rischio & Prevenzione per i medici delle Aziende USL di Versilia,
Massa e Carrara, Empoli, Grosseto
1/04/06, Auditorium, Ospedale Versilia, Lido di Camaiore (Lucca)
Corso di avvio dello studio Rischio & Prevenzione per i medici della Azienda Sanitaria Locale 12
di Biella
5/05/06, Aula riunioni del Poliambulatorio di Cossato (Biella)
Investigator's Meeting - Stato di avanzamento dello studio Prono/Supino II
10/05/06, Sala Bianca, Fiera Campionaria, Milano
Corso di avvio dello studio Rischio & Prevenzione per i medici AUSL Firenze e Arezzo
27/05/06, Aula Magna, Dermatologia Ospedale “Santa Maria Nuova”, Firenze
37° Congresso Nazionale di Cardiologia ANMCO, Riunione degli Infermieri partecipanti al
sottoprogetto QDF–Qualità della Vita Depressione Funzioni Cognitive dello studio GISSI-HF
1/06/06, Congresso Nazionale ANMCO, Fortezza da Basso (Aula Vasari), Firenze
37° Congresso Nazionale di Cardiologia ANMCO, Riunione degli Sperimentatori dello studio
GISSI-HF
3/06/06, Congresso Nazionale ANMCO, Fortezza da Basso, Firenze
37° Congresso Nazionale di Cardiologia ANMCO, Riunione degli Sperimentatori dello studio
GISSI-AF
3/06/06, Congresso Nazionale ANMCO, Fortezza da Basso, Firenze
Riunione dei Monitors per l’avvio del piano di monitoraggio nei centri partecipanti allo studio
clinico sull’assocazione n-3 PUFA e Statina
11/07/06, Istituto Mario Negri, Milano
Investigators’ Meeting - Riunione dei Ricercatori dello Studio GISSI-AF
18/09/06, Sala Aquarius, Livello 1, Nuovo Polo della Fiera di Milano, Rho-Pero (Milano)
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Investigators’ Meeting – Studio MICHELANGELO: OASIS-5 e 6
19/09/05, Sala Aquarius, Livello 1, Nuovo Polo della Fiera di Milano, Rho-Pero (Milano)
Investigators’ Meeting - Riunione dei Ricercatori dello Studio GISSI-AF
21/09/06, Sala “Biblioteca Grande”, Starhotel Termius, Napoli
02/10/06, Royal Hotel Carlton, Bologna
Investigator's Meeting - Riunione dei Ricercatori dello Studio GISSI-HF: un modello di ricerca
collaborativa
03/10/06, Royal Hotel Carlton, Bologna
I° Incontro dei medici ricercatori partecipanti allo studio Rischio & Prevenzione per l’area NordCentro Italia: Rischio & Prevenzione come modello della gestione del rischio cardiovascolare in
Medicina Generale.
28/10/06, Palazzo della Gran Guardia, Verona
I° Incontro dei medici ricercatori partecipanti allo studio Rischio & Prevenzione per l’area CentroSud Italia: Rischio & Prevenzione come modello della gestione del rischio cardiovascolare in
Medicina Generale.
18/11/06, Hotel Hilton Nova Yardinia, Marina di Castellaneta (Taranto)
Investigator's Meeting - Stato di avanzamento dello studio Prono/Supino II
14/12/06, Sala Platone, Royal Garden Hotel, Assago (Milano)
INVOLVED
Gruppo GISSI Prevenzione - Mario Negri Sud. International forum on n-3PUFA, 19-20/01/06,
Grand Hotel Parco dei Principi, Roma, Italy
- Basso - vs alto – dosaggio di n-3 PUFA: tempi e livello di incorporazione nei tessuti corporei
- Prevenzione Primaria
Heart Failure Association of the European Society of Cardiology. From cardiac adaptation to
failure and back, 26-28/01/06, Garmisch-Partenkirchen, Germany
- Effect of aerobic training on endothelial progenitor cells in patients with heart failure.
Preliminar results
MNIAA – Mario Negri Insitute Alumni Association. Cellule staminali oggi nella ricerca e nella
terapia, 2/02/06, Sala Meili, Milano, Italy
- Terapia dell’infarto miocardico con cellule staminali: le evidenze sperimentali
American College of Cardiology. 55th Annual Scientific Session, 12-14/03/06, Atlanta, USA
- Direct comparison of the prognostic value of brain natriuretic peptide (BNP) and N-terminal
ProBNP in a large population of patients with choronic and symptomatic heart failure. The
valsartan in heart failure (Val-HeFT) data
- Cardiac troponin T in heart failure: results from Val-HeFT
- Do biomarkers add prognostic information to routine measures of the severity of heart failure?
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Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) e Unità Operativa di
Cardiologia dell’Ospedale di San Bonifacio, Corso di Aggiornamento – L’infermiere, la ricerca
e le sperimentazioni cliniche. Nuovi ruoli nella realtà sanitaria italiana, 8/04/06, Centro
Congressi, Polo Unico, San Bonifacio (VR), Italy
- Che cosa la cardiologia italiana ha imparato e sperimentato nel campo della ricerca clinica ed
epidemiologia: il ruolo dell’ANMCO e dell’Istituto Mario Negri
Associazione Nazionale Medici Cardiologi Ospedalieri. XXXVII° Congresso Nazionale di
Cardiologia, 31/05-3/06/06, Firenze, Italy
- Clopidogrel, aspirina, indobufene: quali spazi
- AREA-IN-CHF: dati basali della popolazione arruolata
- Effetto dell’età sulla geometria e sulla funzione ventricolare sinistra nello scompenso cardiaco
lieve-moderato. Analisi dello studio AREA-IN-CHF
- Disfuzione ventricolare sinistra all’ecocardiografia e livelli plasmatici di peptide natriuretico
di tipo B in pazienti con scompenso cardiaco cronico
- La variabilità della frequenza cardiaca nella componente LF è strettamente correlata ai livelli
di BNP nei pazienti con insfufficienza cardiaca. Dati dallo studio Valsartan in Heart Failure
(Val-HeFT)
- Funzione diastolica nello scompenso cardiaco lieve-moderato: caratteristiche basali della
popolazione dello studio Antiremodelling Effect of Canrenore in patients with mild Chronic
Heart Failure (AREA-IN-CHF)
- Confronto diretto fra BNP e NT-proBNP in pazienti con insufficienza cardiaca. Dati dallo
studio Valsartan in Heart Failure trial (Val-HeFT)
- Brain natriuretic peptide predicts postoperative survival and long-term clinical improvement
- La troponina T ad alta sensisibilità (hsTnT) è un forte predittore di esito clinico in pazienti con
insufficienza cardiaca cronica. Dati dallo studio clinico Val-HeFT
- Nei pazienti con insufficienza cardiaca la variabilità della frequenza cardiaca nella
componente LF si conferma un importante predittore di eventi. Dati dallo studio Valsartan in
Heart Failure (Val-HeFT)
Heart Failure Association of European Society of Cardiology. Heart Failure 2006, 17-20/06/06,
Helsinki, Finland
- Prognostic value of anemia and additional role of NT-proBNP in patients with heart failure
- Antiremodeling effect of canrenone in patients with mild chronic heart failure: AREA-INCHF study. Baseline data of patients
- Age effect in mild to moderate heart failure: baseline echocardiographic data from the
AntiRemodeling Effect of cAnrenone IN patients with mild Chronic Heart Failure (AREA-INCHF) study
- Left ventricular filling characteristics in mild to moderate heart failure: baseline data from the
AntiRemodeling Effect of CAnrenone IN patients with mild Chronic Heart Failure (AREA-INCHF) study.
Medizinische Klinik und Poliklinik I, Julius Maximilians Universitat Würzburg and Deutsche
Akademie der Naturforscher Leopoldina. III Symposium on Cardiovascular Healing. Focus on
Inflammation, 23-23/06/06, Würzburg, Germay
- Cytokines and heart failure
Consortium for Biomolecular Medicine (CBM), AREA Science Park and the Central European
Initiative (CEI), Summer School. Advanced Topics in Molecular Medicine, 15-18/07/06,
Congress Centre of Area Science Park, Trieste, Italy
- Stem cell-based therapy in animal model of cardiac injury
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WONCA Europe 2006. 12th Conference of the European Society of General Practice/Family
Medicine, 27-30/08/06, Firenze, Italy
- The attainment of target levels of cardiovascular risk factors in every daty practice:
preliminary results of the Risk and Prevention Study
- Socieconomics variables and cardiovascular risk: preliminary results of the Risk and
Prevention Study
Framework Program, Unione Europea. Second European Vascular Genomics Network, Summer
School in Vascular Biology, 10-14/09/06, Fondazione E. Majorana, Erice, Italy
- The short pentraxin PTX3 is cardioprotective in experimental myocardial infarction. Possible
involvemente of coronary vascular bed and complement activation
SMART Promotion Srl, 3rd SMART Summer 2006. Feasibility, limits and problems of clincal
studies in ICU, 15-17/09/06, Hotel Meliá, Poltu Quatu (SS), Italy
- Two tails and p < 0.05: are they dogmas?
Società di Farmacia Ospedaliera e dei Servizi Farmaceutici delle Aziende Sanitarie. XXVII
Congresso Nazionale SIFO, La prevenzione e la cura del paziente nelle politiche sanitarie
regionali, 27-30/09/06, Magazzini del cotone, Genova, Italy
- Il punto di vista di un’organizzazione che promuove ricerche indipendenti in un ambito
epidemiologicamente diffuso e clinicamente rilevante sia per l’ospedale che per il territorio
- Sindromi coronariche acute: i risultati degli studi OASIS5 ed OASIS 6
CNR – Istituto di Fisiologia Clinica. 2° Simposio, Il Laboratorio per la cardiologia, 6-8/10/06,
Area di Ricerca CNR, Pisa, Italy
- L’utilità dei peptidi natriuretici nel monitoraggio dello scompenso cronico
AstraZeneca, Chiesi Farmaceutici, Boehring Ingelheim Italia SpA, BioXell SpA, Fondazione
Cariplo, CONGENIA Srl, Heart Care Foundation, Istituto Nazionale Neurologico C. Besta, ISS
Programma Cellule Staminali, Kinetic Concepts Inc., Medtronics Italia S.p.A., Novartis
Pharma, Oxford University, Population Health Research Institute-Mc Master University,
Pharmacia Upjohn, Roche Diagnostics, Sigma Tau, SPA Società Prodotti Antibiotici S.p.A.,
Takeda Italia S.p.A.
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The ACTIVE Steering Committee, on behalf of the ACTIVE Investigators
Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular
events
Am Heart J 2006; 151: 1187-1193
The ACTIVE Writing Group, on behalf of the ACTIVE Investigators
Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial
with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial
Lancet 2006; 367:1903-1912
Avanzini F, Alli C, Boccanelli A, Chieffo C, Franzosi MG, Geraci E, Maggioni A P, Marfisi RM, Nicolosi L,
Schweiger C, Tavazzi L, Tognoni G, Valagussa F, Marchioli R, on behalf of the GISSI-Prevenzione Investigators
High pulse pressure and low mean arterial pressure: two predictors of death after a myocardial infarction
J Hypertens 2006; 24: 2377-2385
Barzi F, Woodward M, Marfisi RM, Tognoni G, Marchioli R, on behalf of the GISSI-Prevenzione Investigators
Analysis of the benefits of a Mediterranean diet in the GISSI-Prevenzione study: A case study in imputation of
missing values from repeated measurements
Eur J Epidemiol 2006; 21: 15-24
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
Disertori M, Latini R, Maggioni AP, Delise P, Di Pasquale G, Franzosi MG, Staszewsky L, Tognoni G, on behalf of
the GISSI-AF Investigators
Rationale and design of the GISSI-Atrial Fibrillation trial: a randomized, prospective, multicentre study on the use of
valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial fibrillation recurrence
J Cardiovasc Med 2006; 7: 29-38
Farrall M, Green FR, Peden JF, Olsson PG, Clarke R, Hellenius ML, Rust S, Lagercrantz J, Franzosi MG, Schulte H,
Carey A, Olsson G, Assman G, Tognoni G, Collins R, Hamsten A, Watkins H, on behalf of the PROCARDIS
Consortium
Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome
17
PLoS Genet 2006 - http://genetics.plosjournals.org/archive/1553-7404/2/5/pdf/10.1371_journal.pgen.0020072-L.pdf
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
Franzosi MG
Should we continue to use BMI as a cardiovascular risk factor?
Lancet 2006; 368: 624-625
Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Yung S, Chimenti S, Landsman L, Abramovitch R,
Keshet E
VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells
Cell 2006; 124: 175-189
Latini R, Masson S, Wong M, Barlera S, Carretta E, Staszewsky L, Vago T, Maggioni AP, Anand IS, Tan LB,
Tognoni G, Cohn JN, on behalf of the Val-HeFT Investigators
Incremental prognostic value of changes in B-type natriuretic peptide in heart failure
Am J Med 2006; 119: 70.e23-70.e30
Macchia A, Levantesi G, Borrelli G, Franzosi MG, Maggioni AP, Marfisi RM, Scarano M, Tavazzi L, Tognoni G,
Valagussa F, Marchioli R, on behalf of the GISSI-Prevenzione Investigators
A clinically practicable diagnostic score for metabolic syndrome improves its predictivity of diabetes mellitus: The
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. (GISSI)-Prevenzione scoring
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Am Heart J 2006; 151: 754.e7-754.e17
Madeddu P, Emanueli C, Spillmann F, Meloni M, Bouby N, Richer C, Alhenc-Gelas F, van Weel V, Eefting D, Quax
PHA, Hu Y, Xu Q, Hemdahl AL, van Golde J, Huijberts M, de Lussanet Q, Struijker Boudier H, Couffinhal T,
Duplaa C, Chimenti S, Staszewsky L, Latini R, Baumans V, Levy BI
Murine models of myocardial and limb ischemia: Diagnostic end-points and relevance to clinical problems
Vascul Pharmacol 2006; 45: 281-301
Mantovani A, Garlanda C, Bottazzi B, Peri G, Doni A, Martinez de la Torre Y, Latini R
The long pentraxin PTX3 in vascular pathology
Vascul Pharmacol 2006; 45: 326-330
Marchioli R, Levantesi G, Macchia A, Marfisi RM, Nicolosi GL, Tavazzi L, Tognoni G, Valagussa F, on behalf of
the GISSI-Prevenzione Investigators
Vitamin E increases the risk of developing heart failure after myocardial infarction: results from the GISSIPrevenzione trial
J Cardiovasc Med 2006; 7: 347-350
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
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
Mengozzi M, Latini R, Salio M, Sfacteria A, Piedimonte G, Gerwien J, Leist M, Siren AL, Ghezzi P, Chimenti S
Increased erythropoietin production after myocardial infarction in mice
Heart 2006; 92: 838-839
Monesi L, Avanzini F, Roncaglioni MC
Response to Naunton and Duyvendak re "Appropriate use of antiplatelets: is prescription in daily practice influenced
by the global cardiovascular risk?"
Eur J Clin Pharmacol 2006; 62: 79-80
The OASIS-5 (The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators)
Comparison of fondaparinux and enoxaparin in acute coronary syndromes
N Engl J Med 2006; 354: 1465-1476
The OASIS-6 Trial Group
Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial
infarction: The OASIS-6 randomized trial
JAMA 2006; 295: 1519-1530.
Wong M, Staszewsky L, Carretta E, Barlera S, Latini R, Chiang YT, Glazer RD, Cohn JN
Signs and symptoms in chronic heart failure: Relevance of clinical trial results to point of care-data from Val-HeFT
Eur J Heart Fail 2006; 8: 502-508
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Franzosi M G
Le principali ricadute dello studio OASIS-6
Medici Oggi 2006; 10: 128
Latini R, Masson S, Staszewsky L, Barlera S
Neurohormonal modulation in heart failure of ischemic etiology: correlates with left ventricular remodeling
Curr Heart Fail Rep 2006; 3: 157-163
Masson S, Latini R, Vago T
The prognostic value of NT-proBNP in chronic heart failure
Clinical Laboratory 2006; 30: 35-37
Piccoli M, Di Giulio P, Ruffino E, Zollesi G, Dello Russo C
Nursing care priorities and problems: the nurses point of view
Assist Inferm Ric 2006; 25:123-130
Tognoni G
Opportunità imperdibili
Giornale Italiano Farmacia Clinica 2006; 20: 1-2
Tognoni G
Infermieri prescrittori
Assistenza Infermieristica e Ricerca 2006; 25: 146-148
Tognoni G
Mongering: esercizi estivi
Informazioni sui Farmaci 2006; 30: 85-86
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RESEARCH ACTIVITIES
Laboratory of Cardiovascular Clinical Pharmacology
The effects of mesoangioblasts of different origin in structural and
functional repair of the heart 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. Our published work on the
transplantation of mouse mesangioblasts (mesodermal embryonic stem cells) in mice after left
coronary artery occlusion, demonstrates that mesangioblasts significantly reduce the damage
induced by experimental infarct, in a manner similar to that of bone marrow progenitor cells.
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.
The potential for repair of mesoangioblasts has been explored by comparing cells of embryonic
origin with lines derived from the adult mouse. Within the same context, two different models
of infarction and three routes of administration have been tested: ischemia followed by
reperfusion leads to higher homing of injected stem cells; mesoangioblasts derived from the
heart of young adult mice give best results in terms of homing and long-term survival and
differentiation in the infarcted myocardium. Experiments are being conducted on humanderived mesoangioblasts injected in immunodeficient mice after infarction: results derived from
these esperiments, are relevant for possible future clinical applications.This research is mostly
done within the sixth EU program, European Vascular Genomics Network (EVGN,
www.evgn.org).
Characterization of the cardiac phenotype of PTX3 in knock-out mice
PTX3 has been shown to have a non redundant role in reproduction and in the resistance to
fungal infection (Aspergillus fumigatus). However, its role in the cardiovascular apparatus has
not been well defined, though it is an independent prognostic marker after acute myocardial
infarction in man. We are studying the potential role of PTX3 in myocardial infarction by
comparing cardiac structure and function of PTX3 knockout mice with wild-type subjected to
cardiac ischemia and reperfusion. Preliminary data suggest that the lack of PTX3 worsens the
early outcome after infarction: reperfusion is less efficient, infarct is larger, inflammatory
response is more marked in PTX3 null 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. The purpose of this research is to estabilish and characterize under different aspects a
murine model of regional AP, allowing a two week survival of the animals and the evaluation of
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the long term evolution of the injury by multiple tests, computed tomography, biochemical
assays, histological evaluation, lung function and gas-exchange.
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. The Heart-HGF transgenic
model is being used to verify 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
ischemic damage and reperfusion.
Roles of the adaptor protein p66shc in controlling cardiac response to
ischemia/reperfusion
The cytoplasmic signal transducer p66shc is part of a pathway that regulates stress apoptotic
responses and life span in mammals. Its roles have been elucidated by the use of a knock-out
mouse for p66shc, developed by the group of PG Pelicci (IEO, Milano). Mice p66shc null are
more resistant to oxidative stress in vivo, have an attenuated apoptotic response, and their life
span is increased by 30% vs normal mice. The response of the heart to ischemia in vivo has not
been tested, therefore the research focuses on the effects of ischemia/reperfusion in the mouse
on (1) number of apoptotic cardiac myocytes in the infarct area, (2) infarct size, (3) left
ventricular function at 4-6 weeks. The project will include hypoxia/reoxygenation in cardiac
myocytes isolated from p66shc null and wild type mice.
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.
The effects of coronary ligation (with/without reperfusion) will be tested in mice in which
machrophages can be ablated by administration of Difteria toxin: transgenic mice expressing
human difteria toxin receptor (CD11b-DTR) will respond to the toxin. Since machrophages
peak in mouse heart on day 1 after MI and return to baseline by day 7, the ablation should last
no more than 7 days coronary ligation and reperfusion. The heart will be evaluated
histologically for infarct size, myocyte loss, immunostain for machropages and PMN,capillary
density (angiogenic response to ischemia). Cardiac function will be evaluated by
echocardiography at week 6-8. Other experiments might be envisaged to assess the role of
machrophages in modulating homing and/or retention of stem cells administered to mice with
infarction.
GISSI-HF: biohumoral sub-study and microalbuminuria
The clinical trial GISSI-HF (enrolment of patients completed Feb. 2005, follow up to be
completed by 2007) is 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. A biohumoral
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substudy aims at exploring the pathophysiology of heart failure and mechanisms of action of the
treatments in study. In 1200 patients enrolled in the substudy, blood samples are 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), 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 30% 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 cells and their relation to heart failure etiology and study
treatments has been studied 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. Microalbuminuria (defined as the ratio
between urinary concentrations of albumine and creatinine) is being measured in more than
2000 patients enrolled in the GISSI-HF trial as an indicator of renal endothelial dysfunction.
Microalbuminuria (albumine/creatinine = 30-299 mg/g) is present in 19% of the patients and is
associated to inflammation, endothelial dysfunction and neurohormonal activation.
Anti-remodeling effect of aldosterone receptors blockade with canrenone
in mild chronic heart failure: the AREA IN-CHF
The RALES study has shown that spironolactone, an aldosterone receptor antagonist, reduces
the risk of morbidity and mortality both from progressive heart failure (HF) and sudden death in
patients with moderate to severe HF. Aldosterone antagonists may be effective because they
oppose the effects of aldosterone on sodium retention, loss of magnesium and potassium,
sympathetic activation, vascular compliance and cardiac fibrosis. In AREA IN-CHF, a
multicentre randomized, placebo-controlled clinical trial, the effect of canrenone, a metabolite
of spironolactone, is assessed in patients with mild chronic HF (n= 500) in terms of
echocardiographic left ventricular remodeling and a combined end-point of mortality and
morbidity. The design of the study includes blood collection in all patients at randomization and
after 6 months to determine the plasma concentration of aldosterone, brain natriuretic peptide
and a circulating marker of collagen turnover (propeptide N-terminal of collagen III). These
biohumoral factors are assayed centrally at the Department of Cardiovascular Research and
should give insight on the effect of canrenone on these markers and on their relation with study
outcome. Final results are expected in 2007.
PTX-3, a novel long pentraxin is an marker of severity of disease and of
outcome in cardiovascular diseases
PTX-3 is a novel long pentraxin whose expression is induced by cytokines in endothelial and
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 will be
assayed in 1200 patients with symptomatic heart failure (GISSI-HF), in 400 patients with atrial
fibrillation (GISSI-AF) and in 1400 patients with heart failure (CandHeart) to explore its role in
other cardiovascular diseases.
Echocardiographic and biohumoral substudy – GISSI-AF trial
The GISSI Atrial Fibrillation trial (GISSI-AF) tests 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 is currently ongoing to evaluate the potential role of biohumoral
factors and cardiac structural remodeling 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 are performed. Left ventricular and atrial
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dimensions will be determined by echocardiography, whereas plasma levels of BNP, NTproBNP, troponin T (high sensitive method), endothelin-1 and inflammatory markers (CRP,
PTX3) will be 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 expected enrolment was completed by January 2007.
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
trial is to assess the effects Candesartan on circulating levels of brain natriuretic peptide (BNP)
in patients suffering from CHF with depressed or preserved left ventricular (LV) systolic
function. The patients (approx. 1400) will be followed for 1 year. Serial biohumoral and
echocardiographic determinations will be performed at randomization, and after 3 and 12
months (end of study). Besides BNP, other biohumoral markers such as aldosterone, C-reactive
protein, PTX3 and the microalbuminuria will be measured. The first patient was randomized in
Dec. 2005.
Trial Prone/Supine 2: effects of prolonged prone position on survival in
severe acute respiratory distress syndrome (ARDS)
This trials extends the findings of the previous Prone/Supine trial that showed in 304 patients
with ARDS that 6-hour pronation in the first 10 days improved blood gas parameters, but did
not reduce mortality (around 50% in the first 6 months). This was one of the rare example of a
multicenter trial in Intensive Care performed entirely in Italy. The same group of Centers
(headed by the Istituto di Anestesia e Rianimazione from the Policlinico di Milano, L Gattinoni)
has launched a new trial that aims at evaluating the effect of a protocol of prolonged pronation
(20 hours a day) in patients with severe ARDS, a subgroup that showed a trend towards
improved survival on pronation in the previous study. Two hundred and fifty patients have been
enrolled in 18 centers; the target number of patients should be reached by the end of 2007.
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 will be monitored during a 2-year follow-up using ECG and
echocardiography. The Biomarker Core Laboratory will evaluate 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.
PUFAxStatin: a clinical study on the interaction between statins and n-3
polyunsaturated acids (PUFA) on the lipid and inflammatory profile of
diabetic patients at cardiovascular risk.
There are potential beneficial pharmacological interactions between statins and n-3 PUFA on
lipid and inflammatory metabolism. The present study assesses the effects of these two drugs,
alone or in combination on circulating biomarkers of inflammation and on the lipid profile of
diabetic patients at high cardiovascular risk (hypertension, ischemic heart disease, smoking).
120 patients are expected to be enrolled by the end of February 2007. In collaboration with the
Laboratory of Neuroimmunology, the effect of statin and n-3 PUFA on the ex-vivo production
of pro-inflammatory cytokines by stimulated whole blood will be evaluated. C-reactive protein,
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adhesion molecules, tissue factor and microalbuminuria will also be measured. Final results are
expected in 2007.
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 Münster, 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 recruited
2,658 ASPs with onset of CAD before age 66 y from four European countries. ASPs were
defined as having CAD phenotype if both had CAD, or myocardial infarction (MI) phenotype if
both had a MI. In a first study, involving a genome-wide linkage screen, tentative loci were
mapped to Chromosomes 3 and 11 with the CAD phenotype (1,464 ASPs), and to Chromosome
17 with the MI phenotype (739 ASPs). In a second study, these loci were examined with a dense
panel of grid-tightening markers in an independent set of families (1,194 CAD and 344 MI
ASPs). This replication study showed a significant result on Chromosome 17 (MI phenotype;
p1/40.009 after adjustment for three independent replication tests). An exclusion analysis
suggests that further genes of effect size ksib. 1.24 are unlikely to exist in these populations of
European ancestry. This is the first genome-wide linkage analysis to map, and replicate, a CAD
locus. The region on Chromosome 17 provides a compelling target within which to identify
novel genes underlying CAD. Understanding the genetic aetiology of CAD may lead to novel
preventative and/or therapeutic strategies.
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 by
bringing study subjects in to dedicated clinics; these data will allow mapping of known and
novel quantitative risk factors which will be important in prioritising positional candidate genes
at mapped chromosomal loci. The serum concentration of lipoprotein Lp(a), known to be highly
heritable and associated with cardiovascular risk, was analyzed using a genome-wide linkage
analysis. A highly significant linkage was confirmed at LPA locus on chromosome 6q27, as
well as another region of significant linkage was detected on chromosome 13q22-31. These
results provide a basis for further studies of candidate genes in these regions.
GISSI-HF: A large scale clinical trial testing the effects of n-3 PUFA and
Rosuvastatin on mortality/morbidity of patients with symptomatic
Congestive Heart Failure
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 is the fifth large scale clinical trial conducted by the Group.
While pharmacological treatments specifically targeted to the cardio-circulatory system have
been largely investigated, scanty controlled data are available concerning the role of dietary and
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metabolic approaches in the management/outcome of patients with heart failure. The GISSI-HF
is a prospective, multicenter, randomized, double blind, placebo controlled study, with
randomized allocation of patients with a clinical diagnosis of heart failure to:
Randomization 1 (R1): n-3 PUFA vs corresponding placebo;
Randomization 2 (R2): rosuvastatin vs corresponding placebo.
The primary objective of the GISI-HF is to demonstrate that, in patients with heart failure
treated at the best of recommended treatment, long term administration of (a) n-3 PUFA, (b)
rosuvastatin is more effective than the corresponding placebo in the reduction of all-cause
mortality and all-cause mortality or hospitalizations for any reason.
The study follow-up will last at least 3 years. The study started in September 2002 with the
participation of 364 departments of cardiology. The recruitment phase has been completed with
more than 7000 patients randomized.
Several substudies focus on possible mechanistic effects of the study treatments:
ventricular remodeling (echo);
biohumoral;
genetic;
arrhythmic and autonomic pattern (Holter monitoring);
exercise capacity;
cognitive function;
burden of care.
The follow-up will be completed by the end of 2007. The project is conducted in collaboration
with the Laboratory of Cardiovascular Clinical Pharmacology.
GISSI-HF Genetic Substudy
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). A genetic substudy to GISSI-HF (see "ad hoc" section) offers 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 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.
The genetic markers to be studied will initially focus on polymorphisms of genes involved in
lipid metabolism and inflammation. However, as new genetic information is being accumulated
continually, at present it is not known if other polymorphisms/genes will be important at the
time of study completion. The possibility to assay other allelic variants is then foreseen. The
GISSI-HF genetic substudy is conducted by nearly 100 Centres that have included 2200
patients.
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 has been collected and stored with the
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collaboration of SIBioC (Società 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.
ACTIVE study (Atrial Fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events)
The ACTIVE study is a randomized, multinational, multicenter trial conducted by 600
departments of cardiology of 40 countries that are part of the OASIS (Organization to Assess
Strategies in Ischaemic Syndromes) network. The Population Health Research Institute,
McMaster University, Hamilton, Ontario, is the ACTIVE study coordinating center. The
Laboratory of Clinical Drug Evaluation is responsible for the scientific coordination in Italy.
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 favor 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 are continuing.
MICHELANGELO: OASIS-5 & OASIS-6 studies
The MICHELANGELO: OASIS-5 & OASIS-6 studies are multinational, multicenter trials
aimed to assess the efficacy of fondaparinux, a synthetic oligosaccharide, antithrombindependent, indirect inhibitor of activated factor X (factor Xa), in acute coronary syndromes. The
OASIS-5 & OASIS-6 studies are conducted by 600 departments of cardiology of 40 countries
that are part of the OASIS (Organization to Assess Strategies in Ischaemic Syndromes)
network. The Population Health Research Institute, McMaster University, Hamilton, Ontario is
the OASIS studies coordinating center. The Laboratory of Clinical Drug Evaluation is
responsible for the scientific coordination in Italy.
The OASIS-5 study is a randomized, double blind study evaluating the efficacy and safety of
fondaparinux versus the low-molecular-weight heparin, enoxaparin, in the acute treatment of
patients with Unstable Angina (UA) and Non ST-segment Elevation Myocardial Infarction
(NSTEMI). This is the largest cardiovascular trial investigating the use of antithrombotics ever
conducted in patients with UA and NSTEMI. The primary efficacy outcome is the first
occurrence of death, myocardial infarction, or refractory ischemia up to day 9. The recruitment
in the OASIS-5 study was completed with 20000 patients randomized. The results have been
published in detail (N Engl J Med 2006; 354: 1465-1476). Fondaparinux, the new anti-Xa
inhibitor, is as effective as enoxaparin in reducing cardiovascular events in the short term, while
causing half the amount of bleeding. By 30 days this benefit in bleeding has translated into a
significant reduction in mortality.
The OASIS-6 study was a randomized double blind trial evaluating fondaparinux versus control
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in a broad range of patients presenting with ST segment elevation acute coronary syndrome
(STE-ACS or myocardial infarction STEMI) and receiving background therapy. The primary
efficacy outcome for fondaparinux versus placebo was a composite of death or reinfarction at 30
days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months).
Among 12 092 patients from 447 hospitals in 41 countries, the primary outcome was
significantly reduced from 11.2% in the control group to 9.7% in the fondaparinux
group. Mortality was significantly reduced throughout the study. Significant benefits were
observed in those receiving thrombolytic therapy and those not receiving any reperfusion
therapy. However, there was no benefit in those undergoing primary percutaneous coronary
intervention. There was a tendency to fewer severe bleeds, with significantly fewer cardiac
tamponade with fondaparinux at 9 days. In conclusion, fondaparinux significantly reduced
mortality and reinfarction without increasing bleeding and strokes.
INTER-HEART Study
INTER-HEART is case-control study sponsored by the World Health Organization and the
World Heart Federation aimed to determine the association between risk factors and acute
myocardial infarction within populations defined by ethnicity and/or geographic region, and to
assess the relative importance of risk factors across these populations. The project is coordinated
by the Population Health Research Institute, McMaster University, Hamilton, Canada. The
Clinical Drug Evaluation Laboratory is the National Coordination Office for Italy.
INTER-HEART was conducted in 52 countries in Asia, Europe, Middle East, Africa, Australia,
and North and South America, utilizing a standardized protocol. The study evaluated the
importance of conventional and emerging risk factors within each geographic region, and
whether their impact varies by region.
Cases were patients with acute myocardial infarction admitted within 24 hours of symptom
onset to the coronary care unit of participating centres and controls are individuals with no
history of heart disease matched by age and sex. The study questionnaire collected data on
demographic factors (country of origin, first language), socioeconomic status (education,
occupation, income), lifestyle (tobacco use, physical activity, dietary patterns), and personal and
family history of cardiovascular disease and risk factors.
Data collection started in April 2000 and has been completed by December 2002. A population
of nearly 28000 individuals has been recruited. The study has documented that nine simple
modifiable risk factors can account for over 90% of the population attributable risk for heart
disease globally. More importantly, these risk factors appear to have similar predictability in all
regions of the world, as well as in all ethnic groups.
A further analysis published in the 2005 redefines obesity: traditional definitions have been
based on Body Mass Index (BMI), but this paper very clearly showed that, irrespective of BMI,
the waist-to-hip ratio (WTHR) is a far better predictor of myocardial infarction risk across
diverse populations. The observations carry important implications for people and populations
hitherto considered to be low risk on the basis of their BMIs.
In 2006 INTERHEART study established that all forms of tobacco exposure, such as smoking,
chewing tobacco or inhaling second hand smoke, increase the risk of heart attack. Compared to
people who had never smoked, smokers had a three-fold increased risk of a heart attack.
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
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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 “remodeling” 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 1400 patients which will be treated for 12
months. A biohumoral and echo substudy including 400 patients will be integral part of the
main study and will focus on how possible prognostic factors can be affected by the study
treatment.
According to the GISSI philosophy, GISSI-AF is a pragmatic trial, with broad selection criteria
to mimic real clinical practice as much as possible.
The project is conducted in collaboration with the Laboratory of Cardiovascular Clinical
Pharmacology.
Laboratory of General Practice Research
Risk and Prevention Study (R&P)
R&P is a study on the optimisation 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 comorbidity with an unfavourable prognosis over the short term (e.g. cancer);
- expected non-compliance over a long period of time; contraindications (known allergies to n3)
- 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 placebo in reducing: overall mortality and major cardiovascular events (non fatal
myocardial infarction and stroke) overall major cardiovascular events (cardiovascular mortality,
non-fatal strokes and myocardial infarction); coronary-related mortality and sudden death.
Randomisation is central, stratified by GP.
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The experimental treatment consists of one capsule containing 1g of n-3 PUFA, or the
corresponding placebo, to be taken daily.
The duration of follow-up is 5 years.
In order to document with sufficient statistical reliability that the experimental treatment with n3 PUFA reduces the incidence of events [-15% total death, non fatal myocardial infarction and
stroke; -20% cardiovascular death and non fatal myocardial infarction and stroke; -30%
cardiovascular death; -40% sudden death] a total of 12,000 patients is required.
Up-date of the study
Randomisation started on February 2004 and at the end of 2006, 11842 patients have been
enrolled by 831 GPs. The Local Health Authority (ASL) so far involved are 57 and in each one
investigator’s meeting has been organised.
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.
Pharmaco-epidemiology studies on administrative databases: the “Drugdrug interactions" Project
This is a study aimed to develop and implement a database on drug-drug interaction to be put
into a prescription computerised system of the Regione Lombardia (Italy) as a support for the
general practitioners (GPs) to assess the risk of potential drug interactions. The study was also
set up to assess the prevalence of drug-drug interaction in a sample of prescriptions of a cohort of
GPs. During 2006, has been developed a model for the epidemiological analyses of the drug
prescriptions’ database of Lecco Local Health Authority. The analyses have been performed on
the cohort of subjects > 65 years (58.800 subjects, mean age of 75.2 years) on a total of 964.858
prescription records. Eighty-six % of the subjects received al least one prescription per year,
overall men were more treated than woman and the class of drugs most frequently prescribed
was the cardiovascular one (63.8% of the population). The analysis on drug-grug interactions are
ongoing.
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%).
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•
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 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 aim of the study is to describe the
evolution of depression, cognitive problems and the quality of life in a planned sample of 1500
heart failure patients; assess the use of common instruments that measure QDF variables and
compare the assessment of the instrument (Geriatric Depression scale, Mini Mental State
Examination, Kansas City Cardiomiopathy Questionnaire) with the clinical perception of the
nurses; 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.The study is ongoing and follow up is under completion.
Epidemiology of nursing problems and pharmacosurveillance in nursing
homes and home care
The aim of the study is to describe problems nurses that require nursing decisions, and nurses
encounter in the care of patients admitted to nursing home and home care, with specific
attention to drug-related problems. In fact an adverse drug reaction is likely to be the cause of
most unexpected problems that arise in elderly patients.
The project has been completed and more than 350 nurses have been involved in 95 Nursing
Homes and Districts. In the 6 observation days 8000 patients per day were observed. The
analysis of data is ongoing.
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DEPARTMENT OF MOLECULAR
BIOCHEMISTRY AND
PHARMACOLOGY
STAFF
Head
Mario SALMONA, Sci.Prep.Alim.D., Ph.D.
Laboratory of Biochemistry and Protein Chemistry
Head
Mario SALMONA, Sci.Prep.Alim.D.,Ph.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 Neuroimmunology
Head
Pietro GHEZZI, Ph.D.
Pharmacology of Septic Shock Unit
Head
Pia VILLA, Pharm.D.
Metabolic Neuropathies Unit
Head
Roberto BIANCHI, Biol.Sci.D.
Laboratory of Molecular Pathology
Head
Lavinia CANTONI, Biol.Sci.D.
Laboratory of Systems Biology
Head
Gianfranco BAZZONI, M.D.
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CURRICULA VITAE
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
•
Gerstmann-Straussler-Scheinker disease amyloid protein polymerizes according to the “dock-and-lock” model Gobbi M.,
Colombo L., Morbin M., Mazzoleni G., Accardo E., Vanoni M., Del Favero E., Cantù L., Kirschner D.A., Manzoni C.,
Beeg M., Ceci P., Ubezio P., Forloni G., Tagliavini F., Salmona M. J. Biol. Chem.
http://www.jbc.org/cgi/doi/10.1074/jbc.M506164200
•
Tetracycline and its analogues as inhibitors of amyloid fibrils: searching for a geometrical pharmacophore by theoretical
investigation of their conformational behaviour in aqueous solution U. Cosentino, M.R.Varì, A.A. G. Saracino, D. Pitea,
G. Moro, M. Salmona Journal of Molecular Modelling, 2005, 11: 17-25
•
Role of Plasminogen in Propagation of Scrapie Salmona M., Capobianco R., Colombo L., De Luigi A., Rossi C.,
Mangieri M., Giaccone G., Quaglio E., Chiesa R., Donati M.B., Tagliavini F. and Forloni G. Journal of Virology 2005,
79: 11225-11230
•
The role of platelet activating factor in prion and amyloid-beta neurotoxicity Bate C, Salmona M, Williams A
Neuroreport 2004; 15: 509-513
•
Squalestatin cures prion-infected neurons and protects against prion neurotoxicity. Bate C, Salmona M, Diomede L,
Williams A. J Biol Chem. 2004; 279:14983-90
•
Channels formed with a synthetic mutant prion protein PrP(82-146) homologous to a 7 kDa fragment in diseased brain of
GSS patients Bahadi R., Farrelly P.V., Kenna B.L., Kourie J.I., Tagliavini F., Forloni G., Salmona M. Am.J.Physiol.
(Cell Physiology) 2003; 285: C862-C872
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
•
Huang H, Cruz F, Bazzoni G. Junctional Adhesion Molecule-A Regulates Cell Migration and Resistance to Shear Stress.
J Cell Physiol 2006; 209: 122-130.
•
Bazzoni G. Endothelial tight junctions: permeable barriers of the vessel wall. Thromb Haemost 2006; 95(1): 36-42.
•
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) 2005; 288:
L1081-L1088.
•
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 2005; 118: 623-632.
•
Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol
Rev 2004; 84(3): 869-901.
•
Bazzoni G. The family of junctional adhesion molecules. Curr Op Cell Biol 2003; 15: 525-530.
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Lavinia Cantoni obtained her degree in Biological Sciences (summa cum laude) in 1973 at the
University of Milan. Then she specialized in pharmacological research at the Mario Negri Institute
(1974-1977).
In the area of pharmacology and toxicology, her main interest is the study of the biochemical-molecular
mechanisms activated by oxidative stress in target organs (the liver and, at present, mainly the spinal
cord).
1977-1978 Postdoctoral Researcher at the Medical Research Council, Toxicology Unit, Carshalton, UK
1980-1990 for short research periods Researcher at the same Toxicology Unit and at the Cornell Medical
Center, New York, USA
1983-1998 Head, Unit of Heme and Hemoprotein Metabolism, Mario Negri Institute.
1998 to date, Head, Laboratory of Molecular Pathology at the Mario Negri Institute.
Member of the National Roll of Biologists and of the Italian Toxicology Society and author of about 70
articles published in international journals/books and about 50 communications at scientific meetings.
Referee for international scientific journals, tutor for university degree theses and teacher in a
pharmacological research specialisation course for graduates held at the Mario Negri Institute.
•
Rizzardini M., Chiesa R., Angeretti N., Lucca E., Salmona M., Forloni G., Cantoni L. Prion protein fragment 106-126
differentially induces heme oxygenase-1 mRNA in cultured neurons and astroglial cells. J.Neurochem. 68: 715-720,
1997
•
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
•
Cantoni L.,Valaperta R.,.Ponsoda X., Castell, J.V., 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
•
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
•
Rizzardini M., Lupi M., Mangolini A., Babetto E., Ubezio P., Cantoni L. Neurodegeneration induced by complex I
inhibition in a cellular model of familial amyothrophic lateral sclerosis. Brain Res. Bull., 69: 465-474, 2006
•
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 ALSlinked G93ASOD1. Eur. J. Neurosci. 24: 387-399, 2006
Enrico Garattini obtained his degree in Medicine and Surgery with full marks (110/110) in 1982 at the
University of Milan. His scientific interests relate to problems of Cellular Biology and Molecular
Biology.
1982-1990 Research Fellow of the National Research Council, Mario Negri Institute
1983-1987 Postdoctoral Researcher at the Roche Institute of Molecular Biology, Department of
Neurosciences Nutley, New Jersey, US
1991-1997 Senior Researcher Regione Lombardia and Head of the Molecular Biology Unit, Mario Negri
Institute
1997 to date Head, Laboratory of Molecular Biology, Mario Negri Institute
From 2005 Dean, Advanced School of Pharmacology (Philosophy Doctor), Mario Negri Institute
Member of the Editorial Board of the European Journal of Cancer and of Current Cancer Therapy
Reviews
Member of the American Society of Biochemistry and Molecular Biology (ASBMB)
•
Gianni M, 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. 2006 Feb
22;25(4):739-51
•
Parrella E, Gianni M, Fratelli M, Barzago MM, Raska I Jr, Diomede L, Kurosaki M, Pisano C, Carminati P, Merlini L,
Dallavalle S, Tavecchio M, Rochette-Egly C, Terao M, Garattini E.
Antitumor activity of the retinoid-related molecules (E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid (ST1926)
and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) in F9 teratocarcinoma: Role of
retinoic acid receptor gamma and retinoid-independent pathways.
Mol Pharmacol. 2006 Sep;70(3):909-24
•
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 2004; 103: 194-207
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•
•
•
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 2004; 279: 8668-8683
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 2004; 279: 50482-50498
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 2002; 100: 3719-3730
Pietro Ghezzi
Research Areas: Cytokines and inflammation; redox regulation
1979-1990: Researcher, Mario Negri Institute
1991 to date: Head, Laboratory of Neuroimmunology, Mario Negri Institute
1998-2000: Research Associate at Stanford University School of Medicine, Department of Genetics
2000 to date: Member, Kenneth Warren Laboratory, Ossining, NY (USA)
•
Leist M, Ghezzi P, et al.. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004 Jul
9;305(5681):239-42.
•
Fratelli M, Goodwin LO, Orom UA, Lombardi S, Tonelli R, Mengozzi M, Ghezzi Gene expression profiling reveals a
signaling role of glutathione in redox regulation.Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13998-4003.
•
Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, Viviani B, Marinovich M, Cerami A, Coleman TR,
Brines M, Ghezzi P. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia
by targeting neuronal apoptosis. J Exp Med. 2003 Sep 15;198(6):971-5.
•
Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A,
Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P. Erythropoietin prevents neuronal apoptosis after cerebral
ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4044-9.
•
Laragione T, Bonetto V, Casoni F, Massignan T, Bianchi G, Gianazza E, Ghezzi P. Redox regulation of surface protein
thiols: identification of integrin alpha-4 as a molecular target by using redox proteomics. Proc Natl Acad Sci U S A.
2003 Dec 9;100(25):14737-41.
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
(Max-Plank-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.
•
Beghi E, Bendotti C, Mennini T. 2005. Merits of a new drug trial for ALS? Science 308:632-633
•
Gobbi M, Mennini T. 2001. Is St John's wort a 'Prozac-like' herbal antidepressant? Trends Pharmacol Sci 22:557-559.
•
The Italian ALSSG. 1996. Ceftriaxone in amyotrophic lateral sclerosis. Eur J Neurol 3:295-298.
•
Mennini T, Mocaer E, Garattini S. 1987. Tianeptine, a selective enhancer of serotonin uptake in rat brain. NaunynSchmiedebergs Arch Pharmacol 336:478-482.
•
Mennini T, Garattini S. 1983. Benzodiazepines receptor binding in vivo: pharmacokinetic and pharmacological
significance. Advances Biochemical Psychopharmacol 38:189-199.
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Mennini T, Bernasconi S, Manara L, Samanin R, Serra G. 1977. The effect of intracerebral 6-hydroxy dopamine on 3Hreserpine binding to different brain regions of the rat. Pharmacol Res Commun 9:857-862.
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Roberto Bianchi got his degree in Biological Sciences at University of Milan, Italy in 1992. Since 1975
he served as student teacher and supervisor at Mario Negri Institute and from 1989 to 1997 at Houston
University. His main interests are diabetic complications (peripheral and autonomic neuropathies) and
neurodegenerative disorders (Multiple Sclerosis, drugs induced neuropathies).
1971 Technician in the Laboratory of Biochemical Pharmacology, Mario Negri Institute
1980-1981 Visiting Scientist in the Center for Neurosciences Behavioral Research, The Weizmann
Institute of Science, Rehovot, Israel
1981-1995 Research Assistant in the Laboratory of Biochemical Pharmacology, Mario Negri Institute
1988-1997 Research Fellow in the Dept. Biochemical Biophysical Sciences, University of Houston, US
1993-1995 Research Fellow in the Dept. Medicine, Case Western Reserve University, Cleveland, US
Since 1996 Head, Unit of Metabolic Neuropathies, Mario Negri Institute
•
Bianchi R., Berti-Mattera L.N., Fiori M.G., Eichberg J.:Correction of altered metabolic activities in sciatic nerves of
streptozotocin-induced diabetic rats. Effects of ganglioside treatment. Diabetes 39: 782-788 (1990).
•
Scarpini E., Bianchi R., Moggio M., Sciacco M., Fiori M.G., Scarlato G.: Decrease of nerve Na+,K+-ATPase activity in
the pathogenesis of diabetic neuropathy. J. Neurol. Sci. 120: 159-167 (1993).
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Conti G., Scarpini E., Baron P.L., Livraghi S., Tiriticco M., Bianchi R, Vedeler C., Scarlato G.: Macrophage infiltration
and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitant with
endoneurial induction of IL-1 and p75NTR. J. Nuerol. Sci. 195: 35-40 (2002)
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Bianchi R., Buyukakilli B., Brines M., Savino C., Cavaletti G., Oggioni N., Lauria G., Borgna M., Lombardi R., Cimen
B., Comelekoglu U., Kanik A., Tataroglu C., Cerami A., Ghezzi P. Erythropoietin both protects from and reverses
experimental diabetic neuropathy. Proc Natl Acad Sci USA 101: 823-828 (2004)
•
Leist M., Ghezzi P., Grasso G, Bianchi R., Villa P., Fratelli M., Savino C., Bianchi M., Nielsen J., Gerwien J., Kallunki
P., Larsen A.K., Helboe L., Christensen S., Pedersen L.O., Nielsen M., Troup L., Sager T., Sfacteria A., Erbayktar S,
Erbayktar Z., Gokmen N., Yilmaz O., Cerami-Hand C., Xie, Q-W., Coleman T., Cerami A., Brines M. Erythropoietinderived tissue-protective cytokines that do not bind to the classical erythropoietin receptor. Science, 305(5681) 239-242,
2004.
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Savino C., Pedotti R., Baggi F., Furlan R., Ubiali F., Gallo B, Nava S., Bigini P., Barbera S., Fumagalli E., Mennini T.,
Vezzani A., Rizzi M., Coleman T., Cerami A.,Brines M., Ghezzi P., Bianchi R.Delayed administration of erythropoietin
and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis. Journal of
Neuroimmunology, 2005, E-pub December 6, 2005
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
•
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. 2005;102:13998-4003.
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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. Proc Natl Acad Sci U S A. 2004; 101:14907-12.
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Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P,
Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S,
Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M. Derivatives of
erythropoietin that are tissue protective but not erythropoietic. Science. 2004; 305:239-42
•
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. 2003; 5:229-35
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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. Proc Natl Acad Sci U S A. 2002; 99:3505-10
•
Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A,
Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P. Erythropoietin prevents neuronal apoptosis after cerebral
ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001; 98:4044-9
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Marco Gobbi got his degree in Pharmacy at the University of Milan, Italy, in 1989.
Currently, his main fields of interest are: 1) the study of presynaptic mechanisms, such as
neurotransmitter release/reuptake with a particular focus on plasma membrane transporters; and 2) the
study of protein misfolding and aggregation and in particular the characterization of the prion protein
amyloid formation, investigated by different approaches including surface plasmone resonance.
Since 1981, Researcher in the Laboratory of Neuropharmacology and, from 1988, in the Laboratory of
Receptor Pharmacology, Mario Negri Institute
Starting from 1989 Chief, Unit of Synaptic Transmission, Mario Negri Institute
In Jan 2006, his group joined the Laboratory of Biochemistry and Protein Chemistry, Mario Negri Institute
Co-author in more than 70 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.
•
Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantù L Kirshner DA, Manzoni
C, Beeg M, Ceci P, Ubezio P, Forloni G, Tagliavini F, Salmona M. Epub 2005. Gerstmann-Sträussler-Scheinker
disease amyloid peptide polymerises according to the “dock-and-lock” model. J Biol Chem,
http://www.jbc.org/cgi/doi/10.1074/jbc.M506164200
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Funicello M, Conti P, De Amici M, De Micheli C, Mennini T, Gobbi M. 2004. Dissociation of [3H]L-glutamate uptake
from L-glutamate-induced [3H]D-aspartate release by 3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-4carboxylic acid and 3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-6-carboxylic acid, two
conformationally constrained aspartate and glutamate analogs. Mol Pharmacol 66:522-529.
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Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T. 2002. 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.
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Gobbi M, DallaValle F, Ciapparelli C, Diomede L, Morazzoni P, Verotta L, Caccia S, Cervo L, Mennini T. 1999.
Hypericum perforatum L. extract does not inhibit 5-HT transporter in rat brain cortex. Naunyn Schmiedebergs Arch
Pharmacol 360:262-269.
•
Gobbi M, Gariboldi M, Piwko C, Hoyer D, Sperk G, Vezzani A. 1998. 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.
•
Crespi D, Mennini T, Gobbi M. 1997. Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by
(+)-amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine. Br J Pharmacol
121:1735-1743.
Mineko Terao obtained her doctorate degree in Pharmaceutical Science from the Kobe Women’s
College of Pharmacy, Japan in 1978. Her scientific interests relate to problems of Cellular Biology and
Molecular Biology.
1983 Ph.D in Molecular Biology, Kyoto University, Japan
1982-1983 Research Fellow, Department of Medical Chemistry, Kyoto University Faculty of Medicine,
Japan
1983-1987 Postdoctoral Associate of the Institute for Cancer Research, Philadelphia, US
From 1987 Visiting Scientist of Mario Negri Institute
From 1998 Head of the Unit of Gene Structure and Regulation, Mario Negri Institute
•
Terao M, Kurosaki M, Barzago 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. 2006 Jul 14;281(28):19748-61
•
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 2004; 103: 194-207
•
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 2004; 279: 8668-8683
•
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 2004; 279: 50482-50498
•
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 2004; 279: 42026-42040
•
Garattini E, Gianni’ M and Terao M. Retinoid related molecules an emerging class of apoptotic agents with promising
clinical potential in oncology: pharmacological activity and mechanisms of action. Curr Pharm Design 2004, 10: 433448
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Pia Emilia Villa got her degree in Pharmaceutical Chemistry and Technology at the University of Pavia
in 1975 and the specialisation in Pharmacological Research at the Mario Negri Institute, Milan in 1978.
Her scientific interests are the physiopathologic factors of sepsis and their pharmacological modulation,
the cellular and molecular mechanisms of neurodegeneration and neuroprotection in experimental
cerebral ischemia.
1976-1992: Research fellow, laboratory of Perfusion of Isolated Organs and Toxicology, Mario Negri
Institute
1979-1980: Visiting fellow, laboratory of Cultured Hepatocytes, Toxicology Unit, MRC, Carshalton,
England
1983: Visiting fellow, Unité de Recherche Hépatologique, Rennes, France
1993-1995: Research Scientist, laboratory of Neuroimmunology, Mario Negri Institute
1995 to date: Head, Unit of Pharmacology of Septic Shock, Mario Negri Institute
1982 Regular member of the Italian Society of Toxicology
1992 Regular member of Celltox
1996 Regular member of the International Cytokine Society.
•
Villa P, Shaklee CL, Meazza C, Agnello D, Ghezzi P, Senaldi G. Granulocyte colony-stimulating factor and antibiotics
in the prophylaxis of a murine model of polymicrobial peritonitis and sepsis. J Infect Dis. 1998; 178: 471-7.
•
Villa P, Saccani A, Sica A, Ghezzi P. Glutathione protects mice from lethal sepsis by limiting inflammation and
potentiating host defense. J Infect Dis. 2002; 185: 1115-20.
•
Erbayraktar S, Grasso G, Sfacteria A, Xie QW, Coleman T, Kreilgaard M, Torup L, Sager T, Erbayraktar Z, Gokmen N,
Yilmaz O, Ghezzi P, Villa P, Fratelli M, Casagrande S, Leist M, Helboe L, Gerwein J, Christensen S, Geist MA,
Pedersen LO, Cerami-Hand C, Wuerth JP, Cerami A, Brines M. Asialoerythropoietin is a nonerythropoietic cytokine
with broad neuroprotective activity in vivo. Proc Natl Acad Sci U S A. 2003;100 (11):6741-6.
•
Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, Viviani B, Marinovich M, Cerami A, Coleman TR,
Brines M, Ghezzi P. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by
targeting neuronal apoptosis. J Exp Med. 2003;198 (6):971-5.
•
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. 2004;305: 239-42.
•
Garau A, Bertini R, Colotta F, Casilli F, Bigini P, Cagnotto A, Mennini T, Ghezzi P, Villa P. Neuroprotection with the
CXCL8 inhibitor repertaxin in transient brain ischemia. Cytokine. 2005;30:125-31.
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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.
Identification of tetracylines as potential anti-prion drugs.
Synthesis and physicochemical and biological characterization of peptides deduced from the
primary sequence of prion protein.
Identification of a relationship between cholesterol synthesis and production of prion protein.
Protein identifications by mass spectrometry (MS) and data base searching using a combination
of techniques.
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.
Development of an inducible motor neuron cellular model to unravel the toxicity of mutant
G93A superoxide dismutase 1 identified in some familial amyotrophic lateral sclerosis patients.
Expression of human mutant G93A superoxide dismutase 1 alters morphology and membrane
potential of motor neuron mitochondria.
Conditions of oxidative stress or the presence of compounds impairing the electron transport
chain are a risk factor for motor neurons of individuals carrying mutant forms of superoxide
dismutase 1.
Mitochondria are damaged by human mutant G93A superoxide dismutase 1 selectively in motor
neurons.
Mitochondrial damage by human mutant G93A superoxide dismutase 1 in motor neurons is
modulated by level of expression of the mutant protein.
Identification and characterization of a novel class of retinoids endowed with strong and
selective apoptogenic acivity 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.
Identification of erythropoietin as a neuroprotective agent and of new molecules with
neuroprotective activity.
Identification of the pharmacological action of erythropoietin against peripheral neuropathy of
diabetes.
Identification of erythropoietin derivatives that retain its neuroprotective actions but have lost
its hemopoietic ones.
Discovery of proteins that are regulated by the redox state through the formation of reversible
disulfide bonds with glutathione (protein glutathionylation).
Identification of exofacial proteins undergoing thiol redox regulation.
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The use of antioxidant molecules in models of sepsis and inflammation diminishes the
inflammatory response while potentiates the innate immune response.
Identification of the gene expression profile regulated by thiols.
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 vescicle
trafficking, the wobbler mouse.
Treatment with a soluble TNF receptor in the wobbler mouse, reduces motor neuron
degeneration and the phosporylation 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 signaling in the pathology of Neuronal
Ceroid Lipofuscinosis
The affinity of pergolide for human cloned 5-HT2A and 5-HT2B receptors is similar and higher
that that for the human cloned D2L receptor. These findings, together with the fact that it acts as
agonist at both h5-HT2A and h5-HT2B receptors, could explain its potential toxicity mediated by
activation of cardio-pulmonary 5-HT2B receptor.
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- -S binding; but does not interfere with the europium
labeled GTP binding determined by “time-resolved fluorescence” .
Advanced Biology Center, Genoa
Centro Anemie Congenite, Ospedale Maggiore Policlinico, IRCCS, Dip. Medicina Interna,
University of 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
ANNUAL REPORT
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GlaxoSmithkline, Verona
Harlan, 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 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
Newron Pharmaceuticals, Milan
Ospedale Maggiore Policlinico, Milan
Ospedale Pediatrico Bambino Gesu', Rome
Ospedale Pediatrico "Gaslini", Genoa
Ospedale S. Gerardo, Monza, Milan
Primo Dipartimento di Ostetricia e Ginecologia, Clinica Mangiagalli, University of Milan
Sigma-Tau, Pomezia, Rome
Zambon, Milan
Babraham Institute, Cambridge, UK
Boston College, Boston, MA, USA
Case Western Research University, Cleveland, OH, USA
Dept. de Biologia Cellular, Fac de Ciences Biologiques, Valencia University, Spain
Dept. de Bioquimica, Fac. Medicina/Centro de Investigacion, Hospital Universitario La Fe,
Valencia, Spain
Dept. de Quimica-Fisica de Macromoleculas Biologicas, CSIC, Madrid, Spain
Faculdad de Ciencias Medicas, Universidad de Santiago de Chile, Chile
Dept. of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The
Hebrew University of Jerusalem, Jerusalem, Israel
Flanders Interuniversity Institute for Biotechnology (VIB) University of Gent, Belgium
FMP, Berlin, Germany
Giessen Polyclinic University, Giessen, Germany
Houston University, TX, USA
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
Kenneth S. Warren Institute, Ossining, NY, USA
Max-Planck-Institut für experimentelle Medizin, Göttingen, Germany
National Institute of Health, Bethesda, MD, USA
Nippon University, Tokyo, Japan
North Shore University Hospital, Manhasset, NY, USA
Pepscan System BV, Lelystad, Holland
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Polichem S.A., Lugano, Switzerland
Stanford University School of Medicine, Stanford, CA, USA
Technical University Braunschweig, Germany
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 Birmingham, UK
University of Cardiff, UK
University of Colorado, School of Medicine, Denver, CO, USA
University of Glasgow, UK
University of Gottingen, Germany
University of Muenster, Germany
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)
Neuroimmunomodulation (P. Ghezzi)
Newsletters of the International Cytokine Society (P. Ghezzi)
European Journal of Cancer (E. Garattini)
American Journal Physiology, Biochemical Journal, Biochemical Pharmacology, Biochimica
Biophysica Acta, Brain Research, Cancer Research, Cell Death and Differentiation, Cell
Research, 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 Translational
Medicine, Neuroscience Letters, Pharmacological Research, Physiological Genomics,
Proceedings of the National Academy of Sciences, Life Sciences.
Referee for MRC Career Development Award, Medical Research Council, 20 Park Crescent,
London W1B1AL, U.K.
ANNUAL REPORT
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INVOLVED
Conference: “The Annual Global Conference on Neuroprotection and Neurodegeneration”,
“TNFR p55 is involved in motoneuron degeneration in wobbler mice”, 1-3 March, Uppsala,
Sweden
Workshop: “EMBO-FEBS Workshop. Structure, mechanism of formation and cellular effects of
amyloid aggregates”, “Molecular properties and biological effects of different oligomeric states
of PRP82-146”, 25-28 March, Florence, Italy
Meeting: “97th Annual Meeting 2006 – American Association for Cancer Research”, “Inhibition
of the prolyl-isomerase PIN-1 enhances the cyto-differentiating activity of retinoids in myeloid
leukaemia cells”, 1-5 April, Washington, DC, USA
Congress: “32° Congresso dell’Associazione Italiana Ricerca Invecchiamento Cerebrale
(AIRIC)”, “P35- ST1859: a potential drug for protein misfolding disorders?”, “Glutamatergic
alteration in a transgenic mouse model of Alzheimer disease”, 24-27 May, Rome, Italy
Workshop: “4th European ALS Consortium Research Workshop”, “Glutamate uptake by
presynaptic compartment and potential role in animal models of neurodegenerative diseases”.
9-11 June, Utrecht, The Netherlands
Congress: “5th Forum of European Neuroscience”, “TNF-alpha and TNF receptor 1 in retinal
and optic nerve degeneration of the CLN8 mutant mouse”, 8-12 July, Wien, Austria
Conference: “ICAD - The 10th International Conference on Alzheimer Disease and Related
Disorders”, “Treatment of Transmissible Spongiform Encephalophaties with Doxycycline”, 1520 July, Madrid, Spain
Symposium: “XIXth International Symposium on Medicinal Chemistry ISMC 2006”,
“Enantiomeric Forms of (±)-HIP-A and (±)-HIP-B: Synthesis and Evaluation of their Activity at
the Excitatory Amino Acid Transporters”, “2,3-Benzodiazepine-based noncompetitive AMPAR
antagonists: design, synthesis, binding affinity and mechanism of inhibition of the GluR2Qflip
homomeric receptor channel”, 29 August – 2 September, Istanbul, Turkey
Conference: “EuroStemCell International Conference, Advances in Stem Cell Research, Ecole
Polytechnique Fédérale de Lausanne”, “Human cord Blood cells reduce symptoms progression
and neuromuscular decay in a murine model of motoneuron disease , the wobbler mouse”, 8-10
September, Losanna, Switzerland
Congress: “Molecular and cellular mechanisms of axon degeneration”, “ Effect of all transretinoic acid on the morphology of murine motor neuron-like cell lines”, 10-12 September,
Cambridge, UK
Congress: “XXII Congresso Nazionale della Società Chimica Italiana - SCI 2006”, “La chimica
e le grandi domande della scienza e della società l’eredità di Avogadro”, “Synthesis and binding
properties of new endothelins receptor ligands”, “Synthesis of Endothelin Receptor Affinity of a
Novel Class of 2-Substituted-4-aryl-3-quinolinecarboxiyic Acid Derivatives”, 10-15
September, Florence, Italy
ANNUAL REPORT
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Conference: “14th Euroconference on Apoptosis and 3rd Training course on Concepts and
Methods in Programmed Cell Death”, “AMPA receptor activation can induce both apoptotic
and necrotic cell death in primary cultured motoneurons”, 29 September - 4 October, Cagliari,
Italy
Congress: “The role and the network/ the fundamental contribution of Camillo Golgi to Modern
Neuroscience, Camillo Golgi Nobel Prize centennial, 1906-2006”, “Adult neural stem cells
(ANSCs) from the subventricular zone (SVZ) of wobbler motor neuron disease mouse as a
model to study the mechanisms leading to neurodegeneration”, “Characterization of the
integration, diffusion, survival, differentiation and clinical outcomes of adult neural stem cells
transplanted in a murine model of motoneuron disease, the wobbler mouse”, 2-4 October, Pavia,
Italy
Conference: “Prion 2006” - Strategies, advances and trends towards protection of society”,
“Evaluation of the neurotoxic properties of stabilized PrP82-146 oligomers”, “Structure of
PrP82-146 aggregates and cross-linked oligomers”, “Studies on the polymerization reactions of
Gerstmann-Straussler-Scheinker disease prion peptide using surface plasmon resonance”, “Role
of prion neurotoxicity in TSE pathogenesis”, “Use of tetracyclines for therapeutic intervention
of transmissible spongiform encephalopathies”, “Analysis of synaptic dysfunction in a
transgenic mouse model of inherited prion disease”, 3-6 October, Turin, Italy
Congress: “XXII encuentro cientifico de la Mediteterranea. Nanociencia y nanotecnologia.
celebrados en Maò”, “Prion protein aggregation triggered dy acetylcholinesterase: an AF
study”, November, Mao, Menorca
Symposium: “VI Simposio de Neurobiologia Experimental”, “Acetylcholinesterase
proaggregating effects on PrP82-146”, 23 November, Barcellona, Spain
Meeting: “The annual meeting of the Israel Society of Neuroscience (ISFN)”, “Impairment the
blood brain barrier upon exposure to prion “, 3-5 December, Eliat, Israel
Biotecnologies BT - Perugia, Italy
Dompè, L' Aquila, Italy
Eurand, Pessano con Bornago, Milan, Italy
European Union, Bruxelles, Belgium
Indena, Milan, Italy
Istituto Auxologico Italiano, Milan, Italy
Istituto Nazionale Neurologico "C. Besta", Milan, Italy
Italian Association for Cancer Research (AIRC), Milan, Italy
Italian Ministry of University and Research (MIUR), Rome, Italy
Kenneth S. Warren Institute, NY, USA
Lundbeck A/S, Copenhagen, Denmark
Cariplo Foundation, Milan, Italy
Don Gnocchi Foundation, Milan, Italy
Mariani Foundation, Milan, Italy
Monzino Foundation, Milan, Italy
Ministry of Health, Rome, Italy
ANNUAL REPORT
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National Research Council (CNR), Palermo, Italy
North Shore University Hospital, NY, USA
Perfetti-Van Melle, Lainate (Mi), Italy
Sigma Tau, Pomezia (Rome), Italy
Telethon, Milan, Italy
University of Florence, Italy
University of Milan-Bicocca, Italy
University of Siena, Italy
Weizmann-Pasteur-Negri Foundation, Paris, France
Zambon Group, Bresso (Mi), Italy
ANNUAL REPORT
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Clos MV, Pera M, Ratia M, Roman S, Camps P, Munoz-Torrero D, Colombo L, Salmona M, Badia A. Effect of
acetylcholinesterase inhibitors on AChE-induced PrP106-126 aggregation.
J Mol Neurosci. 2006 30(1-2):89-90.
Basso M, Massignan T, Samengo G, Cheroni C, De Biasi S, Salmona M, Bendotti C, Bonetto V. Insoluble mutant
SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice.
J Biol Chem. 2006 Nov 3;281(44):33325-35.
Mariggio S, Bavec A, Natale E, Zizza P, Salmona M, Corda D, Di Girolamo M. Galpha13 mediates activation of the
cytosolic phospholipase A2alpha through fine regulation of ERK phosphorylation.
Cell Signal. 2006 Dec;18(12):2200-8
Pera M, Roman S, Ratia M, Camps P, Munoz-Torrero D, Colombo L, Manzoni C, Salmona M, Badia A, Clos MV.
Acetylcholinesterase triggers the aggregation of PrP 106-126.
Biochem Biophys Res Commun. 2006 Jul 21;346(1):89-94.
Ricchelli F, Buggio R, Drago D, Salmona M, Forloni G, Negro A, Tognon G, Zatta P. Aggregation/fibrillogenesis of
recombinant human prion protein and Gerstmann-Straussler-Scheinker disease peptides in the presence of metal ions.
Biochemistry. 2006 May 30;45(21):6724-32.
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. 2006 May;6(9):2823-34.
Villa A, Mark AE, Saracino GA, Cosentino U, Pitea D, Moro G, Salmona M. Conformational polymorphism of the
PrP106-126 peptide in different environments: a molecular dynamics study.
J Phys Chem B Condens Matter Mater Surf Interfaces Biophys. 2006 Jan 26;110(3):1423-8.
Ghezzi P, Casagrande S, Massignan T, Basso M, Bellacchio E, Mollica L, Biasini E, Tonelli R, Eberini I, Gianazza
E, Dai WW, Fratelli M, Salmona M, Sherry B, Bonetto V. Redox regulation of cyclophilin A by glutathionylation.
Proteomics. 2006 Feb;6(3):817-25
Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantu L, Kirschner DA,
Manzoni C, Beeg M, Ceci P, Ubezio P, Forloni G, Tagliavini F, Salmona M. Gerstmann-Straussler-Scheinker disease
amyloid protein polymerizes according to the "dock-and-lock" model.
J Biol Chem. 2006 Jan 13;281(2):843-9.
Parrella E, Gianni M, Fratelli M, Barzago MM, Raska I Jr, Diomede L, Kurosaki M, Pisano C, Carminati P, Merlini
L, Dallavalle S, Tavecchio M, Rochette-Egly C, Terao M, Garattini E.
Antitumor activity of the retinoid-related molecules (E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid
(ST1926) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) in F9 teratocarcinoma:
Role of retinoic acid receptor gamma and retinoid-independent pathways.
Mol Pharmacol. 2006 Sep;70(3):909-24
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. 2006 Jul 14;281(28):19748-61
Gianni M, Parrella E, Raska I Jr, Gaillard E, Nigro EA, Gaudon C, Garattini E, Rochette-Egly C. P38MAPKdependent phosphorylation and degradation of SRC-3/AIB1 and RARalpha-mediated transcription. EMBO J. 2006
Feb 22;25(4):739-51
Garattini E, Terao M. Granulocytic maturation in cultures of acute myeloid leukemia is not always accompanied by
increased apoptosis.
Leuk Res. 2006 May;30(5):519-20.
Huang H, Cruz F, Bazzoni G.
Junctional adhesion molecule-A regulates cell migration and resistance to shear stress.
ANNUAL REPORT
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J Cell Physiol. 2006 Oct;209(1):122-30.
Bazzoni G.
Endothelial tight junctions: permeable barriers of the vessel wall.
Thromb Haemost. 2006 Jan;95(1):36-42.
Mennini T, De Paola M, Bigini P, Mastrotto C, Fumagalli E, Barbera S, Mengozzi M, Viviani B, Corsini E,
Marinovich M, Torup L, Van Beek J, Leist M, Brines M, Cerami A, Ghezzi P.
Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo.
Mol Med. 2006 Jul-Aug;12(7-8):153-60.
Laragione T, Gianazza E, Tonelli R, Bigini P, Mennini T, Casoni F, Massignan T, Bonetto V, Ghezzi P.
Regulation of redox-sensitive exofacial protein thiols in CHO cells.
Biol Chem. 2006 Oct-Nov;387(10-11):1371-6.
Bigini P, Gardoni F, Barbera S, Cagnotto A, Fumagalli E, Longhi A, Corsi MM, Di Luca M, Mennini T.
Expression of AMPA and NMDA receptor subunits in the cervical spinal cord of wobbler mice.
BMC Neurosci. 2006 Oct 26;7:71.
Mereghetti I, Cagnotto A, Mennini T.
Dimethyl sulfoxide: An antagonist in scintillation proximity assay [(35)S]-GTPgammaS binding to rat 5-HT(6)
receptor cloned in HEK-293 cells?
J Neurosci Methods. 2006 Oct 16
Elger B, Schneider M, Winter E, Carvelli L, Bonomi M, Fracasso C, Guiso G, Colovic M, Caccia S, Mennini T.
Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of
neuronal ceroid lipofuscinosis.
ChemMedChem. 2006 Oct;1(10):1142-8.
Beghi E, Bendotti C, Mennini T.
New ideas for therapy in ALS: critical considerations.
Amyotroph Lateral Scler. 2006 Jun;7(2):126-7
Beghi E, Chio A, Logroscino G, Hardiman O, Hernandez E H, Leone M A, Millul A, Mitchell D, Esteban J, Salas T,
Stevic Z, Swingler R, Traynor B, Mennini T, EURALS
127th ENMC international workshop: implementation of a European Registry of ALS Naarden, The Netherlands, 810 October 2004
Neuromuscul Disord 2006; 16: 46-53
Fumagalli E, Bigini P, Barbera S, De Paola M, Mennini T.
Riluzole, unlike the AMPA antagonist RPR119990, reduces motor impairment and partially prevents motoneuron
death in the wobbler mouse, a model of neurodegenerative disease.
Exp Neurol. 2006 Mar;198(1):114-28
Savino C, Pedotti R, Baggi F, Ubiali F, Gallo B, Nava S, Bigini P, Barbera S, Fumagalli E, Mennini T, Vezzani A,
Rizzi M, Coleman T, Cerami A, Brines M, Ghezzi P, Bianchi R.
Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine
autoimmune encephalomyelitis.
J Neuroimmunol. 2006 Mar;172(1-2):27-37
Pittala V, Romeo G, Salerno L, Siracusa MA, Modica M, Materia L, Mereghetti I, Cagnotto A, Mennini T, Marucci
G, Angeli P, Russo F.
3-Arylpiperazinylethyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives as novel, high-affinity and
selective alpha(1)-adrenoceptor ligands.
Bioorg Med Chem Lett. 2006 Jan 1;16(1):150-3
Inforzato A, Peri G, Doni A, Garlanda C, Mantovani A, Bastone A, Carpentieri A, Amoresano A, Pucci P, Roos A,
Daha MR, Vincenti S, Gallo G, Carminati P, De Santis R, Salvatori G. Structure and function of the long pentraxin
PTX3 glycosidic moiety: fine-tuning of the interaction with C1q and complement activation. Biochemistry. 2006 Sep
26;45(38):11540-51
Camozzi M, Rusnati M, Bugatti A, Bottazzi B, Mantovani A, Bastone A, Inforzato A, Vincenti S, Bracci L,
Mastroianni D, Presta M. Identification of an antiangiogenic FGF2-binding site in the N terminus of the soluble
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pattern recognition receptor PTX3.
J Biol Chem. 2006 Aug 11;281(32):22605-13
Bottazzi B, Bastone A, Doni A, Garlanda C, Valentino S, Deban L, Maina V, Cotena A, Moalli F, Vago L, Salustri
A, Romani L, Mantovani A.
The long pentraxin PTX3 as a link among innate immunity, inflammation, and female fertility.
J Leukoc Biol. 2006 May;79(5):909-12
Villa P, van Beek J, Larsen AK, Gerwien J, Christensen S, Cerami A, Brines M, Leist M, Ghezzi P, Torup L.
Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by
nonerythropoietic erythropoietin derivatives.
J Cereb Blood Flow Metab. 2006 Jul 1
Mengozzi M, Latini R, Salio M, Sfacteria A, Piedimonte G, Gerwien JG, Leist M, Siren AL, Ghezzi P, Chimenti S.
Increased erythropoietin production after myocardial infarction in mice.
Heart. 2006 Jun;92(6):838-9.
Bianchi R, Brines M, Lauria G, Savino C, Gilardini A, Nicolini G, Rodriguez-Menendez V, Oggioni N, Canta A,
Penza P, Lombardi R, Minoia C, Ronchi A, Cerami A, Ghezzi P, Cavaletti G.
Protective effect of erythropoietin and its carbamylated derivative in experimental Cisplatin peripheral neurotoxicity.
Clin Cancer Res. 2006 Apr 15;12(8):2607-12.
Garau A, Bertini R, Mosca M, Bizzarri C, Anacardio R, Triulzi S, Allegretti M, Ghezzi P, Villa P.
Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in a model of
transient cerebral ischemia in the rat.
Eur Cytokine Netw. 2006 Mar;17(1):35-41
Coleman TR, Westenfelder C, Togel FE, Yang Y, Hu Z, Swenson L, Leuvenink HG, Ploeg RJ, d'Uscio LV, Katusic
ZS, Ghezzi P, Zanetti A, Kaushansky K, Fox NE, Cerami A, Brines M.
Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and
vasoactive activities.
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5965-70
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 Jun 6;79(2):121-9.
Raimondi A, Mangolini A, Rizzardini M, Tartari S, Massari S, Bendotti C, Francolini M, Borgese N, Cantoni L,
Pietrini G.
Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALS-linked
G93ASOD1.
Eur J Neurosci. 2006 Jul;24(2):387-99.
Rizzardini M, Lupi M, Mangolini A, Babetto E, Ubezio P, Cantoni L.
Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis.
Brain Res Bull. 2006 Apr 28;69(4):465-74
Pallavicini M, Fumagalli L, Gobbi M, Bolchi C, Colleoni S, Moroni B, Pedretti A, Rusconi C, Vistoli G, Valoti E
QSAR study for a novel series of ortho disubstituted phenoxy analogues of alfa1-adrenoceptor antagonist WB4101
Eur J Med Chem 2006; 41: 1025-1040
Pallavicini M, Budriesi R, Fumagalli L, Ioan P, Chiarini A, Bolchi C, Ugenti M P, Colleoni S, Gobbi M, Valoti E
WB4101-related compounds: new, subtype-selective alfa1-adrenoceptor antagonists (or inverse agonists?)
J Med Chem 2006; 49: 7140-7149
Bigini P, Gardoni F, Barbera S, Cagnotto A, Fumagalli E, Longhi A, Corsi M M, Di Luca M, Mennini T
Expression of AMPA and NMDA receptor subunits in the cervical spinal cord of wobbler mice
BMC Neuroscience 2006; : http://www.biomedcentral.com/1471-2202/7/71
Noe' F, Nissinen J, Pitkanen A, Gobbi M, Sperk G, During M, Vezzani A.
Gene therapy in epilepsy: The focus on NPY.
Peptides. 2007 Feb;28(2):377-83.
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RESEARCH ACTIVITIES
Laboratory of Receptor Pharmacology
Neurodegeneration (I): Studies on the dysfunction of the endoplasmic
reticulum (ER) or the Golgi apparatus (GA)
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.
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).
Neurodegeneration (II): Mutation of CLN8, a membrane protein resident of
the ER, causes neuronal ceroid lipofuscinosis
The NCLs are a group of autosomal recessive neurodegenerative diseases and a significant
cause of childhood progressive intellectual and neurological deterioration, for which no curative
or preventive treatment is available. Among them, progressive epilepsy with mental retardation
is the newest form with mutation in the CLN8 gene encoding a novel ER transmembrane protein
with undefined function. An orthologue of CNL8 is mutated in the motor neuron degeneration
mouse (mnd) which shows early retinopathy and delayed motor neuron dysfunction without
degeneration. How CLN8 mutation leads to NCL defect is unknown. We have already reported
decreased spinal cord GLT-1 glial glutamate transporter and increased plasma glutamate
concentration already at presymptomatic stage in mnd mice, with increased GluR2 and lowered
GluR3 AMPA receptor subunits in the lumbar spinal cord. The AMPA receptor antagonists ZK
187638 (non-competitive), like NBQX (competitive), ameliorate motor behavior in mnd mice.
We also found that TNF and TNFR1 is increased in the spinal cord of mnd mice already at
presymptomatic stage, when intensive astrocytes and microglial proliferation occurs. The rate of
oxygen consumption (QO2), and mitochondrial functions were decreased in mnd spinal cord.
The level of lipid peroxide derivatives reacting with thiobarbituric acid (TBARS) were
increased in mnd spinal cord and retina. L-carnitine treatment delayed the onset of motor
behavior impairment, increased the mitochondrial enzyme activities and was effective in
enhancing QO2 and decreasing TBARS levels.
Further experiments are in progress to evaluate: i) the sensitivity of hippocampal and spinal
cord cell cultures against ER−specific stress, to exitotoxicity and oxidative stress; ii) the
sensitivity of mnd mice to convulsion and the expression of GABA and glutamate receptor in
the hippocampus; iii) the effect of treatments aimed at stabilizing Ca ++ levels in ER on motor
neuron dysfunctions, neuronal excitability and blindness.
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Neurodegeneration (III): mutation of Vps54, a protein of the GARP
complex, causes motor neuron degeneration
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder involving
primarily motor neurons in the spinal cord, brainstem and cerebral motor cortex and leading to
denervation, muscular atrophy and paralysis. The disease is sporadic in approximately 90% of
cases, and the mechanism(s) responsible for the selective motor neuron degeneration are far
from being elucidated.
The remaining 10% of ALS cases are classified as familial (fALS). In subsets of patients
affected by fALS, mutations have been identified in the genes encoding alsin (ALS2), which,
among others, has a functional Vps9 domain, and VAPB (ALS8), a vesicle−trafficking protein.
A missense mutation in Vps54 has been described in the wobbler mouse, which share many
pathological features with ALS patients. In mammalian cells Vps54 forms heterotrimeric
complexes with Vps52 and Vps53 to form the GARP complex, involved in retrograde transport
of endosomes to the trans GA network. Thus we use the wobbler mouse as a reliable tool to
understand the interplay between endosomal dynamics and the selective loss of motor neurons.
A series of experiments are in progress in cultured neural cells obtained from wobbler and
healthy homozygous mice to investigate the possible effect of Vps54 mutation on intracellular
trafficking, mitochondrial activity, and lysosome accumulation.
We have already reported that wobbler mice are sensitive to riluzole treatment, without marked
changes in AMPA/NMDA receptor subunits expression in motor neurons of early symptomatic
mice. In addition we found increased levels of TNF and TNFR1 in the cervical spinal cord and a
significant effect of chronic treatment with a soluble h-TNF binding protein, resulting in slower
clinical symptoms progression, reduced motor neuron loss and selective inhibition of the two
main stress-kinases (p38 and JNK) associated to TNF receptors activation.
Finally we investigated 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).
Neurodegeneration (IV): studies on cells cultures
AMPA receptor-mediated excitotoxicity is one of the main events involved in motor neuron
degeneration in ALS pathogenesis. In our in vitro model (primary cultured motor neurons from
spinal cord anterior horns) AMPA receptor agonists can induce both apoptotic and nonapoptotic death pathways depending on their concentrations. We are now studying the main
intracellular biochemical pathways involved in these neurodegenerative mechanisms (such as
calcium influx) and testing new potential treatments to selectively interfere with each of them.
We are also considering the interaction between excitotoxicity and other potentially neurotoxic
factors, such as the inflammatory mediators, by utilizing co-cultures of motor neurons over an
astrocyte feeder layer. We have reported the neurotoxic role of CXCR2, the main receptor for
the pro-inflammatory chemokine IL-8; and we have ongoing studies on the in vitro effect of
TNF-alpha, whose levels were found increased in the spinal cords of animal models of motor
neuron degeneration.
Studies on primary spinal cord or hippocampal neuronal cultures from wild type or mnd mice
are in progress in order to investigate their sensitivity to AMPA receptor agonists and
antagonists, and to evaluate the role of astrocytes obtained from mnd mice in affecting motor
neuron viability.
Finally, studies on astrocytes derived from neural stem cells of wobbler or control mice are in
progress, to evaluate the activity of glial glutamate transporters and their potential role on motor
neuron death
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Neuropharmacology (I): studies on glutamate transporters
Excessive stimulation of glutamate receptors is harmful for neurons thus the extracellular
glutamate concentration has to be maintained at physiological level by active uptake mediated
by specific transporters (Excitatory Amino Acid Transporters, EAATs) located on the plasma
membranes of neurons and glia. A research project is in progress in order to better characterize
the involvement and the role of the neuronal compartment in the general process of glutamate
homeostasis. The functional properties are evaluated using biochemical assays and the
quantitative characteristics are evaluated by western blot for specific neuronal and glial proteins
and flow cytometry analysis (in collaboration with Dr. Bernasconi, Department of Oncology,
IRFMN). These evaluations are done on purified preparations from mouse spinal cord. The
same characteristics are evaluated on two different animal models of motor neuron
degeneration, the wobbler mouse and the transgenic SOD1G93A mouse (in collaboration with
Dott. Bendotti, Department of Neuroscience, IRFMN), in order to understand the possible
involvement in neurodegenerative diseases.
Moreover, it has been suggested that reversed glutamate transport and EAAT-mediated
glutamate release in the extracellular space could represent an early event in acute ischemia.
Thus, compounds interfering with such a reversed transport by blocking EAATs might be useful
to prevent the glutamate-mediated excitotoxicity. A research project is in progress in
collaboration with Dr. Gobbi (Unit of Synaptic Transmission, IRFMN) for the pharmacological
characterization of new aspartate derivatives, synthesised by Prof. De Micheli (University of
Milano), in order to find preferential inhibitors of reversed transport and/or selective inhibitors
for neuronal transporters. Different biochemical approaches are used to test the new compounds,
allowing to differentiate them as “blockers” or ”substrates”, using synaptosomal and glial
preparations from rat brain and spinal cord and HEK 293 cell lines stably expressing
recombinant EAATs.
Neuropharmacology (II): studies on receptors
The Laboratory of Receptor Pharmacology is maintaining, since many years, collaborations
with medicinal chemistry laboratories to characterize the affinity and selectivity of newly
synthesized compounds on neurotransmitter receptors using in vitro binding methods. The
results are utilized for molecular modeling (QSAR) studies and/or for further pharmacological
evaluations. Particularly, a collaboration is ongoing with Prof. S. Grasso (University of
Messina) and Prof. C. De Micheli (University of Milan), for the development of new noncompetitive AMPA receptor antagonists.
A useful application of this technique is also the evaluation of the agonist/antagonist activity of
compounds acting on G-protein coupled receptors (GPCR), measuring their effects on 35SGTP-γ-S binding. New non-radioactive methods based on “time-resolved fluorescence” are
under characterization as functional assays to monitor GPCR activity on cell membranes.
Recently we have verified the effect of dimethyl sulfoxide, a solvent commonly utilized to
dissolve hydrophobic compound for in vitro experiments, on different in vitro assays utilizing
HEK 293 cells expressing the 5-HT6 serotonin receptors. Our results indicate that dimethyl
sulfoxide interferes with the agonist activity on 5-HT6 receptor when the scintillation proximity
assay 35S-GTP-γ-S binding is used. On the contrary, it does not interfere with europium labeled
GTP binding determined by “time-resolved fluorescence”.
In addition, the laboratory performs autoradiography binding studies in order to evaluate ex vivo
drug-receptor occupancy.
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Laboratory of Neuroimmunology
Redox regulation
The study of the so-called oxidative stress has led to the identification of biochemical events
that are modified by antioxidant molecules even in the absence of oxidative stress intended as
overproduction of toxic oxygen intermediates (free radicals). We use the term redox regulation
to define the pattern of cell functions (gene expression, activity of enzymes or transcription
factors) that are in some way modified by the redox state of the cell, defined as the ratio
between oxidizing and reducing species (usually: the oxidized glutathione / reduced glutathione
ratio). Our work focuses on the molecular mechanisms by which small changes in the redox
state can affect proteins, with particular attention to the reversible modification of cysteines to
form disulfide bonds (with proteins or with small molecular weight thiols such as glutathione).
We recently focused our attention on the identification of the redox state of proteins present on
the outside of the plama membrane since these often have key functions (e.g.: transporters,
receptors) and are the closest target of extracellular oxidants. We also apply proteomics
techniques and gene expression profiling using DNA microarrays to identify the pathways
susceptible of redox regulation.
Neuroprotection
The pathologies of the central or peripheral nervous systems studied in the lab are: cerebral
ischemia, experimental autoimmune encephalomyelitis, and diabetic neuropathy). Using animal
models and cell culture, we try to clarify the relationships between neuronal death and
inflammation, and to intervene with protective agents. Among the latter, we are studying
endogenous molecules that have shown an unexpected anti-apoptotic action on neuronal cells,
particularly erythropoietin and anti-inflammatory drugs.
Laboratory of Molecular Biology
Novel retinoids for the treatment of acute myeloid leukemia
The synthetic and natural derivatives of retinoic acid (retinoids) have shown promising activity
in the treatment of leukemia and solid cancer. Retinoids exert their therapeutic activity through
three distinct types of effects: cyto-differentiation, growth inhibition and apoptosis. The three
effects can be dissociated, albeit partially, as retinoids endowed primarily with cytodifferentiating or anti-proliferative activities are known. Recently, we identified and
characterized a novel class of retinoids with strong and selective apoptotic activity towards the
neoplastic cell. These compounds (RRMs, retinoid related molecules), which were originally
developed as selective agonists of the gamma-types of the nuclear receptors of retinoic acid
(RARy), induce apoptosis in different types of leukemia and solid cancer cells through a largely
unknown mechanism. The process of apoptosis set in motion by RRMs is different from that of
other known chemotherapeutic agents and does not require the activation of the nuclear retinoic
acid receptors. RRMs are active not only in vitro but also in vivo on a number of pre-clinical
models of acute myeloid leukemia. Currently, some of these innovative molecules are in an
advanced phase of pre-clinical development.
Novel retinoic-acid-based pharmacological combinations for the treatment
of acute leukemia
The clinical use of retinoic acid for the treatment of acute promyelocytic leukemia (APL) is
based on the ability of this compound to induce the maturation of the leukemic blast along the
normal myelocytic/granulocytic pathway. At present, the clinical use of retinoic acid for the
treatment of patients suffering from APL is the sole example of differentiation therapy.
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Differentiation therapy is worth pursuing as it is theoretically associated with a lower level of
toxicity relative to what observed following treatment with the classical cyto-toxic agents.
However, the clinical use of retinoic acid is still burdened by a number of problems including
natural and induced resistance as well as systemic and local toxicity. One of the possible ways
to increase the therapeutic index of retinoic acid is based on the identification of compounds or
drugs that potentiate the pharmacological activity of the retinoid. We have recently
demonstrated that a series of agents, such as G-CSF, interferons, cAMP analogs,
phosphodiesterase IV inhibitors and a number of other novel compounds sensitize the leukemic
blast to the pharmacological activity of retinoic acid. In the long run, it is our objective to
develop novel combinations and bring some of the above mentioned retinoic-acid-based
combinations to the clinic. In addition we intend to use some of the combinations as
pharmacological tools to dissect the intricacies of the cyto-differentiation process set in motion
by retinoic acid in the leukemic blast.
The family of molybdo-flavoproteins
Molybdo-flavoenzymes are proteins of medical and industrial interest. They are the sole
enzymes that require molybdenum, in the form of the molybdenum cofactor, for their catalytic
activity. The laboratory has a long-standing and specific interest in the biochemistry and
biology of mammalian molybdo-flavoproteins. In the past, the laboratory contributed to the
elucidation and characterization of the primary structure of the two mammalian molybdoflavoproteins, aldehyde oxidase (AOX1) and xanthine oxidoreductase (XOR). In the last few
years, the group identified and cloned the cDNAs and the genes coding for three novel mouse
molybdo-enzymes (AOH1, AOH2 and AOH3) belonging to the sub-family of molybdoflavoproteins. The long-term goal of our studies is to define the structure, the substrate
specificity, the mechanisms of catalysis as well as the physo-pathological function of the three
new proteins. We will also continue the biochemical and functional studies on mammalian
AOX1 and XOR. To achieve our aims, we have recently developed cell lines over-expressing
XOR in a tetracycline inducible fashion. In addition, we have generated knock-out mice for the
genes encoding AOH2 and AOH3.
Laboratory of Biochemistry and Protein Chemistry
Lipid metabolism and prion protein
The existence of a relationship between cholesterol levels and prion protein has been recently
suggested, although the underlying cellular and molecular mechanisms are not clear.
The inhibition of cholesterol synthesis by statins, selective inhibitors of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase activity, not only affect cholesterol but,
limiting the synthesis of mevalonate-derived molecules, increase the in vitro and in vivo
production of anti-inflammatory cytokines. Cholesterol biosynthesis and uptake is regulated by
two transcriptional factors, known as sterol regulatory element binding protein (SREBP)-1 and
SREBP-2, which promote the activation of genes encoding for key enzymes, such as HMGCoA synthethase, HMG-CoA reductase, farnesyl diphosphate synthethase and squalene
synthethase. We demonstrated that the pharmacological reduction of cellular cholesterol levels
reduces the production of prion protein.
Oxidative stress and protein aggregation in amyotrophic lateral sclerosis:
a proteomic approach
The molecular mechanisms at the basis of neurodegenerative diseases including the geneticallylinked ones, such as amyotrophic lateral sclerosis (ALS), are still unknown. However, there is
evidence that oxidative stress and protein aggregation play central roles in the pathogenesis of
such diseases. The Proteomic Unit of Dulbecco Telethon Institute, conducted proteome analysis
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of an animal model of familial ALS. In collaboration with the laboratory of Molecular
Neurobiology, we focused the attention on the analysis of protein expression changes and
protein modifications, such as tyrosine nitration and ubiquitination, 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 have revealed that there is 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 may have important consequences on the cellular
metabolism and catabolism, and therefore may be at the basis of the molecular mechanisms
leading to neurodegeneration. In addition, by mass spectrometry, we have identified the specific
nitrated tyrosines for a number of proteins. We have observed that al least enolase and
glyceraldehyde 3-phosphate dehydrogenase are nitrated at the same tyrosine site known to be
phosphorylated. This is an important finding, which is worthwhile further studying. In fact, it
may indicate a possible involvement of nitration in signaling pathways and phosphorylation
cascades. Regarding the aggregation studies, we have isolated detergent insoluble-protein
fractions from spinal cord of G93A SOD1 mice and we are now completing the comprehensive
characterization of all the proteins contained. With this study we will identify the protein
constituents of aggregates, still unknown, and therefore contribute to the comprehension of the
role of protein inclusions in ALS pathogenesis.
Studies on the conformation of prion protein and peptides deduced
thereof
Prion protein fibril formation is associated with neuronal cytotoxicity and astrogliosis observed
in prion diseases. The formation of fibril is the consequence of a conformational switch between
the structure of the native and the pathological proteins. Fibril formation is considered of pivotal
importance in the appearance and progression of prion protein diseases. Identifying the
molecular determinants responsible for the conphormational transition observed in prion
proteins is likely to give insight into the pathogenetic process leading to prion diseases. A
reductionist appraoch to the problem calls for the generation of simple experimental models in
which the dynamics of the conformational transition can be studied in detail. In our laboratory
we developed synthetic peptides that mimic the fibrillogenic properties of pathological prion
protein. With the use of various types of biochemical and biophysical techniques we studied the
conformation of these peptides through the evaluation of their secondary structure, the
resistance to protease digestion as well as the aggregating and amyloidogenic properties. Our
approach gave detailed information on the conformational plasticity of various types of prion
protein fragments.
The biochemical mechanism and the molecular determinants of prion
protein toxicity
The aim of this line of research was to understand the biochemical mechanism and the
molecular determinants underlined the cytotoxicity and the astrogliosis observed in prion
protein diseases. The study called for the use of synthetic peptides corresponding to the
fibrillogenic domains of prion proetein and appropriate cellular models. This approach aimed at
establishing a correlation between the chemico-physical properties of prion protein-derived
peptides and their biological effects. With the use of proteomics we determined the changes in
the profile of protein synthesis triggered by neurotoxic prion protein-derived peptides. The
identification of the profile of differentially expressed proteins is likely to give insight into the
processes of prion-protein-induced neurodegeneration and may give clues as to potentially
useful therapeutic targets.
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Development of a therapeutical strategy against prion-related diseases
Currently, no therapeutic options for the treatment of prion-related diseases are available. It is
likely that small organic molecules capable of interfering with the process of fibril formation
may be of therapeutic significance. In collaboration with the laboratory of the Laboratory of the
Biology of the Neurodegenerative Disorders we have identified a number of compounds
endowed with anti-fibrillogenic activity. For this type of studies we set up a simple screening
test based on the fibrillogenic properties of the two peptides PrP106-126 and PrP82-146, which
are characterized by a high level of ß-sheet conformation and the propensity to form
amyloidogenic fibrils. The most promising molecules were tested in vivo pre-clinical models of
prion protein diseases in hamsters and mice.
Laboratory of Molecular Pathology
Novel in vitro models for investigating motor neuron pathologies
Presence of mutant forms of specific proteins plays 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. Recently it was developed a new methodology (pTet-On/pTet-Off) to
control gene expression through the level of tetracyclines. We have applied the pTet-Off system
to a motor neuron-like cell line (NSC-34) establishing NSC-34 tTA cell lines for tetracyclineregulated gene expression. These lines are suitable to study the pathogenetic mechanisms of
motor neuron diseases after transient/stable transfection with genes of interest for these
pathologies.
We further used this approach to establish NSC-34 tTA cell lines that express in a doxycycline
inducible fashion the human G93A mutant Cu/Zn superoxide dismutase. Mutant forms of
superoxide dismutase 1 are responsible for some of the familial forms of amyotrophic lateral
sclerosis. This model allows to develop novel approaches to study pathologic effects of mutant
superoxide dismutase 1.
Novel intracellular targets in the selective degeneration of motor neurons
in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis is a rapidly fatal neurodegenerative disease characterized by loss
of motor neurons. The management remains essentially supportive and symptomatic.
Understanding the mechanisms underlying the disease is a way to favor more efficient
therapeutic strategies. Mitochondrial morphological alterations were observed in the early
stages of the disease in the motor nerve terminals of ALS patients and in murine experimental
models. For these reasons we addressed our studies to determine biochemical-molecular
alterations involved in the mitochondrial damage utilizing the cellular models developed in our
laboratory. In particular we have studied the toxicity of mutant forms of superoxide dismutase
1, found in some patients with familial forms of amyotrophic lateral sclerosis. Results show that
human mutant superoxide dismutase 1 altered the mitochondrial morphology selectively in
motor neurons. Furthermore it increased the susceptibility of motor neurons to inhibitors of the
electron transport chain and to oxidants. Exposure to compounds impairing ETC could thus be a
risk factor for motor neurons of individuals carrying mutant forms of superoxide dismutase 1.
Cytochrome P-450 superfamily
Cytochrome(s) P-450 have evolved into a large superfamily that varies enormously in substrate
affinity and product formation. This system 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 of Molecular
Pathology has a long-standing interest in the induction/degradation mechanisms of specific
cytochrome P-450 families due to drug administration or to disease states. Our recent research
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focused on cytochrome P-450 induction by herbal remedies such as Hypericum perforatum
extracts (St. John’s Wort), which have an alleged activity in mild to moderate depression but
interfere with the effect of several drugs.
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. However it
was recently discovered that products formed by the catalytic activity of HO - carbon monoxide
and bile pigments - are important regulating factors in the cell. Increase in 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 for the Study of Biological Systems
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 PDZ-type intracellular proteins. In the
course of these studies, we have discovered that JAM-A 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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LABORATORY OF REGULATORY
POLICIES
STAFF
Head
Vittorio BERTELE’, M.D.
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CURRICULUM VITAE
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 hemostatic 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, and member of the
Committee for Drug Price Negotiation at the Italian Ministry of Health5,6.
At present he is Head of the Regulatory Policies Laboratory at the "Mario Negri" Institute, and member
of the Technical-Scientific Committee at the Italian Drug Agency.
•
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
•
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: 14601466 (1984).
•
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
•
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
•
Garattini S, Bertele’ V. Adjusting regulatory rules to public health needs. Lancet 2001; 358: 64-67
•
Garattini S, Bertele’ V, Li Bassi L. How can research ethics committees protect patients better? BMJ 2003; 326:1199–
201
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INTRODUCTION TO THE LABORATORY 'S ACTIVITIES
Evaluation of marketing authorization applications submitted to the European regulatory agency
(EMEA) and of subsequent variations (extension of indication, line extension, safety variation,
etc).
School of assessors of drug dossiers.
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.
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.
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 scheme.
Training of assessors of drug dossiers.
Italian Drug Agency (AIFA)
Department of Health Lombardy Region
European Medicine Agency (EMEA)
World Health Organisation (Department of Essential Drugs and Medicines Policy)
Association of South East Asian Nations (ASEAN)
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Ricerca & Pratica
Dialogo sui Farmaci
European Journal of Clinical Pharmacology
Technical Scientific Committee at the Italian Drug Agency (AIFA)
Subcommittee of the Community Procedures at the Italian Drug Agency (AIFA)
European Medicine Agency (EMEA)
Italian Drug Agency (AIFA)
Joppi R, Bertele' V, Garattini S. Orphan drug development is progressing too slowly. Br J Clin Pharmacol 2006; 61:
355-360
Garattini S, Bertele' V. Le false novità della ricerca clinica. Recenti Prog Med 2006; 97: 611-617
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RESEARCH ACTIVITIES
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.
Assessment of drug dossiers for regulatory approvals
Expert support to the Rapporteurship for two new marketing authorisation applications and for
a number of Psur, post-marketing commitments and pharmaceutical 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.
Activities for the sub-committee for the European Procedures
Assessment of the dossiers for marketing authorisation applications through mutual recognition
procedures involving Italy as either Reference or Concerned Member State.
Drug Evaluation School (DESch)
DESch is a three-year training course for drug assessors. The School aims at providing
scientific, methodological, and regulatory knowledge in order to form experts in drug evaluation
able to assess marketing authorisation applications in Europe.
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LABORATORY FOR MOTHER AND
CHILD HEALTH
STAFF
Head
Maurizio BONATI, M.D.
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CURRICULUM VITAE
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).
•
Impicciatore P, Pandolfini C, Casella N, Bonati M. Reliability of public-oriented health care resources on the World
Wide Web the home management of fever in children. BMJ 1997;314: 1875-1881.
•
Cazzato T, Pandolfini C, Campi R, Bonati M, and the ACP Puglia-Basilicata Working Group. Drug prescribing in outpatient children in Southern Italy. Eur J Clin Pharmacol 2001;57:611-616.
•
Clavenna A, Pandolfini C, Bonati M. Public disclosure of clinical trials in children. Curr Ther Res 2002;63:707-716.
•
Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Ped 2005;164: 552-558.
•
Bonati M, Clavenna A. The epidemiology of psychotropic drug use in children and adolescents. International Review of
Psychiatry 2005;17:181-188.
•
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.
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INTRODUCTION TO THE LABORATORY'S ACTIVITIES
Research, as a multidimensional approach to producing knowledge, characterises the
Laboratory’s activity.
Research provides the basis for planning and carrying out the Laboratory’s activity in a critical
way and involves the participation of health professionals, social workers, mothers, children,
and parents.
Special attention is given to activities involving countries in the north and south of the world.
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.
The Drug and Health Information Centre (Centro di Informazione sul Farmaco e la Salute),
whose main activity entails promoting rational drug use during breastfeeding and in childhood,
is part of the Laboratory.
Associazione Culturale Pediatri
AIFA, Agenzia Italiana del Farmaco
Centre for Poison Control - Clinical Toxicology Unit - Ospedali Riuniti of Bergamo
Centre for Child Health
CINECA, Interuniversity Consortium, Casalecchio di Reno (Bologna)
FEDERFARMA Lombardia
Il Pensiero Scientifico ed.
ISS, Istituto Superiore di Sanità
Osservatorio Italiano Salute Globale (OISG)
University of Milan-Faculty of Political Sciences
University of Milan-Bicocca-Faculty of Medicine-Pediatric Clinic
UONPIA, Neuropsychiatry Operative Unit of Childhood and Adolescence, Hospital Foundation
of Milan
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European Union (EU)
Centro de Epidemiologia Comunitaria y Medicina Tropical (CECOMET), Ecuador Colsubsidio,
Colombia
European Network Drug Investigation Children (ENDIC)
European Society for Developmental Perinatal & Paediatric Pharmacology (ESDPPP)
Fundacio Institut Catala de Farmacologia, Barcelona, Spain
Hôpital Robert Debré, Paris, France
Hospital Pediatrico Provincial Docente Dr. Eduardo Agramonte Pina, Camaguey, Cuba
International Society of Drug Bulletins (ISDB)
The European Agency for the Evaluation of Medicinal Products (EMEA)
The University of Nottingham - Derbyshire Children's Hospital
World Health Organization (WHO)
Dr. Maurizio Bonati, head of the Laboratory, is a member of the following editorial boards:
Dialogo sui Farmaci, European Journal of Clinical Pharmacology, Paediatric & Perinatal Drug
Therapy, Pediatria (Sao Paulo), Quaderni ACP, Ricerca & Pratica, Saludarte.
Archives of Disease in Childhood, Drug Safety, Expert Opinion on Pharmacotherapy, European
Journal of Clinical Pharmacology, Major Drug Safety Information on the Internet, Pediatric
Drugs, Pediatric and Perinatal Drug Therapy, Pediatrics, Prescrire, The Italian Journal of
Pediatrics.
ADHD Scientific Committee - ISS
Technical-scientific commission for the planning and verification of vaccinations Lombardy Region
Scientific committee of the “Farmaci e Bambini” workgroup - AIFA
Technical commission for the elaboration of the regional therapeutic formulary - Valle d’Aosta
Autonomous Region
Workgroup of the Italian network for the promotion of Folic Acid - ISS
Paediatric Workgroup - AIFA
"Promozione allattamento al seno" workgroup- Lombardy Region
Paediatric Expert Group (P.E.G.)- EMEA
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PARTICIPATION IN EVENTS IN WHICH THE LABORATORY WAS
INVOLVED
February
- CÓMO INVESTIGAR IDENTIFICANDO LOS OBETIVOS PRIMARIES. QUÉ
ANALIZAN LOS RESULTADOS I LOS MÉTODOS ESTADÍSTICOS SIMPLES. Taller
International Salud Infanto Juvenil Camagüey 2006. Direción Provincial de Salud, Camagüey,
Cuba.
- IMPACT OF COMPLIANCE IN CHILDREN, THE ROLE OF PROPER INFORMATION
TO CHILDREN AND PARENTS. Evaluation of medicinal products in children - 4th course.
Eudipharm, Brussels.
March
- LA SALUTE MATERNO INFANTILE. Corso “Le Politiche Globali per la Salute”.
Osservatorio Globale per la Salute; Melegnano (MI).
- MAGGIOR RIGORE NEL MONDO DEI FARMACI. Congresso “Farmaci: tra mito e
realtà”. F.I.D.A.P.A. Sezione di Terni; Terni.
- PSICOFARMACI E MEDICINA DELL’EVIDENZA NEL BAMBINO E
NELL’ADOLESCENTE. Seminari di aggiornamento 2006 “L’Urgenza in Neuropsichiatria
dekk’Infanzia e dell’Adolescenza”. Facoltà di Medicina e Pediatria di Varese, Ospedale di
Circolo e Fondazione Macchi; Varese.
- LA SALUTE INFANTILE IN UN MONDO GLOBALE TRA PROGRAMMA E DIRITTI.
Corso di Laurea Infermieristica “La tutela della salute dei bambini disparità di risorse e diritti
negati”. AO della Valtellina e della Valchiavenna Sez. di Sondrio, Facoltà di Medicina e
Chirurgia Università degli Studi Milano-Bicocca; Faedo (SO).
- REVISIONE SISTEMICA E METANALISI. Corso: La risoluzione di scenari clinici con il
supporto della EBM come strumento di formazione continua per il pediatra. Associazione
Culturale Pediatri (ACP); Bologna.
April
- CRITERI DI VALUTAZIONE DI UNA PUBBLICAZIONE SCIENTIFICA IN GENERE ED
APPLICAZIONE AL CAMPO SPECIFICO DELLA PSICOFARMACOLOGIA. Piano
Formativo Dipartimentale 2006 “Psicofarmacologia: qualità dell’informazione della lettura
scientifica”. Azienda Ospedaliera Ospedale di Circolo di Melegnano; Vizzolo (MI).
- LETTURA CRITICA DELLA LETTERATURA SCIENTIFICA.BANCHE DATI
BIBLIOGRAFICHE - PERCORSI DI RICERCA. I DATABASE DELLE AGENZIE
INTERNAZIONALI: IL GIOCO DEGLI INDICATORI. Corso di perfezionamento in
Medicina Tropicale e Salute Internazionale. Università degli Studi di Brescia; Brescia.
May
- UTILIZZO DEGLI PSICOFARMACI IN ETÀ PEDIATRICA. Congresso. Dipartimento di
Medicina Sperimentale Sezione di Farmacologia “L. Donatelli” Centro di Farmacovigilanza e
Farmacoepidemiologia - Seconda Università degli Studi di Napoli, Facoltà di Medicina e
Chirurgia; Napoli (NA).
- L’AIDS UCCIDE L’AFRICA? Incontri: “L’Africa tra noi”. Comune di Ponteranica;
Ponteranica (BG).
- QUANDO LE EVIDENZE SCARSEGGIANO: I DISTURBI NEUROPSICHIATRICI
DELL’Età EVOLUTIVA. Corso “Introduzione alla metodologia della salute mentale basata
sulle prove. Dipartimento di Salute Mentale AO Ospedale Niguarda Ca’Granda; Milano.
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- APPROPRIATEZZA PRESCRITTIVA IN ANTIBIOTICOTERAPIA. Corso aggiornamento
PLS. ASL Milano Due, Dipartimento Cure Primarie; San Donato Milanese (MI).
- COMUNICAZIONE SANITARIA VIA INTERNET: SPECIALITA’ PER LA FIBROSI
CISTICA. IV Seminario di Primavera “Progressi Recenti e Sviluppi Futuri nella Ricerca sulla
Fibrosi Cistica”. Fondazione per la Ricerca sulla Fibrosi Cistica - onlus; Verona.
- TRATTAMENTO PEDIATRICO E RELATIVE ESIGENZE TERAPEUTICHE. Corso
“Preparazioni pediatriche allestite in farmacia: normativa e protocolli tecnici”. Società Italiana
Farmacisti Preparatori; Roma.
- REAZIONI AVVERSE IN GRAVIDANZA. REAZIONI AVVERSE IN PEDIATRIA. Master
Farmacovigilanza. SEFAP, Milano.
- GLI STUDI DIAGNOSTICI. TRA SIGNIFICATIVITA’ STATISTICA E RILEVANZA
CLINICA: I LIMITI DELLE EVIDENZE. Corso: La risoluzione di scenari clinici con il
supporto della EBM come strumento di formazione continua per il pediatra. Associazione
Culturale Pediatri (ACP); Bologna.
June
- EPIDEMIOLOGY OF PSYCHOTROPIC DRUGS IN ITALY. 10th Biannual Congress
Stockholm. European Society for Developmental Perinatal & Paediatric Pharmacology ESDPPP; Stoccolma, Svezia.
- IL TRIAL CLINICO: LETTURA E INTERPRETAZIONE. Corso di formazione e
aggiornamento “Come interpretare un trial clinico”. Associazione Italiana Informatori
Scientifici del Farmaco; Lodi.
- LA TERATOGENICITA’ DEI FARMACI ANESTETICI. 4° Congresso Nazionale. Società
Italiana di Anestesia Rianimazione Emergenza e Dolore (SIARED); Napoli.
July
- USE OF ANTIDEPRESSANT DRUGS IN CHILDHOOD AND ADOLESCENCY. Quarta
scuola estiva di Neuroscenze “I disturbi depressivi: dalla neurobiologia al trattamento
farmacologico”. Federazione delle Società Europee di Farmacologia (EPHAR), Società Italiana
di Farmacologia (SIF); Catania.
September
- 8 PASSI DI PREVENZIONE A TUTELA DELLA SALUTE DEI BAMBINI. Quaderni ACP;
camera dei Deputati, Roma
- FARMACOTERAPIA IN PEDIATRIA. XXVII Congresso Nazionale SIFO “La prevenzione
e la cura del paziente nelle politiche sanitarie regionali”. Società Italiana di farmacia
Ospedaliera (SIFO); Genova.
October
- ANTIBIOTICI. USO/ABUSO. “62° Congresso Nazionale Società Italiana di Pediatria”.
Società Italiana di Pediatria (SIP); Catania.
- RICERCA TRASLAZIONALE ED ENDPOINTS SURROGATI. 18° Congresso Nazionale
dell’ACP “Il mondo per i bambini”. Associazione Culturale Pediatri (ACP); Asolo, TV.
- LA PRESCRIZIONE DEGLI ANTIBIOTICI IN PEDIATRIA: DALL’EPIDEMIOLOGIA
ALLEEVIDENZE. Corso d’aggiornamento Pediatri “La terapia antibiotica in pediatria”.
Azienda USL Roma C, Regione Lazio; Roma.
- OSPEDALE E TERRITORIO. I NOSTRI CASI CLINICI. Congresso. Antonio Cardarelli,
Scuola Medica Ospedaliera della Campagna. Napoli.
November
- LA SALUTE INFANTILE IN UN MONDO GLOBALE TRA PROGRAMMI E DIRITTI
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NEGATI. Congresso “L’isola che non c’è. Diritti negati ai bambini e ragazzi”. Dipartimento di
Psicologia Università Cattolica del Sacro Cuore; Milano.
December
- PRODURRE FARMACI PER LE PERSONE SANE: SOGNO O REALTA’. Incontro
pubblico “A un bambino darei le ali, ma lascerei che imparasse a volar da solo”. Assessorato ai
Diritti della Persona - Comune di Malgrate; Malgrate, Lecco.
Boehringer Ingelheim
Cineca, Interuniversity Consortium
European Union
Il Pensiero Scientifico Editore
Monzino Foundation
Regione Lombardia
Regione Valle d'Aosta
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Bonati M, Breitkreutz J, Choonara I, Hoppu K, Jacqz-Aigrain E, Langhendries JP, Pons G, Rane A, Seyberth H, van
den Anker J on behalf of the ENDIC. Paediatric Clinical Pharmacology in Europe. Paed Perinat Drug Ther
2006;7:134-37.
Bonati M, Clavenna A, Rossi E, De Rosa M. Antidepressant prescriptions in children and adolescents in general
practice. BMJ.com 2006;http://bmj.bmjjournals.com/cgi/eletters/331/7530/1451#125977.
Bonati M, Maschi S, Clavenna A. Differences in generic sertraline for children: real or artifact from cost containing
to clinical quality of generics use. Eur J Clin Pharmacol 2006;62:1083-85.
Bonati M, Pandolfini C. Trial registration, the ICMJE statement, and paediatric journals. Arch Dis Child 2006;91:93.
Bonati M, Pandolfini C. Trial registration, the International Committee of Medical Journals Editors statement, and
paediatric journals. Pediatr Anesth 2006;16:92-99.
Bonati M, Pandolfini C, Rossi V, santoro E, Arnau de Bolos JM, Danes Carreras I, Fuentes Camps I, Castel Llobet
JM, Jacqz-Aigrain E, Zarrabian S, Choonara I, Sammons H, Smith C. Registering paediatric clinical trials. Paed
Perin Drug Ther 2006;7:170-171.
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.
Varona Rodriquez F, Bonati M, Reder M, Choonara I. Health care in Cuba. Lancet.com 2006;
http://www.thelancet.com/journals/lancet/article/PIIS014067360669171X/comments?page=2&prev=1&totalcommen
ts=3#645.
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Bonati M. Guida ai perchè delle scienze infermieristiche. Quaderni ACP 2006;13: 26.
Bonati M, Campi R e Gruppo di Lavoro per la Convenzione sui Diritti dell’Infanzia e dell’Adolescenza. I diritti
dell’Infanzia e dell’Adolescenza in Italia. In: II rapporto di aggiornamento sul monitoraggio della convenzione sui
diritti dell’infanzia e dell’adolescenza in Italia anno 2005-2006. Gruppo di Lavoro per la CRC c/o Save the Children
Italia, Roma. 2006;7-70.
Bonati M, Campi R. Salute e assistenza. In: I diritti dell’infanzia e dell’adolescenza in Italia. 2° rapporto di
aggiornamento sul monitoraggio della convenzione sui diritti dell’infanzia e dell’adolescenza in Italia. Anno 20052006. 2006;25-34.
Bonati M, Campi R, Labate L. La ripartizione del Fondo Sanitario Nazionale non dovrebbe anche considerare le
disuguaglianze di sviluppo tra le Regioni? R&P 2006; 22:61-64.
Bonati M, Clavenna A, Maschi S, Biasini G, Campi R, Labate L, Longoni P, Miselli M, Narducci M, Nobili A, Zanfi
D. Le inserzioni pubblicitarie pubblicate sulle riviste del medico di famiglia. R&P 2006;22:65-78.
Bonati M, Pandolfini C. Perchè gli studi clinici vanno registrati? @Partecipasalute
http://www.partecipasalute.it/partecipa/commenti-001.php:2006.
Bonati M, Zuddas A, Panei P, Masi G. Psicofarmaci e bambini. R&P 2006;22:184-188.
Centro Informazione sul Farmaco e la Salute. Bambini e Farmaci. Quaderni ACP 2006;13:226.
Cerzani M, Pasina L, Clavenna A, Nobili A, Garattini L. Uso dei nuovi farmaci antinfiammatori non steroidei in
medicina generale. R&P 2006;22:152-167.
Clavenna A. L’ospedale a portata di ... mouse. R&P 2006;22:222-223.
Clavenna A, Bonati M. Bambini e Farmaci. Quaderni ACP 2006;13:173.
Colombo C, Clavenna A. Farmaci per curare la febbre nei bambini? Meglio usarli con moderazione.
@Partecipasalute http://partecipasalute.it/rubrica-1/rubrica017.php:2006.
Gangemi M, Siani P, Bonati M. Cultura, intelligenza ed etica al XVII Congresso Nazionale dell’Associazione
Culturale Pediatri. Quaderni ACP 2006;13:18-19.
Garattini S, Bonati M. L’informazione indipendente sul farmaco: un’urgenza inderogabile. R&P 2006;22:105-107.
Gruppo di Lavoro multidisciplinare sul metilfenidato. Disturbo da Deficit di Attenzione con Iperattività (ADHD): le
tappe per un uso razionale dei farmaci. BIF 2006;5:197-203.
Jacqz-Aigrain E, Zarrabian S, Pandolfini C, Bonati M, Sammons H, Choonara I, Danés I, Fuentes I, Arnau J. DECnet, le registre européen des essais cliniques pédiatriques, est une réalité. An european clinical trial register in the
paediatric field: DEC-net. Archives de Pédiatrie 2006;13:333-335.
Jacqz-Aigrain E, Zarrabian S, Pandolfini C, Bonati M, Sammons H, Choonara I, Danes I, Fuentes I, Arnau J. Le
registre européen des essais clniques pédiatriques est une réalite. [A complete clinical trial register is already a reality
in the paediatric field]. Thérapie 2006;61:121-4.
Labate L. L’analisi della concordanza. R&P 2006;22:114-118.
Maschi S, Clavenna A, Bonati M. Sertralina in età pediatrica: un caso di (dis)equivalenza. Informazione sui Farmaci
2006;30:26-28.
Pandolfini C. ProMED-mail. R&P 2006;22:222-223.
Pandolfini C, Bonati M. Comunicazione e informazione sanitaria via internet. Come navigare fra i siti web sulla
Fibrosi Cistica. In: IV seminario di primavera. Progressi recenti e sviluppi futuri della ricerca in fibrosi cistica.
Verona, 20 maggio 2006;21-27.
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Clavenna A, Bonati M. Epidemiological aspects of drug use in children. In: Textbook on Paediatric Pharmacology.
Jacqz-Aigrain E, Choonara I eds. Taylor & Francis Group, New York 2006;73-83.
Pandolfini C, Bonati M. A register of clinical trials in children. In: Textbook on Paediatric Pharmacology. JacqzAigrain E, Choonara I eds. Taylor & Francis Group, New York. 2006;63-72.
Bonati M. The Italian saga of ADHD and its treatment. In: Lloyd G,Cohen D, Stead J, eds. International Critical
Perspective on ADHD. Routledge, Abingdon, Oxon (UK) 2006;128-136.
Bonati M, Campi R. La salute materno infantile. In: A caro prezzo. Le diseguaglianze nella salute. 2° Rapporto
dell’Ossevatorio Italiano sulla Salute Globale. Edizioni ETS, Sesto Fiorentino (FI) 2006;71-84.
Bonati M, Clavenna A. Malattie rare, farmaci orfani, ricerca clinica in pediatria. In: Dermatologia basata sulle prove
di efficacia. ed Masson, Milano 2006;376-381.
Bonati M, Clavenna A, Rossi E, De Rosa M. Nuovi farmaci e loro utilizzo con piccoli pazienti. Scheda 24. In: 7°
Rapporto Nazionale sulla Condizione dell’Infanzia e dell’Adolescenza. Eurispess e Telefono Azzurro, Roma
2006;369-377.
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RESEARCH ACTIVITIES
Briantea Paediatric Surveillance Unit
The Laboratory for Mother and Child Health is co-ordinator of the Briantea Paediatric
Surveillance Unit group, in which paediatric wards from 7 different hospitals in the Lombardy
region participate. The aim of the group is to monitor paediatric hospital admissions and the
health care and services offered to patients with any of 15 diseases chosen for their relatively
low incidence/prevalence but their importance for public health and clinical research.
During 2006, a total of 87 children were reported to have: 31 cases of Schonlein-Henoch
purpura, 9 of idiopathic thrombocytopenic purpura, 7 of bacterial meningitis, and 7 of
complications caused by chicken pox.
DEC-net: the European register of paediatric clinical trials
The DEC-net register, a project which began in 2003, was the basis of a three-year feasibility
project funded by the European Community, under its Fifth Framework Programme, and has
been completed.
DEC-net was created at the ideal moment, when the registration of clinical trials was becoming
increasingly recognised as a priority in the scientific and lay communities, and was being
followed closely by the media. During the project’s three years, several, large initiatives with
the same final goal of transparency of information were set up or implemented. Given the power
and/or legal backing of a few of these developments, such as the International Committee of
Medical Journal Editors’ (ICMJE) initiative and the consequent empowerment of a single,
existing register, or the World Health Organization’s register platform project, DEC-net’s
potential has been surpassed.
DEC-net remains the only paediatric-oriented register of clinical trials (although this aspect
caused it to be left out of the more powerful initiatives) and, with its multilingual characteristic,
it could be considered more user-friendly for the general public than most international registers
that only provide (often limited) information in English.
We are satisfied with the project’s success and are reluctant to conclude such an
accomplishment, however, we are also glad for the ongoing, powerful, worldwide movement
towards trial registration and openness of information to the public and the scientific
community, to which we feel DEC-net may also have contributed. We are also confident that all
the developments brought about in the last few years will lead to improved scientific testing and
interpretation of its results, especially for children.
The DEC-net register will remain online and accessible to the public for a few more months, but
the information will not be updated.
We wish to thank all those who helped create the DEC-net register and who helped build it up
by contributing trial data.
National ADHD register
The marketing authorisation for methylphenidate and atomoxetine in Italy makes monitoring the
use of this drug in children with attention deficit hyperactivity disorder (ADHD) necessary in
order to assure the safety of its use. In order to meet this need, a national registry co-ordinated
by the Istituto Superiore di Sanità was set up. The registry’s aims are to monitor the use of
methylphenidate and atomoxetine, evaluate the safety and compliance of therapies with
methylphenidate and atomoxetine, alone or in combination with other therapeutic interventions
(pharmacological or not) in the medium and long term, identify the probability of having
ADHD in the school-age population, define the optimal management strategy for ADHD
through the standardisation of the most appropriate diagnostic and therapeutic strategies,
evaluate the effectiveness of psychotropic drugs and/or behavioural therapy in the evolution of
ADHD in school-aged children, and calculate the long term risk of persistence of the disorder,
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of being left behind in school, and of the development of psychosis or other psychiatric
disorders.
The first evaluation of the outcomes will be made after 24 months of the register’s activation.
ARNO paediatric project
The ARNO Observatory (http://osservatorioarno.cineca.org) was set up in 1986, following the
experience acquired at the CINECA (Consorzio Interuniversitario di Bologna; www.cineca.it)
through the collaboration with the drug services of the local health units that are part of the
ARGO system for the online monitoring of the drug prescription data. The Observatory is a
multicentre system that is distributed throughout the territory and that uses an epidemiologic
approach focused on the populations and its problems. The ARNO Paediatric Project, active
since 1998 and in collaboration with the “Mario Negri” Pharmacological Research Institute in
Milan, evaluates drug prescriptions in paediatric primary care.
The ARNO Paediatric Project (but, more generally, the entire ARGO-ARNO database), follows
one and a half million children aged less than 18 years (15% of the Italian population of the
same age group), one third of whom have been followed for the past 6 years. These children
make the project and efficient tool for evaluating outcomes (the health of children and their
parents), which are made available both to health care workers who guarantee clinical assistance
in primary health care and to those working towards the planning and organisation of health
care services and policies. The project represents a unique tool at the national level and a rare
one at the international level.
An evaluation of the psychotropic drug prescribing profile was carried out in addition to the
analysis of the data collected by the ARNO Observatory during 2005. During this period,
psychotropic drugs (antidepressants and/or antipsychotics) were prescribed to 2 per thousand)
children and adolescents. Antidepressants were prescribed to 1.7‰ of the children and
antipsychotics to 0.4‰.
Four percent of the children and adolescents treated with psychotropic drugs were given both
antidepressants and antipsychotics.
Antidepressants were prescribed mostly to females (M/F=0.7), while the prevalence of
antipsychotics was higher in males (M/F=2). The prevalence increased with age, reaching a
maximum among the adolescents: 7 females in 1000 between 14 and 17 years old received at
least one psychotropic drug prescription.
SSRIs were the most common antidepressant drug class and were prescribed to 79% of patients
treated with drugs from this class; 14% received tricyclics and 12% atypical antidepressants.
Five percent received antidepressants belonging to two different classes.
A total of 16 antidepressants and 20 antipsychotics was prescribed. Sertraline was the most
prescribed antidepressants (0.6‰) ,followed by paroxetine (0.3‰) and citalopram (0,2‰),
while, among the antipsychotics the most prescribed were risperidone (0,2‰) and olanzapine
(0,1‰).
The psychotropic drug prescription prevalence increased in the 1998-2005 period, reaching a
maximum in 2002 (2.8‰). The overall antidepressant drug prevalence pattern is similar to that
of all psychotropic drugs, while the prevalence of antipsychotics did not vary over time.
The increase in antidepressant prescriptions is mostly due to SSRIs, whose prevalence increased
by 4,5 times between 2000 and 2002.
Ricerca & Pratica
Ricerca & Pratica was born in January, 1985, as a manifestation of the “Mario Negri” Institute
for Pharmacological Research. Today, the journal is enhanced by the collaboration of the most
advanced clinical research groups in Italy and by national, independent journals belonging to the
International Society of Drug Bulletins (ISDB).
How should a clinical study be interpreted?
How can the difference between real and false news in the drug market be distinguished?
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How can the quality of health interventions be determined?
R&P has helped readers respond to such questions for more than twenty years by addressing
issues that are fundamental to research and practice in an in-depth manner.
These issues involve clinical epidemiology, medical statistics, clinical pharmacokinetics, drug
interactions, and drug-related economic and epidemiological investigations.
The journal is appreciated for its independence, as well as that of its authors, and for its
presence as an arena for all those professionals that 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.
R&P aims to continue in this direction, dedicating space to paediatrics and to issues related to
public health as well, also at the European level.
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.
Health and Drug Information Centre
The Health and Drug Information Centre, initially created to promote the policy on hospital
drug formularies, progressively expanded to cover out-of-hospital practice and to involve
different types of users, including professionals and members of the public.
The core of the CIFS’s activities is the daily telephone service providing information and advice
on drug therapy and needs during breastfeeding and in childhood. In January 2004, the centre’s
activity concerning drug information in pregnancy was taken over by Bergamo’s Clinical
Toxicology Unit’s Poison Control Centre (Centro Antiveleni, Unità di Tossicologia Clinica,
Ospedali Riuniti di Bergamo). Together, the Poison Control Centre and the Laboratory of
Mother and Child Health form the Department of Clinical Pharmacy and Pharmacology.
All queries, and their replies, are inputted into a database in order to monitor the centre’s
activity with respect to both pharmacoepidemiological analysis and follow-ups performed.
During 2006, 948 people contacted the Health and Drug Information Centre with a total of 1589
questions. In all, 74% were from women who were directly involved, 14% from
general/hospital paediatricians, 7% from general practitioners or other non-paediatric
specialists, and 5% from other health care workers. A total of 1309 requests for information
concerned drug use, 280 the use of parapharmaceuticals, general information, and diagnostic
exams. In all, 95% of the questions received by the centre concerned the safety of drugs during
breastfeeding, while 5% concerned the administration of drugs to children. Although people
called from all of Italy, most called from the north of the country (68%), especially from the
Milan (403) and Brescia provinces (45). 18% of the requests were received from central Italy
and 13% from the south.
Technical commission for the elaboration of the regional therapeutic
formulary
The Valle d’Aosta Autonomous Region set up an agreement with the “Mario Negri”
Pharmacological Research Institute, assigning the Laboratory for Mother and Child Health, as
temporary representative of the “Mario Negri” Institute, the periodic task of providing technical
advice on the fulfilment of the following activities: updating and revision of the regional
therapeutic formulary (PTR), predisposing opinions on trial protocols on pharmaceutical drug
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products and other therapeutic remedies, creating documentation material concerning the topics
on which the collaboration is based.
Vaccine commission
The Laboratory for Mother and Child Health is part of the Technical Consultation Commission
in order to guide the activities concerning vaccine prophylaxis. The group is called the
“Technical-scientific commission for the planning and verification of vaccinations”, based on its
assigned tasks.
The main goals are: the elaboration of vaccine strategies, based on epidemiologic profiles,
evaluation of the ongoing interventions, in terms of protective efficacy and unwanted effects,
promotion of the qualitative improvement of vaccine management difficulties, including the
vaccine registry.
During 2006, the commission created a document entitled “Form for the evaluation of vaccine
interventions - heptavalent antipneumococcal vaccine” and addressed the preparation of the
antipneumococcal vaccine.
Workgroup on the “Convention for child and adolescent rights”
The Laboratory for Mother and Child Health is part of the Workgroup on the “Convention for
child and adolescent rights (CRC) in Italy.
The group was set up in December 2000 with the main goal to prepare a report on the state of
children in Italy that would act as a supplementary (not an alternative) report to that presented
by the Italian government, to be submitted to the United Nations Committee on child and
adolescent rights. The first report was presented in Rome in 2001 and underwritten by 42
associations and non-governmental organisations.
While carrying out the monitoring activity, the workgroup decided to set up an annual, updated
report on the status of children and adolescents in Italy and on the related United Nations
Committee’s recommendations, which focuses on priority issues.
The report is not only intended to criticise our health system’s faults, but also to be an
opportunity to prompt a timely and constructive debate among the institutions responsible for
the state of children and adolescents in Italy, and, therefore, for the implementation of the rights
guaranteed by the convention.
In the 2006 update report, the second one created by the group, the issues already addressed in
the first report concerning the overall action measures (Chapter I) and the special measures for
the protection of vulnerable groups (Chapter IV), are taken up again and updated, enriching the
analysis with additional contributions and more detailed observations. Two new chapters have
been added, concerning health and care (Chapter II), education, and recreational and cultural
activities (Chapter III).
All this is carried out with the hope that it will stimulate, and contribute to, the development of
standard procedures and legislative reforms that will bring about a tangible improvement in the
condition of all youths in Italy.
Co-operation with countries with limited resources
Regulatory activity. As part of widespread initiative led by the World Health Organization,
aimed at promoting a more rational use of drugs, the Laboratory organised a formal
international course in several countries on the strategies for evaluating the available evidence
for use during the drug registration process. This activity was aimed at national regulatory
agencies and involved the setting up of formal, international, pharmaco-epidemiologic research
projects.
In this context, the laboratory hosted health care workers from Brazil and the Balkans for brief
training periods in 2006.
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Decrease in the high maternal mortality in the town of Tinguipaya, Department of Potosì:
The program began in 2005 with a contribution by the Lombardy Region and will last 2 years.
The programme’s aims are to improve the health of women during pregnancy and of young
mothers by facilitating access to health centres through initiatives aimed at integrating the
official health system with the traditional and community health systems. The Laboratory for
Mother and Child Health is the scientific and working partner for the project in Italy.
Taller Internacional Salud Infanto Juvenil Camagüey 2006:
In February, in Camaguey, the first international course on child health was held in Cuba. The
Laboratory participated in its implementation and participated in the course, along with 20
delegates plus several speakers.
The course’s aims were to inform participants of Cuba’s health system concerning paediatric
care and to encourage and support local physicians in their research and in publishing its results.
Ecuador: The Laboratory for Mother and Child Health, as epidemiologic scientific advisor and
organisational partner, has participated since 2005 in the project entitled “Project for the
reduction of maternal and perinatal mortality in the S.Lorenzo District -Esmeraldas-Ecuador
Region”. The project is co-ordinated by the Bussolengo’s (VR) local health unit as part of its
work in carrying out decentralised cooperation interventions for international development and
solidarity.
The Laboratory has two other projects in Ecuador, in collaboration with Cecomet (Centro de
Epidemiologia comunitaria y Medicina tropical) in Bourbon’s health district, situated north of
the Esmeraldas province, Ecuador’s rural area. The names of the projects are “Improving
vaccine coverage along the Santiago and Cayapas rivers” and “Reducing child mortality through
the supplementation of vitamins and nutritional elements”.
Colombia: Prize was initiated in Colombia in 1992 with the aim to develop and promote
paediatric research. The prize, which has social and community connotations, is aimed at health
care workers in Central and South America and was designed to form a network though which
knowledge,analysis, study, and equity involving child health can be exchanged.
This network joins ethical solidarity with social and professional responsibility. The prize is set
up by Colsubsidio (Caja Colombiana Subsidio Familiar), a private, mutual society with more
than 500.000 members.
Colsubsidio is a non-profit organisation that has been working in the social, health, and
economic areas in different sectors of society since 1957 and is known for its high quality,
professional work. Over 90 projects from 10 countries were submitted for the 2004 edition. The
projects represented over 200 authors and were evaluated by an international jury (Maurizio
Bonati, Italy; Celia Beatriz Gianotti, Brazil; Raúl Mercer, Argentina; Sergio Riestra, Mexico;
Gloria Arias e Mauricio Palau, Colombia).
The abstracts and integrated texts of the projects that received an award are published on the
SaludArte journal.
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LABORATORY OF GENERAL
EPIDEMIOLOGY
STAFF
Head
Carlo LA VECCHIA, M.D.
Cancer Epidemiology Unit
Head
Cristina BOSETTI, Mat.Sci.D.
Chronic Disease Epidemiology Unit
Head
Alessandra TAVANI, Biol.Sci.D.
Epidemiological Methodology Unit
Head
Eva NEGRI, Mat.Sci.D.
Lifestyle Habits and Prevention Unit
Head
Liliane CHATENOUD, Biol.Sci.D.
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CURRICULA VITAE
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 Laboratory 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 and
Adjunct Professor of Medicine, School of Medicine, Vanderbilt University, Nashville, TN.
Dr. La Vecchia is an Honorary Senior Lecturer in Oral Medicine at the Eastman Dental Institute at the
University College of London, 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 Adjunct
Associate Professor of Epidemiology at the Harvard School of Public Health between 1996 and 2001. He
is Associate Editor to: European J. of Cancer Prevention and presently serves on the editorial boards of
the: American J. of Epidemiology, Asian Pacific J. of Cancer Prevention, Cancer Causes and Control,
Current Cancer Therapy Reviews, Digestive and Liver Disease, Economia Politica del Farmaco,
European J. of Cancer, European J. of Cancer Prevention, European J. of Clinical Nutrition, European J.
of Nutrition, Scope Oncology & Hematology, Int. J. Cancer, J. of Nephrology, Nutrition and Cancer,
Oncology, Oral Oncology, Revisiones en Ginecología y Obstetricia, Revista Española de Nutrición
Comunitaria, Revue d'Epidémiologie et de Santé Publique, Sozial und Praeventivmedizin, The Lancet
(Italian edition), Tumori, Alimentazione e Prevenzione. In 1993, he received the Glaxo Prize for medical
publication.
He has authored or co-authored over 1,300 publications in peer reviewed journals, with over 21,000
quotations.
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: Since Sept. 2005: Unit Head, Unit of Cancer Epidemiology, Laboratory
Epidemiology; 1998-2005: Researcher at the Laboratory of Epidemiology; 1996-1997: Researcher at the
Laboratory of Mother and Child Health.
•
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.
•
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.
•
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.
•
Bosetti C, Negri E, Kolonel L, Ron E, Franceschi S, Preston-Martin S, et al. A pooled analysis of case-control studies of
thyroid cancer. VII. Cruciferous and other vegetables (International). Cancer Causes Control 2002; 13: 765-775.
•
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.
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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 100 publications on these topics, 1993-2005).
Work experiences: Since Sept. 2005: Unit Head, “Lifestyle and Prevention”, Laboratory of
Epidemiology. 1993-2005: Researcher at the Laboratory of Epidemiology; 1988-1990: Staff Statistician
Bracco S.p.A., Milan.
•
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.
•
Chatenoud L, Tavani A, La Vecchia C, Jacobs D R, Negri E, Levi F, Franceschi S. Whole grain food intake and cancer
risk. Int J Cancer 1998; 77: 24-28.
•
Chatenoud L, Parazzini F, Di Cintio E, Zanconato G, Benzi G, Bortolus R, La Vecchia C. Paternal and maternal smoking
habits before conception and during the first trimester: Relation to spontaneous abortion. Ann Epidemiol 1998; 8: 520526.
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 1992: 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.
•
Negri E, La Vecchia C, Pelucchi C, Tavani A The risk of acute myocardial infarction after stopping drinking Prev Med
2005; 40: 725-728
•
Negri E, Pelucchi C, Talamini R, Montella M, Gallus S, Bosetti C, Franceschi S, La Vecchia C Family history of cancer
and the risk of prostate cancer and benign prostatic hyperplasia Int J Cancer 2005; 114: 648-652
•
Negri E, Little D, Boiocchi M, La Vecchia C, Franceschi S. B-cell non-Hodgkin's lymphoma and hepatitis C virus
infection: A systematic review Int J Cancer 2004; 111: 1-8
•
Negri E, Ron E, Franceschi S, La Vecchia C, Preston-Martin S, Kolonel L, et al. Risk factors for medullary thyroid
carcinoma: A pooled analysis Cancer Causes Control 2002; 13: 365-372
•
Levi F, La Vecchia C, Boyle P, Lucchini F, Negri E Western and eastern European trends in testicular cancer mortality
Lancet 2001; 357: 1853-1854
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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: Head of the Unit of Epidemiology of Chronic Diseases of the Laboratory 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.
•
Tavani A, Negri E, Franceschi S, Talamini R, Serraino D, La Vecchia C. Hair dye use and risk of lymphoid neoplasms
and soft tissue sarcomas. Int J Cancer 2005; 113: 629-631
•
Tavani A, Bravi F, Bosetti C, Franceschi S, Levi F, Talamini R, La Vecchia C. Diabetes mellitus and subsite-specific
colorectal cancer risks in the Iowa Women's Health Study. Cancer Epidemiol Biomarkers Prev 2005; 14: 2277
•
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
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The Laboratory 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 the incidence and mortality from lung and other tobacco-related neoplasms. The
analytic epidemiology activities include the conduction and analysis of case-control studies,
aimed at identifying and better quantifying the association between genetic factors (family
history), selected lifestyle habits (diet, tobacco, alcohol, etc.), use of exogenous hormones and
exposure to various substances and the development of various forms of cancers and
cardiovascular diseases. In particular, the laboratory 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 thyroid, breast, ovary, and cervix;
epidemiological and clinical studies in dermatology; the analysis of historical cohort studies of
occupational exposures to aromatic amines, asbestos, herbicides and other known carcinogens;
monitoring and prevention of injuries.
We observed a reduction in risk of colorectal cancer with increasing levels of intake of
isoflavones, anthocyanidins, flavones and flavonols. No meaningful association was found with
other flavonoids, including flavanones, flavan-3-oils, and total flavonoids.
Fried foods do not play an important role on the risk of colorectal cancer in the Italian
population, and that use of (fried) olive oil could reduce the risk of colon cancer.
Consumption of skim milk was inversely associated with colon, rectal, breast and ovarian
cancer. On the other hand, consumption of whole milk increased the risk of rectal (RR=1.22),
breast and ovarian cancers.
Use of artificial sweeteners was not significantly associated with risk of any of the neoplasms
considered, except for the inverse relations between use of saccharin and risk of ovarian cancer
and between use of other sweeteners (mainly aspartame) and risk of breast cancer.
Onion and garlic use is a favorable correlate of cancer risk in our population, with significantly
reduced relative risk for cancers of the colorectum, upper aero-digestive tract and ovary,.
Wine is the alcoholic beverage more frequently consumed and more strongly associated with
laryngeal cancer in this Italian population.
A possible relation between hypercholesterolaemia and prostate cancer has been suggested.
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IRFMN
No increase in the risk of prostate cancer was found in childless men.
An inverse association between history of benign ovarian cysts and risk of breast cancer was
found.
In a case-control study on oesophageal cancer, we observed an inverse association with
consumption of flavanones, a subgroup of flavonoids.
In a study on laryngeal cancer, we found a consistent relation between leanness and risk of
laryngeal neoplasm. In particular, the risk was more than 4-fold elevated in men at the lowest
levels of abdominal fat.
In a quantitative review of the scientific literature, aspirin use was inversely related with cancers
of the colorectum, esophagus, stomach, breast, ovary and lung, while a direct association
emerged with kidney cancer.
In a systematica review of 28 cohort and 15 case-control studies on the relation between
occupational exposure to crystalline silica and risk of lung cancer, we estimated overall relative
risk of lung cancer of 1.34 from cohort studies and 1.41 from case-control studies that
considered occupational silica exposure, with a stronger association in subjects with silicosis.
In the Italian population, dietary intake of iron, anthocyanidins, α-carotene, β-carotene and βcriptoxanthin reduced the risk of myocardial infarction, while no association with the disease
emerged for other flavonoids (isoflavones, flavanones and flavones), total carotenoids,
lycopene, lutein plus zeaxanthin and retinol.
In spite of recent declines, the wide variability in the mortality rates from laryngeal cancer
indicate that there is still ample scope for prevention in Europe.
The drop in smoking prevalence and consumption may be due, particularly for younger
generations, to the comprehensive smoke-free legislation adopted in Italy.
The point prevalence of Actinic Keratoses in the Italian population is 1.4%. It is higher in men
(1.6%) than women (1.4%) and steadily increase with age.
In a study of cutaneous basal-cell carcinoma, the role of (intermittent) sun exposure and
phenotypic characteristics on cutaneous basal-cell carcinoma was confirmed, and etiological
differences between nodular and superficial histotypes and between head/neck and truncal
locations were suggested.
Overweigh and obesity increase the risk of cutaneous malignant melanoma, accounting for
about 30% of the cases of melanoma in our Italian population.
No meaningful association between cutaneous malignant melanoma at a specific anatomical site
and number of nevi at the same site was found.
ANNUAL REPORT
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IRFMN
Centro Cardiologico Monzino, IRCCS, Milano
Centro di Riferimento Oncologico, Servizio di Epidemiologia, Aviano (PN)
Chiron Vaccines SpA, Siena
Gruppo Italiano Studi Epidemiologici in Dermatologia GISED, Bergamo
International Centre for Pesticides and Health Risk Prevention, Busto Garolfo, Milano
Istituto Auxologico Italiano, Divisione Malattie Metaboliche III, IRCCS, Piancavallo (VB)
Istituto Auxologico Italiano, Laboratorio Sperimentale di Ricerche Endocrinologiche (LSRE),
IRCCS, Milano
Istituto di Fisiologia Clinica CNR, Sezione di Milano, Milano
Istituto di Medicina del Lavoro, CTO, Torino
Istituto Europeo di Oncologia, Divisione di Epidemiologia e Biostatistica, Milano
Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione (INRAN), Roma
Istituto Nazionale Neurologico "Carlo Besta", Milano
Istituto Nazionale per la Ricerca sul Cancro, Genova
Istituto Nazionale per lo Studio e la Cura dei Tumori, Oncologia Sperimentale, Unità di Eredità
Poligenica, Milano
Istituto Tumori “Fondazione Pascale”, Servizio di Epidemiologia, Napoli
Ospedale Niguarda, Dipartimento Cardiologico “A. De Gasperis”, Milano
Prima Clinica Ostetrico Ginecologica, Mangiagalli, Milano
Università degli Studi di Milano - Bicocca, Dipartimento di Statistica, Milano
Università degli Studi di Milano, 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, Milano
Università di Milano, Prima Clinica Ostetrico Ginecologica, Milano
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.
Centre for Research in Environmental Epidemiology (CREAL) and Municipal Institute of
Medical Research (IMIM), Barcelona, Spain
Harvard School of Public Health, Department of Epidemiology, Boston, USA
Hôpital Necker - Enfants Malades, Centre of the Association Claude Bernard on Auto-immunes
diseases, Paris, France
International Agency for Research on Cancer, Lyon, France
International Epidemiology Institute, Rockville, USA
International Life Science Institute (ILSI), Bruxelles, Belgium
MRC Biostatistics Unit, Cambridge, UK
National Cancer Institute, Environmental Studies Section, Bethesda, USA
National Cancer Institute, Radiation Epidemiology Branch, Bethesda, USA
National Institute of Public Health and the Environment, Laboratory for Pathology and
Immunobiology, Bilthoven, The Netherlands
Environ, Amherst, MA, USA
National School of Public Health, WHO, Athens, Greece
National University of Ireland, Department of Psychology, Galway, Ireland
ANNUAL REPORT
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2006
IRFMN
Center of Oncology, Dept. of Epidemiology and Cancer Prevention, Warsaw, Poland
Registre Vaudois des Tumeurs, Institut Universitaire de Médecine Sociale et Préventive,
Lausanne, Switzerland
Universitat Pompeu Fabra, Department of Experimental and Health Sciences, Barcelona, Spain.
University of Athens Medical School, Department of Hygiene and Epidemiology, Athens,
Greece
University of Kuopio, Department of Pharmacology and Toxicology, Kuopio, Finland.
University of Maastricht (UNIMAAS), Department of Epidemiology, Maastricht, The
Netherlands
University of Toronto and the Clinical Nutrition and Risk Factor Modification Centre, Toronto,
Canada
University of Las Palmas de Gran Canaria, Department of Clinical Sciences, Las Palmas de
Gran Canaria, Spain.
Department of Nutritional Sciences, Faculty of Medicine, St Michael’s Hospital, Toronto,
Canada
Vanderbilt University, Department of Medicine, School of Medicine, Nashville, USA
Advances in Therapy (Eva Negri)
Alimentazione e Prevenzione (Carlo La Vecchia)
Asian Pacific Journal of Cancer Prevention (Carlo La Vecchia)
Digestive and Liver Disease (Carlo La Vecchia)
European Journal of Cancer (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)
International Journal of Cancer (Carlo La Vecchia)
Italian Journal of Obstetrics and Gynecology (Fabio Parazzini)
Journal of Nephrology (Carlo La Vecchia)
Nutrition and Cancer (Carlo La Vecchia)
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)
Sozial und Praeventivmedizin (Carlo La Vecchia)
The Lancet, italian edition (Carlo La Vecchia)
Tumori (Carlo La Vecchia)
Acta Psychiatrica Scandinavica, American Journal of Epidemiology, British Journal of Cancer,
British Medical Journal, Canadian Journal of Physiology and Pharmacology, Cancer, Cancer
Causes and Control, Cancer Epidemiology Biomarkers and Prevention, Digestive Liver Disease,
Epidemiology, Epidemiology & Biostatistic, European Journal of Cancer, European Journal of
Cancer Prevention, European Journal of Clinical Nutrition, European Journal of Epidemiology,
European Journal of Public Health, Gynecological Endocrinology, Hepatology, Human
Reproduction, International Journal of Cancer, International Journal of Epidemiology,
ANNUAL REPORT
194
2006
IRFMN
International Journal of Obesity, JAMA, Journal of Clinical Endocrinology and Metabolism,
Journal of Epidemiology and Community Health, Journal of the National Cancer Institute,
Maturitas, Nutrition and Cancer, Obstetric and Gynecology, Oncology, Preventive Medicine,
Radiation Research, Revue d’Epidèmiologie et de Santé Publique, The Breast, The Cancer
Journal, The Lancet, 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
Consiglio Superiore di Sanità, Gruppo di lavoro sul Metodo Di Bella
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”
IARC/OMS di Lione e OMS di Geneva
Istituti Clinici di Perfezionamento, Milano
Progetto Menopausa Italia, Associazione Ostetrici Ginecologi Italiani
Scientific Review Committee del UND/WHO/World Bank Human Reproduction Program
Società Italiana della Riproduzione
Ministero della Sanità, Sottocomitato fumo.
EVENT ORGANIZATION
Convegno su: "Caffè e patologie digerenti". 18 November 2006, Massafra (TA)
ANNUAL REPORT
195
2006
IRFMN
INVOLVED
Workshop. “Epidemiology of long-term air pollution effects”. Bilthoven, The Netherlands 1920 January 2006.
IARC retreat. “Liver cancer, prostate cancer, bio-repositories”. St. Jean d’Ardieres 15 February
2006.
2° Workshop Nazionale. Utilizzo degli archivi elettronici per scopi epidemiologici. “Studio di
coorte basato sul record linkage tra il database di una rete di studi epidemiologici e banche dati
automatizzate”. Milano 21 February 2006.
IARC Handbookds, Tabacco Unit. Reversal of risk after quitting smoking. “Status of the
evaluation of evidence for changes in cancer risk following cessation. Chairman epidemiology
group. Lione 9-20 March 2006.
1° Corso Metodologia della ricerca clinica nell’infezione da HIV. “Analisi statistica degli studi
clinici” Milano 9-10 March 2006.
Cancer Research in the 7th Framework Programme. “Clinical Cancer Research”. Brussels,
Belgio 10 March 2006.
Conferenza: Prevenzione del cancro. S Colombano al Lambro, 10 March 2006.
Gli incontri della verità 5. La Terapia delle Malattie Epatiche. “Caffè, cirrosi epatica ed
epatocarcinoma. Roma, 16-17 March 2006.
SIR. IX Week-end clinico. Contraccezione: rilevanti aspetti clinici, recenti acquisizioni e nuovi
comportamenti. “Pillola e neoplasie”. Roma 23-24 March 2006.
IARC. Fellowship selection committee 2006. Lione. 27-28 March 2006.
12° Congresso Nazionale delle Malattie Digestive. “Dieta mediterranea e rischio in oncologia
digestiva”. Napoli 4 April 2006.
ILSI Europe. “Expert group on obesity related parameters database”. Brussels, Belgio 5 April
2006.
International Symposium on Cancer Prevention & early detection. “The changing cancer
epidemiology in countries undergoing industrialisation, affluence & westernisation”. Beijing,
China, 21-24 April 2006.
41st Annual Meeting of the European Association for the study of the liver. “Female hormones
and benign liver tumors: lessons from epidemiology”. Vienna, Austria 26-30 April 2006.
9th Congress of the European Society of Contraception. “Coronary heart and cardiovascular
disease”. Istanbul, Turkey 3-6 May 2006.
7th Meeting of Participants. European Cancer Mortality Atlas. IARC. Lione, France 10-11 May
2006.
Meeting ISA. Aspartame roundtable. “Artificial sweeteners and cancer risk in a network of
case-control studies”. Parigi, France 30 May 2006.
81° Congresso Nazionale Sidemast. “E’ possibile ridurre le ustioni solari nei bambini? Il
progetto “SoleSi SoleNo-GISED”. Torino 31 May 2006.
Giornata mondiale senza tabacco. VIII Convegno Nazionale Tabagismo e servizio sanitario
nazionale. “I rischi del fumo e i benefici della cessazione”. Roma 31 May 2006.
EMAS. 7th European Congress on Menopause. “Hormone replacement therapy and colorectal
cancer”. Istabul, Turchia 3-7 June 2006.
Working meeting of principal co-investigators on further implementation on the project
“Closing the gap”. “Alcohol and cardiovascular diseases”. Varsavia, Poland 19-20 June 2006.
45° Congresso Nazionale ADOI. “Fattori di rischio modificabili della psoriasi. Una possibile
prevenzione?” Loreto, Recanati 13-16 September 2006.
36th Annual European Society for Dermatological Research Meeting. “Improving sun
protection behaviour in children: results of a cluster-randomized trial in Italian elementary
schools. The “SoleSi-SoleNo GISED” project.” Paris, France 7-9 September 2006.
ANNUAL REPORT
196
2006
IRFMN
XXI Meeting annuale. La dermatologia in un moderno sistema sanitario. “Sorveglianza caso
controllo dei tumori cutanei in dermatologia: esperienza degli ultimi 10 anni”. “Un nuovo
programma di ricerca: Il progetto “SoleSi SoleNo Coorte”.”The EDEN International study on
the prevalence of contact allergy to fragrances”. Taranto 29-30 September 2006.
Conferenza LILT. Un treno a vapore contro i tumori. Mantova 16 September 2006.
ILSI Joint meeting. Weight management in public health task force/export group on obesity
related parameters. Brussels, Belgium. 19 September 2006.
I Word Congress of Public Health Nutrition. “Crossfire: relationship between obesity and
mortality risk. Do we know the cut-off points?” “Traditional Mediterranean diet and cancer:
Open issue”. Barcelona, Spain. 28-30 September 2006.
Conferenza. Abitudini alimentari e malattie correlate – suggerimenti e possibili rimedi. “Dieta
mediterranea e tumori”. Istituto Italiano di Cultura. Budapest, Hungary. 2 October 2006.
48° Congresso Nazionale Società Italiana di Cancerologia. “Coffee and Cancer”. Bari. 1-4
October 2006.
I° Forum Meridiano Sanità. Quale Agenda per l’Italia. Studio Ambrosetti. Cernobbio, Como. 5
October 2006
International Training centre of the ILO. Postgraduate course on Occupational Health and
Safety in the Workplace. “Epidemiology: fundamentals”. Torino 10 October 2006.
Fondazione Policlinico di Monza. Corso. Fattori di rischio e diagnosi precoce del cancro colorettale. “La dimensione del problema”. “I fattori di rischio”. Vercelli. 14 October 2006.
II Working meeting on adult premature mortality in European Union. Institute of Oncology.
Warsaw, Poland. 15-17 October 2006.
World Health Organization. UNDP/UNFPA/WHO/World bank special programme of research,
development and research training in human reproduction. Specialist panel and scientific and
ethical review group. Geneva, Switzerland. 16-20 October 2006.
Conferenza su “Progressi nel controllo dei tumori” e “Dieta e cancro”. Bariano (BG) 26 October
2006.
Convegno. Caffè e patologie digerenti. “Introduzione”“Caffè e rischio di tumori del colon
retto””L’esperto risponde”. Taranto. 18 November 2006.
Convegno nazionale. Questioni aperte in tema di cancerogenesi ambientale: quali le possibili
risposte. “Interazione gene ambiente, modelli epidemiologici”. Torino. 11 December 2006.
Associazione Italiana per la Ricerca sul Cancro
Lega Italiana Lotta contro i Tumori
European Commission (FP6)
Ministero della Sanità
OM Pharma
Weber Shandwick Italia
3M Italia
Istituto Nazionale Neurologico “Carlo Besta”
Saint-Gobain Vetrotex
ANNUAL REPORT
197
2006
IRFMN
Tavani A., Gallus S., Bosetti C., Parpinel M., Negri E., La Vecchia C.
Dietary iron intake and risk of non-fatal acute myocardial infarction.
Publ. Health Nutr., 9: 480-484 (2006).
Bosetti C, Talamini R, Negri E, Franceschi S, Montella M, La Vecchia C.
Aspirin and the risk of prostate cancer.
Eur. J. Cancer Prev., 15: 43-45 (2006).
Gallus S, Naldi L, Martin L, Martinelli M, La Vecchia C, on behalf of the
Oncology Study Group of the Italian Group for Epidemiologic Research in
Dermatology (GISED).
Anthropometric measures and risk of cutaneous malignant melanoma:
a case-control study from Italy.
Melanoma Res., 16: 83-87 (2006).
Gallus S, Talamini R, Bosetti C, Negri E, Montella M, Franceschi S, Giacosa A,
La Vecchia C.
Pizza consumption and the risk of breast, ovarian and prostate cancer.
Eur. J. Cancer Prev., 15: 74-76 (2006).
Garavello W, Bosetti C, Gallus S, Dal Maso L, Negri E, Franceschi S, La Vecchia C.
Type of alcoholic beverages and the risk of laryngeal cancer.
Eur. J. Cancer Prev., 15: 69-73 (2006).
Gallus S, Fernandez E, Pacifici R, Colombo P, Zuccaro P, Bosetti C, Apolone G,
La Vecchia C.
Channels of cigarette distribution, price and tobacco consumption in Italy.
Prev. Med., 42: 132-134 (2006).
Tavani A, Giordano L, Gallus S, Talamini R, Franceschi S, Giacosa A, Montella M,
La Vecchia C.
Consumption of sweet foods and breast cancer risk in Italy.
Ann. Oncol., 17 341-345 (2006).
Pelucchi C, Galeone C, Levi F, Negri E, Franceschi S, Talamini R, Bosetti C,
Giacosa A, La Vecchia C.
Dietary acrylamide and human cancer.
Int. J. Cancer, 118: 467-471 (2006).
Gallus S, Pacifici R, Colombo P, Scarpino V, Zuccaro P, Bosetti C, Fernandez E,
Apolone G, La Vecchia C.
Prevalence of smoking and attitude towards smoking regulation in Italy, 2004.
Eur. J. Cancer Prev., 15: 77-81 (2006).
Randi G, Franceschi S, La Vecchia C.
Gallbladder cancer worldwide: Geographical distribution and risk factors.
Int. J. Cancer, 118: 1591-1602 (2006).
Rodriguez T, Malvezzi M, Chatenoud L, Bosetti C, Levi F, Negri E, La Vecchia C.
Trends in mortality from coronary heart and cerebrovascular diseases in the
Americas, 1970-2000.
Heart, 92: 453-460 (2006).
Negri E, Bertuccio P, Talamini R, Franceschi S, Montella M, Giacosa A, Pelucchi C,
La Vecchia C.
A history of cancer in the husband does not increase the risk of breast cancer.
Int. J. Cancer, 118: 3177-3179 (2006)
Gallus S, Schiaffino A, La Vecchia C, Townsend J, Fernandez E.
ANNUAL REPORT
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2006
IRFMN
Price and cigarette consumption in Europe.
Tobacco Control, 15: 114-119 (2006).
La Vecchia C.
Hormone replacement therapy in menopause and lung cancer: an update.
Eur. J. Cancer Prev., 15: 189-190 (2006).
Levi F, Moeckli R, Randimbison L, Te V-C, Maspoli M, La Vecchia C.
Skin cancer in survivors of childhood and adolescent cancer.
Eur. J. Cancer., 42: 656-659 (2006).
Gallus S, Colombo P, Scarpino V, Zuccaro P, Negri E, Apolone G, La Vecchia C.
Overweight and obesity in Italian adults 2004, and an overview of trends since 1983.
Eur. J. Clin. Nutr., 60: 1174-1179 (2006).
Tavani A, Spertini L, Bosetti C, Parpinel M, Gnagnarella P, Bravi F, Peterson J,
Dwyer J, Lagiou P, Negri E, La Vecchia C.
Intake of specific flavonoids and risk of acute myocardial infarction in Italy.
Public Health Nutr., 9: 369-374 (2006).
Galeone C, Pelucchi C, Levi F, Negri E, Talamini R, Franceschi S, La Vecchia C.
Folate intake and squamous-cell carcinoma of the oesophagus in Italian and Swiss men.
Ann. Oncol., 17: 521-525 (2006).
Gallus S, Bravi F, Talamini R, Negri E, Montella M, Ramazzotti V, Franceschi S,
Milk, dairy products and cancer risk (Italy).
Cancer Causes Control, 17: 429-437 (2006).
Bravi F, Bosetti C, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V,
Franceschi S, La Vecchia C.
Food groups and the risk of benign prostatic hyperplasia.
Urology, 67: 73-79 (2006).
La Vecchia C.
Oral contraceptives and ovarian cancer : an update, 1998-2004.
Eur. J. Cancer Prev., 15: 117-124 (2006).
Pelucchi C, Talamini R, Negri E, Franceschi S, La Vecchia C.
Genital and urinary tract diseases and prostate cancer risk.
Eur. J. Cancer Prev., 15: 254-257 (2006).
Tavani A, Bosetti C, Franceschi C, Talamini R, Negri E, La Vecchia C.
Occupational exposure to ultraviolet radiation and risk of non-Hodgkin Lymphoma.
Eur. J. Cancer Prev.,15: 453-457 (2006).
Kreimer AR, Randi G, Herrero R, Castellsagué X, La Vecchia C, Franceschi S,
For the IARC Multicenter Oral Cancer Study Group.
Diet and body mass, and oral and oropharyngeal squamous cell carcinomas:
Analysis from the IARC multinational case-control study.
Int. J. Cancer, 118: 2293-2297 (2006).
Talamini R, Polesel J, Montella M, Dal Maso L, Crovatto M, Crispo A, Spina M,
Canzonieri V, La Vecchia C, Franceschi S.
Food groups and risk of non-Hodgkin lymphoma: A multicenter, case-control study
in Italy.
Int. J. Cancer, 118: 2871-2876 (2006).
Maule M, Merletti F, Mirabelli D, La Vecchia C.
Spatial variation of mortality for common and rare cancers in Piedmont, Italy,
from 1980 to 2000: a Bayesan approach.
Eur. J. Cancer Prev., 15: 108-116 (2006).
ANNUAL REPORT
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IRFMN
Negri E, Talamini R, Bosetti C, Montella M, Franceschi S, La Vecchia C.
Risk of prostate cancer in men who are childless.
Int. J. Cancer, 118: 786-787 (2006).
Bulliard J-L, La Vecchia C, Levi F.
Diverging trends in breast cancer mortality within Switzerland.
Ann. Oncol., 17: 57-59 (2006).
Bosetti C, Gallus S, La Vecchia C.
Aspirin and cancer risk: an update quantitative review to 2005.
Cancer Causes Control, 17: 871-888 (2006).
Polesel J, Talamini R, Montella M, Parpinel M, Dal Maso L, Crispo A, Crovatto A,
Spina M, La Vecchia C, Franceschi S.
Linoleic acid, vitam D and other nutrient intakes in the risk of non-Hodgkin Lymphoma:
an Italian case-control study.
Ann. Oncol., 17: 713-718 (2006).
Naldi L, Chatenoud L, Piccitto R, Colombo P, Benedetti Placchesi E, La Vecchia C, for the
Prevalence of Actinic Keratoses Italian Study (PraKtis) Group.
Prevalence of actinic keratoses, and associated factors in a representative sample
of the Italian adult population. Results form the Prevalence of Actinic Keratoses Italian
Study, 2003-2004.
Arch. Dermatol., 142. 722-726 (2006).
Tavani A, Longoni E, Bosetti C, Dal Maso L, Polesel J, Montella M, Ramazzotti V,
Negri E, Franceschi S, La Vecchia C
Intake of selected micronutrients and the risk of surgically treated benign prostatic hyperplasia:
a case-control study from Italy.
Eur. Urol.,50: 549-554 (2006).
Bravi F, Bosetti C, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V,
Macronutrients, fatty acids, cholesterol, and risk of benign prostatic hyperplasia.
Urology, 67: 1205-1211 (2006).
Gallus S, Zuccaro P, Colombo P, Apolone G, Pacifici R, Garattini S, La Vecchia C.
Effects of new smoking regulations in Italy.
Ann. Oncol., 17: 346-347 (2006)
Zatonski W, Mikucka M, La Vecchia C, Boyle P.
Infant mortality in Central Europe: effects of transition.
Gac. Sanit., 20: 63-66 (2006).
Negri E, Talamini R, Montella M, Dal Maso L, Crispo A, Spina M, La Vecchia C,
Franceschi S.
Family history of hemolymphopoietic and other cancers and risk of
non-Hodgkin’s lymphoma.
Cancer Epidemiol. Biomarkers Prev., 15: 245-250 (2006).
Apolone G, La Vecchia C, Garattini S.
Targeted kinase inhibitors in lung cancer: From EGFR to patients.
Eur. J. Cancer, 42: 124-125 (2006).
Tavani A., Gallus S, Negri E, Parpinel M, La Vecchia C.
Dietary intake of carotenoids and retinol and the risk of acute myocardial infarction in Italy.
Free Radical Res., 40: 659-664 (2006).
Bosetti C, Garavello W, Levi F, Lucchini F, Negri E, La Vecchia C.
Trends in laryngeal cancer mortality in Europe.
Int. J. Cancer, 119: 673-681 (2006).
Franceschi S, Montella M, Polesel J, La Vecchia C, Crispo A, Dal Maso L, Casarin P,
ANNUAL REPORT
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2006
IRFMN
Izzo F, Tommasi LG, Chemin I, Trépo C, Crovatto M, Talamini R.
Hepatitis viruses, alcohol and tobacco in the etiology of hepatocellular carcinoma in Italy.
La Vecchia C.
Estrogen-progestogen replacement therapy and ovarian cancer: an update.
Eur. J. Cancer Prev., 15: 490-492 (2006).
Dal Maso L, Zucchetto A, Tavani A, Montella M, Ramazzotti V, Polesel J, Bravi F,
Talamini R, La Vecchia C, Franceschi S.
Lifetime occupational and recreational physical activity and risk of benign
prostatic hyperplasia.
Int. J. Cancer, 118: 2632-2635 (2006).
Pelucchi C, Bosetti C, Negri E, Malvezzi M, La Vecchia C.
Mechanisms of disease: the epidemiology of bladder cancer.
Nature Clin. Pract. Urol., 3: 327-340 (2006).
Negri E., Randi G, La Vecchia c.International Collaboration of Epidemiological
Studies of Cervical Cancer.
Cervical carcinoma and reproductive factors: Collaborative reanalysis of individual
data on 16,563 women with cervical cancer and 33,542 women without cervical cancer
from 25 epidemiological studies.
Int. J. Cancer, 119: 1108-1124 (2006).
Pelucchi C, Pira E, Piolatto G, Coggiola M, Carta P, La Vecchia C.
Occupational silica exposure and lung cancer risk: a review of epidemiological
studies, 1996-2005.
Ann. Oncol., 17: 1039-1050 (2006).
Bosetti C, Negri E, Gallus S, Dal Maso L, Franceschi S, La Vecchia C.
Antropometric and multiple myeloma.
Epidemiology, 17: 340-341 (2006).
La Vecchia C.
Both active and passive smoking were associated with an increased risk
of cervical neoplasia.
Evidence-Based Obstet. Gynecol., 8: 56-57 (2006).
Boffetta P, Hashibe M, La Vecchia C, Zatonski W, Rehm J.
The burden cancer attributable to alcohol drinking.
Int. J. Cancer, 119: 884-887 (2006).
Bosetti C, Scotti L, Negri E, Talamini R, Levi F, Franceschi S, Montella M,
Benign ovarian cysts and breast cancer risk.
Int. J. Cancer, 119: 1679-1682 (2006).
La Vecchia C, Tavani A.
Female hormones and benign liver tumors.
Digest. Liver Dis., 38: 535-536 (2006).
Bravi F, Scotti L., Bosetti C, Talamini R, Negri E, Montella M, Franceschi S, La Vecchia C.
Self-reported history of hypercholaesterolaemia, and gallstones and the risk of prostate cancer.
Ann. Oncol., 17: 1014-1017 (2006).
Levi F. Lucchini F, La Vecchia C.
Trends in cancer mortality in Switzerland, 1980-2001.
Eur. J. Cancer Prev., 15: 1-9 (2006).
Rossi M, Negri E, Talamini R, Bosetti C, Parpinel M, Gnagnarella P, Franceschi S,
Dal Maso L, Montella M, Giacosa A, La Vecchia C.
Flavonoids and colorectal cancer in italy.
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Negri E, La Vecchia C, International Collaboration of Cervical Cancer
Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual
data on 13,541 women with carcinoma of the cervix and 23,017 women without
carcinoma of the cervix from 23 epidemiological studies.
Int. J. Cancer, 118: 1481-1495 (2006).
Levi F, Randimbison L, Te V-C, La Vecchia C.
Cancer risk after radiotherapy for breast cancer.
Br. J. Cancer, 95: 390-392 (2006).
Pelucchi C, Galeone C, Talamini R, Bosetti C, Montella M, Negri E, Franceschi S,
La Vecchia C.
Lifetime ovulatory cycles and ovarian cancer risk in 2 Italian case-control studies.
Am. .J Obstet. Gynecol., 196: 83.e1-83.e7 (2007).
Levi F, Colombo P, La Vecchia C.
Effects of new smoking regulations.
Ann. Oncol., 17: 1335 (2006).
Gallus S, Talamini R, Fernandez E, Dal Maso L, Franceschi S, La Vecchia C.
RE: Carbonated soft drink consumption and risk of esophageal adenocarcinoma.
JNCI, 98: 645-646 (2006).
Naldi L, Randi G, Di Landro A, La Vecchia C, Oncology Study Group
of the Italian Group for Epidemiologic Research in Dermatology (GISED).
Red hairs, number of naevi and risk of cutaneous malignant melanoma:
Results from a case-control study in Italy.
Arch. Dermatol., 142: 935-936 (2006).
Bosetti C, Garavello W, Gallus S, La Vecchia C.
Effects of smoking cessation on the risk of laryngeal cancer:
An overview of published studies.
Oral. Oncol., 42: 866-872 (2006).
Levi F, Te V-C, Randimbison L, Maspoli M, La Vecchia C.
Second primary oral and pharyngeal cancers in subjects diagnosed with oral
and pharyngeal cancer.
Int. J. Cancer, 119: 2702-2704 (2006).
Levi F, Randimbison L, Maspoli M, Te V-C, La Vecchia C.
High incidence of second basal cell skin cancers.
Int. J. Cancer, 119: 1505-1507 (2006).
Bosetti C, Gallus S, Garavello C, La Vecchia C.
Smoking cessation and the risk of oesophageal cancer: An overview of published studies.
Oral Oncol., 42: 957-964 (2006).
Naldi L, La Vecchia C, Chatenoud L.
Response to cigarette smoking, metabolic gene polymorphism, and psoriasis.
J. Invest. Dermatol., 126: 695 (2006).
Galeone C, Pelucchi C, Levi F, Negri E, Franceschi S, Talamini R, Giacosa A, La Vecchia C.
Onion and garlic use and human cancer.
Am. J. Clin. Nutr., 84: 1027-1032 (2006).
Garavello W, Randi G, Bosetti C, Dal Maso L, Negri E, Barzan L, Franceschi S,
La Vecchia C.
Body size and laryngeal cancer risk.
Ann. Oncol., 17: 1459-1463, 2006.
Bravi F, Bosetti C, Scotti L, Talamini R, Montella M, Ramazzotti V, Negri E, Franceschi S,
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La Vecchia C.
Food groups and renal cell carcinoma: a case-control study from Italy.
Int. J. Cancer, 120: 681-685 (2006)
Negri E, Foschi R, Talamini R, Montella M, Ramazzotti V, Dal Maso L, Bosetti ,
Franceschi S, Zucchetto A, La Vecchia C.
Family history of cancer and the risk of renal cell cancer.
Cancer Epidemiol. Biomark. Prev., 15: 2441-2444 (2006).
Rossi M, Negri E, Foschi R, Franceschi S, La Vecchia C.
Relation between goiter and autoimmune thyroid disease, and gastric cancer.
Int. J. Cancer, 120: 951-952 (2006).
Bosetti C, Scotti L, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V,
Micronutrients and the risk of renal cell cancer: a case-control study from Italy.
Int. J. Cancer, 120: 892-896 (2006).
Fernandez E, Gallus S, La Vecchia C.
Nutrition and cancer risk. an overview.
J. Br. Menop. Soc., 12: 139-142 (2006).
La Vecchia C, Chatenoud L.
Cenni di statistica e metodologia epidemiologica.
In: Ginecologia e Ostetricia, vol. 1. G.C. Di Renzo.
Verduci Editore, Roma, 2006, Cap. 15, pp.459-469.
La Vecchia C.
Contraccettivi orali e tumori
In: Contraccezione: rilevanti aspetti clinici, recenti acquisizioni e nuovi comportamenti.
IX Week-end Clinico: Contraccezione: rilevanti aspetti clinici, recenti acquisizioni e nuovi
comportamenti, Atti, a cura di G.P. Crosignani, Roma 23-24 marzo 2006.
Società Italiana della Riproduzione, Roma; 2006, pp. 55-59
Naldi L, Chatenoud L, La Vecchia C.
Importanza sanitaria e prevenzione delle malattie dermatologiche.
In: Naldi L, Rebora A: Dermatologia Basata sulle prove di Efficacia.
Milano, Masson, 2006, Cap. 6, pp.56-62.
Rodriguez T, Gallus S, Chatenoud L, Zuccaro P, Colombo P, Apolone G, Pacifici R,
Garattini S, La Vecchia C.
Efecto de la nueva regulacion antitabaco en Italia.
Rev. Salud Publ. Mexico, 48: Suppl. 1: S137-S-139 (2006).
Gallus S, Bravi F, La Vecchia C.
Prodotti lattiero-caseari e cancro.
In: Libro bianco sul latte e i prodotti lattiero caseari.
Assolatte, Milano, 2006. Cap. V, 11, pp. 508-516.
La Vecchia C.
Contraccettivi orali e tumori.
Minerva Ginecologica, 58: 209-214 (2006).
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RESEARCH ACTIVITIES
Data analysis and management
Collection of epidemiological data has continued as planned, and also data checking, entry and
input have been pursued. The overall dataset now includes 1,250 cases of oral and pharyngeal
cancers, 700 of esophageal, 1,100 of stomach, 6,500 of colorectal, 600 of primary liver, 120 of
gallbladder and bile duct cancers, 600 of pancreatic, 850 of laryngeal, 500 of cutaneous
malignant melanoma, 7,000 of breast, 1,000 of cervical and 1,000 of endometrial cancers, 200
of gestational trophoblastic disease, 200 of vulvar, 2,000 of ovarian, 1,300 of prostatic, 700 of
bladder, 800 of kidney and renal pelvis, 600 of thyroid cancer, 200 of Hodgkin’s disease and
500 of other lymphomas, 150 sarcomas, 300 myelomas and about 18,000 controls. Biological
samples have been collected for cancers of the upper digestive and respiratory tract, lung and
bladder cancer to investigate genetic polymorphisms, and for ovarian and endometrial cancers
for the analysis of insulin growth factor (IGF) system, adiponectin and other hormonal
correlates.
Dietary factors and colorectal cancer
With reference to colorectal cancer, we examined the relation with flavonoids intake using data
of a case-control study conducted in Italy between 1992 and 1996, including 1,225 cases of
colon cancer, 728 of rectal cancer, and 4,154 controls. Taking into account the main potential
confounding factors as well as energy intake, we observed a reduction in the risk of colorectal
cancer with increasing levels of intake of isoflavones (RR=0.76, for the highest quintile vs. the
lowest one), anthocyanidins (RR=0.67), flavones (RR=0.78) and flavonols (RR=0.64). No
meaningful association was found with other flavonoids, including flavanones (RR=0.96),
flavan-3-ols (RR=0.98), and total flavonoids (RR=0.97). Results were similar for cancers of the
colon and rectum, when considered separately.
Further, we analyzed data from the same study of colorectal cancer in relation to fried foods
consumption and to fats mainly used for frying. Beyond 1,953 cases and 4,154 controls from the
Italian study, data included 169 cases of colon cancer, 158 of rectal cancer and 611 controls
enrolled in a companion study conducted in Switzerland. For an increase of consumption of a
portion of fried foods per week, the RR of colon cancer was 0.97 and the RR of rectal cancer
was 1.04. Cancer risks were also considered separately by type of fats used for frying. We found
RRs of colorectal cancer of 0.93 for subjects using olive oil and of 1.00 (95% CI, 0.95-1.06) for
those using mixed seeds oil for frying. Olive oil use for frying was inversely associated with
colon (RR=0.89), but not rectal cancer. Therefore, our study suggested that fried foods do not
play an important role on the risk of colorectal cancer in the Italian population, and that use of
(fried) olive oil could reduce the risk of colon cancer.
Milk and dairy products consumption and cancer risk
We examined data from a series of Italian and Swiss case-control studies in order to give further
information on the role of consumption of milk and dairy products on the risk of several
cancers, including those of the breast, colon-rectum, ovary and larynx. For all the neoplasms
considered, a high consumption of milk was not significantly associated with cancer risk. A
statistically significant inverse trend in risk was found for colon cancer only (RR=0.77 for the
highest vs. lowest level of consumption). Consumption of skim milk was inversely associated
with colon (RR=0.84), rectal (RR=0.76), breast (RR=0.87) and ovarian cancer (RR=0.77). On
the other hand, consumption of whole milk increased the risk of rectal (RR=1.22), breast
(RR=1.11) and ovarian cancers (RR=1.25). A high consumption of cheese was inversely
associated with risk of colon cancer (RR=0.80), while a moderate protective effect of yogurt
consumption was observed for cancers of the breast (RR=0.90), oral cavity and pharynx
(RR=0.75), and larynx (RR=0.74).
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Artificial sweeteners use and cancer risk
With reference to artificial sweetener use and cancer risk - an issue that has been debated over
the last few decades -we investigated data from case-control studies on cancers of the breast,
colon-rectum, prostate, upper aero-digestive tract, ovary and kidney. Use of artificial sweeteners
was not significantly associated with risk of any of the neoplasms considered, except for the
inverse relations between use of saccharin and the risk of ovarian cancer (RR=0.46, 95% CI,
0.29-0.74) and between use of other sweeteners (mainly aspartame) and risk of breast cancer
(RR=0.80, 95% CI, 0.65-0.97). This study indicated a lack of association between use of
artificial sweeteners and the risk of several common cancers.
Onion and garlic use and risk of various cancers
Onion and garlic were found to be protective on several cancers in studies conducted in Eastern
countries, particularly in China where allium vegetables consumption is elevated. Since data on
this topic from Western countries are scanty, we considered the issue in our group of casecontrol studies. Our results supported the hypothesis of an anti-carcinogenic effect of onion and
garlic consumption, with risks of colorectal cancer reduced by 56% and 26% for subjects with
high consumption of onion and garlic, respectively, as compared to non-users. RRs were
significantly reduced also for cancers of the upper aero-digestive tract and ovary, even after
adjustment for vegetable consumption and other potential confounding factors. Moreover, an
inverse association, although not significant, emerged with breast, prostate and kidney cancers.
Onion and garlic use is therefore a favorable correlate of cancer risk in our population, too.
Type of alcoholic beverage and laryngeal cancer
With reference to laryngeal cancer, the role of various types of alcoholic beverages has been
quantified using data from two Italian case-control studies conducted between 1986 and 2000,
including a total of 672 incident cases and 3,454 hospital controls. Laryngeal cancer risk
increased with total alcohol consumption, up to a RR of 4.83 for subjects consuming more than
12 drinks per day as compared to non-drinkers or moderate drinkers. RRs for wine consumption
were 1.12 for 3-4 drinks/day, 2.45 for 5-7 drinks/day, 3.29 for 8-11 drinks/day and 5.91 for
more than 12 drinks/day. RRs for beer consumption were 1.65 for 1-2 drinks/day and 1.36 for 3
or more drinks/day, and the corresponding risks for spirits were 0.88 and 1.15. Wine is the
alcoholic beverage more frequently consumed and more strongly associated with laryngeal
cancer in this Italian population.
History of selected diseases and risk of prostate cancer
The role of selected diseases was evaluated in relation to prostate cancer risk in a case-control
study conducted in Italy between 1991 and 2002. Cases were 1,294 patients under 75 years of
age, with an incident, histologically confirmed carcinoma of the prostate; controls were 1,451
subjects under 75 years of age, admitted to the same hospitals of cases for a wide spectrum of
acute, non neoplastic diseases. A direct association emerged between history of
hypercholesterolaemia and prostate cancer (RR=1.51, 95% CI, 1.23-1.85), and this was stronger
in older subjects (RR=1.80). Further, we observed a moderate direct association with gallstones
(RR=1.26). This study suggested a possible relation between hypercholesterolaemia and
prostate cancer.
Childless men and prostate cancer
Following recent findings of a possible increase of prostate cancer risk in childless men, we
examined the issue in our case-control study of prostate cancer. Our study found no meaningful
associations, since after adjustment for several potential confounding factors, and keeping as
reference category men with 2 or more children, the RR of prostate cancer were 1.17 (95% CI,
0.94-1.47) in men with 1 child and 1.10 (95% CI, 0.74-1.62) in childless men.
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History of benign ovarian cysts and breast cancer
We analyzed data from 3 case-control studies of breast cancer conducted in the period 19832001 in Italy and Switzerland, including 6,315 cases and 6,038 controls, with the aim to
investigate the relation between history of benign ovarian cysts and the risk of breast cancer.
Overall, 4.9% of cases and 6.6% of controls reported a history of benign ovarian cysts, and the
corresponding relative risk (RR) was 0.72. Risks were consistent in strata of selected covariates,
including age at menopause, reproductive and menstrual factors. The inverse association
observed in this study between history of benign ovarian cysts and risk of breast cancer could
depend on some hormonal correlates of ovarian cysts, but a biological explanation is still
unclear.
Other factors considered in various cancer studies
In our case-control study on oesophageal cancer, we observed an inverse association with
consumption of flavanones, a subgroup of flavonoids. In fact, the risk of oesophageal cancer
was reduced by 62% for subjects in the upper vs. those in the lowest quintile of consumption,
suggesting that flavanones, together with vitamin C, could explain the protective effect of
consumption of fruit, and particularly citruses, towards the risk of oesophageal cancer.
In our study on laryngeal cancer, we analyzed the effect of various anthropometric measures at
different ages. Data showed a consistent relation in both sexes between leanness and risk of
laryngeal neoplasm. In particular, the RR was more than 4-fold elevated in men at the lowest
levels of abdominal fat.
In a quantitative review of the scientific literature, aspirin use was inversely related with cancers
of the colorectum (RR=0.71), esophagus (RR=0.72), stomach (RR=0.84), breast (RR=0.91),
ovary (RR=0.89) and lung (RR=0.94), while a direct association emerged with kidney cancer.
However, results were often heterogeneous between studies and study designs, with greater
reductions in risk observed among case-control studies. Further, several uncertainties remain on
the optimal dose and duration of aspirin treatment.
Occupational silica exposure and lung cancer
We systematically reviewed the large amount of epidemiological data (28 cohort and 15 casecontrol studies) on the relation between occupational exposure to crystalline silica and risk of
lung cancer that followed the publication, in 1997, of a Monography from the International
Agency for Research on Cancer (IARC) that classified occupational exposure to crystalline
silica as carcinogenic to humans. We examined different types of study separately, and
estimated overall RRs of lung cancer of 1.34 from cohort studies and 1.41 from case-control
studies that considered occupational silica exposure. The association with lung cancer was
stronger in studies that included subjects with silicosis only, moderate in studies on workers
exposed to silica without information on silicosis status and absent in studies on non-silicotics
(but based on two investigations only). On the basis of these results and a critical reappraisal of
each study, available data of the last decade still leave open the debate on this topic, i.e. whether
exposure to silica per se materially increases the risk of lung cancer in the absence of silicosis.
Conversely, the association between silicosis and lung cancer is confirmed, in agreement with
previous studies and meta-analyses.
Record-linkage for cohort analyses
With reference to our project to create an Italian cohort study based on record-linkage, during
2006 we prepared the archives that will allow to link data between our network of case-control
studies (conducted since 1982) and those from the historical archives of the Local Health Unit
(ASL) of Milan, that include several health information such as vital status and date of death of
the subjects.
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Several stages of the project have been undertaken and completed during the year. In particular,
we finished the identification of subjects recruited in the case-control studies among the
historical archives of the ASL, and a database with univocal information on subjects from the
two sources is now available, thus allowing a linkage of the archives; at the same time, we
completed data collection from all case-control studies in a unique database (using original data
and through the preparation of a codebook that allowed to re-codify studies conducted in
various periods and on several diseases) that includes information from interviews to
approximately 27,000 subjects.
Preliminary results indicate that 18,229 (69%) of the interviewed subjects, including 8,743 cases
(61%) and 9,486 controls (79%), have been identified in at least one of the Milan ASL archives.
Thus, we estimated that the cohort will include a total of about 180,000 person-years of followup (about 80,000 person-years for cases and 100,000 person-years for controls). Moreover,
9,466 (4,604 cases and 4,862 controls) out of 18,229 subjects have been identified in the Milan
registry office. Of these, 3,549 (37%) subjects were reported dead (2,337 cases, 51%, and 1,212
controls, 25%).
Risk factors for acute myocardial infarction
We have conducted a case-control study to assess the risk of on nonfatal acute myocardial
infarction in the Italian population. In 2006 we have analyzed the role of selected variables:
In the Italian population dietary iron intake was inversely related to myocardial infarction risk,
while in other populations it is not or it is slightly directly related. This inverse association may
depend on other nutrients present in the major sources of iron in the Italian diet (e.g. wine,
vegetables and not meat as in other countries).
High dietary intake of anthocyanidins reduced the risk of myocardial infarction even after
allowance for alcohol, fruit and vegetables, supporting a real inverse association between this
class of flavonoids and this disease risk. No association emerged for other flavonoids, including
isoflavones, flavanones and flavones.
Dietary α-carotene, β-carotene and β-criptoxanthin had a weak protective effect on the risk of
myocardial infarction, while total carotenoids, lycopene, lutein plus zeaxanthin and retinol were
not related to the risk of the disease.
Trends in laryngeal cancer mortality rates in Europe
After a steady increase since the 1950s, laryngeal cancer mortality had tended to level off since
the early 1980s in men from most European countries. We have updated the analysis of trends
over the period 1980–2001. In the European Union (EU) as a whole, male mortality declined by
0.8% per year between 1980 and 1989, by 2.8% between 1989 and 1995, by 5.3% between 1995
and 1998, and by 1.5% thereafter (rates were 5.1/100,000 in 1980–1981 and 3.3/100,000 in
2000–2001). This mainly reflects a decrease in rates in men from western and southern
European countries, which had exceedingly high rates in the past. Male laryngeal mortality rose
up to the early 1990s, and leveled off thereafter in several countries from central and eastern
Europe. In 2000– 2001 there was still a 10–15-fold variation in male laryngeal mortality
between the highest rates in Croatia (7.9/100,000) and Hungary (7.7/100,000) and the lowest
ones in Sweden (0.5/100,000) and Finland (0.8/100,000). Laryngeal cancer mortality was
comparatively low in women from most European countries, with stable rates around
0.3/100,000 in the EU as a whole over the last 2 decades. Laryngeal cancer trends should be
interpreted in terms of patterns and changes in exposure to alcohol and tobacco. Despite recent
declines, the persistence of a wide variability in male laryngeal cancer mortality indicates that
there is still ample scope for prevention of laryngeal cancer in Europe.
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Trends in mortality from coronary heart and cerebrovascular disease in
the Americas
We have described trends in mortality from coronary heart disease (CHD) and cerebrovascular
accidents (CVAs) over the period 1970 to 2000 in the Americas. In the USA and Canada, both
CHD and CVA mortality rates declined by about 60% in both sexes. In Latin America, falls in
CHD mortality were observed for Argentina, Brazil, Chile, Cuba, and Puerto Rico. The falls
were smaller (about -25% to -40% among men and -20% to -50% among women) in Puerto
Rico, Argentina, Chile, and Costa Rica and only minor in Ecuador, Mexico, and Venezuela. In
conclusion, recent falls in CHD and CVA were less favorable in Latin America than in the USA
and Canada. This may reflect unfavorable changes in nutrition (including obesity), physical
activity, and smoking in most Latin American countries, together with less effective control of
hypertension and management of the diseases.
Strategies and best practices for the reduction of injuries
Since June 2006, our laboratory is involved in the Apollo Project, an European project aiming at
identifying strategies and best practices for the reduction of injuries. Within this project, our
laboratory is coordinator of the Workpackage 4 on the development and implementation of
recommendations for preventing falls among the elderly in the European Union. A list of the
interventions to prevent falls in older people in the general population, which were considered
sufficiently promising has been prepared, including programs of muscle strength and balance
training, Tai Chi exercises, mental health monitoring and social welfare issues, visual and
hearing monitoring, cardiac pacing, withdraw of psychotropic medications, education or raising
awareness on the issue of falls, environmental hazard assessment and modification. A search of
the published literature on these interventions has been performed, and several relevant papers
have been retrieved. Meanwhile a search of the grey literature on interventions for the
prevention of falls in the elderly has been performed. A database form has been prepared for the
extraction of data from the published papers, in order to classify interventions according to
effectiveness, characteristics of the target population, participation and compliance, resources
needed for the implementation. Besides the information collected, the principal investigators of
each paper will be contacted and invited to fill in a questionnaire on barriers and facilitators
found in the implementation of their interventions. Another questionnaire will be developed to
perform a survey on the attitudes of the elderly on interventions for the prevention of falls; this
survey will be conducted in Italy and in two/three other European countries.
Smoking prevalence in Italy
On 10 January 2005, Italy became the first large European country adopting a comprehensive
smoke-free legislation. To provide information on smoking prevalence in Italy and evaluate the
effects of the 2005 regulation, we considered data from three companion surveys on smoking
conducted in 2004, 2005 and 2006 in Italy. Each survey included more than 3,039 subjects
(1,461 men and 1,578 women) aged 15 or over, representative of the general Italian adult
population. Current smokers declined from 26.2% (30.0% of men, 22.5% of women) in 2004, to
25.6% (29.3% of men, 22.2% of women) in 2005, and to 24.3% (28.6% of men, 20.3% of
women) in 2006. While no significant difference was found comparing smoking prevalence in
2003-2004 vs 2001-2002, the drop in smoking prevalence in 2005-2006 vs 2003-2004 was
significant (p<0.05) in the total population, in men and in subjects aged 15-44 years. Smokers
consumed a mean of 15.4 cigarettes per day in 2004, 14.6 in 2005 and 13.9 cigarettes per day in
2006. The drop in smoking prevalence and consumption may be due, particularly for younger
generations, to the comprehensive smoke-free legislation adopted in Italy.
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“Sole-si/Sole-no GISED” project
Dermato-epidemiology has been present in our laboratory since the early 1990’s as a result of
continuous collaboration with the “Italian Group for Epidemiologic Research in Dermatology“
(GISED). In the context of this collaboration, a randomized study on the effectiveness of a
school-based intervention program on sun exposure behaviors in primary-school children
(“SoleSi SoleNo-GISED”) started on 2001 and finished in 2004. In 2006, the analyses of this
study were finished. After one year from the intervention, no meaningful differences were
observed between the two groups of randomization, neither in terms of number of sunburns nor
of variables associated to a correct sun exposure. These results may be a consequence of a
general good knowledge of and attention towards correct sun exposure behaviors in parents.
Prevalence of actinic keratoses in Italy
In the context of this collaboration, in 2006, we published the results of a population study on
actinic keratoses prevalence. The Prevalence of Actinic Keratoses Italian study (PraKtis) was
designed to estimate the point prevalence of actinic keratoses (AKs) and associated factors in a
representative sample of the Italian adult population. The study was conducted in collaboration
with DOXA, the Italian branch of the Gallup International Association. A representative sample
of people aged 45 years or older was selected from the electoral rolls according to a stratified
random sampling design. A total of 180 interviewers specifically trained contacted the sampled
subjects and performed a face-to-face computer assisted interview and skin assessment. From
March 1st 2003 to April 30th 2004, a total of 12,483 subjects were contacted and interviewed.
Overall, an estimated 34% of Italian people reported having undergone a dermatological
examination ever in the past. History of AKs was reported by 0.3% of the total sample. Topical
therapy was the most popular treatment (39%) while no therapy was reported by 25% of
subjects. Based on the interviewer’s judgement, the point prevalence of AKs was 1.4% (95%
confidence interval: 1.2-1.8%). Forty-two percent of people with AKs were unaware of their
condition. The prevalence was higher among men (1.6%) than women (1.4%) and increased
steadily with age. The prevalence increased with lighter phenotype, and with more severe facial
wrinkling. It also increased with the reported number of hours spent in the sun during the week
and on holidays. No clear variation was observed according to the reported use of sunscreens.
Lesions were usually multiple (median number 4). There was a strong association (RR=4.5)
between a history of non-melanoma skin cancers and the presence of AKs. The prevalence of
AKs in our study was remarkably lower than expected based on data from USA and Australia.
Our study confirmed that age, skin phenotype, and sun exposure strongly influence the
prevalence of AKs. AKs appeared to be under-diagnosed and under-treated in our population.
Risk factors for histological types and anatomic sites of cutaneous basalcell carcinoma
Since different clinico-pathologic subtypes and anatomic sites of basal-cell carcinoma (BCC)
may display distinct characteristics and mechanisms of development, we analyzed data from an
Italian case–control study, including 528 subjects with newly diagnosed, histologically
confirmed BCC and 512 controls admitted to the same hospitals. The risk of nodular (RR=1.53)
but not superficial (RR=0.71) BCC was increased for occupational exposure to sunlight.
Considering the anatomic site of BCC, the corresponding values were 1.46 for head/neck and
0.74 for truncal location. Direct associations were observed with recreational sunlight exposure,
eye color, red hair, and number and early age of severe sunburn episodes, along with some
differences in risk between histotypes and anatomic sites. Therefore, this study confirmed the
role of (intermittent) sun exposure and phenotypic characteristics as risk factors for BCC, and
suggested etiological differences between nodular and superficial histotypes and between
head/neck and truncal locations.
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Risk factors for cutaneous malignant melanoma
Several studies have investigated the effect of various anthropometric factors on the risk of
cutaneous malignant melanoma (CMM). As the results are controversial, we analysed the issue
in a case-control study conducted in Italy between 1992 and 1994, including 542 patients with
CMM and 538 control subjects admitted to the same hospitals as cases for non-dermatological
and non-neoplastic diseases. The RRs for the highest versus the lowest quartile were 2.06 for
weight, 1.16 for height, 1.90 for body mass index (BMI) and 1.87 for body surface area (BSA).
When allowing for BMI and BSA in the same model, the RRs were 1.55 for BMI and 1.41 for
BSA. The present findings confirm that obesity increases the risk of CMM. BSA is also related
to the risk of CMM. In terms of population attributable risks, overweight and obesity would
account for 31% of the cases of CMM in this Italian population, indicating the scope of
prevention.
In the same case-control study, we analyzed the association between CMM at a specific
anatomical site and number of nevi at the same site. Cases and controls were examined by
trained dermatologists who counted the number of melanocytic nevi. The RRs of CMM for the
highest versus the lowest tertile of number of nevi at the corresponding site was 1.4 at face and
neck, 2.3 at anterior trunk, 4.9 at posterior trunk, 2.9 at upper limbs and 5.0 at lower limbs. In a
case-case analysis, comparing CMM cases at a specific site and CMM cases at all other sites,
the only excess risk was found for the posterior trunk, the RR being 2.1 for the highest versus
the lowest tertile of number of nevi. Our data do not support the hypothesis of a specific effect
of nevi at each single anatomical site.
Public health prevention and information
The major products of our activity, mainly related to diet, tobacco and alcohol have also been
published in the lay press, in order to increase the project impact on prevention and public
health.
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LABORATORY OF MEDICAL
INFORMATICS
STAFF
Head
Eugenio SANTORO, Comp.Sci.D.
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CURRICULUM VITAE
Eugenio Santoro was born in Milan, on the 21th of October 1965, and 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. 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). Another recent area of interest is the Internet and
its application in the medical field and in clinical research through the development of health related
websites. He is author or co-author of more than 130 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 two books (available in Italian) about
the use of the Internet in medicine (“Guida alla medicina in rete” and “Internet in medicina. Guida
all’uso e applicazioni pratiche”, both 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 2006). He also collaborates to the publication of the Italian
National Bioethics Committee’s guidelines about ethics, health, and the new information technologies.
He is a member of the Society for Clinical Trials and of the Society for Internet in Medicine.
•
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
•
Bonati M, Pandolfini C, Rossi Valentina, Santoro E, Carreras I D, Castel Llobet J M. Launch of a European paediatric
clinical trials register. Paediatric Perinatal Drug Therapy 2004; 6: 38-39
•
Santoro E. Internet and information on breast cancer: an overview. Breast 2003; 12: 424-431
•
Santoro E, Nicolis E, Franzosi M G, Tognoni G. Internet for clinical trials: Past, present, and future. Control Clin Trials
1999; 20: 194-201
•
Franzosi M G, Santoro E, Zuanetti G, Latini R, Maggioni A P, Tognoni G, GISSI. Indications for ACE inhibitors in the
early treatment of acute myocardial infarction. Systematic overview of individual data from 100.000 patients in
randomized trial. Circulation 1998; 97: 2202-2212
•
Franzosi M G, Santoro E, De Vita C, Geraci E, Lotto A, Maggioni A P, Mauri F, Rovelli F, Santoro L, Tavazzi
L, Tognoni G, GISSI.
Ten-year follow-up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction.
Results of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto-1 study. Circulation 1998; 98: 2659-2665
•
Franzosi M G, Latini R, Maggioni A P, Barlera S, Negri E, Nicolis E, Santoro E, Santoro L, Tognoni G, Garattini
S, GISSI-3.
GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on six-week mortality and
ventricular function after acute myocardial infarction. Lancet 1994; 343: 1115-1122
•
Maggioni A P, Maseri A, Fresco C, Franzosi M G, Mauri F, Santoro E, Tognoni G, GISSI-2. Age-related increase in
mortality among patients with first myocardial infarctions treated with thrombolysis. N Engl J Med 1993; 11: 1442-1448
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The Laboratory of Medical Informatics is involved in the following activities:
- coordination of the computer center and users supporting;
- development of medical websites;
- development of the Istituto Mario Negri’s website;
- training activities on issues related to “Internet and medicine”, medical informatics, and
computer science;
- statistical analyses of clinical trials’ databases.
Development of an European Clinical Trials Register in pediatrics (WWW.DEC-NET.ORG)
Maintenance of the Istituto Mario Negri’s website
Maintenance of the CARDIO.CARE, ONCO.CARE, NEURO.CARE, GASTRO.CARE,
PNEUMO.CARE, PAIN.CARE and DERMA.CARE websites
Maintenance of the website for the RISCHIO&PREVENZIONE clinical trial
Development and maintenance of the CAESAR (www.caesar-project.eu) and RAINBOW
(www.rainbow-project.eu) websites
Italian National Bioethics Committee
Fondazione LuVI
Associazione Nazionale dei Medici Cardiologi Ospedalieri (ANMCO)
Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED)
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)
Società Italiana Attività Regolatorie
Dipartimento di Ricerca Cardiovascolare – Istituto “Mario Negri”
Dipartimento Ambiente e Salute – Istituto “Mario Negri”
Laboratorio per la Salute Materno Infantile - Istituto “Mario Negri”
Laboratorio Ricerca sul Coinvolgimento dei Cittadini in Sanità
Laboratorio Ricerca Translazionale e di Outcome in Oncologia
Laboratorio di Ricerca in Medicina Generale
Servizio Biblioteca - Istituto “Mario Negri”
Society for Internet in Medicine
Senologic International Society
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Partecipasalute.it web portal – http://www.partecipasalute.it (Eugenio Santoro)
Società Italiana Attività Regolatorie News, SIARNews (Eugenio Santoro)
Computer Methods and Programs in Biomedicine
Scientific Review Committee, 11° World Congress on Internet in Medicine, Toronto, 13-20
ottobre 2006
Consorzio Italiano per la Ricerca Medica
Society for Internet in Medicine
Senologic International Society
INVOLVED
XIII Congresso Nazionale della Società Italiana di Cure Palliative, Bologna 26-29 April 2006.
Titolo relazione: “Internet come strumento di ricerca e informazione sul dolore cronico nel
paziente con cancro”.
Corso “Evidence Based Medicine per bibliotecari-documentalisti biomedici” promosso dal
Centro Cochrane Italiano, April-May 2006. Titolo della lezione “Strumenti per ricercare,
filtrare e valutare le fonti di informazioni in Internet”.
Corso ECM, Utilizzo delle banche dati in medicina. Siti e applicazioni Internet in ambito medico:
tipologia di informazioni e metodologia di reperimento. Centro Malattie Rare Aldo e Cele Daccò,
Istituto Mario Negri, Ranica (BG), 21 e 28 September 2006.
AstraZeneca Italia
Unione Europea Fifth Framework Programme
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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
Bonati M, Pandolfini C, Rossi V, Santoro E, Arnau J, Danés I, Fuentes I, Llobet J, Jacqz-Aigrain E, Zarrabian
S, Choonara I, Sammons H, Smith C. Registering paediatric clinical trials. Paed Perinat Drug Ther 2006;7: 170-171
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. Registri di sperimentazioni cliniche pubblici e privati: è possibile un accordo? Ricerca & Pratica 2006;
n.130: 173-175
Santoro E. Osservatorio Nazionale sulla Sperimentazione Clinica dei medicinali e registri pubblici. SiarNews 2006;
n.49: 44-45
Santoro E. L’Osservatorio nazionale sulla sperimentazione clinica dei medicinali è ora aperto al pubblico.
http://www.partecipasalute.it
Santoro E. “Internet e medicina”. In Enciclopedia Medica Italiana, aggiornamento III, Tomo 1, pp. 1699-1722.
UTET 2006 (a cura del Prof. L. Vella)
Presidenza del Consiglio dei Ministri - Comitato Nazionale per la Bioetica. “Internet e Medicina - Etica, Salute e
Nuove Tecnologie dell’Informazione”. Roma 21 aprile 2006 (writing and reviewing collaboration of the report).
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RESEARCH ACTIVITIES
Research Project DEC-NET: Drug Evaluation in Children – Clinical Trials
in Europe
In 2003 the Laboratory of Medical Informatics has been involved in the development of a web
based register of pediatrics clinical trials. The project is in collaboration with the Laboratory for
Mother and Child Health and is funded through the European Union's Fifth Framework
Programme (QLRT-2001-01054). Four European partners are involved in the project in order to
develop on the Internet a free of charge tool to locate information about clinical trials conducted
in Europe in the pediatrics field. The DEC-NET website (http://www.dec-net.org) including
information about the project and the first research protocols entered by the partner, has been
launched in 2003. In 2004-2006 new features have been developed for this website, including
the data collection and the search tools.
Maintenance of the website for the RISCHIO&PREVENZIONE clinical trial
In collaboration with the Laboratory of General Practice Research (Department of
Cardiovascular Research) we have developed a website for the RISCHIO&PREVENZIONE
clinical trial. Through this website (http://www.rischioeprevenzione.it) 370 general practitioners
involved in the trial may be informed about the study progress and obtain information about the
correct application of the study protocol.
Maintenance of the Istituto Mario Negri's website
In 2003 the new Istituto Mario Negri's website has been released (http://www.marionegri.it).
The layout has been completely modified and the contents re-organized to fit with the new
dynamic structure of the website. New contents and services have been published, including a
"news" section addressed to consumers and health operators. In 2004 the English version of this
website has been released. New features such as the improvement of the Intranet section and the
development of a webmail service have also been added. In 2006 this maintenance activity has
been continued.
Maintenance of the CARDIO.CARE, ONCO.CARE, GASTRO.CARE,
NEURO.CARE, PNEUMO.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), 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).
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Internet as a research and formative tool on the chronic pain in cancer
patient
This researcj project was born in the framework of the project "Pain in the patient with cancer" .
Its aim is to make available for doctors, patients and families correct information about
therapies for cancer pain and to produce greater tests on the effectiveness of therapies based on
the use of analgesic drugs. This project is articulated in two main activities:
- Paincare, set-up a catalogue of selected web pages dedicated to the cancer pain and relative
periodical up-to-date, http://www.paincare.it;
- adaptation of the methods and instruments of Evidence Based Medicine to the resources
available on the Internet about chronic pain in patients with cancer. This is done through a
specific questionnaire. We are also considering the opportunity to set up a new Italian cancer
pain website.
In collaboration with the Laboratory of Medical Research and Consumer Involvement and the
Laboratory of Translational and Outcome Research in Oncology.
Computer center
One of the activities of the Laboratory is the coordination of the computer center. This includes:
supporting users for hardware and software issues on clients and servers computers, the
management of the e-mail service, the administration of the Internet connection and the
Institute’s LAN, the development and maintenance of the Institute’s website, and the software
development for administrative purposes.
Training activities
In 2006 the Laboratory continued its training activity on issues related to “Internet and
Medicine”. The members of the laboratory staff activated (or attended as invited teachers) a
number of training courses and workshops.
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ITALIAN COCHRANE CENTRE
STAFF
Head
Alessandro LIBERATI, M.D.
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CURRICULUM VITAE
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 della Assistenza Sanitaria - Centro Cochrane Italiano (AREAS-CCI); since 2005 he is President
of the Local Ethics Committee of the Local Health Unit of Bologna; 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. Etica conoscenza e sanità. Evidence-based medicine fra ragione e passione. Pensiero Scientifico Editore,
Roma 2005
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Liberati A., D’Amico R., Pifferi S., Leonetti C., Torri V., Brazzi L., Tinazzi A. Antibiotics for preventing respiratory
tract infections in adults receiving intensive care. The Cochrane Library 2005;Issue 4
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Moja L., Telaro E., D’Amico R., Moschetti I., Coe L., Liberati A. Assessment of methodological quality of primary
studies by systematic reviews: results of the metaquality cross sectional study. British Medical Journal 2005;330:10531055
•
GRADE working group (including Liberati A. as member). Grading quality of evidence and strength of
recommendations. British Medical Journal 2004;328:1490-96
•
Liberati A, Moja LP, Moschetti I.The future of clinical research: why do we need an ecological approach? Recenti Prog
Med. 2006; 97:604-10.
•
Vigna-Taglianti F, Vineis P, Liberati A, Faggiano F. Quality of systematic reviews used in guidelines for oncology
practice. Ann Oncol. 2006 ;17:691-701.
•
Clinical Evidence Italian Edition, IV edition, 2006 Zadig, Milano.
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INTRODUCTION TO THE CENTRE'S ACTIVITIES
The Italian Cochrane Centre (ICC) (http://www.cochrane.it) was founded in 1994 and is
affiliated to the Cochrane Collaboration (CC). The CC is an international non profit
organization that prepares, maintains and promotes systematic reviews of the effects of health
care interventions. The main product of the Cochrane Collaboration is the Cochrane Library, a
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.
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.
Agenzia Italiana del Farmaco (AIFA), Roma
Istituto Superiore di Sanità, Roma
Ministero della Salute, Roma
Centro Valutazione Efficacia Assistenza Sanitaria (CeVEAS), Modena
Dipartimento di Epidemiologia della ASL Roma E
Istituto Neurologico "Carlo Besta", Milano
Agenzia Sanitaria Regionale, Regione Emilia Romagna, Bologna
Università degli Studi di Milano
Università di Modena e Reggio Emilia
Azienda Sanitaria Locale 20, Alessandria
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
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Clinical Evidence (Alessandro Liberati)
Evidence Based Health Policy and Research (Alessandro Liberati)
Journal of Clinical Epidemiology (Alessandro Liberati)
Journal of Health Services Research (Alessandro Liberati)
Annals of Internal Medicine (Alessandro Liberati)
British Medical Journal (Alessandro Liberati)
JAMA (Alessandro Liberati)
Evidence Based Health Policy and Research (Alessandro Liberati)
Canadian Medical Association Journal (Alessandro Liberati)
EVENT ORGANIZATION
IV Edition Master on "Evidence Based Medicine and the methodology in healthcare research",
February 2006 –October 2007, Università di Modena e Reggio Emilia
Workshops on " Evidence-based medicine fro librarians and information specialists" April-May
2006, Milan
III Workshop " Systematic reviews diagnosis", II session for junior reviewers May 14-16 2006,
Milan
XI Annual Meeting of the Italian Cochrane Network, November 28 2006, Rome
PARTICIPATION IN EVENTS IN WHICH THE CENTRE WAS
INVOLVED
IV Edition Master on "Evidence Based Medicine and the methodology in healthcare research",
February 2006 –October 2007, Università di Modena e Reggio Emilia
Course on “Systematic reviews and guidelines in nursing”, Nursing School Program 2005/2006
“Cochrane Continental European Entities" April 28- 29 2006, Copenhagen, Denmark
XIV Cochrane Colloquim, 23-26 October 2006, Dublin, Ireland
Istituto di Ricerche Farmacologiche Mario Negri, Milano
AIFA - Agenzia Italiana del Farmaco, Roma
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Amato B, Panico S, Persico G, Rispoli C, Rocco N, Moschetti I, Moja L. Shouldice technique versus other techniques
for inguinal hernia repair. (Protocol) The Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.:
CD001543. DOI: 10.1002/14651858.CD001543.pub2
Floriani I, Torri V, Rotmensz N, Martini N, de Rosa M, de Braud F, Moja L. Approaches to interim analysis of
randomized clinical trials in cancer: a survey from the Italian National Monitoring Centre for Clinical Trials.
Abstracts of the XIV Cochrane Colloquium, p.179. Dublin, Ireland, 23-26 October 2006.
Liberati A, Moja L, Moschetti I. Quali prove di efficacia per quali decisioni? Neurological Science 2006; 27:S1-S5
Moja L, Moschetti I, Liberati A, Gensini GF.Renaissance of a res publica clinical research: global access to trial
registers. Intern Emerg Med. 2006;1:310-1.
Moja L, Brambilla C, Compagnoni A, Pistotti V. Trastuzumab containing regimens for early breast cancer (Protocol)
The Cochrane Library, 2006
Moja L, Brambilla C, Compagnoni A, McGowan JL, Nurbhai M, Pistotti V. Trastuzumab containing regimens for
metastatic breast cancer (Protocol) The Cochrane Library, 2006
Moschetti I, Moja L, Colombo C, Carra L, Satolli R, Mosconi P, Liberati A. How Cochrane reviews can be used in a
dissemination project: preliminary findings from the “PartecipaSalute” project in Italy. Abstracts of the XIV
Cochrane Colloquium, p.93. Dublin, Ireland, 23-26 October 2006.
Parmelli E, D’Amico R, Bassi C, Bonacini I, Coco L, Falcone C, Filippini G, Galletti C, Grisolia D, Lazzeri S,
Magnano L, Minozzi S, Moja PL, Moschetti I, Papini D, Pistotti V, Sala V, Telaro E, Vignatelli L, Viviano M,
Liberati A Where the outcomes reported in systematic reviews stated in protocols?
Poster, 14 Cochrane Colloquium, Dublin, October 2006
.
Deligant C, Dri P, Liberati A, Manfrini R, Moschetti I, Moja L, Satolli R. Il Progetto ECCE: i risultati di un modello
di formazione a distanza orientato sul caso clinico. Bollettino d’Informazione sui Farmaci 2006; 1(XIII):10-18
Mosconi P, Liberati A, Satolli R
Il corso di PartecipaSalute allo specchio: i commenti del comitato organizzatore
http://www.partecipasalute.it/attivita/corso-001-comm-com-org.php 2006
Liberati A, Moja L, Moschetti I
Le mete per un'ecologia della ricerca clinica
Recenti Prog Med 2006; 97: 604-610
Liberati A, Moja LP, Moschetti I.The future of clinical research: why do we need an ecological approach? Recenti
Prog Med. 2006; 97:604-10.
Mosconi P, Liberati A, Satolli R
Il corso di PartecipaSalute allo specchio: i commenti del comitato organizzatore
http://www.partecipasalute.it/attivita/corso-001-comm-com-org.php 2006
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RESEARCH ACTIVITIES
Educational and dissemination activities
During 2006 the ICC contributed to the organization of the “Master in Evidence-based
Medicine and Methodology of Healthcare Research”, held at the University of Modena
and Reggio Emilia
During 2006 the ICC has continued its collaboration to the project “ECCE” (Continuing
Education Clinical Evidence), started in 2005 as part of a national program of CME (Continuing
Medical Education) of the Italian National Health Service.
In 2006 the ICC, under the aegis of the Italian Ministry of Health, prepared the fourth Italian
edition of “Clinical Evidence”, a summary of the best evidence of effectiveness produced by the
BMJ Publishing Group, largely based on the systematic reviews of the Cochrane Collaboration.
The ICC and the researchers associated with it have collaborated in the production of
different Cochrane systematic reviews. In December 2006 there were seven reviews and seven
protocols available on the Cochrane
Research activities
a) Methodology of systematic reviews
The ICC staff is involved in several projects (together with other international research groups)
aimed at identifying valid and reproducible methodological tools to measure the quality of
systematic reviews.
b) Assessing the impact of educational interventions
In the framework of the ECCE project the ICC is conducting a systematic review of the effects
of distance learning programs.
The results of the review will be instrumental to the design of a randomised trials that the ICC
has been conducted in 2006, in collaboration with the Italian Drug Agency - sponsor of the
ECCE project - to assess the impact of ECCE.
c) Dissemination and implementation of evidence based information to consumers groups
In 2006 the ICC has continued its collaboration with the Laboratory of Medical Research and
Consumer Involvement directed by Paola Mosconi and Zadig, Editorial Publishing Company, to
a project aimed at promoting a strategic alliance between scientific societies and patient
advocacy groups. The objectives of the project are:
1.to orientate patients, citizens and their associations towards active participation in healthcare
and choices in medicine;
2.to orientate the professional and scientific organizations towards creating a constructive
relationship with patients and citizens;
3.to start a transparent partnership between patients and citizens and the health care system.
This project also included the maintenance of the "Partecipasalute" website
(http://www.partecipasalute.it). This web portal is aimed at providing patients, citizens and their
associations with the critical tools necessary to participate more actively and to be better
informed on healthcare topics and choices.
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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. The Center, built in 1987 thanks to a donation from Mrs. Angela
Marchegiano Borgomainerio, consists of three floors and houses the Molecular Biology
Laboratory, the General Epidemiology Laboratory, the Translational and Outcome Research in
Oncology Laboratory, the New Drugs Development Strategies Laboratory, the Oncological
Studies Office and Documentation Laboratory, the Neurological Disorders Laboratory, the
Clinical Trials Laboratory, the Laboratory of Medical Research and Consumer Involvement and
the Italian Cochrane Center.
However, the original purpose of this building was as 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.
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 which are
both located in Milan.
More information about the Center can be found in the activity report of each Laboratory.
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G.A. PFEIFFER MEMORIAL 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 200 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 five of the most important databases: Medline, Cinhal, 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.
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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2006 PUBLICATIONS
Pistotti V, Colombo Cinzia
Navigare sulla rete alla ricerca della buona informazione
http://www.partecipasalute.it/informati-bene/navigare-001.php 2006
Parmelli E, D’Amico R, Bassi C, Bonacini I, Coco L, Falcone C, Filippini G, Galletti C, Grisolia D, Lazzeri S,
Magnano L, Minozzi S, Moja PL, Moschetti I, Papini D, Pistotti V, Sala V, Telaro E, Vignatelli L, Viviano M,
Liberati A
Where the otcomes reported in systematic reviews stated in protocols?
Poster, 14 Cochrane Colloquium, Dublin, October 2006
Mosconi P, Colombo C, Apolone G, Pisottti V, Zucchetti E, Santoro E, Tamburini M
Internet come strumento di ricerca e informazione sul dolore cronico nei pazienti con cancro,
XIII Congresso Nazionale Società Italiana di Cure Palliative, Bologna, Aprile 2006
Pistotti V
Impact factor: luci e ombre
La Pubblicazione scientifica in medicina: tools per l’autore, Congress Perugia, June 2006
http://www.spvet.it/arretrati/numero-37/007.html
CONTRACTS
Since 1994 the library has been part of the Lombard Biomedical Library System. Sixteen
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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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 Genetics of Rare Diseases
Head
Jessica CAPRIOLI, 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 VITAE
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.
Employement: in 1983 Scientist, IRFMN, Laboratory of Kidney Disease, Bergamo, Italy; in 1990-1994
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 2000Head, Department
of Molecular Medicine, IRFMN, Bergamo, Italy.
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S. Tomasoni, N. Azzollini, F. Casiraghi, M.C. Capogrossi, G. Remuzzi, A. Benigni. CTLA4Ig gene
transfer prolongs survival and induces donor-specific tolerance in a rat renal allograft. J Am Soc
Nephrol 2000;11:747-752.
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G. Remuzzi, N. Perico, A. Benigni. New therapeutics that antagonize endothelin: promises and frustrations. Nature
Reviews Drug Discovery 2002;1:986-1001.
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Benigni, E. Gagliardini, S. Tomasoni, M. Abbate, P. Ruggenenti, R. Kalluri, G. Remuzzi. Selective impairment of gene
expression and assembly of nephrin in human diabetic nephropathy. Kidney International 2004; 65: 2193-2200.
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Benigni, D. Corna, C. Zoja, L. Longaretti, E. Gagliardini, N. Perico, T.M. Coffman, G. Remuzzi. Targeted deletion of
angiotensin II type 1A receptor does not protect mice from progressive nephropathy of overload proteinuria. J Am Soc
Nephrol 2004;15:2666-2674.
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M. Morigi, S. Buelli, S. Angioletti, C. Zanchi, L. Longaretti, C. Zoja, M. Galbusera, S. Gastoldi, P. Mundel, G. Remuzzi,
A. Benigni. In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication
for permselective dysfunction of chronic nephropathies. Am J Pathol 2005;166:1309-1320.
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.
Murine embryonic stem cell therapy to correct the genetic defect characteristic of Fabry disease in an
experimental mouse model.
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M. Morigi, B. Imberti, C. Zoja, D. Corna, S. Tomasoni, M. Abbate, D. Rottoli, S. Angioletti, A. Benigni, N. Perico, M.
Alison, G. Remuzzi. Mesenchymal Stem Cells Are Renotropic, Helping to Repair the Kidney and Improve Function in
Acute Renal Failure. J Am Soc Nephrol 2004;15:1794-1804.
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C. Zoja, M. Morigi, A. Benigni, G. Remuzzi. Genetics of rare diseases of the kidney: learning from mouse models.
Cytogenet Genome Research 2004;105: 479-484.
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Remuzzi, S. Mantero, M. Colombo, M. Morigi, E. Binda, D. Camozzi, B. Imberti. Vascular smooth muscle cells on
hyaluronic acid: culture and mechanical characterization of an engineered vascular construct. Tissue Eng 2004;10:699710.
M. Galbusera, S. Buelli, S. Gastoldi, D. Macconi, S. Angioletti, C. Testa, G. Remuzzi, M. Morigi. Activation of porcine
endothelium in response to xenogeneic serum causes thrombosis independently of platelet activation. Xenotransplantation
2005:12;110-120.
M. Morigi, S. Buelli, S. Angioletti, C. Zanchi, L. Longaretti, C. Zoja, M. Galbusera, S. Gastoldi, P. Mundel, G. Remuzzi,
A. Benigni. In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication
for permselective dysfunction of chronic nephropathies. Am J Pathol 2005;166:1309-1320
Marina Noris got her degree in Pharmaceutical Chemistry and Technologies in 1986 at the University
of Rome “La Sapienza) and the Ph.D. at Maastricht University, Netherlands, in 2005.
Educational training: in 1984-1986 Fellow, Istituto di Chimica Farmaceutica e Tossicologica, University
of Rome, Italy; in 1986-1987 Post Doctoral Fellow, Istituto di Chimica Farmaceutica e Tossicologica,
University of Rome, Italy; in September 1987-March 1994 Post Doctoral Fellow, IRFMN, Unit of
Mediators of Inflammation and Tissue Damage, Laboratory of Kidney Disease, Bergamo, Italy.
Areas of interest: immunology of transplantation, tolerance induction; genetics of hemolytic uremic
syndrome, thrombotic thrombocytopenic purpura, focal segmental glomerulosclerosis, diabetic
nephropathy, role of nitric oxide and arginine dysfunctions in uremia and in pre-eclampsia.
Employment: in 1994-1996 Head, Unit of Endothelial Cell Pathophysiology, IRFMN, Bergamo, Italy;
1996-1999 Head, Laboratory of Cellular and Molecular Biology of the immune response and
autoimmunity, IRFMN, Italy; from January 2000: Head, Laboratory of Immunology and Genetics of Rare
Diseases and Organ Transplantation, Department of Molecular Medicine, IRFMN, Bergamo, Italy.
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Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PF. Mutations in
factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J
Clin Invest 2003; 111: 1181-1190.
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; 362:15421547.
Caprioli J, Castelletti F, Bucchini S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M, on
behalf of the International Registry of Familial and Recurrent HUS/TTP. Complement factor H mutations and gene
polymorphisms in hemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly
associated with the disease. Hum Mol Genet 2003; 12:3385-3395.
Noris M, Bucchioni s, Galbusera M, Donadelli R, Bresin E, Castelletti F, Caprioli J, Brioschi S, Scheiflinger F, Remuzzi G and
the International Registry of Recurrent and Familial HUS/TTP. Complement factor H mutation in familial thrombotic
thrombocytopenic purpura with ADAMTS13 deficency and renal involvement. J Am Soc Nephrol 2005; 16:1177-1183
G. Remuzzi, P. Ruggenenti, D. Codazzi, M. Noris, J. Caprioli, G. Locatelli, B. Gridelli. Combined kidney and liver
transplantation for familial hemolytic uraemic syndrome. Lancet 2002; 359:1671-1672.
M. Noris, D. Cugini, F. Casiraghi, N. Azzollini, L. De Deus Viera Moraes, M. Mister, A. Pezzotta, R. Aparecida Cavinato, S.
Aiello, N. Perico, G. Remuzzi. Thymic microchimerism correlates with the outcome of tolerance-Inducing protocols for solid
organ transplantation. J Am Soc Nephrol 2001;12:2815-2826
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.
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.
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C.Zoja, S. Angioletti, R. Donadelli, C. Zanchi, S. Tomasoni, E. Binda, B. Imberti, M. te Loo, L. Monnens, G.Remuzzi,
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M. Morigi. Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-kB dependent up-regulation
of IL-8 and MCP-1. Kidney Int 2002;62:846-856.
C. Zoja, D. Corna, D. Camozzi, D. Cattaneo, D. Rottoli, C. Batani, C. Zanchi, M. Abbate, G. Remuzzi. How to fully
protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol
2002;13:2898-2908.
A. Benigni, C. Zoja, D. Corna, C. Zatelli, S. Conti, M. Campana, E. Gagliardini, D. Rottoli, C. Zanchi, M.
Abbate,
S. Ledbetter, G. Remuzzi. Add-on anti-TGF-b antibody to ACE inhibitor arrests progressive diabetic nephropathy in the
rat. J Am Soc Nephrol 2003;14:1816-1824.
R. Donadelli, C. Zanchi, M. Morigi, S. Buelli, C. Batani, S. Tomasoni, D. Corna, D. Rottoli, A. Benigni, M. Abbate, G.
Remuzzi, C. Zoja. Protein overload induces fractalkine upregulation in proximal tubular cells through NF-kB and p38
MAPK dependent pathways. J Am Soc Nephrol 2003; 14:2436-2446.
Benigni, C. Zoja, S. Tomasoni, M. Campana, D. Corna, C. Zanchi, E. Gagliardini, E. Garofano, D. Rottoli, T. Ito, G.
Remuzzi, Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-gamma agonist:
molecular mechanism of the antiproteinuric effect of pioglitazone. J Am Soc Nephrol, 2006; 17; 1624-32.
C.Zoja, D. Corna, D. Rottoli, C. Zanchi, M. Abbate and G. Remuzzi. Imatinib ameliorates renal diseases and survival
in murine lupus autoimmune diseases. Kidney International 2006; 70; 97-103.
Mauro Abbate got his M.D. degree in 1988 at the University of Brescia.
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.
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Abbate M, Zoja C, Rottoli D, Corna D, Tomasoni S, Remuzzi G: Proximal tubular cells promote fibrogenesis by TGF1-mediated induction of peritubular myofibroblasts. Kidney International 2002;61,2066-2077.
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Abbate M, Zoja C, Morigi M, Rottoli D, Angioletti S, Tomasoni S, Zanchi C, Longaretti L, Donadelli R, Remuzzi G:
Transforming Growth Factor- 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.
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Ruggenenti P, Chiurchiu C, Brusegan V, Abbate M, Perna A, Filippi C, Remuzzi G: Rituximab for idiopathic
membranous nephropathy: a one year prospective study. J Am Soc Nephrol. 2003; 14,1851-1857.
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Benigni A, Gagliardini E, Tomasoni S, Abbate M, Ruggenenti P, Kalluri R, Remuzzi G.: Selective impairment of gene
expression and assembly of nephrin in human diabetic nephropathy. Kidney Int. 2004; 65:2193-200.
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Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M, Rottoli D, Angioletti S, Benigni A, Perico N, Alison M,
Remuzzi G.:Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal
failure. J Am Soc Nephrol. 2004;15:1794-804.
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Abbate M, Corna D, Rottoli D, Zanche C, Cassis P, Morigi M, Zoja C, Remuzzi G: An intact complement pathway is not
dispensable for glomerular and tubulointerstitial injury induced by protein overload. J Am Soc Nephrol 2004;15:479A.
Sistiana Aiello got the Biol.Sci. degree in 1993 at the University of Milano, Italy, and the Specialization
in Pharmacology Research in 1996, at IRFMN, Bergamo, Italy.
Educational training: in 1990-1993 research training, IRFMN, Bergamo; in 1993-2000 post doctoral
fellow, IRFMN, Bergamo.
Areas of interest: transplant immunology with a particular interest on dendritic cell biology and
mechanisms by which T regulatory cells arise and work; in vitro and in vivo studies on new compounds
with immunosuppressive capacity or capable to prevent ischemia/reperfusion tissue injury; vasoactive and
inflammatory mediators of progressive renal injury with a particular emphasis on platelet activating factor
(PAF) and nitric oxide (NO).
Employement: since 2000 Scientist within Laboratory of Immunology and Genetics of Rare disease and
Organ Transplantation; IRFMN, Bergamo; since 2006 Head, Unit of Cellular Biology of Autoimmunity
and Transplant Rejection, IRFMN, Transplant Research Center “Chiara Cucchi de Alessandri e Gilberto
Crespi”, Ranica.
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S. Aiello, P. Cassis, L. Cassis, S. Tomasoni, A. Benigni, A. Pezzotta, R.A. Cavinato, D. Cugini, N. Azzollini, M. Mister,
L. Longaretti, A.W. Thomson, G. Remuzzi, M. Noris. DnIKK2-transfected dendritic cells induce a novel population of
iNOS-expressing CD4+CD25- cells with tolerogenic properties. Transplantation 2007; in press.
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S. Tomasoni, S. Aiello, L. Cassis, M. Noris, L. Longaretti, R.A. Cavinato, N. Azzollini, A. Pezzotta, G. Remuzzi, A.
Benigni. Dendritic cells genetically engineered with adenoviral vector encoding dnIKK2 induce the formation of potent
CD4+ T regulatory cells. Transplantation 2005;79:1056-1061.
L. Cassis, S. Aiello, M. Noris. Natural versus adaptive regulatory T cells. Contrib Nephrol 2005; 146: 121-131.
M. Mister, M. Noris, J. Szymczuk, N. Azzollini, S. Aiello, A. Arduini, L. Trochimowicz, E. Gagliardini, M. Abbate, N.
Perico, G. Remuzzi. Propionyl-L-carnitine prevents renal function deterioration due to ischemia/reperfusion in isolated
perfused rat kidney and in kidney graft. Kidney Int 2002; 61:1064-1078.
S. Aiello, M. Noris, G. Piccinini, S. Tomasoni, F. Casiraghi, S. Bonazzola, M. Mister, M.H. Sayegh, G. Remuzzi.
Thymic dendritic cells express inducible nitric oxide synthase and generate nitric oxide in response to self- and
alloantigens. J Immunol 2000;164:4649-4658.
Jessica Caprioli got the Biological Science degree in 1994 at the University of Pavia, Italy, and the
Specialization in Medical Genetics in 2001 at the University of Milano, Italy.
Educational training: stage at St. John’s College in Cambridge for studies at the Department of Genetics,
1994. Medical Research Assistant, Lundbeck Italia S.p.A, 1995. Training for Biological Scientist
Professional Qualification at the Laboratory of cellular and molecular biology of the immune response
and autoimmunity, IRFMN, Negri Bergamo Laboratories (qualification obtained in 1997). School of
Professional Education in Pharmacological Research of Regione Lombardia (Specialization obtained in
1998). Specialization School in Medical Genetics (University of Milano), obtained in 2001.
Areas of interest: Role of the complement system in the pathogenesis of hemolytic uremic sindrome and
thrombotic thrombocytopenic purpura. Research of the genes involved in the predisposition to focal
segmental glomerulosclerosis. Study of the genes that determine the onset of proteinuria in an
experimental animal model. Research of the genes involved in the pathogenesis of uric acid
nephrolithiasis.
Employement: 1995-2001 grant recipient at the Laboratory of cellular and molecular biology of the
immune response and autoimmunity, IRFMN, Negri Bergamo Laboratories. 2002-2006 researcher at the
Laboratory of immunology and genetics of rare diseases and transplantation, IRFMN, Negri Bergamo
Laboratories. Since 2006 head of the Unit of genetics of renal diseases.
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M. Galbusera, M. Noris, C. Rossi, S. Orisio, J. Caprioli, Z.M. Ruggeri, B. Amadei, P. Ruggenenti, B. Vasile, G. Casari
and G. Remuzzi on behalf of the Italian Registry of Familial and Recurrent HUS/TTP. Increased fragmentation of von
Willebrand factor, due to abnormal cleavage of the subunit, parallels disease activity in recurrent hemolytic uremic
syndrome and thrombotic thrombocytopenic purpura (HUS/TTP) and discloses genetic predisposition in families. Blood,
1999; 94: 1-12.
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J. Caprioli, P. Bettinaglio, PF Zipfel, B. Amadei, E. Daina, S. Gamba, C. Skerka, N. Marziliano, G. Remuzzi and M.
Noris on behalf of the Italian Registry of Familial and Recurrent HUS/TTP. The molecular basis of familial hemolytic
uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. Journal of the
American Society of Nephrology, 2001; 12:297-307.
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J. Caprioli, F. Castelletti, S. Bucchioni, P. Bettinaglio, E. Bresin, G. Pianetti, S. Gamba, S. Brioschi, E. Daina, G.
Remuzzi and M. Noris. For the International Registry of Recurrent and Familial HUS/TTP. Complement Factor H
mutations and gene polymorphisms in hemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T
polymorphisms are strongly associated with the disease Human molecular genetics, 2003; 12:1-11.
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M. Noris, S. Brioschi, J. Caprioli, M. Todeschini, E. Bresin, F. Porrati, S. Gamba and G. RemuzziFor the International
Registry of Recurrent and Familial HUS/TTP. Mutation in membrane cofactor protein of the complement system in
familial hemolytic uraemic syndrome. Identification of a second disease-associated gene The Lancet, 2003; 362:15421547.
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Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F,
Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: the
impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood, 2006;
108(4):1267-79.
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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:
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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; in press
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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.
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Zoja C, Benigni A, Noris M, Corna D, Casiraghi F, Pagnoncelli M, Rottoli D, Abbate M, Remuzzi G. Mycophenolate
mofetil combined with a cyclooxygenase-2 inhibitor ameliorates murine lupus nephritis. Kidney Int. 2001; 60(2): 65363.
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Tomasoni S, Noris M, Zappella S, Gotti E, Casiraghi F, Bonazzola S, Benigni A, Remuzzi G. Upregulation of renal and
systemic cyclooxygenase-2 in patients with active lupus nephritis.
J Am Soc Nephrol.1998; 9(7): 1202-12.
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Casiraghi F, Ruggenenti P, Noris M, Locatelli G, Perico N, Perna A, Remuzzi G. Sequential monitoring of urinesoluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or
laboratory signs of renal dysfunction. Transplantation 1997; 63(10): 1508-14.
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.
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Tripodi, A., Chantarangkul, V., Bohm, M., Budde, U., Dong, J.-F., Friedman, K.D., Galbusera, M., Girma, J.-P., Moake,
J., Rick, M.E., Studt, J.-D., Turecek, P.L., Mannucci, P.M.: Measurement of von Willebrand factor cleaving protease
(ADAMTS-13): results of an international collaborative study involving 11 methods testing the same set of coded
plasmas. J Thromb Haemost 2004; 2:1601-1609.
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Galbusera, M., Morigi, M., Buelli, S., Gastoldi, S., Macconi, D., Testa, C., Angioletti, S., Remuzzi, G.: Xenogeneic
serum-induced thrombus formation on porcine endothelium is mediated by vitronectin receptor and P-selectin: role of
reactive oxygen species. Xenotransplantation 2005;12:110-120.
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Ruiz-Torres, M.P., Casiraghi, F., Galbusera, M., Macconi, D., Gastoldi, S., Todeschini, M., Porrati, F., Belotti, D.,
Pogliani, E.M., Noris, M., Remuzzi, G.: Complement activation: the missing link between ADAMTS13 deficiency and
microvascular thrombosis of thrombotic microangiopathies. Thromb Haemost 2005; 93:443-452.
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Noris, M., Bucchioni, S., Galbusera, M., Donadelli, R., Bresin, E., Castelletti, F., Caprioli, J., Brioschi, S., Scheiflinger,
F., Remuzzi, G.: Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13
deficiency and renal involvement. J Am Soc Nephrol 2005; 16:1177-1183.
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Galbusera, M., Bresin, E., Noris, M., Gastoldi, S., Belotti, D., Capoferri, C., Daina, E., Perseghin, P., Scheiflinger, F.,
Fakhouri, F., Grunfeld, J-P., Pogliani, E., Remuzzi, G.: Rituximab prevents recurrence of thrombotic thrombocytopenic
purpura: a case report. Blood 2005;106:925-928.
•
Rieger, M., Mannucci, P.M., Kremer Hovinga, J.A., Herzog, A., Gerstenbauer, G., Konetschny, C., Zimmermann, K.,
Scharrer, I., Peyvandi, F., Galbusera, M., Remuzzi, G., Böhm, M., Plaimauer, B., Lämmle, B., Scheiflinger, F.:
ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood
2005;106:1262-1267.
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Susanna Tomasoni got her Biological Science degree in 1991 at the University of Milan.
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; in 1995 PhD degree in Physiological Science, University of Bologna;
1995-1998: Post Doctoral Fellow, IRFMN, Bergamo, Italy.
Areas of interest: construction of adenoviral vectors for gene therapy; gene transfer to the kidney in the
context of transplantation; transfection of dendritic cell for cell therapy; progression of renal disease.
Employement: in 1998-2000 Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of Gene Therapy,
IRFMN, Bergamo, Italy
•
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: 747-752.
•
Tomasoni S, Benigni A. Gene therapy: How to target the kidney. Promises and pitfalls. Curr Gene Ther 2004; 4: 115122.
•
Tomasoni S, Longaretti L, Azzollini N, Gagliardini E, Mister M, Buehler T, Remuzzi G, Benigni A. Favorable effect of
cotransfection with TGF-beta and CTLA4Ig of the donor kidney on allograft survival. Am J Nephrol 2004; 24: 275-283
•
Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M, Rottoli D, Angioletti S, Benigni A, Perico N, Alison
M, Remuzzi G. Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal
failure. J Am Soc Nephrol 2004; 15: 1794-1804
•
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: 1056-1061.
•
Benigni A, Tomasoni S, Turka LA, Longaretti L, Zentilin L, Mister M, Pezzotta A, Azzollini N, Noris M, Conti S,
Abbate M, Giacca M, Remuzzi G, Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched
renal allografts from chronic rejection. J Am Soc Nephrol, 2006, 17: 1665-72.
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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.
Loss of factor H-dependent complement regulation mediates proximal tubular cell dysfunction
on protein overload
Treatment with a platelet derived growth factor receptor inhibitor prolongs survival in mice with
lupus nephritis.
Anti-TGF-beta antibody therapy protects mice against cisplatin-induced acute renal failure.
Gene therapy to the donor organ with adeno-associated virus prevents chronic rejection of the
graft without the need of immunosuppressants.
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A novel population of T regulatory cells with immuno modulatory properties on allogenic graft
rejection has been identified.
Mechanisms and mediators responsible for T regulatory cell expansion have been identified in
transplant patients.
The presentation, the response to therapy and the outcome of the disease are influenced by the
genotype in patients with familial HUS.
Dipartimento di Scienze Farmacologiche, Università di Milano
Laboratorio di Terapia genica e cellulare, G. Lanzani, Divisione di Ematologia, Ospedali Riuniti
di Bergamo
Laboratorio di Tecnologie riproduttive, Istituto Sperimentale Lazzaro Spallanzani, Cremona
Centro Trasfusionale e di Immunologia dei Trapianti, IRCCS Ospedale Maggiore, Milano
Dipartimento di Istologia Microbiologia e Biotecnologie Mediche, Università di Padova
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
I.R.C.C.S. Ospedale Pediatrico Bambino Gesù, Roma
I.R.C.C.S. Policlinico San Matteo, Pavia
Azienda Sanitaria Ospedaliera O.I.R.M. - S. Anna, Torino
U.O. Reumatologia, Azienda Ospedaliera Spedali Civili di Brescia
Istituto Gaslini, Laboratorio di Nefrologia, Genova
Academisch Ziekenhuis Maastricht, Interne Geneeskunde, Maastricht, The Netherlands
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA
Children's Hospital and Regional Medical Center, University of Washington, Seattle, USA
Erasmus University of Rotterdam, The Netherlands
Hans-Knoll Institute for Natural Products Research, Jena, Germany
Inselspital, University of Bern, Switzerland
INSERM, Paris, France
Max Delbruck Center for Molecular Medicine, Berlin, Germany
Monash Medical Center, Melbourne, Australia
National Institute of Health, Bethesda, USA
Osaka University School of Medicine, Osaka, Japan
Pediatric Nephrology and Hypertension, University of Utah, USA
Rosalind Franklin University of Medicine and Science, Chicago, USA
The Scripps Research Institute, La Jolla, USA
Universitaet Hamburg, Institut fur Molekulare Neuropathobiologie, Hamburg, Germany
University of Colorado Cardiovascular Institute, Denver, USA
University of Groningen, The Netherland
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University of Iowa, Department of Internal Medicine and Pediatrics, Iowa City, USA
University of Liverpool, School of Biological Sciences, UK
University of Pittsburgh School of Medicine, Pittsburgh, USA
Weizman Institute of Science, Rehovot, Israel
Kidney International (Ariela Benigni)
Journal of American Society of Nephrology (Carla Zoja)
American Journal of Kidney Diseases
American Journal of Nephrology
American Journal of Pathology
American Journal of Physiology-Renal Physiology
American Journal of Transplantation
BMC Cancer
British Journal of Hematology
Current Medicinal Chemistry
Diabetes
Gene Therapy
Kidney International
Laboratory Investigation
Journal of American Society of Nephrology
Journal of Clinical Investigation
Journal of Immunology
Journal of Rheumathology
Journal Laboratory Clinical Medicine
Nature Medicine
Nephrology, Dialysis and Transplantation
Nephron
New England Journal of Medicine
Plos
Pnas
PPAR Research
Transplantation
Transplant International
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INVOLVED
39th annual meeting of American Society of Nephrology, San Diego, November 14-19, 2006.
Advanced workshop on nephroprotection – Nephrology workshop for Turkish Nephrologists,
“Stem cells to repair the kidney”, Ranica, May 26-27, 2006
3rd AISF Single Topic, Application of experimental hepatology on stem cells, Padova, 26-27
May 2006
Corso di aggiornamento “Insufficienza renale acuta nel paziente critico: aspetti fisiopatologici e
approccio terapeutico”, Parma, 5-6 June 2006
2nd Bergamo Workshop on Hemolytic Uremic Syndrome, Centro Daccò, Ranica (BG),
November 30th and December 1st 2006
EHA Scientific Workshop on Biology and Clinical application of Mesenchimal Stem Cells,
Cannes, 6-8 October 2006
48° Congresso dell’American Society of Heamatology (ASH), Orlando, Florida (USA), 9-12
December 2006.
4th PhD Meeting, Riva del Garda (TN), January 23-25 2006
GRIP Meeting, LaJolla, California, November 19-20, 2006
World Transplant Congress, Boston (USA), 22-27 July 2006
Remission Clinic, Bergamo, 15-16 September 2006
World Health Organization, “Screening for preeclampsia: evaluation of the predictive ability of
angiogenic factors for preeclampsia”, Lisbona, 30 June - 1 July 2006
6th International Podocyte Conference, “Transcriptional regulation of nephrin gene by PPARGAMMA agonist: molecular mechanism of the antiproteinuric affetc of piglitazone”, Helsinki,
Finland, 8-11 June 2006
Vascular complications of systemic disbase: mechanisms and consequences. “Endothelial
factors and renal vascular diseases”, Royal college of Physicians, Londra, 7 July 2006
Associazione Ricerca Trapianti
Comitato Telethon Fondazione ONLUS
Commissione Europea
Fondazione Aiuti per la Ricerca sulle Malattie Rare
Fondazione Cariplo
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Johnson & Johnson Pharmaceutical
Amgen Inc
ACRAF (Aziende Chimiche Riunite Angelini Francesco Spa)
AstraZeneca Ltd
Farmaceutici Damor Spa
Genzyme Corporation
Giuliani Spa
Novartis Farma SpA
Speedel Pharma Ltd
D. Macconi, M. Bonomelli, A. Benigni, T. Plati, F. Sangalli, L. Longaretti, S. Conti, H. Kawachi, P. Hill, G.
Remuzzi, A. Remuzzi. Pathophysiologic implications of reduced podocyte number in a rat model of progressive
glomerular injury. Am J Pathol 2006;168:42-54.
G. Remuzzi, A. Benigni, A. Remuzzi. Mechanisms of progression and regression of renal lesions of chronic
nephropathies and diabetes. J Clin Invest 2006;116:288-296.
E. Bresin, E. Daina, M. Noris, F. Castelletti, R. Stefanov, P. Hill, T.M. Goodship, G. Remuzzi for the International
Registry of Recurrent and Familial HUS/TTP. Outcome of renal transplantation in patients with non-Shiga Toxinassociated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol
2006;1:88-99.
M. Galbusera, M. Noris, G. Remuzzi. Thrombotic thrombocytopenic purpura – Then and now. Semin Thromb
Hemost 2006;32:81-89.
C. Zoja, M. Abbate, G. Remuzzi. Progression of chronic kidney disease: insights from animal models. Curr Opin
Nephrol Hypertens 2006;15:250-257.
D. Macconi, M. Abbate, M. Morigi, S. Angioletti, M. Mister, S. Buelli, M. Bonomelli, P. Mundel, K. Endlich, A.
Remuzzi, G. Remuzzi. Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the
molecular target for renoprotective intervention. Am J Pathol 2006;168:1073-1085.
A. Remuzzi, E. Gagliardini, F. Sangalli, M. Bonomelli, M. Piccinelli, A. Benigni, G. Remuzzi. ACE inhibition
reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease. Kidney Int
2006;69:1124-1130.
L. Gallon, E. Gagliardini, A. Benigni, D. Kaufman, A. Waheed, M. Noris, G. Remuzzi. Immunophenotypic analysis
of cellular infiltrate of renal allograft biopsies in patients with acute rejection after induction with Alentuzumab
(Campath-1H). Clin J Am Soc Nephrol 2006;1:539-545.
C. Zoja, D. Corna, D. Rottoli, C. Zanchi, M. Abbate, G. Remuzzi. Imatinib ameliorates renal disease and survival in
murine lupus autoimmune disease. Kidney Int 2006;70:97-103.
A. Benigni, S. Tomasoni, L.A. Turka, L. Longaretti, L. Zentilin, M. Mister, A. Pezzotta, N. Azzollini, M. Noris, S.
Conti, M. Abbate, M. Giacca, G. Remuzzi. Adeno-Associated Virus-mediated CTLA4Ig gene transfer protects
MHC-mismatched renal allografts from chronic rejection. J Am Soc Nephrol 2006;17:1665-1672.
A. Benigni, C. Zoja, S. Tomasoni, M. Campana, D. Corna, C. Zanchi, E. Gagliardini, E. Garofano, D. Rottoli, T. Ito,
G. Remuzzi. Transcriptional regulation of nephrin gene by peroxisome proliferators-activated receptor- agonist:
molecular mechanism of the antiproteinuric effect of pioglitazone. J Am Soc Nephrol 2006;17:1624-1632.
J. Caprioli, M. Noris, S. Brioschi, G. Pianetti, F. Castelletti, P. Bettinaglio, C. Mele, E. Bresin, L. Cassis, S. Gamba,
F. Porrati, S. Bucchioni, G. Monteferrante, C.J. Fang, M.K. Liszewski, D. Kavanagh, J.P. Atkinson, and G. Remuzzi
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for the International Registry of Recurrent and Familial HUS/TTP. Genetics of HUS: the impact of MCP, CFH, and
IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108:1267-1279.
M. Morigi, A. Benigni, G. Remuzzi, B. Imberti. The regenerative potential of stem cells in acute renal failure. Cell
Transplant 2006;15(Suppl. 1):S111-S117.
R. Donadelli, F. Banterla, M. Galbusera, C. Capoferri, S. Bucchioni, S. Gastoldi, S. Nosari, G. Monteferrante, Z.M.
Ruggeri, E. Bresin, F. Scheiflinger, E. Rossi, C. Martinez, R. Coppo, G. Remuzzi, M. Noris on behalf of the
International Registry of Recurrent and Familial HUS/TTP. In-vitro and in-vivo consequences of mutations in the
von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura. Thromb Haemost
2006;96:454-464.
M. Abbate, C. Zoja, G. Remuzzi. How does proteinuria cause progressive renal damage? J Am Soc Nephrol
2006;17:2974-2984.
C. Zoja, G. Remuzzi. Interstitial nephritis. In: Principles of Molecular Medicine, 2nd ed. chapter n° 62. Edited by
M.S. Runge, Humana Press, Totowa, New Jersey 2006, pp. 636-642
R. Donadelli, J.N. Orje, C. Capoferri, G. Remuzzi, Z.M. Ruggeri. Size regulation of von Willebrand factor-mediated
platelet thrombi by ADAMTS13 in flowing blood. Blood 2006;107:1943-1950.
M. Noris, G. Remuzzi. Non-Shiga toxin-associated hemolytic uremic syndrome. In: Complement and Kidney
Disease. Edited by P.F. Zipfel, Birkhauser Verlag, Basel. Switzerland 2006, pp. 65-83.
M. Noris, G. Remuzzi. Complement factor H gene abnormalities in hemolytic uraemic syndrome: from point
mutations to hybrid gene. PLoS Med 2006;3:1719-1720.
M. Morigi, S. Buelli, C. Zanchi, L. Longaretti, D. Macconi, A. Benigni, D. Moioli, G. Remuzzi, C. Zoja. Shigatoxininduced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol
2006;169:1965-1975.
A. Benigni, C. Zoja, M. Campana, D. Corna, F. Sangalli, D. Rottoli, E. Gagliardini, S. Conti, S. Ledbetter, G.
Remuzzi. Beneficial effect of TGF antagonism in treating diabetic nephropathy depends on when treatment is
started. Nephron Exp Nephrol 2006;104:e158-e168.
M. Noris, G. Remuzzi. Complement factor H gene abnormalities in hemolytic uraemic syndrome: from point
mutations to hybrid gene. PLoS Med 2006;3:1719-1720.
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RESEARCH ACTIVITIES
Laboratory of Cell Biology and Xenotransplantation
Loss of factor H-dependent complement regulation mediates proximal
tubular cell dysfunction on protein overload
Complement activation has a pivotal role in progression of renal injury in chronic proteinuric
nephropathies. Recent studies have documented that proximal tubular epithelial cells (PTEC)
are able to activate complement proteins, via the alternative pathway, leading to complement
deposition. Our study showed that ultrafiltered proteins, such as albumin and transferrin,
followed by incubation with human serum –as a source of complement- enhanced C3 and MAC
deposition on the apical side of PTEC in culture compared with cells exposed to human serum
alone. Moreover, the combination of albumin and serum challenge resulted in a further increase
of fractalkine and TGF expression - known mediators of tubulointerstitial inflammation and
fibrosis - as compared to each stimulus alone. To identify the mechanisms underlying the
increased C3 and MAC deposition on PTEC cell surface in response to protein overload, we
focused on factor H, one of the principal natural inhibitors of the alternative pathway of
complement, theoretically acting on PTEC. For this purpose, we studied whether albumin and
transferrin could modulate factor H binding to cell surface on PTEC exposed to control medium
or in the presence of plasma proteins. Our results showed that exogenous factor H markedly
bound to PTEC. The binding of factor H on cell surface was decreased by pre-treatment with
albumin and transferrin. With immunofluorescence studies we documented that factor H
binding to PTEC surface occurred through heparan sulfate residues whose expression was
clearly reduced by cell exposure to albumin and transferrin, thus leading to a reduced factor H
binding to cell surface. In conclusion, protein overload alters tubular cell phenotype by reducing
the cell capability to counteract complement activation. These effects can be instrumental to
renal disease progression and suggests an important role for factor H-dependent complement
regulation in protecting the kidney against progressive tubulointerstitial damage.
Laboratory of Experimental Models of Kidney Diseases
Imatinib ameliorates renal disease and survival in murine lupus
autoimmune disease.
New Zealand Black/White (NZB/W)F1 hybrid mice spontaneously develop an autoimmune
disease with immune complex glomerulonephritis, proteinuria and progression to renal
insufficiency, reminiscent of human systemic lupus erythematosus (SLE). It is a disease of T
and B cell dysfunction with autoantibodies generated in excess amount capable to react with
nuclear, cytoplasmic or cell surface antigen to form immune complexes that deposit in various
organs, including the kidney. In the kidney glomerular immune deposits evoke an
inflammatory reaction due to the recruitment of mononuclear cells. Cytokines and
chemoattractants generated by renal resident and infiltrating cells amplify and perpetuate
immune complex-mediated injury. Therapies include immunosuppressants associated with
steroids. Both categories of drugs, however, despite their effectiveness cause significant sideeffects.
Platelet derived growth factor (PDGF) has been proved to play an important role in progressive
glomerular disease of SLE. PDGF can be synthesized both by inflammatory cells and resident
renal cells. Its biological effects include promotion of cell proliferation and extracellular matrix
synthesis, chemotaxis, modulation of synthesis of various growth factors, regulation of
inflammatory responses. PDGF isoforms signal through cell surface PDGF receptor tyrosine
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kinase (RTK), the alpha- and the beta-receptors, with different affinities. Ligand binding
induces receptor dimerization and autophosphorylation, leading to activation of cytoplasmic
SH2 domain containing signal transduction molecules thereby initiating various signaling
pathways, including tyrosine phosphorylation and c-fos mRNA induction. Inhibitors of PDGF
receptor tyrosine kinases have been developed recently. Imatinib mesylate (Glivec) is a
selective inhibitor of the tyrosine kinases ABL, PDGF receptors and c-kit. Because of its
capacity to block BCR-ABL oncoprotein it is used clinically in chronic myeloid leukemia.
We investigated whether imatinib could represent a novel therapeutic approach for the cure of
lupus nephritis in NZB/W F1 hybrid mice with established disease. Two groups of NZB/W
mice, starting at five months of age, were given by gavage vehicle or imatinib. Results
showed that imatinib significantly ameliorated animal survival in respect to vehicle. The drug
delayed the onset of proteinuria and limited the impairment of renal function. Imatinib
protected the kidney against glomerular hypercellularity and deposits, tubulointerstitial
damage, and accumulation of mononuclear cells and -smooth actin-positive myofibroblasts.
The abnormal transforming growth factor- mRNA expression in kidneys of lupus mice was
reduced by imatinib. An interesting observation was that the treatment retarded anti-DNA
antibody formation as compared to vehicle, thereby reflecting the immunoregulatory potential
of imatinib in NZB/W mice. In conclusion, findings of amelioration of animal survival and of
renal manifestations in NZB/W lupus mice with established disease by tyrosine kinase
inhibition, suggests the possibility to explore whether imatinib may function as steroidsparing drug in human lupus nephritis.
Anti-TGF-beta antibody treatment attenuates cisplatin-induced acute
renal failure in mice.
Cisplatin is one of the most widely used chemotherapeutic agent for treatment of solid organ
tumors. However, 28 to 36% of patients receiving an initial dose of cisplatin develop acute
renal failure (ARF), due to the preferential drug accumulation within the proximal tubular cells.
Although recent insights into the pathophysiology of ARF have provided new targets for
therapy, there is no currently specific treatment that alters the course of cisplatin-nephrotoxicity.
TGF-beta is a multifunctional cytokine with diverse biological effects on cellular processes
including proliferation, migration, differentiation and apoptosis. TGF-beta isoforms (TGF-b1, b2, and -b3) act by engaging an intracellular signaling cascade of Smad family proteins through
ligand-induced activation of heteromeric transmembrane TGF-beta receptor kinases. Receptoractivated Smad protein complexes accumulate in the nucleus, where they participate in
transcriptional activation of target genes. TGF-beta has been demonstrated to be up-regulated in
response to ischemic events in experimental animals. Inflammatory cytokines, including TGFbeta, are upregulated in the kidney of mice with cisplatin-induced nephrotoxicity. We therefore
explored the effect of an anti-TGF-beta antibody (Ab) in cisplatin-induced ARF in mice and
whether renoprotective effect of TGF-b blockade occurred via inhibition of TGF-beta/Smad
signaling.
ARF was induced in three groups of C57BL6 mice by subcutaneous injecton of cisplatin. At
day 1 and 3 mice received, intraperitoneally the murine anti-TGF-beta antibody, 1D11 (0.5 and
5 mg/kg) or 13C4 irrelevant antibody. At day 4, mice were sacrified. Untreated mice served as
control. Both 1D11 doses significantly protected mice with cisplatin-induced ARF against renal
function impairment. Histologic examination of kidneys from cisplatin-mice given irrelevant
Ab showed proximal tubular cell degeneration, hyaline casts, and cell loss. Kidneys of mice
receiving 1D11 exhibited significantly less tubular damage. Tubular cell apoptosis was limited
by 1D11 in respect to irrelevant Ab. Abnormal expression of TGF-beta mRNA in kidney of
cisplatin-mice was abrogated by 1D11, indicating a positive feedback system for
autostimulation of TGF-beta in cisplatin-induced ARF in mice. Nuclear accumulation of
phosphorylated Smad2 and Smad3 in kidney of cisplatin-mice was suppressed by 1D11,
thereby limiting Smad-SBE complex-forming activity. These results indicate that TGF-beta
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antagonism protects mice against cisplatin-induced ARF, tubular cell damage and apoptosis via
inhibition of activated TGF-beta-Smad signaling.
Laboratory of Immunology and Genetic of Rare Diseases and
Organ Transplantation
DnIKK2-transfected dendritic cells induce a novel population of iNOSexpressing CD4+CD25- cells with tolerogenic properties
In collaboration with the Unit of Gene Therapy
We previously documented that rat bone marrow-derived DCs transfected with an adenovirus
encoding a dominant negative form of IKK2 (dnIKK2), have impaired allostimulatory capacity
and generate CD4+ T cells with regulatory function. Here we investigated the potency, the
phenotype and the mechanism of action of dnIKK2-DC-induced regulatory cells and we
evaluated their tolerogenic properties in vivo. Brown Norway (BN) transfected dnIKK2-DCs
were cultured with Lewis (LW) lymphocytes in primary MLR. CD4+ T cells were purified from
primary MLR and incubated in secondary co-culture MLR with LW lymphocytes. Phenotypic
characterization was performed by FACS and real-time PCR. The tolerogenic potential of CD4+
T cells pre-exposed to dnIKK2-DCs was evaluated in vivo in a model of kidney
allotransplantation. CD4+ T cells pre-exposed to dnIKK2-DCs were CD4+CD25-/dim and
expressed IL-10, TGF-beta, IFN-gamma, IL-2 and inducible nitric oxide synthase (iNOS).
These cells (dnIKK2-Treg), co-cultured (at up to 1:105 ratio) with a primary MLR, suppressed T
cell proliferation to alloantigens. The regulatory effect was cell-to-cell contact-independent
since it was also observed in a transwell system. A NOS inhibitor significantly reverted
dnIKK2-Treg-mediated suppression whereas neutralizing antibodies to IL-10 and TGF-beta had
no significant effect. DnIKK2-Treg given in vivo to LW rats prolonged the survival of a kidney
allograft from BN rats (the donor rat strain used for generating DCs). DnIKK2-Treg is a unique
population of CD4+CD25- T cells expressing high levels of iNOS. These cells potently inhibit T
cell response in vitro and induce prolongation of kidney allograft survival in vivo.
Regulatory T cells and T cell depletion: role of immunosuppressive drugs
Allogeneic immune responses are modulated by a subset of host T cells with regulatory function
(Treg) contained within the CD4+CD25high subset. Evidence exists that Treg expand after peritransplant lymphopenia, inhibit graft rejection and induce and maintain tolerance. Little,
however, is known about the role of Treg in clinical setting. Interleukin (IL)-2 and activation by
T-cell receptor (TCR) engagement are instrumental to generate and maintain Treg, but the
influence of immunosuppressants on Treg homeostasis in humans in vivo has not been
investigated. We monitored Treg phenotype and function during immune reconstitution in renal
transplant recipients undergoing profound T-cell depletion with Campath-1H, who received
sirolimus (SRL), or cyclosporine (CsA), as part of their maintenance immunosuppressive
therapy. CD4+CD25high cells expressing FOXP3 underwent homeostatic peripheral expansion
during immune reconstitution, more intense in patients receiving SRL than in those given CsA.
T cells isolated from peripheral blood long-term post-transplant were hyporesponsive to
alloantigens in both groups. In SRL- but not CsA-treated patients hyporesponsiveness was
reversed by Treg depletion. T cells from CsA-treated patients were anergic. Thus, lymphopenia
and calcineurin-dependent signaling appear primary mediators of CD4+CD25high Treg expansion
in renal transplant patients. The present findings are instrumental to develop ‘tolerance
permissive’ immunosuppressive regimens in clinical setting.
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Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical
presentation, response to treatment, and outcome
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of
hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that
mutations in complement regulatory proteins predispose to non–Shiga toxin–associated HUS
(non-Stx–HUS). We undertook genetic analysis on membrane cofactor protein (MCP),
complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx–HUS. Fourteen, 11,
and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation
frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations
resulted in either reduced protein expression or impaired C3b binding capability. MCPmutated
patients had a better prognosis than CFH-mutated and non-mutated patients. In MCP-mutated
patients, plasma treatment did not impact the outcome significantly: remission was achieved in
around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation
outcome was favorable in patients with MCP mutations, whereas the outcome was poor in
patients with CFH and IF mutations due to disease recurrence. This study documents that the
presentation, the response to therapy, and the outcome of the disease are influenced by the
genotype. Hopefully this will translate into improved management and therapy of patients and
will provide the way to design tailored treatments. (Blood. 2006;108:1267-1279).
Genetic analysis of the Complement Factor H related 5 gene in hemolytic
uraemic syndrome
Several mutations in the CFH gene have been described in non Shiga-toxin-associated
hemolytic uraemic syndrome (non-Stx-HUS), a rare syndrome characterized by hemolytic
anemia, thrombocytopenia and acute renal failure. Mutations in genes encoding other
complement regulatory proteins, membrane cofactor protein (CD46) and complement factor I
(CFI), were also involved in the pathogenesis of the disease. Anyway, mutations in the three
genes account for no more than 50% of cases of non-Stx-HUS.
Human complement factor H related 5 (CFHR5) is a recently characterized member of the
human complement factor H (CFH) family that has been found as a component of immune
deposits in human kidney with sclerotic lesions from different causes. CFHR5 possesses
cofactor activity and has been proposed to play a role in complement regulation in the
glomerulus.
We screened CFHR5 gene for variations potentially involved in the etiology of HUS. Forty-five
patients with HUS and 80 controls were analyzed. Altogether, 5 genetic variants in CFHR5
were found in overall 9/45 HUS patients and in 4/80 controls. Statistical analysis showed that
allelic variants in CFHR5 were preferentially associated with HUS. Based on these data, we
conclude that, though not causative, CFHR5 genetic alterations may play a secondary role in the
pathogenesis of HUS.
Unit of Gene Therapy
AAV-mediated CTLA4Ig gene transfer protects MHC-mismatched renal
allografts from chronic rejection
In collaboration with the Laboratory of Immunology and Genetics of Rare Diseases and Organ
Transplantation
Short-term results of renal transplantation have improved considerably in the past 20 years,
however similar improvements in long-term outcome have not been achieved. This is essentially
due to the rise of chronic rejection that in the kidney is characterized by glomerular membrane
changes and sclerosis, severe tubular atrophy and interstitial fibrosis. We previously
demonstrated that, by the means of gene therapy, it is possible to prevent acute rejection of the
transplanted kidney. Indeed, prolonged survival of the graft was obtained by the delivery into
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the donor kidney of an adenovirus encoding for CTLA4Ig whose protein product was able to
impair locally the contact between transplant antigen and the host immune system without
compromising the generalized immune competence of the recipient. Despite these positive
results, the donor kidney developed chronic rejection that caused the loss of renal allografts.
Crucial for long-term immunomodulation via gene therapy is the use of a vector able to induce
high-level transgene expression when infecting the graft and to drive expression of the
therapeutic gene for a prolonged period without exerting any cytotoxic effect or eliciting any
inflammatory or immune response. To this aim, we transfected the kidney with an adenoassociated vector encoding for a reporter gene to evaluate both the efficiency of transfection and
the transgene expression time. Injection of the vector into the renal artery before transplantation
resulted in the transfection of proximal tubular cells with high efficiency and the virus was still
present 120 days after transplantation. Next experiments were performed transfecting the donor
kidney with an adeno-associated vector encoding for CTLA4Ig. We demonstrated that, in a
fully MHC-mismatched rat strain combination, AAVCTLA4Ig-gene transfer prevented
progressive proteinuria and protected transplant kidneys from renal structural injury completely
halting the progression of glomerular lesions and reducing the severity of tubulointerstitial
injury. AAVCTLA4Ig caused a marked and significant reduction in macrophage infiltration in
respect to untransduced allografts. Moreover, a population of anergic T cells with regulatory
activity, eventually responsible for the induction of tolerance, was found in recipient lymph
nodes and in the graft as long as 120 days after transplantation. These data indicate that AAVmediated CTLA4Ig gene transfer to donor graft represents a promising tool to prevent the onset
of the chronic rejection circumventing the unwanted systemic side effects of the administration
of immunomodulatory protein.
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DEPARTMENT OF BIOMEDICAL
ENGINEERING
STAFF
Head
Andrea REMUZZI, Res.Eng.
Laboratory of Renal Biophysics
Head
Daniela MACCONI, Biol.Sci.D.
Laboratory of Biomedical Technologies
Head
Bogdan ENE-IORDACHE, Res.Eng.
Unit of Tissue Engineering
Head
Marina FIGLIUZZI, Biol.Sci.D.
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CURRICULA VITAE
Andrea Remuzzi got his degree in Mechanical Engineering (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. Since 1998
contract professor Dipartimento di Bioingegneria, Politecnico di Milano.
•
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
•
Morigi M, Micheletti G, Figliuzzi M, Imberti B, Karmali MA, Remuzzi A, Remuzzi G, Zoja C. Verotoxin-1 promotes
leukocyte adhesion to cultured endothelial cells under physiologic flow conditions. Blood. 1995 Dec 15;86(12):4553-8.
PMID: 8541545
•
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
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
•
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.168:42-54, 2006.
•
Ruiz-Torres MP, Casiraghi F, Galbusera M, Macconi D, Gastoldi S, Todeschini M, Porrati F, Belotti D, Pogliani EM, Noris
M, Remuzzi G: Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis
of thrombotic microangiopathies. Thromb Haemost. 93:443-52, 2005.
•
Galbusera M, Buelli S, Gastoldi S, Macconi D, Angioletti S, Testa C, Remuzzi G, Morigi M: Activation of porcine
endothelium in response to xenogeneic serum causes thrombosis independently of platelet activation. Xenotransplantation.
12:110-20, 2005.
•
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
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•
Macconi D, Ghilardi M, Bonassi ME, Mohamed EI, Abbate M, Colombi F, Remuzzi G, Remuzzi A: Effect of angiotensinconverting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in
MWF rats. J Am Soc Nephrol 11:477-89, 2000
Bogdan Ene-Iordache got his MSc in Mechanical Engineering in 1990 at the Oil & Gas Institute in
Ploiesti (Romania). After a short experience in a refinery, in 1992 he moves to Bergamo, Italy. In 1992,
he joins the Bioengineering Lab headed by Andrea Remuzzi as Visiting Scientist at NegriBergamo
Laboratories.
His main interests are on renal research (theoretical modeling of glomerular membrane filtration and
morfometrical analysis of glomerular capillaries, hemodynamics and remodeling of arteriovenous fistula
for vascular access), and on controlled clinical trials (data management and data analysis for the clinical
studies conducted in the “Aldo e Cele Daccò” centre). He is also coordinating the system administration
activity for the local network and web sites of the “Aldo e Cele Daccò” centre and is collaborating for
applied clinical informatics with the medical staff of Nephrology, Diabetology ed Hematology Units of
the Bergamo Hospital.
During his activity at the Mario Negri several students performed their master’s degree thesis under his
supervision or performed training stages, and is also tutor for the Professional Training Regional School
of Lombardy.
Since January 2000 he is the head of the of Biomedical Technologies Laboratory created as part of the
new born 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): 19411951, 2004.
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.
Chronology of appointment: From 2000 Head Unit of Tissue Engineering, Department of Biomedical
Engineering; 1991-2000 fellow laboratory of Renal research, Mario Negri Institute for Pharmacological
Research, Bergamo, Italy.
•
Figliuzzi M, 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
•
Morigi M, Micheletti G, Figliuzzi M, Imberti B, Karmali MA, Remuzzi A, Remuzzi G, Zoja C. Verotoxin-1 promotes
leukocyte adhesion to cultured endothelial cells under physiologic flow conditions. Blood.: 86 4553-58, 1995.
•
Zoja C, Morigi M, Figliuzzi M, Bruzzi I, Oldroyd S, Benigni A, Ronco P, Remuzzi G. Proximal tubular cell synthesis and
secretion of endothelin-1 on challenge with albumin and other proteins. Am J Kidney Dis.26: 934-41, 1995.
•
Morigi M, Zoja C, Figliuzzi M, Foppolo M, Micheletti G, Bontempelli M, Saronni M, Remuzzi G, Remuzzi A. Fluid shear
stress modulates surface expression of adhesion molecules by endothelial cells. Blood. 85:1696-703, 1995.
•
Morigi M, Zoja C, Figliuzzi M, Remuzzi G, Remuzzi A. Supernatant of endothelial cells exposed to laminar flow inhibits
mesangial cell proliferation. Am J Physiol. 264:C1080-3, 1993.
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The research activity of the Department of Biomedical Engineering is based on the use of
engineering methods for the study of biological processes responsible for pathological
conditions and for the development of innovative therapeutic strategies. Research activities in
progress belong to basic and applied research. They are based on the following techniques.
Theoretical models, histological analysis, digital image processing for the quantification of
three-dimensional structures at macro- and microscopic level, direct measure of physicalchemical parameters at experimental and clinical level, cell culture and computer based data
management. There are mainly four areas of research at the moment: the study of renal disease
progression at experimental and clinical level, investigation of vascular flow dynamics, cell
culture for in vitro tissue engineering and the development of information systems for clinical
data management in clinical trials and in conventional medical activities.
Set up of a new computational method for 3D reconstruction of cerebral aneurysm using DSA.
Demonstration of a significant correlation between morphometric parameters of renal
parenchyma and renal functional loss in patients affected by polycistic kidney disease.
Accuracy evaluation of a new computational technique based on MR investigations and digital
image processing for the geometrical reconstruction of arteries and veins used for vascular
accesses for hemodialysis.
Demonstration of effective regression of glomerulosclerosis and increase in podocyte number in
glomerular capillaries in a model of progressive nephropathy by angiotensin converting enzyme
inhibition.
Effect of angiotensin II on glomerular epithelial cells and glomerular permselectivity loss in a
model of spontaneous progressive renal disease.
Development of a novel culture method for in vitro generation of 3D cellularized tissue.
Unità di Diabetologia, Ospedali Riuniti, Bergamo
Dipartimento di Bioingegneria, Politecnico di Milano, Milano.
Fidia Advanced Biopolymers, Abano Terme, Padova.
Instituto di Fisiologia Clinica CNR, Pisa.
Tecnobiomedica, Roma.
Unità di Anatomia Patologica, Ospedale San Paolo, Milano.
Ospedale Niguarda, Milano.
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Massachusetts Institute of Technology, Cambridge MA, USA.
National Alliance for Medical Imaging Computing, USA.
Politecnico Federale di Zurigo, Dept. of Material Science, Zurich.
Institute of Nephrology, Dept. of Cell Biology, Niigata University Graduate School of Medical
and Dental Sciences.
University of Toronto, Ontario, Canada.
Ghent University, Ghent, Belgium.
Technical University, Eindhoven, The Netherlands.
University Hospital, Maastricht, The Netherlands.
Centre Européen d’Etudes du Diabètes, Strasburg, France
Drugs of Today, (Andrea Remuzzi)
International Journal of Artificial Organs, (Andrea Remuzzi)
Journal of the American Society of Nephrology
American Journal of Physiology – Renal Physiology
Physiological Reviews
Medical & Biological Engineering & Computing
IEEE Transactions on Medical Imaging
IEEE Transactions on Biomedical Engineering
Medical Physics
Journal of Biomechanics
Medical Engineering and Physics
Artificial Organs
International Journal of Artificial Organs
Biomaterials
Contemporary Clinical Trials
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EVENT ORGANIZATION
Seminar: “Perdita delle proprietà selettive del podocita indotta da Angiotensina II”, January 31 ,
Ranica, Bergamo
Seminar: “Imaging vascular access: a pre- and postoperative approach”, February 2, Ranica,
Bergamo
Seminar: “Regressione della glomerulosclerosi e rigenerazione del tessuto glomerulare in un
modello di malattia renale progressiva”, February 17, Ranica, Bergamo
Seminar: “Diffusion e perfusion cerebrale nelle lesioni ischemiche”, February 23, Ranica,
Bergamo
Seminar: “Evoluzione temporale della geometria della biforcazione carotidea ed implicazioni
per lo sviluppo di aterosclerosi”, March 16, Ranica, Bergamo
Seminar: “Analisi geometrica dei vasi cerebrali: applicazione allo studio degli aneurismi
cerebrali”, April 20, Ranica, Bergamo
Seminar: “Sviluppo di algoritmi per il post-processing in simulazioni CFD. Applicazione alla
emodinamica computazionale degli aneurismi cerebrali”, May 8, Ranica, Bergamo
Seminar: “Effetti del condizionamento biochimico e meccanico su costrutti vascolari
ingegnerizzati”, May 15, Ranica, Bergamo
Corso: “Corso di formazione in elaborazione digitale delle immagini per la medicina “, June 2829, Ranica, Bergamo
Meeting annuale: FP6 UE – “BARP+ - Development of a bioartificial pancreas for type I
diabetic patients”. PNR 505614-1, July10-12, Bergamo
Seminar: “Implementazione di uno strumento per la gestione e l’analisi di dati clinici finalizzato
al monitoraggio delle patologie nefrovascolari nei paesi in via di sviluppo”, September 20,
Ranica, Bergamo
Seminar: “Introduzione alla risonanza magnetica: presentazione cd”, September 22, Ranica,
Bergamo
Seminar: “Sviluppo di una metodologia per l'analisi della concatenazione genica (linkage)
mediante data retrieval ed elaborazione multiallelica”, October 11, Ranica, Bergamo
Seminar: “Valutazione di 2 metodiche di coltura dinamica per costrutti vascolari
ingegnerizzati”, December 7, Ranica, Bergamo
Seminar: “Sviluppo e sperimentazione di un dispositivo da laboratorio per la misura del
consumo di ossigeno di cellule in coltura”, December 15, Ranica, Bergamo
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INVOLVED
3rd International Symposium on Modeling of Physiological Fluids, Ranica (BG), Italy,
“Hemodynamics and cerebral aneurysms: the role of geometry”.
5th World Congress of Biomechanics, Munich, Germany, “Flow instability in a failed brachiocephalic graft for hemodialysis: a computational study”.
5th World Congress of Biomechanics, Munich, Germany. “Geometric intra-subject variability
of arm vessels assessed by MRA: a challenge for quantification and modeling of the vascular
access for hemodialysis”.
5th World Congress of Biomechanics, Munich, Germany. “Computational geometric analysis of
cerebral aneurysms and their parent vasculature from CRA”.
5th World Congress of Biomechanics, Munich, Germany. “Influence of siphon bends on the
flow patterns of the internal carotid artery: implications for the study of aneurysm
development”.
5th World Congress of Biomechanics, Munich, Germany. “Statistical and numerical
investigations of cerebral aneurysms' morphology and hemodynamics”.
ISMRM 14th Scientific Meeting, Seattle, Washington, USA. “Numerical simulation of MRI
using unstructured grids”.
CSCBC 2006, Kingston, Ontario, Canada, March 2006.”Towards a new framework for
simulating magnetic resonance imaging”.
Annual meeting of the American Society of Nephrology, San Diego, USA, November 2006.
“ACE inhibition induced regression of glomerular lesions in spontaneously proteinuric rats is
associated with increased number of podocytes.”
25th Workshop of the AIDIPIT Study Group, Pisa, Italia February 2006. “Xenotransplantation
of microencapsulated bovine pancreatic islets”.
Research project financed by MIUR "FIRB-Ingegneria del Tessuto Vascolare" PNR PNR
RBNF01EBES_002;
Research project financed by Fondazione SAN PAOLO "Trapianto di isole pancreatiche
mediante un dispositivo per immunoisolamento";
Research project - FP6 UE-BARP+ - "Development of a bioartificial pancreas for type I
diabetic patients".PNR 505614-1;
Research project – FP6 UE-STEPS – "A system approach to tissue engineering products and
processes". FP6-500465
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Antiga L, Piccinelli M, Fasolini G, Ene-Iordache B, Ondei P, Bruno S, Remuzzi G and Remuzzi A. Computed
tomography evaluation of ADPKD progression: a progress report. Clin J Am Soc Nephrol 1: 754-760, 2006.
Arrigoni C, Camozzi D, Imberti B, Mantero S, Remuzzi A. The effect of sodium ascorbate on the mechanical
properties of hyaluronan-based vascular constructs. Biomaterials 2006; 27: 623-630.
Arrigoni C, Camozzi D, Remuzzi A. Vascular tissue engineering Cell Transplant 2006; 15 Suppl 1: S119-S125.
Dodesini AR, Lepore G, Neotti C, Ene-Iordache B, Remuzzi A and Trevisan R. Blood pressure and lipids in an
Italian outpatient cohort of type 2 diabetic patients: comparison with the general population. Nutrition, Metabolism &
Cardiovascular Diseases, 16(6): e1-e3, 2006.
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.
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 2006; 168: 42-54.
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.
Morigi M, Buelli S, Zanchi C, Longaretti L, Macconi D, Benigni A, Moioli D, Remuzzi G, Zoja C. Shigatoxininduced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling.
Am J Pathol. 2006 Dec;169(6):1965-75.
Moyle KR, Antiga L and Steinman DA. Inlet conditions for image-based CFD models: is it reasonable to assume
fully-developed flow? Journal of Biomechanical Engineering, 128(3), Jun 2006.
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; 69:
1124-1130.
Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic
nephropathies and diabetes. J Clin Invest. 2006 Feb;116(2):288-96.
Ruggenenti P, Perna A, Ganeva M, Ene-Iordache B and Remuzzi G. Impact of Blood Pressure Control and
Angiotensin-Converting Enzyme Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: a Post Hoc
Analysis of the BENEDICT Trial. J Am Soc Nephrol 17: 3472-3481, 2006.
Ruggenenti P, Ene-Iordache B, Remuzzi G. “Excellent survival using kidney transplants from older donors” Diabetic
Microvascular Complications Today, March/April 2006
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RESEARCH ACTIVITIES
Laboratory of Renal Biophysics
3D reconstruction of the glomerular capillary tuft
We have recently documented that angiotensin II inhibition, that is primarily used to slow the
rate of progression of kidney diseases, can also induce partial regression of glomerular lesions.
To quantify the extent of sclerotic lesion regression and whether new glomerular tissue is
formed by ACE inhibition therapy, we are developing techniques for 3D reconstruction of
tissue.
Glomerular capillary structure concentrates in a small volume a capillary network that can filter
plasmatic water and retain circulating proteins. The estimation of capillary structural changes is
conventionally performed with observations of single sections at optical or electron microscope.
Alterations of the capillary 3D structure can seriously affect the capillary function and blood
flow in some capillary segments. In order to study in details the structure of this
microcirculation we are using techniques base on a series of numbered sections digitally
elaborated for 3D reconstruction.
Permselective dysfunction of podocyte-podocyte contact upon
angiotensin II unravels the molecular target for renoprotective
intervention
Ameliorating the function of the glomerular barrier to circulating proteins by blocking
angiotensin II (Ang II) translates into less risk of progression toward end stage renal failure both
in diabetic and non-diabetic nephropathies. Mechanisms underlying the protection to the barrier
are not clear. Specialized contacts between adjacent podocytes are major candidate target and
the actin cytoskeleton is emerging as regulatory element. The present report documents that Ang
II induced reorganization of F-actin fibers and redistribution of zonula occludens-1 (ZO-1) that
is physically associated with actin in murine podocytes. These effects were paralleled by
increased albumin permeability across podocyte monolayers. Jasplakinolide -an F-actin
stabilizer- prevented both ZO-1 redistribution and albumin leakage suggesting that actin
cytoskeleton rearrangement is instrumental to podocyte permselective dysfunction induced by
Ang II. Changes in both F-actin and ZO-1 patterns were confirmed in glomeruli of rat isolated
perfused kidneys upon short infusion of Ang II leading to increased protein excretion. Podocyte
dysfunction was Ang II type 1 receptor-mediated and partly dependent on Src kinasephospholipase C activation. Strategies aimed at stabilizing podocyte-podocyte contacts and
targeting the relevant intracellular signal transduction are crucial to renoprotection.
(In collaboration with the Department of Molecular Medicine).
Angiotensin converting enzyme (ACE) inhibition induced regression of
glomerular lesions in a model of chronic nephropathy is associated with
increased number of podocytes
Podocyte depletion has been suggested as a causal mechanism of glomerulosclerosis and
progressive impairment of renal function both in experimental animals and in humans.
Progressive loss of podocytes associated with glomerular hypertrophy is key determinant of
podocyte dysfunction leading to massive proteinuria and renal scarring in a rat model of
spontaneous glomerular injury. Our recent finding that ACE inhibitors given to Munich Wistar
Fromter (MWF) rats at the late stage of kidney disease induced regression and regenerate
glomerular tissue prompted us to investigate whether renoprotection was related to the effect of
drug on glomerular podocyte number. Male MWF rats were studied at 40 weeks of age, when
ANNUAL REPORT
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podocyte loss is associated with massive proteinuria and glomerulosclerosis, and after 20 weeks
of observation without or with treatment with the ACE inhibitor lisinopril. A group of 40 week
old male Wistar rats was used as control. Podocytes were identified as WT1-positive cells by
immunofluorescence. Glomerular volume, the percentage of glomerular volume affected by
sclerosis and the number of podocytes per glomerulus, were assessed by digital morphometry.
In untreated MWF rats proteinuria further increased and hypertension and renal function
worsened over the 20 week period. At 60 weeks, more larger glomerular volume was occupied
by sclerosis. As expected, the antihypertensive effect of lisinopril was associated with
regression of proteinuria, stabilization of serum creatinine and reversal of sclerotic lesions.
Treatment significantly decreased glomerular hypertrophy. Surprisingly, ACE inhibition not
only halted the progressive podocyte loss observed with age but also enhanced the podocyte
number per glomerulus above baseline values. ACE inhibition induced increased in podocyte
number might result from podocyte proliferation or differentiation of podocyte precursors.
Studies are ongoing in our laboratory to investigate the mechanism underlying ACE inhibitioninduced increase in glomerular podocyte number.
Laboratory of Biomedical Technologies
Development of computerized systems for controlled clinical trials
Many clinical trials, in collaboration either with national or international research groups, are
conducted in the Clinical Research Center for Rare Diseases “Aldo e Celè Daccò”. These
studies must be carried out respecting the GCP (Good Clinical Practice) guidelines and require
high quality in handling clinical information. Every clinical study requires a paper case report
form (CRF) where investigators could compile patients’ data at the time of clinical observation.
Subsequently, these data must be error checked by dedicated monitoring staff, and then
recorded electronically. In our laboratory we develop applications for the clinical studies using
relational databases systems (RDBMS) and specific programs aimed to data elaboration,
validation and extraction for subsequent statistic analyses. For the DEMAND study we have
developed an innovative system of data handling using electronic CRFs instead of the usual
paper ones. The system is based on the use of personal notebooks by the clinical investigators
working in eight different diabetes centers. This electronic approach to clinical trials allows
direct electronic data capture, with a consequent decrease of patient recruitment time, immediate
data analysis and of course, a decrease of paper consumption. Recently we have set up an
application to assist the bio-medical staff during the process of human pancreatic islets isolation
and subsequent transplantation of islets in diabetic patients. By using a Web-based interface,
different staff could access the system either from Intranet (internal laboratories) or from
Internet (NIT, Ospedali Riuniti di Bergamo), making the team collaborative work easier.
KDDC – a coordinating center 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. The prevalence and
incidence of renal diseases in developing countries are not known, and this is an obstacle to the
adoption of preventive measures, 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
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Pharmacological Research at the Clinical Research Center “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 a
national basis by means of interventions of the local ministries of health at a governmental and
financial level.
The Kidney Disease Data Center (KDDC) is headed in our Laboratory and is dedicated to data
management for all prevention programs started in emerging countries. We have actually
collected data from participating centers from Moldova, Bolivia, Nepal and China, while other
countries are willing to start their programs (Marocco, Mongolia, Mozambique, Mexico,
Argentina). We set up an instrument to collect the clinical data from different centres (via email), and then to perform reliable statistical analyses and produce reports for the medical staff.
This will make it possible to monitor the course of the program in the participating centers,
fitting the needs and characteristics of every country.
Three-dimensional reconstruction and hemodynamic simulation of
vascular segments from CT and MR imaging
Evidence that atherosclerotic plaques form mainly at bifurcations of the arterial system led to
the hypothesis that impaired hemodynamic conditions may favour the initiation and progression
of atherosclerosis. Furthermore, it has been demonstrated how initial hyperplasia, cause of
failure of grafts and arterovenous fistulas, is also localized at sites of complex hemodynamics.
Analogously, recent studies on formation, localization and growth of cerebral aneurysms have
underlined the importance of hemodynamics on the development of this pathology. Given the
influence of vessel shape on hemodynamics, it is important to dispose of accurate and fast
methods for three-dimensional reconstruction of vascular geometry. Modern angiographic
techniques, such as computed tomography (CT) and magnetic resonance (MR), allow to obtain
detailed information on vascular structures. In our laboratory, we developed techniques for
three-dimensional reconstruction, geometric analysis, computational mesh generation and fluiddynamic simulation of vascular tracts from CT and MR angiography. CT and MR images are
transferred from clinical scanners on local workstations and are then processed with modeling
algorithms to generate three-dimensional surfaces representing the interface between the
vascular wall and its lumen. The accuracy of the reconstruction has been experimentally
validated by us. Accurate measurements are then performed on the generated model using
computational geometry algorithms. These techniques have been applied to several vascular
segments, mainly cerebral aneurysms, arterovenous fistulas and grafts for hemodialysis access.
The pathologies studied include atherosclerosis, intimal hyperplasia, development of cerebral
aneurysms and Takayasu's arteritis, a rare disease affecting the arterial system.
Quantification of anatomical structures from CT and MR imaging
The introduction of non-invasive three-dimensional imaging techniques, such as computed
tomography (CT) and magnetic resonance (MR), in the clinical setting has opened the
possibility to analyze the anatomical structures of organs in high detail. The non-invasiveness of
such techniques allows to extend the observation to populations of patients followed over time.
The evaluation of natural evolution of diseases or of treatment efficacy often requires a detailed
morphological quantification which cannot be uniquely performed by visual inspection. In this
context, we developed image-based quantification techniques characterized by high accuracy
and reproducibility. Wevare applying these tools to a study on patients affected by autosomal
dominant polycystic disease (ADPKD) with the aim of testing the efficacy and safety of some
treatments. Volumes of kidneys and their main tissue components (cysts and parenchyma) have
been quantified from CT o RM images.
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Development of devices for the transplantation of immunoisolated islets
Transplantation of immunoisolated pancreatic islets is a promising approach for the treatment of
insulin dependent diabetes. A semipermeable membrane protect islets from the host immune
system and enclosed islets are able to detect blood glucose levels and produce insulin to
maintain glycemic control. In our laboratory we have developed two immunoisolation systems
for transplantation of bovine pancreatic islets in the diabetic rat. The first system is a device
made using parallel array of hollow fibers with a planar geometry that facilitate implantation
and retrieval under the skin. The results indicated that the islets contained within
immunoisolation devices are functional for more than 20 days after implantation and the
membrane provide functional immunoprotection of bovine islets. The second system consisted
of alginate microcapsules. Alginate protects islets from the immune system reaction.
Microcapsules were implanted into the peritoneal cavity of diabetic rats. Microcapsules
containing bovine islets reduced blood glucose levels of rats for several weeks. To evaluate if
immunoisolate islets have adequate oxygen supply we set up an experimental technique to
measure oxygen consumption rate by islet contained in immunoisolated devices and by freely
suspended pancreatic islets. The results show that islet encapsulation in alginate microcapsules
as well as in hollow fibers did not influence oxygen consumption indicating that islets are
adequately oxygenated. The aim of our studies in the next months will be to improve the
function of devices using new fibers with major porosity to obtain a log-term normalization of
glycemia. To improve microcapsule transplantation we will study optimal conditions to reduce
the number of implanted islets.
Islet transplantation program in insulin dependent diabetic patients
Clinical islet transplantation shows insulin independence with adequate metabolic control in
patients with type I diabetes. Advances in the rate of success of human islet transplantation are
due in part to the great number of islets transplanted. Approximately 10000 islet equivalents/Kg
of the recipient have to be transplanted to establish insulin independence. To transplant this
number of islets we have to perform two or three implantations. The main focus of the program
is to optimize the procedures of pancreas digestion and purification to obtain high yields of
functional islets from one donor pancreas. To this purpose we have developed a system that
allows to maintain the pancreas at a temperature of 4°C and a method for the perfusion of
pancreas with a low pressure to avoid the destruction of pancreatic tissue. To evaluate viability
of obtained islets, we performed a technique to stain in fluorescent green live cells and in
fluorescent red dead cells. With a confocal microscopy analysis we can quantify the number of
live or dead cells in one islet. This data is important to predict the number of effectively
functional cells transplanted. Aim of our studies in the next months is to certify islet separation,
purification and culture to begin a clinical trial for the islet transplant.
Differentiation of adult pancreatic precursor cells
Type I diabetes is characterized by the autoimmune destruction of insulin-producing pancreatic
islets and exogenous insulin administration is the traditional treatment for this disease. The
replacement of the beta cell mass is a potential cure for type I diabetes, but this procedure suffer
from a shortage of available donor tissue in comparison to the number of potential recipients. In
our laboratories we have studied the method to differentiate beta cells from progenitor cells
contained in exocrine tissue or in pancreatic islets obtained from bovine or rat pancreas. Since
the level of insulin is much lower than that contained in fresh islets, we have in program to
develop new strategies to characterize and select for pancreatic precursor cells with the purpose
of increase their differentiation.
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Transplantation of pancreatic islets in syngenic and allogenic model
Recent studies have shown that pancreatic islet transplantation is better than pancreas
transplantation in terms of efficiency and security. In our laboratories we have developed a
technique for isolation of rat pancreatic islets with collagenase digestion of pancreas and
density gradient purification. Rat islets are implanted under the kidney capsule in rats with
diabetes induced with a single injection of streptozotocin. We use two models of
transplantation, a syngenic transplantation based on the use of rat islets in inbreed rats and an
allogenic transplantation based on the use of rat islets into outbreed rats. In syngenic model
normoglycemia conditions are maintained for several months. In allogenic transplantation islets
induce normoglycemia conditions for a long time period, but Cyclosporin has been
administrated to avoid rejection. These models will be used to develop new strategies to
increase the survival and the function of transplanted pancreatic islets.
Vascular tissue engineering
Artificial vascular prosthese can be used in patients only if the caliber is larger than 6 mm. A
lower caliber prosthesis implies a high trombotic risk. For this reason, several investigators are
developing bioartificial biological vascular substitute using tissue engineering technique. In our
laboratories we used a biodegradable ialuronic acid matrix as a scaffold to produce cellularized
vascular constructs. We set up culture and seeding conditions both for smooth muscle cells and
mesenchymal bone marrow cells. To obtain physiological mechanical conditioning of the
tubular constructs we developed a new type of rotating wall bioreactor that allows to keep in
culture vascular constructs. This simple method allows to decrease apoptosis incidence and to
increase matrix depositions.
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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.
Unit of Drug Monitoring
Head
Giulia GHERARDI
Laboratory of Clinical Chemistry
Head
Flavio GASPARI, Chem.D.
Laboratory of Advanced Development of Drugs
Head
Norberto PERICO, M.D.
Unit of Pharmacology and Pharmacogenetics
Head
Dario CATTANEO, Chem.Pharm. D., Ph.D
Unit of Early Clinical Evaluation of Drugs
Head
Aneliya PARVANOVA, M.D.
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CURRICULA VITAE
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 ed 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.
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P. Ruggenenti, A. Perna, L. Mosconi, M. Matalone, G. Garini, M. Salvadori, C. Zoccali, F. Scolari, Q. Maggiore, G.
Tognoni, G. Remuzzi (for The GISEN Group). Randomised placebo-controlled trial of effect of ramipril on decline in
glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet
1997;349:1857-1863
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P. Ruggenenti, A. Perna, G. Gherardi, F. Gaspari, R. Benini, G. Remuzzi, on behalf of GISEN. Renal function and
requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet
1998;352:1252-1256.
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P. Ruggenenti, A. Perna, G. Gherardi, G. Garini, C. Zoccali, M. Salvadori, F. Scolari, F.P. Schena, G. Remuzzi.
Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet
1999;354:359-364.
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G. Remuzzi, C. Chiurchiu, M. Abbate, V. Brusegan, M. Bontempelli, P. Ruggenenti. Rituximab for idiopathic
membranous nephropathy. Research Letter. Lancet 2002;360:923-924.
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P. Ruggenenti, A. Fassi, A. Parvanova, S. Bruno, I. Iliev, V. Brusegan, N. Rubis, G. Gherardi, F. Arnoldi, M. Ganeva, B.
Ene-Iordache, F. Gaspari, A. Perna, A. Bossi, R. Trevisan, A.R. Dodesini, G. Remuzzi for the Bergamo Nephrologic
Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J
Med 2004;351:1941-1951
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G. Remuzzi, P. Cravedi, A. Perna, B.D. Dimitrov, M. Turturro, G. Locatelli, P. Rigotti, N. Baldan, M. Beatini, U.
Valente, M. Scalamogna, P. Ruggenenti Dual Kidney Transplant Group. Long-term outcome of renal transplantation
from older donors. N Engl J Med 2006;354:343-352.
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 Chief of Laboratory of Pharmacokinetics and Clinical Chemistry since January 2000 and
he was Chief of this Unit since 1991.
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Gotti E, Perico N, Gaspari F, Cattaneo D, Lesti MD, Ruggenenti P, Segoloni G, Salvadori M, Rigotti P, Valente U,
Donati D, Sandrini S, Federico S, Sparacino V, Mourad G, Bosmans JL, Dimitrov BD, Iordache BE, Remuzzi G. Blood
cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate
Steroid-Sparing Trial. Transplant Proc. 2005 Jun;37(5):2037-40.
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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.
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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.
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Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, EneIordache 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. Epub 2004 Oct 31.
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.
Cattaneo D, Merlini S, Pellegrino M, Carrara F, Zenoni S, Murgia S, Baldelli S, Gaspari F, Remuzzi G, Perico N.
Related Articles, Links Therapeutic drug monitoring of sirolimus: effect of concomitant immunosuppressive therapy and
optimization of drug dosing. Am J Transplant. 2004 Aug;4(8):1345-51.
Norberto Perico got his Medicine degree in 1983 at the University of Milano, Italy. He got his specialization
in Pharmacological Research in 1986 at IRFMN, Bergamo and in Clinical Nephrology in 1989 at the
University of Verona, Italy.
Educational training: in 1982 Fellow, Department of Pharmacology, New York Medical College, Valhalla,
New York, USA; in 1984-1988 Post Doctoral Fellow, Laboratory of Kidney Diseases, IRFMN, Bergamo, Italy;
in 1988-1989 Researcher in the same laboratory.
Areas of interest: pathophysiology and pharmacology of cyclosporine nephrotoxicity; new
immunosuppressive strategies to prevent renal graft rejection; innovative approach to induce tolerance to organ
transplantation; mechanism(s) and management of progression of chronic renal diseases.
Employment: in 1990-1994 Head, Renal Physiology Unit, Laboratory of Kidney Diseases, IRFMN, Bergamo,
Italy; in 1990-2000 Assistant Professor, Division of Nephrology and Dialysis, Ospedali Riuniti di Bergamo,
Italy; in 1994 –1999 Head, Laboratory of Transplant Immunology, IRFMN, Bergamo, Italy; from January 2000
Head, Laboratory of Drug Development, Department of Renal Medicine, IRFMN, Bergamo, Italy; from
September 2000 Health Director, Daccò Center, IRFMN, Bergamo, Italy. From October 2002 he’s Member,
ISN-COMGAN Research Committee of the International Society of Nephrology.
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E. Gotti, N. Perico, A. Perna, F. Gaspari, D. Cattaneo, R. Caruso, S. Ferrari, N. Stucchi, G. Marchetti, M. Abbate, G.
Remuzzi. Renal transplantation: can we reduce calcineurin inhibitor/stop steroids? Evidence based on protocol biopsy
findings. J Am Soc Nephrol 2003;14:755-766.
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N. Perico, P. Ruggenenti, G. Remuzzi. Losartan in diabetic nephropathy. Expert Rev. Cardiovasc. Ther. 2004; 2(4): 473483.
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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. mofetil
versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. Lancet. 2004
Aug 7;364(9433):503-12.
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Rigotti P, Valente U, Donati D, Sandrini S, Sparacino V, Remuzzi G, Perico N; MY.S.S. Study Investigators. of different
prediction equations for estimating renal function in kidney transplantation. Am J Transplant. 2004 Nov;4(11):1826-35.
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Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004 Nov
13;364(9447):1814-27.
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Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G, Perico N. Influence of co-medication with sirolimus or
cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant. 2005 Dec;5(12):293744.
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).
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Ruggenenti P, Perna A, Loriga G, Ganeva M, Ene-Iordache B, Turturro M, Lesti M, Perticucci E, Chakarski IN,
Leonardis D, Garini G, Sessa A, Basile C, Alpa M, Scanziani R, Sorba G, Zoccali C, Remuzzi G for the REIN-2 Study
group. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2):
multicentre, randomised controlled trial. Lancet 365:939-946, 2005
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Schieppati A, Perna A, Zamora J, Giuliano AG, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic
membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. Oct 18(4):CD004293, 2004
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Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, EneIordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G. Preventing microalbuminuria in type 2
diabetes. N Engl J Med 351(19)1941-51, 2004
Remuzzi G, Ruggenenti P, Perna A, Dimitrov BD, de Zeeuw D, Hille DA, Shahinfar S, Carides GW, Brenner BM for
the RENAAL Study Group. Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a
post hoc analysis of the RENAAL trial results. J Am Soc Nephrol 15(12):3117-25, 2004
The BENEDICT Group. The Bergamo NEphrologic Diabetes Complications Trial (BENEDICT): design and baseline
characteristics. Control Clin Trials 24(4): 442-461, 2003
Plata R, Cornejo A, Arratia C, Anabaja A, Perna A, Dimitrov BD, Remuzzi G, Ruggenenti P for the Commission on
Global Advancement of Nephrology (COMGAN), Research Subcommittee of the International Society of Nephrology.
Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial. Lancet 359:
663-66, 2002
Dario Cattaneo got the Pharmacy degree in 1996 at the University of Milan, and the specialisation in
Pharmacology (2001) awarded by the same University. In 2000 he got the specialization in
“Pharmacological Research” at the Mario Negri Institute for Pharmacological Research (IRFMN) and in
2005 he has been awarded the PhD degree by the Open University of London, UK.
Educational Training: in 1997 Post Doctoral Fellow, IRFMN, Laboratory of Pharmacokinetics and
Clinical Chemistry; in 2000 beneficiary of the Fellowship “Girola” and from 2001 to 2005 recipient of
the “Monzino” Fellowship for his research activity done at the IRFMN.
Areas of interest: pharmacology (pharmacokinetics, pharmacodynamics and pharmacogenetics) of
immunosuppressants, antiviral agents and hypolipidemic drugs; study of secondary forms of
dyslipidemia; polypharmacological approaches for the treatment of chronic kidney diseases; assessment
of humoral response as predictor of acute or chronic rejection after organ transplantation.
Employement: in 1997 researcher, IRFMN, Laboratory of Pharmacokinetics and Clinical Chemistry,.
Since 2006, Head of the Unit of Pharmacology and Pharmacogenetics, IRFMN, Ranica Bergamo.
Component of the Ethical Committee (2003) of the Hospital “Bolognini” (Seriate, Italy) and the
Hospital “E.Medea” (Bosisio Parini, Italy) since 2006. Member of the editorial board of Current
Clinical Pharmacology and affiliate of the International Association of Therapeutic Drug Monitoring
and Clinical Toxicology (IATDMCT) since 2005.
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Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G, Perico N. Influence of co-medication with sirolimus or
cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant. 2005 Dec;5(12):293744.
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Cattaneo D, Gotti E, Perico N, Bertolini G, Kainer G, Remuzzi G. Cyclosporine formulation and Kaposi's sarcoma after
renal transplantation. Transplantation. 2005 Sep 27;80(6):743-8.
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Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004 Nov 1319;364(9447):1814-27.
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Cattaneo D, Merlini S, Pellegrino M, Carrara F, Zenoni S, Murgia S, Baldelli S, Gaspari F, Remuzzi G, Perico N.
Therapeutic drug monitoring of sirolimus: effect of concomitant immunosuppressive therapy and optimization of drug
dosing. Am J Transplant. 2004 Aug;4(8):1345-51.
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Cattaneo D, Perico N, Gaspari F, Gotti E, Remuzzi G. Glucocorticoids interfere with mycophenolate mofetil
bioavailability in kidney transplantation. Kidney Int. 2002 Sep;62(3):1060-7.
Giulia Gherardi got her Scientific High School Diploma on 1989 at the Liceo Scientifico Marie Curie in
Zogno (Bergamo), the Nurse Diploma on 1995 at the Scuola per Infermieri Professionali, Ospedali
Riuniti, Bergamo.
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,
diabetology; the organisation and the monitoring of clinical trials.
Emplyment: In1997-2003 involved as co-organazing, 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;
since 2000 Monitoring Unit Chief.
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Rigotti P, Valente U, Donati D, Sandrini S, Sparacino V, Remuzzi G and Perico N on the behalf of the MY.S.S. study
investigators. Performance of different prediction equations for estimating renal function in kidney transplantation.
American Journal of Transplantation. 2004; 4: 1826-1835.
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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
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Med. 2004; 351: 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, for the
MY.S.S. Group. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation
(MYSS): a randomized trial. Lancet. 2004 Aug 7; 364: 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 Jan;
35 (6): 1155 – 65.
Ruggenenti P, Perna A, Zoccali C, Gherardi G, Benini R, Testa A, Remuzzi G. Chronic proteinuric nephropathies. II.
Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in
relation to the ACE polymorphism. Gruppo Italiano di Studi Epidemiologici in Nefrologia. J Am Soc Nephrol. 2000
Jan; 11 (1): 88 – 96.
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.
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 specialisation in
Pharmacology in Department of Pharmacology, Faculty of Medicine, of the same university in 1992.
Educational training: 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. 1993:
Course on investigation of isolated organs – Bulgarian Academy of Sciences, Sofia. 1998: Visiting
scientist, IRFMN, Ranica, Bergamo, Italy. 1998: Proficiency in the methods for insulin sensitivity
evaluation (hyperinsulinemic euglicaemic clamp technique) and glomerular filtration rate evaluation
(plasma clearance of iohexol).
Areas of interest: primary and secondary prevention of the chronic microvascular diabetic complications
(diabetic nephropathy, diabetic retinopathy and diabetic neuropathy); role of insulin resistance and
hyperhomocysteinemia in these pathologies.
Employment: She participated as investigator in several clinical studies. She is Chief 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), and member of the Union of
Scientists in Bulgaria (since 1991).
•
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.
ANNUAL REPORT
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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 three
Laboratories and two 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
Molecolar Medicine, the Department of Bioengineering and the Public-Private Department of
Specialist and Transplant Medicine. This cooperation allows to plan the research activities of
the Department on the basis of new information derived from basic research and of problems of
major clinical relevance emerging from routine clinical activities.
Definition and validation of specific treatments aimed to prevent the developing of
nephropathies 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
Characterization of the antiproteinuric, nephroprotective and cardioprotective effect of
maximized and polypharmacologic renin-angiotensin system inhibition
Identification of acquired or congenital risk factors for chronic complications of diabetes
Definition and validation of new, specific treatments for idiopathic membranous nephropathy
and factor H associated HUS
Definition and validation of new laboratory procedures and predictive models to help
monitoring and optimizing immunosuppressive therapy in clinical transplantation
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Definition and validation of selection and allocation criteria of kidneys from marginal donors to
increase the donor pool and the transplant activity Optimization of Doppler ultrasound
techniques for the diagnosis and monitoring of vascular complication of renal transplant and
chronic dialysis patients
Finalization and activation of multicenter clinical trials aimed to prevent diabetic nephropathy,
the progression of chronic nephropathies, acute and chronic allograft rejection and to identify
predictors and promoters of target organ damage
Computerization of data acquisition and monitoring procedures for the conduction of controlled
clinical trials
Lombardia
- Ospedale C. Cantù, Abbiategrasso (MI)
- Ospedale Civile di Asola, Asola (MN)
- Ospedale Fenaroli, Alzano Lombardo (BG)
- Azienda Ospedaliera OO.RR., Bergamo
- Ospedale Caduti Bollatesi, Bollate (MI)
- Azienda Ospedaliera Spedali Civili, Brescia
- Ospedale San Biagio, Clusone (BG)
- Ospedale S. Anna, Como
- Azienda Ospedaliera Istituti Ospedalieri, Cremona
- Ospedale di Desio (MI)
- Ospedale Briolini, Gazzaniga (BG)
- Azienda Ospedaliera di Melegnano, Melegnano – Vizzolo Predabissi (MI)
- Ospedale San Leopoldo Mandic, Merate (LC)
- Ospedale Maggiore Policlinico, Milano
- Ospedale Provinciale San Carlo Borromeo, Milano
- Azienda Ospedaliera - Polo Universitario L. Sacco, Milano
- Ospedale Fatebenefratelli, Milano
- Ospedale Niguarda Ca' Granda, Milano
- Clinica Pediatrica “G. e D. De Marchi’, Milano
- Ospedale San Raffaele, Milano
- Ospedale Pediatrico di Montichiari, Montichiari (BS)
- Ospedale San Gerardo, Monza (MI)
- Istituti Clinici Zucchi, Monza (MI)
- Università degli Studi di Pavia, Dipartimento di Medicina Interna e Terapia Medica, Pavia
- Centro Antidiabetico, Ponte San Pietro (BG)
- Azienda Ospedaliera Ospedale Treviglio Caravaggio, Romano di Lombardia (BG)
- Istituto clinico Humanitas, Rozzano (MI)
- Ospedale Bolognini, Seriate (BG)
- Azienda Ospedaliera Ospedale Treviglio Caravaggio, Treviglio (BG)
- Ospedale Regionale di Circolo Fondazione Macchi, Varese
- USL 60, Unità Operativa di Nefrologia e Dialisi, Vimercate (LC)
Piemonte
ANNUAL REPORT
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- Azienda Ospedaliera Santa Croce e Carli, Cuneo
- Ospedale Civile, Ivrea
- A.S.O. Maggiore della Carità, Novara
- Azienda Ospedaliera San Giovanni Battista, Torino
- Ospedale Mauriziano Umberto I, Torino
- Ospedale Regina Margherita, Torino
- Ospedale Martini, Torino
- Ospedale Luigi Einaudi, Torino
Veneto, Trentino Alto-Adige e Friuli Venezia Giulia
- Casa di Cura Abano Terme, Abano Terme (PD)
- Ospedale Civile, Belluno
- Ospedale S. Giacomo Apostolo, Castelfranco Veneto, Treviso
- Ospedale Provinciale Umberto I, Mestre (VE)
- Ospedale Giustinianeo, Padova
- Università degli Studi di Padova, Istituto di Anatomia Patologica, Padova
- Ospedale Civile, Padova
- Ospedale S. Camillo dé Lellis, Schio (VI)
- Ospedale Regionale Santa Maria dei Battuti, Treviso
- Ospedale Civile Maggiore Borgo Trento, Verona
- Ospedale Policlinico Borgo Roma, Verona
- Ospedale Civile San Bortolo, Vicenza
- Ospedale Santa Chiara, Trento
- Istituto Scientifico per l'infanzia Burlo Garofalo, Trieste
- Ospedale S. Antonio, S. Daniele del Friuli, Udine
- Università degli Studi di Udine, Centro Trapianti Fegato-Rene-Pancreas, Udine
Liguria, Emilia Romagna e Toscana
- Azienda Ospedaliera San Martino, Genova
- Istituto “G. Gaslini”, Genova
- Ospedale S. Orsola Malpighi, Bologna
- Ospedale Policlinico, Modena
- Istituto di Clinica Medica e Nefrologia, Parma
- Ospedale Santa Maria delle Croci, Ravenna
- Arcispedale Santa Maria Nuova, Reggio Emilia
- Ospedale Santa Maria Annunziata, Bagno a Ripoli, Firenze
- Azienda Ospedaliera Careggi-Monna Tessa, Firenze
- Ospedale Nuovo “S. Giovanni di Dio”, Firenze
- Azienda Ospedaliera Meyer, Firenze
- Ospedale di S. Miniato, S. Miniato (FI)
- Azienda Ospedaliera Cisanello, Pisa
- Ospedale di Pistoia, Pistoia
Marche
- Ospedale Regionale Torrette, Torrette di Ancona, Ancona
- Ospedale I.N.R.C.A., Ancona
- Azienda Ospedaliera S. Salvatore, Pesaro
Lazio, Basilicata e Campania
- Ospedale Polispecializzato, Anzio, Roma
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- Ospedale Fatebenefratelli, Roma
- Ospedale Pediatrico Bambino Gesù, Roma
- Policlinico Gemelli, Roma
- Ospedale Policlinico Umberto I, Roma
- Ospedale San Camillo Forlanini, Roma
- Università Cattolica del Sacro Cuore, Roma
- Dipartimento di Biopatologia Umana, Università La Sapienza, Roma
- Ospedale Grande degli Infermi, Viterbo
- Ospedale Riuniti, Matera
- Azienda Ospedaliera Ospedale Civile, Caserta (NA)
- Università Federico II di Napoli, Cattedra di Nefrologia, Napoli
- Azienda Ospedaliera “S. G. di Dio e Ruggi d’Aragona”, Salerno
Abruzzo
- Ospedale G. Bernabeo, Ortona, Chieti
- Presidio Ospedaliero “San Massimo”, Penne (PE)
- Presidio Ospedaliero "G.Mazzini", Teramo
Puglia, Calabria, Sicilia e Sardegna
- Ospedale Regionale “Miulli”, Acquaviva delle Fonti, Bari
- Ospedale Pediatrico “Giovanni XXIII”, Bari
- Ospedale Policlinico, Bari
- Azienda Ospedaliera V.Fazzi, Lecce
- Ospedale Casa Sollievo dalla Sofferenza, S.Giovanni Rotondo (FG)
- Presidio Ospedaliero di Martina Franca, Martina Franca, Taranto
- A.U.S.L. TA/1 - Presidio Ospedaliero, Taranto
- Azienda Ospedaliera Ospedale Pugliese Ciaccio, Catanzaro
- Ospedale dell'Annunziata, Cosenza
- Centro di Fisiologia Clinica del CNR, Divisione di Nefrologia, Reggio Calabria
- Azienda Ospedaliera “Bianchi-Melacrino-Morelli”, Reggio Calabria
- Ospedale “N. Giannettasio”, Rossano Calabro, Cosenza
- Nuovo Presidio Ospedaliero, Acireale, Catania
- Azienda Ospedaliera "Ferrarotto", Catania
- Ospedale Zonale Maggiore, Modica (RG)
- Ospedale Civico, Palermo
- Ospedale “V. Cervello”, Palermo
- Azienda Ospedaliera "Umberto I", Siracusa
- Azienda Sanitaria G. Brotzu, Ospedale San Michele, Cagliari
- Istituto di Clinica e Biologia dell’Età Evolutiva, Cagliari
- Ospedale A. Segni, Ozieri, Sassari
- Ospedale SS. Annunziata, Sassari
- Ospedale Policlinico, Sassari
Umbria
- Azienda Ospedaliera di Perugia, Perugia
ANNUAL REPORT
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IRFMN
- University Hospital Ziekenhuius, Edegem Antwerpen, Belgium
- Clinique de Nephrologie-Dialyse Chu Brugmann, Bruxelles, Belgium
- University Ziekenhuius Gent, Gent, Belgium
- 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
- Department of Nephrology, University of Wien, Wien, Austria
- 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
- Hospital Ntra Sra. de Sonsoles, Avila, Spain
- Hospitalet de Llobregat, Institut Català de la Salut, Barcellona, Spain
- Fundacion Jimenez Diaz, Madrid, Spain
- Hospital Clinico Martin Logas, Madrid, Spain
- Hospital 12 de Octubre, Madrid, Spain
- Hospital Gregorio Maranon, Madrid, Spain
- Hospital La Paz, Madrid, Spain
- Hospital Puerta de Hierro, Madrid, Spain
- Hospital Ramon y Cajal, Madrid, Spain
- Hospital Severo Ochoa, Leganes, Madrid, Spain
- Hospital Universitario de Tarragona Joan XXIII, Tarragona, Spain
- Hospital Garcia de Orta, Almada, Portugal
- Brigham & Women's Hospital, Boston, USA
- Hennepin County Medical Center, Minneapolis, USA
- SIU School of Medicine, Springfield, USA
- The Toronto Hospital, Toronto, Canada
- INCUCAI, Buenos Aires, Argentina
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
ANNUAL REPORT
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- Hospital Regional de Valdivia, Valdivia, Cile
- Soroka Medical Center, Beer Sheva, Israel
Journal of the American Society of Nephrology (Piero Ruggenenti)
Journal of Nephrology (Piero Ruggenenti)
Current Diabetes Reviews (Piero Ruggenenti)
Clinical Journal of the American Society of Nephrology (Piero Ruggenenti)
Adis Drugs Evaluation
American Journal of Hypertension
American Journal of Kidney Disease
American Journal of Nephrology
American Journal of Physiology-Renal Physiology
American Journal of Transplantation
BMC Medicine
Clinical JASN
Clinical Nephrology
Current Diabetes Reviews
Current Medicinal Chemistry
Diabetologia
Diabetes Care
Expert Opinion on Pharmacothrapy
Journal of American Society of Nephrology
Journal of Artificial Organs
Journal of Hypertension
Journal Laboratory Clinical Medicine
Journal of Thrombosis and Haemostasis
Internal and Emergency Medicine
Nephrology Dialysis and Transplantation
New England Journal of Medicine
Plos
The Lancet
Transplant International
Transplantation
ANNUAL REPORT
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INVOLVED
"Local Investigators Meeting PLANET Study". 11 December 2006, Villa Camozzi - Ranica
(Bergamo).
“Le dislipidemie: ruolo dei farmaci ipolipidemizzanti nel trattamento del paziente con
nefropatia cronica”. Le nefropatie croniche progressive, Università degli Studi di Sassari,
Sassari, 25 February 2006.
“L’ipercolesterolemia come fattore di progressione delle malattie renali croniche”,
Ipercolesterolemia nel paziente complesso: aspetti fisiopatologici e terapeutici, Bergamo, 8
April 2006.
“Pharmacological treatment of dyslipidemia and obesity”, Advanced workshop on
nephroprotection for Turkish nephrologists, Ranica, 26-27 May 2006.
“Obesità: un fattore di rischio congenito o acquisito?”. All’interno del convegno: Remission
Clinic. Nefropatie croniche e complicanze cardiovascolari. Centro Congressi Giovanni XXIII,
Begamo 15-16 September 2006
“Progressione del danno renale e cardiovascolare nelle nefropatia croniche: razionale studi
PLANET”, Local Investigator’s Meeting, Ranica, 11 December 2006
“Diabetic nephropaty”, European Renal Research Initiative (ERRI), Bruxells, 1 February 2006
“Preventing microalbuminuriua in type 2 diabetes”, V International Conference on
Hypertension and the kidney, Madrid, 16-18 February 2006
“Curare il cuore fa bene al rene e viceversa: l’ipertensione e la microalbuminuria come segnali
sinergici di futuri danni cardiorenali”, IX Forum sul sistema renina-angiotensina, Capri, 7 April
2006
“Never to early to protect the kidney for limitino cardiovascular diseaes of diabetes”, 11th
Scientific Meeting EASD Hypertension in diabetes study group, Belgrado, 6-8 April, 2006
“Combinazione ACE-inibitori e sartani nel trattamento della malattia renale e cardiovascolare”,
11° Congresso nazionale FADOI, Torino, 17-20 May 2006
“La prevenzione della nefropatia”, Controversie in patologie cardiovascolari, Napoli, 19-20
May, 2006
“Nephroprotection in hypertensive patients with type 2 diabetes: DEMAND Study”, 16th
European Meeting on Hypertnsion-Chiesi satellite symposium, Madrid, 14 June 2006
“The pathophysiological mechanisms underlying renal disfunction in heart failure”, Heart
failure 2006, Helsinki, 17-20 June 2006
“Renoprotection: is it blood pressare or proteinuria that matters?”, ERA-EDTA XLIII Congress,
Glasgow 15-18 July 2006
ANNUAL REPORT
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IRFMN
“Meccanismi di progressione e di regressione delle nefropatie croniche diabetiche e non
diabetiche “, V Corso di aggiornamento in malattie endocrino-metaboliche, Foggia, 22-23
September 2006
“Si stabilizza il numero di nuovi casi di insufficienza renale terminale dopo che da 20 anni c’era
un incremento di anno in anno”; 11° Minicorso di nefrologia, Alberobello, 23 September 2006
“Progressione delle malattie renali: proteggere il rene per proteggere il cuore”, Seminario
internazionale di cardio-nefrologia, Ferrara, 27 October 2006
“Renal faliure Epidemic: what we can do to prevent it”, 5th Think Kidney International
Symposium Meeting, Muscat (Oman), 24-25 January 2006
Chronic Kidney Diseases Project in India, New Delhi, 15-17 February 2006
“Remission, regression of chronic renal disease: can it really happen?”, Assembly of the Polish
Society in Nephrology, Torun (Polonia), 1-2 June 2006
American Society of Nephrology, San Diego California, 14-20 November2006
AIFA (Agenzia Italiana del Farmaco)
Abbott GmbH & Co.
Astrazeneca SPA
Aventis Pharma SA
Dompè Spa
Farmaceutici Damor SpA
Keryx Biopharmaceuticals
King Pharmaceuticals Inc.
Merck Sharp & Dohme Italia SpA
Novartis Farma
Roche SpA
Sanofi-Aventis Spa
Sigma Tau Spa
Solvay Pharmaceuticals
Speedel Pharma Ltd
ANNUAL REPORT
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IRFMN
A. Schieppati, P. Ruggenenti, G. Remuzzi. Diabetic Nephropathy: present and future challenges. In:
Kidney Diseases in the Developing World and Ethnic Minorities. Chapter 8. Edited by M. El-Nahas,
Taylor & Francis Group, New York 2006, pp. 161-189.
I. Codreanu, N. Perico, A. Anabaya, G. Remuzzi. Links between Bolivia, Moldova, and Italy for
prevention of chronic nephropathies. In: Kidney Diseases in the Developing World and Ethnic
Minorities. Chapter 8. Edited by M. El-Nahas, Taylor & Francis Group, New York 2006, pp. 457-467.
N. Perico, P. Cravedi, P. Ruggenenti, E. Gotti, G. Rota, G. Locatelli, V. Gambara, A. Perna, S. Rota, G.
Remuzzi. The Bergamo Kidney Transplant Program. In: Clinical Transplants 2005. Chapter 7. Edited by
J.M. Cecka and P.I. Terasaki, UCLA Immunogenetics Center, Los Angeles, California 2006, pp. 85-100.
F. Gaspari, N. Perico, G. Remuzzi. Timed urine collections are not needed to measure urine protein
excretion in clinical practice. Am J Kidney Dis 2006;47:1-7.
G. Remuzzi, P. Cravedi, A. Perna, B.D. Dimitrov, M. Turturro, G. Locatelli, P. Rigotti, N. Baldan, M.
Beatini, U. Valente, M. Scalamogna, P. Ruggenenti. Dual Kidney Transplant Group. Long-term outcome
of renal transplantation from older donors. N Engl J Med 2006;354:343-352.
G. Remuzzi, M. Macia, P. Ruggenenti. Prevention and treatment of diabetic renal disease in type 2
diabetes: the BENEDICT Study. J Am Soc Nephrol 2006;17:S90-S97.
D. Cattaneo, N. Perico, G. Remuzzi. Let’s assume that hepatitis C reduces the cardiovascular risk in
dialysis patients. Are there practical implications? J Hepatol 2006;44:837-838.
A.I. Parvanova, R. Trevisan, I.P. Iliev, B.D. Dimitrov, M. Vedovato, A. Tiengo, G. Remuzzi, P.
Ruggenenti. 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;55:14561462.
P. Ruggenenti, I. Codreanu, P. Cravedi, A. Perna, E. Gotti, G. Remuzzi. Basiliximab combined with lowdose Rabbit Anti-Human Thymocyte Globulin: a possible further step toward effective and minimally
toxic T cell-targeted therapy in kidney transplantation. Clin J Am Soc Nephrol 2006;1:546-554.
I. Codreanu, N. Perico, S.K. Sharma, A. Schieppati, G. Remuzzi. Prevention programmes of progressive
renal disease in developing nations. Nephrology 2006;11:321-328.
L. Gallon, N. Perico, B.D. Dimitrov, J. Winoto, G. Remuzzi, J. Laventhal, F. Gaspari, D. Kaufman.
Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression
comparing sirolimus vs. MMF. Am J Transpl 2006;6:1617-1623
G. Remuzzi, P. Ruggenenti. Overview of randomised trials of ACE inhibitors (Comment). Lancet
2006;368:555-556.
D. Cattaneo, S. Merlini, S. Baldelli, B. Bartolini, A. Nicastri, E. Gotti, G. Remuzzi, N. Perico.
Mycophenolic acid formulation affects cyclosporine pharmacokinetics in stable kidney transplant
recipients. Ther Drug Monit 2006;28:643-649.
P. Ruggenenti, G. Remuzzi. Time to abandon microalbuminuria? Kidney Int 2006;70:1214-1222.
P. Ruggenenti, C. Chiurchiu, M. Abbate, A. Perna, P. Cravedi, M. Bontempelli, G. Remuzzi. Rituximab
for idiopathic membranous nephropathy: who can benefit? Clin J Am Soc Nephrol 2006:1;738-748.
G. Tessari, L. Naldi, L. Boschiero, C. Cordiano, S. Piaserico, A. Belloni Fortina, D. Cerimele, I. Lesnoni
La Parola, M. Capuano, E. Gotti, P. Ruggenenti, F. Sassi, G. Remuzzi, G. Girolomoni. Incidence and
clinical predictors of Kaposi’s sarcoma among 1721 Italian solid organ transplant recipients: a
multicenter study. Eur J Dermatol 2006;16:553-557.
ANNUAL REPORT
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IRFMN
P. Ruggenenti, G. Remuzzi. Is mycophenolate mofetil better than azathioprine in organ transplantation?
Transplantation 2006;82:1242-1243.
P. Ruggenenti, A. Perna, M. Ganeva, B. Ene-Iordache, G. Remuzzi for the BENEDICT Study Group.
Impact of blood pressure control and angiotensin-converting enzyme inhibitor therapy on new-onset
microalbuminuria in type 2 diabetes: a post hoc analysis of the BENEDICT trial. J Am Soc Nephrol
2006;17:3472-3481.
P. Ruggenenti, G. Remuzzi. Ways to boost kidney transplant viability: a real need for the best use of
older donors. Am J Transpl 2006; 6:2543-2547.
Ruggenenti P, Remuzzi G. What blood-pressure level provides greatest renoprotection in patients with
diabetic nephropathy and hypertension? Nat Clin Pract Nephrol 2006;2:250-251.
P. Ruggenenti, G. Remuzzi. Is mycophenolate mofetil better than azathioprine in organ transplantation? (Letter to the
Editor) Transplantation 2006;82:1242-1243.
ANNUAL REPORT
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RESEARCH ACTIVITIES
Laboratory of Biostatistics
Mycophenolate Steroid Sparing Study (MYSS) Follow-Up extension study:
final analyses
MYSS study results did not show any significant difference between Mycophenolate Mofetil
(MMF) and Azathioprine (AZA), combined with Cyclosporine Neoral and steroids, in reducing
acute rejection in cadaveric kidney allograft recipients. Due to the relatively limited follow-up,
however, the above study could not assess the effects of MMF and AZA on the onset and
progression of chronic allograft dysfunction, a syndrome of proteinuria and worsening renal
function with progressive nephron loss and scarring of the graft (chronic allograft nephropathy).
This is a key issue since, after recipient death, chronic allograft dysfunction represents the major
cause of graft loss in the long-tem. Moreover, results from registry analyses showed that
continued treatment with MMF versus AZA was associated with a protective effect against
renal function deterioration beyond 1 year after transplantation and superior graft survival at 4
years. Despite the limitations of the retrospective design of the above analyses, these data
further limited the possibility to use results of the MYSS trial to change the practice of most
transplant centres to regard MMF as a key component of immunosuppressive drug regimens
based on ciclosporine microemulsion. To address this issue, we designed the MYSS follow-up
study. This was an extension of the MYSS study, prospectively comparing long-term outcomes
of the two cohorts of MYSS patients in the setting of a similar immunosuppressive regimen
based on the microemulsion Neoral, according to their original randomization to MMF or AZA.
Preliminary analyses have been already completed and results are expected to be published this
year.
Remission Clinic Program: final analyses
From January 1999 to November 2004, patients referred to the Unit of Nephrology of the
Azienda Ospedaliera, ‘Ospedali Riuniti di Bergamo’ who had a 24 h urinary protein excretion
rate of 3 grams or more for at least six months entered the Remission Clinic program. The
program included patients who were treated and monitored according to a sequential, stepwise,
multimodal protocol titrated to urinary protein excretion. After a period of up-titration during
the first month, patients were maintained on ramipril (dose range: 2.5-20 mg/day) and losartan
(dose range: 50-200 mg/day) doses allowed as deemed appropriate according to blood pressure
control and tolerability. At 3 months after inclusion into the Remission Clinic program, those
patients who had an heart rate > 60 beats/min and were not receiving a beta-blocker for a
specific indication were prescribed a fixed dose (80 mg/day) of a ndCCB (verapamil) that, if
tolerated, was up-titrated to 120 mg/day. Three months later, a fixed dose (10 mg/day) of a
statin (atorvastatin) was prescribed and, if tolerated, was up-titrated to 20 mg/day. Then patients
were seen every 3-6 months up to study end. Stopping rules for safety/tolerability reasons were
applied. The primary target of treatment was twenty-four hour urinary protein excretion rate.
Three categories of response to treatment were a priori defined on the basis of 24 h urinary
protein excretion achieved after inclusion into the Remission Clinic program: 1. Residual 24 h
proteinuria in clinical range (i.e. persistently more than 1.0 g); 2. Reduction of 24 h proteinuria
to sub-clinical range (1.0 g or less, but more than 0.3 g in 2 consecutive visits); 3. Reduction of
24 h proteinuria to normal range (0.3 g or less in 2 consecutive visits). The primary efficacy
variable was the rate of estimated GFR decline (eGFR). Hard end-points were all-cause and
cardiovascular deaths, non-fatal cardiovascular events and ESRD, considered either
individually, either as a composite end point including all the events. During 2006 we
completed data collection and data analysis.
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Preprocessing of hospital clinical data for comparing different
immunosuppressive therapies in renal transplanted patients.
Since August 2005 the Unit of Nephrology of the Azienda Ospedaliera ‘Ospedali Riuniti di
Bergamo’ outlined an immunosuppressive regimen based on low doses of timoglobulins RATG
(Rabbit Anti-human Thymocyte Globulinin) in association to basiliximab. This induction
therapy attempted to minimize or eliminate steroids, with aim to reduce acute rejections. In
order to facilitate statistical evaluation of acute rejection, of adverse drug reactions due to
immunosuppressive therapies and of renal and patient survival hospital clinical data were
preprocessed, extracted and elaborated by means of dedicated software. For data retrieval we
used a relational database, Microsoft Access®, where the records of all subjects referring to the
Unit of Nephrology are stored.. An ‘ad hoc’ program coding previous and concomitant diseases
was built up. By means of SQL and Visual Basic we facilitated the choice and description of
the disease within a pre-defined list. For previously archived data, an algorithm for an automatic
research of key words was implemented, adding the identified code to the corresponding
diseases. Finally demographic and clinical data at baseline and on follow up were extracted for
data analysis. For follow up visits an ad hoc algorithm searching the nearest visit to a predefined time window was implemented. The above data were extracted and subsequently
imported in SAS System® and submitted to statistical analysis.
BENEDICT Phase A - Retinopathy substudy: final analyses
Diabetic retinopathy is the most frequent cause of blindness in adults in developed countries.
Whether regression of established retinopathy is achievable and which antihypertensive
medication may regress the disease more effectively is unknown. We compared the incidence of
disease regression in hypertensive type 2 diabetics included in the Bergamo Nephrologic
Diabetes Complications Trial (BENEDICT) – Phase A, who had been randomly allocated to
blinded angiotensin-converting-enzyme (ACE) inhibition with trandolapril or to non-ACE
inhibitor therapy, and had established diabetic retinopathy at baseline funduscopy evaluation. In
the 2006 we completed data collection and data analysis.
BENEDICT Phase A - ECG substudy: final analyses
Electrocardiographic left ventricular hypertrophy (ECG LVH) predicts cardiovascular morbidity
and mortality and its prevention is cardioprotective. However, which antihypertensive drugs
better prevent ECG LVH is uncertain. We compared the 2-year incidence of ECG LVH by
Sokolow-Lyon and Cornell voltage criteria in hypertensive type 2 diabetics included in the
Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) who had been randomly
allocated to blinded angiotensin-converting-enzyme (ACE) inhibition with trandolapril or to
non-ACE inhibitor therapy and had no ECG evidence of LVH at baseline. In the 2006 we
completed data collection and data analysis.
Study on long-term renal allograft function on a tacrolimus-based
prednisone-free maintenance immunosuppression comparing sirolimus
versus MMF
It is not known how different steroid-free immunosuppressive combinations affect renal graft
survival and long-term kidney transplant function. Here we sought to compare the impact on
graft survival and long-term graft function of two tacrolimus (Tac)-based, prednisone-free
maintenance immunosuppressive protocols: Tac/Mycophenolate Mofetil (MMF) vs.
Tac/Sirolimus (SRL). Renal transplant patients given induction therapy with IL2-RA and
methylprednisolone on days 0, 1 and 2 post-transplant were prospectively randomized to two
maintenance immunosuppressive regimens with Tac/MMF (n = 45) or Tac/SRL (n = 37).
During the 3-year follow-up the following data were collected: patient survival, renal allograft
survival, incidence of acute rejection and glomerular filtration rate (GFR) at different time-
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points post-transplant. Cumulative graft survival was significantly different in the two groups:
one kidney loss in the Tac/MMF vs. six kidney losses in the Tac/SRL (logrank test p = 0.04).
GFR at different time-points post-transplant was consistently better and statistically significant
in the Tac/MMF than in the Tac/SRL group. The slope of GFR decline per month was flatter in
the Tac/MMF than in the Tac/SRL group. This study showed that renal graft survival and graft
function were significantly lower in the combination of Tac/SRL than Tac/MMF. We performed
statistical analyses of this study conducted by the Northwestern University School of Medicine
of Chicago (USA).
Laboratory of Clinical Chemistry
Reliability of neutrophil gelatinase-associated lipocalin (NGAL) as an early
marker in predicting acute renal dysfunction in patients with solid organ
cancer given cisplatin as chemotherapeutic agent
Acute renal failure represents a very important and potentially devastating disorder in clinical
medicine. Despite substantial technical improvements in treatments, mortality and morbidity
associated with acute renal failure remain dismally high. Ischemic and nephrotoxic insults to the
kidney are the leading cause of acute renal failure and most often manifest as acute tubular
necrosis. While several anti-neoplastic agents frequently exhibit nephrotoxicity, the platinum
derivatives are among the most frequent compounds leading to renal injury. Since its
introduction into clinical trials, cisplatin has had a major impact in cancer medicine, changing
the course of therapeutic management of several tumors, such as those of ovary, testes, and the
head and neck. Unfortunately, approximately 25-35% of patients develop evidence of
nephrotoxicity following an initial dose of cisplatin. Overall these findings indicate that there is
a pressing need for way to protect the kidney while administering effective chemotherapeutic
agents such as cisplatin. Unfortunately, creatinine is an unreliable indicator during acute
changes in kidney function. Among compounds that might serve as a novel biomarkers for the
initiation phase of acute renal failure, neutrophil gelatinase-associated lipocalin (NGAL) has
been identified as one of the most strikingly upregulated genes and overexpressed proteins in
the kidney after ischemia. Markedly increased NGAL concentrations were easily detected in
urine early after renal ischemia in mouse and rat models. Recent studies have demonstrated that
NGAL is a useful early predictor of acute renal failure also in humans. Thus, it has been shown
that the concentration of NGAL in urine and serum is strikingly raised in children with acute
renal failure after cardiopulmonary bypass. Interestingly, urine and serum concentrations of
NGAL markedly increased 2 h after surgery.
Taken altogether these findings indicate that urinary and/or serum NGAL concentration
monitoring may represent a sensitive, specific, and highly predictive early biomarker for acute
renal failure. So far, however, no data are available on the reliability of urine and/or serum
NGAL to predict the development of acute renal dysfunction in cancer patients receiving
cisplatin treatment.
A study in 46 adult patients with solid tumors is in progress and is aimed to evaluate the
suitability of early changes increase in urinary and/or serum NGAL concentrations (determined
by ELISA assay) soon after cisplatin infusion, to predict development of subsequent acute renal
dysfunction. The study is also aimed to determine, by means of receiver-operating
characteristics curve (ROC) analysis, the accuracy of NGAL urinary and/or serum
concentrations to predict acute renal injury; to define a cut-off level of NGAL in both urine and
serum samples to predict subsequent acute renal dysfunction; and to evaluate a possible
correlation between urinary and/or serum NGAL concentrations and the degree of renal function
impairment, as the peak of serum creatinine concentration and the nadir of GFR estimated by
the Calvert equation.
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Comparison between different analytical methods for albumin
determination in urine
Although the limit of urinary albumin excretion rate (UAE) of 20 μg/min was chosen as a
definition of microalbuminuria because 95% of normal individuals had excretion rates below
that limit, it is recognized that the risk of cardiovascular events and of progression to overt
nephropathy is elevated also in subjects in the “high normal” range (10 – 20 μg/min). Mounting
evidence indicates a continuous relationship between UAE and risk since epidemiological data
suggest an inconsistency with the concept of threshold level. Thus, both reliability and
sensitivity of the chosen method for urinary albumin determination may play an important role
in patients monitoring.
Immunochemical assays are the most widely used methods for microalbuminuria measurement.
Recent works have demonstrated that intact albumin in urine may exist in two forms,
immunoreactive and immuno-unreactive, but only the immunoreactive form can be detected by
conventional immunochemical methods. With the purpose of measuring both forms of intact
albumin, we recently developed a high performance size-exclusion liquid chromatography
(HPLC) method which is capable to determine both immunoreactive and immuno-unreactive
albumin moieties. On the other hand, HPLC methods to measure albumin, are not commonly
available in clinical laboratories. Other immunochemical methods that use less demanding
instruments as been recently proposed as point-of-care testing (POTC) to assess albumin loss
resulting from diabetes or other chronic kidney disease states. These instruments offer rapid
results and are also good candidates to become the instrument of choice for prevention programs
in developing countries due to no need of technical assistance, minimal performance required
for the personnel and relatively low cost per test.
In a study aimed to evaluate the performance of different analytical methods, we compared the
determination of albumin urinary levels in diabetic patients as measured by conventional
(nephelometric) and the chromatographic method developed by our laboratory as well as by
HemoCue 201, a commercially available POTC instrument, which performs a highly specific
turbidymetric assay for human albumin excreted in the urine.
Preliminary data indicate that especially for albuminuria <50 μg/min, nephelometry
underestimated UAE as compared to HPLC. A highly significant correlation was found between
albumin concentration determined by conventional nephelometric assay and those determined
by HemoCue 201. Data analysis revealed that there was a good agreement between the methods
over the entire range of linearity of HemoCue 201 (5−150 μg/mL).
Development of HPLC methods for inulin and p-aminohippuric acid in
urine and plasma samples
Measurement of renal function is important in the diagnosis and management of renal disease.
Assessment of glomerular filtration rate (GFR) is the most useful quantitative index of renal
function in health and disease, and is currently used to determine the effectiveness of therapies
designed to slow the progression of renal diseases. For the evaluation of GFR, 24-hour urinary
creatinine clearance is widely used, but it is inconvenient and sometimes inaccurate due to
variable creatinine metabolism and tubular secretion in each subject and between individuals
with tendency to increase with decline of renal function. At variance, inulin is freely filtered at
glomerular level but not acted on by the tubules, is not synthesized or degraded by the body and
is physiologically inert and fulfill the criteria for an ideal filtration marker. Measurement of
inulin with conventional colorimetric methods is a cumbersome and time consuming procedure.
Thus, we have developed a reliable simple high performance liquid chromatographic (HPLC)
method to measure inulin concentration in plasma and urine samples.
The developed HPLC method has acceptable performance and sensitivity and accurately
quantifies inulin in plasma and urine specimens.
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The performance of this HPLC assay was evaluated in a large number of patients with diabetic
and non-diabetic chronic nephropathies enrolled in different clinical trials and regularly
monitored for GFR at the Clinical Research Center for Rare Diseases “Aldo e Cele Daccò” of
the Mario Negri Institute.
The same chromatographic assay allows the simultaneous determination of p-aminohippuric
acid, a marker used to determine the effective renal plasma flow being extracted almost
completely from plasma during its passage trough the kidneys.
Ficoll analysis by high performance chromatography
Ficoll fractional clearance determination is a reliable tool to assess size-selectivity property of
the glomerular capillary barrier in animal models. For this purpose, we used a high performance
liquid chromatographic technique for measurement of FITC-labeled Ficoll developed by our
laboratory. The developed method requires the injection of as low as 5 μl of plasma and urine
samples onto a TSK G4000 PWXL column and fluorescence detection to measure FITC-Ficoll.
It is fast, reliable, simple and allows the evaluation of the FITC-Ficoll fractional clearance for
radii at least up to 80 Angstrom.
Due to the rapidity of sample handling and the analytical specificity for FITC-Ficoll it has been
used in a study aimed to evaluate the effect of different doses statins given alone or in
association with ACE inhibitors on renal hemodynamics, permselective properties of glomerular
capillary barrier and tubular function in rats with renal mass reduction.
The results have shown that the HPLC method to measure FITC-Ficoll can be considered a
reference tool for routine assessment of glomerular size-selective function in animal models.
Reliability of 13 different GFR prediction equations in type 2 diabetic
patients
Diabetic nephropathy affects 25-40% of diabetic patients, and diabetes is the leading cause of
end-stage renal disease. Evaluation of glomerular filtration rate (GFR) is therefore of critical
importance in the clinical management of both clinic and outclinic diabetic patients. However,
the measurement of the true GFR either by the renal clearance of the gold standard inulin or by
plasma clearance of contrast agents is time consuming, difficult to perform and cannot be easily
implemented in clinical daily practice. Urinary creatinine clearance is widely used to measure
GFR, but it is inconvenient and sometimes inaccurate due to variable creatinine metabolism and
tubular secretion. To circumvent these drawbacks, a number of equation has been developed to
provide an estimate of renal function from serum creatinine and demographic characteristics.
Despite being widely used, their performance and suitability to monitor renal function in
patients with type 2 diabetes have not been assessed so far.
In 279 normoalbuminuric patients and 134 microalbuminuric subjects enrolled in the
BENEDICT and in the DEMAND study we compared with the “gold standard” plasma iohexol
clearance the performance in monitoring renal function of 13 different GFR equations.
Data analysis showed that GFR was markedly underestimated in both groups of patients. The
Rule and Ibrahim formulas performed slightly better than the other models with about 50% the
estimated GFR within +10% error as compared to the reference iohexol.
To better investigate the performance of the 13 prediction equations in dependence of the
kidney function, the diabetic patients were stratified according in the following GFR ranges:
from 60 to 89 ml/min/1.73m2, from 90 to 119 ml/min/1.73m2, and > 120 ml/min/1.73m2.
Almost all the tested model underestimated GFR and this behavior was more evident at higher
range of renal function, however both Rule and Ibrahim showed a marked overestimation in the
low range of GFR. These findings showed that, irrespectively of albumin excretion rate, none of
the 13 GFR models seems to safely substitute for the direct measurement of the renal function
by means of an affordable and suitable reference methods, such as iohexol plasma clearance.
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The development of a new robust GFR prediction equation in type 2 diabetic patients is still
needed.
Laboratory of Drug Development
Indications for rituximab therapy in patients with membranous
nephropathy
Rituximab, a chimeric monoclonal antibody able to deplete CD20 positive B cells effectively
reduces proteinuria in patients with idiopathic membranous nephropathy (IMN), but response to
treatment may vary from patient to patient. Retrospective analyses of heterogeneous patient
populations given different immunosuppressive regimens failed to identify determinants of
response. Aim of the present study was to assess the possible determinants of response to
rituximab, in order to identify those patients who may benefit the best of this therapy
To this purpose, we retrospectically evaluated by multivariate analyses the association between
baseline clinical, laboratory and histology covariates and proteinuria reduction achieved after 4
weekly rituximab infusions (375 mg/m2) in IMN patients with proteinuria >=3.5 g/24h while on
ACE-inhibition for at least 6 months and no previous remissions. Glomerular and tubulointerstitial (TI) scores at baseline biopsy predicted the outcome. Among glomerular and TI score
components, tubular atrophy and interstitial fibrosis were significantly associated with threemonth proteinuria. Urinary protein excretion decreased from 9.1±4.0 g/24h to 4.6±3.5 g/24h
(p<0.001) in 8 patients with TI score <1.7, but did not change in 6 with a score >1.7. Nine
additional IMN patients were then prospectively allocated to rituximab treatment on the basis of
a TI score <1.7. Three-month proteinuria decreased in all patients from 8.9±5.3 g/24h to 4.9±3.9
g/24h (p<0.001) and serum albumin increased from 2.2±0.6 mg/dl to 2.8±0.5 mg/dl (p<0.01).
Rituximab achieved B cell depletion in all patients. These results suggest that in IMN patients
with nephrotic proteinuria despite ACE inhibition therapy, renal biopsy findings may help
predicting response to rituximab and defining selection criteria for randomized trials aimed to
assess the risk/benefit profile of B cell target therapy as compared to aspecific
immunosuppressants and/or conservative therapy alone.
Finding the ideal dose for rituximab therapy in patients with membranous
nephropathy
Rituximab has been shown to reduce proteinuria and suppress symptoms over at least one year
follow-up in IMN patients with heavy (>3g/24h) proteinuria that could not be lowered by ACE
inhibitor (ACEi) therapy for at least six months. The rationale for this therapeutic approach is
that by eliminating B cells, rituximab may prevent the generation of clones involved in the
neosynthesis of autoantibodies. With this approach, however, we observed that B cells
disappeared from the circulation just after the first Rituximab administration. Conceivably, this
should also translate in a complete inhibition of autoantibodies production. Should this be the
case, additional administration of Rituximab would not achieve further effect in term of B cells
depletion and autoantibodies inhibition, and would unnecessarily expose the patient to the risk
of sensitization and reactions.
To address this issue, since December 2005 all patients with nephrotic range proteinuria (in
spite of at least 6 months of ACEi therapy) referred to our Nephrology Unit were treated with a
schedule of Rituximab titrated to circulating B cells. Rituximab was infused weekly until full
depletion of B cells was achieved for a maximum of 4 doses. To assess the cost/effectiveness of
this novel regimen, we designed a matched-cohort analysis comparing the course of proteinuria
in patients treated with B cell count-based strategy and in a cohort of patients treated with a
standard course of 4 administrations. Preliminary results suggest that B cell count-based
strategy may offer the same antiproteinuric effect, but remarkably reduces costs and risk of
adverse events as compared with the standard course of 4 administrations.
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Comparison of whole blood everolimus levels measured with the FPIA
immunoassay and with a validated HPLC method using samples from
heart transplant recipients
Therapeutic monitoring of everolimus with chromatographic methods (HPLC) has shown to
provide effective immunosuppression while limiting the incidence of drug-related adverse
events. However, this technique is cumbersome, time consuming and seldom feasible in the
routine clinical practice. A fluorescence polarization immunoassay (FPIA) has been recently
developed for the assessment of everolimus levels. Previous studies have shown, however, that
immunoassays can overestimate drugs concentrations, mainly due to cross-reactivity of
antibodies used with drug metabolites, ultimately resulting in unacceptable performance. In
collaboration with the Department of Clinical Medicine of the Ospedali Riuniti of Bergamo,
with have carried out a formal comparison between HPLC and FPIA. The performance of both
methods was initially tested using drug-free whole blood spiked with different amount of
everolimus concentrations and, subsequently, by analyzing 120 trough blood samples from heart
transplant recipients chronically given everolimus as part of their immunosuppressive regimen.
Inaccuracy and imprecision of both methods were below 15%, and in agreement with FDA
guidelines. The correlation between everolimus concentrations measured FPIA and HPLC was
good. The FPIA gave a mean overestimation of 20% as compared with HPLC. These data
suggest that the performance of the FPIA is satisfactory and can be, therefore, reliably used to
measure everolimus concentrations in the routine clinical practice.
Simultaneous assessment of everolimus and cyclosporine whole blood
levels: development of an HPLC method and clinical applications
Everolimus (RAD) is a novel antirejection drug recently introduced on the market. According to
actual protocol, it is suggested that this drug may be given in combination with low-doses of
cyclosporine. Recent studies have documented a strong correlation between everolimus whole
blood concentrations and drug efficacy and toxicity, as previously documented for cyclosporine.
Due to the narrow therapeutic index, a tight simultaneous monitoring of both these drugs is
needed to optimize the risk/benefit profile for each patient. All available methods require the
use of mass spectrophotometric detection, an equipment not commonly available in the clinical
laboratories, which limits their use in clinical practice. To address this issue, we developed a
high-performance liquid chromatographic (HPLC) method with ultraviolet detection (common
in most laboratories). The samples were purified by precipitating blood matrix with zinc sulfate,
drugs were then extracted with acetone followed by solid-phase extraction. The assay had no
interference peaks with immunosuppressive drugs commonly given to transplant patients, and
had a wide range of linearity and adequate levels of sensibility and reproducibility. Moreover,
this simplified extraction procedure allowed to measure at least 60-70 samples in a single run.
Of note, this novel tecnique was succesfully used to assess everolimus and cyclosporine levels
in heart transplant recipients randomized for a multicenter phase III clinical trial.
Pharmacokinetics of mycophenolic acid from mycophenolate sodium and
comparison with that from mofetil formulation in kidney transplant
recipients
The introduction of mycophenolate mofetil (MMF) has improved long-term graft survival after
organ transplantation. However the use of this agent may be limited by gastrointestinal and
hematological side-effects. To overcome these problems, an enteric-coated formulation of
mycophenolate sodium (EC-MPS) has been recently developed. Detailed data on the
pharmacokinetics of MPA released from EC-MPS are lacking. To compare the profiles of
mycophenolic acid (MPA) derived from the two formulations, we have performed
pharmacokinetic studies in 20 kidney transplant recipients given EC-MPS (n=10) or MMF
(n=10) as a part of their immunosuppressive regimes. At month 6 and 12 post-surgery, despite
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no differences in mean MPA Cmax and AUC between the two formulations, aberrant and
extremely variable pharmacokinetic curves were found in all patients given EC-MPS.
Additionally, these patients presented MPA Tmax ranging from 0 to 480 minutes and doseadjusted MPA trough (C0) 4.7-fold higher compared to patients given MMF. Given the
emerging strong support for the clinical outcome benefit of MPA monitoring in transplant
setting, the manufacturer should face with all the potential problems related with the enteric
coating of EC-MPS that limit the application of therapeutic drug monitoring, before promoting
an extensive use of this novel formulation.
Mycophenolic acid formulation affects cyclosporine pharmacokinetics in
stable kidney transplant recipients
A novel monitoring strategy based on the blood concentration at two hours post-dose (C2) has
been recently proposed for the assessment of cyclosporine (CsA) absorption and daily exposure,
and therapeutic windows for C2 levels have been identified. These guidelines have been derived
from patients given mycophenolate mofetil (MMF) or azathioprine, and never tested in those
treated with the enteric-coated formulation of mycophenolic acid (EC-MPS).
The authors have compared full CsA pharmacokinetic evaluations in 12 kidney transplant
recipients given EC-MPS with those from 20 patients on MMF at months 6, 12, 18 and 24 postsurgery. At month 6 post-Tx patients on EC-MPS had a shift to right in the CsA peak
concentration as compared to that in patients given MMF, an effect associated with significant
differences in CsA Tmax (1.9 + 0.3 vs 1.5 + 0.6 h, p<0.05), C2 (988 + 259 vs 720 + 214 ng/mL,
p<0.01), and C3 levels (539 + 119 vs 435 + 119 ng/mL, p<0.05). Interestingly, the authors found
that the majority of patients on EC-MPS had CsA peaking at 2-h post dosing, whereas most of
patients on MMF had CsA Cmax at 1 h. Similar results were observed also at months 12, 18, and
24 post-surgery.
These findings indicate that the pharmacokinetics of CsA is significantly affected by the
concomitant administration of different MPA formulations. This would imply the need of
specific algorithms to adequately estimate CsA dose adjustment in patients given, in addition to
CsA, EC-MPS or MMF.
Limited sampling strategies for the estimation of sirolimus daily exposure
in kidney transplant recipients
Sirolimus (SRL) is a powerful immunosuppressive agent successfully used in organ
transplantation, characterized by a narrow therapeutic index and variable absorption. SRL dose
is a poor predictor of drug exposure. The area under the time-concentration curve (AUC) is
generally accepted as the best surrogate marker of daily drug exposure, which in turn, correlates
with therapeutic/toxic effects. A full time SRL profile (AUC0-24), however, requires the
collection of multiple blood samples throughout the dosing period, causing both time and cost
restraints. The development of limited sampling strategies (LSS), would be of clinical relevance
to improve the therapeutic drug monitoring of SRL.
The authors have applied stepwise multiple regression analysis to pharmacokinetic profiles from
adult kidney recipients subjected to a calcineurin free regimen, to identify several single and
multiple points equations based on samples collected within the 6th hour after dosing. The
performance of these equations were tested in a separate validation group to determine the
effectiveness by means of Bland and Altman approach.
The algorithms proposed were associated with good correlations with the real AUC. Two of
them, based on two time points within the first 4 hours after dosing, show high correlation
(r2>0.9), are capable of a good prediction of drug exposure (95% of the estimations within the
range of ± 2 SD), and would help to optimize SRL therapeutic drug monitoring in renal
transplant recipients, minimizing the discomforts and efforts for both patients and clinical staff.
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Genetics partly explains patient variability of mycophenolic acid
pharmacokinetics in renal transplant recipients
Mycophenolic acid (MPA) is widely used as immunosuppressive agent in renal transplantation.
It is mainly metabolized by uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9) to 7O-glucuronide (MPAG). The UGT1A9 gene that encodes for the UGT protein is localized on
chromosome 2q37 and several single nucleotide polymorphisms (SNPs) in the gene have been
described. Moreover, excretion in the bile of MPAG occurs through membrane drug efflux
protein, the more relevant being MRP2. This protein is encoded by a gene located on the
chromosome 10q24 from whom different SNPs have been so far identified that could also affect
the expression of the protein. The present study was designed to study the impact of the
polymorphisms of UGT1A9 and to investigate the role of polymorphisms in MRP2 in renal
transplant patients MPA pharmacokinetics.
Thirty-four patients were enrolled in the pharmacogenetic study. Patients had clinical
evaluations and laboratory tests at 6 month after transplantation, as well as the assessment of the
complete MPA pharmacokinetic profiles and MPAG measurement. They were genotyped for
single nucleotide polymorphism (SNPs) in UGT1A9 C-1252T, T-1887G, C-665T, C-440T, T331C, T-275A, T98C and for MRP2 SNPs C-24T and G1249A. Association of polymorphisms
with MPA and MPAG pharmacokinetic parameters was studied.
Great MPA pharmacokinetic variability was found, confirmed by values of MPA/MPAG
metabolic ratio ranging from 0.012 to 0.195 among the study patients. In particular, a
multimodal frequency distribution was documented that highlighted the presence of at least two
different phenotypes.. Significant higher MPA trough levels were found in patients carrier of C665T polymorphism. MPA and MPAG AUC were significantly associated with the presence of
UGT1A9 -440/-331 genotype. The presence of MRP2 promoter C-24T and exon 10 SNPs
G1294A did not cause any significant variation in any MPA and MPAG pharmacokinetic
parameters.
The study has demonstrated a significant impact on MPA pharmacokinetics in renal allograft
recipients of different polymorphisms in the promoter region of the UGT1A9 in particular C440T/T-331C and C-665T.
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LABORATORY OF CLINICAL
EPIDEMIOLOGY
STAFF
Head
Guido BERTOLINI, M.D.
Clinical Knowledge Engineering Unit
Head
Davide LUCIANI, M.D.
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CURRICULA VITAE
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 was 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. Since 2001 he is Vice-chairman of
the Research Group on Cost-effectiveness, Section on Health Services Research and Outcomes –
European Society of Intensive Care Medicine and, since 2004, he is President of the Scientific Committee
of the “Ospedale maggiore” in Crema.
•
Livigni S, Maio M, Ferretti E, Longobardo A, Potenza R, Rivalta L, Selvaggi P, Vergano M, Bertolini G. Efficacy and
safety of a low-flow veno-venous carbon dioxide removal device: results of an experimental study in adult sheep. Crit
Care 2006; 10: R151.
•
Rossi C, Simini B, Brazzi L, Rossi G, Radrizzani D, Iapichino G, Bertolini G. Variable costs of ICU patients: a
multicenter prospective study. Intensive Care Med. 2006;32:545-52
•
Bertolini G, Confalonieri M, Rossi C, Rossi G, Simini B, Gorini M, Corrado A. Costs of the COPD. Differences between
intensive care unit and respiratory intermediate care unit. Respir Med 2005; 99: 894-900.
•
Malacarne P, Rossi C, Bertolini G; GiViTI Group. Antibiotic usage in intensive care units: a pharmaco-epidemiological
multicentre study. J Antimicrob Chemother. 2004 Jul; 54:221-4
•
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.
•
Simini B, Bertolini G. Should same anesthetist do preoperative anesthetic visit and give subsequent anesthetic?
Questionnaire survey of anesthetists. BMJ 2003; 327: 79-80.
Davide Luciani got his Medical Degree at the University of Bologna in 1995, and the Diploma 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 modeling 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.
•
Bertolini G, Luciani D, Gridelli B. Day surgery: where do our efforts need to be focused? Ambulatory Surgery,
2004(10): 211-216
•
Luciani D, Marchesi M, Bertolini G. The role of Bayesian Network in the diagnosis of pulmonary 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 Oct 15;102(8):2717-23Haemostasis, 2003 Apr;1(4):698-707
•
Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than
anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood , 2003 Mar
1;101(5):1827-32
•
Brazzi L, Bertolini G, Arrighi E, Rossi F, Facchini R, Luciani D. Top-down costing: problems in determining staff costs
in intensive care medicine. Intensive Care Medicine, 2002 Nov;28(11):1661-3
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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 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 favoring the evaluation and the continuous improvement of complex clinical activities.
The participation to the Margherita project on the quality of care assessment in intensive care
unit (ICU), which started in 2002, has further increased during this year. The patients recruited
in 2006 were more than 50.000. This allowed the development of a highly accurate model for
the prediction of hospital mortality in critically ill patients. Each participating ICU has received
both a general and an individual report. In the latter, in addition to a detailed description of the
case-mix, we supplied each ICU with the comparison of its own performance with that of
others.
We monitored, on behalf of the Italian Ministry of Health, the clinical use of Drotrecogin alfa
(activated) in ICU. This is a new drug for critically ill patients with severe sepsis or septic
shock. In the framework of a general appropriate utilization, we found some problems and, thus,
the possibility to further increase the quality of care in this field. We provided each ICU with a
detailed report on the results of the project.
We realized one of the biggest continuous infection surveillance program in ICU. We identified
the major problems of each unit in the diagnosis and treatment of infections.
We developed the first version of an electronic clinical record for the ICU: a clinical record
shared by many units that will allow to compare their process of care in the framework of a
continuous quality of care improvement
We realized a survey on end-of-life decisions in ICU which involved 90 centres. Results will be
available early in 2007.
We further developed an expert system to assist physicians in the complex diagnosis of
Pulmonary Embolism. The new version showed excellent validity.
We eventually contributed to the set-up of a European network for the study of patients with
paraneoplastic syndrome.
Dipartimento di Neurologia, Clinica Medica II, Azienda ULSS 16, Università di Padova.
Dipartimento di Specialità Chirurgiche, Scienze Radiologiche e Medico Forensi, Cattedra di
Anestesia dell’Università degli Studi di Brescia.
Servizio Anestesia e Rianimazione, Osp. San Giovanni Bosco, Torino.
Divisione di Medicina Interna, Università di Trieste.
Divisione di Fisiopatologia Respiratoria, Università di Firenze.
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo.
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Istituto di Anestesia e Rianimazione, Università di Milano.
Servizio Anestesia e Rianimazione, Osp. Civile, Belluno.
Bloomsbury Institute of Intensive Care Medicine, Institute of Biomedical Research, University
College London, UK.
Department of Statistical Science, University College London, UK.
Machine Intelligence Group, University of Aalborg, Denmark.
Ricerca & Pratica (Guido Bertolini)
Dedalo. Gestire i sistemi complessi in sanità (Guido Bertolini)
Intensive Care Medicine
Criticale Care Medicine
Ricerca & Pratica
Scientific Committee, azienda ospedaliera “Ospedale maggiore” di Crema.
EVENT ORGANIZATION
Educational course, Statistica multivariata per la ricerca biomedica, February-May, Ranica
(BG).
Workshop, Le decisioni di fine-vita in rianimazione, September 10, Ranica (BG).
Workshop, Startup Meeting Compact, September 12, Ranica (BG).
Educational course, Utilizzo delle banche dati in medicina, September 21-28, Ranica (BG).
Congress, GiViTI Annual Meeting, October 18-20, Pesaro.
Educational course, Statistica per medici, November 7-14, Ranica (BG).
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INVOLVED
Meeting, PNS, Additional Outcomes from the Statistical Analysis, February 24, Treviso
Workshop, Come raccogliere i dati in medicina, L’esperienza del GiViTI: il progetto Margherita
Due, March 16, Firenze
Congress, BRAIN06, Hot Topic, April 27, Brescia
Congress, SMART, Alternative ai trial controllati randomizzati nella ricerca clinica, May 11,
Milano
Congress, III Meeting di Formazione e Aggiornamento sugli Interventi in TI, Gli aspetti
metodologici della valutazione degli interventi nutrizionali nel paziente critico, May 30,
Calampiso
Meeting, Antibiotici: attualità, riflessioni, Farmacoepidemiologia degli antibiotici: il casomodello delle terapie intensive, June 19, Seriate
Meeting, POR Sardegna 2000-2006 - Seminario finale misura 5.3, La valutazione della
performance della TI: quali dati raccogliere e come utilizzarli, July 30, Oristano
Meeting, II Meeting GiViTI Regione Veneto, Il SAPS III e i nuovi progetti GiViTI, Come
estrarre i dati dalla propria Terapia Intensiva, Presentazione di Margherita, September 29,
Treviso
Congress, 60° SIAARTI, Le eterne dicotomie della sperimentazione clinica, October 11,
Perugia
Workshop, “Salute e malattia nell’era della tecnica”, November 10, Spiazzi di Gromo (BG)
Meeting, “Farmaci: usarli bene per stare meglio. Presentazione di un progetto integrato tra
Ospedale e Territorio, Il ruolo tra formazione ed informazione”, November 18, Bergamo
Meeting, Registro scompenso cardiaco, La metodologia dei registri epidemiologici, November
25, Palermo
Workshop, Formazione degli operatori, Presentazione del software Margherita Tre, December
11-12, Livorno
Meeting, Progetto Sorveglianza Infezioni, Lettura dei dati della TI di Cesena, December 12,
Cesena
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Regione Lombardia
Regione Toscana
Regione Veneto
Regione Piemonte
ARS Toscana
AstraZeneca Italia
Sanofi-Synthelabo Italia
Draeger Italia
Bellco SpA
Ministero della Salute
Azienda ULSS 16, Padova - Italia
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo
Livigni S, Maio M, Ferretti E, Longobardo A, Potenza R, Rivalta L, Selvaggi P, Vergano M, Bertolini G.
Efficacy and safety of a low-flow veno-venous carbon dioxide removal device: results of an experimental study in
adult sheep. Crit Care. 2006;10(5):R151.
Rossi C, Simini B, Brazzi L, Rossi G, Radrizzani D, Iapichino G, Bertolini G.
Variable costs of ICU patients: a multicenter prospective study. Intensive Care Med. 2006 Apr;32(4):545-52.
Radrizzani D, Bertolini G, Facchini R, Simini B, Bruzzone P, Zanforlin G, Tognoni G, Iapichino G
Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe sepsis: a randomized
clinical trial. Intensive Care Med 2006; 32(8): 1191-1198
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; 72:419-32.
Rossi C, Bertolini G. Monitoraggio dell’uso di Xigris® nelle Terapie Intensive italiane. Risultati della seconda fase di
raccolta dati. BIF 2006; 2: 70-75.
Boffelli S, Rossi C, Bertolini G. Progetto Margherita. Promuovere la ricerca e la valutazione in Terapia Intensiva.
Rapporto 2005. Bergamo: Ed. Sestante, 2006.
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RESEARCH ACTIVITIES
Appropriateness in Intensive Care Units
The main purpose of these research activities 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 half of the Italian ICUs and coordinated by the
Laboratory. The main focus is the “Margherita” project. 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 implemented. Such an activity, lead by the
Unit of Clinical Knowledge Engineering, and also involving the Department of Statistical
Science (University College London) and 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
pharamcovigilance 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.
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).
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
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contemplated observations, would overcome the main reasons which prevented ordinary clinical
guidelines to be largely accepted. Moreover, the results of the retrospective validation of the
system have been obtained.
The Unit started a project for the realization of a software assisting the physician in tracing back
the basis of his clinical decisions before the description provided by clinical reports, among
those that are typical of particular medical specialty. The software has the double target to create
specific applications based on probabilistic models representing complex clinical decision
problems, and to involve physicians in their construction. The last target is achievable given the
strong analogy between the causal structure of the exploited models (bayesian networks) and the
pathophysiological structure of medical knowledge. By this, it will be given the chance to adopt
this system within medical training projects, with a special attention to e-learning programs.
Clinical Epidemiology of rare diseases and orphan medicine
Our purpose is to find out and describe clinical and research problems related either to rare
diseases or to neglected aspects of well-known diseases. We also focus on the needs of the
patients with rare diseases. A specific project is connected with this research activity: “PNS –
Euronetwork”. It is a European project on paraneoplastic neurological syndromes that is
financed by the Fifth and Sixth Framework Program of the European Community. Its purposes
are various: to develop a network of reference centers for these pathologies all sharing a
common database; to organize a sample bank of biological fluids and cerebrospinal 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.
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LABORATORY OF COORDINATION OF
DIAGNOSIS AND INFORMATION ON
RARE DISEASES
STAFF
Head
Arrigo SCHIEPPATI, M.D.
Information Centre for Rare Diseases
Head
Erica DAINA, M.D.
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CURRICULA VITAE
Arrigo Schieppati got his degree in Medicine at the University of Milan in 1978 and the specialization in
Medical Nephrology in 1984 at the same University.
He performed his training at the Mario Negri Bergamo Laboratories with Dr. Remuzzi, and completed it
with stages at the laboratories of prof. Patrono (Catholic University in Rome), prof. John Gordon
(Cambridge, GB), and at the Division of Renal Diseases - University of Colorado Medical School,
directed by Dr. Schrier (Denver, USA). Since 1982 he works at the Division of Nephrology and Dialysis
– Riuniti Hospital – Bergamo, where he is in charge of Outpatients Clinic and Day Hospital. From 1992
to 1995 he was Head of the Information Center for Rare Diseases and since 1996 he is Head of the
Laboratory for Coordination of Information and Diagnosis of Rare Disease at the Clinical Research
Center for Rare Diseases Aldo e Cele Daccò of the Mario Negri Institute.
Areas of interest: diagnosis and therapy of chronic renal diseases, hypertension and rare kidney diseases.
Affiliations: ethical committee Riuniti Hospital - Bergamo; member of the working group of the regional
network for rare diseases in Lombardy; scientific committee Bolognini Hospital – Seriate (BG); member
of the Task Force on Rare Diseases (DG Health and Consumer Protection); International Society of
Nephrology; American Society of Nephrology; Editorial Board Journal of Nephrology, Editorial Board of
JASN - Nephrology Self Assessment Program.
•
Schieppati A, Remuzzi G. Chronic renal diseases as a public health problem: epidemiology, social, and economic
implications. Kidney Int Suppl. 2005 Sep;(98):S7-S10.
•
Remuzzi G, Schieppati A, Boissel JP, Garattini S, Horton R. Independent clinical research in Europe. Lancet. 2004 Nov
6-12;364(9446):1723-6.
•
Schieppati A, Perna A, Zamora J, Giuliano GA, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic
membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004293.
•
Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med.
2002 Apr 11;346(15):1145-51.
•
Schieppati A, Remuzzi G, Garattini S. Modulating the profit motive to meet needs of the less-developed world. Lancet.
2001 Nov 10;358(9293):1638-41.
•
Ruggenenti P, Schieppati A, Remuzzi G. Progression, remission, regression of chronic renal diseases. Lancet. 2001 May
19;357(9268):1601-8.
Erica Daina got his 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.
Since 1996 she is Unit Head – Information Center for Rare Diseases. Areas of interest: rare diseases,
Takayasu arteritis, Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura, Fabry’s
disease, Alport’s syndrome. Since January 2002 she is representative of Coordinating Centre - Regional
Network for Rare Diseases - and collaborates to didactics activity at the University of Turin (Clinical
Pathology of Rare Diseases - School of Clinical Pathology Specialization).
•
Vanoli M, Daina E, Salvarani C, Sabbadini MG, Rossi C, Bacchiani G, Schieppati A, Baldissera E, Bertolini G; Itaka
Study Group. Takayasu's arteritis: A study of 104 Italian patients. Arthritis Rheum. 2005 Feb 15;53(1):100-7.
•
Remuzzi G, Galbusera M, Noris M, Canciani MT, Daina E, Bresin E, Contaretti S, Caprioli J, Gamba S, Ruggenenti P,
Perico N, Mannucci PM; Italian Registry of Recurrent and Familial HUS/TTP. von Willebrand factor cleaving protease
(ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic
syndrome. Blood. 2002 Aug 1;100(3):778-85.
•
Noris M, Daina E, Gamba S, Bonazzola S, Remuzzi G. Interleukin-6 and RANTES in Takayasu arteritis: a guide for
therapeutic decisions? Circulation. 1999 Jul 6;100(1):55-60.
•
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.
•
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
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INTRODUCTION TO THE LABORATORY’S ACTIVITIES
Rare Diseases (RD) represent about ten percent of all human medical illnesses and infirmities. It
is hard to define what a RD is exactly. The US Congress in the Orphan Drug Act has given the
first definition in 1983. Under this law a disease is considered rare when it affects less than 200
000 Americans (prevalence 0.75 per 1 000).
Recently, the European Parliament adopted a more strict definition; they consider rare a
condition that affects not more than five individuals per 10000 in the European Community
(prevalence 0.5 per 1 000). Besides the epidemiological parameter, RD have certain
characteristics in common: 1) most of them are of genetic origin; 2) rarity often brings a
difficult and/or late diagnosis; 3) generally, RD are a heavy social burden both for the family
and the community and cause early mortality.
The greatest barrier to prevention, diagnosis and treatment of RD is inadequate knowledge.
Once a RD is diagnosed, a major complaint of patients and those involved in their care is the
difficulty to obtain pertinent information about causes, symptoms and either established or
experimental treatments. Often, patients with RD are willing to participate in clinical studies,
but they do not know where and how, and physicians or health authorities are seldom able to
help them.
RD is not a very attracting field for basic and clinical investigators for several reasons: it is
difficult to find adequate animal models for many rare disorders; clinical trials may require
more patients than available; financial support is insufficient.
Few countries have a central body or system to disseminate information on RD. Accurate
information on the incidence and prevalence of RD is extremely important for both basic and
clinical investigators. Invaluable help to research advances in RD would come from the
availability of registries and databases containing diagnostic, clinical and biological data of
patients with rare disorders.
A pilot experience has been established at the Clinical Research Centre for Rare Diseases “Aldo
and Cele Daccò” since 1992. This Centre is unique with its integration of an Information Centre
for Rare Diseases, clinical facilities for the implementation and development of clinical studies,
educational activities for physicians, nurses and patients.
In 2001 it has been nominated Coordinating Centre of the Regional Network for Rare Diseases
in the Lombardy Region, an area of 9 million people in Northern Italy. It also collaborates with
the National Centre of Rare Diseases at the Istituto Superiore di Sanità. All the up-to-date
information regarding the activities of the Coordinating Centre are available on this web site:
http://malattierare.marionegri.it
The database of the Information Centre for Rare Diseases contains data about 10105 patients
affected by 763 different rare disorders.
In the Bank of biological materials, samples from 1097 patients with rare conditions and their
families have been collected.
The Centre has established contacts with more than 295 Italian Associations for rare diseases. It
was even possible for patients with more than 79 different rare diseases - for which no
Associations have been established in Italy yet - to meet each other.
In July 2000, the European Commission recognized the Laboratory as a site for "Postgraduate
training on rare diseases" (contract No. QLK4-1999-50547).
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In December 2001 (Delibera della Giunta Lombarda N. 7328), the Centre was identified as
"Coordinating Centre of the Regional Network for Rare Diseases".
The Laboratory coordinates the International Registry of Recurrent and Familial Hemolytic
Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP), since 1996. The
research projects developed in collaboration with the Laboratory of Immunology and Genetic of
Rare Diseases and Organ Transplantation have allowed to better comprehend the pathogenesis
of these diseases and to identify some genetically determined forms of HUS, associated to
defects of complement regulatory factors, and of TTP, associated to congenital deficiency of
ADAMTS13 enzyme.
Italian National Institute of Health
G. Bosco Hospital, Turin, Regional Coordinating Center for Rare Diseases
Riuniti Hospital, Bergamo
Italian Takayasu's Arteritis Study Group - ITAKA Group
Biotechnology Laboratory, IRCCS Policlinico San Matteo, Pavia
Assessorato alla Sanità, Lombardy Region
Anderson-Fabry Disease Italian Multicentric Study Registry - SMIMAF
University of Torino, School of Clinical Pathology, Faculty of Medicine and Surgery
Italian Network for Promotion of Folic Acid to Prevent Birth Defects
University of Turin, Department of Experimental Medicine and Oncology, 2nd Level Master in
Rare Diseases
Italian Society of Neonatology (Lombary section), Rare Congenital Respiratory Diseases Study
Group
University of Milan, 1st Level Master in Clinical Research
Department of Molecular Biology, Unit of Medical Genetics, Policlinico “Le Scotte”, Siena
Unit of Cytogenetics and Genetics, Careggi Hospital, Firenze
Laboratory of Biochemistry and Genetics, National Neurological Institute “Carlo Besta”,
Milano
“BergamoScienza” Association
European Community
International Registry of Recurrent and Familial Hemolytic Uremic Syndrome and Thrombotic
Thrombocytopenic Purpura
Information Centre for Rare Diseases and Orphan Drugs – ICRDOD, Bulgaria
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EDITORIAL COMMITTEE MEMBERSHIP
Journal of American Society of Nephrology - Nephrology Self Assessment Program (Arrigo
Schieppati)
Journal of Nephrology (Arrigo Schieppati)
Quaderni di Farmacoeconomia (Erica Daina)
Network for Rare Diseases – Lombardy Region (Delibera Regione Lombardia N°7328,
11/12/2001).
Task Force on Rare Diseases (established by DG Health and Consumer Protection on 21
January 2004).
Scientific Committee A.O. Bologni di Seriate.
Ethical Committe, A.O. Ospedali Riuniti di Bergamo
EVENT ORGANIZATION
“2nd Bergamo Workshop on Hemolitic Uremic Syndrome”
Clinical Research Centre for Rare Diseases “Aldo and Cele Daccò” – Mario Negri Institute
Ranica (Bergamo), November 30-December 1st 2006
INVOLVED
9° Convegno “Patologia Immune e Malattie Orfane”
Torino, January 20-21, 2006
European Human Genetics Conference 2006
Amsterdam, May 6-9, 2006
Clinical and Experimental Rheumatology
I Corso teorico-pratico. La Settimana delle malattie rare in Reumatologia
San Miniato/Buti, May 8-13, 2006
“Symposium on Rare diseases and Orphan Drugs”
Università degli studi
Pavia, June 9, 2006
“L’integrazione della Consulenza Genetica nella pratica clinica: il modello della malattie ad
esordio tardivo”
Collegio Ghisleri
Pavia, June 30, 2006
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Malattie Autoimmuni Sistemiche: L’approccio diagnostico
Treviglio (Bergamo), September 9, 2006
The Second Eastern European Conference on Rare Diseases and Orphan Drugs “Fostering
Research on Rare Diseases in Eastern European Countries”
Plovdiv, Bulgaria, September 8-9, 2006
“Network of Public Health Institutions on Rare Disease (NEPHRID conference)”
Aula Marotta, Istituto Superiore di Sanità
Roma, September 18-23, 2006
“Malattie Croniche e Malattie Rare: inquadramento normativo, percorsi assistenziali, aspetti
relazionali”
Aula Montini-Azienda Ospedaliera Spedali Civili
Brescia, September 29, 2006
European Commission
"Fondazione Ricerca Malattie Rare", Bergamo
Ministry of Health
Lombardy Region
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Daina E, D'Ovidio F, Sabbà C
Introduction: hereditary hemorrhagic telangiectasia as a rare disease.
Curr Pharm Des; 2006;12(10):1171-2
Codreanu I, Perico N, Schieppati A, Remuzzi G
Prevention programs of progressive renal disease in developing nations
Nephrology 2006; 11: 321-328
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
Longo I, Scala E, Mari F, Caselli R, Pescucci C, Mencarelli MA, Speciale C, Giani M, Bresin E, Caringella DA,
Borochowitz ZU, Siriwardena K, Winship I, Renieri A, Meloni I
Autosomal recessive Alport syndrome: an in-depth clinical and molecular analysis of five families.
Nephrol Dial Transplant; 2006 Mar; 21(3): 665-71
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 Aug 15; 108(4):1267-79
Donadelli R, Banterla F, Galbusera M, Capoferri C, Bucchioni S, Gastoldi S, Nosari S, Monteferrante G, Ruggeri
ZM, Bresin E, Scheiflinger F, Rossi E, Martinez C, Coppo R, Remuzzi G, Noris M
In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in
thrombotic thrombocytopenic purpura.
Thromb Haemost; 2006 Oct; 96(4):454-64
Giuseppe Remuzzi, Schieppati Arrigo. Ipertensione arteriosa: per saperne di più. Lions Club Bergamo San Marco,
Bergamo, 2006
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RESEARCH ACTIVITIES
Information Centre for Rare Diseases
In 1992, the Information Centre for Rare Diseases was established within the Clinical Research
Centre for Rare Diseases “Aldo e Cele Daccò” .
The Information Service is available to patients with rare diseases, their families and doctors. It
offers information, update and useful addresses free of charge with particular emphasis on
etiology, pathogenesis, genetics, treatments and availability of referral research centers.
Some of the most difficult issues to address when studying rare diseases are those, related to the
recruitment of a sufficient number of patients with a given disease. The database of the
Information Centre for Rare Diseases has become a useful tool for the identification of
potentially eligible patients for clinical studies. Till now, the Information Centre for Rare
Diseases has collected patients’ clinical data for about 200 different rare conditions with 10 or
more cases. Furthermore, intensive collaboration with groups with the same interest from Italy
and abroad provides many possibilities for starting of clinical projects with a multicentral
design.
Bank of biological samples and description of hereditary nephropathies
The aim of this project is to collect clinical data and biological samples from patients and their
families with rare genetic conditions. A database with clinical data and a Bank for biological
samples collection and preservation has been created.
The availability and disposition of clinical data and biological samples is useful to perform new
biochemical and genetic tests within specific research projects aimed to better reveal the
mechanisms of the diseases, their manifestation and therapeutic opportunities.
In particular, the attention is focused on rare genetic disorders of the kidney. A thorough clinical
evaluation, including clinical data collection, medical physical examination, renal
ultrasonography, laboratory tests of blood and urine is offered to patients, affected by hereditary
nephropathies (Alport syndrome, Fabry disease, Focal Segmental Glomerulosclerosis,
Glomerulopathy with Fibronectin deposits, Medullary Cystic Kidney disease, Cystinuria), who
are addressing our Centre. After obtaining a written informed consent, biological samples from
patients and their relatives are collected, labeled with specific codes to assure the anonymity and
kept in the Bank for biological samples. In case the responsible gene for a hereditary
nephropathy is known (Alport syndrome, Fabry disease, Cystinuria), the blood samples are
redirected to the relevant Laboratory of reference. For other nephropathies, where the
identification of the gene mutation is unknown or still in course, the blood samples are
conserved with the aim to be used in specific future research projects.
Evaluation of the long term efficacy of enzyme replacement therapy in
Fabry disease
Fabry disease is an X-linked disorder of the glycosphingolipid catabolism caused by the
deficient activity of the lysosomal hydrolase alfa-galactosidase A (A-gal A) in tissues and fluids
of affected hemizygous males. Most heterozygous females have an intermediate level of
enzymatic activity.
The enzymatic defect leads to a systemic deposition of glycosphingolipid in the heart, kidneys,
eyes and other organs and tissues. Preliminary studies of enzyme replacement therapy
demonstrate that periodic infusions of recombinant human Alfa-galactosidase A are safe (in
terms of infusion reactions) and effective in patients with Fabry disease.
The purpose of this study is to evaluate the long term efficacy of enzyme replacement therapy in
patients with Fabry disease and renal involvement.
Twenty patients (males and females) referred to the SMIMAF (Studio Multicentrico Italiano
sulla Malattia di Anderson-Fabry) will be enrolled.
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Anderson-Fabry Disease Italian Multicentric Study (SMIMAF)
Our Center played a coordinating role in the SMIMAF Registry, whose first aim is to monitor
the incidence, distribution and natural history of the Anderson-Fabry Disease on the national
area.
The Registry has been constituted through the collaboration with the main Italian centers of
Nephrology and Dialysis, Dermatology, Ophthalmology, Cardiology.
Detailed questionnaire forms have been sent; they asked specific questions about clinical
findings in single anatomic districts, histological and enzymatic data. Filled forms were then
registered on the database of the Center; a total of 51 patients were studied so far.
International Registry of Recurrent and Familial Hemolytic Uremic
Syndrome and Thrombotic Thrombocytopenic Purpura
Hemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP) are
rare diseases of microangiopathic hemolytic anemia and thrombocytopenia with signs of renal
(most prevalent in HUS) and cerebral (most prevalent in TTP) damage. There are extremely rare
forms of HUS and TTP, often occurring in families, in which patients relapse even after
complete recovery of the first episode with permanent renal and neurological sequelae. In the
familial and recurrent forms of HUS and TTP, the attention is concentrated mainly on the
genetic predisposition to the disease.
The Laboratory coordinates the International Registry of Recurrent and Familial HUS/TTP,
since 1996. The Registry has collected more than 400 cases of HUS/TTP referred from 86
Italian and 56 European and extra-European Centers. Clinical and laboratory data of all patients
referred to the Registry are collected by a uniform data extraction form. The family history and
also the personal data of the unaffected relatives are collected, when possible. Biological
samples are collected from all patients and available relatives, for the biochemical and genetic
analyses. Many research projects in collaboration with the Laboratory of Immunology and
Genetic of Rare Diseases and Organ Transplantation and the Laboratory of Cellular Biology –
Negri Bergamo are developed and have still allowed to identify some genetically determined
forms of HUS and TTP. The maintenance of a centralized bank of biological samples ensures
the availability of clinical material for new investigative approaches as they are developed.
Rituximab in relapsing and chronic thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is a rare disease characterized by
thrombocytopenia, microangiopathic hemolytic anemia and neurological signs. In most cases,
TTP is related to an acquired deficiency of ADAMTS13 activity, due to the presence of
autoantibodies anti-ADAMTS13. The absence of ADAMTS13 activity leads to the
accumulation of von Willebrand Factor ultralarge multimers (normally cleaved to smaller
molecular forms by ADAMTS13 enzyme), which probably induces platelets aggregation and
the ensuing process of thrombotic microangiopathy.
The purpose of the project is to evaluate the use of a monoclonal anti-CD20 antibody
(Rituximab) in patients with relapsing and chronic thrombotic thrombocytopenic purpura,
related to the presence of anti-ADAMTS13 antibodies. Rituximab is a humanized monoclonal
antibody that targets the CD20 molecule on B cells (white cells producing antibodies).
Administration of Rituximab leads to a selective B cell depletion that usually lasts 6 to 9
months. Inhibition of B cell activation or growth by rituximab treatment limit the uncontrolled
synthesis of autoantibodies, that may predispose to chronic relapsing TTP.
Rituximab is infused intravenously once weekly for a total of four infusions. After Rituximab
treatment, the patients are periodically controlled with medical examination, blood and urine
exams, and with ADAMTS13 plasma activity assay and research of anti-ADAMTS13
autoantibodies, in collaboration with the Laboratory of Cellular Biology – Negri Bergamo.
Observational period lasts 12 months.
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Evaluation of urinary podocyte excretion
Recent evidence recognize an important role for podocytes in the progression of renal diseases.
Podocytes contribute to glomerular permeability and are an important target cell for renal
disease progression. Glomerular injury is usually associated with the leakage of protein across
the filter into the urine and with the disappearance of podocyte foot process. Injuried podocytes
either undergo apoptosis or detach from the glomerular basement membrane, with subsequent
appearance in the urine. Urinary excretion of podocytes has been reported as possible predictor
of disease progression in a number of progressive glomerular diseases, such as IgA
nephropathy, focal segmental glomerulosclerosis, diabetic nephropathy. During the past years
the Clinical Research Center for Rare Diseases, in collaboration with the Department of
Molecular Medicine at Mario Negri Institute, has established an indirect immunohistochemistry
method for the detection of podocytes in urinary sediments. This method has allowed to identify
and quantify the extent of urinary podocyte loss in patients with glomerular disease. The present
study has the aim to evaluate excretion of urinary podocytes in rare genetic renal diseases. This
methodology, applied on a larger number of patients, could provide a non invasive way of
indexing the extent of glomerular damage and a useful instrument to evaluate the response to
treatment.
Genetic study of nephrolithiasis in gouty diatesis
Gouty diathesis describes uric acid or calcium oxalate nephrolithiasis and low urinary pH (<5.5)
in the absence of excessive gastrointestinal alkali losses or dietary animal protein excess. Two
factors that strongly influence the activity of the disease are age and sex. The peak incidence is
in ages 20s to 40s. Men are affected two to three times more often than women.
The study is aimed at identifying the genetic factors that predispose to the development of
nephrolithiasis in patients with gouty diathesis associated to a familial form of nephrolithiasis.
Understanding of the genetic factors that contribute to the development of this disorder may
lead to earlier diagnosis, thus allowing to identify, within a family, subjects that are at risk to
develop nephrolithiasis before manifestation of the disease. These subjects may have access to
counseling aimed at modifying their dietetic and sanitary attitudes and/or to pharmacological
treatments in order to prevent the manifestation of the renal disease or to slow its progression.
Fifteen consecutive unrelated patients with familial form of nephrolithiasis associated with
gouty diatesis (at least two affected subjects within a family) will be recruited through the stone
clinic ambulatory of the Unit of Nephrology, Ospedali Riuniti di Bergamo.
All patients affected by gouty diathesis and their selected relatives will undergo to the following
evaluations: clinical history collection, renal ultrasound examination, metabolic analyses,
genetic analyses.
Development of a model for Integrated Genetic Counseling in late onset
hereditary diseases
The aim of this project is to elaborate and to test a model of genetic counseling for late onset
hereditary diseases, based on a multidisciplinary integrated approach, as a result of the cooperation between clinicians and geneticists with psychological/psychiatric support.
The model is developed in collaboration with Laboratory of Biotechnologies (IRCCS
Policlinico San Matteo) of Pavia and is applied to patients with Fabry disease. Fabry disease is
an X-linked disorder of glycosphingolipid catabolism caused by the deficient activity of the
lysosomal alpha-galactosidase A (AgalA) enzyme, in tissues and fluids. The recent increased
awareness of the disease and the availability of the genetic tests, allow the identification of
relatives at risk of the known patients, and also women who are carriers.
The main tasks of the project are: to help the subjects at risk (relatives of the affected subjects)
to overcome emotionally the bad news received after the predictive test; to increase the
professional competences of the medical team and to improve the overall quality of the service.
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The main results obtained are: 1) the achievement of a medical team constituted by a clinician, a
medical geneticist, a psychologist and a research nurse; 2) the realization of the Clinical
Conference, as point of meeting and discussion of the medical team; 3) the elaboration of an
“ideal course” for the subjects at risk who wants to undergo the predictive test for Fabry disease.
Effects of an intensified treatment with ACE-inhibitors, Angiotensin II
receptor antagonists and Statins in Alport syndrome
Alport syndrome (AS) represents a form of progressive hereditary nephritis in which the genetic
defect resides in the synthesis of one of several subunits of type IV collagen, the predominant
constituent of basement membranes in renal glomeruli. Renal impairment occurs with time and
severe renal failure with hypertension and uremia represent the end stage of the disease, even if
a high variability in the rate of progression is described. The prognosis is variable. Males are
usually affected by a progressive form of the disease. Affected females with X-linked syndrome
usually have a good prognosis with a mild renal impairment. Other clinical manifestations are
anterior lenticonus which occur in about one third of patients. Other findings are myopia, lens
opacities and retinal pigment abnormalities and corneal vesicles or erosions. The disease is also
associated to a sensor neural deafness which can occur in approximately half of the patient
affected and usually correlates with renal impairment.
No definite treatment exists in order to delay the time of dialysis or a kidney transplant. Many
studies showed that Angiotensin converting enzyme (ACE) inhibitors slow glomerular filtration
rate (GFR) decline and limit progression to end stage renal disease (ERDS) and dialysis in
several chronic nephropathies associated with proteinuria. The combination of ACE-I with
Angiotensin II receptor antagonists may reduce proteinuria more effectively than the two drugs
alone. Moreover the addition of Statins may synergize the antiproteinuric effects of ACE-I and
ATAII antagonists in experimental models of chronic renal diseases.
The purpose of this study is to evaluate the effect of a standardized multimodal
nephroprotection intervention (Remission Clinic) in Alport patients with renal involvement.
Nine patients with Alport syndrome and macroalbuminuria will be enrolled in this study.
Recruitment of normo or microalbuminuric patients will be stopped and the analysis will be
performed on the patients that will be available when the recruitment phase of
macroalbuminuric patients will be completed.
Regional network to improve diagnosis, treatment and epidemiological
survey of rare diseases
The project is coordinated by the Center for Immunopathology Research and Documentation on
Rare Diseases (G. Bosco Hospital, Turin).
The specific objectives of the project are:
1) Creation of a regularly updated prospective Registry for rare diseases to improve knowledge
about their epidemiology on regional bases;
2) Definition of protocols for genetic analysis and diagnostic guidelines;
3) Implementation of diagnostic/therapeutically protocols for different rare diseases with the
aim to improve patient’s assistance
4) Develop and implement an online network to offer easily accessible information and increase
the knowledge of medical doctors and patients, providing all available information on a topic by
the means of new, fast and reliable methods of communication.
Our Laboratory participate in the project with the aim to develop and implement a Database of
Clinical Trials on rare disease with open Internet access to all interested users - patients,
doctors, public health professionals and pharmaceutical companies.
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“I would like to know somebody with the same health problem…”
Observational study on Information Centre for Rare Diseases service for
patients who have not a specific Italian Association.
One of the most frequently asked questions from patients and their families is about the
possibility to know somebody with the same health problem. Since the beginning of its
activities, the Information Centre for Rare Diseases has established close collaboration with
more than 295 Italian Associations dedicated to a specific rare condition. Unfortunately, not all
rare diseases have dedicated Associations, particularly those “ultra rare” conditions. The Centre
has therefore activated a special service aimed to help these twice orphan patients (and their
families) to meet other people with the same health problem.
The primary aim of this survey is:
• to verify the real usefulness of this specific service
The secondary aims of this survey are:
• to investigate about the general and demographic characteristics of these patients’ subgroup with rare diseases
• to investigate the major problems for these families related to the lack of a specific
patients Association
In our activity as an Information service to patients with rare diseases, we routinely provide
information and address of patient support group. Whenever we are contacted by people whose
disease has not a support group, we ask patients if they are interested in meeting other people
with similar problem.
If they agree, they send us a written authorization. We then favor the exchange of experience
between interested parties, by contacting other patients with that given rare disease. To
investigate the results and the effects of the service, we sent a questionnaire to 112 families we
had been in contact with.
After their written authorization, it was possible to meet other persons for about 62% of
respondents (mainly by phone calls). About 50% of the families are yet in contact themselves.
This experience mainly contributed to improve the knowledge about the disease and also to give
comfort and psychological support. Note that in 4 cases, thanks to the opportunity given to
patients to know other people with the same rare condition, it was moreover possible to create 3
specific organization and 1 self-help group before this survey.
Update of the Congenital Respiratory Malformations database
This Project originated from the collaboration between the Study Group on Respiratory Disease
of the newborn and the Coordinating Centre for Rare Diseases.
The Congenital Respiratory malformations database was conceived to facilitate the diagnostic
and assistance procedures for pediatricians facing with more frequent respiratory
malformations. The update consisted of a review of the lists of malformation categories and of
all syndromes previously included; more syndromes have been added.
Furthermore, in the brief description, more detailed than the previous version, the Code for Rare
Disease was added, allowing to address the patient to the Referral Centers for Lombardy.
A link with the OMIM database is provided for each syndrome for a better description of the
disease.
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CESAV
A. and A. Valenti Health Economics Center
STAFF
Head
Livio GARATTINI, Econ.D.
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CURRICULUM VITAE
Livio Garattini: got his degree in Economics in March 1983 c/o the Bocconi University in Milan.
Educational activities: “King’s Fund College”, London: courses of health care management; “Centre for
Health Economics”, York: bibliographic analysis of publications on NHS; “Ecole Nationale de la Santé
Publique”, Rennes: courses of health policy.
Areas of interest: Health Economics and health care management.
At present he is the Director of CESAV (Centre of Health Economics A. e A. Valenti - M. Negri
Institute);
1981-1983: researcher c/o M. Negri Institute; 1983-1984: clerk c/o Banca Commerciale Italiana in Milan;
1984- 1985: senior consultant c/o “Sogess srl” in Milan; 1985-1990: researcher c/o Bocconi University in
Milan.
•
Garattini L, De Compadri P, Clemente R, Cornago D (2003) “Economic Evaluations in Italy: a Review of the Literature”
International Journal of Technology Assessment in Health Care 19(4): 685-697.
•
Beghi E, Garattini L, Ricci E, Cornago D, Parazzini F on behalf of the EPICOS Group (2004) “Direct Cost of Medical
Management of Epilepsy among Adults in Italy: A Prospective Cost-of-Illness Study (EPICOS)” Epilepsia 45(2): 171178.
•
Garattini L, Barbui C, Clemente R, Cornago D, Parazzini F on behalf of the Study Group SCORE (2004) “Direct Costs
of Schizophrenia and Related Disorders in Italian Community Mental Health Services: A Multicenter, Prospective 1Year Follow up Study” Schizophrenia Bulletin 30(2): 295-302.
•
Ghislandi S, Krulichova I, Garattini L (2005) “Pharmaceutical policy in Italy: towards a structural change?” Health
Policy 72: 53-63.
•
Garattini L, Ghislandi S (2006) “Off-patent drugs in Italy- A short-sighted view?” The European Journal of Health
Economics 7(1): 79-83.
•
Garattini L, Cornago D (2006) “Pharmaceutical policy in Italy” (Editoriale) The European Journal of Health Economics
7(2):89-90.
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INTRODUCTION TO THE CENTER'S ACTIVITIES
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 programs) and Comparative Health Policy Analysis (i.e. study of foreign health care
systems, in particular aimed at identifying possible innovation for European countries).
In 2006 economic evaluations regarded the costs of the following pathologies: glaucoma, COPD
and multiple myeloma. The studies of comparative analysis were focused only on the European
Union countries in the light of an increasing future harmonization. We mainly studied the
systems of Continuous Medical Education in the European countries where this was either
mandatory or subjected to financial incentives.
On a national level, we analyzed the differences on the regulation of medical scientific
information among Italian regions, and drug pricing regulation in French hospital services.
Public and private institutions, other health care organizations (Ministry of Health, Regional and
Local Health Authorities, Hospital Trusts).
Cambridge Consultancy Company
CES (Collège des Economistes de la Santé) of Paris
Corvinus University of Budapest
Global Fund of Geneva
WidO of Bonn
University Carlos III of Madrid
University of Hannover
University of York
University Pompeu Fabra of Barcelona
University Erasmus of Rotterdam
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Acta Bio Medica (Livio Garattini)
Applied Health Economics and Health Policy (Livio Garattini)
Economia e Politica del Farmaco (Livio Garattini)
Eurohealth (Livio Garattini)
FarmacoEconomia News (Livio Garattini)
Farmeconomia e Percorsi Terapeutici (Livio Garattini)
Health Policy (Livio Garattini)
L'Internista (Livio Garattini)
Journal of Medical Economics (Livio Garattini)
PharmacoEconomics Italian Research Articles (Livio Garattini)
Quaderni di FarmacoEconomia (Livio Garattini)
The European Journal of Health Economics (Livio Garattini)
Applied Health Economics and Health Policy
Epidemiologia e Psichiatria Sociale
Epilepsia
Health Policy
The European Journal of Health Economics
The European Journal of Neurology
The European Journal of Public Health
PharmacoEconomics
PharmacoEconomics Italian Research Articles
Value in Health
EVENT ORGANIZATION
Congress: Convegno Nazionale di Farmacoeconomia-“Gli studi di farmacoeconomia: un
approccio critico alla materia”.
”Nozioni base di valutazione economica in sanità”.
“Gli aspetti economici del dolore in medicina generale”.
“Pharmacoeconomic studies: tricks and traps”.
“Gli studi di farmacoeconomia in Italia: fra scienza e marketing”.
“Gli aspetti economici del cancro al colon retto”.
10th-11th of May, Ranica (BG)
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PARTICIPATION IN EVENTS IN WHICH THE CENTER WAS
INVOLVED
Congress: “La terapia del paziente con dolore in Medicina Generale: evidenze cliniche e
farmacoeconomia”.
“Un quadro clinico epidemiologico del dolore in medicina generale: lo studio Pa.Co.-fase I”.
“L’impatto economico delle terapie per il dolore cronico ricorrente in medicina generale: lo
studio Pa.Co.-fase II”.
“Gli studi italiani di farmacoeconomia sul dolore cronico ricorrente: una revisione critica della
letteratura esistente e delle fonti di efficacia utilizzate negli studi economici”.
11th of February, Trento.
Congress: “La Razionalizzazione della Spesa Farmaceutica”.
“Farmacoeconomia e Farmacoutilizzazione”.
22th of March, Bari.
Congress: “Opportunities in 2006 and beyond”.
7th-9th of June, Cambridge.
Congress: “La ricerca economica al servizio della salute-5° Convegno Nazionale di
Farmacoeconomia”.
13th-14th of June, Milan.
Congress: “La ricontrattazione nelle gare per l’acquisto dei farmaci”.
“Il punto di vista dell’economista sanitario”.
20th of June, Milan.
Congress: “6th European Conference on Health Economics”.
“A comparative analysis of pricing and reimbursement for in-patent drugs in 7 EU countries”.
“A review of the pharmacoeconomic studies conducted in Italy”.
“Reference price on off-patent drugs: an analysis of the Italian and the Spanish experience”.
“Optimal pricing with endogenous reference price”.
6th-9th of July, Budapest.
Workshop: “Health Access-Mapping Health Services Access: National and Cross-border
Issues”.
21th of September, Leuven.
Course: “La Farmacoeconomia nella ASL Salerno 3- La qualità totale nell’azienda sanitaria
locale Salerno 3: possibili scenari di sviluppo”.
“Peculiarità economiche del mercato sanitario”.
“Approccio critico agli studi di farmacoeconomia”.
“La Banca Dati Europea EURONHEED”.
25th of September, Salerno.
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Abbott
EG
Grunenthal-Prodotti Formenti
Jannsen Cilag
Novartis Ophtalmics
Ratiopharm
Sanofi Aventis
Sanofi Pasteur MSD
Teva Pharma Italia
Vivisol
European Union
Barbui C, Motterlini N, Garattini L. “Health status, resource consumption, and costs of dysthymia. A multi-center
two-year longitudinal study” Journal of Affective Disorders 90: 181-186.
Garattini L, Ghislandi S “Off-patent drugs in Italy- A short-sighted view?” The European Journal of Health
Economics 7(1): 79-83.
Garattini L, Cornago D “Pharmaceutical policy in Italy” (Editorial) The European Journal of Health Economics
7(2):89-90.
Motterlini N, Cornago D, Garattini L “I costi di struttura dei reparti di oftalmologia in Italia” FarmacoEconomia
News 2: 3-7.
Cerzani M, Cornago D, Garattini L “I dispositivi per assorbenza: modalità di acquisto e distribuzione in Italia”
Economia & Politica del Farmaco 7: 20-26.
Cerzani M, Barbui C, Garattini L “Le valutazioni economiche del trattamento farmacologico con antipsicotici nella
schizofrenia: una rassegna degli studi italiani” Epidemiologia e Psichiatria Sociale 15(2): 153-160.
Cerzani M, Pasina L, Clavenna A, Nobili A, Garattini L “Uso dei nuovi farmaci antinfiammatori non steroidei in
medicina generale” Ricerca & Pratica 22(4): 152-167.
De Compadri P, Cerzani M, Zaniboni A, Garattini L “Una revisione sistematica delle valutazioni economiche
complete sui regimi di chemioterapia nel cancro al colon retto” Quaderni di Farmaco Economia 1: 15-23.
Garattini L “Tra realismo e buoni propositi-In attesa delle elezioni” Dialogo sui farmaci 1:24-25.
Garattini L “I rischi di una visione a breve, tra RP, limiti alla diffusione e riallocazione della domanda”About Pharma
39: 37-38.
Mc Nee W, England S (translation: De Compadri P and Garattini L “L’Agenzia PHARMAC in Nuova Zelanda-Un
esempio di sfide e successi” Dialogo sui farmaci 2:78-81.
Garattini L “La liberalizzazione nel settore delle farmacie al pubblico: è ora di cambiare anche in Italia?”
Consumatori, Diritti e Mercato 3:57-64.
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RESEARCH ACTIVITIES
Educational activity
Educational activities are developed only if linked to research studies, in order to offer original
contributions which naturally reinforce the research aims.
Economic Evaluation of Health Care Programmes
The aim of this research area is to assess the costs of illnesses and the cost-effectiveness ratios
of the diagnostic/therapeutic existing alternatives. Roughly, analyses can be classified into two
groups: partial economic evaluations (i.e. observational studies on the costs of pathologies) 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 is crucial.
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The Transplant Research Center
Chiara Cucchi De Alessandri e
Gilberto Crespi
The Transplant Research Center (CRT) was set up in 2002 to support and promote the work of
outstanding research scientists throughout the world and to carry out major organ transplant
research programs.
The Center is housed in the Villa Camozzi, at Ranica, under the same roof as the Mario Negri
Institute in Bergamo and is managed in collaboration with the Institute.
The Center’s staff is mainly made up of senior and junior researchers that were trained in the
laboratories of the Mario Negri Institute in Bergamo, focusing on transplant immunology,
research for less toxic immunosuppressant drugs, and new gene therapy techniques to prevent
acute rejection of transplanted organs.
Information on the Center’s activities can be found in the sections addressed to the Department
of Molecular Medicine (Laboratory of Immunology and Genetics of Organ Transplantation and
Rare Diseases) and the Department of Renal Medicine (Laboratory of Pharmacokinetics and
Clinical Chemistry).
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EDUCATIONAL ACTIVITIES
Dean, Mario Salmona, PH.D.
The Institute's training programs fall under the heading of biomedical science, and are part of
the Lombardy Region's professional training schemes. There are courses for specialized
laboratory technicians, and for graduates intending to do research. Special training for clinical
trial nurses is provided at the Aldo and Cele Daccò Clinical Research Center for Rare Diseases,
at Ranica, near Bergamo. In 1999 the Institute has up a Ph.D. course, in collaboration with the
Open University of London. This degree is recognised throughout Europe and in the USA. In
2006 the Institute also set up a First Level master Course in Clinical Research, in collaboration
with the Milan University. Students enrolled in formal courses receive three months' preparatory
training, after which they are assigned study grants. Between 1963 and 2004 the Mario Negri
Institute awarded 6,123 grants, 668 of them to foreign researchers who came to the Institute
for special training.
Everything possible is done to help students find work once they finish the course. The main
feature of these courses is that technicians and researchers receive their training "on site". They
work full-time in research programs of a high scientific standard, using advanced equipment and
learning the latest methods, in regular contact with colleagues in different countries. Besides its
scientific value, this approach provides an excellent preparation on the human and personal
scale.
Students are usually assigned to one of the Institute’s Laboratories, where they gradually gain
specialized skills by working on specific research projects. They are expected to attend lessons,
seminars, courses and congresses and learn to make full use of the Institute’s well-stocked
library. Students all have access to the internet and to biomedical database and can print out
copies of articles they need to consult, from major international journals. Should the opportunity
arise, students are expected to be available for trips abroad, to participate in conferences or
courses.
The Pharmacological Research Specialists and Biochemical Research Technicians will receive
diplomas issued officially by the Lombardy Region and the Mario Negri Institute for
Pharmacological Research. These have legal value throughout Italy, and are recognised in
competitions for public posts, where they are worth a certain number of points. Mario Negri
Institute diplomas are widely considered a guarantee of an excellent theoretical and practical
training. The Open University of London Ph.D. degree earned at the Institute has legal value
throughout Europe and in the USA.
Once they have their diploma or Phd., graduates who want to continue doing research at the
Institute may be offered a chance to spend a year or two abroad.
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At the moment these courses are available:
Three-year course for graduates, in Milan or Bergamo, leading to a diploma as
Pharmacological Research Specialist.
Three-year course for diploma-holders, in Milan or Bergamo, leading to a diploma as
Biochemical Research Technician.
Research doctorates (Ph.D.), run under an agreement with the Open University of London.
Two-year courses are run at the Daccò Center, in Ranica, near Bergamo, for nurses intending to
work in clinical trials. These give a diploma as Professional Clinical Trial Nurse.
Other training opportunities
PREPARING A THESIS FOR A DEGREE:
Students can prepare their thesis in scientific subjects at the Institute, with the approval of their
university faculty. These students must work at the Institute for at least two years.
SUMMER STUDENTS
In June and July each year the Institute accepts a certain number of students in their last two
years at high school, to give them experience as part of school/work programs.
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STAFF
Executive Offices
Services and Offices
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Prof. Silvio Garattini
Silvio Garattini was born in Bergamo (Italy) on 12th Nov 1928. Diploma in Chemistry. Degree in
Medicine. Lecturer in Chemotherapy and Pharmacology. Assistant then Deputy Professor at the Milan
University Institute of Pharmacology until 1962.
Founder in 1963 and director of the Mario Negri Institute for Pharmacological Research. The Institute has
now four locations (Milan, Bergamo, Ranica (Bg), S. Maria Imbaro (Ch)) and more than 850 people.
He is a member of the Gruppo 2003 (a group of the most cited Italian scientists in international scientific
literature). Garattini's publications in Italian and in English in international scientific journals, and texts
on pharmacology, run into the hundreds. Founder of the European Organisation for Research
and Treatment of Cancer (EORTC).
During the last ten years professor Garattini has been a member of various organizations, among which:
the Italian National Research Council (CNR) - Committee on Biology and Medicine; the National Health
Council, the Committee for Italian Research Policy, set up by the Presidency of the Council of Ministers;
the Commissione Unica del Farmaco (CUF) of the Ministry of Health.
He has held the following posts: President of the UICC Committee on Antitumoral Chemotherapy,
President of the European Organisation for Research and Treatment of Cancer (EORTC), Consultant to
the World Health Organisation.
He was President of the European Society of Biochemical Pharmacology; member of the Committee for
Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal
Products (EMEA), Member of the CEPR (Committee of Experts of Research Policy) at the Ministry for
University and Scientific and Technological Research; Member Scientific Committee of the Lega Italiana
per la Lotta Contro i Tumori; member of the Board of the Istituto Superiore di Sanità.
Vice-president of the Consiglio Superiore di Sanità; President of the research and Development
Commission of the Agenzia Italiana del Farmaco (AIFA); President of the Angelo and Angela Valenti
Foundation and of the "Via di Natale" Foundation; President of the Technical Commission for
Pharmaceutical Assistance of the Regione Autonoma of Sardegna; Member of the Strategic Committee
for Welfare, Regione Lombardia. Member of the Consiglio Superiore di Sanità and the Comitato
Nazionale di Bioetica.
Silvio Garattini is a Fellow of the New York Academy of Sciences, the American Association for the
Advancement of Science, Honorary Fellow of the Royal College of Physicians (Pharmaceutical
Medicine), London, and a member of numerous other Italian and international scientific societies.
He has received many awards for his work, including the French Legion d'Honneur for scientific merit,
and the Grand Ufficiale della Repubblica Italiana, and holds honorary degrees from the Universities of
Bialystok in Poland, and Barcelona in Spain. Most recent prizes: Prize Ippocrate, 2003; Prize Mens Sana
in Corpore Sano; Prize Nuova Spoleto, 2003; Prize Angelo dell’anno; Alkmeon International Prize;
International Prize Sant’Agostino Città di Bergamo; Prize Il Campione della Scienza; Medal Natta; Prize
Coppola.
In its 40-plus years, the Mario Negri Institute for Pharmacological Research, under Professor Garattini's
leadership, has published more than 10000 scientific papers and about 200 books, on topics ranging from
cancer and its treatment to tumour immunology, neuropsychopharmacology, and cardiovascular and renal
pharmacology. More than 4000 young Italian and 600 foreigner graduates and technicians have obtained
specialist qualifications at the Institute.
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Prof. Giuseppe Remuzzi
Giuseppe Remuzzi got his M.D. degree (cum laude) in 1974 at the University of Pavia and the
specialization in Laboratory and Clinical Hematology in 1977 at the University of Milan and the
Specialization in Clinical Nephrology (cum laude) in 1980 at the University of Milan.
Research experience: 1974 - 1975 Resident Fellow, Division of Internal Medicine, Ospedale Briolini,
Gazzaniga, Bergamo; 1979 Research Fellow at Cell Biology Laboratory, Institute of Animal Physiology,
Babraham, Cambridge, U.K.; 1980 Research Fellow at Clinical Science Laboratory, Guy's Hospital
Medical School, London, U.K.
Areas of interest: Pathophysiology and biochemistry of blood platelets; Pathophysiology and
pharmacology of platelet and vascular prostaglandins; Coagulation and renal diseases; Pathogenesis and
management of uremic bleeding; Prostaglandins and renal diseases; Pathogenesis of pre-eclampsia and
hypertension in pregnancy; Experimental models of glomerular damage; Non-immunological mediators
of glomerular injury; Factors influencing the evolution of experimental renal diseases to
glomerulosclerosis; Pathophysiology of renal disease progression; Immunology of transplantation;
Innovative anti-rejection strategies; Transplant tolerance.
Employment: 1975–1986 Assistant Professor, Division of Nephrology and Dialysis, Ospedali Riuniti,
Bergamo; 1980-1983 Consultant Nephrologist at "Mario Negri" Institute for Pharmacological Research,
Milan; 1984 Head, Laboratory of Kidney Disease, "Mario Negri", Bergamo; 1984–present, Director,
"Mario Negri" Institute for Pharmacological Research, Bergamo; (opened January 1984); 1986-1999
Associate Professor, Division of Nephrology and Dialysis, Ospedali Riuniti, Bergamo; 1992 Director,
Clinical Research Center for Rare Diseases ‘Aldo e Cele Daccò, Mario Negri Institute, Ranica, Bergamo;
1996–present, Director, Public-Private Department of Medicine and Transplantation, Ospedali Riuniti di
Bergamo/Mario Negri Institute; 1999 Director, Division of Nephrology and Dialysis, Ospedali Riuniti di
Bergamo; 2004 (november) Director, Department of Immunology and Transplantation”, Azienda
Ospedaliera Ospedali Riuniti di Bergamo/Mario Negri Institute.
•
G. Remuzzi, A. Benigni, P. Dodesini, A. Schieppati, M. Livio, G. de Gaetano, J.S. Day, W.L. Smith, E. Pinca, P.
Patrignani, C. Patrono. Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclooxygenase
defect. J Clin Invest 1983;71:762-768.
•
A. Benigni, G. Gregorini, T. Frusca, C. Chiabrando, S. Ballerini, A. Valcamonico, S. Orisio, A. Piccinelli, V. Pinciroli,
R. Fanelli, A. Gastaldi, G. Remuzzi. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by
platelets in women at risk for pregnancy-induced hypertension. N Engl J Med 1989;321:357-362.
•
A. Remuzzi, S. Puntorieri, C. Battaglia, T. Bertani, G. Remuzzi. Angiotensin converting enzyme inhibition ameliorates
glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest 1990;85:541549.
•
P. Ruggenenti, G. Remuzzi, E.C. Rossi. Epidemiology of the hemolytic uremic syndrome. N Engl J Med 1991;324:10651066.
•
A. Schieppati, L. Mosconi, A. Perna, G. Mecca, T. Bertani, S. Garattini, G. Remuzzi. Prognosis of untreated patients
with idiopathic membranous nephropathy. N Engl J Med 1993;329:85-89.
•
G. Remuzzi, E. Gotti. Clinical Problem Solving: The girl with the curl. N Engl J Med 1995;333:928-931.
•
G. Remuzzi, T. Bertani. Pathophysiology of progressive nephropathies. N Engl J Med 1998;339:1448-1456.
•
M. Furlan, R. Robles, M. Galbusera, G. Remuzzi, P.A. Kyrle, B. Brenner, M. Krause, I. Scharrer, V. Aumann, U.
Mittler, M. Solenthaler, B. Lammle. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura
and the hemolytic-uremic syndrome. N Engl J Med 1998;339:1578-1584.
•
B. Gridelli, G. Remuzzi. Strategies for making more organs available for transplantation. N Engl J Med 2000;343:404410.
•
B.M. Brenner, M.E. Cooper, D. de Zeeuw, W.F. Keane, W.E. Mitch, H-H. Parving, G. Remuzzi, S.M. Snapinn, Z.
Zhang, S. Shahinfar. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med 2001;345(12):861-869.
•
G. Remuzzi, A. Schieppati, P. Ruggenenti. Clinical Practice: Nephropathy in patients with type 2 diabetes. N Engl J Med
2002;346:1145-1151.
•
P. Ruggenenti, A. Fassi, A. Parvanova, S. Bruno, I. Iliev, V. Brusegan, N. Rubis, G. Gherardi, F. Arnoldi, M. Ganeva, B.
Ene-Iordache, F. Gaspari, A. Perna, A. Bossi, R. Trevisan, A.R. Dodesini, G. Remuzzi for the Bergamo Nephrologic
Med 2004;351:1941-1951.
•
G. Remuzzi, P. Cravedi, A. Perna, B.D. Dimitrov, M. Turturro, G. Locatelli, P. Rigotti, N. Baldan, M. Beatini, U.
Valente, M. Scalamogna, P. Ruggenenti, Dual Kidney Transplantation Group. Long-term outcome of renal
transplantation from older donors. N Engl J Med 2006; 354: 343-352.
•
G. Remuzzi, J.R. Ingelfinger. Correction of anemia-payoffs and problems (Editorial). N Engl J Med 2006; 355:2144-46.
ANNUAL REPORT
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Mario Negri Institute Milan
Executive Office
Director
Prof. Silvio GARATTINI, M.D.
Administrative Office
Maria Grazia PEZZONI, Chief
Studies Office
Armanda JORI, Pharm.D.
Press Office
Isabella BORDOGNA, Phil. D.
Public Relations Office
Claudio PANTAROTTO, Chemist
Prevention and Safety Office
Emilio BENFENATI, Chem.D.
Annamaria SEGALINI, Phys.D.
English Style Editor
Judi BAGGOTT
General Maintenance
Alessandro CAMPOSARCONE
Photography and Audio-Visual Service
Felice DE CEGLIE
Purchasing Office
Eufrasia COVIELLO
Director’s Office
Rosanna MAPELLI, Chief
General Secretariat
Elena POZZOLI
Custodians
Elisabetta and Romano BERTOLI
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Negri Bergamo Laboratories
Executive Offices
Director
Research Coordinator
Scientific Secretariat
Giuseppe REMUZZI, M.D.
Administration of Research Projects/Admn. Assistance
Daniela MELACINI, Biol.Sci.D.
Press and Communication Office
Francesca Di Fronzo, Mod. Lit. D.
Audio-Visual Service
Antonella PICCINELLI, Biol.Sci.D.
Prevention and Safety Office
Chief
Flavio GASPARI, Chem.D.
Library
Chief
Anna BOZZALE
Valeria MIGLIOLI
General Maintenance
Giancarlo GASPARI
Director’s Office
Antoinette van ENGELEN, Chief
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Centro Aldo e Cele Daccò Ranica (Bg)
Executive Offices
Director
Research Coordinator
Scientific Secretariat
Health Director
Giuseppe REMUZZI, M.D.
Norberto PERICO,M.D.
Press and Communication Office
Francesca Di Fronzo, Mod. Lit. D.
Prevention and Protection Office
Chief
Paola BOCCARDO, Biol.Sci.D.
Library ‘Mansueto Astori’
Chief
Anna BOZZALE
Monica MINALI
Director’s Office
Daniela RICEPUTI, Chief
Clinical Trials Office
Paola BOCCARDO, Biol.Sci.D.
Custodian/general maintenace
Giovanni GERVASONI
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Annual Report 2006 - Istituto di Ricerche Farmacologiche Mario Negri

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