scientific report - Ospedale San Raffaele
Transcript
scientific report - Ospedale San Raffaele
San Raffaele Scientific Institute Via Olgettina, 60 20132 Milano Tel. 02 26431 www.sanraffaele.org 2008 SCIENTIFIC REPORT 2008 SCIENTIFIC REPORT San Raffaele Scientific Institute S C I E N T I F I C R E P O R T 2008 COVER IMAGES top left and right: Unpublished image by Patrizia Rovere-Querini (see Innate immunity and tissue remodelling, page 80) top middle: Unpublished image by Gian Giacomo Consalez (see Developmental neurogenetics Unit, pages 31-32) bottom: © 2009 American Society of Hematology Cover image of a coming issue of Blood, 2009 Molteni, R; Lage Crespo, C.; Feigelson, S; Moser, C; Fabbri, M; Grabovsky, V; Krombach, F; Laudanna, C; Alon, R and Pardi, R* ?-arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation Blood: 2009, May 8 (epub ahead of print) doi: 10.1182/blood-2008-10-183699 * see Leukocyte biology Unit, page 101 Images 1. and 3. have been taken at the San Raffaele’s Advanced Light and Electron Microscopy BioImaging Center (see ALEMBIC, page 160) Some ot the images in this volume has been published in scientific papers: Fig. 1, p. 20: Journal of the National Cancer Institute Fig. 5, p. 45: PLoS One (in press) Fig. 16, p. 120: Current Diabetes Reports Fig. 23, p. 139: Nature Genetics Fig. 26, p. 150: Nucleic Acids Research Edited by the San Raffaele Library Layout by Roberto Cremonesi Printed by Grafiche Parole Nuove, Brugherio INDEX - III INDEX INTRODUCTIONS VII Introduzione del Presidente Introduction by the President Introduction by the Scientific Director Introduction by the Chief Operating Officer IX X XII XVI San Raffaele Scientific Retreat 2008 photo gallery XVIII 3rd International Congress – Aortic Surgery and Anesthesia “How to do it” XX Introduction by the General Director Clinical Area XXII DIVISION OF MOLECULAR ONCOLOGY Introduction by the Directors Research Units Lymphoid malignancies Unit B-cell neoplasia Biology of multiple myeloma Cell activation and signalling Dynamic fluorescence spectroscopy in biomedicine Lymphoid organ development Preclinical models of cancer Tumor microenvironment Immuno-biotherapy of melanoma and solid tumors Unit Cancer gene therapy Functional genomics of cancer Unit Model genetics of membrane trafficking Unit Molecular histology and cell growth Unit Tumor biology and vascular targeting Unit 1 5 7 7 8 8 9 9 10 11 11 12 12 13 13 14 Clinical Research Units Digestive and pancreatico-biliary endoscopy Unit Endosonography: diagnostic and therapeutic endoscopic ultrasound Gastrointestinal surgical oncology Unit Head and neck oncology Unit Multidisciplinary group for thoracic surgical oncology Oncogenesis in liver neoplasms Unit Onco-hematology Unit Pancreatic cancer Unit: biology and new therapeutic approaches Clinical lymphoid malignancies Gynecologic oncology Medical oncology Unit - Clinical trials Medical oncology Unit - Phase I and lung cancer clinical trials Urological Research Institute (URI) 14 15 15 16 17 17 18 18 19 19 20 20 21 DIVISION OF NEUROSCIENCE 23 Introduction by the Directors Research Units 28 Neuropsychopharmacology Unit Cell adhesion Unit Cellular and molecular neurobiology Unit Cellular neurophysiology Unit Developmental neurogenetics Unit Neurobiology of learning Unit Proteomics of iron metabolism Unit Molecular genetics of mental retardation Unit Neural degeneration Unit Stem cells and neurogenesis 29 30 30 31 31 32 33 33 34 34 IV - SAN RAFFAELE SCIENTIFIC INSTITUTE Clinical Research Units Acute brain protection, Acute post-operative pain, Drugs and central nervous system Unit 35 Eye repair Unit 36 Cognitive neuroscience Unit 36 Experimental neurosurgery Unit 37 Functional neuroradiology Unit 37 In vivo Human molecular and structural neuroimaging Unit 38 Neuroothology Unit 38 Psychiatry and clinical psychobiology 39 Sleep medicine 39 Clinical psychology 40 Motor function rehabilitation 40 INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE) 41 Introduction by the Director Research Units 41 Experimental neuropathology Experimental neurophysiology Molecular genetics of behaviour Neuromuscular repair Neuroimmunology Unit Clinical neuroimmunology CNS repair Neuroimaging research Unit Neuroimaging of CNS white matter Human inherited neuropathies Unit Axo-glia interactions Unit 42 42 43 43 44 44 45 46 46 46 47 Clinical Research Units Inflammatory CNS disorders Unit Cerebrovascular disorders Memory disorders Movement disorders Neuromuscular disorders Paroxysmal events DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES 47 48 49 49 49 50 Coagulation service & thrombosis research Unit Cardiodiabetes & core lab Pediatric endocrinology research 59 59 60 Clinical Research Units Diabetes and endocrinology Unit Cardiodiabetes and clinical trials Clinical pediatric endocrinology Diabetes and metabolic diseases in children and adolescents Neonatology Foetal-maternal medicine Infertility Cardiovascular interventions Unit Clinical cardiovascular biology Unit Ischaemic heart disease, heart failure and echocardiography Unit Organ protection in critically ill patients, advanced cardiac failure and mechanical supports Unit Structural heart disease Unit Study and treatment of aortic disease Unit Center for arrhythmia research 60 61 61 62 62 62 63 63 64 65 65 66 67 67 DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY 71 Introduction by the Directors Research Units 75 Skeletal muscle development and therapy Unit Functional genetics of muscle regeneration Gene expression and muscular dystrophy Unit Molecular and functional immunogenetics Neural stem cell biology Autoimmunity & vascular inflammation Unit Innate immunity and tissue remodelling Cellular pharmacology Unit Experimental hematology Unit Angiogenesis and tumor targeting 76 76 77 78 78 79 80 80 81 81 Clinical Research Units 53 Introduction Research Units 56 Amino acid and stable isotopes Unit Complications of diabetes Obesity and metabolic related diseases Bone metabolism Unit 57 57 58 58 Hematology and hematopoietic stem cell transplantation Unit Immunohematology and transfusion medicine Unit PSIEP - Strategic Program of Pediatric Immunohematology THE SAN RAFFAELE TELETHON INSTITUTE FOR GENE THERAPY (HSR-TIGET) Introduction by the Director 82 82 83 84 84 INDEX - V Research Units Clinical Research Units Gene transfer technologies and new gene therapy strategies Unit Gene/neural stem cell therapy for lysosomal storage diseases Hematopoietic stem cell based gene therapy for the treatment of lysosomal storage disorders Safety of gene therapy and insertional mutagenesis Gene transfer into stem cells Unit Immunological tolerance Unit From FOXP3 mutation to IPEX syndrome Tolerogenic dendritic cells Pathogenesis and therapy of ADA-SCID Unit Gene therapy for WASP/Omenn Neurovirology Vaccine and Immunotherapy Clinical immunopathology and advanced medical therapeutics Unit Clinical transplant Unit Gynecological cancers immunology Immunology in liver neoplasms Obesity Pancreatic tumors: immunotherapy and β cell function substitution Clinical hepato-gastroenterology Digestive pathophysiology Transplant surgery DIABETES RESEARCH INSTITUTE (DRI) 85 85 86 86 87 87 88 89 89 90 Clinical Research Units Pediatric Clinical Research Unit - Gene therapy for Wiskott-Aldrich Syndrome Pediatric Clinical Research Unit - ADA gene transfer into hematopoietic stem cells for the treatment of ADA-SCID Pediatric Clinical Research Unit - Clinical trial of gene therapy in metachromatic leukodystrophy 111 112 112 113 114 114 115 115 116 116 116 117 90 Introduction by the Directors Research Units 117 91 Immune tolerance Experimental diabetes β cell biology Cell imaging 118 119 119 120 92 Clinical Research Units DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES 95 Introduction by the Directors Research Units 100 Leukocyte biology Unit Cellular and molecular allergology Human virology Infection and cystic fibrosis Protein engineering and therapeutics γδ T cells in innate and adaptive Immunity Immunobiology of HIV Immunological diagnostics of tuberculosis AIDS immunopathogenesis Unit Biocrystallography Unit Cellular immunology Unit Emerging bacterial pathogens Unit Experimental immunology Unit Immunopathology Unit Lymphocyte activation Unit Tumor immunology Unit Viral evolution and transmission Unit Viral pathogens and biosafety Unit 101 102 102 103 103 104 105 105 106 106 107 107 108 109 109 110 110 111 Islet transplantation Prevention in type 1 diabetes Epidemiology & data management Childhood diabetes Islet processing activity 121 122 122 123 123 DIVISION OF GENETICS AND CELL BIOLOGY 127 Introduction by the Directors Research Units 130 Protein transport and secretion Unit Age related diseases Molecular immunology Chromatin dynamics Unit In vivo Chromatin and transcription Biology of myelin Unit Biomolecular mass spectrometry Unit Gene expression Unit Genetics of common disorders Unit Molecular basis of polycystic kidney disease Unit Molecular genetics Unit Molecular dynamics of the nucleus NeuroGlia Unit 131 131 132 132 133 134 134 135 136 136 137 137 138 VI - SAN RAFFAELE SCIENTIFIC INSTITUTE Regulation of iron metabolism Unit Molecular genetics of renal disorders Unit 139 139 Clinical Research Units Dento-facial histopathology Unit Genomics of renal diseases and hypertension Unit Tissue engineering and biomaterials CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS 140 141 141 THE CLINICAL DEPARTMENTS 145 Introduction by the Director Research Units 146 Neurogenomics Unit Theoretical biology Biogenesis and motility of secretory organelles Unit Genomic Unit for the diagnosis of human pathologies Proteome biochemistry Unit Biomolecular NMR laboratory 147 147 148 CENTER FOR IMAGING 149 149 150 153 Introduction Clinical Research Units 154 Clinical and experimental radiology Unit High technology in radiation therapy Unit Molecular imaging Unit Neuroradiology research group 155 155 156 157 FACILITIES ALEMBIC, Advanced Light and Electron Microscopy Bioimaging Center CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications Laboratory CERMAC, Centre of Excellence of High Field Magnetic Resonance Mouse histopathology Department of arrhythmology Cardio-thoracic-vascular Department Department of general and specialistic surgery Head and neck Department Department of infectious diseases Maternal and child health Department Department of internal and specialistic medicine Department of clinical neuroscience Department of neurology Department of oncology Department of radiology Department of urology CLINICAL SERVICES Medical physics Pathology Laboratory medicine Service of immunohematology and transfusion medicine Emergency medicine General intensive care Anaesthesia and neurointensive care Unit 161 161 162 165 166 167 170 172 174 176 178 180 182 183 185 187 188 190 190 191 191 192 192 193 159 160 160 PUBLICATIONS Best papers 2008 List of 2008 publications 195 196 196 INTRODUCTIONS - VII INTRODUCTIONS INTRODUCTIONS - IX Introduzione del Presidente Sono particolarmente felice di presentare anche quest’anno il lavoro dei nostri ormai numerosi ricercatori. Sono convinto da sempre che non si può scegliere alcune linee di ricerca senza coltivare le molte altre. È perciò che mi sento soddisfatto di vedere ormai una piattaforma scientifica del San Raffaele di così vaste proporzioni. Una piattaforma che comprende in una unità strettamente organizzata e integrata la ricerca di base, la ricerca traslazionale, la ricerca clinica e applicata. È chiaro che su questa base io aspiro ad una continuità, anzi ad una intensificazione esplorativa in tutti i campi dello scibile e questo perché l’Uomo: corpo, intelletto, spirito è una unità integrata, anche se le tre componenti sembrano essere tra loro molto diverse. Infatti, io credo che il rilancio del valore Uomo non può prescindere dalla unitarietà delle linee della di lui conoscenza, sia come σοµα (corpo), νουs (intelletto), ψυχη (anima, spirito). È questa la strada per farlo vivere sincrasicamente nell’ambiente e nel tempo. Voglio anche aggiungere che l’Uomo per venire lucidamente inteso va considerato per quello che egli è come sua genesi: l’Uomo, cioè, non è un Ente in sé; è un Ente nell’Ente essenzializzato, cioè nel Creatore Dio che all’uomo ha comunicato per sinaptogenesi il suo potere di intelligere. Da ciò la imprescindibilità di una struttura come il San Raffaele tipo “città dell’Uomo” dove le scienze, tutte le scienze, sono di casa, sono cioè a disposizione di tutti. Anche le Scienze umanistiche, la Metafisica e cioè la Ontologia, la Antropologia, la Teodicea ecc. e con tutte le altre conoscenze che fanno dell’uomo: Uomo in progressione verticale. La nostra Identità Universitaria, cioè altamente culturale, dev’essere per ogni suo componente il vero crocevia della cultura universale. È perciò che l’Uomo non può far senza di quell’Ente in sé che chiamiamo Dio e che si è rivelato nel Λογοs divino incarnandosi quale terminale facile all’uomo per giungere direttamente a Dio. Cari ricercatori comprendete Voi tutto ciò? Per comprenderlo occorre sapere amare. Io, a novant’anni, ci sono quasi arrivato e ho tentato di descriverlo plasticamente nel Vostro Ciborio e nella Vostra Cupola. Vostro Don Luigi Maria Verzé Presidente e Rettore X - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the President I am particularly delighted to present this Annual Report of the scientific research work carried on by the numerous researchers operating in our University and Research Centers. I personally believe that it is impossible to choose a path of research while not following at the same time different others: a research is made out of different paths interweaved together. Thus, I cannot help but notice my satisfaction in observing such an important and great scientific platform as San Raffaele is. Such platform includes the basic research, the translational research and the clinic and applied researches into a joined unity. It is clear that I aspire to a continuity of research between all the different fields of knowledge which are to be interconnected on the basis that the human being – body, mind and soul – has to be considered an integrated unity. Even though the three elements which shape the human being are very different from each other, they compose a single blend. Indeed, I strongly believe that the importance and the value of the human being has to be raised in the unity of these three lines of knowledge, which pertain to the human being: the knowledge of the σοµα (body), the knowledge of the νουs (mind), the knowledge of the ψυχη (soul). This is the way necessary in order for the human being to live in space and time synchronously. I would like to add that to understand what the human being is, it is necessary to consider him for what he is in his/her genesis. In other words, the human being is not a being per se. On the contrary, the human being is a being in the Absolute being, created by God and to whom God transferred his power of knowledge by way of the synapses. As a consequence, the whole San Raffaele has to be shaped as a “city of the Human being”, where different fields of sciences, of all kinds of science, are to be welcomed, that is: they are to be available to everybody. Even those humanistic sciences, such as Metaphysics – i.e. Ontology, Anthropology, Theodicy and so on – are to be embraced together with those others which make the human being progressing forward, toward the highness. The identity of our University must be, to each of its members, the crossroad of the universal culture. For these reasons, the human being can neither act nor do anything without God, who revealed himself in the form of the divine Λογοs which can be easily grasped by each man and woman to arrive directly to God. Dear researchers, do you understand all that I am saying here? To understand it, it is necessary to have the capacity to love. I am ninety years old and I can say I have almost achieved such capacity and I have tried to described it physically to you with Your newly built Ciborio and Your Dome. Yours, Don Luigi Maria Verzé President and Chancellor INTRODUCTIONS - XI Scientific Directorate SCIENTIFIC DIRECTOR: Maria Grazia Roncarolo CHIEF OPERATING OFFICER: Maurizio Savi HEAD OF SCIENTIFIC OFFICE: Giulio Negri ASSISTANT TO THE SCIENTIFIC DIRECTOR: Laura Reiss GRANT OFFICE: Paola Rebagliati, Riccarda Daneri HEAD OF CLINICAL TRIAL OFFICE: Elisabetta Riva Grazia Roncarolo CLINICAL TRIAL OFFICE: Raffaella Biagetti, Giovanna Bombelli, Anna Negri, Giliola Calori, Margherita Ianniello, Maria Rosa Mandelli, Rossella Stefani HEAD OF BIOTECHNOLOGY TRANSFER OFFICE: Daniela Bellomo BIOTECHNOLOGY TRANSFER OFFICE: Lucia Faccio, Paola Pozzi, Roberto Santarella, Fabrizio Bacchi, Simona Locatelli HEAD OF LIBRARY: Laura Tei LIBRARY: Diego Maria Bertini, Francesco Curci, Elena Ponzi, Maria Samarati Maurizio Savi XII - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Scientific Director The mission of the San Raffaele del Monte Tabor Foundation is to conduct innovative research benefiting the care and cure of our patients and to provide state of the art education and training for new generations of doctors and scientists, with a high level of social responsibility. The San Raffaele Scientific Institute (SRSI) was one of the first private hospitals established in Italy in 1971. In 1972 it was granted by the Italian Ministry of Health the status of “Research Hospital” (IRCCS: “Istituto di Ricovero e Cura a Carattere Scientifico”), with a main focus on diabetes and metabolic diseases. In 1992 a new research building (42.125 sq m) was open to accommodate the Department of Biotechnology (DIBIT1). The initial areas of research covered by DIBIT1 were genetics, cell biology and immunology while in the late 90’s gene therapy, stem cell biology and molecular mechanisms of diseases were added. In recognition of its status as a center of excellence in Molecular Medicine, in 2001 the Italian Ministry of Health granted the SRSI the status of Molecular Medicine Research Institute. In 2006 the construction of a second (51.930 sq m) research building (DIBIT2) was initiated to allow the much needed growth of the various SRSI research groups, to accommodate the new, centrally organized, state of the art technology platforms supporting our research activities and importantly, to expand our translational research efforts in key disease areas such as regenerative medicine, neuroscience, cardiovascular and oncology. The construction of DIBIT 2 progressed amazingly fast, and several Research Units moved already in. At present approximately 660 scientists and technicians are working in DIBIT1 and DIBIT 2, including postdoctoral fellows, PhD students and undergraduate students. Furthermore, 20 associates provide research services. In addition, 670 physicians work in clinical research projects (see also introduction by Maurizio Savi, chief operating officer for research). DIBIT1 and DIBIT2 are part of the San Raffaele Biomedical Science Park, which is the largest of its kind in Italy and includes the San Raffaele Hospital, with more than 1350 beds, and the Vita-Salute San Raffaele University, which was established in 1996. The University hosts the faculties of medicine, psychology and philosophy and provides specialized post graduate courses, resident programs in various medical specialties, and international PhD programs in Cellular/Molecular Biology and Molecular Medicine. INTRODUCTIONS - XIII 2008 was a year of important chances for SRSI. A new redefined research strategy and organization have been designed and implemented to create optimal synergies between the different research areas, including clinical research, to prepare us for the future challenges and to increase our competitiveness in the international scientific arena. In this new strategic vision, research represents the backbone of our institution and the intersection that connects clinical and teaching activities. In this new model, research activities are consolidated in 6 Research Divisions whereas clinical activities are organized in 12 Clinical Departments (see also introduction by Renato Botti, general director of clinical area). The Research Divisions are crossing many Clinical Departments in a matrix model, in which research units and clinical units are fully integrated. In addition, 3 specialized Research Core and Centers have been established to meet the increasing need for state of the art imaging technologies, molecular pathology, functional genomics, proteomics and bioinformatics. Research at the SRSI covers many disciplines, which include genetics, cell biology, stem cell biology, gene therapy, immunology, and focuses on several diseases, which include cancer, transplant rejection, autoimmunity and infections, neurodegenerative, cardiovascular and metabolic diseases. Research conducted in these areas has the common goal to advance knowledge about molecular basis of diseases and to identify innovative therapies and new diagnostic options. The 6 Research Divisions and 3 Research Cores (see list at page XXIV) approved by the Board and implemented in 2008 represent existing areas of expertise and excellence as well as new strategic area of research in which we want to invest for the future according to our strategic plan. Within this new divisional organization, 3 major research Institutes continue to operate: the San Raffaele Telethon Institute for Gene Therapy of Genetic Diseases (HSR-TIGET), which is pioneering gene therapy to cure patients with monogenic diseases, the Institute for Experimental Neurology (INSPE), which investigates the biological and molecular mechanisms underlying diseases of the nervous system with a strong focus on clinical translation, and the recently established Diabetes Research Institute (HSR-DRI) whose main objective is to identify and apply novel treatments to prevent islet beta cell destruction and to restore sufficient insulin production in type 1 diabetes. Furthermore, the SRSI hosts several scientists belonging to the Dulbecco-Telethon Institute (DTI) working on molecular and biological mechanisms of gene regulation and genetic diseases. In 2008 we also defined the areas in which interdivisional and interdepartmental research programs have to be consolidated or implemented. The research Divisions are led by the Directors, appointed for three years and nominated by the President of the Board of Directors, with the approval of the President of the Board of Director of the University Vita-Salute San Raffaele. A Scientific and Technical Committee has also been appointed to support the scientific and operating directors in the strategic research planning and in the definition of new initiatives. In parallel to the implementation of this new research structure, the administrative and supporting research structure was also extensively reorganized with the hiring of the Chief Operating Officer for research (see introduction by Maurizio Savi). In this new organization, the administrative office, the research development and quality control office, the grant office, the library, the office of biotechnology transfer and the office for clinical experimentation are under the direct responsibility of the scientific and operating directors. 2008 has been another very productive year for the SRSI. The high productivity and quality of our research in 2008 is reflected by the total number and the total impact factor of our publications, with a remarkable number of manuscripts published in top level scientific journals, as illustrated in figures 1 and 2: Publications and total Impact Factor 2006-2008 Publications 2006-2008 distributed in Impact Factor ranges 100% 3561,234 693 719 740 Percentage of publications 3870,073 3785,464 80% 65% 63% 62% 60% 40% 26% 28% 30% 20% 9% 10% 0% 2006 (average IF: 5,265) 2007 (average IF: 5,139) Total IF 2006-2008 2008 (average IF: 5,230) Publications 2006-2008 <5 5-10 ≥10 Impact Factor ranges 2006 2007 2008 8% XIV - SAN RAFFAELE SCIENTIFIC INSTITUTE Furthermore, the close links and synergy between the Research Institute and the Hospital is documented by the number and quality of our clinical trials, with around two hundreds clinical trials evaluated and approved by our Ethical Committee and a significant proportion of investigator initiated trials in several therapeutic area, as illustrated in the figures below: Clinical trials evaluated by the HSR Ethical Committee in 2008 Pharmaceutical companies sponsored trials No-profit groups sponsored trials HSR investigators initiated trials 28% 50% Pharmacological protocols Observational procotols Basic research protocols Medical device protocols 1% 25% 55% 19% 22% Clinical trials approved in 2008 by therapeutic area Infectious diseases Oncology/Hematology Neurology Diabetology Cardiology/Arrhythmology Urology Ophthalmology Anaesthesiology and intensive care No-profit trials Sponsored trials 8% 7% 1% 18% 3% 11% 8% 5% 1% 5% 11% 35% 35% 19% 14% 19% The competitiveness of the SRSI is also demonstrated by its ability to attract funding not only from public (Ministry of Health, Superior Institute of Health, Ministry of University and Research) but also from private Italian sources (mainly Telethon, the Italian Association for Cancer Research and Bank Foundations) and from international sources (e.g. European Community, European Research Council, American National Institute of Health, World Health Organization, Association for International Cancer Research, Gates Foundation, Wellcome Trust, Juvenile Diabetes Research Foundation). Finally, SRSI is an attractive partner for big pharmaceutical and biotechnology companies, as it is reflected by the many collaborations with our scientists which were supported by the office of biotechnology transfer which has the mission to create value from the intellectual property and know-how of the SRSI and Hospital. These achievements have been made possible by the excellence of our scientists and clinicians, as also documented by the prestigious international awards won in 2008. In addition, the strong sense of community and the synergy and cooperation between different teams were highlighted by our yearly Scientific Retreat where basic and clinical scientists were brought together to discuss scientific progress and future plans. Finally, in 2008 a number of important educational initiatives, scientific events and prestigious international meetings have been organized and hosted by our basic and clinical scientists. INTRODUCTIONS - XV LOOKING FORWARD We are very much looking forward to occupy the new buildings and to use the new space to consolidate the research divisions, to build state of the art technology platforms and to enter into new research areas. SRSI will continue to be a multidisciplinary Institute, but we will also pay particular attention to invest into research in diseases with a high unmet medical need and into therapeutic areas of increasing medical demand such as oncology. We will continue to strengthen our position as a leading center for translational medicine with strong links to high quality clinical research. In this context, close collaborations between basic (fundamental) researchers, clinical investigators and physician scientists will be strongly solicited and favored with the ultimate goal to apply new therapeutic principles, invented at the laboratory benches, as efficiently as possible to our patients. We will continue to build expertise in the field of molecular and experimental medicine, including wide genome analysis of complex diseases, stratification of patients by genotyping and phenotyping, farmacogenetics and farmacogenomics. We will implement a competitive postdoctoral program to attract international young scientists and foster international exchanges. In addition, we will establish a career path for physician scientists and young investigators. I am confident that this research strategy and structure will further enhance SRSI’s position as an Institute of excellence conducting innovative science in the field of Molecular Medicine, which at the end benefit our patients. In the coming future this strategy and structure will be presented to our internationally renowned scientific advisory board which will not only give us valuable suggestions but play a particular important role as we establish high research standards. The worldwide financial and economical crisis that looms over all of us as we write this scientific report threatens the implementation of our new strategic research plan and organization. However, the unconditioned support of our President, as well as the trust of our Board, the motivation of our research directors and the enthusiasm of our scientists and clinical researchers help us to be optimistic and confident that SRSI will continue to grow and operate at the leading edge of biomedical research. In addition, the moral obligation and responsibility we have towards the younger generations of scientists and physicians to create an environment where they will be allowed to grow and to build their careers gives us strength and determination. I like to express my gratitude to the scientists, physicians, staff, post-doctoral fellows and students that with their work, effort, enthusiasm and passion contributed to the research progress illustrated in this 2008 scientific report. I hope you will find our report interesting and inspiring. Maria Grazia Roncarolo Scientific director XVI - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Chief Operating Officer The San Raffaele Scientific Institute’s biomedical research covers several areas, all closely related to the theme of Molecular Medicine, which brings together basic research, clinical research and healthcare with the common goal of transferring preclinical research to the bedside and of translating scientific findings into innovative therapies. With this global strategic vision, the San Raffaele Scientific Institute strives to enhance its position as a Center of Excellence in Molecular Medicine by strengthening its infrastructure and redrawing its organization. The new organization is the result of a project started in 2008 and it is based on a macro-structure processes model, which aims at: 1. Creating a common scientific direction inside the Opera, which inspires and supports the San Raffaele Scientific Institute. 2. Guaranteeing a complete integration between the main three areas of activities: scientific research, health and education. 3. Ensuring the sustainability of the Research Area on the basis of efficacy, efficiency and economy criteria. 4. Creating an infrastructure and organization based on the individual value by promoting professional valorization and establishing a working environment where people are able to develop and express competences and expertise in the best way. In order to reach these goals we have: • Identified the criteria and the rules for the establishment and functioning of the Research Divisions and Research Cores. • Defined the modalities to implement efficient and valid guidelines for the organization of both scientific and administrative activities, establishing clear levels of managerial, administrative and technical responsibilities . • Ensured an efficient communication system and a flow of information continuously and efficiently open to all users. The San Raffaele Scientific Institute firmly believes in the value of communication and, since 2008, it has strengthened its Marketing and Fund Raising Staff with the aim to improve the general knowledge on its activities, results and projects by using the main communication media, but also with the goal to better support its funding possibilities by potentiating the relationships with the main National and International funding agencies for scientific research. FOCUS ON SOME NUMBERS RESEARCH - TOTAL REVENUES YEAR 2008 OTHER REVENUES; 10,86% OTHER REVENUES -YEAR 2008 EXTERNAL SERVICES; 10,45% RESEARCH INCOME - YEAR 2008 DONATIONS INTERNAL SERVICES SPONSORED RESEARCH; 4,48% DONATIONS; 38,59% EXTERNAL GRANTS; 43,78% INTERNAL SERVICES; 37,38% RESEARCH INCOME; 89,14% RESEARCH INCOME OTHER INCOME; 13,58% EXTERNAL SERVICES CLINICAL TRIALS; 7,84% PUBLIC FUNDS; 43,91% OTHER INCOME OTHER REVENUES SPONSORED RESEARCH CLINICAL TRIALS PUBLIC FUNDS EXTERNAL GRANTS INTRODUCTIONS - XVII BUILDING UP THE FUTURE At the end of this year the new construction called “Dibit2” will be completed and equipped. These buildings represent the “hearth” of the scientific long term vision of our Institute. The construction consists of three buildings: In the center there is the “Basilica” building, which, as its name suggests (taken from the Greek culture), represents a space where people can meet, interact, and discuss to advance scientific knowledge and promote scientific culture. In this block there are the Faculty of Medicine and Surgery and the Faculty of Psychological Sciences. Furthermore the advanced technological research based on DNA discovery and function will be conducted in this building by the Genetic and Cell Biology Research Division and the Research Center for Genomics, Bioinformatics and Biostatistics. The Research Center for Imaging and an Open Lab conceived as a common area for the Research Divisions and the Clinical Groups will also be located in this area. On each side of the Basilica there are two buildings. The first building is occupied by the Neurosciences Research Division and the Diagnostic Division; whereas the Research Division of Regenerative Medicine, Stem Cells and Gene Therapy and the Research Division of Molecular Oncology will move into the second building. The Research Division of Immunology, Transplantation and Infectious Diseases and the Metabolic and Cardiovascular Disease Division will maintain their actual location in Dibit1. The total space dedicated to the research activity at San Raffaele will cover about 75.000 square meters with about 1.350 operators: 660 for Basic Research Units, 670 for Clinical Research Groups and 20 for Facilities. Maurizio Savi Chief Operating Officer XVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE SAN RAFFAELE SCIENTIFIC RETREAT 2008 INTRODUCTIONS - XIX XX - SAN RAFFAELE SCIENTIFIC INSTITUTE 3RD INTERNATIONAL CONGRESS - AORTIC SURGERY AND ANESTHESIA “HOW TO DO IT” Scientific promoter: prof. Roberto Chiesa December 11-13, 2008 INTRODUCTIONS - XXI Health Care Directorate HEALTH CARE SUPERVISOR: Gianna Zoppei GENERAL DIRECTOR: Renato Botti HOSPITAL DIRECTOR: Roberts Mazzuconi PLANNING & CONTROL DIRECTOR: Alessandro Longo INFORMATION SYSTEMS DIRECTOR: Carla Masperi PROCUREMENT & LOGISTIC DIRECTOR: Alberto Russo HEALTH AREA PROJECT DEVELOPMENT DIRECTOR: Maria Romano CUSTOMER SERVICE DIRECTOR: Riccardo Pizzo TECHNICAL AREA DIRECTOR: Andrea Roma E-SERVICES FOR LIFE AND HEALTH DIRECTOR: Alberto Sanna PROMOTION & DEVELOPMENT MANAGER: Alberto Galliani ORGANIZATION & DEVELOPMENT MANAGER: Margherita Gambaro LEGAL OFFICE MANAGER: Piergiorgio Sammartino Renato Botti XXII - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the General Director Clinical Area San Raffaele Hospital is a private no-profit Foundation classified as Istituto di Ricovero e Cura a Carattere Scientifico (Research Hospital). It is relentlessly pursuing its three interrelated lines of clinics, research and education since 1971, when it was established, and represented one of the first examples of a fully independent private hospital in Italy. In 1972 the Italian Ministry of Health granted to San Raffaele the status of IRCCS (Research Hospital), which favoured its development as a site for clinical research. Originally specialized in diabetes and metabolic diseases, the status of research hospital was confirmed for the area of Molecular Medicine in 2001 and renewed in 2004 and 2008. San Raffaele IRCCS is a qualified hospital, which is well known in Italy for specific and relevant pathologies. Furthermore it is recognized as a highly specialized Emergency Center and it is a teaching Hospital linked with the Faculties of Medicine and Surgery and Psychology of the University Vita-Salute San Raffaele. Its high quality medical assistance and the availability of a vast area of about 300.000 square metres have led to a fast growth of the services provided by the Institute. San Raffaele Hospital is part of the Italian National Health Service, in fact it has 1.397 beds accredited with the National Health Service, 47 of them dedicated to the independent medical activities and 50 dedicated to day surgery and day hospital treatments. In 2008 the San Raffaele Hospital’s activity counts 47.492 in-patients, 61.773 admittance at Emergency Room, more than 7.700.000 outpatients and diagnostic test. The Hospital counts about 3.600 employees. In January 2008, after the approval by the Board of Directors, the Hospital started to organize the medical area in Clinical Departments. Due to the complexity of the Institution, this process required an effort for the analysis and definition of area of aggregation, operation procedures and for the definition of the performance indicators. The process is still ongoing, but almost completed. The goal of this new organizational model is to integrate and coordinate the resources and the processes of the different Clinical Units, to render them more flexible and efficient with regard to the structural and management costs, to improve their specific role in the management of the patients and increase the quality of their medical activity. At page XXIII is included the list of the Clinical Departments approved by the Board of Directors. Such Areas, coordinated directly by the Health Direction, may enclose Units of different Clinical Departments and Units that not belong to Departments (Emergency Medicine, Services of Transfusion Medicine, Pathological Anatomy). The objective of these areas is to promote standardization of the activities, to realize common projects and synergies, to encourage the interexchange of human and technological resources, to promote communication between the Departments. The activation of the 12 Clinical Departments was made possible thanks to the strict collaboration between the medical areas and the San Raffaele’s management. All the procedures and processes were discussed and approved jointly, deriving from the common objective to increase the quality of the medical treatments and the efficiency of the Institute. The project management has been played and is played by the Health Direction, supported by the commitments of Board of Directors and General Direction. The Clinical Departments are led by the Directors, appointed for three years and nominated by the President of the Board of Directors, with the approval of the President of the Board of Director of the University VitaSalute San Raffaele. Each Director has been assigned several measurable objectives included in the so-called Cruscotto Dipartimentale. The Cruscotto Dipartimentale is aimed to monitor yearly the reaching of the goals assigned and the proper enforcement of the Department processes. The Departmental Director is assisted by a Director Management Assistant (DMA), a person with management background, with the function to co-ordinate the Department as far as the administrative issues are concerned and to facilitate the relation between the Department and the hSR Health Direction and the Institute management. The Departmental Director, is also supported by a so- called Department Area Coordinator (DAC) that performs clinical activity and, in addition, is responsible for the coordination and the management of a specific Departmental Area of activity (i.e. Research, Information Technology, Quality…). The clinical activity and resources management of the departmental Units is attributed to the Clinical Unit Leader (CUL). The implementation of the Departmental Model at the San Raffaele hospital is progressively reaching its goals with regard to economic efficiency and clinical effectiveness mantaining the central role of the patient through the full integration and co-sharing of the human, technologic and logistic resources. Renato Botti General Director Clinical Area INTRODUCTIONS - XXIII CLINICAL DEPARTMENTS 1. Department of Arrhythmology 2. Cardio-thoracic-vascular Department 3. Department of General and Specialistic Surgery 4. Head and Neck Department 5. Department of Infectious Diseases 6. Maternal and Child Health Department 7. Department of Internal and Specialistic Medicine 8. Department of Clinical Neuroscience 9. Department of Neurology 10. Department of Oncology 11. Department of Radiology 12. Department of Urology CROSS DEPARTMENT AREAS Clinical Laboratory Diagnostics • Service of Immunohematology and Transfusion Medicine • Pathology • Laboratory Medicine Imaging • Radiology HSR • Radiology SRT • Neuroradiology • Nuclear Medicine Anesthesia and Resuscitation • Intensive Care Cardiac Surgery • General Intensive Care • Neuro Intensive Care • UTIC Rehabilitation • Neurologic Rehabilitation • Orthopedic Rehabilitation • Cardiovascular Rehabilitation Emergency Medicine On October 29th 2007, the Fondazione Centro San Raffaele’s Board of Directors has officially approved the re-structure of the Clinical Area in Clinical Departments. XXIV - SAN RAFFAELE SCIENTIFIC INSTITUTE RESEARCH DIVISIONS AND CORES 1. Division of Molecular Oncology 2. Division of Metabolic and Cardiovascular Sciences 3. Division of Neuroscience 4. Division of Regenerative Medicine, Stem Cells, Gene Therapy 5. Division of Immunology, Transplantation and Infectious Diseases 6. Division of Genetics and Cell Biology RESEARCH CORES 1. Experimental Imaging 2. Bioinformatics and Biostatistics 3. Pathology (not activated yet) On March 7th 2008, the Fondazione Centro San Raffaele’s Board of Directors has officially approved the restructure of the Research Area in Divisions and Cores. This new structure is the result of over one year of activity of the Strategic Research Committee. The matrix model DC = Clinical Department DR = Research Division CR =Research Core Research Divisions cross one or more Clinical Departments. Research Cores cross both Clinical Departments and Research Divisions because of their technological value. INTRODUCTIONS - XXV INTERACTIONS bw RESEARCH AND CLINIC Research Divisions/Cores Neurology Clinical Neuroscience Molecular Oncology Metabolic & Cardio Vascular Sciences Neuroscience Regenerative Medicine, Stem Cells & Gene Therapy Immunology, Transplant. & Infectious Diseases Genetics & Cell Biology Imaging Genomics, Bioinformatics & Biostatistics Pathology Clinical Departments Internal Medicine Infectious Diseases Mother & Child Cardio Arrhythmology General & Radiology Vascular Spec. Surg. Urology Head & Neck Oncology INTRODUCTIONS - XXVII SCIENTIFIC REPORTS La “squadra” The Scientific Director, the Chief Operating Officer, the Directors and Associated Directors of the Research Divisions, the Directors of the Institutes, and the Scientific and Technical Committee DIVISION OF MOLECULAR ONCOLOGY - 1 DIVISION OF MOLECULAR ONCOLOGY Director: Federico Caligaris-Cappio* Associate Director: Giorgio Parmiani Research Units Lymphoid malignancies Unit HEAD OF UNIT: Federico Caligaris-Cappio* POST-DOCTORAL FELLOWS: Maria Teresa Sabrina Bertilaccio, Cristina Scielzo PHD STUDENT: Michela Frenquelli** FELLOWS: Benedetta Apollonio**, Giorgia Simonetti B-Cells neoplasia GROUP LEADER: Paolo Ghia* POST-DOCTORAL FELLOW: Claudia Fazi** PHD STUDENT: Antonis Dagklis FELLOW: Lydia Scarfò Biology of multiple myeloma GROUP LEADER: Marina Ferrarini POST-DOCTORAL FELLOW: Daniela Belloni Cell activation and signalling GROUP LEADER: Marta Muzio PHD STUDENT: Stavroula Ntoufa Dynamic fluorescence spectroscopy in biomedicine GROUP LEADER: Valeria R. Caiolfa POST-DOCTORAL FELLOW: Christian Hellriegel FELLOW: Moreno Zamai Lymphoid organ development GROUP LEADER: Andrea Brendolan PHD STUDENT: Laura Castagnaro FELLOW: Elisa Lenti Preclinical models of cancer GROUP LEADER: Rosa Bernardi POST-DOCTORAL FELLOW: Nadia Coltella PHD STUDENT: Ylenia Guarnerio** TECHNICIAN: Federica Ferenderes Tumor microenvironment GROUP LEADER: Elisabetta Ferrero PHD STUDENT: Lorenzo Veschini 2 - SAN RAFFAELE SCIENTIFIC INSTITUTE Immuno-biotherapy of melanoma and solid tumors Unit HEAD OF UNIT: Giorgio Parmiani RESEARCHER: Cristina Maccalli PHYSICIAN: Lorenzo Pilla POST-DOCTORAL FELLOW: Tiziano Di Tomaso TECHNICIAN: Gloria Sovena Cancer gene therapy GROUP LEADER: Vincenzo Russo PHD STUDENTS: Raffaella Fontana**, Cristina Rainelli, Laura Raccosta FELLOW: Maria Alessandra Meini TECHNICIAN: Daniela Maggioni Functional genomics of cancer Unit HEAD OF UNIT: Giovanni Tonon PHD STUDENTS: Aurora Negro**, Beatrice Rondinelli** Model genetics of membrane trafficking Unit HEAD OF UNIT: Ottavio Cremona* POST-DOCTORAL FELLOWS: Simona Ferron, Elisabetta Raiteri, Alessandra Zatti Molecular histology and cell growth Unit HEAD OF UNIT: Stefano Biffo FORMER HEAD OF UNIT: Pier Carlo Marchisio* POST-DOCTORAL FELLOWS: Daniela Brina , Stefano Grosso PHD STUDENT: Viviana Volta FELLOWS: Anne Beugnet, Simone Gallo, Elisa Pesce, Valentina Ruggeri TECHNICIAN: Annarita Miluzio Tumor biology and vascular targeting Unit HEAD OF UNIT: Angelo Corti RESEARCHER: Flavio Curnis PHD STUDENT: Eleonora Dondossola** FELLOW: Luca Crippa TECHNICIANS: Barbara Colombo, Anna Gasparri, Angelina Sacchi DIVISION OF MOLECULAR ONCOLOGY - 3 Clinical Research Units Digestive and pancreatico-biliary endoscopy Unit HEAD OF UNIT: Pier Alberto Testoni* PHYSICIANS: Lorella Fanti, Alberto Mariani, Edi Viale RESIDENTS: Antonella Giussani, Chiara Notaristefano, Cristian Vailati FELLOWS: Milena Di Leo, Sabrina Testoni Endosonography: diagnostic and therapeutic endoscopic ultrasound CLINICAL GROUP LEADER: Paolo Giorgio Arcidiacono PHYSICIANS: Silvia Carrara, Gianni Mezzi, Maria Chiara Petrone RESIDENT: Cinzia Boemo Gastrointestinal surgical oncology Unit HEAD OF UNIT: Carlo Staudacher* PHYSICIANS: Paolo Aldo Raul Baccari, Paola De Nardi, Saverio Di Palo, Elena Orsenigo, Andrea Marco Tamburini, Andrea Vignali RESIDENTS: Maria Chiara Salandini, Ilaria Santagostino PHD STUDENT: Alessandra Castiglioni** FELLOWS: Michele Carvello, Paolo Gazzetta, Luca Ghirardelli, Shigeki Kusamura , Francesco Luparini Alessio Mocci, Jacopo Nifosi Head and neck oncology Unit HEAD OF UNIT: Mario Bussi* PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Matteo Trimarchi RESIDENTS: Chiara Bellini, Beatrice Fabiano, Pietro Limardo, Paola Recanati TECHNICIANS: Daniela Gherner, Barbara Ramella Multidisciplinary group for thoracic surgical oncology HEAD OF UNIT: Piero Zannini* PHYSICIANS: Angelo Carretta, Paola Ciriaco, Giulio Melloni, Giampiero Negri*, Armando Puglisi, Carlopietro Voci* RESIDENTS: Alessandro Bandiera, Michele Giovanardi, Annamaria Gremmo, Stefano Sestini, Antonio Tuoro Oncogenesis in liver neoplasms Unit HEAD OF UNIT: Gianfranco Ferla* PHYSICIANS: Mvunde Mukenge, Michele Paganelli RESIDENT: Eleonora Guzzetti Onco-Hematology Unit HEAD OF UNIT: Fabio Ciceri PHYSICIANS: Massimo Bernardi, Consuelo Corti, Elena Guggiari, Francesca Lunghi, Matteo Carrabba, Magda Marcatti RESIDENTS: Alessandro Crotta, Fabio Giglio, Simona Malato POST-DOCTORAL FELLOW: Michela Tassara TECHNICIAN: Roberta Mattarucchi Pancreatic cancer Unit: biology and new therapeutic approaches HEAD OF UNIT: Valerio Di Carlo* PHYSICIANS: Gianpaolo Balzano, Walter Zuliani RESIDENTS: Federica Milani, Cristina Ridolfi FELLOW: Greta Grassini Clinical lymphoid malignancies HEAD OF UNIT: Federico Caligaris-Cappio* CLINICAL GROUP LEADER : Andrès Jose Maria Ferreri PHYSICIANS: Matteo Carrabba, Silvia Govi, Silvia Mappa RESIDENT: Marta Bruno Ventre TECHNICIAN: Arianna Vino 4 - SAN RAFFAELE SCIENTIFIC INSTITUTE Gynecologic oncology HEAD OF UNIT: Augusto Ferrari* CLINICAL GROUP LEADER: Giorgia Mangili PHYSICIANS: Patrizia De Marzi, Elisabetta Garavaglia, Micaela Petrone, Emanuela Rabaiotti, Riccardo Viganò RESIDENTS: Cinzia Gentile, Serena Montoli, Francesca Pella PHD STUDENTS: Jessica Ottolina, Cristina Sigismondi Medical oncology Unit HEAD OF UNIT: Eugenio Villa Clinical trials CLINICAL GROUP LEADER: Michele Reni PHYSICIANS: Daniela Aldrighetti, Elena Mazza, Monica Ronzoni, Giordano Pietro Vitali FELLOWS: Katia Bencardino, Stefano Cereda, Alessia Rognone Phase I and lung cancer clinical trials CLINICAL GROUP LEADER: Vanesa Gregorc POST-DOCTORAL FELLOW: Carmen Belli PHD STUDENTS: Anna Spreafico FELLOWS: Monica Giovannini, Maria Grazia Viganò URI, Urological Research Institute HEAD OF UNIT: Patrizio Rigatti* CLINICAL GROUP LEADER: Francesco Montorsi* PHYSICIANS: Roberto Bertini, Alberto Briganti, Renzo Colombo, Marco Roscigno, Andrea Salonia, Vincenzo Scattoni, Nazareno Suardi RESIDENTS: Marco Bianchi, Umberto Capitanio, Andrea Gallina, Lorenzo Rocchini URI Urological Research Institute, Ville Turro HEAD OF UNIT: Giorgio Guazzoni* CLINICAL GROUP LEADER: Francesco Montorsi* PHYSICIANS: Nicolò Maria Buffi, Andrea Cestari, Luciano Nava, Emanuele Scapaticci RESIDENT: Giovanni Lughezzani * Professor at: Università Vita-Salute San Raffaele ** Università Vita-Salute San Raffaele DIVISION OF MOLECULAR ONCOLOGY - 5 Introduction by the Directors Oncology bears a particular potential for translating research findings from the laboratory into clinical applications. Innovative strategies are urgently needed in the areas of diagnosis, patient risk stratification and treatment. The focus of the Division is to develop translational research programmes and clinical research. The tenet of the Division is that any significant progress toward the cure of cancer can only be based on an improved understanding of its pathogenesis, which, in turn, will lead to the development of improved diagnostics and more rationale therapeutic interventions. Federico Caligaris Cappio Accordingly we aim at fostering extensive collaborations between basic scientists and clinicians. These collaborations will allow to conduct projects and achieve results otherwise unattainable. Joint activities will accelerate the implementation of translational research through access to a large number of patients and samples and combined resource platforms. To this end the Division of Molecular Oncology intends: a) to join efforts with the Clinical Department of Oncology to create a network organization, multidisciplinary teams and defined programmes for different tumors b) to establish the collaborative use of resources and platforms with other Research Divisions c) to develop research programmes in specific areas of cancer where we are internationally competitive d) to establish infrastructure facilities that favour the Division development (patient’s data base, bio-bank, mouse and cell lines registers) e) to collaborate with other Research Divisions in establishing technical platforms available for researchers and clinicians as well f) to establish a clinical trial unit especially devoted to Phase I and I/II studies Giorgio Parmiani The activity will take advantage of existing competences and infrastructures that include: • long-standing expertise, spanning from development and study of transgenic and KO mouse models to molecular and cellular systems for analysis of human (and mouse) cells in vivo and in vitro • availability of mouse models in which various cellular components can be tracked by noninvasive imaging technologies • recent recruitments of scientists with experience in genomics and in preclinical modelling of cancer • potential therapeutic reagents to be systematically analysed in a preclinical setting coupled with direct clinical experience in applying new therapies to patients 6 - SAN RAFFAELE SCIENTIFIC INSTITUTE Four major areas of investigation have been identified and the research activity will develop along these areas that will be implemented and potentiated: a) Cancer Genetics b) Cancer Microenvironment c) Cancer Immunology and Immunotherapy d) Cancer Stem Cells Two scientific programs have been so far planned: a) Strategic Research Program in Immunology and Bio-Immunotherapy of Cancer (PIBIC) that represents the merging of two previous programs and is co-organized with the Division of Immunology. b) Microenvironment and Genes in Cancers of the Blood (MAGIC). DIVISION OF MOLECULAR ONCOLOGY - 7 Research Units LYMPHOID MALIGNANCIES UNIT The principal aim of our Unit is to to dissect the elements responsible for the clinical presentation and the natural history of Chronic Lymphocytic Leukemia (CLL). It is plausible to consider that besides “causal genes” a number of other “influential genes” operate and that the products of all these genes interact with the microenvironment inducing proliferation, survival and clonal expansion of CLL cells within the tissues. The investigation of these elements is leading to the identification of molecules and mechanisms that could be exploited as potential therapeutic targets. This has been approached by analyzing two major aspects. First, we have investigated the intracellular protein HS1 and its role in controlling the CLL cell capacity to migrate and home to specific tissue compartments. Second, we have established new mouse models that may help analyzing the role of by-stander cells including stroma and accessory cells in favouring the proliferation, survival and accumulation of CLL cells within the invaded tissues. We previously showed that the presence of hyperphosphorylated HS1 molecule, observed in a subset of CLL patients, correlated with bad prognosis. In the current year we have started defining the functional role of HS1; in vitro and vivo data indicate that HS1 play a key role in the regulation of leukemic B-cell cytoskeleton organization, which in turn controls the leukemic cell traffic, migration and homing to specific tissues; a protein knock-down approach in human cells was complemented by the analysis of HS1 deficient mice. Next we have established a new mouse model by crossing the classic “leukemic” EmuTCL1 transgenic mouse with HS1 deficient mice. This model suggests that the impairment of HS1 influences the localization and dissemination of leukemic clones in a manner similar to the presence of hyperphosphorylated HS1 in humans. Third, we have established and characterized a novel xenotransplanted mouse model by injecting the CLL cell line MEC1 into adult immunodeficient rag2-/-g-/- mice. This xenotrasplant model may be proposed as a simple tool to explore in vivo the leukemic tissue microenvironment and follow its interactions with CLL cells; it may also be explored as a preclinical model of CLL for novel therapeutic approaches validation. Federico Caligaris-Cappio B-CELL NEOPLASIA The main focus of our research is on tumors of mature B-cells and in particular on tumours of the chronic type that are virtually incurable. In the past year, we aimed at identifying relevant molecules and pathways that can be selectively targeted for therapeutic purposes in a patient-tailored fashion. Strong evidence suggest that stimulation through the B-cell antigen receptor (BCR) is involved in the selection and expansion of the malignant clone in a number of chronic B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL). That notwithstanding, some CLL cases respond to the in vitro crosslinking of surface immunoglobulin with effective activation while others do not. We have published that, in the CLL cases not responding to BCR ligation, leukemic cells express constitutively phosphorylated ERK1/2 and MEK1/2 together with NF-AT transcription factor transactivation in the absence of AKT activation. This molecular profile recapitulates the biochemical signature of anergic murine B cells and interestingly significantly correlates with a low stage disease at diagnosis. The binding of each particular antigen to a leukemic BCR may provide either anergizing or activating stimuli, being likely responsible for different biological and clinical behaviour. The actual stage of the natural history of CLL at which the antigenic exposure occurs is poorly defined. As we and others have identified the presence of monoclonal B cells (MBL) resembling CLL cells and circulating in the peripheral blood of otherwise healthy individuals, we aimed at characterizing the immunoglobulin receptors and repertoire expressed by these cells, in order to identify features that are associated with the risk of 8 - SAN RAFFAELE SCIENTIFIC INSTITUTE leukemic evolution. We studied MBL in the general population, where these cells account for a minority of all circulating B cells and we showed that the IGHV gene usage is not CLL-biased. These findings suggest that the detection of MBL does not indicate, in most cases, a pre-leukemic state. The presence of few unmutated and stereotyped cases suggests that some MBL cases at higher risk of evolving into a clinically relevant disease do exist. A detailed IG molecular analysis of individual MBL might then become a promising tool helping to identify those particular cases. Paolo Ghia BIOLOGY OF MULTIPLE MYELOMA New insights into the anti-myeloma activity of proteasome inhibitors Multiple Myeloma (MM) is a tumor of plasma cells (PC) growing almost exclusively within the Bone Marrow (BM), which delivers pro-survival signals and confers chemo-resistance to neoplastic cells. BM angiogenesis also deeply contributes to MM development and progression. Despite the use of new therapeutic approaches, the disease remains ultimately fatal. The proteasome inhibitor Bortezomib has been a major advance in the treatment of MM, but less than half of the patients achieve either a complete or a partial response. A better understanding of the mechanisms of action and of the cellular targets of proteasome inhibitors is therefore needed to improve their therapeutic potential and to identify new combination strategies. We found that treatment with Bortezomib induces redox perturbations in MM cell lines and PC from MM patients and that, conversely, sensitivity to the drug could be modulated by modifying redox homeostasis. This mechanism can be exploited to potentiate the response to proteasome inhibitors. Bortezomib has also antiangiogenic properties. In particular, we have demonstrated that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Quiescent EC are resistant to Bortezomib, while the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on sub-confluent, spontaneously proliferating HUVEC. In addition, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of sub-confluent EC is preceded by signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3Methyladenine prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC. Interfering with the autophagic response may potentiate the antiangiogenic effect of the drug. Marina Ferrarini CELL ACTIVATION AND SIGNALLING The principal aim of our Unit is to dissect the molecular events which regulate cell activation and signalling, in particular focussing our attention on the B-cell receptor (BCR) and Toll-like receptors (TLR) signalling pathways in normal and malignant B lymphocytes. The investigation of these elements is leading to the identification of molecules and mechanisms that could be exploited as potential therapeutic targets. Stimulation through the BCR is involved in the natural history of chronic lymphocytic leukemia (CLL). Some cases respond to the in vitro cross-linking of surface immunoglobulin (sIg) with effective activation. In contrast, the remaining cases do not respond to such stimulation, thereby resembling B cells anergized after antigen encounter in vivo. However the biochemical differences between the 2 groups were ill defined, and in humans the term B-cell anergy lacks a molecular definition. We examined the expression and activation of key molecules in- DIVISION OF MOLECULAR ONCOLOGY - 9 volved in signalling pathways originating from the BCR, and we report that a proportion of CLL patients a) expresses constitutively phosphorylated ERK in the absence of AKT activation; b) displays constitutive phosphorylation of MEK and increased NF-AT transactivation; and c) is characterized by cellular unresponsiveness to sIg ligation. This molecular profile recapitulates the signalling pattern of anergic murine B cells. Our data indicate that MAPK cascade may be exploited as a novel therapeutic target in a selected group of pERK positive CLL patients. Mature B-cells can recognize microbial antigens via BCR in a specific way and via TLR in a costimulatory manner. A wealth of information is gathering on the possible role of antigenic stimulation in the natural history of CLL. However little is known regarding the repertoire and function of TLR in CLL cells. CLL cells were found to express several functional pattern recognition receptors including TLR1, 2, 6, 10, NOD. Leukemic cells, upon stimulation with TLR2 ligands, such as bacterial lipopeptides, activated the NF-kB signalling pathway, expressed activation molecules, and were protected from spontaneous apoptosis. These findings suggest a potential role of TLR in modulating CLL cell response in the context of specific antigen recognition. Marta Muzio DYNAMIC FLUORESCENCE SPECTROSCOPY IN BIOMEDICINE Spatial and temporal resolution of receptor signaling in cell-cell and cell-microenvironment cross-talk The systems biology challenge is to understand the functional interplay and dynamic organization of complex cellular protein machineries as they react to stimuli. In contrast to the static hard-wired diagrams, most proteins interact dynamically and conditionally with biochemical modifications, giving rise to the mechanisms that cells employ for rapid and accurate discrimination of signals in physiological and oncogenic conditions. We aim at substituting the hard-wired diagrams of receptor interactomes (i.e. a schematic representations of signaling pathways), with the real time dynamics of multi-protein complexes, as they assembly, translocate and disassembly in living cells, governing the mechanisms of cellular adhesion and migration. During last year, we have been pursuing two main goals. The first was to progress in the development of sensitive molecular imaging approaches that have the potential of following the dynamics of complex protein ensembles at real time, in live cells and with nanometric resolution. We have taken well-known fluorescence spectroscopy tools such as fluorescence lifetime and brightness, that for years have been applied only by a restricted number of specialized laboratories in physics, and developed new algorithms for exporting them into the cell biology world, transforming spectroscopy into microscopy [Digman, Caiolfa, et al., Bioph. J, 2008; Malengo, Zamai et al., J Biomed. Opt, 2008]. The second goal was to unravel fundamental mechanisms of protein segregation and re-localization during cell-to-cell adhesion and/or cell-to-ECM interaction. We have contributed to demonstrate for the first time the existence of tetraspannin-based microdomains in the plasma membrane of primary endothelial cells. These are the adhesive platforms (EAP) for leukocyte adhesion. We discovered by the new phasor-FLIM-FRET imaging that EAP microdomains are present in the membrane prior to leukocyte adhesion, and contains tetraspanninspecific CAM receptors. We studied the dynamics of the individual EAP components and their specific interactions that result in the docking structures by which the leukocyte is trapped on the surface of the endothelium [Barreio, Zamai et al., J Cell Biology 2008]. Valeria R. Caiolfa LYMPHOID ORGAN DEVELOPMENT The research in our laboratory is focussed on identifying the molecular and cellular mechanisms underlying lymphoid organ development. We are interested to uncover the developmental programs responsible for specification and differentiation of stromal progenitors within lymphoid organs. Furthermore, we aim at identifying how the stromal cell pool contribute to the formation and function of the lymphoid microenvironment and ultimately to understand how stromal cells support the function of normal lymphoid and leukaemia/lymphoma 10 - SAN RAFFAELE SCIENTIFIC INSTITUTE cells. Concomitantly, we are translating our knowledge on how secondary lymphoid organs develop to construct functional artificial lymph nodes that could serve as a novel approach to enhance anti-tumor immunity. 1) Elucidating the roles of oncogenic transcription factors in secondary lymphoid organ development. We have uncovered a genetic and transcriptional network underlying spleen development and demonstrated the essential role for the oncogenic transcription factor Pbx1, Hox11 and Nkx2.5 during spleen organogenesis. Specifically, by exploiting in vivo mouse models and well as cellular and biochemical approaches, we have identified the CDK inhibitor p15Ink4b as a target of the oncogenic transcription factor Pbx1 during organ development. 2) Uncovering the differentiation pathways of stromal progenitors during lymphoid tissue development. By using a genetic approach to label in vivo mesenchymal cells we have traced spleen and lymph nodes stromal descendants during embryogenesis, and uncovered their differentiation pathways and their relationship with lymphoid cells in adult organs. 3) Generating functional artificial lymphoid organs (aLOs). By exploiting murine mesenchymal cells as a new source of stromal progenitors, we have succeeded in constructing aLOs with features similar to normal lymphoid organs such as presence of T- and B-cell compartments as well as a stromal-cell network. Our long term goal is to transplant aLOs loaded with tumor antigens into tumor-bearing mice and seek to control tumor growth by inducing long lasting anti-tumor immunity. Andrea Brendolan PRECLINICAL MODELS OF CANCER Role of angiogenesis in leukemogenesis The main research focusis of our Unit has been to evaluate the role of pro-angiogenic factors in leukemogenesis by using mouse models. Leukemia patients express high levels of pro-angiogenic factors such as VEGF and have increased angiogenesis in their bone marrow, suggesting that angiogenesis may foster leukemogenesis. However, the molecular mechanisms leading to high VEGF production in leukemia are not known. We hypothesized that upregulation of the transcription factor HIF-1a, the main positive regulator of VEGF expression in solid tumors, may cause high VEGF expression also in some forms of leukemia. In this past year: 1) we have optimized a transduction protocol, in the mouse, allowing to transduce hematopoietic stem cells with oncogenic fusion proteins in order to establish acute myeloid leukemia and chronic myeloid leukemia mouse models. These will be then utilized to measure the expression of HIF-1a and VEGF in preleukemic and leukemic bone marrow in comparison with bone marrow angiogenesis and leukemia progression. At the same time, in collaboration with the Unit of Pathology and the Hematology and Transplantation Unit at our Institution, we have started to analyze bone marrow samples of human leukemia for HIF-1a and VEGF expression. We have optimized an immunohistochemistry protocol on leukemic bone marrow smears and we are currently collecting newly diagnosed leukemia samples that will be soon analyzed. 2) We have established lentiviral vectors to transduce mouse hematopoietic cells with HIF-1a and VEGF to verify whether overexpression of pro-angiogenic factors accelerates leukemogenesis. We tested a series of vectors that allow tracking of the transduced mouse hematopoietic cells with GFP and we are currently setting up co-infection protocols with leukemogenic fusion proteins. 3) We have begun to assess expression levels of HIF-1a and VEGF in normal hematopoiesis in the mouse. Preliminary real-time PCR analysis results indicate that HIF-1a is not regulated during differentiation, while VEGF expression decreases. Future experiments will better elucidate the relative expression of these genes in hematopoietic stem cells compared to progenitors and committed cell. Rosa Bernardi DIVISION OF MOLECULAR ONCOLOGY - 11 TUMOR MICROENVIRONMENT Set-up of a new 3-D approach in bioreactor for the study of Multiple Myeloma microenvironment Multiple Myeloma (MM) is a tumor of fully differentiated plasma cells (PC), growing almost exclusively within the Bone Marrow (BM). The essential role of BM in disease maintenance and progression has been highlighted, with particular emphasis on angio-vasculo-genesis contribution. Indeed, direct and indirect interactions between PC and other cells and extracellular matrix (ECM) within the BM environment are key requirements for MM pathogenesis, MM cell growth, survival and drug resistance. The generation of in vitro models able to recapitulate MM microenvironment is crucial to both the understanding of MM biology and the assessment of its vulnerability to drugs. To this purpose, we applied a 3-D culture innovative technology based on the use of the Rotatory Cell Culture System (RCCSTM) bioreactor. The suitability of RCCSTM bioreactor for the 3-D culture of tissue samples was first assessed using skin biopsies that maintained intact architecture and viability. We then cultured in bioreactor samples obtained from two bone marrow samples from MM patients, with opposite clinical histories and response to therapy. Histological examinations performed on samples from the two patients up to 3 weeks, allowed to identify and characterize MM plasma cells and vessel structures. Response to Bortezomib could also be assessed. Notably, supernatants retrieved during 3-D cultures at different time intervals, showed increasing secretion and activity of MMP-2, at variance from that obtained culturing rib fragments from healthy donors. This indicates that the system has the potential to allow monitoring of metabolism and preserves viability, functionality and differentiation of tissue samples. In parallel, we are exploiting the model in Bioreactor to assess the relative contribution of different cellular components, in particular endothelial cells, to plasma cells survival/growth modalities. We are then aiming at comparing this culture system with conventional 2-D cultures. Elisabetta Ferrero IMMUNO-BIOTHERAPY OF MELANOMA AND SOLID TUMORS UNIT The main objective of our research Unit is the molecular characterization of new and more immunogenic tumor antigens (TA) recognized by T cells and their use in translational protocols of immunotherapy. We intend to improve the knowledge of the relationship between tumor and host immune cells. This information will be used to design new translational immunotherapy protocols for metastatic human solid tumors (melanoma; glioblastoma - GBM - colon, prostate and pancreatic carcinomas). The objectives of our research are: 1) molecular characterization of new TA recognized by T cells in HLA class I- e class II restriction, particularly those that may derive from tumor cell somatic mutations; 2) assessment of the role of NKT lymphocytes as anti-tumor effectors by the analysis of their NKG2D receptor and of its ligands expressed by melanoma and other human tumors; 3) immunologic antigen profiling and immunogenicity and/or immunsuppression function of cancer stem cells (CSC) obtained from melanoma; GBM; pancreatic, colorectal tumors; analysis of the role of regulatory T cells in patients undergoing immunotherapy. In addition, translational clinical studies will be activated to enroll patients with metastatic melanoma or other tumors in protocols of immuno-biotherapy particularly in studies of combination of vaccines and other biological agents (e.g. anti-vascular compounds). Results of 2008. In 2008 we have concluded the first part of the project on the immunologic analysis of human CSC of GBM in parallel with the tumor line from which CSC have been obtained. The CSC showed a weak expression of class I and II MHC and of NKG2D ligands. However, in vitro treatment with IFN−α increased MHC and NKG2D ligand expression in CSC thus allowing CSC of GBM to be recognized and lysed by autologous T and NKT cells in at least a fraction of patients. We have also shown that CSC and their GBM line may express antigens like SOX-2, NY-ESO1, COA-1 that represent potentially specific targets for immunotherapy. In a different project, an analysis of expression of OX-40 and other T cell activation markers was performed in more than 100 samples of human tumors to see whether a correlation may occur between expression of expression of these markers and tumor growth control. Giorgio Parmiani 12 - SAN RAFFAELE SCIENTIFIC INSTITUTE CANCER GENE THERAPY Several pre-clinical and clinical studies have demonstrated that the immune system plays a key role in controlling tumor growth. That notwithstanding, the clinical exploitation of this discovery is far from being successful. Indeed, the results from the current cancer immunotherapy studies have been disappointing, leading to a limited clinical efficacy. Several reasons can be responsible for that, such as the bias in selecting patients eligible for these treatments as well as the antigens and/or the strategies used. In this context, pathways perturbing the tumor microenvironment have recently been demonstrated to condition the antitumor immune response allowing the tumor cells to escape immune surveillance. These pathways may act on the priming and/or on the effector phase of the antitumor immune response. In recent years, these mechanisms have been extensively investigated, leading to the identification of molecules and immune suppressive circuits responsible for the inhibition of the antitumor immune response. The research of our group is focused on the investigation of the cellular mechanisms underlying immune responses to solid tumors, with the final goal to improve this response. Particularly, we have recently developed a novel strategy of active immunotherapy based on the in vivo loading of antigen presenting cells (i.e. dendritic cells), with tumor-antigens. The clinical translation of this approach has led to the development of antitumor effectors correlating with a favorable clinical outcome in melanoma patients. In addition, we have recently identified a novel mechanism of tumor immune escape that dampens the spontaneous immune-mediated control of tumor growth by impairing the functional expression of the lymphoid-organ homing receptor CCR7 on maturing dendritic cells. Noteworthy, the use of drugs interfering with this pathway restores the spontaneous antitumor immune response and, as a consequence, the control of tumor growth in different murine tumor models. Vincenzo Russo FUNCTIONAL GENOMICS OF CANCER UNIT Transcriptomic, genetic and epigenetic reprogramming of cancer cells Our laboratory has been pursuing the following lines of research: 1. Role of histone methylation and demethylation in cancer development. In the nuclei of eukaryotic cells, DNA is packed into chromatin. The basic constituent of chromatin, the nucleosome, is comprised of 147 bp of DNA wound around an octamer of core histone proteins. Post-translational modifications of the N-terminal tails of these core histone proteins, modulate chromatin configuration, resulting in changes in transcriptional regulation. These epigenetic modifications are controlled by complex enzymatic machinery that, when deregulated, disrupt normal transcriptional programs. Indeed, genomic alterations of MLL, NSD1, CREBBP, WHSC1L1 and WHSC1, all encoding proteins involved in histone modification, have been implicated in several cancer types. Through genomic analysis and large-scale high-throughput sequencing, we have identified genetic lesions affecting histone methylases and demethylases and we are exploring the role of the genes implicated in these genomic rearrangements in the development of multiple myeloma, lung cancer and pancreatic adenocarcinoma. 2. Receptor tyrosine kinase receptors in the development of Multiple Myeloma. The protein kinase is the most commonly represented Pfam domain encoded by cancer genes. Many carcinogenic tyrosine kinases are receptors, which are often overexpressed and/or mutated in a variety of tumors. Therapeutic agents targeting this class of receptors have proven to be highly effective in the clinical setting. Multiple Myeloma (MM) is the second most frequent hematological cancer and remains incurable. Several RTKs are expressed in MM and there is mounting evidence of their pathogenetic importance in this disease. We have conducted a genomic and proteomic survey of primary MM samples and identified two RTKs that were overexpressed relative to levels present in plasma cells derived from normal donors. Strikingly, both RTKs tap into developmental pathways that are highly relevant in cancer biology and demonstrated robust transforming activity. We are now aiming at elucidating the nature of the signaling mediated by these RTKs in MM, both in vitro and in vivo, with the final goal of identifying more effective drugs against MM. Giovanni Tonon DIVISION OF MOLECULAR ONCOLOGY - 13 MODEL GENETICS OF MEMBRANE TRAFFICKING UNIT In the last few years, endocytosis has considerably expanded its action spectrum from a general tool to internalize plasma membrane and extracellular components to a specific mechanism for fine-tuning of a variety of cellular functions, including cell signaling and neurotransmission. Here we report the analyses of the function of two key endocytic adaptor families, namely the epsin and dynamin families, by a genetic approach in mice. Epsin 1/2 KO mice. A manuscript addressing the first characterization of the epn1/2 DKOs is currently in press on PNAS. Here, an outline of the results is reported. Epsins are endocytic adaptors with putative functions in general aspects of clathrin-mediated endocytosis. We have now tested the role of the ubiquitously expressed epsin genes, Epn1 and Epn2, by murine gene KO models. While either gene is dispensable for life, their combined inactivation results in embryonic lethality at E9.5-E10, i.e. at the beginning of organogenesis. Consistent with studies in Drosophila, where epsin endocytic function was linked to Notch activation, developmental defects observed in epsin 1/2 double knockout (DKO) embryos recapitulated those produced by a global impairment of Notch signaling. Accordingly, expression of Notch primary target genes was severely reduced in DKO embryos. However, housekeeping forms of clathrin-mediated endocytosis were not impaired in cells derived from these embryos. These findings support a role of epsin as a specialized endocytic adaptor, with a critical role in the activation of Notch signaling in mammals. Dynamin1 KO mice. Mutant mice for Dnm1, a GTPase implicated in the fission of synaptic vesicles, fail to thrive and exhibit severe activity-dependent endocytic defects at their synapses. We used electron tomography to investigate the accumulation of coated pits in a subset Dnm1 KO primary neuron cultures under conditions of spontaneous network activity. We found that this increase occurs selectively at inhibitory synapses and, more generally, that these latter synapses are uniquely sensitive to perturbation of endocytic proteins. Our findings reveal a striking heterogeneity in the mode of presynaptic endocytosis in different synapses and functional states. Ottavio Cremona MOLECULAR HISTOLOGY AND CELL GROWTH UNIT Translational control in cancer cells Translational control (regulation of protein synthesis) has acquired unexpected importance in cancer therapy. Briefly, translation is controlled by initiation factors (eIF). The clearest example of an eukaryotic Initiation Factor (eIF) affecting cancer is eIF4E, as demonstrated by its ability to transform fibroblasts through overexpression. Tumorigenic properties of eIF4E are explained by the facts that it is rate-limiting in formation of the eIF4F complex and that many mRNAs involved in cell cycle progression and tumorigenesis (c-my c, VEGF)have a structured 5’UTR that requires eIF4F activity. Consequently, indirect inhibition of eIF4F formation by rapamycin analogues (mTORC1 blockers) is effective in cancer therapy. Other regulators of translation have been suggested to play a role in cancer, though unfortunately no evidence of targetability has been so far provided: eIF2-based control of hypoxia in tumors; IRES-based control of survival genes/oncogenes; miRNAs in tumorigenesis and tumor dissemination. Are there other translational targets as good as eIF4F? A new translation initiation factor that can be a target in cancer therapy is eIF6. The activity of eIF6 is essential for both the generation of 60S subunits, and for efficient translation. eIF6 is overexpressed in cancer cells and is rate-limiting for growth, translation and transformation of cells. We have shown that a reduction of 50% of eIF6 reduces tumorigenicity, of cells without affecting the viability of normal cells. The mechanism of action of eIF6 may be dual: on one side, it may affect micro-RNA based translational repression; on the other, by impairing improper subunit joining, it is able, downstream of growth factor signaling, to increase translation in conditions of high demand of growth. Notably, eIF6 is acting downstream of the growth factor cascade. We have found that several signaling pathways may act on eIF6 activity. In this context, we have demonstrated that in several tumors eIF6 is both overexpressed and yperphosphorylated. The research activity in our Unit is now aiming at defining the tumors in which eIF6 activity is essential and to develop blockers of eIF6 activity. Stefano Biffo 14 - SAN RAFFAELE SCIENTIFIC INSTITUTE TUMOR BIOLOGY AND VASCULAR TARGETING UNIT Tumor necrosis factor-α and chromogranin A (CgA) in inflammation, angiogenesis and tumor microenvironment biology Our studies focus on the role of Tumor Necrosis Factor-α (TNF) and of other proteins containing NGR, RGD and isoDGR motives (such as fibronectin and chromogranin A) in tumor vascular biology and angiogenesis. In addition, we are interested in developing new strategies for cancer therapy based on the manipulation of the tumor microenvironment. We have found that circulating chromogranin A (CgA), an RGD-containing protein secreted by many neuroendocrine cells, is elevated in patients with cancer, heart failure, rheumatoid arthritis, and other inflammatory diseases, with important prognostic implications. In these patients we observed a significant correlation between CgA and tumor necrosis factor-α (TNF), an inflammatory cytokine capable to exert a variety of biological effects on tumor cells and microenvironment. In vitro and in vivo experiments have shown that CgA can inhibit tumor growth, by affecting tumor microenvironment and vasculature, can affect fibroblast and endothelial cell adhesion, and can inhibit TNF-induced vascular leakage, suggesting that CgA plays a role in tumor vascular physiology. Another line of research is focused on the asparagine-glycine-arginine (NGR) motif, a sequence that is present in many molecules of the extracellular matrix. We have demonstrated that an NGR site of fibronectin, a protein of the extracellular matrix (ECM), can undergo rapid deamidation reactions generating the isoAsp-GlyArg (isoDGR) sequence. Peptides and fibronectin fragments containing the isoDGR motif in turn can bind αvβ3, an integrin expressed in angiogenic vasculature, can affect endothelial cell functions and can inhibit tumor growth. We have hypothesized that the NGR-to-isoDGR switching in fibronectin and in other proteins of the ECM might work as a “molecular timer” for generating new binding sites for integrins. Finally, we have found that peptides containing the NGR, isoDGR and RGD motives can be exploited for delivering TNF and other cytokines to tumors vessels. One of these compounds, called NGR-TNF, can induce vascular damage and can increase the penetration of various chemotherapeutic drugs in tumors. Because of these properties, NGRTNF is currently tested in Phase I and II clinical studies, alone and in combination with chemotherapy. Angelo Corti Clinical Research Units DIGESTIVE AND PANCREATICO-BILIARY ENDOSCOPY UNIT The Unit is involved in the development and clinical application of advanced endoscopic imaging and endoluminal therapy for recognition and treatment of high-grade dysplasia and early cancer of the gastrointestinal tract (G.I.) and pancreatico-biliary system. Advanced endoscopic imaging. In the last years the research has been focused mainly on the use of Optical Coeherence Tomography (OCT) for detecting and characterizing mucosal and submucosal lesions of the G.I. tract and for differential diagnosis of structures of unknown aetiology of the main pancreatic and common bile duct. OCT is an optical imaging modality that performs high-resolution, cross-sectional, subsurface tomographic imaging of the microstructure of the tissue. The physical principle of OCT is similar to that of B-mode ultrasound imaging, except that it uses infrared light waves; the depth of penetration into the tissue is limited to 1-3 mm, so the technique is useful to investigate the mucosa and submucosal layers of the G.I. wall. OCT has been previously used for investigating dysplasia and early neoplasia in Barrett’s esophagus and ulcerative colitis. We first used OCT imaging to investigate the layers of the main pancreatic and common bile duct in ex-vivo studies and in humans, by ERCP. Using this technique, we were able to characterize the intraductal tissue structure and differentiate between neoplastic and inflammatory strictures, as documented by recent publications. At present, surface and contrast enhanced endoscopic imaging is used to investigate mucosal flat lesions (pre- DIVISION OF MOLECULAR ONCOLOGY - 15 neoplastic and neoplastic); the technique appeared particularly useful in Barrett’s esophagus, gastric dysplasia, and colonic flat adenomas. Confocal microscopy will be the next step in the endoscopic imaging. Endoluminal therapy. Endoscopy is commonly used for treatment of superficial lesions of the G.I. tract, since the technique permits to remove tissue by mucosal resection and submucosal dissection. The Unit is involved in the development of new devices for tissue removal, including knife models and water jet probes for tissue lifting. By using these devices, dysplastic epithelium and early cancer within Barrett’s esophagus, as well as in the stomach and colon, can be completely removed. Pier Alberto Testoni ENDOSONOGRAPHY: DIAGNOSTIC AND THERAPEUTIC ENDOSCOPIC ULTRASOUND The focus of the Endosonography Unit is to develop research programmes in diagnosis and treatment of premalignant and malignant pancreatic disorders. The importance of diagnostic Endoscopic Ultrasound (EUS), the therapeutic and interventional applications of EUS are expanding and may become a major breakthrough in the management of pancreatic diseases. The diagnosis of premalignat lesions such as intraductal papillary mucinous neoplasms (IPMN) is necessary to avoid that most patients have advanced disease at the time of diagnosis. We are cooperating with Mayo Clinic Jacksonville for an international registry for multi-center collaboration in IPMN research and clinical management, with the aim of identifying clinical and morphological predictors of cancer in patients with IPMN who undergo surgery, and to identify predictors of progression to cancer or high grade dysplasia among patients who are followed in surveillance programs. The ability to perform EUS-guided fine needle aspiration (EUS-FNA) to acquire tissue samples allow us to perform molecular analysis. We have demonstrated that RNA extraction from EUS-FNA of pancreatic lesions is feasible and gives a sufficient quantity to analyze the pattern of expression of mucins. MUC expression profile can orientate the diagnosis and evolution of pancreatic lesions. Patients with unresectable locally advanced pancreatic disease don’t have many chances and chemoradiation confers them only a minimal symptomatic improvement. Radiofrequency ablation is a local thermal therapy used for palliative treatment of solid tumours. We have developed a new flexible bipolar ablation probe combining radiofrequency and cryotechnology applied under EUS-guided and we have demonstrated the feasibility and efficacy of this new treatment, using it in a porcine model. We have also evaluated the efficacy of this new hybrid cryotherm probe in destroying neoplastic tissue of explanted pancreas of patients with pancreatic adenocarcinoma, analyzing both the tissue histological changes and relationship between application time and long axis diameter of necrosis obtained. The application provokes selective necrosis in neoplastic tissue, and there was a statistical significant correlation between necrosis diameter and application time. Paolo Giorgio Arcidiacono GASTROINTESTINAL SURGICAL ONCOLOGY UNIT Translational research in gastrointestinal oncology Our Unit’s research activity has been focussed on several different relevant topics in gastrointestinal oncology: 1) Role of the induction of innate and adaptive antitumor immunity in nonmetastatic rectal cancer patients treated with neoadjuvant CT-RT and its relationship with pCR and survival. The aim is to verify whether innate factors influence the outcome of antineoplastic treatment, and whether they may predict in selected patients the clinical response and survival. 2) Evaluation of the clinical significance of CTCs in blood from patients with gastrointestinal cancers. The aim is to determine and quantify CTCs in all patients with any stage of gastrointestinal malignancy, as well as correlate its presence with clinical and pathological factors. Our second endopoint is testing the prognostic value regarding disease free overall survival. 16 - SAN RAFFAELE SCIENTIFIC INSTITUTE 3) Pharmacokinetics of intraperitoneal administration of antiblastic drugs. Aim of our study, conducted in collaboration with Harvard University, was to test in a rat model the pharmacokinetics of intraperitoneal administration of new antiblastic drugs 4) HIPEC in the treatment of locally advanced gastric cancer following preoperative chemotherapy and curative surgery. The purpose of the present protocol is to investigate the feasibility, morbidity, toxicity, mortality and oncological outcome of HIPEC in patients with locally advanced gastric cancer. 5) Cytoreductive surgery and HIPEC in the treatment of peritoneal carcinomatosis from colon cancer. The purpose of the present pilot study is to investigate the feasibility, morbidity, toxicity, mortality and survival of the cytoreductive surgery and HIPEC in colon cancer patients with primary/relapsing peritoneal carcinomatosis or at a high risk for peritoneal dissemination. 6) Sentinel node mapping during laparoscopic gastrectomy fro gastric cancer. Laparoscopic modified surgery based on sentinel node status would be the goal of a minimally invasive approach for pathologically node negative early gastric cancer. The aim is to evaluate the feasibility in gastric cancer patients who underwent laparoscopic detection of sentinel node. Carlo Staudacher HEAD AND NECK ONCOLOGY UNIT Our Unit’s main research focus is the investigation on functional problems and outcomes of advanced larynx cancer bearers. A new technique of subtotal laryngectomy has been performed, in cooperation with other Ear, Nose and Throat (ENT) oncological departments, to preserve the voice in advanced larynx cancers, extended to the subglottis. Phonatory and deglutition results have been studied, together with the satisfaction degree. As far as total laryngectomy concerns satisfaction and quality of life after voice prosthesis rehabilitation have been investigated. New functional surgical techniques and psychooncological studies will be carried on in the next period to guarantee the best social outcome in subjects undergoing organ sacrificing surgery for advanced larynx cancer. A series of 214 cases of parotidectomies performed in 6 years has been investigated from a clinical and statistical point of view Attention was paid to correlation between Fine Needle Aspiration Citology (FNAC) and definitive histological examination, to facial palsy, Frey’s syndrome and relapses; statistical analysis was performed on the grouped data. FNAC sensitivity was 81%, while specificity was 99%. Frey’s syndrome complicated the clinical outcome in 35.04% of the cases. Temporary facial nerve palsy happened in 12% of the patients (18 to 65% of cases in the literature) Multivariate analysis was performed to investigate if there were some prognostic factors causing relapses, that we had in the 5.6% of the cases. Previous surgery was found the only predisposing factor. Over past 20 years, high risk human papilloma virus (HPV) infections has been established as a risk factor for developing head and neck squamous cell carcinoma, independent of tobacco and alcohol use. In our cases we found HPV positivity in 17% of oropharyngeal cancer patients and in a small minority of oral cavity cancers ( 5%). The most common high-risk subtypes are HPV-16 and 18; HPV-positive HSNCC has decreased expression of wild-type p53, additionally these tumours do not show p16 depletion. As it has been proved in the literature, we found an improved survival in oropharyngeal HPV tumors with overexpression of p16 level. Feasibility and efficacy of targeted HPV16 vaccination will be investigated in the future. Mario Bussi DIVISION OF MOLECULAR ONCOLOGY - 17 MULTIDISCIPLINARY GROUP FOR THORACIC SURGICAL ONCOLOGY Multidisciplinary approach for patients affected by non-small cell lung cancer and colorectal and renal cancer lung metastases Surgery remains the best treatment for patients affected by non-small cell lung cancer (NSCLC). Advanced age, cardiorespiratory comorbidities and pathological mediastinal lymph nodes represent some contraindication to surgical resection. To extend possibility of surgical treatment we undertook the following lines of research. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a potential alternative to mediastinoscopy to confirm or exclude lymph nodes metastases. Preliminary studies have demonstrated that it may lead to improvement in the results of N-staging decreasing the morbidity correlated to mediastinoscopy. The aim of this study is to assess the effectiveness and safety of EBUS-TBNA in staging NSCLC patients. Advanced emphysema is frequently associated with lung cancer and can impede surgical treatment. New therapeutic strategies such as bronchoscopic lung volume reduction (BLVR) have been developed recently. The goal of BLVR is to obtain a functional improvement by endoscopically-positioning one-way endobronchial valves which divert ventilation from the emphysematous areas to more normal lung regions. The aim of this study is to assess the results of BLVR in terms of post-treatment morbidity and improvement of respiratory function aimed to perform surgery on patients affected by NSCLC. Advanced age and associated cardiac and pulmonary diseases may however be a contraindication to surgical treatment. The aim of the study is to assess the results of new treatment-strategies as percutaneous radiofrequency thermoablation and tomotherapy, a recently-developed radiotherapy technique, in patients with earlystage NSCLC with a contraindication to surgical treatment. Surgical resection both for colorectal and renal cancer lung metastases are well-accepted treatment modalities. Identification of new tumor markers to supplement clinical and pathological staging may make possible to identify those patients with lung metastases from colorectal and renal cancer at highest risk of recurrence following surgery. The aim of this study is to evaluate the use of immunohistochemical analysis to assess the prognostic value of some tumor markers (microsatellite instability and S100a4 protein) in colorectal and renal cancer metastases. Piero Zannini ONCOGENESIS IN LIVER NEOPLASMS UNIT The Hepatobiliary Unit is a multidisciplinary clinical unit where the traditional gap between physicians and surgeons has been overcome to reach the optimal standards of patient care. Indeed, the medical staff includes hepatologists and hepatobiliary surgeons who share their specific competences to treat in an unique environment both “internal” and “surgical” patients. Clinical activities are mainly focused on hepatobiliary tumors and chronic liver diseases, including primary (hepatocellular carcinoma and cholangiocarcinoma) and metastastic liver tumors (mainly liver metastases from colorectal cancer), liver cirrhosis and related complications (portal hypertension, ascites, esophageal varices), benign and malignant diseases of the biliary tract, acute and chronic hepatitis. As far as concern liver tumors, the research activities are mainly focused on the outcome (in term of overall survival and disease-free survival) of patients affected by liver metastases from colorectal cancer and treated by surgery and adjuvant/neoadjuvant chemotherapy. Studies regarding the prognostic factors of survival after surgery and the impact of locoregional chemotherapy on the outcome after surgery have been published (World J Surg, Ann Surg Oncol). Among the speculative studies about the liver metastases from colorectal cancer, the hepatobiliary unit have been involved in cooperative protocols of study with the unit of Unit of Immuno-biotherapy of Melanoma and Solid Tumors (Prof. Parmiani). Surgical specimens have been collected after liver resection for colorectal liver metastases to characterize the expression of OX40 and 4-1BB on peripheral blood lymphocytes and in tumor and lymphoid tissue of oncological patients. The study has ended the phase of case collection and it is still ongoing as far as concern the final results. Further cooperative studies about carcinogenesis in patients affected by hepatocellular carcinoma and HCV infection are under evaluation at the present time. Gianfranco Ferla 18 - SAN RAFFAELE SCIENTIFIC INSTITUTE ONCO-HEMATOLOGY UNIT The San Raffaele Onco-Hematology Group of Clinical Research Oncology Department is active in basic research, clinical research and routine patient care for acute leukemias, myelodisplasia, mieloproliferative disorders, and myelomas. One of our main goals is implementation of Investigator-Initiated clinical research. To this purpose, the infrastructures comprise a clinical care facility with ISO-9001 accreditation comprising all the requirements for care of patients affected by acute and chronic leukemia’s, a bone marrow transplantation unit and a dedicated Day Hospital Unit. We participate and contribute to national and international disease networks (NILG, Gimema, Leukemianet). Clinical research is organized in Diseases Units. The clinical research activity in ongoing clinical trials is organized in several disease-specific master trials: NILG-AML master trial of the cooperative group NILG in AML at diagnosis; NILG-ALL 10/07 master trial of the cooperative group NILG in ALL patients at diagnosis with a systematic application of an MRD-oriented strategy to post remission therapies; salvage chemotherapy with clofarabine in relapsed AML; molecular bone marrow analysis at diagnosis to establish the predictive significance of disease persistence or relapse by MRD to tailor adoptive immunotherapy strategies post allogeneic bone marrow transplantation; MDS-WT1 trial with quantification of WT1 in bone marrow and peripheral blood at diagnosis to establish the predictive significance of disease persistence or relapse (MRD) to tailor adoptive immunotherapy strategies post allogeneic bone marrow transplantation; a trial using lenalidomide in multiple myeloma at diagnosis. Several trials with new drugs (perixafor, romiplostim, clofarabine, polo-like kinase inhibitor) are ongoing for advanced phase leukemias, myelomas and MDS. Fabio Ciceri PANCREATIC CANCER UNIT: BIOLOGY AND NEW THERAPEUTIC APPROACHES The Unit of Pancreatic Surgery during 2008 performed 168 resections, a surgical volume among the highest in Europe. These cases are a great source of data and material for every type of research in this field. Pancreatic ductal adenocarcinoma was the cause of resection in 98 patients. Pancreatic cancer is the fourth leading cause of cancer mortality in the Western world and, despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, little improvement in the outcome has been achieved. Complete surgical resection is considered the only therapy associated with a chance of cure, but 80 to 85% of patients have inoperable disease at the time of initial diagnosis. Furthermore, even in the favourable prognostic group of patients undergoing resection, 5-year survival is around 15-20%. To improve discouraging present results, different new therapeutic strategies are under evaluation at our unit. The first one is a more effective adjuvant therapy: preliminary results of a prospective randomised trial comparing standard Gemcitabine with 4-drugs combination therapy showed a benefit in disease-free survival in favour of new combination therapy (1-year disease-free survival 65% versus 46%). Further, we analyzed the timing and the sites of recurrence after resection to better understand the natural course of recurrent cancer: 192 patients with pancreatic cancer treated by resection between 1997 and 2007, strictly followed-up by CT scan every 3-4 months were reviewed. Recurrence was observed in 81.9% of patients, and distant metastases were the most frequent site of failure (72.1%), whereas local recurrence occurred in 46.1%. There was no difference in the timing of failure between distant (11.5 months) and local recurrence (12.2 months). These data suggest that: 1) pancreatic cancer is a systemic disease in most patients, even if it seems localized to the pancreas at preoperative imaging 2) the correct approach to adjuvant (or neoadjuvant) treatment is chemotherapy first, followed by radiotherapy. In order to improve the cure rate of resection, we are now planning a prospective multicenter study on a neoadjuvant approach to resectable/borderline pancreatic cancer. Valerio Di Carlo DIVISION OF MOLECULAR ONCOLOGY - 19 CLINICAL LYMPHOID MALIGNANCIES The scientific activity of our Unit is focused on the study of distinct forms of extranodal lymphomas, in particular ocular adnexal MALT lymphomas (OAML), primary central nervous system lymphoma (PCNSL) and intravascular large B-cell lymphoma (IVLBCL). We demonstrated that Chlamydophiila psittaci (Cp) is associated with development of OAML; immunoistochemistry, immunofluorescence and laser-capture microdissection-assisted PCR showed that monocytes/macrophages are carriers of this micro-orgainsm; electron microscopy showed the presence of intact Cp elementary bodies into these cells. Patients often presented a history of chronic conjunctivitis, resided in rural areas and prolonged contact with household animals. In the clinical setting, Cp-eradicating antibiotic therapy has been followed by lymphoma regression in a substantial proportion of OAML patients. High-dose methotrexate (HD-MTX)-based chemotherapy is the conventional approach to primary CNS lymphomas (PCNSL). A benefit of adding high-dose cytarabine (araC) to MTX has been suggested by a metaanalysis and a large retrospective series. We conducted an international randomized phase II trial comparing HD-MTX monochemotherapy versus HD-MTX plus HD-araC as primary chemotherapy in immunocompetent patients with PCNSL. This is the unique worldwide randomized trial in PCNSL patients with completed accrual. The addition of HD-araC to HD-MTX resulted in significantly better outcome and acceptable toxicity, thereby indicating MTX+araC as the standard chemotherapy approach to these patients. IVLBCL is a rare, aggressive and disseminated neoplasm, characterized by the absence of lymphoadenophaty and tumor masses and the localization of neoplastic cells within blood vessel. Each organ can be virtually involved by this malignancy. Using CHOP-based chemotherapy only 20% of patients are still alive at three years of follow-up. In the context of an international cooperation, we demonstrated that the addition of Rituximab, an anti-CD20 monoclonal antibody, to anthracycline-based chemotherapy improved the clinical outcome of these patients, with a 3-year overall survival of >80%. CNS was the principal site of IVL failure: the addition of drugs with a better CNS bioavailability is now under investigation. Andres J. M. Ferreri GYNECOLOGIC ONCOLOGY In 2008 the gynecology oncology unit has been involved in endometrial ovarian and trophoblastic tumor research in order to improve the quality of clinical activity. We studied biologic and clinical prognostic factors that may help the physician in decision making process. Endometrial Cancer: Definition of high risk stage I endometrial cancer and new prognostic factors as ploidy. The introduction of DNA ploidy in clinical practice reduced of about 70% the adiuvant treatment. We took part in a multicentric study which investigated the role of systematic lymphadenectomy in early stage endometrial cancer. Although systemic pelvic lymphadenectomy improved surgical staging it did not improve disease-free or overall survival. Ovarian Cancer: We took part in multicentric study (SOCRATES) which demonstrated that Mucinous ovarian carcinioma are less sensitive to platinum based chemiotherapy. We also work to improve quality of life of patients during chemotherapy treatment: We introduced the ice therapy to prevent EPP syndrome in patients treated with Liposomal doxorubicin. The use of ice packs around wrists and ankles is a simple and well tolerated prevention strategy. Much effort has been invested in order to preserve fertility in young patients submitted to gynecology surgery. Trophoblastic tumors were studied to evaluate the current clinical presentation that changed in the last 20 years. We introduced the intensive use of transvaginal ultrasound in the management of trophoblastic tumor. We are now able to reduce follow up period in patients with a strong desire of pregnancy. Giorgia Mangili 20 - SAN RAFFAELE SCIENTIFIC INSTITUTE MEDICAL ONCOLOGY UNIT - CLINICAL TRIALS The Unit is involved in clinical trials addressing the role of anti-neoplastic drugs and strategies in the therapeutic management of pancreatic, central nervous system (CNS), prostate, renal, colo-rectal, gastric, biliary tract, and breast cancer. Scientific activity regards also translational research and studies aimed to identify new prognostic and predictive biological markers. Regarding pancreatic cancer, scientific activity included: a) a single-institution phase II randomized trial comparing two different combination chemotherapy regimens as firstline treatment in advanced disease; b) a phase II trial randomizing patients with metastatic disease to receive maintenance therapy with sunitinib or observation and exploring the role of potential surrogate biomarkers; c) a study to individuate a proteomic profile predictive of the outcome of patients with advanced disease; d) a pharmacogenetic trial to assess the impact on the outcome of the SNPs involved in the metabolism of antiblastic agents administered in advanced disease; e) a series of trials testing the activity of different chemotherapy regimens as salvage therapy and contributing to identify prognostic variables; f) assessment of the role of radiotherapy (RT) after induction chemotherapy in stage III disease and of intra-operative RT in resected disease; g) a randomized phase II trial comparing two different adjuvant chemotherapy regimens. Regarding CNS tumors, ongoing trials are aimed at: a) identifying a proteomic profile able to predict the outcome of newly diagnosed glioblastoma multiforme treated by chemoRT (GBM); b) assessing the role of temozolomide associated to RT in newly diagnosed GBM in elderly patients; c) assesssing the role of cilengitide in association with standard chemoRT in newly diagnosed GBM and methylated MGMT gene promoter; d) assessing the role of temozolomide concurrent to RT and adjuvant in non-1p/19q deleted anaplastic glioma; e) analyzing the role of primary chemotherapy with temozolomide versus RT alone after stratification for 1p loss in diffuse astrocytoma; f) exploring the role of salvage therapy with temozolomide in pituitary neoplasms; g) exploring the role of salvage therapy with hydroxyurea alone or in combination with imatinib in meningiomas. Michele Reni MEDICAL ONCOLOGY UNIT - PHASE I AND LUNG CANCER CLINICAL TRIALS The research activity of our Unit has been focussed focusing on improving understanding the molecular mechanisms through which new and standard therapies are effective and induce specific toxicities and the pathways involved in drug resistance, with the aim of defining more personalized therapies. Phase I studies: Our experience with regards to Phase I studies started in 2003, with the new antiangiogenic molecule, NGR-h-TNF, which has been designed and tested originally at the DIBIT at our institution and then developed as first in man in clinical setting at our Department of Oncology. Since then, seven phase I studies have been conducted. We are currently improving our knowledge in pre-clinical drug development in order to potentiate and favor first in man studies. The research activity of the Lung Cancer group is divided into two main areas: no profit and pharmaceutical companies sponsored trials. Non profit trials are focussed on improving knowledge on molecular mechanisms related to new and standard therapies, specific toxicities and pathways of drug resistance for defining personalized therapies. Seven studies have been conducted in 2008: 1. ECD-EGFR study is a single institution study, monitoring serum extracellular EGFR domain during therapy with EGFR Tyrosin Kinase Inhibitors (TKIs) in NSCLC patients 2. A longitudinal proteomic single institution study is evaluating VeristratTM algorithm created and validated in collaboration with Vanderbilt University and University of Colorado Cancer Centre, and Biodesix Company Figure 1. Clinical benefit by plasma proteomic profile of patients with NSCLC treated with EGFR-Tki DIVISION OF MOLECULAR ONCOLOGY - 21 3. A proteomic profile evaluation was also conducted on 145 NSCLC patients treated with chemotherapy 4. Association between proteomic profile and clinical and known molecular features in NSCLC is ongoing 5. PROSE is a phase III multicentre Italian proteomic study created by our group and currently ongoing in 13 different Institutions. 76 out of 275 planned patients have already been enrolled in order to validate protemic profile as predictive factor for personalizing treatment between chemotherapy and EGFR-Tkis 6. Identification of underlying specific proteins of NSCLC patients Veristrattm proteomic profile is ongoing. Four out of 8 picks have been already identified. Vanesa Gregorc UROLOGICAL RESEARCH INSTITUTE (URI) In 2008 the main research areas consisted of: • Prostate cancer • Kidney cancer • Bladder cancer • Infertility and andrology • Female sexual medicine • Benign prostatic hyperplasia The clinical research relied on analyses of clinical, pathological and follow-up prospectively collected data regarding thousands of patients treated at San Raffaele Hospital. The records were collected within specific databases developed in the last years. Currently, the prostate cancer dataset consists of more than 5000 patients treated with a radical prostatectomy since 1986. The database includes information about diagnosis, surgery technique, pathological outcome, oncological follow up and quality of life. Such dataset represents one of the biggest and most accurate available databases. The kidney cancer database collects more than 1000 patients treated with either partial or radical nephrectomy for a kidney cancer. The bladder cancer database was recently developed and today it includes prospectively collected data regarding 700 patients treated with radical cystectomy. The Urogenital Research Institute holds unique opportunities within one single unit to address and investigate a variety of aspects of urogenital disorders (epidemiological, genetic, molecular, cellular, physiological, pharmacological, clinical) of immediate relevance for the individual patient as well as the community healthcare system. Adaptive evidence-based and parallel investigative functions and objectives have been established to study targets of disease, diagnosis, therapy, or prevention at multiple levels (genetic, proteonomic, cellular, tissue, intact biological systems). The operational structure with several integrated methodological processes “door-to-door” within one research unit not only optimizes the access to and utility of, but also improve cost benefit ratio to function of the core facilities (expertise, technical platform) that belong to the Urogenital Research Institute. This structure is further aimed to produce an inspiring scientific environment that unifies clinical research and basic science in urology and urological pharmacology. Francesco Montorsi 22 - SAN RAFFAELE SCIENTIFIC INSTITUTE Preclinical models of cancer Molecular histology and cell growth Unit Tumor biology and vascular targeting Unit Pancreatic cancer Unit: biology and new therapeutic approaches URI – Urological Research Institute DIVISION OF NEUROSCIENCE - 23 DIVISION OF NEUROSCIENCE Director: Gianvito Martino Associate Director: Flavia Valtorta * Research Units Neuropsychopharmacology Unit HEAD OF UNIT: Flavia Valtorta* POST-DOCTORAL FELLOW: Francesca Botti PHD STUDENTS: Serena Bellani**, Eugenio Fornasiero** FELLOW: Laura Perlini TECHNICIANS: Marta Monari, Giuseppina Sessa Cell adhesion Unit HEAD OF UNIT: Ivan De Curtis* POST-DOCTORAL FELLOWS: Manuela Gavina, Roberta Pennucci PHD STUDENTS: Claudia Asperti**, Antonio Totaro** FELLOWS: Veronica Astro, Luisa Micheletti TECHNICIANS: Sara Corbetta, Simona Paris Cellular and molecular neurobiology Unit HEAD OF UNIT: Jacopo Meldolesi* RESEARCHER: Paola Podini PHD STUDENT: Ilaria Prada** FELLOW: Rosalba D’Alessandro TECHNICIANS: Anna Lorusso, Gabriella Racchetti Cellular neurophysiology Unit HEAD OF UNIT: Fabio Grohovaz* RESEARCHER: Daniele Zacchetti PHD STUDENTS: Barbara Bettegazzi**, Romina Macco**, Ilaria Pelizzoni** FELLOW: Alessandra Consonni** TECHNICIAN: Franca Codazzi Developmental neurogenetics Unit HEAD OF UNIT: Gian Giacomo Consalez POST-DOCTORAL FELLOW: Paola Zordan PHD STUDENTS: Ilaria Albieri**, Valeria Barili**, Giovanna Calabrese, Giacomo Masserdotti TECHNICIANS: Aurora Badaloni, Laura Croci Neurobiology of learning Unit HEAD OF UNIT: Antonio Malgaroli* RESEARCHER: Vincenzo Zimarino POST-DOCTORAL FELLOW: Maddalena Ripamonti PHD STUDENT: Marcello Belfiore** FELLOWS: Mattia Ferro, Laura Tambani Proteomics of iron metabolism Unit HEAD OF UNIT: Sonia Levi* RESEARCHERS: Anna Cozzi, Paolo Santambrogio PHD STUDENT: Alessandro Campanella** FELLOW: Elisabetta Rovelli 24 - SAN RAFFAELE SCIENTIFIC INSTITUTE Molecular genetics of mental retardation Unit (Dulbecco Telethon Institute) GROUP LEADER: Patrizia D’Adamo POST-DOCTORAL FELLOW: Maila Giannandrea PHD STUDENT: Veronica Bianchi Neural degeneration Unit (Dulbecco Telethon Institute) GROUP LEADER: Manolis Fanto PHD STUDENTS: Piera Calamita**, Ilaria Nisoli**, Simona Occhi FELLOW: Francesco Napoletano Stem cells and neurogenesis GROUP LEADER: Vania Broccoli RESEARCHER: Nicoletta Landsberger PHD STUDENTS: Gaia Colasante**, Serena Giannelli**, Dionigio Prodi, Alessandro Sessa FELLOWS: Bruno Di Stefano,Sara Lopalco, Sara Ricciardi, Federica Ungaro Clinical Research Units Acute brain protection, Acute post-operative pain, Drugs and Central Nervous System Unit HEAD OF UNIT: Luigi Beretta* PHYSICIANS: Maria Rosa Calvi, Assunta De Vitis, Marco Gemma, Davide Poli Eye repair Unit HEAD OF UNIT: Paolo Rama PHYSICIANS: Paolo Bettin, Stefania Bianchi Marzoli, Marco Codenotti, Ugo Introini, Rosangela Lattanzio, Gisella Maestranzi, Giulio Modorati, Luisa Pierro RESIDENTS: Umberto De Benedetto, Federico Di Matteo, Silvia Giatsidis, Laura Regali CONSULTANTS: Carlo Ciampi, Annalisa Colucci, Marco Gagliardi, Maria Pia Manitto, Elena Mantovani, Lisa Melzi, Elisabetta Miserocchi, Andrea Ramoni, Fabrizio Scotti, Marco Setaccioli, Alessandra Spinelli, Gemma Tremolada TECHNICIANS: Giorgio Alto, Alessio Buzzotta Cognitive neuroscience Unit HEAD OF UNIT: Stefano F. Cappa* RESEARCHERS: Jubin Abutalebi*, Andrea Moro* PHYSICIANS: Maria Cristina Giusti, Sandro Iannaccone, Marco Lacerenza Alessandra Marcone, Michele Zamboni POST-DOCTORAL FELLOWS: Pasquale Della Rosa, Nicola Canessa PHD STUDENTS: Federica Alemanno**, Eleonora Catricalà, Monica Consonni**, Rosa Manenti Experimental neurosurgery Unit HEAD OF UNIT: Pietro Mortini* PHYSICIANS: Lina Raffaella Barzaghi, Nicola Boari, Alberto Franzin, Marco Losa, Carlo Mandelli, Piero Picozzi POST-DOCTORAL FELLOWS: Olga Passarin, Marco Riva PHD STUDENT: Silvia Snider** RESIDENTS: Luca Attuati, Paola Castellazzi, Filippo Gagliardi, Marzia Medone, Davide Milani, Alda Rocca, Carlo Serra Functional neuroradiology Unit HEAD OF UNIT: Andrea Falini PHYSICIANS: Nicoletta Anzalone, Cristina Baldoli, Valeria Blasi, Silvia Pontesilli, Roberta Scotti, Paolo Vezzulli PHD STUDENT: Monia Cabinio** RESIDENTS: Antonella Castellano, Elisa Scola TECHNICIAN: Antonella Iadanza** DIVISION OF NEUROSCIENCE - 25 In vivo Human molecular and structural neuroimaging Unit HEAD OF UNIT: Daniela Perani* RESEARCHERS: Chiara Agosta, Barbara Borroni, Assunta Carpinelli, Isabella Castiglioni, Mario Matarrese, Rosa Maria Moresco, Alessandro Padovani, Paola Scifo, Marco Tettamanti POST-DOCTORAL FELLOWS: Valentina Garibotto, Cristina Saccuman FELLOWS: Paola Buffo, Danilo Spada TECHNICIAN: Maria Grazia Minotti Neuroothology Unit HEAD OF UNIT: Mario Bussi* PHYSICIAN: Lucia Oriella Piccioni CONSULTANTS: Fabrizio Ferrario, Roberto Teggi Psychiatry and clinical neurosciences Unit HEAD OF UNIT: Francesco Benedetti Psychiatry and clinical psychobiology HEAD OF UNIT: Francesco Benedetti RESEARCHERS: Sara Angelone, Cinzia Arancio, Barbara Barbini, Laura Bellodi*, Laura Bianchi, Marco Catalano, Roberto Cavallaro, Maria Cristina Cavallini, Paolo Cavedini, Federica Cocchi, Cristina Colombo, Stefano Erzegovesi, Linda Franchini, Marco Locatelli, Adelio Lucca, Giampaolo Perna, Ernestina Politi, Laura Sforzini, Raffaella Zanardi FELLOWS: Simona Anselmetti, Margherita Bechi, Alessandro Bernasconi, Sara Dallaspezia, Danilo Dotoli, Mara Cigala Fulgosi, Cristina Lorenzi, Elena Marino, Adele Pirovano, Adriana Pontiggia RESIDENTS: Marta Bosia, Eugenia Fauci, Laura Liperi, Alessia Malaguti, Fausto Panigada, Chiara Ruffini Sleep medicine CLINICAL GROUP LEADER Luigi Ferini-Strambi* RESEARCHERS: Mauro Manconi, Alessandro Oldani, Marco Zucconi Clinical psychology CLINICAL GROUP LEADER: Cesare Maffei* RESEARCHERS: Andrea Fossati*, Mariagrazia Movalli, Laura Vanzulli, Raffaele Visintini PHD STUDENTS: Francesco Fresi, Sara Poletti FELLOW: Serena Borroni RESIDENTS: Roberta Alesiani, Ilaria Aina, Silvia Boccalon, Alessandra Bosaia, Naima Coppolino, Cinzia Facchi, Gianluca Franciosi, Roberta Gallese, Laura Giarolli, Valeria Parlatini, Maria Monica Ratti, Caterina Antonia Eloisa Rocco di Torrepadula, Erica Rossi, Martina Testa Motor function rehabilitation HEAD OF UNIT: Alessandra Raschi CLINICAL GROUP LEADER: Roberto Gatti PHYSICAL THERAPIST: Andrea Tettamanti 26 - SAN RAFFAELE SCIENTIFIC INSTITUTE INSPE, Institute of Experimental Neurology Director: Giancarlo Comi* Research Units Experimental neurology Unit HEAD OF UNIT: Giancarlo Comi* Experimental neuropathology GROUP LEADER: Angelo Quattrini PHYSICIANS: Maurizio De Pellegrin, Marina Scarlato PHD STUDENTS: Patrizia Dacci, Nilo Riva** FELLOW: Daniela Triolo RESIDENT: Federica Cerri TECHNICIAN: Giorgia Dina Experimental neurophysiology GROUP LEADER: Letizia Leocani BIOENGINEER: Marco Cursi PHD STUDENTS: Ninfa Amato**, Marco Cambiaghi**, Alberto Inuggi, Kara Sinem, Svetla Velikova FELLOW: Javier Gonzalez-Rosa RESIDENTS: Mariangela Bianco, Raffaella Chieffo, Francesca Spagnolo, Laura Straffi TECHNICIAN: Samantha Guzzoni Molecular genetics of behaviour GROUP LEADER: Riccardo Brambilla PHD STUDENTS: Angela D’Antoni, Raffaele D’Isa**, Daniel Orellana**, Alessandro Papale** FELLOW: Stefania Fasano TECHNICIAN: Marzia Indrigo Neuromuscular repair GROUP LEADER: Stefano C. Previtali POST-DOCTORAL FELLOW: Domi Teuta PHD STUDENT: Emanuela Porrello** RESIDENT: Ignazio Diego Lopez TECHNICIAN: Isabella Lorenzetti Neuroimmunology Unit HEAD OF UNIT: Gianvito Martino RESEARCHER: Luca Muzio POST-DOCTORAL FELLOW: Erica Butti PHD STUDENTS: Cecilia Laterza**, Cinzia Marinaro**, Annamaria Nigro** TECHNICIANS: Andrea Bergamaschi, Alessandra Bergami, Elena Brambilla Clinical neuroimmunology GROUP LEADER: Roberto Furlan PHD STUDENTS: Marianna Esposito, Chiara Maiorino RESIDENT: Dacia Dalla Libera TECHNICIANS: Francesca Ruffini CNS repair GROUP LEADER: Stefano Pluchino PHD STUDENTS: Chiara Cossetti, Melania Cusimano, Elena Giusto, Lucia Zanotti RESIDENTS: Marco Bacigaluppi, Luca Peruzzotti Jametti TECHNICIAN: Giuliana Salani DIVISION OF NEUROSCIENCE - 27 Neuroimaging research Unit HEAD OF UNIT: Massimo Filippi BIOENGINEERS: Elisabetta Pagani, Paola Valsasina RESIDENTS: Martina Absinta, Sebastiano Galantucci, Elisabetta Stefania Perego FELLOWS: Federica Agosta**, Antonella Ceccarelli, Giulia Longoni, Michela Pievani**, Stefania Sala** TECHNICIANS: Luca Dall’Occhio, Alessandro Meani, Melissa Petrolini, Roberto Vuotto Neuroimaging of CNS white matter GROUP LEADER: Maria Assunta Rocca FELLOW: Valeria Barcella PHD STUDENT: Gianna Riccitelli** TECHNICIANS: Paolo Misci, Mauro Sibilia Human inherited neuropathies Unit (Dulbecco Telethon Institute) HEAD OF UNIT: Alessandra Bolino PHD STUDENTS: Annalisa Bolis, Silvia Coviello, Ilaria Vaccari FELLOWS: Enrico Fragasso, Lara Piantoni TECHNICIAN: Patrizia Cassella Axo-Glia interactions Unit (FISM) GROUP LEADER: Carla Taveggia POST-DOCTORAL FELLOWS: Amelia Trimarco FELLOWS: Alberto Monti TECHNICIANS: Rosa La Marca Clinical Research Units Inflammatory CNS disorders Unit HEAD OF UNIT: Vittorio Martinelli RESEARCHERS: Filippo Martinelli-Boneschi, Lucia Moiola, Mariaemma Rodegher PHYSICIAN: Paolo Rossi PHD STUDENTS: Federica Esposito**, Marta Radaelli** RESIDENTS: Sebastiano Bucello, Elda Judica Cerebrovascular disorders CLINICAL GROUP LEADER: Maria Sessa RESEARCHER: Francesco Corea PHYSICIANS: Silvia Mammi, Antonella Poggi, Luisa Roveri PHD STUDENTS: Grazia Nuzzaco**, Maria Carmela Spinelli** RESIDENTS: Chiara Ghidinelli, Sara La Gioia Memory Disorders CLINICAL GROUP LEADER: Giuseppe Magnani RESIDENTS: Francesca Caso, Eliana Schiatti, Chiara Vismara Movements disorders CLINICAL GROUP LEADER: Ubaldo Del Carro PHYSICIANS: Stefano Amadio, Roberta Guerriero, Stefania Medaglini, Maria Grazia Natali Sora, Maria Antonietta Volontè RESIDENTS: Calogera Butera, Daniela Ceppi, Luisa De Toni Franceschini, Habtom Tesfaghebriel, Daniela Ungaro Neuromuscular disorders CLINICAL GROUP LEADER: Raffaella Fazio PHD STUDENT: Daniela Privitera** Paroxysmal events CLINICAL GROUP LEADER: Fabio Minicucci PHYSICIANS: Bruno Colombo, Giovanna Franca Fanelli, Fabio Formaglio, Paolo Marchettini RESIDENTS: Beatrice Benedetti, Francesca Fumagalli, Giulia Pavan, Francesco Peschechera * Professor at: Università Vita-Salute San Raffaele ** Università Vita-Salute San Raffaele 28 - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Directors The Division of Neuroscience is made up of 369 scientists – rostered in 21 basic research units and 17 clinical research groups – whose scientific endeavours are described under the sections dedicated to each Unit. The clinical research groups are affiliated to three clinical departments: the Dept. of Neurology, the Dept. of Clinical Neuroscience and the Dept. of Head and Neck, whereas the units involved in translational medicine (11 basic research units and 6 clinical research groups) form the Institute of Experimental Neurology (INSPE). Gianvito Martino Members of the Division are part of the faculty of the Schools of Medicine, Biotechnology, Psychology and Philosophy. In addition, the Division is actively involved in the training of graduate students, organizing Ph.D. Courses in Neuroscience, Experimental Neurology, Neurobiotechnology, Developmental Psychopathology, and taking part in the Ph.D. Course in Cellular and Molecular Biology. The scientific interests in the Division are wide, and range from the molecular analysis of brain development and function to the development and validation of novel therapeutic approaches for neurological and psychiatric disorders. Since the beginning, the final aim of the Division has been the integration of basic research with clinical applications. Given the diverse backgrounds of the scientists affiliated to the Division, considerable effort has been dedicated to the creation of a scientific community, by implementing divisional seminars and journal clubs and by organizing the research units into four thematic areas, i.e. development and plasticity, molecular and cellular neuroscience, neurobiology of diseases, and cognitive and systems neuroscience. During the past year research has developed along a variety of lines, all within the long-term goal of enhancing our comprehension of the normal function of the brain and discovering cures for the nervous system ravaged Flavia Valtorta by disease. The following main themes can be identified: (i) understand the healthy nervous system; (ii) understand neurological and psychiatric diseases; (iii) enable early and routine diagnosis of neurological and psychiatric conditions; (iv) develop new therapeutic strategies; (v) accelerate the process of therapy development; (vi) develop new technologies for observing the nervous system; and, (vii) develop new strategies to probe neural functions. Two interdivisional research programs which see the primary involvement of the Division of Neuroscience have been planned and designed and will be implemented in the next years: BRAINMAP (HUMAN BRAIN IN-VIVO MAPPING WITH NEUROIMAGING) BRAINMAP develops, in the field of basic technology research, and applies, in that of clinical research, conventional as well as novel neuroimaging techniques for the evaluation of the physiological maturation and aging processes of the CNS and the assessment of the different pathological substrates of the main neurological and psychiatric diseases. BRIDGE (BRAIN REGENERATION USING MEDICAL DEVICES, GENE VECTORS, AND STEM CELLS) BRIDGE exploits premiere knowledge derived from state-of-the-art stem cell and gene therapy trials to be conducted in our Institute for a number of inflammatory and neurodegenerative conditions. It also combines powerful new stem cell isolation and gene transfer approaches to state-of-the-art neuroimaging, immunological and neurophysiological readouts to test new therapeutic strategies in relevant animal model of neurodegenerative diseases. DIVISION OF NEUROSCIENCE - 29 Research Units NEUROPSYCHOPHARMACOLOGY UNIT Comprehensive goal of our research is the elucidation of the molecular mechanisms which underlie communication between cells of the brain, both in the adult and during development. The main form of communication between neurons is achieved through regulated secretion of neurotransmitter occurring at synapses. This process is therefore of paramount importance for information processing in the central nervous system and is known to be deranged in a number of pathological states. Research in our group has focused on two main topics: 1) Diseases of synaptic origin The main focus has been on the family of the synapsins and their link to epilepsy. Synapsins are a family of brain phosphoproteins involved in neurotransmitter release through regulation of synaptic vesicle availability. Synapsin KO mice develop an epileptic phenotype, and mutations in the human synapsin I gene has been recently associated with epilepsy. We have completed the study of the molecular mechanisms by which the reported mutation in the human SYN1 gene leads to the development of an epileptic phenotype. We have also found that networks formed by synapsin KO neurons are characterized by hyperexcitability, which is due to both enhancement in excitatory transmission and impairment in inhibitory transmission. In addition, KO mice show cognitive impairment and behavioral abnormalities which worsen with age. 2) Membrane trafficking in neuronal development, The process that leads from undifferentiated, round neuronal precursors to fully differentiated, highly polarized neurons is extremely complex. Among the various phenomena which drive this process, those associated with membrane trafficking are of fundamental importance, but are as yet poorly characterized. We are interested in studying membrane trafficking in the very early steps of neuronal development. In this respect, we have identified a process of developmentally-regulated, high-capacity endocytosis as one of the earliest marker of neuronal polarity. In the next future, we will investigate the possible causative role of such process in driving neuronal differentiation and its contribution to axonal navigation and pathfinding. Flavia Valtorta Figure 2. Axonal growth cone of a live embryonic hippocampal neuron in culture showing intense endocytic activity (red, uptake of the lipophilic dye FM4-64) 30 - SAN RAFFAELE SCIENTIFIC INSTITUTE CELL ADHESION UNIT Molecular networks for the regulation of cell motility Rho GTPases are implicated in cell motility and neuronal differentiation. We have shown that two Rac genes are needed for neuronal and mammalian brain development. For this, we obtained 3 lines of mice with mutation in the Rac3 gene (Rac3 KO), conditional mutation of Rac1 in neurons (Rac1N), or mutation of both GTPases (Rac3 KO/Rac1N). Rac3KO and Rac1N mice develop normally, while double KO mice are heavily impaired neurologically (ataxic, uncoordinated, epileptic). Morphological analysis has revealed alterations in the hippocampal organization, with lack of most hilar mossy cells, an important class of excitatory interneurons. Dendrites, axons and synapses are strongly reduced in the dentate gyrus, suggesting that the alteration of hippocampal synaptic connectivity underlies the neurological defects observed. We have also compared synaptic development in hippocampal cultures from wild-type, single, and double KO mice. Depletion of both Rac genes strongly impaired synaptic formation by affecting the development of dendritic spines, while neurons lacking either Rac were either normal or slightly affected. These results reinforce the notion that two Rac genes are required for late neuronal development in mammals. The multi-molecular GIT complexes are involved in the regulation of cell migration. These complexes are assembled by the multi-domain proteins GIT1 and GIT2, which functionally interacts with Arf and Rac GTPases. We found that GIT1 interacts also with Liprin-α’s, a family of adaptor proteins involved in the assembly of neuronal synapses and in the organization of focal adhesions. We found that Liprin-α1 interacts with the carboxy-terminal portion of GIT1, and competes with paxillin for binding to GIT1. Expression of Liprin enhances cell spreading, while its downregulation prevents spreading and formation of lamellipodia. Analysis in cell cultures including time-lapse imaging on living cells has shown that Liprin affects the dynamics of endogenous β1 integrins activation and focal adhesion formation at the cell edge, thus regulating cell motility. The comprehensive molecular/cellular analysis performed by us has established Liprin-α as a novel essential regulator of cell motility and of invasion by tumor cell lines. Ivan de Curtis Figure 3. Liprin-α1 expression (green) induces enhanced cell spreading on fibronectin and the redistribution of activated β1 integrin receptors (red) CELLULAR AND MOLECULAR NEUROBIOLOGY UNIT Membrane traffic and neurosecretion expression in nerve cells Our research was developed along two main line. First, we have pursued the investigation of the enlargeosomes, the exocytic organelles discovered in the lab in 2002, working on the defective neurosecretory cell clone PC12-27. In the meantime this organelle has been shown to be expressed by many, but not all types of cells, neurosecretory and non-neurosecretory. The main step forward of this year has been the identification of DIVISION OF NEUROSCIENCE - 31 VAMP4 as the vSNARE specific for their exocytosis. This results is important because VAMP4 was believed to be involved only in the membrane traffic in the Golgi-TGN area and in endocytosis. In contrast, it had never been identified in exocytoses. Therefore enlargesomes appear as the only organelles employing VAMP4 for this process. Based on this consideration we have already started to use VAMP4 as a marker of the involvement of enlargeosomes in physiological processes such as neurite outgrowth. In addition, we have continued the study of the specific plasma membrane patches that result from the exocytosis of enlargeosomes involved in the generation of small shedding vesicles released to the extracellular space upon cell stimulation. These vesicles, that appear to play an essential role in the horizontal transfer of proteins and nucleic acids, are now recognized to participate in physiological and pathological processes, incuding tumor spreading. Our second line concerns the transcription repressor REST. We have shown that this factor controls neurosecretion. Neurons and wt neurosecretory cells, such as PC12, have low levels of REST. If the level is increased, neurosecretion tends to disappear. Conversely, when the level was decreased in the defective clones PC12-27 and PC12-Trk, which are rich of the factor, neurosecretion was found to reappear.These results might be of great importance in the study of diseases, such as type 2 diabetes, in which the activity of a neurosecretory cell type is diminished, and in various tumors that are known to be sustained in their growth by a defect of REST. We have also initiated the study of REST function showing that it depends not only on its level, but also on the modulation of its activity by a protein participating in one of its effector complexes. Jacopo Meldolesi CELLULAR NEUROPHYSIOLOGY UNIT Physiopathological mechanisms in neuroprotection and neurodegeneration Neurodegenerative pathologies are a great and growing social problem, with Alzheimer’s disease representing the most frequent form of degenerative dementia. Our research is aimed to understand the balance between neuroprotection and neurodegeneration under physiological and pathological conditions. BACE1 is the β-secretase responsible for the production of the neurotoxic amyloid-β peptide that accumulates in the brain of patients affected by Alzheimer’s disease. We have investigated the complex mechanisms that control transcription (effect of growth factors), translation (phosphorylation state of initiation factors) and activity (modulation of amyloid-β production) of the endogenous BACE1 in brain and primary cultures from brain. We have also found that astrocyte-derived amyloid-β is produced by the action of BACE2, the BACE1 homolog, and that this production is modulated by the activation state of the astrocytes. We started a characterization of the molecular mechanisms of astrocyte activation by investigating: different protocols of stimulation leading to specific phenotypes; the underlying intracellular pathways; the upregulation of proteins and the release of molecules in the extracellular milieu. A parallel research line investigated in primary cultures of neurons and astrocytes, the neurotoxic role of iron accumulation. We studied the pathways of iron entry, iron-mediated ROS accumulation, Ca2+ changes and cell death. Our results indicate that iron can enter neurons through both Voltage Operated Calcium Channels (VOCCs) and, during strong synaptic activity, NMDA receptors. Our results also indicate that mitochondria are the main target of iron toxicity and that defense mechanisms are less efficient in primary cultures than in all brain-derived cell lines analyzed. Interestingly, activation of astrocytes by exposure to proinflammatory cytokines, enhances the resistance to oxidative stress. We are currently studying the effects mutations in the ferritin light chain (inherited in the hereditary neuroferritinopathy disease) have in iron control and overall neuronal survival (in collaboration with the Proteomics of iron metabolism Unit). Fabio Grohovaz DEVELOPMENTAL NEUROGENETICS UNIT From in vivo lineage analysis to neural stem cell manipulation Our laboratory focuses on neurogenesis during embryonic development and is moving into the field of neural regeneration. During embryonic development, neurogenesis requires a perfect balance between mechanisms that support self-renewal of undifferentiated progenitors and others that push progenitors towards commit- 32 - SAN RAFFAELE SCIENTIFIC INSTITUTE ment and post-mitotic differentiation. The mammalian cerebellum is a perfect example of this: in the mouse, cerebellar neurogenesis starts on embryonic day 11 and is completed only around postnatal day 20, featuring repeated events of self-renewal, cell fate determination, clonal expansion and neuronal migration. Numerous spontaneous and induced mutations are providing precious information on the molecular mechanisms that regulate these phenomena, and on their links with human diseases of the cerebellum. Our group is contributing to this knowledge with studies of cerebellar patterning (Masserdotti et al, submitted), cerebellar cortical boundary formation (Croci et al., 2006, Chung et al, 2008), cerebellar GABAergic neurogenesis and Purkinje cell specification (Zordan et al., 2008, Zordan et al., in progress), and of Purkinje cells survival (Croci et al., submitted). Furthermore, we have contributed to the characterization of a novel type of neural stem cells (Calabrese et al., submitted) to attempt to recapitulate in vitro the regulatory cascade that govern cerebellar neurogenesis in vivo. We are now planning to put our experience to task in order to assess the ability of in vitro implemented neural stem cells to integrate into the postnatal cerebellum of wild type mice and models of cerebellar ataxias. Gian Giacomo Consalez Figure 4. A Purkinje neuron (green) whose progenitor was labeled indelibly during early cerebellar development by activation of a genetic tag. This approach makes it possible to uncover the lineage relationships between early progenitors and mature neurons, as well as between different neuronal types. This information is a pre-requisite for the rational manipulation of neural stem cells and for the generation of specific mature neurons in vitro. NEUROBIOLOGY OF LEARNING UNIT A novel family of indicators to monitor synaptic activity in vivo One of the most fascinating avenue in neuroscience is to find a more informative way to correlate behavior to specific patterns of synaptic activity in subgroups of brain cells. As imaginable, besides addressing the functional wiring of the brain and understanding the basis of complex behaviors, this line of research would facilitate the detection of several types of brain diseases in their early phases, when brain morphology is still fully intact but somewhere in the brain an anomalous state of activity is already present. The most refined electrophysiological techniques available today can directly sample electrical activity with very high fidelity but their readout is limited to one or just a few neuronal cells. Therefore most of our current knowledge about brain activity and the functional wiring of behavior comes from certain modalities of recordings (functional brain imaging techniques) whose readout is more global, although, unfortunately, distantly related to the most important parameter i.e. neuronal and synaptic activity. In addition they do not provide the necessary spatial resolving power to study small brain circuits which are made of neurons (10 -100 ?m) and their synapses (200 nm - 1 ?m). In line with this idea our laboratory is currently developing a series of innovative genetically encoded indicators that can be used to report synaptic trasmission both in vitro and in vivo. These new tools are based on the expression of engineered synaptic constructs which have been assembled starting from the moiety of the vesicular protein VAMP2 with the insertion at the intraluminal ending of an aminoacidic cassette which contains a sequence recognized by a bait, a small peptide of ~ 4 KDa conjugated with a fluorophore. When these constructs DIVISION OF NEUROSCIENCE - 33 are expressed in neurons they are sorted to synaptic vesicles which are fusion competent and can take up in an activity dependent manner the fluorescent bait from the extracellular environment. The specificity and the signal to noise ratio of these tools are both extremely high and synaptic activity can be visualized in cultured neurons but more importantly in brain slices and in the vivo brain. We believe that the confluence of advances in these genetically encoded indicators with modern optical imaging will soon allow the in-vivo imaging of activity in defined neuronal ensembles in the brain of freely behaving animals. Antonio Malgaroli PROTEOMICS OF IRON METABOLISM UNIT The role of iron in neurodegenerative disorders Neurodegenerative diseases with brain iron accumulation are a group of extrapyramidal disfuctions characterized by radiographic evidence of excessive brain iron content. We are investigating the patophysiological mechanisms leading to two of these disorders: Neuroferritinopathies, which are dominant movement disorders associated to mutations on the L-ferritin and the Pantothenate Kinase Associated Neurodegeneration (PKAN), the disease with the highest brain iron accumulation, associated with several mutations in the Pantothenate Kinase 2 (Pank2) gene. We produced cellular HeLa stable clones and the lentiviral-transduced SH-SY5Y neuroblastoma cells expressing L-ferritin (Lwt) and variants causing neuroferritinopathies. The L-variants expression caused a lower efficiency in ferritin iron incorporation, determining the cellular iron homeostasis alteration. In HeLa cells the deregulation of iron homeostasis determined a modification of cellular oxidative status related to cells apoptosis, while the SH-SY5Y appeared to be subjected to necrosis after treatment with iron. As occurs in patients, the variants clones showed ferritin and iron aggregates and a strong decrease in proteasomal activity respect to the Lwt cells. The aggregates formation seemed not to be responsible for cells death while they appear an epiphenomenum of the increased oxidative stress. The L-ferritin pathogenic mutations act in a dominant-negative way on ferritin functionality, indicating that the disorder is linked to iron deregulation, rather than being a protein conformational disease. To investigate the link between the PKAN defect and iron accumulation we analyzed skin fibroblasts from three PKAN patients compared with three healthy controls. Fibroblasts from three patients showed differences in iron manipulation during prolonged mild iron supplementation, with a reduced ferritins up-regulation and minor Transferrin Receptor 1 down-regulation. Defective modulation of these proteins reflected abnormalities in the cytosolic Labile Iron Pool and consequent higher ROS generation. Our data propose that all Pank2 mutations affect cellular iron homeostasis and that the severity of the defects probably relies on the specific mutations that differently influence activity and protein length. Sonia Levi MOLECULAR GENETICS OF MENTAL RETARDATION UNIT Lack of aGDI causes a defect in synaptic vesicle recycling responsible for cognitive impairment and altered social behaviour in Gdi1 knockout mice Our research is focused on the understanding of the molecular causes leading to Retardation (MR), a common cause of inherited intellectual disability in the human population, with a reported prevalence of about 0,91,4/1000 males. Mutations in GDI1 are responsible for X-linked MR. Gdi1 knock out (Gdi1 KO) mice were generated and they are viable and fertile and did not present visible morphological or neuropathological alterations. They are impaired in associative memory detected with two hippocampus dependent tests: the radial maze and trace fear conditioning. They also showed inappropriate social behaviour, when tested in the resident-intruder paradigm, they lacked any sign of aggressive behaviour and they displayed signs of a friendly interaction with the intruder. The behavioural deficits showed that Gdi1 KO have specific and limited dysfunctions of hippocampal formation and amygdala. 34 - SAN RAFFAELE SCIENTIFIC INSTITUTE αGDI is one of the proteins controlling the activity of small GTPases of the Rab family in intracellular trafficking. Gdi1 KO mice presented alterations in a specific set of few Rab whose amount and intracellular distribution appeared altered in KO brain extracts. The functional impact of Gdi1 deletion on short-term plasticity at CA1 excitatory synapses of the hippocampus, showed that under a prolonged high-frequency stimulation of Shaffer collateral induces a stronger synaptic facilitation in KO synapses, followed by a depressing phase. The subsequent recovery from depression was significantly slowed down in KO, suggesting an impairment in synaptic vesicles (SV) recruitment possibly related to the marked reduction in the SV reserve pool. Hippocampal Gdi1 KO SV pool was directly analyzed by electron microscopy on P10, P23, and P90 mice, to monitor SV density during SV formation. A SV significant reduction was observed in all stages analyzed, regarding the reserve SV pool. We are able to reverse the specific short-term memory deficit of Gdi1 KO mice by using a “spaced” instead to “massed” training protocol in trace fear conditioning and radial maze tasks. The data suggest that lack of Gdi1 alters steps controlling the formation and maintenance of the SV pools possibly through changes in the Rab cycle and interfering with the efficiency of mental processing. Patrizia D’Adamo NEURAL DEGENERATION UNIT Dentatorubropallidoluysian Atrophy (DRPLA) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Atrophin-1 gene. As for the other diseases of the polyglutamine family the precise mechanisms through which neurodegeneration and the neurological manifestations arise are not clear. To address these issues we have generated several Drosophila models for DRPLA by expressing wt and mutated forms of human Atrophin-1 and Drosophila Atro. It has been proposed that polyQ diseases are transcriptionopathies, in which toxicity first arises from large scale alterations of transcription due to the entrapment of many transcription factors in polyQ inclusions. We have monitored by microarrays transcriptional alterations due to polyQ Atrophin expression through an inducible system in the Drosophila retina, a dispensable part of the fly nervous system widely used in polyQ modelling. This analysis has shown that upon polyQ Atrophins expression retinal cells tend to de-differentiate and re-enter the cell cycle before degenerating. Degeneration is preceded by the upregulation of cdc25 and histones transcription and by the downregulation of the tumour suppressor and cell adhesion molecule Fat. We are currently verifying the functional significance of the transcriptional alterations for neurodegeneration and identifying which genes are directly regulated by Atro. In 2008 we have established that the fat tumour suppressor gene mediates neurodegeneration induced by the polyglutamine protein Atrophin via deregulation of autophagy. Polyglutamine Atrophins induce autophagic neurodegeneration with lysosomal blockage and repress fat transcription. Fat is known to interact with Atrophin to regulate planar cell polarity, however it protects from autophagic degeneration and Atrophin toxicity through the Hippo tumour suppressor pathway. Our data thus provide a crucial insight into the specific mechanism of a polyglutamine disease and reveal an unexpected neuroprotective role of Fat and its growth control pathway in the regulation of autophagy and cellular homeostasis, linking tumour suppression and neurodegeneration. Manolis Fanto STEM CELLS AND NEUROGENESIS Functional analysis of Arx and Tbr2, two genes causing neurodevelopmental diseases in humans The Arx transcription factor is expressed in the developing ventral telencephalon and subsets of its derivatives. Mutation of the human ARX ortholog causes neurological disorders including epilepsy, mental retardation and epilepsy. We investigated the nature, origin and evolution of these severe neurological alterations in Arx mutant mice. In these animals we described a severe reduction in migration of cortical GABAergic neurons DIVISION OF NEUROSCIENCE - 35 from the basal ganglia to the developing cerebral cortex. Indeed, Arx mutant interneurons retained their differentiation potential but exhibited deficits in their migration ability in vitro. These findings and others imply that cell-autonomous defects in neuronal migration are the main molecular cause of the neurological manifestations. Altogether, these results highlight the critical functions of Arx in promoting neural migration and, thereby, regulating basal ganglia differentiation and supply of cortical interneurons, consistent with the phenotype exhibited by the patients. Tbr2 gene silencing has been previously associated to microcephaly in humans. To clarify the mechanisms at the foundation of this malformation, Tbr2 conditional mice were crossed with Emx1-cre transgenic mice in order to delete Tbr2 in the cerebral cortex. Tbr2 mutants displayed small cerebral cortices with hypoplastic olfactory bulbs, resembling the pathological phenotype observed in microcephalic patients. We confirmed that Tbr2 expression is selectively confined to the intermediate neuronal progenitors (INPs), a class of precursors which constitutes the subventricular zone during corticogenesis. Interestingly, Tbr2 microcephalic phenotype is the direct result of the loss of the majority of cortical INPs. We provided evidence that INPs are a crucial source of cortical neurons contributing to the establishment of all the cortical layers and olfactory bulbs. To note, the in vivo overexpression of Tbr2 is sufficient to revert radial glial cells into INPs. Thus, Tbr2 should be considered the molecular determinant responsible for the fate switch between the two different types of cortical progenitors. Future studies will aim to unravel the Tbr2 dependent molecular pathway, which might lead to identify candidate genes for other forms of inherited microcephaly. Vania Broccoli Clinical Research Units ACUTE BRAIN PROTECTION, ACUTE POST-OPERATIVE PAIN, DRUGS AND CENTRAL NERVOUS SYSTEM UNIT Neurosurgical Intensive Care Diagnostic and prognostic value of Magnetic Resonance Imaging and CT scan in comatose patients with Diffuse Axonal Injury (DAI) after brain trauma. DAI is frequently observed in the Intensive Care Unit since it is typically caused by the acceleration forces of high speed impacts. Patients exhibit immediate severe impairment of consciousness but few CT scan alterations. An early evaluation of the prognostic factors associated with neuroradiological imaging may lead to more correct treatment options and to an improvement of communication with the patients’ relatives. CT perfusion study of the improvement of cerebral perfusion after cranioplasty in patients formerly submitted to osteodural decompression for intractable intracranial hypertension after acute brain injury. Osteodural decompression may save the life of patients with intractable intracranial hypertension. As patients recover from the acute phase of trauma, cranioplasty is performed for mechanical protection and on aesthetic grounds. The observation of clinical neurological improvement after cranioplasty in these patients suggests a possible improvement of cerebral perfusion after cranioplasty. Neuroanesthesia Evaluation of the impact of different sedative regimens on cortical activation during Functional Magnetic Resonance (fMRI) in children of different ages. Sedation is needed in children to warrant immobility during fMRI. Sedatives alter cerebral activation after sensorial stimulation: an evaluation of their impact on fMRI may indicate which the best sedative in this setting. 36 - SAN RAFFAELE SCIENTIFIC INSTITUTE Comparison of Total Intravenous Anesthesia and Sevoflurane anesthesia during elective neurosurgery (multicentre study). The impact of these different anesthetic strategies in neurosurgery is a cool matter of debate. Recovery time, neurovegetative activation, adverse events and costs are evaluated. Evaluation of the miocardial effects of elective neurosurgery by echocardiography and perioperative evaluation of serum troponine and BNP. Acute brain injury is a well known possible cause of miocardial impairment. This has been previously studied in the setting of head trauma, subarachnoid hemorrhage, stroke, but not in patients submitted to major elective neurosurgery. Luigi Beretta EYE REPAIR UNIT Clinical and basic research in ophthalmology Transplantation of cultivated corneal limbal epithelial stem cells:technique indicated for corneal surface reconstruction due to deficiency of limbal stem cells (burns). Biophysical study of cornea and sclera: analysis of normal and pathological response to create a model of engineered cornea. Transplant of oral mucous stem cells for treatment of limbal bilateral deficiency. Retrospective evaluation of clinical management of patients affected by Acanthamoeba keratitis:a future prospective trial will be conducted. Randomized multicentric clinical trials for treatment of: neovascular age-related macular degeneration: test safety and efficacy of new anti-VEGF drugs retinal vein occlusion due to diabetes: test new therapies to avoid/treat macular edema and retinal ischemia. Endothelial Progenitor Cells in Age Related Macular Degeneration: evaluate the behaviour of EPCs in relation to new onset CNV,anti-VEGF treatment and CNV response to anti-VEGF drugs; demonstrate that number of circulating EPCs is higher than normal at the time of CNV development and not reduced by intravitreally anti-VEGF drugs. Genetic of DME: identify specific genetic markers in diabetic patients, affected by macular edema, leading to high activity of poliol-pathway and damage of Muller cells. Endothelial Progenitor Cells (EPCs) and retinopathy in type1 diabetes:investigate the role of bone marrowderived EPCs in the pathogenesis of diabetic retinopathy leading to new therapeutic approaches. Combined Intravitreal Ranibizumab and Verteporfin Photodynamic Therapy for Choroidal Neovascularization in Angioid Streks: evaluation of double treatment of neovascular membranes in an uncommon disease,charactirezed by unsuccessful responses to usual care. Visual Impairment on Leber Hereditary Optic Neuropathy:from advanced diagnosis to rehabilitation: to identify the clinical, morphological and genetic characteristics of patients affected by Leber and define visual prognosis parameters; to identify morphofunctional alterations in asymptomatic subjects with genetic mutations to define the risks of manifested disease growth. Analysis of neurogenic and regenerative potential of Muller Glial Cells in both healthy and diseased the mammalian retina: in collaboration with Dr Broccoli’s Unit; study of Muller Glia cells in-vitro and in-vivo. Paolo Rama COGNITIVE NEUROSCIENCE UNIT This is a multi-disciplinary Unit, which combines expertises from different backgrounds (neurology, neuropsychology, linguistics, cognitive psychology, epistemology), with the general aim to investigate the neural mechanisms of language and high-order cognition. The experimental approaches include behavioural studies in normal subjects and in neurological patients, brain imaging using magnetic resonance techniques and positron DIVISION OF NEUROSCIENCE - 37 emission tomography, and neurophysiological investigations based on evoked responses and transcranial magnetic stimulation. The unit is involved in several research projects related to the investigation of the neural basis of knowledge representation (semantic memory) for entities belonging to different categories; to the neurological mechanisms involved in syntax, in particular in relation to the question of its language specificity; to the representation of multiple languages in the polyglot brain and their impact on other cognitive functions; to the brain foundations of social interaction, with a special emphasis on empathic phenomena; to the brain mechanisms responsible for decision making in uncertainty and their possible implications for economic choice and managerial processes. These areas of basic cognitive neuroscience research are fully integrated with a clinical research program, wich is based on the development and application of innovative neuropsychological tests based on cognitive models to patients affected by cognitive disorders due to acquired focal and degenerative brain damage. From this point of view an area of special interest is the investigation of patients affected by clinical conditions belonging to the fronto-temporal dementia spectrum. The main areas of dysfunction in these patients are language and social cognition; they thus provide an excellent pathological model for the cognitive areas investogated in normal subjects. The patients are studied with functional and structural imaging, in order to investigate the correlation with neuropsychological findings. The same approach is also applied to Alzheimer and Parkinson disese patients, which are providing important evidences about the neurological underpinnings of semantic and syntactic processing, as well as to selected patients with focal brain damage. Stefano F. Cappa EXPERIMENTAL NEUROSURGERY UNIT Developments in the investigation of hypothalamic-pituitary diseases Research on pituitary diseases last year had as its principal focus the results of trans-sphenoidal surgery, analyzed in terms of efficacy and safety in patients with pituitary adenomas, operated in our center since 1990. In more detail, we have published the data of 491 patients operated for a nonfunctioning pituitary adenoma, one of the largest series in the world. The results confirmed the good efficacy and safety of pituitary surgery in this disease and the value of adjuvant radiation therapy. Another paper reported the results in the group of patients with “giant” adenomas, a very demanding and rare condition. We have also presented the data on the results of gamma Knife radiosurgery as adjuvant treatment in acromegalic patients. The final report is under review. Our continuing cooperation with other groups inside and outside our University led to a series of papers exploring the mechanisms of GH action on osteoblastic function in vitro, the effect of ghrelin on ACTH secretion in cultured ACTH-secreting human adenomas and the metabolic profile of patients with Cushing’s disease as compared to subjects with the metabolic syndrome. Pietro Mortini FUNCTIONAL NEURORADIOLOGY UNIT The Unit is composed by different groups that apply conventional and advanced MR techniques to investigate brain structure and functions in normal subjects, during physiological and pathological development, during normal and pathological aging, in neuro-oncology and neurovascular diseases. The neuropediatric group has addressed its attention on the process of myelination in normal and preterm neonates; diffusion techniques have been employed to follow the modification of white matter over time. Functional MR techniques have been used to test the possibility to investigate auditory and language areas in same subjects. Functional MRI has been used to investigate lateralization of the mirror neuron system in normal adult subjects and to verify the influence of experience on some specific motor functions, like digit skill, in musicians (in collaboration with Experimental Neurophysiology Unit). Volumetric techniques (VBM analysis) and diffusion based techniques have been employed to study subjects affected by neurodegenerative diseases like MCI, Alzheimer Disease and the Fronto-Temporal Dementia. Aim of the project was to identify functional MR markers for an early diagnosis of MCI and of those changes associated with the conversion of MCI to dementia. Similar techniques have been employed trying to characterize the selective involvement of different brain areas in different form of fronto- 38 - SAN RAFFAELE SCIENTIFIC INSTITUTE temporal dementia patient group (in collaboration with Cognitive Neuroscience Unit). The vascular group applied new high resolution techniques to identify vulnerability characteristics in patients with severe carotid stenosis and their correlation with cerebral ischemia and to test new contrast media. Finally, the neuro-oncology group focused on the clinical validation and utility of tractography, a new diffusion based MR technique able to depict the main white matter tracts in vivo, in patients with gliomas. A second topic was the development of new alghoritm based on tensorial diffusion, potentially useful to better characterize the different cellular and extracellular components of brain tumors and adjacent normal structures. Other topics like the study of inflammatory diseases or optic nerve degeneration have been performed in collaboration with other units of Neuroscience Division (Neuroimaging Research Unit, Neuroimaging of CNS White Matter Unit, Eye Repair Unit). Andrea Falini IN VIVO HUMAN MOLECULAR AND STRUCTURAL NEUROIMAGING UNIT Researches were aimed at investigating using PET and SPECT the brain functional parameters and neurotransmission systems in neurological and psychiatric diseases. In particular, 18F FDG is used for the evaluation of glucose metabolism, 11C Raclopride and 11C Fe CIT for the dopaminergic system, 11C FMZ for the evaluation of the gabaergic system, and 11C MP4 for measuring the AchE activity. fMRI and MRI structural studies were also used to address functional changes and morphometric changes (voxel-based-morphometry (VBM) and diffusion tensor imaging (DTI) techniques) in neurological and psychiatric diseases. The research protocols include Alzheimer and MCI, fronto-temporal dementia and its variants, early and late onset of Parkinson’s disease, both sporadic and genetically determined, primary dystonia (genetic and sporadic), and rare conditions such as Fatal Familial Insomnia, an inherited prion disease. Among the psychiatric disease, obsessive compulsive disorders (OCD) were studied with PET and 11C raclopride for the evaluation of dopaminergic system, and 11C MDL for the evaluation of 5HT2 serotonin receptors. OCD selected cases were also included in morphometric measurement of selected fiber tracts. Depending on the pathological condition, PET and specific radiotracers reveal functional and neurotransmission changes which are also correlated with clinical symptoms and their severity. MRI brain morphology and fiber tracts also showed brain anatomical changes related to the underlying neuropathological disease condition. Using ad hoc experimental paradigms we also addressed functional changes (fMRI), morphometric changes (VBM and DTI) in developmental dyslexia (sporadic, familial and in genetic association studies). The results were also correlated to reading disabilities and neuropsychological deficits. Daniela Perani NEUROOTHOLOGY UNIT Little is known regarding the cortical areas involved in human vocalization. The study aim is to investigate larynx cortical area involved in phonation. A 3 Tesla Magnetic Functional Resonance is performed in 6 healthy adults to evaluate voice production related brain activations, using 5 tasks involving laryngeal muscles motor control. We analyzed cerebral network modifications caused by a damage to the laryngeal structures. The fMRI is used to examine 12 patients underwent to laryngeal surgery from January 2007 to February 2008. The pts will be evaluated with the same fMRI tasks used in the healthy population and the results obtained about the two study groups (healthy and surgical group) will be compared in order to obtain informations about the neuronal plasticity following the laryngeal surgery. In a sample of 30 pts referring dizziness and migraine we found a higher prevalence of vestibular abnormalities than in a normal dizzy group. We found increased stabilometric parameters and visual dependence. We compared the rate of vestibular anomalies and the presence of definite migrainous vertigo in a sample of 52 pts DIVISION OF NEUROSCIENCE - 39 with Panic Disorders and agoraphobia, 30 pts with Panic Disorders without agoraphobia and 20 pts with depression, all referring dizziness. Agoraphobic pts presented a higher rate of vestibular anomalies and definite migrainous vertigo. Vestibular anomalies may play a role in the arise of agoraphobic symptoms. We demonstrated an increased body sway during non foveal visual stimulation in agoraphobic pts compared with normal subjects. Establish a role of genetically determined alterations of ionic transporters in inner ear in predisposing to develop Meniére Syndrome (MS). We demonstrated a higher rate of Adducin mutation in a sample of 30 pts with definite MS than in 2 different normal control group. Pts with MS presented a lower serum levels of ouabaine, an hormone controlling ionic transporters activity. The results underline the possibility that an increased pump activity and a lack of feed-back mechanisms may change osmolarity of endolymph. Establish the efficacy of low level laser therapy in tinnitus treatment. Our results on a sample of 30 pts with tinnitus did not demonstrate any therapeutic results. Mario Bussi PSYCHIATRY AND CLINICAL PSYCHOBIOLOGY During the year 2008 we continued our research activities at the interface between neuroscience and behavioral disorders, with the aim of increasing scientific knowledge and developing effective diagnosis and treatment options in the broad field of Psychiatry and Clinical Psychobiology. In the field of mood disorders, we discovered new influences of gene variants in the monoaminergic pathways and in the biological clock on core feature of the illness and on response to treatments. In particular, we published the first reports on the influence of COMT variants on response to antidepressant drugs in naturalistic settings, of 5-HT2A on response to chronotherapeutics, of PER3 and GSK3β on psychopatology, and discovered a method to overcome the detrimental influence of 5-HTTLPR short alleles by administering chronic lithium. Moreover, we created a new animal model of mania based on the manipulation of the sleep wake rhythm. In the field of imaging genetics we produced the first report that CLOCK genes variants affect information processing and neural correlates of moral decision making in bipolar depression, and that 5-HT2A and D2 are dysfunctional in drug-naive obsessive-compulsive disorder. In other psychiatric disorders, we discovered a new effect of transcranial magnetic stimulation in reducing cocaine craving in drug addicts; we produced the first normative data for the Italian population of the Brief Assessment of Cognition in Schizophrenia, to be used to assess rehabilitation outcome; and continued the characterization of comorbidities and psychopatological features of eating disorders. All these findings were obtained in the context of research activities that had been ongoing since 1988 and have continued thereon. Francesco Benedetti SLEEP MEDICINE Sleep related movement disorders Restless Legs Syndrome (RLS) is a motor sleep disorder characterized by disagreeable sensitive symptoms in the lower limbs occurring at evening/night, at rest and improving with movement. RLS is often associated with Periodic Limb Movements (PLMs) during sleep. A dysfunction in the dopaminergic nervous system seems to play a significant role in the pathogenesis. Our group proved the efficacy of pramipexole (dopamine D3 receptor agonist) in suppress RLS symptoms and PLM since the first night of treatment and even at very low dosage. Polysomnographic features of PLM and its specific response to dopamine agonists have been also studied, founding that the periodicity of the motor events is the crucial aspect to predict the efficacy of the dopaminergic treatment. A reliable method of polysomnographic automatic detection and scoring of PLM has been validated by our group. Differences in term of the electromyographic time-structure between the PLM of restless legs syndrome and those found in REM behaviour disorders and in narcolepsy have been enhanced by our analysis, with the intent to improve the polysomnographic diagnosis of the sleep related movement disorders. We demonstrated that PLM in RLS are associated with specific autonomic dysfunctions such as an increase of 40 - SAN RAFFAELE SCIENTIFIC INSTITUTE the heart-rate variability. This finding may represent the reason of the increased risk for cardio-vascular diseases in patients with RLS, recently relieved by large epidemiological surveys. We described the recovery of PLM and its autonomic related dysfuncions by the dopamine agonists treatment, which might represent a promising extension of the well know beneficial effects of the drug, ranging from the RLS symptoms to the autonomic perturbations, with a potential protective effect on the cardiovascular system. By three large and multicenter studies we demonstrated that multiple sclerosis is a significant risk factor for RLS and, by unconventional MRI analysis, we showed that spinal cord lesions represent a specific risk for RLS. Luigi Ferini-Strambi CLINICAL PSYCHOLOGY Mentalized affectivity, emotion instability, disorders of the Self, and aggression The research project aimed at assessing the role of deficits in mentalization and emotion dysregulation in aggressive behaviors. A major result was that deficits mentalized affectivity significantly mediated the effects of attachment styles on impulsive aggressiveness, at least in nonclinical participants. A second major findigs was the evidence of a dissociability of proactive aggression - from reactive aggression based on measures of emotional instability. Interestingly, different manifestations of narcissistic personality were shown to have distinct patterns of associations with reactive and proactive dimensions of aggression. Finally, over narcissistic personality features were shown to mediate the relation between the edonistic style of prosocial moral reasoning and proactive aggression. Cesare Maffei MOTOR FUNCTION REHABILITATION Analysis and rehabilitation of motor function Research activities focuses on interactions between physiological aspects of motor control and motor performance in healthy subjects and subjects with motor impairments. Among the physiological variables involved in the motor control, the studies concentrated on movement biomechanics and cortical brain activations, measured during the execution of motor tasks which are performed with different cognitive facilitations. Biomechanical studies were carried out in the Lab of movement analysis of the School of physiotherapy, measuring the gesture kinematics, the ground reaction forces, the surface electromyography and the muscular torque. Topics were the gait analysis and the study of motor coordination. An example of gait analysis is the biomechanical study of gait after knee replacement with different kinds of prosthesis. An example of study on coordination regards the activation of agonist and stabilization muscles during the movement of lower limbs, studied through surface electromyography in subjects with multiple sclerosis. Moreover, a collaboration with the Functional Unit of Quantitative Neuroimaging of the San Raffaele Hospital, allowed to study the effect of cognitive facilitations such as the execution of transitive versus intransitive task, the use of a video showing the movement to be executed and the use of a mirror reflecting the movement of the contra lateral hand on brain activation of healthy subjects. Finally, we studied clinical applications of the facilitations analyzed with the fRMI. Examples are the observation training, the mirror therapy and the task-oriented movement. Observation training is a new approach where patients watch videos showing an action and then are asked to perform it. In mirror facilitation patients look at mirror that, reflecting movements of the sound side of the body, produces the illusion of movement of the affected side. Task oriented exercises insert the motor impairment in a known and transitive gesture. A particular kind of task oriented exercise that we are studying is the application of the constraint induced movement therapy to the lower limbs of subjects affected by stroke. These subjects have to execute functional activities wearing devices like a knee brace and a skate on the sound lower limb. Roberto Gatti DIVISION OF NEUROSCIENCE - 41 INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE) Director: Giancarlo Comi* Introduction by the Director The Institute of Experimental Neurology (INSPE) constitutes one of the major European institutes primarily dedicated to translational research in the neuroscience field. The overall ambition is to conjugate high level of basic research with the specific competences in pre-clinical and clinical research. This is achievable considering that INSPE includes both research laboratories and the Neurological Department of the San Raffaele Scientific Institute. Multiple sclerosis, stroke, traumatic injuries of the central and peripheral nervous system, and neuromuscular diseases do represent the primary targets of the INSPE reGiancarlo Comi search although research in neurodegenerative disorders is also in the pipeline of the institute. The primary goal is to better understand the molecular mechanisms that sustain inflammatory and degenerative pathogenic mechanisms underlying neurological disorders so to identify therapeutic targets, validate in co-operation with third parties new treatments, develop new disease biomarkers for both clinical trials and patients monitoring. The neurological department is deeply involved in the definition of new treatment algorithms for stroke, inflammatory and neurodegenerative diseases. The molecular and functional bases for central and peripheral nervous system recovery processes and the potential to modulate them by cellular and gene therapy and by specific rehabilitation interventions are another area of interest of INSPE. The INSPE laboratories spans on three different levels in a newly established building within the DIBIT II. One floor is dedicated to neuropathlogy, experimental neurophysiology, neurogenetics of monogenic and complex diseases. Another floor is dedicated to basic and clinical neuroimmunology, neurobiology and neural stem cell research. The third floor is mainly focused on neuroimaging of neuro-inflammatory and neuro-degenerative disorders. Other laboratories involved in behavioral research and in signals that regulate myelination and in clinical neurophysiology are also part of the Institute. 42 - SAN RAFFAELE SCIENTIFIC INSTITUTE Research Units EXPERIMENTAL NEUROPATHOLOGY Implementation of new biomedical devices to promote nerve regeneration. Proposal and validation of new histopathological criteria for early diagnosis of Motor Neuron Disease Collagen-based scaffold for peripheral nerve regeneration: in vivo regeneration of human sural nerve. The aim of the project is to evaluate the efficacy of collagen devices (MD) in order to facilitate the regeneration of the PNS. Innovative is the use of a new biomaterial, which consists of a collagen tube in order to induce the regeneration of the nerve. The MD is based on the pattern of micropores acting as guides for regeneration processes. We evaluated first the biocompatibility and the activity in nerve regeneration following implantation of the MD. The functions of the MD are multiple: guidance regeneration; minimizing the infiltration of fibrous tissue; possessing an adequate mechanical resistance and flexibility supporting the nerve regeneration; being bio-compatible and bio-absorbable. The second objective of this study is to evaluate the regeneration of the adult human sural nerve using this MD. A tube will be implanted into a 10-mm long gap in the sural nerve resulting from a biopsy taken for diagnosis of neuropathies. In case of positive result, the MD will be applied in the neurosurgery field. Early Diagnosis of Motor Neuropathy (MN) and Lower Motor Neuron Disease (LMND) by Motor Nerve and Muscle Biopsy. Amyotrophic Lateral Sclerosis (ALS) is a severe degenerative disorder of the Central Nervous system CNS characterized by the destruction of upper motor neurons (UMNs) in the motor cortex and lower motor neurons (LMNs) in the spinal cord and brainstem. The differential diagnosis is particularly important in the first stages of the disease as some forms of MN,are potentially treatable conditions with a normal life expectancy,whereas ALS is an irreversible and fatal disease. We prospectively studied 21 consecutive patients with a suspected diagnosis of MN or LMND. All patients were submitted to motor nerve biopsy of the obturator nerve and gracilis muscle. In 13 patients pathological findings suggested a suspected diagnosis of LMND. A pathological diagnosis of suspected MN was made in 8 patients. At two years of follow-up we confirmed all the diagnosis made on histopathological basis.We propose new histopathological diagnostic criteria to differentiate these two different conditions. Angelo Quattrini EXPERIMENTAL NEUROPHYSIOLOGY Our unit is involved in the non-invasive assessment of central nervous system function in physiological conditions and in diseases affecting the sensorimotor system, both in humans and in rodent models of neurological diseases. We use electrophysiological methods (EEG, evoked potentials, transcranial magnetic stimulation), alone or in combination with psychophysiological testing or functional-anatomical imaging techniques such as magnetic resonance imaging. In the past year, we investigated: 1) the reorganization of the motor system occurring with healthy aging, by mapping the motor representation of the upper limb at rest using transcranial magnetic stimulation (evoking muscle responses) and by mapping the spatiotemporal cortical activation during motor performance using high-resolution EEG. We found decreased selectivity and speed of muscle activation with aging, together with a reduced hemispheric dominance in muscle cortical representation and segregation at TMS. We also investigated patients with stroke and Parkinson’s disease and are currently performing correlation between the pattern of cortical changes in the motor representation and the severity of neurological involvement. 2) functional cortical changes occurring in adults with Down syndrome using low-resolution tomography (LORETA) of EEG rhythms at rest. Topographic abnormalities of EEG sources, analyzed in 34 patients, was significantly correlated with the severity of cognitive involvement at neuropsychological testing, suggesting that DIVISION OF NEUROSCIENCE - 43 this EEG methodology may be applied in the investigation of cognitive functions in other neuropsychiatric conditions leading to cortical and subcortical dementia. 3) effects of neuromodulation to transcranial direct stimulation (tDCS) in mice. In a pilot study we investigating whether the effects of tDCS, which in humans has been been shown to enhance motor responses evoked by TMS, could be replicated in mice on motor responses to transcranial electrical stimulation(TES). Similarly to human findings, we found that anodal tDCS enhances muscle responses evoked by TES, while the opposite occurs with cathodal tDCS. This findingopens the way to further studies aimed at investigating specific cortical/subcortical mechanisms on the effect of tDCS on the brain. Letizia Leocani MOLECULAR GENETICS OF BEHAVIOUR The role of Ras-ERK signalling in behavioural plasticity and brain diseases Our laboratory has focussed for a number of years on the Ras-ERK intracellular signalling pathway that is crucially involved in transducing signals from the neurotransmittter receptors to the nucleus, hence controlling chromatin remodelling and gene expression, key steps involved in synaptic remodelling, long-term plasticity and formation of long-term memory. Once receptors are activated, specific guanine exchange factors (GEFs) are able to catalyse the exchange of GTP for GTP on Ras proteins, thus activating this class of small GTPases. One of these GEFs is Ras-GRF1, which is exclusively expressed in the CNS. Conversely, GTPase Activating Proteins do exactly the opposite and by removing a phosphate from GTP bound Ras inactivates the signalling. Importantly, loss of function mutations in NF1 gene product neurofibromin, that preferentially activates the KRas isoform, lead to Neurofibromatosis type 1 disease. Activated Ras proteins then stimulate the core element of the signalling pathway, the Ras-MEK-ERK protein kinase cascade. Our laboratory is especially interested in investigating how the modulation of this pathway influences the physiological response to different neurotransmitter systems and drugs of abuse. In that respect we have paid particular attention to the striatum. This brain structure is a collection of several nuclei involved in a variety of behaviours and brain diseases, including procedural and motor learning, drug addiction and Parkinson’s disease. We have recently completed the analysis of several mouse strains bearing mutations affecting striatum-dependent behavioural plasticity. For instance, mice deficient for Ras-GRF1 show major impairments in the process of memory consolidation as revealed by several striatum-dependent learning tasks and also manifest deficits in behavioural responses to drugs of abuse. Moreover, we showed that expression in the dorsal portion of the striatum of a potent inhibitor of the CREB family of transcription factors in a reversible manner results in significant alterations at the level of procedural memory and drug-dependent behaviour. Finally, we showed that a conditional, forebrain specific gain of function mutation in K-Ras (K-RasG12V) largely recapitulates the cognitive impairments found in NF1 mutant mice. Riccardo Brambilla NEUROMUSCULAR REPAIR The role of adhesion in neuromuscular disorders Progressive tissue degeneration and defective regeneration are responsible for disability in most chronic neuromuscular disorders, including hereditary neuropathies (HN) and muscular dystrophies. Although in many cases the genetic causes and the clinical manifestations are well described, much remains unknown about the pathogenetic mechanisms and in almost all the cases no reliable therapy is still available. The research field of the unit is to investigate the pathogenetic role of adhesion in neuromuscular disorders, and its involvement in tissue regeneration. Our main aims of studies are: 1) The efficacy of extracellular matrix (ECM) remodeling to promote regeneration in HN and congenital muscular dystrophy (CMD). We are exploiting drug and cell therapy to interfere with ECM composition in animal models of HN and CMD. For example, mesoangioblasts has been revealing as good carrier cells 44 - SAN RAFFAELE SCIENTIFIC INSTITUTE to deliver in muscle and nerve cross-linker molecule to re-connect cells to the basement membrane in CMD models. Preliminary studies showed amelioration of functional performances and muscle histology. 2) Role of the Schwann cell cytoskeleton in nerve development and regeneration. We are studying the consequences of the disruption of the Schwann cell cytoskeleton constituents, such as the intermediate filaments, on peripheral nerve development, function and regeneration. We observed that Vimentin deletion in transgenic mice alters the Schwann cell-axon relationship and interfere with nerve regeneration. 3) The adhesion-derived intracellular signaling in nerve development and regeneration: the role of Jab-1. We are investigating the role of the intracellular signaling molecule Jab-1 in nerve development and repair. Jab-1 is modulated by ECM and surface receptor signals, and is involved in the control of the cell cycle, protein degradation and gene transcription. Jab-1 is expressed by Schwann cells and modulated during myelination and nerve regeneration. Stefano Carlo Previtali NEUROIMMUNOLOGY UNIT Neuroinflammation promotes damage and inhibits central nervous system repair in multiple sclerosis by different molecular pathways The role of inflammatory pathways in promoting vs. protecting from widespread damage in chronic inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS), is still far from being elucidated. To dissect the inflammatory-mediated mechanisms leading to tissue damage vs. protection in MS, mice with experimental autoimmune encephalomyelitis (EAE) have been used as experimental tool. On one hand, we have found that inflammation is capable to enhance glutamate transmission in the striatum, and to promote synaptic degeneration and dendritic spine loss. These alterations occur early in the course of EAE, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor (TNF) α from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided upon pharmacological blockade of AMPA receptors. On the other hand, we have found pro-inflammatory cytokines (e.g. TNF-α, IFN-γ), inducing an increase of several cyclin-dependent kinase inhibitors (in particular of those inhibiting both M and S phase cell entry), induces morphological and functional alterations of neural precursor/stem cell (NPCs) in the germinal niches. As a net effect, a reduced number of type C (transit amplifying cells) and B (bona fide true stem cells) cells differentiating into type A (neuroblasts) and type C cells is observed early after disease onset. To better understand the role of endogenous NPCs and further explore the molecular mechanisms underlying the inflammatory-related impairment during EAE, we have now generated a transgenic mouse line expressesing the ligand-dependent CRE/ERT2 gene under the control of AspM regulatory regions and a second line in which the TK killing gene is under the control of the nestin promoter. Our data indicate that neuroinflammation might promote damage and inhibit CNS repair in MS by different, and only apparently distinct, pathways. Gianvito Martino CLINICAL NEUROIMMUNOLOGY The Unit of Clinical Neuroimmunology is currently active in both experimental and clinical neuroimmunology with the aim to have a bi-directional transfer of scientific questions and experimental data between the two. Active projects are: • Gene therapy of experimental autoimmune encephalomyelitis (EAE). Our group established a CNS-targeted gene-delivery approach using non-replicative viral vectors injected in the cerebrospinal fluid (CSF) circulation. We are using newly prepared IL-25 and IL-27-expressing lentiviral vectors to address the involvement of these molecules, part of a novel pathway in mice models and in human multiple sclerosis (MS). DIVISION OF NEUROSCIENCE - 45 • • • • • Role of Treg cells in the modulation of EAE. We are assessing the role of FoxP3+ Treg cells in the modulation of chronic and relapsing EAE, and their potential therapeutic potential both in a cell therapy setting and using drugs able to increase their number or recruitment. The role of shed-vesicles of neural origin in EAE. Shed vesicles are newly described particles released by several cell types through membrane budding whose physiological and patho-physiological role is unclear. We are currently investigating their production, content, and fate in EAE and MS. The role of Treg cells in MS and related treatments. We are currently establishing, also on the basis of what we have learned in mice, the best way to monitor Treg modulation in human MS patients. We are investigating their contribution in the different disease phases and clinical forms, and their modulation by treatments, such as immunomodulatory drugs, or bone marrow transplantation. Immunological markers in MS and psychiatric disorders. We use several different technological platforms, spanning from gene expression to microRNA, to multiparametric protein detection. We have ongoing investigations on MS patients, undergoing or not immunomodulatory or immunosuppressive treatments. We have recently extended our activity to patients affected by major psychoses such as schizophrenia, major depression, and bipolar disorder. Identification of auto-antibodies in neurological disorders. We are screening sera from patients affected by optic neuritis, retinitis, myelitis, and movement disorder to identify novel autoantibodies, and their corresponding auto-antigen. Roberto Furlan CNS REPAIR Somatic stem cell-based therapies of central nervous system (CNS) diseases The development of cell-based therapies aimed to promote tissue repair in central nervous system (CNS) diseases, represents one of the most challenging areas of investigation in the field of regenerative medicine. Several cell-replacement strategies have been developed in the last few years. Recent evidence from our and other labs indicates that undifferentiated neural stem/precursor cells (NPCs) might very efficiently protect the CNS from chronic degeneration induced by inflammation both in small rodents as well as in primates (Nature 2003, 422: 688-694; Nature 2005, 436: 266-271; Stem Cells 2007, 5: 2583-2592; Ann Neurol, in the press). However, before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions: the ideal stem cell source for transplantation; the ideal route of cell administration; the differentiation and persistence of stem cells into the targeted tissue and - last but not least - the functional and long-lasting integration of transplanted cells into the host tissue (Nat Rev Neurosci 2006, 7: 395-406). Current projects in the laboratory have been further exploring the cellular and molecular mechanisms regulating the therapeutic plasticity of NPCs in inflammatory CNS diseases such as multiple sclerosis, ischemic stroke and spinal cord injury, both in rodents as well as in non-human primates (Ann Neurol, in the press; Brain, in the press; PLoS One, in the press). Stefano Pluchino Figure 5. Transmission electron microscopy (TEM) images a large-size immunogold-labelled GFP+ NPC within a cervical lymph node of a R-EAE mouse at 72 days after cell injection. These GFP+ cells display morphological and ultrastructural features similar to individual NPCs from neurospheres in vitro. The NPC (pseudocolor green) takes contact with four individual lymph node cells (pseudocolor orange). The NPC shows an irregular and invaginated nucleus (n) with a single nucleolus (nu), and its cytoplasm contains abundant organelles (from Pluchino et al., PLoS One, in the press). 46 - SAN RAFFAELE SCIENTIFIC INSTITUTE NEUROIMAGING RESEARCH UNIT Assessment of Treatment Efficacy in MS Clinical Trials: treatment with glatiramer acetate (GA) of patients with clinical isolated syndromes suggestive of MS reduces the conversion to clinically definite MS; in relapsingremitting (RR) MS, short-term combination of GA with IV Methylprednisolone may result in an early and sustained reduction of disease activity; Protiramer is safe and well tolerated in patients with RRMS. In vivo Assessment of MS Pathophysiology by Quantitative MRI: grey matter (GM) volume loss follows different patterns of regional distribution according to the clinical MS phenotypes; over a one-year period, cortical lesions increase their number and size in a relevant proportion of MS patients; in benign MS the cortex is relatively spared, cognitive dysfunction is associated with the extent of corpus callosum damage, absence of cognitive impairment and longer disease duration or lower disability identify patients with favorable disease evolution. Functional MRI in MS: large multicenter fMRI studies of brain activations and effective connectivity in MS are feasible; pediatric MS is associated with a preserved brain functional reserve (i.e., maintenance of selective and strictly lateralized pattern of movement-associated activations and modulation of its functional connections); tactile-associated cervical cord overactivation is more prominent in relapse-onset MS patients with more severe locomotor disability, and occurs also in primary progressive MS patients. Structural and Functional MRI in Aging and Neurodegenerative Diseases: apoE4 is associated with a more severe disease-specific pattern of brain atrophy in Alzheimer’s disease (AD) and frontotemporal dementia at presentation; a widespread brain functional rewiring with increasing structural damage rather than a specific response to cognitive network injury occurs in AD; semantic dementia is associated with anatomical damage to the major temporal connections involved in semantic/lexical processes, with relative sparing of fronto-parietal network; over less than 1 year, amyotrophic lateral sclerosis patients show cervical cord tissue loss and microstructural injury (which are independent of brain changes), and progression of GM atrophy in motor cortex and basal ganglia. Massimo Filippi NEUROIMAGING OF CNS WHITE MATTER In vivo assessment of pathophysiology of MS and other white matter diseases using MR-based techniques Using functional magnetic resonance imaging (fMRI) and quantitative MR-based techniques, we found that: 1) large multicenter fMRI studies of functional activations and effective connectivity changes in MS people are feasible and can facilitate studies with sample sizes large enough for robust outcomes; 2) patients with pediatric MS maintain a selective and strictly lateralized pattern of movement-associated brain activations and functional connections, suggesting a preserved functional reserve in these patients, which, in turn, might contribute to explain their favorable clinical evolution at short/medium term; 3) patients with relapsing-remitting MS with a normal level of function have an increased activation of regions which are part of the mirror neuron system, despite the presence of widespread central nervous system damage, suggesting a possible adaptive role of these fMRI changes; 4) in patients with benign (B) MS, abnormal activations of cognitive-related network as well as abnormal coefficients of connectivity inside this network occur during the performance of the Stroop task. The correlation found between measures of abnormal functional connectivity and structural MRI metrics of tissue damage within intra- and inter-hemispheric cognitive related white matter (WM) fiber bundles suggest that functional cortical changes in BMS might represent an adaptive response driven by damage to specific WM structures; 5) in patients at presentation with clinically isolated syndromes suggestive of MS, macroscopic focal lesions but not "diffuse" brain damage measured using magnetization transfer MRI are associated to an increased risk of subsequent development of definite MS; 6) diffusion tensor tractography discloses optic radiation changes in patients with migraine with aura, which might represent a phenotypic biomarker of the disease given the lack of a correlation with clinical and structural MRI metrics. Maria Assunta Rocca HUMAN INHERITED NEUROPATHIES UNIT MTMR2 phospholipid phosphatase as a regulator of membrane biogenesis during Schwann cell myelination Myelin biogenesis is a major event during development of glial cells whose perturbation causes severe neurological disorders. Since myelin is a highly polarized structure, myelin biogenesis involves sorting and targeting DIVISION OF NEUROSCIENCE - 47 of selected lipids, proteins, and mRNAs to specific sub-domains, with a strong analogy to the polarized transport in epithelial cells and neuronal synapses. However, the molecular machinery that directs the sorting and mediates polarized transport and targeting in myelin-forming glial cells is largely unknown. Myotubularin-related (MTMR) 2 protein represents a ubiquitously expressed phospholipid phosphatase whose loss in human and mouse causes Charcot-Marie-Tooth type 4B1 neuropathy with myelin outfoldings, aberrant foldings of excessive membrane. We first generated a Mtmr2-null mouse which reproduces the neuropathy. We also found that in Schwann cells Mtmr2 interacts with Dlg1, a scaffold involved in cell polarity and membrane addition. As already demonstrated in differentiating oligodendrocytes and neuronal synapses, multidomain scaffolds play a role in membrane polarity and protein trafficking. We therefore exploited the Mtmr2-null mouse and myelin outfoldings as a model to assess whether also in Schwann cells membrane addition/remodeling might be regulated by a multi-molecular complex organized by the Dlg1 scaffold. We provided evidence of the first machinery that in Schwann cells titrates myelin formation during myelination. Alessandra Bolino AXO-GLIA INTERACTIONS UNIT Role of secretases in type III Neuregulin-1 cleavage and myelination Myelin is a highly specialized membrane which wraps around the axons in the peripheral (PNS) and central nervous system (CNS) and is required to facilitate the efficient and rapid propagation of nerve impulses. Myelin formation is tightly regulated and while the molecular events controlling the development of Schwann cells (SC) and oligodendrocytes (OL) have been characterized, the axonal mechanisms directing its production have been only recently identified. Alteration in myelination can have dramatic consequences that can span from reduction of the conduction of the nerve impulses to neuronal cell death, with a significant impairment of normal functionality in patients affected by demyelinating disorders. The development of OL and SC critically depends on axonal contact. Axons promote the proliferation, survival and differentiation of myelinating glia. Glial cells, in turn, promote neuronal survival and regulate the organization and maintain the integrity of axons. We have recently demonstrated that type III NRG1, a member of the NRG1 family of growth factors, is the instructive signal for myelination in the PNS. Above a threshold level of expression of type III NRG1, axons are myelinated and the amount of myelin is proportional to the levels of type III NRG1 present on the axons. We have also showed that in the CNS, type III NRG1 is not essential for OL myelination and the regulation of myelination in PNS and CNS is distinct. In our laboratory we investigate the signals on the axon, and the downstream signaling pathways they activate in myelinating glia, that regulate the formation of glial cells and maintenance of the myelin sheath. NRG1 are proteolytically cleaved in their extra and intracellular domains, thus, we are examining the role of this cleavage events in NRG1 cleavage and in myelination. Upon cleavage in the juxtamembrane region type III NRG1 remains tethered on the axonal surface and acts as a juxtacrine signal. We are now investigating the identity of the secretases involved in NRG1 cleavage and their role in myelination. Our preliminary observations suggest the ADAM 17 participates in type III NRG1 cleavage and, in vitro and in vivo studies, suggest that this cleavage event controls myelination. Carla Taveggia Clinical Research Units INFLAMMATORY CNS DISORDERS UNIT Our Clinical Unit was involved in many International RCTs (phase II, III or IV) to evaluate the safety and efficacy of newly-developed immunosuppressive or immunomodulatory drugs (Fingolimod, Laquinimod, Cladribine, Teriflunomide, Firategrast Ocrelizumab and Alemtuzumab) or symptomatic therapies (Sativex and 48 - SAN RAFFAELE SCIENTIFIC INSTITUTE Naltrexone) on MS patients. We coordinated a multicentre RCT on the long term benefits of a sequential therapy with Mitoxantrone (MTX) followed by Β-Interferon (IFN) on patients with bad prognostic factors in the early phase of the disease. Moreover, we concluded 2 multicentre RCTs in patients with a first demyelinating clinical event suggestive of MS; both RCTs demonstrated a significant beneficial effect of Glatiramer Acetate (GA) (PRECISE) or IFN (BENEFIT) in delaying the conversion to MS. We collected and analyzed, using a computerized database, clinical and laboratory data on more than 3000 MS patients, treated with immunomodulatory and immunosuppressive drugs, to identify possible predictors of clinical efficacy or safety. In particular, we conducted a retrospective analysis on the efficacy of MTX treatment in patients with RR and SP MS. Moreover we were the promoting centre of a national multicentre retrospective study to evaluate the incidence of Acute Leukaemia in patients who had undergone MTX therapy. We conducted a study with a whole-genome case-control approach using the Illumina platform, to identify allelic variants associated with the risk to develop MS and its variant “primary progressive”. We planned a study to assess the efficacy of different aspects of intensive rehabilitation in MS patients with and without fatigue. We conducted a study to evaluate the psychological correlates and the coping strategies developed by patients with an early diagnosis of MS as well as the impact of MS diagnosis on the psychological aspects of sexuality and maternity. We were also involved in an Italian co-operative study to explore both the affective and cognitive correlates of IFN and GA in adult and childhood-juvenile MS patients. Finally, we evaluated the clinical, immunological, and MRI characteristics of “atypical” forms of MS, to define an algorithm able to differentiate CNS demyelinating diseases from other primary CNS inflammatory diseases. Vittorio Martinelli CEREBROVASCULAR DISORDERS The cerebrovascular patient: from bedside to bench and vice versa The Stroke Team is involved in: a) Optimization of the diagnostic workup and therapeutic management, in accordance with the requests of the International Joint Commission for the recognition of the standard of excellence. We are the coordinator of a multicentric project aimed at the definition of outcomes of efficacy and efficiency in the management of the cerebrovascular patients. b) International clinical trials evaluating therapeutic strategies in primary and secondary prevention. c) Individuation and validation of diagnostic/prognostic markers. • Biochemical markers – within a collaborative project funded by the Ministry of Health we are collecting samples from patients undergoing thrombolysis in order to study the possible prognostic role of markers of haemostasis and inflammation. • Cognitive markers - all consecutive patients admitted to the Stroke Unit are evaluated in the acute phase and with repeated neuropsychological testings. Preliminary results indicate that executive dysfunctions are one of the most relevant consequences of stroke and TIA and that the Frontal Assessment Battery represents a good measure of these dysfunctions and a good predictor of long-term cognitive outcome (Arcari C et al). d) Studies aimed to the identification of markers of instability of the carotid plaque. In collaboration with the Cardiovascular Dept, we studied 32 patients with asymptomatic and symptomatic carotid stenosis with Color or Power B-mode Ultrasonography (US) and histopathological analysis of the carotid plaque (CP). Preliminary results show that US allow a detailed in vivo study of CP morphology and that CP unstable by US are more often characterized by intra-plaque thrombosis/ hemorrhage (Piscopiello M, Spinelli M et al). e) Studies aimed at the characterization of genetic determinants of ischemic stroke risk, with a whole genome approach using a Bead Station 500® (Illumina®). f) Studies aimed at the identification of the physiopathological role of patent forame ovale in patients with migraine and/or stroke. 48 subjects were screened for the persistence of right-to-left shunt (RLS) with transcranial Doppler and for the presence of white matter lesions (WMLs) using a 3.0 Tesla MRI. Preliminary results indicate that the presence of RLS does not increase WMLs. Maria Sessa DIVISION OF NEUROSCIENCE - 49 MEMORY DISORDERS The aim of our Unit is to identify early markers of disease to achieve the diagnosis in the early stage of Alzheimer’s Disease (AD) and other dementias (non-AD dementia). The concept of the boundary between normal aging and very early or mild dementia has become an area of interest for theoretical and practical reasons. Therefore, identification of early clinical AD has become an important public health priority as new treatments have emerged. The main task of our unit is primarily the recruitment and proper diagnostic classification of patients with memory disorders and dementias respecting international diagnostic criteria: the correct identification of patients with dementia is the cornerstone of any type of study (neuroradiological, epidemiological, neurophysiological, genetics). Our Unit works in close collaboration with the Neuroimaging Research Unit (M. Filippi and F. Agosta) and Functional Neuroradiology Unit (A. Falini) to identify structural and functional MR markers for the early diagnosis of the mild cognitive impairment (MCI), to define the structural and functional CNS changes associated with the conversion of MCI to dementia and to characterize the structural and functional substrates of the non-AD dementia (i.e., frontotemporal dementia). Additional approaches in close collaboration with the Experimental Neurophysiology Unit (L. Leocani) have been based on studies on programming of voluntary movement and motor control in aged normal subjects, MCI and AD patients. Our interest is also focused on the genetic components of AD. The Center is engaged in the collection of blood samples to create a clinical database and biological bank of subjects suffering from dementia with the aim to identify genetic factors involved in the risk of developing dementia and in the individual response to drugs (F. MartinelliBoneschi; Laboratory of neurological complex disorders), for which a -genome-wide study has been recently completed on 180 AD-treated patients. We are also involved in clinical pharmacological trials to provide to AD patients innovative drugs. Giuseppe Magnani MOVEMENT DISORDERS Our group is working on different fields of interest, in particular: 1)clinical and neurophysiological study on safety and efficacy of botulinum toxin type A (BT-A) therapy in different muscular fiber hyperactivity disorders. Notably we are studying the functional recovery after BT-A therapy in patients with focal spasticity in multiple sclerosis (MS) and identification of guidelines for the treatment with BT-A in MS patients with neurogenic bladder without urine retention. Moreover, it just started transcranial magnetic stimulation (TMS) study of the exteroceptive suppression (“geste antagoniste”) in cervical dystonia. 2) research of new targets and optimization of the procedures of surgical neurostimulation in Parkinson disease and correlate disorders with particular focus on the mechanisms of action of the neurostimulation through functional studies of cerebral metabolism and on the neuropsychological and behavioral modifications. 3) the interoperating monitoring (IOM). In the past year we perfected the protocol: ‘clinical and neurophysiological study of the efficacy and safety of the repetitive transcranial magnetic stimulation (rTMS) in chronic neurogenic pain (CNP)’ and now almost all question with ethic committee are clear up. We are also keeping on our animal neurophysiological studies in several model of experimental peripheral neuropathy, like the nervous regeneration after crush, and verify whether the association of classical neurophysiological tests and stimulated single fiber electromyography (SFEMG) may contribute to better describe axonal and muscle fibers regeneration. Ubaldo Del Carro NEUROMUSCULAR DISORDERS My group is working on two different topics Neuromuscular diseases and Clinical Neuroimmunology. Neuromuscular diseases are a very heterogeneous group of neurological diseases including muscular diseases, peripheral neuropathies and motor neuron diseases. The pathogenic mechanisms underlying these diseases are heterogeneous too, including inflammation, au- 50 - SAN RAFFAELE SCIENTIFIC INSTITUTE toimmunity, degenerative damage and genetic one. The aims of our clinical studies is to give the best medical supports to our patient through new diagnostic tools (i.e. detecting new markers, for example new antigens targets for autoimmune response against neuromuscular system, assessment of cutaneous biopsies in sensitive neuropathies), new therapeutic strategies (e.i. FKT in ataxic patients ), new management of disability (i.e. timing of ventilations or PEG in ALS patients) new drugs not only directed against the cause of the disease (immunomodulation in autoimmune peripheral neuropathies, talampanel and lithium in ALS patients) but also drugs inducing amelioration of the clinical symptoms (e.i. fatigue or pain in peripheral neuropathy) and signs in order to improve the life quality of our patients, new modality for drugs intake (as subcutaneous immunoglobulins instead of ev immunoglobulins in dysimmune neuropathies). These clinical trials are organized in different experimental designs from controlled multi centric trials to local observational and retrospective studies. About clinical neuroimmunology we studied the presence of anti AQ4 antibodies in neuromyelitis optica (Devic disease). We created an Italian multicentric web to collect sera from patients with Devic disease and we analysed patient sera by tissue immunocytochemistry, immunofluorescence on stable cell line, and cell FACS analysis in order to give an easy diagnostic tool for the detection of this inflammatory disease. We are evaluating if these antibodies have a prognostic value in a prospective longitudinal study on relapsing myelitis. Furthermore we are screening sera from patients affected by optic neuritis, retinitis, myelitis, and movement disorders with the aim to identify new autoantibodies, and their corresponding auto-antigen. Raffaella Fazio PAROXYSMAL EVENTS Our unit is principally involved in the evaluation of epileptic patterns during status epilepticus and single seizures. Status epilecticus is a medical emergency and the times for its identification and treatment influence the prognosis of the patient. The current limits are especially connected to the possibilities of access of instrumental diagnosis and to the lack of therapeutic protocols universally acknowledged. For a correct diagnosis of non convulsive status epilepticus and to verify the effects of the therapies is essential the contribution of neurophysiological diagnostic and, in particular, the electroencephalographic one. Long term EEG monitoring (LTM) is a well-established procedure in the evaluation of epilepsy patients. The analysis of EEG recordings is necessary to determine the seizure onset zone. LTM is also particularly useful in the evaluation of critically ill patients, in which seizures are frequently silent, and in the pre-surgical evaluation of patients with pharmacorefractory epilepsy. Main goal of our studies is related to the automatic analysis of seizures EEG pattern in order to obtain a 24 hours of monitoring of patiens. We are also involved in the neurophysiological evaluation of mechanisms mediating epileptogenesis in Tuberous Sclerosis Complex in mice and in the human evaluation of therapy with Rapamycin. This drugs has no documented properties as an anticonvulsant agent but it has strong efficacy for preventing epileptic encephalopathy in animal model of Tuberous Sclerosis. Fabio Minicucci DIVISION OF NEUROSCIENCE - 51 Cellular neurophysiology Unit Proteomics of iron metabolism Unit Molecular genetics of mental retardation Unit Cognitive neuroscience Unit 52 - SAN RAFFAELE SCIENTIFIC INSTITUTE Motor function rehabilitation Clinical Neuroimmunology CNS repair Neuroimmunology Unit DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 53 DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES Research Units Amino acid and stable isotopes Unit HEAD OF UNIT: Livio Luzi RESEARCHERS: Andrea Caumo, Stefano Benedini, Roberto Codella, Ileana Terruzzi FELLOWS: Anna Montesano, Pamela Senesi Complications of diabetes GROUP LEADER: Gianpaolo Zerbini RESEARCHERS: Mara Lorenzi, Anna Maestroni PHD STUDENT: Silvia Maestroni CONSULTANT: Gemma Tremolada TECHNICIAN: Daniela Gabellini Obesity and metabolic related diseases GROUP LEADER: Gianluca Perseghin RESEARCHER: Guido Lattuada TECHNICIAN: Francesca Ragogna Bone metabolism Unit HEAD OF UNIT: Alessandro Rubinacci RESEARCHER: Isabella Villa POST-DOCTORAL FELLOW: Emanuela Mrak CONSULTANTS: Giovanna Mignogna, Gianluigi Moro, Marcella Sirtori TECHNICIAN: Ennio Leporati Coagulation service & thrombosis research Unit HEAD OF UNIT: Armando D’Angelo RESEARCHERS: Luciano Crippa, Patrizia Della Valle, Annalisa Fattorini, Silvana Viganò FELLOW: Giulia Pavani TECHNICIAN: Francesca Sampietro Cardiodiabetes & Core Lab HEAD OF UNIT: Emanuele Bosi* GROUP LEADER: Lucilla D. Monti FELLOW: Elena Galluccio TECHNICIANS: Sabrina Costa, Barbara Fontana Pediatric endocrinology research HEAD OF UNIT: Giuseppe Chiumello* GROUP LEADER: Stefano Mora FELLOWS: Silvia Carlucci, Annalisa Donini, Silvia Genovese, Ilaria Zamproni TECHNICIAN: Maria Puzzovio 54 - SAN RAFFAELE SCIENTIFIC INSTITUTE Clinical Research Units Diabetes and endocrinologyUnit HEAD OF UNIT: Emanuele Bosi* PHYSICIANS: Alberto Davalli, Gabriella Galimberti, Roberto Lanzi, Marco Federico Manzoni, Alessandro Saibene RESIDENTS: Chiara Cappelletti, Valentina Crippa, Valentina Doria, Ilaria Formenti, Manuela Fortunato, Andrea Laurenzi, Sara Madaschi, Elena Peretti, Francesca Perticone, Cecilia Piani, Maria Grazia Radaelli, Alessandro Rossini, Annachiara Uccellatore, Valentina Villa TECHNICIAN NUTRITIONIST: Monica Marchi Cardiodiabetes and clinical trials CLINICAL GROUP LEADER: Piermarco Piatti FELLOWS: Emanuela Setola, Pietro Lucotti Pediatrics Unit HEAD OF UNIT: Giuseppe Chiumello* Clinical pediatric endocrinology CLINICAL GROUP LEADER: Giovanna Weber* RESEARCHERS: Stefania Di Candia, Gabriella Pozzobon, Gianni Russo, Maria Cristina Vigone Diabetes and metabolic diseases in children and adolescents CLINICAL GROUP LEADER: Franco Meschi RESEARCHERS: Karen Marenzi, Matteo Viscardi Neonatology CLINICAL GROUP LEADER: Graziano Barera RESEARCHERS: Antonella Poloniato, Rosanna Rovelli RESIDENT: Patrizia Corsin Gynecology and Obstetrics Unit HEAD OF UNIT: Augusto Ferrari* Foetal-maternal medicine CLINICAL GROUP LEADER: Maria Teresa Castiglioni RESEARCHERS: Susanna Rosa, Maddalena Smid, Luca Valsecchi PHD STUDENT: Paolo Cavoretto FELLOWS: Federica Pasi, Serena Pirola, Audrey Serafini Infertility CLINICAL GROUP LEADER: Francesco Fusi RESEARCHERS: Ilaria Cino, Lucia De Santis, Michela Molgora, Nicoletta Panacci, Enrico Papaleo, Simone Rofena POST-DOCTORAL FELLOW: Elena Gismano Cardiovascular interventions Unit HEAD OF UNIT: Antonio Colombo PHYSICIANS: Mauro Carlino, Alfredo Castelli, Alaide Chieffo, Iassen Michev, Matteo Montorfano FELLOWS: Marta Bande, Cosmo Godino, Alfonso Ielasi, Azeem Mohamed Latib, Valeria Magni RESIDENTS: Raffaele Lacquaniti, Marco Mussardo TRIAL COORDINATOR: Angela Ferrari DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 55 Clinical cardiovascular biology Unit HEAD OF UNIT: Domenico Cianflone* PHYSICIANS: Enrico Ammirati, Stefano Coli, Nicole Cristell, Marco Magnoni RESIDENT: Anna Chiara Vermi POST-DOCTORAL FELLOWS: Dina Ianzano, Norma Maugeri MD STUDENTS: Alessandro Durante, Alberto Monello TECHNICIANS: Michela Banfi, Fabrizio Sioli RESEARCH NURSE: Barbara Pontiroli Ischaemic heart disease, heart failure and echocardiography Unit HEAD OF UNIT: Alberto Margonato PHYSICIANS: Eustachio Agricola, Alberto Capelletti, Andrea Conversano, Gabriele Fragasso, Stefano Gerosa, Andrea Macchi, Michele Oppizzi RESIDENTS: Michela Cera, Irene Franzoni, Chiara Gardini, Annalisa Pessina, Anna Salerno POST-DOCTORAL FELLOWS: Fabio Buzzetti, Matteo Pisani PHD STUDENTS: Francesco Maranta, Monica Mazzavillani, Claudio Montanaro, Isabella Rosa, Camilla Tarlasco Organ protection in critically ill patients, Advanced cardiac failure and mechanical supports Unit HEAD OF UNIT: Alberto Zangrillo* PHYSICIANS: Elena Bignami, Tiziana Bove, Luca Cabrini, Giuseppina Maria Casiraghi, Sergio Colombo, Remo Daniel Covello, Giovanni Landoni, Giovanni Marino, Federico Pappalardo, Davide Salaris, Paolo Silvani RESIDENTS: Giulia Maj, Anna Maria Mizzi, Giacomo Monti, Stefano Turi POST-DOCTORAL FELLOWS: Ilaria Belloni, Laura Corno, Alberto Facchini, Reem Nassif, Laura Ruggeri Structural heart disease Unit HEAD OF UNIT: Ottavio Alfieri* PHYSICIANS: Stefano Benussi, Michele De Bonis, Francesco Maisano FELLOWS: Flavia Bondardo, Andrea Guidotti, Valerio Zerbi Study and treatment of aortic disease Unit HEAD OF UNIT: Roberto Chiesa* PHYSICIANS: Renata Clotilde Castellano, Efrem Civilini, Laura Dordoni, Gloria Esposito, Enrico Maria Marone, Massimiliano Marrocco-Trischitta, Germano Melissano, Yamume Tshomba RESIDENTS: Fabio Massimo Calliari, Giovanni Coppi, Andrea Kahlberg, Davide Logaldo, Daniele Psacharopulo, Sara Spelta FELLOWS: Luca Bertoglio, Barbara Catenaccio Center for arrhythmia research HEAD OF UNIT: Carlo Pappone CLINICAL GROUP LEADER: Vincenzo Santinelli POST-DOCTORAL FELLOWS: Giuseppe Augello, Alessia Pappone, Simone Sala, Nicoleta Sora, Pasquale Vergara RESIDENTS: Giuseppe Ciconte, Andrea Radinovic, Massimo Saviano TECHNICIAN: Giorgio Maida * Professor at: Università Vita-Salute San Raffaele 56 - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction Metabolic and cardiovascular diseases represent a major area of clinical care and research at San Raffaele Research Institute. Several leading groups of cardiologists, cardiac and vascular surgeons and diabetologists pioneered over the years the development and application of many innovative therapeutic approaches in patients with different types of cardiovascular and metabolic diseases. The scientific productivity of physicians and clinical scientists from the Division is remarkable, with internationally recognized areas of excellence in arrhythmology, cardiac valve and aortic surgery, coronary revascularization, vascular inflammation, insulin resistance, diabetic macro- and microangiopathy, intermediary and energetic metabolism, bone pathophysiology. This excellent clinical research traditionally pursued by individual research groups has been reinforced by establishment of the Research Division of Metabolic and Cardiovascular Sciences where a strong basic research is going to be developed offering the opportunity for close interaction between clinical investigators and basic scientists and the implementation of translational research projects.. DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 57 Research Units AMINO ACID AND STABLE ISOTOPES UNIT The group is pursuing several major research areas. In details we are studying: the association among gene polymorphisms, DNA methylation and metabolism in diabetes, obesity and athletes. Diabetes and obesity are conditions often associated with altered levels of plasma homocysteine (Hcy) concentrations. Recently the interrelation between physical exercise and higher Hcy plasma levels have been studied in athletes. We are investigating the effect of in vitro DNA demethylation on MyoD, Myogenin, MHC, PPARã and leptin expression to evaluate the effect of deficiency in DNA methylation by polymorphisms on cells myogenesis and adipogenesis promotion. Metabolic outcome of islet transplantation: using clamp techniques combined with tracer infusions glucose, lipid and amino acids metabolism are studied in type 1 diabetic individuals undergoing islet transplantation Mathematical modelling of metabolic and endocrine systems. The simultaneous assessment of insulin sensitivity and insulin secretion is of paramount importance to evaluate the metabolic status of a subject at risk of becoming diabetic or to monitor the effect of therapies. Aim of our research is to develop methods to perform the simultaneous assessment of insulin secretion and insulin sensitivity. The increasing need to keep the experimental costs as low as possible has given remarkable impulse to the use of indices of derived from an oral glucose tolerance test (OGTT). We are developing a suitable mathematical model that will allow us to reliably estimate these parameters in different physiopathological states from a 3-sample OGTT. Lastly, a nutraceutical line of research was undertaken to discover metabolic effects of plant-derived proteins. Livio Luzi COMPLICATIONS OF DIABETES Prevention, cure and remission of the microvascular complications of diabetes The clinical practice suggests that, despite increasing efforts, there is not yet a final cure for diabetes, whether insulin-dependent or non-insulin-dependent. As a consequence of the above, diabetic complications remain among the major causes of blindness and end stage renal disease in Western countries. The hypothesis we are presently going after is that glucose toxicity represents a compelling challenge for progenitor cells of organs such as the renal glomerulus or the retina known as the major targets of diabetes. To test this hypothesis we are presently involved in two major projects: a) Identification of glomerular progenitor cells. Chronic nephropathies such as diabetic nephropathy are characterized by a progressive loss of proteins through the glomerular filter due to the progressive death of podocytes, the cells responsible for the filtering barrier. This process invariably leads to end stage renal failure. Podocytes are terminally differentiated cells unable to divide, the identification of a podocyte progenitor cell could allow to prevent the progressive loss of filtering capacity that accompanies the progression of diabetic nephropathy but also, at least potentially, to reverse the natural hystory of this life-threatening complication. b) Endothelial progenitor cells (EPCs) and vascular disease in type 1 diabetes. The long-term goal of this study is to clarify whether EPCs can be used in subjects with type 1 diabetes as markers of overall vascular status and occurrence of specific events in the retina. We previously observed that patients with long duration of type 1 diabetes and good glycemic control manifest a reduced number and activity of circulating EPCs. The activity of EPCs is instead significantly increased in patients with proliferative retinopathy. Altogether these findings suggest a possible active role of EPCs in the pathogenesis of the different stages of diabetic retinopathy. To clarify this issue we are presently testing the impact on the number and activity EPCs of diabetes duration, insulin availability, glycemic control, susceptibility or resistance to retinopathy and presence of proliferative retinopathy in patients affected by type 1 diabetes. Gianpaolo Zerbini 58 - SAN RAFFAELE SCIENTIFIC INSTITUTE OBESITY AND METABOLIC RELATED DISEASES The western society is characterized by a large prevalence of obesity and of the metabolic syndrome (2530%). The metabolic syndrome is a cluster of dyslipidemia, diabetes, hypertension, steatohepatitis, and pro inflammatory state but visceral obesity is the major criteria for the diagnosis. The metabolic syndrome is an independent risk factor of cardiovascular disease, and insulin resistance represents its pathogenic process. The onset of insulin resistance in humans is a common adaptive/maladaptive response due to the excess of nutrients in the diet. Under this view we hypothesize that the metabolic syndrome may be secondary to an impaired insulin action at the level of fatty acids metabolism. Insulin in fact is not only able to modulate glucose metabolism but is also involved into the regulation of fatty acids biosynthesis and release at the level of the liver, skeletal muscle, adipose tissue and heart. The understanding of the pathogenic events leading to insulin resistance remains unresolved, eluding the drug-related strategies of intervention. Our working hypothesis is that any perturbation (genetic or acquired) that leads to an increase in intracellular fatty acids concentrations such as 1) acquired or inherited defects in mitochondrial lipid oxidation, 2) defects in adipocyte function 3) increased fat delivery to peripheral tissues due to higher energy intake constitutes a detrimental factor predisposing to the onset of insulin resistance. We were among the first to demonstrate that in humans increased fat accumulation within the skeletal muscle and the liver has systemic deleterious metabolic effects and that increased epicardial fat and intracardiac fat accumulation is a major factor involved in diabetes-induced heart alterations. Therefore, identification of the targets to be treated to reduce fat-induced insulin resistance is of paramount importance. The methodological approach we developed to address this issue is based on in vivo Magnetic Resonance Spectroscopy techniques to study non invasively the alteration of energy metabolism in single organs and tissues and to assess their impact on the whole body system. In particular application of the 31P-MRS at the cardiac and hepatic sites are novel tools to identify targets for potential treatments. Gianluca Perseghin BONE METABOLISM UNIT Aging bone: gene expression and endocrine mileu The three major findings in aging bone, i.e decreased osteoblastogenesis, increased adipogenesis and increased osteoclastogenesis, could be related to altered canonical Wnt signaling. Wnt signaling is emerging as a key regulatory pathway in osteoblast differentiation, bone mass accrual and bone loss. We have therefore studied Wnt signaling in a cohort of aged population of postmenopausal women To this purpose the expression profile of a panel of genes relevant for Wnt signaling have been analyzed by real time PCR. The gene expression analysis was done on trabecular bone samples derived from postmenopausal women divided into two groups, a younger and an older one, according to the donors’ age. Preliminary results showed an increase in the expression of PPAR-γ, β-catenin and DKK1 in the older group while Runx2 was not differently expressed between the two groups. In the older group the expression of RANKL was higher than in the younger one, while that of OPG didn’t show a striking change in expression due to age, although it displayed a trend to decrease. The results suggest that in the older group there is a decrease of Wnt signaling, as a consequence of an upregulation of Dkk1, that might lead to reduced osteoblastogenesis whereas the induction of PPAR-γ expression would drive cell differentiation towards adipogenesis. This shift towards adipogenesis is accompanied by RANKL expression enhancement, which, on the other hand, induces osteoclastogenesis. The gene expression profile here observed is consistent with the major features of aging bone. Collaboratives efforts are also underway to characterize the bone phenotypes of mice models of ADA deficiency, experimental diabetes and MPS as well as bone metabolism in adult GH-deficiency, HIV/HAART, genetic clusters, coronary calcification, ovariectomy and Paget disease. The results of all these studies will lead to improvement of osteoporosis treatment strategies and allow to identify new pharmacological targets. Alessandro Rubinacci DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 59 COAGULATION SERVICE & THROMBOSIS RESEARCH UNIT Our research unit is since a long time interested in the mechanisms whereby natural anticoagulant systems influence the inflammatory response. We have reviewed the anti-inflammatory activity of vitamin K-dependent protein S, and as an introduction to an animal model of severe sepsis (acute lung injury in rats), we have investigated cytokine release, small airway injury, and parenchimal damage during various types of mechanical ventilation (zero end-expiratory pressure, ZEEP; ZEEP plus administration of dioctylsodiumsuccinate, ZEEP-DOSS; negative EEP, NEEP; large tidal volume, LTV) in normal open-chest rats. The control group was ventilated at low tidal volume with PEEP and displayed no change in lung mechanics. Airway resistance and quasi-static elastance increased to different extents in the other groups of rats, which exhibited histologic signs of bronchiolar injury, with parenchymal and vascular injury occurring in the ZEEP-DOSS and LTV groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the control and ZEEP group, but increased in all other groups, and higher in the ZEEP-DOSS and LTV groups. Cytokine levels were correlated with vascular-alveolar damage, suggesting a relationship with stress-related perturbation of endothelial-alveolar cells. Interestingly however, the mechanisms involved in the fall of exhaled nitric oxide (NOe) concentration were independent of TNF-α, and pro-inflamamtory prostaglandins, but they were associated with bronchiolar epithelial damage caused by the abnormal stresses related to cyclic opening and closing of small airways. Our group is also actively involved in the conduct of international multicenter studies on new anticoagulant drugs.We took part in a randomized, open-label non-inferiority trial comparing idraparinux, a long-acting factor Xa inhibitor, with vitamin K antagonists in patients with atrial fibrillation at risk for thromboembolism. The trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux) and a mean follow-up period of less than 1 year because of excess relevant bleeding with idraparinux (19.7 vs 11.3 per 100 pt-yrs; p<0.0001), with higher occurrence of in intracranial bleeding (1.1 vs 0.4 per 100 pt-yrs, p=0.014). Armando D’Angelo CARDIODIABETES & CORE LAB NO produced by eNOS is the key regulator of vascular homeostasis and represents a major second messenger for a plethora of physiological processes. NO from the endothelium is considered an important atheroprotective mediator, and acquired defects in NO generation associated with cardiovascular risk factors cause endothelial dysfunction and may contribute to the development of atherosclerosis. Central to all these physiological functions is the proper eNOS expression and adequate eNOS enzyme activity. Our previous clinical experience demonstrated a specific phenotype characterized by increased fasting nitric oxide levels but reduced response after an insulin stimulus in patients with cardiovascular disease and in type 2 diabetic patients and their first degree relatives. At genetic level we found a strong association between eNOS gene variants and type 2 diabetes and intra-stent restenosis. The polymorphism in intron 18 of eNOS gene affects the physiological mRNA splicing, with skipping of exons 19 and 20. As a result, the alternative transcript does not encode an enzymatically active protein and, when co-expressed, it inhibits enzymatic activity of the full-length, thus acting as dominant negative regulators of nitric oxide synthesis. This suggests that truncated NOS polypeptides have diminished enzymatic activity and it will explain the presence of dramatically increased presence of early restenosis in patients carrying the eNOS SNP in intron 18. Our project is aimed to evaluate eNOS gene function and the mechanisms of gene expression and regulation in the presence of gene variants and the impact at cellular and tissue levels both in an animal model and in arterial or platelet cells of patients carrying the polymorphism. The importance of metabolic factors, i.e. the presence of alterations of glucose or lipid metabolism will be taken into account. Other fields of research are the evaluation of new candidate genes, the definition of the molecular mechanisms involved in early endothelial activation and inflammation in isolated endothelial cells and the evaluation of genes expression for inflammation and oxidative stress in endothelial progenitors cells and the search of new serological indices involved in the pathogenesis of CARDIO-DIABETES. Lucilla D. Monti 60 - SAN RAFFAELE SCIENTIFIC INSTITUTE PEDIATRIC ENDOCRINOLOGY RESEARCH Bone health in childhood and adolescence The interest in children’s bone health has been expanding over the last decade, following the evidence for a role of bone accrual in the determination of fracture susceptibility in adult life. In particular, bone mass gain during childhood and adolescence is regarded as a key factor for the development of senile osteoporosis. Bone mass accrual is determined by the concerted action of bone-forming cells (osteoblasts), and bone-resorbing cells (osteoclasts). The physiologic changes of bone metabolism during growth are still largely unknown. Our group is investigating such changes in healthy children and adolescents. Moreover, we have assessed the possibility of using different kinds of bone densitometers in the bone mass measurement in children. Numerous pediatric disorders are complicated by impaired bone mineral accrual and altered bone metabolism. Our group is investigating skeletal health in young patients with gastrointestinal, endocrine, and chronic infective diseases. We reported alteration of bone metabolism leading to reduced bone mass in celiac children. We are currently exploring the hypothesis of autoimmunity involvement in the genesis of bone mass impairment in celiac patients. The use of antiretroviral drug increased the survival of HIV-infected patients, but they also show important side effects. Among others, low bone density has been described in children. We are currently following a large number of HIV-infected youths, in collaboration with Alessandra Viganò at Sacco Hospital, Milan, to assess the long-term impact of treatment on bone health. Stefano Mora Clinical Research Units DIABETES AND ENDOCRINOLOGY UNIT The research of our unit in the field of type 1 and type 2 diabetes is focused on relevant clinical questions, such as self-monitoring of blood glucose, lifestyle changes (diet and physical activity), disabling diabetic neuropathy: Self-monitoring of blood glucose for the management of patients with type 2 diabetes is a controversial issue. We are conducting a large, Nationwide multicenter randomized clinical trial to study the impact of a program of lifestyle changes based on self-monitoring of blood glucose in patients with type 2 diabetes treated with diet alone or oral agents. The trial will recruit 1000 participants in over 30 diabetes outpatient clinics throughout Italy. Physical activity is one of the cornerstone of diabetes treatment. However, only a small proportion of patients with type 2 diabetes walks at least 10,000 steps/day. Modern technology may help our patients achieve this goal. We are conducting a randomized clinical trial to assess whether providing patients with type 2 with a with a step counter with wireless connection to a cell phone helps achieving the walking goal of 10000 steps/day. Patients with type 1 diabetes need to adjust their pre-meal insulin bolus according to the expected carbohydrate content of their meal. The method of carbohydrate counting has become very popular in Northern America and more recently in Europe. We are conducting a randomized clinical trial to study the impact of carbohydrate counting on glucose control in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion using an external insulin pump. Peripheral neuropathy is a frequent and disabling microvascular complication of both type 1 and type 2 diabetes. Pharmacological treatment of diabetic neuropathy is purely symptomatic and largely unsatisfactory. As a novel and original non pharmacological treatment, a Frequency modulated Electro-Magnetic neural Stimulation (FREMS) method, characterized by sequences of modulated electrical stimuli which vary automatically in pulse frequency, duration and voltage amplitude, has recently been developed by our group. In a pilot trial DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 61 FREMS proved to be safe and efficacious in the treatment of painful diabetic neuropathy, with the evidence of associated enhancement of local tissue microcirculation. An International Multicenter trial is currently ongoing to validate FREMS as an effective treatment of diabetic neuropathy. Emanuele Bosi CARDIODIABETES AND CLINICAL TRIALS The main hypothesis of CARDIO-DIABETES Project is that type 2 diabetes mellitus (DM2) and ischemic cardiomyopathy (CAD) are the same disease. Furthermore, in our opinion, the heart is not only a passive player being affected by the negative effects of DM2 but is also an active player acting as an endocrine-metabolic organ able to induce DM2. The project will help to recognize new pathogenetic mechanisms and innovative therapies with the final goal to prevent endothelial dysfunction (ED), insulin resistance (IR), DM2 and CAD. To screen populations at higher risk to develop DM2, we initiated the characterization of the metabolic and endothelial differences between coronary and carotid atherosclerosis. Preliminary data in a small group of patients suggested that coronary atherosclerosis is characterized by decreased adiponectin levels, insulin resistence and a more proatherogenetic profile than carotid atherosclerosis. Conversely, an increased prothrombotic state and higher platelet activation seem to be present in patients with carotid vasculopathy, suggesting the presence of a marked heterogeneity of coronary and carotid atherosclerosis. In patients with heart valve disease we demonstrated a high prevalence of DM2 associated with increased ANP and FFA levels. In the attempt to evaluate the role of inflammation on insulin resistance, we demonstrated that in first degree relatives normal glucose tolerant women, fasting hyperinsulinemia, independently of the presence of Metabolic Syndrome, is associated with elevated IL-6 and leptin levels, suggesting an increased cardiovascular risk. In the light to evaluate innovative treatments to revert IR and ED, as part of the Cardio-Metabolic and Clinical trials Unit, two intervention studies with L-arginine are ongoing in CAD and IR. In patients with CAD, we showed that chronic oral L-arginine therapy ameliorated insulin sensitivity, glucose tolerance and inflammation. The second study, in patients with glucose intolerance and metabolic syndrome, is ongoing and will enlight the role of L-arginine in the prevention of DM2. The group is also involved in the largest and major world-wide sponsored Clinical Trials for the prevention and cure of DM2 and CAD. Piermarco Piatti CLINICAL PEDIATRIC ENDOCRINOLOGY The incidence of congenital hypothyroidism (CH) has significantly increased in the last few years, also due to the lower TSH cut-off for the recall at newborn screening. We have observed a increase in CH cases with gland in situ. A percentage of these forms can be related to iodine organification defect or mutations in rTSH gene. We continued molecular studies on CH with gland in situ and dyshormonogenesis, in collaboration with the University of Milano. We focused our attention on gene involved in iodide organification: DUOX2 and DUOXA2 and published the first mutation in DUOXA2 in a mild form of permanent CH with gland in situ. Congenital hyperinsulinism of infancy (CHI) is a yet unresolved problem for paediatric endocrinologists. Several genes have been found to be responsible for CHI (ABCC8, KCNJ11, GLUD1, GCK, HADH, PCSK1, phosphomannose isomerase). The patients are screened for mutations in ABCC8 and KCNJ11 by direct sequencing in collaboration with University of Milan. Small for gestational age (SGA) children are at risk for obesity and Metabolic Syndrome (MetS). We hypothesized that overweight SGA children presented more components of the MetS than overweight children born appropriate for gestational age (AGA).The intrahepatic fat (IHF) was measured using localized hepatic 1HMRS. IHF content, whole body energy homeostasis, insulin sensitivity, and body composition were measured in SGA and AGA adolescents. Giovanna Weber 62 - SAN RAFFAELE SCIENTIFIC INSTITUTE DIABETES AND METABOLIC DISEASES IN CHILDREN AND ADOLESCENTS Heterozygous, gain-of-function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood. The aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies.: We reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies. We sequenced the INS gene in these seven patients. In two patients whose diabetes onset had been at 2 years 10 months of age and at 6 years 8 months of age, respectively, we identified the mutation G(B8)S and a novel mutation in the preproinsulin signal peptide (A(Signal23)S). Insulin gene mutations are rare in absolute terms in patients classified as type 1 diabetic (0.6%) but can be identified after a thorough screening of type 1 diabetes autoantibodies. The study was in conducted in collaboration with Fabrizio Barbetti (Laboratory of Molecular Endocrinology, Bambino Gesù Pediatric Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Laboratory of Molecular Endocrinology and Metabolism, San Raffaele Biomedical Park Foundation, Department of Internal Medicine, University of Rome–Tor Vergata, Rome, Italy). Franco Meschi NEONATOLOGY Central nervous system in newborn The study of nervous system maturation is one of the most important research area of our group. We collaborate with Neuroradiology Unit to study CNS maturation in term and preterm newborn. From 2006 a longitudinal study is in progress to evaluate myelinitation and maturation of brain by serial MRI scan in preterm with gestational age inferior to 34 weeks at birth: different imaging tecniques like diffusion tecnique imaging (DTI) and functional MRI are performed with high field MRI. Clinical and psychomotor followup evaluations will be correlated to post-natal clinical datas. Another collaboration with Neuroradiology Unit and Neuroscience Department has studied neuronal processes understanding melodic and language processing in the first week of life. At last a multicentric study on life quality of “wellbeing” preterm infants is in progress with other Italian Neonatology Units: the aim of this study is to evaluate quality of care and its perception till seven years of life. Graziano Barera Figure 6. Preterm infants care FOETAL-MATERNAL MEDICINE Study of new predictors of pregnancy outcomes in women with high risk pregnancies 1. Study of markers of vascular injury Pregnant women with type 1 diabetes have an increased incidence of preeclampsia. Furthermore, among these patients diagnosing preeclampsia may be challenging since microalbuminuria, proteinuria and/or hypertension may be present before pregnancy. We reported that pentraxin 3 (PTX3), a marker of vascular injury, in- DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 63 creases in the plasma of pregnant women several weeks before the clinical onset of preeclampsia. Recent evidences suggest that hyperglycaemia damages the trophoblastic tissue playing a role in the development of eclampsia. We will measure PTX3 during the first trimester to monitor placental development in diabetic pregnancies and to study whether early changes in PTX3 levels may be predictive of preeclamsia in pregnant patients with type 1 diabetes. 2. Study of early morphological markers of abnormal fetal development Despite optimal pre-natal care pregnant patients with type 1 diabetes have an increased risk of macrosomia and fetal distress compared to women without diabetes. Furthermore, the growth pattern of fetuses of diabetic mothers and the timing of growth changes are poorly understood. Recent evidences are highlighting the relevance of first trimester of pregnancy for the development of complications in the last phases of pregnancies. By means of conventional and 3D ultrasound we are studying fetal and placental volumes to document fetal and trophoblastic development during the first trimester and correlating these measurements with pregnancy outcomes in women with type 1 diabetes and women with high risk pregnancies. 3. Study of feto-placentar nucleic acids in maternal plasma During the past year we collaborated with the Genomic Unit for Diagnosis of Human Pathologies to develop a new method for non-invasive pre-natal diagnosis of β-thalassemia based on the study of the fetal DNA present in maternal blood. We are now planning to study transcripts of fetal genes that are found in maternal blood and that are potentially involved in the pathogenesis of preeclampsia and fetal growth restriction. The identification of early markers of these diseases will be important for early diagnosis and prevention. Maria Teresa Castiglioni INFERTILITY Our Group for Research in Infertulity care was involved in several clinical and basic researches. For clinical studies we worked on: a) A phase 3 study for the evaluation of efficacy of LH addition in the ovulation induction for poor responders. b) A study for the evaluation of the efficacy of administration of progesterone in aqueous phase instead than oleous phase in the luteal part of the cycle c) A study for the evaluation of the role of Cabergoline in the prevention and treatment of severe hyperstimulation. For laboratory studies our unit has been involved in two important studies supported by the Istituto superiore di sanità and the Regione Lombardia. 1) The first study is on oocyte cryopreservation. Several experimental designs were performed to understand the best way of freezing human oocytes. 2) The second study is in the right choice of gametes for insemination. Experiments are done to assess the oocyte competency with the study of first polar body, and the sperm morphology using high magnification microscope. Francesco Fusi CARDIOVASCULAR INTERVENTIONS UNIT Complex Coronary Lesions: We have conducted different retrospective multicentre registries in order to evaluate the safety and efficacy of drug-eluting stent (DES) implantation in unprotected left main lesions showing encouraging results. Two randomized trials are also conducted in order to assess the optimal revascularization therapy (CABG vs. DES) in diabetics with multivessel disease (FREEDOM) and 3 vessel disease and/or left main lesions (SYNTAX). The stenting strategy in true bifurcation lesions has been evaluated in the multicenter randomized CACTUS trial (crush vs. provisional stenting technique). A novel dedicated bifurcation stent was indeed evaluated in the Sideguard 2 registry. 64 - SAN RAFFAELE SCIENTIFIC INSTITUTE New Stents: A novel nano-structured titanium nitride stent is currently under investigation in a multicenter randomized trial (MARTIN). Imaging/ Intravascular Ultrasound (IVUS): New criteria for optimal DES deployment were tested in the multicenter randomized “Angiography vs. IVUS Optimisation” (AVIO) study. Adjunctive therapy:In the prospective randomized study (NAPLES II) a single, high loading dose of atorvastatin is evaluated in preventing periprocedural MI. In the SATURN trial the effect on percent atheroma volume of high dosages of atorvastatin vs. rosuvastatin is assessed. Neoangiogenesis: is currently evaluated through intramyocardial injection of autologous stem cells in patients with refractory angina despite optimal medical therapy or not eligible for further revascularization. Structural Heart Disease/ Transcatheter valve therapy: A multidisciplinary program for transcatheter aortic and mitral valve therapy has been developed. Our experience since the beginning of the aortic valve program (November 2007) showed encouraging results.Two devices received CE-mark approval in 2007 and are currently used in our aortic valve program: the balloon-expandable Edwards-Sapien valve, and the self-expanding CoreValve ReValving System. Antonio Colombo CLINICAL CARDIOVASCULAR BIOLOGY UNIT Acute Coronary Syndromes: from bedside to bench Targeted biological strategies to prevent Acute Coronary Syndromes (ACS) are limited despite effective and expensive therapies. Animal models do not incur in ACS thus making necessary the study on patients (pts) to: 1) foster the understanding of the immuno-inflammatory response in the pathogenesis and complications of atherosclerosis; 2) translate novel molecular approaches into the development of innovative diagnostic, preventive, and therapeutic strategies. The key attitude of our Unit is the attempt to create a link between basic multidisciplinary biomedical research and the clinical field making possible a translational medicine. Bedside researches: 1. Active collaboration in phase II and III International Clinical Trials to test newer anti-thrombotic drugs (TIMI-50) 2. As coordinating center, we closed the enrollment of cases and controls in the multi-ethnic First Acute Myocardial Infarction (FAMI) for the study of inflammatory and genetic components that trigger ACS. Initial results were presented (Am.Coll.Cardiology) 3. In-vivo bioimaging of active carotid plaques by echocontrast (JACC - with Roberto Chiesa) Bench researches on: 1. The synergic role of B and T cells and the cytokine milieu in pts with ACS. We documented the presence of an antigen-driven B cell maturation within human coronary lesion (J.Immunol. – with Microbiology Unit, M. Clementi). We defined a specific proatherogenic T-cell subset (TCRz dim) that we found increased during ACS (Arteriosclerosis, Thrombosis and Vascular Biology) by polychromatic flow cytometry (with Flow Cytometry - A. Palini) and analysis are performed exploiting machine learning algorithms on multi-parameter data obtained (with University of California - T. Ravasi). We described a selective cytokine signature in a fraction of pts with ACS, identified by high levels of circulating IL-6 not secondary to myocardial damage. 2. The interaction of circulating neutrophils and platelets occurs during ACS. We have observed and we are characterizing a P-selectin mediated pathway of reciprocal activation of circulating platelets and leukocytes (Blood - with Clinical Immunology Unit, A. Manfredi) to curb artherial thrombosis. 3. Genetic factors that predispose to ACS on the FAMI samples. Analysis are ongoing (with M. Ferrari and G. Casari). Domenico Cianflone DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 65 ISCHAEMIC HEART DISEASE, HEART FAILURE AND ECHOCARDIOGRAPHY UNIT Heart failure 1) ACITRIM: to assess myocardial function and metabolism after acute metabolic modulation. 2) TRIMCAL: to assess myocardial function, after inhibition of FFA oxidation. 3) METNIC: to assess the effetcs of metformin on myocardial function and metabolism, insuline sensivity, effort tolerance, insuline resistance. 4) BEM: to evaluate the expression of mytocondrial ferritin in myocardial biopsies. 5) CREMONO: to evaluate membrane diffusion and CO exhaled. 6) HODIC: to evaluate the effectiveness of heparin anticoagulation therapy in atrial fibrillation. 7) AA/CHF: to evaluate the therapeutic effect of a mix of essential aminoacids. 8) SHIFT: to evaluate the effect of ivabradine on morbility and mortality 9) VILDAGLIPTIN: to evaluate the effect on cardiac function of Vildagliptin, an oral antidiabetic drug. 10) RENO DEFEND-1: to evaluate the safety and efficacy of SLV320 on renal function, in patients with acute heart failure and renal dysfunction. 11) ATMOSPHERE: to evaluate the effect of aliskiren on cardiovascular morbidity and mortality. Ischaemic heart disease 1) Sindrome X: perfusional, metabolic and neuro-endocrinal characteristics in patients with microvascular angina. 2) CAD 1: to evaluate the role of osteoprotegerin in the evolution of coronary lesions. 3) CAD 2: to evaluate the correlation between major risk factors and the severity of coronary disease in Pts with CAD 4) CAD 3: to assess the role of a new test(Loxin test to evaluate LDLC oxidation)to predict events in patients with CAD 5) CAD 4: to evaluate the protective effect of a combination treatment against contrast induced nephropathy. Echocardiography EchoLab of Division of Cardiology was actively involved in 2 research fields: • Translational Research in 3D Echo; • Mitral Valve Disease; Diastolic Heart Failure. In particular, in the field of 3DE we tested: 1) The potential application and the added value of Real-Time 3D Transesophageal Echo in the common clinical scenario; 2) The added value of 3DE in the anatomic and functional delineation of MVD and ASD. Alberto Margonato ORGAN PROTECTION IN CRITICALLY ILL PATIENTS, ADVANCED CARDIAC FAILURE AND MECHANICAL SUPPORTS UNIT Perioperative organ failure is associated to high morbidity and mortality. We are coordinating large multicentre randomized controlled studies at the Italian level on numerous topics. These studies are supported by the two largest and most influential Italian scientific societies in the field of anesthesia and intensive care (SIAARTI and ITACTA). All the studies have been approved by the Ethical committee of San Raffaele Hospital, have been published on www.clinicaltrials.gov and include: • • prevention of dialysis dependent acute renal failure after cardiac surgery is studied with a 20 centres, 1000 patients study (fenoldopam vs placebo) optimization of perioperative cardiac protection (esmolol vs placebo and volatile agents versus total intravenous anesthesia) is studied. Volatile anesthetics, commonly used for general anesthesia during surgery 66 - SAN RAFFAELE SCIENTIFIC INSTITUTE • • • • to induce and maintain hypnosis, analgesia, and amnesia seems to reduce myocardial infarction and improve postischemic recovery at the cellular level. We are studying preventive measures (pharmacological preconditioning with halogenates) that could be transferred to all ischemic patients undergoing procedures that could trigger ischemia and myocardial damage. early treatment of low cardiac output syndrome with pharmacological (levosimendan vs placebo) or mechanical supports (ECMO, VAD) is one of our main topics of interest. We also have a scientific collaboration with the Berlin Hertz Centrum. safety and efficacy or recombinant activated factor VII, of desmopressin, factor XIII, protein C zymogen and protein C activated in patients experiencing excessive bleeding after surgery in large multicentre randomized studies or in patients with severe sepsis admitted in the intensive care unit. anesthesiological challenges of the unfit patients, ideal candidate to transfemoral artery aortic valve implantation. non-invasive ventilation outside intensive care unit and the role of the Medical Emergency Team for a timely treatment of critically ill patients in the hospital ward. We have also published numerous original papers and systematic review of the literature on the above described topics. With 23 papers published in international indexed journals in 2008 we’re the most prolific Italian group publishing in anesthesia and intensive care journals. We are also publishing a new journal “HSR proceedings in Intensive Care and Cardiovascular Anesthesia”, freely available on www.itacta.org Alberto Zangrillo STRUCTURAL HEART DISEASE UNIT Treatment of structural heart disease Heart failure Surgical strategies to treat patients with heart failure due to ischemic or idiopathic cardiomyopathies are investigated. Original procedures to correct secondary mitral and tricuspid regurgitation have been developed and extensively applied with a rigorous long-term follow-up. A multidisciplinary protocol for mechanical circulation assistance has been prepared and selection intense have been established. Cell therapy (myoblast) has been used in patients with post infarction left ventricular dysfunction, in the contest of a multicenter prospective monitorized placebo controlled study (MAGIC study). Heart valve disease Innovative techniques to repair mitral and aortic valve are systematically evaluated. New imaging modalities are applied and correlated to the operative findings. In repair the tricuspid valve, a new prosthetic ring has been developed and tested on the bench Ischemic heart disease Active contribution has been given to the SYNTAX study and the FREEDOM study, both comparing PCI and CABG in multivessel disease Atrial fibrillation New surgical methods to increase the effectiveness of the atrial fibrillation ablation procedures, during open heart surgery, have been developed. A program for the treatment of lone atrial fibrillation via a minimally invasive approach has been initiated, and new technologies have been introduced and meticulously tested. The left atrial remodeling has been studied non only structurally but also at molecular and biochemical level. Transcatheter valve therapy A multidisciplinary program for transcatheter aortic and mitral valve therapy has been developed using a wide spectrum of techniques and technologies. Guidelines have been prepared and extensive investigation in this new area are ongoing. Ottavio Alfieri DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 67 STUDY AND TREATMENT OF AORTIC DISEASE UNIT Our group is conducting several clinical research studies regarding the treatment of abdominal, thoracic, and thoracoabdominal aortic disease. ABDOMINAL AORTA: We are reviewing the early and late results of endovascular infrarenal aortic aneurysm repair with different endograft devices, and particularly in patients at high risk for conventional open repair. We also analysed the outcome of pararenal aortic aneurysms and pseudoaneurysms repair, evaluating the impact of different therapeutic strategies, including open, endovascular, and hybrid (open + endovascular) techniques. In particular, we focused on perioperative determinants of post-operative glomerular filtration rate. Finally, we retrospectively reviewed a large series of patients affected with aortoiliac occlusive disease and treated by bifurcated longitudinally extensible expanded polytetrafluoroethylene bypass grafting. THORACIC AORTA: Endovascular repair has emerged as an extremely valuable alternative modality for the treatment of thoracic aortic diseases due to its reduced invasiveness as compared to open repair. We are studying technical and clinical outcomes recorded in the different anatomical zones especially focusing on the offpump hybrid repair of aortic arch aneurysms. We are also focusing on anatomic and pathophysiological determinants of postoperative spinal cord ischemia, including the preoperative detection of the Adamkiewicz artery by multidetector computed tomography, to develop new prevention strategies. We are also evaluating the perioperative and late results of new devices specifically designed for endovascular repair of type B dissection. In addition, we are reviewing early and long-term results of endovascular repair of traumatic thoracic aortic rupture, and conducted a National survey on endovascular repair of aorto-oesophageal and aorto-bronchial fistulas. THORACOABDOMINAL AORTA: As a Nation referral Center, we are reviewing our large experience of open and hybrid repair of thoracoabdominal aortic aneurysms and dissections with the use of the more innovative technique of extracorporeal circulation, intraoperative hypothermic renal perfusion, and specific graft material. A manuscript on our experience of thoracoabdominal aortic aneurysm hybrid repair (see figure), that represents the largest worldwide single-center series to date, has been also recently published. Roberto Chiesa Figure 7. Picture shows an example of sequential treatment of type B aortic dissection. After TEVAR, a type IA endoleak was discovered on follow-up and required further treatment with proximal extension in zone 1 (revascularization of supra aortic vessels via carotid-carotid-subclavian bypass). Later type IB was discovered. this condition required hybrid treatment with revascularization of the common hepatic artery, superior mesenteric artery, right and left renal artery by a custom made four-branched graft anastomized to the infrarenal aorta and subsequently deployment of a third stentgraft. CENTER FOR ARRHYTHMIA RESEARCH The research activity of the Arrhythmology group of San Raffaele University-Hospital is focused on atrial fibrillation ablation, particularly on remote ablation using tip-irrigated magnetic catheters in 2008. In our center catheter ablation of atrial fibrillation is safely performed in many patients with and without comorbidities. We are conducting a large study in the elderly to assess both efficacy and safety in this patient population. Another area of research is the pathophysiology of atrial fibrillation investigating the natural history of the arrhythmia with its progression from the first symptomatic episode. We are also assessing the effect of catheter ablation on atrial fibrillation progression by the APAF2 study which is a 3-year extension study of the previous 1-year 68 - SAN RAFFAELE SCIENTIFIC INSTITUTE APAF trial. It was designated to compare the long-term outcome of catheter ablation versus conventional antiarrhythmic drug therapy in a large number of patients randomized to both strategies. At 3 years (2008) the results demonstrate a striking superiority of catheter ablation over antiarrhythmic drugs in terms of efficacy, arrhythmia progression and late complications. The identification of asymptomatic subjects at risk of sudden death with either latent Brugada syndrome or Wolff-Parkinson-White syndrome represents another important area of research in our center. Finally, the last area of research is the development of new technologies for catheter design and 3D anatomical reconstruction of cardiac chambers for atrial fibrillation ablation. Vincenzo Santinelli Figure 8. Clinical Research: Light and Hope DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 69 Complications of diabetes Bone metabolism Unit Cardiovascular interventions Unit Structural heart disease Unit Study and treatment of aortic disease Unit DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 71 DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY Director: Giulio Cossu Associate Directors: Fabio Ciceri, Luigi Naldini * Research Units Skeletal muscle development and therapy Unit HEAD OF UNIT: Giulio Cossu RESEARCHER: Graziella Messina POST-DOCTORAL Fellows: Arianna Dellavalle, Jordie Diaz, Hoshia Hidetoshi, Anna Pistocchi, Gonzalo Ugarte PHD STUDENTS: Sara Benedetti, Ornella Cappellari, Saverio Tedesco TECHNICIANS: Diego Covarello, Anna Innocenzi, Stefania Monteverde, Laura Perani, Rossana Tonlorenzi Functional genetics of muscle regeneration GROUP LEADER: Silvia Brunelli POST-DOCTORAL FELLOWS: Stephanie François, Thierry Touvier PHD STUDENTS: Emanuele Azzoni, Patrizia Pessina FELLOWS: Valentina Conti, Stefania De Cesare Gene expression and muscular dystrophy Unit (Dulbecco Telethon Institute) GROUP LEADER: Davide Gabellini POST-DOCTORAL FELLOWS: Sergia Bortolanza, Cristina Godio, Paola Picozzi, Mariaelena Pistoni PHD STUDENT: Daphne Cabianca Molecular and functional immunogenetics GROUP LEADER: Katharina Fleischhauer POST-DOCTORAL FELLOW: Federico Sizzano PHD STUDENT: Pietro Crivello FELLOW: Giandomenico Turchiano TECHNICIAN: Laura Zito Neural stem cell biology GROUP LEADER: Rossella Galli PHD STUDENTS: Daniela Corno**, Laura Magri**, Stefania Mazzoleni** FELLOW: Mauro Pala TECHNICIAN: Vivian Deidda Vigoriti Autoimmunity & vascular inflammation Unit HEAD OF UNIT: Angelo A. Manfredi* PHD STUDENTS: Lidia Bosurgi**, Lucia Cottone FELLOW: Norma Maugeri TECHNICIANS: Annalisa Capobianco, Antonella Monno Innate immunity and tissue remodelling GROUP LEADER: Patrizia Rovere-Querini POST-DOCTORAL FELLOW: Gianfranca Corna PHD STUDENTS: Lara Campana, Alessandra Castiglioni, Michela Vezzoli 72 - SAN RAFFAELE SCIENTIFIC INSTITUTE Cellular pharmacology Unit HEAD OF UNIT: Emilio Clementi POST-DOCTORAL FELLOWS: Clara De Palma, Sestina Falcone, Cristiana Perrotta PHD STUDENTS: Laura Bizzozero, Roberta Buono, Serena Pisoni FELLOW: Sara Baldelli TECHNICIAN: Clara Sciorati Experimental hematology Unit HEAD OF UNIT: Chiara Bonini RESEARCHER: Attilio Bondanza POST-DOCTORAL FELLOW: Luca Vago PHD STUDENTS: Monica Casucci, Elena Provasi FELLOW: Maddalena Noviello RESIDENT: Sara Mastaglio TECHNICIANS: Zulma Magnani, Veronica Valtolina Angiogenesis and tumor targeting HEAD OF UNIT: Luigi Naldini* GROUP LEADER: Michele De Palma POST-DOCTORAL FELLOWS: Roberta Mazzieri, Mary Anna Venneri PHD STUDENTS: Francesco Boccalatte**, Ferdinando Pucci**, Mario Squadrito**, Erika Zonari FELLOW: Daniela Biziato Clinical Research Units Hematology and hematopoietic stem cell transplantation Unit HEAD OF UNIT: Fabio Ciceri PHYSICIANS: Andrea Assanelli, Jacopo Peccatori RESIDENTS: Valeri Calbi, Daniela Clerici, Raffaella Greco POST-DOCTORAL FELLOWS: Maria Teresa Lupo Stanghellini, Annalisa Ruggeri TECHNICIAN: Roberta Mattarucchi Immunohematology and transfusion medicine Unit HEAD OF UNIT: Silvano Rossini RESEARCHER: Laura Bellio FELLOW: Alessandra Venditti PSIEP-Strategic Program of Pediatric Immunohematology HEAD OF UNIT: Maria Grazia Roncarolo* PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Barbara Cappelli, Robert Chiesa, Sarah Marktel RESIDENT: Erika Biral The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Director: Luigi Naldini* Research Units Gene transfer technologies and new gene therapy strategies Unit HEAD OF UNIT: Luigi Naldini* POST-DOCTORAL FELLOWS: Mario Amendola, Bernhard Gentner PHD STUDENTS: Alessio Cantore**, Angelo Lombardo** FELLOW: Pietro Genovese** TECHNICIANS: Giulia Schira, Lucia Sergi Sergi DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 73 Gene/Neural stem cell therapy for lysosomal storage diseases GROUP LEADER: Angela Gritti PHD STUDENTS: Chiara Cavazzin, Margherita Neri, Sara Santambrogio FELLOW: Annalisa Lattanzi TECHNICIAN: Claudio Maderna Hematopoietic stem cell gene therapy for lysosomal storage disorders GROUP LEADER: Alessandra Biffi PHD STUDENTS: Alessia Capotondo**, Martina Cesani**, Ilaria Visigalli** FELLOWS: Stefania Delai, Silvia Ungari Safety of gene therapy and insertional mutagenesis GROUP LEADER: Eugenio Montini PHD STUDENTS: Daniela Cesana**, Marco Ranzani** TECHNICIAN: Fabrizio Benedicenti Gene transfer into stem cells Unit HEAD OF UNIT: Giuliana Ferrari* RESEARCHERS: Maria Rosa Lidonnici, Emanuela Anna Roselli POST-DOCTORAL FELLOW: Rossella Ierardi TECHNICIANS: Giacomo Mandelli, Claudia Rossi, Francesca Tiboni Immunological tolerance Unit HEAD OF UNIT: Maria Grazia Roncarolo* POST-DOCTORAL FELLOWS: Andrea Annoni, Laura Strauss PHD STUDENT: Maura Rossetti TECHNICIANS: Grazia Andolfi, Claudia Sartirana, Eleonora Tresoldi From FOXP3 mutation to IPEX syndrome GROUP LEADER: Rosa Bacchetta PHD STUDENTS: Sara Di Nunzio, Laura Passerini, Giorgia Serafini FELLOW: Giada Alberigo Tolerogenic dendritic cells GROUP LEADER: Silvia Gregori PHD STUDENT: Chiara Magnani TECHNICIAN: Daniela Tomasoni Pathogenesis and therapy of ADA-SCID Unit HEAD OF UNIT: Alessandro Aiuti POST-DOCTORAL FELLOW: Silvia Selleri PHD STUDENTS: Luca Biasco, Immacolata Brigida, Aisha Sauer TECHNICIANS: Raisa Jofra Hernandez, Anna Ripamonti Gene therapy for WASP/Omenn GROUP LEADER: Anna Villa POST-DOCTORAL FELLOWS: Marita Bosticardo, Francesco Marangoni, Samantha Scaramuzza PHD STUDENTS: Marco Catucci, Michela Locci, Veronica Marrella TECHNICIAN: Elena Draghici 74 - SAN RAFFAELE SCIENTIFIC INSTITUTE Clinical research Groups Pediatric clinical research Unit HEAD OF UNIT: Maria Grazia Roncarolo* COORDINATOR: Alessandro Aiuti PROJECT LEADERS: Alessandro Aiuti (ADA-SCID), Maria Grazia Roncarolo* (WAS), Maria Sessa (MLD) PHYSICIAN: Alessandra Biffi RESIDENT: Francesca Fumagalli QUALITY ASSURANCE AND REGULATORY AFFAIRS: Valentina Bergamante FELLOWS: Francesca Ferrua PHD STUDENT: Martina Cesani TECHNICIAN: Tiziana Plati RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi * Professor at: Università Vita-Salute San Raffaele ** Università Vita-Salute San Raffaele DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 75 Introduction by the Directors Giulio Cossu The Division of Regenerative Medicine was created at the end of year 2008, by joining the Telethon Institute of Gene Therapy (TIGET), that remains an independent institute directed by Luigi Naldini, with former Stem Cell Research Institute and also includes researchers with expertise in developmental and stem cell biology, inflammation, immunology, tissue regeneration as well as clinicians actively involved in clinical trials, mainly in hematology. TIGET contributes its expertise and international leadership in gene therapy, including the development of new pre-clinical protocols, vector design and new clinical trials, in addition to the one currently running of congenital immune deficiency do to a mutation in the Adenosine Deaminase gene. The Division currently comprises 10 Principal Investigators/Heads of Unit, 10 Group leaders, and approximately 200 researchers, clinicians, post and predoctoral fellows, undergraduate students and technicians. Projects focus on stem cell biology and physiopathology of the hematopoietic system, skeletal muscle and of the nervous system aiming at elucidating the pathogenesis of certain diseases of these tissues (congenital immune deficiencies, thalassemias, hemophilias, leukemias, muscular dystrophies and tesauris- Fabio Ciceri mosis), at developing pre-clinical models and clinical protocols of gene and cell therapy. Several clinical trials for onco-hematologic pathologies are currently running. 76 - SAN RAFFAELE SCIENTIFIC INSTITUTE Research Units SKELETAL MUSCLE DEVELOPMENT AND THERAPY UNIT 1. Control of skeletal muscle development We have shown that the myogenic bHLH MRF4 is able to replace Myf5 and MyoD during Zebrafish myogenesis, much as it happens during mouse myogenesis. This does not happen when both Myf5 and MyoD are silenced because the natural expression of this gene is late in the fish (Schnapp et al. 2009). We have also shown that the NFI-X transcription factor regulates the transcriptional shift between embryonic and fetal muscle, by repressing embryonic genes and activating fetal ones either alone or forming a ternary complex with MEF2A and PKC theta (Messina et al. submitted). 2. Origin and fate of mesoangioblats Mesoangioblasts, vessel-associated mesoderm progenitors, can be induced to differentiate in several types of solid mesoderm. We have shown that skeletal myogenesis of mesoangioblasts requires Pax3 (Messina et la. 2009). Currently we aim to identify the signaling molecules that commit vessel-associated progenitors to a skeletal myogenic fate. Moreover, by means of Cre-lox lineage marking using an inducible Cre driven by a pericyte specific promoter, we have preliminary evidence that pericytes contribute to muscle fiber formation during unperturbed development of the tissue. 3. Pre-clinical models of cell therapy for muscular dystrophies We are developing new protocols with autogous cells, either reversibly immortalized by floxed lentiviral vectors expressing human telomerase and Bm-1, or with iPS induced to a mesoangioblast fate. Gene correction will be carried out either by lentiviral vectors expressing mini-dystrophin or α sarcoglycan or, alternatively, with a human artificial chromosome containing the whole dystrophin locus. These strategies will be tested in immune deficient, dystrophic mice. 4. A clinical protocol for allo-transplantation of donor mesoangioblasts from an HLA-identical healthy sibling in three patients affected by Duchenne Muscular Dystrophy (DMD). This protocol is the result of pre-clinical studies in dystrophic dogs and mice. Mesoangioblasts will be grown under GMP conditions and transplanted folowing a three-step protocol (intra-muscular; intra femoral artery; multi-district intra-arterial) at escalating doses of cells. A preliminary protocol to validate outcome measures in ongoing. Giulio Cossu FUNCTIONAL GENETICS OF MUSCLE REGENERATION Molecular mechanisms of endogenous stem cells mediated muscle regeneration Regeneration of muscle fibers, lost during pathological muscle degeneration or after injuries, is sustained by generation of new myofibers. Necdin (Ndn) is a MAGE protein expressed in satellite cells derived myogenic precursors during perinatal growth. Following muscle injury necdin null mice showed a significant defect in muscle healing while mice over-expressing necdin showed significantly increased myofiber regeneration. We elucidated the role of necdin in muscle showing that it increases expression of myogenin, by cooperating with MyoD in the transcription of Myogenin promoter and accelerates differentiation (Deponti et al. JBC, 2007). We have also shown that necdin is selectively expressed in the atrophic muscles of cachectic mice (tumor induced cachexia) and proved that its expression is causally linked to a protective response of the tissue against tumor- DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 77 induced wasting, inhibition of myogenic differentiation and fiber regeneration. Necdin plays this role mainly via interference with TNFα signaling, including regulation of expression of TNFRI, of p53 and of the activity of caspase 3 and 9 (Sciorati et al., JCS, 2009). Furthermore we were able to isolate a novel protein that interacts with Necdin, CCAR1/CARP1: the complex Necdin/CCAR1/ p53 appears to mediates the anti-apoptotic action of Necdin in myoblast precursor cells. These data prompted us to investigate whether Necdin could be exploited also to enhance myogenic differentiation and inhibit cell death of other types of stem cells, such as mesoangioblasts (MABs). Overexpression of Ndn in vitro increases the differentiation ability of MABs, and inhibit cell death. In addition muscles of αSarcoglycan dystrophic mice injected with Ndn-MABs showed a greater reconstitution of stem cell derived fibers respect to wt MABs. To investigate in vivo the role of endothelial derived myogenesis, we have generated a transgenic mouse expressing an inducible Cre recombinase (CRE-ERT2) under the control of an endothelial specific promoter (Vascular Endothelial Cadherin). Lineage tracing experiments using ROSAfloxed mice show that endothelial progenitors can give rise to cells of the skeletal muscle lineage at fetal and perinatal stages and contribute to muscle regeneration following acute damage in the adult. Silvia Brunelli GENE EXPRESSION AND MUSCULAR DYSTROPHY UNIT A ncRNA regulates the epigenetic switch at the basis of facioscapulohumeral muscular dystrophy (FSHD) Our group is interested in elucidating the regulatory pathways controlling muscle-specific gene expression and delineate how they become subverted in muscular dystrophy using facioscapulohumeral muscular dystrophy (FSHD) as a paradigm. FSHD is the third most common hereditary disease of muscle. FSHD is an autosomal dominant disorder that is not due to a mutation within a protein-coding gene. Instead, FSHD patients carry deletions of 3.3 kilobase repeat units, termed D4Z4, located at chromosome 4q35. FSHD results form a complex epigenetic cascade activated by deletion of a 3.3 kb repeat (D4Z4) located on chromosome 4q35. D4Z4 appears to regulate chromatin structure and its partial deletion causes over-expression of the 4q45 FRG1 gene. Importantly, transgenic mice over-expressing FRG1 display an FSHD phenotype and are the first animal model of the disease. Figure 9. Current model for the role of the ncRNA in regulating 4q35 gene expression 78 - SAN RAFFAELE SCIENTIFIC INSTITUTE The number of D4Z4 repeats is a critical determinant of the age of onset and clinical severity of FSHD. In general, fewer repeats are associated with a more severe phenotype that presents in childhood. Paradoxically, individuals completely devoid of D4Z4 are normal. This suggests that at least one copy of D4Z4 is required to cause FSHD, possibly through a gain-of-function mechanism. Our preliminary results indicate that a chromatin-bound ncRNA is generated starting from upstream of D4Z4 uniquely in FSHD patients. Notably, shRNA knockdown of this transcript causes a significant reduction of 4q35 gene expression. Hence, it is tempting to speculate that production of this ncRNA activates the epigenetic cascade culminating with 4q35 gene de-repression in FSHD. An attractive hypothesis would be that transcription of the region proximal to D4Z4 may play a role in de-condensation of the 4q35 genomic region, setting the stage for activation of 4q35 genes and, most importantly, preventing re-repression of the region. We are characterizing the ncRNA to determine how it regulates 4q35 gene expression. These studies will provide a critical nexus for revealing the basis of ncRNAs in FSHD etiology and their possible use as therapeutic targets. Our analysis will generate novel insights into the biological role of RNAs in regulating chromatin structure in higher eukaryotes. Davide Gabellini MOLECULAR AND FUNCTIONAL IMMUNOGENETICS Molecular and functional immunogenetics of hematopoietic stem cell transplantation The research activity of the group is focused on the role human leukocyte antigen (HLA) and other polymorphic immune-related molecules in promoting graft versus leukemia (GvL) activity versus adverse clinical effects (graft versus host disease, interference with engraftment, rejection) in the context of hematopoietic stem cell transplantation (HSCT) from partially HLA-mismatched unrelated or haploidentical donors, for the cure of high risk hematopoietic malignancies. In the year 2008, the following main results were obtained: 1. Non-Permissive HLA-DPB1 T cell epitope disparities associated with clinical outcome of unrelated HSCT Summary: In a collaborative study with the 15th International Histocompatibility Workshop, we showed that non-permissive HLA-DPB1 disparity defined according to an algorithm based on T cell alloreactivity patterns, was associated with significantly increased hazards of transplant related mortality, acute graft versus host disease grades 2-4 and 3-4, and overall mortality, in over 5838 unrelated transplants matched for 10/10 of the other HLA alleles. 2. Natural Killer Cell Alloreactivity and Chimerism Monitoring after haploidentical HSCT Summary: In 56 patients receiving haploidentical HSCT for high-risk hematologic malignancies, we could not detect a beneficial effect of natural killer (NK) cell alloreactivity, according to mismatch for killer immunoglobulin like receptor (KIR) ligands, on clinical outcome, consistent with phenotypic and functional immaturity of these cells arising early after transplantation. Post-transplant follow-up of patients transplanted from HLA mismatched donors by HLA typing was introduced and validated as being highly sensitive for detection of disease relapse. Katharina Fleischhauer NEURAL STEM CELL BIOLOGY Glioblastoma multiforme (GBM) is characterized by enhanced tumor cell dispersal into the brain parenchyma. Most of de novo GBMs express the epidermal growth factor receptor (EGFR) unevenly, thus suggesting that it might specifically label subsets of GBM cells that could behave as tumor-initiating cells (TICs). To test this hypothesis, we purified different cell fractions from GBM patient’s specimens by fluorescence activated cell sorting (FACS), based on their relative expression of EGFR and of the putative TIC marker CD133. Remarkably, all these subpopulations were endowed with tumorigenic potential, although to different extent. The pivotal role of EGFR in gliomagenesis was also confirmed by the functional modulation of EGFR expression in CSCs by means of lentiviral-mediated over-expression and silencing. DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 79 Medulloblastoma (MB) is the most common brain tumor in childhood. MB is thought to derive from stem/progenitor cells of the cerebellum (CB) that undergo malignant transformation. In the last year, we isolated several cancer stem cell (CSC) lines from mouse MBs, aiming at the identification of CSC-specific genes by molecular comparison with normal neural stem cells (NSCs). As expected, transcriptome analysis suggested that MB CSCs share many more molecular determinants with cerebellar NSCs than with the subventricular zone (SVZ) NSCs. We are now validating some of the top-ranking genes differentially expressed between CSCs and NSCs, by semi-quantitative RT-PCR and real-time qPCR. Finally, in order to generate a highly representative pre-clinical model of Tuberous Sclerosis Complex (TSC), given the putative correlation between the occurrence of TSC mutations in embryonic ventricular and adult SVZ progenitors and the temporally-regulated onset of TSC-associated brain lesions, we selectively targeted Tsc1 deletion to NSCs and progenitors. During the last year, we have generated and preliminarily characterized Tsc1 mutant mice that display: i) shortened life span; ii) neuropathological features such as alteration in cortical lamination; and iii) spontaneous epileptic seizures. We also provided evidence that, in mutant mice, the adult NSC compartment is severely affected. Rossella Galli AUTOIMMUNITY & VASCULAR INFLAMMATION UNIT Innate and acquired immune response to cell death in autoimmune and rheumatologic diseases Inflammation is a key homeostatic process elicited by microbial components and by tissue damage. Increasing evidence indicates that the outcomes, either tissue repair or persistent inflammatory damage and degeneration, tightly depend on the pattern of cell death in situ and on the features of infiltrating leukocytes and antigen presenting cells that actually dispose of cell death remnants. Defects in the initiation and execution steps of programmed cell death such as in the clearance of cell debris are indeed critical for the pathogenesis of systemic autoimmune diseases, in which the deregulated response to cell death behaves both as an initiator and an amplifying circuit, leading to the specific features of each disease. In particular, during vascular inflammation a self-sustaining circuit attracts and activates inflammatory leukocytes in the wall of vessels of various size and anatomical characteristics. Vascular inflammation fulfils homeostatic roles and the activation of circulating leukocytes, platelets and endothelial cells is under the control of humoral innate immunity. We are directly addressing the molecular mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue injury, with specific attention to the role of injury-associated signals (Damage-Associated Molecular Patterns, DAMPS, or Alarmins) and of acute phase proteins. Angelo A. Manfredi Figure 10. EM imaging of the phagocytic clearance of an activated platelet 80 - SAN RAFFAELE SCIENTIFIC INSTITUTE INNATE IMMUNITY AND TISSUE REMODELLING Macrophages play a dual role in damaged tissues: they enhance local injury through their effectors functions or they favour repair. Two macrophage populations exist, polarized type I (classically activated) and type II (alternatively activated) macrophages. The characteristics of infiltrating macrophages determine whether they increase the healing process or exacerbate tissue damage in response to sustained noxae. The main goal of the research team directed by Dr. Patrizia Rovere-Querini is to molecularly dissect the role of infiltrating polarized macrophages in in vivo models of acute (toxic) and chronic injury of skeletal muscle (muscular dystrophies and inflammatory myopathies) and of the peritoneum, as a consequence of benign (endometriosis) and malign (ovary carcinoma) ectopic cellular growth. Patrizia Rovere Querini Figure 11. Cross-talk between polarized macrophages and vessel-associated stem cells CELLULAR PHARMACOLOGY UNIT Mitochondrial dynamics in myogenesis: endogenous nitric oxide stimulates myogenic differentiation by inhibiting mitochondrial fission Mitochondrial fission and fusion processes participate to cellular adaptation to changing metabolic needs contributing to tissues development and function. Their functional roles in skeletal muscle function are unknown. We found that inhibition of mitochondrial fission with formation of elongated mitochondria is required for myogenesis to occur and that this event depends on endogenous generation of nitric oxide (NO) by the differentiating myogenic cells. Blockade of NO synthesis enhanced activity, translocation and docking to mitochondria of the pro-fission GTPase dynamin related protein 1 (Drp1), inhibiting mitochondrial elongation and myogenic differentiation. A dominant-negative Drp1 reversed the effects due to NO synthesis blockade on fission and myogenesis, establishing a causal relationship between these processes. Under NO synthesis blockade, myogenic precursors displayed a latent mitochondrial dysfunction, compensated under basal conditions but that rendered cells more sensitive to apoptotic clearance. This indicates the existence of a quality control check for myogenesis, dependent on generation of NO and correct mitochondrial morphofunctional status. The effects of NO on mitochondrial fission and myogenesis depended on generation of its physiological messenger cyclic GMP. Thus, NO is a central mediator of myogenesis, exerting a quality control check of the process via regulation of mitochondrial fission and bioenergetics. Emilio Clementi DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 81 EXPERIMENTAL HEMATOLOGY UNIT T-cell Based gene therapy to treat hematologic malignancies Cellular adoptive immunotherapy is a powerful approach to treat cancer; nevertheless limitations still need to be overcome to fully endorse this treatment modality. In the context of allogeneic hemopoietic stem cell transplantation (HSCT) donor lymphocytes are highly effective against leukemia but mediate the detrimental graftversus-host disease (GvHD). Conversely, the adoptive transfer of autologous tumor specific T lymphocytes has an optimal toxicity profile, but is limited by the difficulty in isolating and expanding rare, high-avidity tumorspecific cells. Our lab exploits gene transfer technologies to overcome these limitations. In the context of HSCT, we showed that the transfer of a suicide gene into donor lymphocytes, prior to infusion to transplanted patients, allows selective and complete control of GvHD, while promoting rapid and effective immune reconstitution after HSCT from HLA-identical and haploidentical donors. To further increase the efficacy of adoptive immune-gene therapy, we developed protocols to expand and gene-modify central memory (TCM) T lymphocytes, long-lived cells able, upon antigen re-encounter, to expand extensively, self-renew and differentiate into a progeny of effectors, thus mediating long-term protective immunity. By applying this protocol we observed that: 1.T cell activation with leukemic dendritic cells, obtained upon in vitro differentiation of leukemic blasts, induce the expansion of TCM cells from SCT donors, highly reactive against the original leukemia in vitro and in vivo. 2.T cell activation with co-stimulation and culture with IL7/IL15 promotes retro and lentiviral-mediated transduction of functional TCM cells. By using lentiviral vectors with bidirectional promoters encoding for an optimized TCR specific for the oncogenic WT1 antigen, we generated tumor-specific TCM lymphocytes able to expand, recognize and kill primary leukemic blasts. To reduce variability in transgene expression, and further improve the quality of gene-modified lymphocytes, we exploited the ZFN technology, and developed a protocol for integration of a desired transgene in CCR5, a safe genetic harbor for TCM cells. Efficient and targeted integration of genes in TCM lymphocytes might overcome all major hurdles of adoptive cancer T cell therapy. Chiara Bonini ANGIOGENESIS AND TUMOR TARGETING Tie2-expressing monocytes (TEMs): targets and vehicles of anticancer therapy Increasing data indicate that tumor-infiltrating myeloid cells promote tumor angiogenesis. We contributed to this concept by describing a novel myeloid cell type, the Tie2-expressing monocyte (TEM), which is implicated in this process. Indeed, the specific elimination of TEMs inhibits tumor angiogenesis and growth in several mouse models (De Palma et al., Nat Med 2003; Cancer Cell 2005). Yet, little is known of the biological bases of TEMs’ activity in tumors. By comparing the gene expression profile of TEMs with that of classic tumor-associated macrophages (TAMs), we found that the two macrophage subsets were highly related. However, several genes were differentially expressed, highlighting a TEM gene signature consistent with enhanced proangiogenic/tissue-remodeling activity and lower proinflammatory activity. Interestingly, resident monocytes and TEMs on one hand, and inflammatory monocytes and TAMs on the other hand, expressed coordinated gene expression profiles, suggesting that the two blood monocyte subsets are committed to distinct extravascular fates in the tumor microenvironment (Pucci et al., Blood 2009). Ongoing studies are aimed at identifying the signals that govern the lineage determination of TEMs and their recruitment to sites of active tissue morphogenesis. To achieve this goal, we are developing a lentiviral vector (LV)-based platform to knock selected genes down specifically in TEMs using a BM transplantation approach. We also exploited the tumor-homing ability of TEMs to target biotherapeutics to tumors. The toxicity of high-dose, systemic interferon-α (IFN-α) in cancer therapy provided the rationale for exploring the benefits of targeted gene delivery. By transplanting hematopoietic progenitors transduced with a Tie2p-Ifna1 LV, we efficiently targeted the IFN response to orthotopic human gliomas and spontaneous mouse mammary carcinomas and obtained substantial antitumor responses. TEM-mediated IFN delivery inhibited tumor angiogenesis and activated innate and adaptive immune cells, but did not impair myelopoiesis and wound healing detectably (De Palma et al., Cancer Cell 2008). Thus, TEMs may represent both targets of anticancer therapies and ideal vehicles for the targeted delivery of cancer biotherapeutics. Michele De Palma 82 - SAN RAFFAELE SCIENTIFIC INSTITUTE Clinical Research Units HEMATOLOGY AND HEMATOPOIETIC STEM CELL TRANSPLANTATION UNIT Since 1991 at the San Raffaele Scientific Institute is active an Hematology and Bone Marrow Transplantation (BMT) Unit. The staff is build on 3 MD consultants, 6 junior physicians and 12 fellows in hematology. The Unit is site of the school in Hematology of the San Raffaele University. The stem cell transplantation activity is integrated with the Blood Bank Unit (Director Silvano Rossini) in a Stem Cell transplantation Program as member of European Group for Blood and Marrow Tranplantation, EBMT (www.ebmt.org), in the file for Jacie-EBMT accreditation. Overall, the Unit is the largest Italian Unit for allogeneic HSC transplantation, performing since 2006 around 100 allogeneic tranplants/year. The Unit has long-lasting experience in transplantation from family mis-matched haploidentical donors, with programs of cell therapy with suicide-gene modified donor T lymphocytes and cell therapy with IL-10 induced T-regulatory cells for the control of Graft-versus-Host disease in this context. The Unit has a wide-range activity on all hematological malignancies and non-malignant hematological disorders. In particular programs are ongoing for acute leukemias (NILG, www.leukemianet.org ), multiple myeloma, lymphomas, with more than 20 ongoing investigator-sponsored trials (IST). Our aim is to develop new modalities for hematopoietic stem cells transplantation (HSCT) both in autologous and allogeneic setting to reduce transplant related toxicity, testing new conditioning regimens based on reduced-toxicity drugs (i.e. treosulfan, clofarabine) and new anti-infective drugs (i.e. posaconazole, anidulafungin, maribavir) for patients with leukemia, lymphoma, myelosisplasia, myeloma, bone marrow failure syndromes and inherited disorders such as hemoglobinopaties and immunodeficiencies Several phase II trials with these drugs are ongoing. Fabio Ciceri IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE UNIT The Unit of Immunohematology and Transfusion Medicine is responsible for the collection and testing of blood to be transfused into patients at San Raffaele Hospital (traditional “”blood banking””). This Laboratory is responsible for ensuring that only the highest quality and safest blood products are given to the patients. New technologies such as genetic red blood cell typing are being investigated. An RFID project is underway with the goal of increasing safety by implementing radiofrequency identification technology in the daily management of transfusions and transfusion products. This system is a model for process traceability from donor to patient, for automation in the identification of patients, blood units and/or cellular products. The Unit is responsible for collecting and processing hematopoietic stem cells and performs the necessary diagnostic testing required for bone marrow transplantation procedures. The lab supplies hematopoietic stem cells and relevant cells in support of clinical trials for allogenic bone marrow and peripheral blood transplantations, and offers a Stem Cell Cryo Banking service for autologous and allogeneic bone marrow products. Our objective is to provide clinical grade human cells for therapeutic use and translational trials. This unit also performs therapeutic apheresis procedures to treat patients with neurologic and blood diseases. Silvano Rossini DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 83 PSIEP - STRATEGIC PROGRAM OF PEDIATRIC IMMUNOHEMATOLOGY The Strategic Program of Pediatric Immunohematology is a pediatric Unit dedicated to translational and clinical research in children with immunological, hematological and other genetic disorders. In this context children are offered in addition to the standard care also experimental therapeutic option, among these cellular therapy and gene therapy. From 2005 in partnership with the Mediterranean Institute of Hematology, our Unit has developed a program for research, diagnosis and cure of blood disorders in patients from the Middle East. This partnership allowed children affected by β thalassemia from Syria, Lebanon, Palestine, Iraq, Jordan and Egypt to receive bone marrow transplantation (BMT) at HSR. During 2007 and 2008 the Unit has conducted a project aimed at transferring the BMT technology to Syria. This has involved the training of 22 Syrian professionals (physicians, nurses, lab technician and transfusion biologists). The first BMT was performed in Damascus in September 2008 and the Syrian BMT Unit is running autonomously at present. In 2008 the Strategic Program of Pediatric Immunohematology has performed 17 allogeneic bone marrow transplantations for β thalassemia and 2 gene therapy procedures for ADA-SCID. The clinical performance of the Unit in 2008 was very high as demonstrated by an engraftment rate of 95% and a treatment related mortality of 5%. The Program is collaborating with HSR-TIGET on the study of pathogenesis and therapy for genetic diseases, with particular regards to primary immunodeficiencies and autoimmune diseases with known or unknown genetic defect. In synergy with the Pediatric clinical research Unit of HSR TIGET, clinical studies for gene therapy of pediatric genetic diseases are ongoing (ADA-SCID) or in preparation (Wiskott-Aldrich Syndrome, Metachromatic Leukodystrophy, thalassemia). Finally, the Program is implementing a cell therapy clinical study for Duchenne muscular dystrophy (project leader Prof Cossu). Maria Grazia Roncarolo Figure 12. A drawing by one of the children cured at the PSIEP 84 - SAN RAFFAELE SCIENTIFIC INSTITUTE THE SAN RAFFAELE TELETHON INSTITUTE FOR GENE THERAPY (HSR-TIGET) Director: Luigi Naldini* Introduction by the Director The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) was created in 1995 as a joint-venture between the San Raffaele Scientific Institute and the Telethon Foundation for the implementation of basic and clinical research for genetic diseases. The mission of the Institute is to perform cutting edge science in the field of gene and cellular therapy and to promote the translation of basic discoveries into therapeutic advances. The research projects span from basic studies aiming to: • identify the genetic bases of inherited diseases; • develop new gene transfer technologies for more efficient and safe genetic modification of target cells; • establish procedures for isolation, gene transfer and and transplantation of stem cells; Luigi Naldini • modulate immune response to gene and cell products to improve efficacy and stability of the therapy, to pre-clinical studies testing the experimental therapeutic strategies in disease models and eventually to the establishment of clinical trials of the new therapies in human patients. The genetic diseases, which are presently under investigation (from those in advanced clinical experimentation to those in early pre-clinical development) include primary immunodeficiencies and some autoimmune disease, leukodystrophies and other lysosomal storage disorders, thalassemias, type I diabetes, hemophilia. Furthermore, we have established a Pediatric Clinical Research Unit that focuses on the diagnosis, treatment and follow up of patients with primary immunodeficiencies, hematologic and metabolic disorders, including those enrolled in the gene therapy trials. The TIGET clinical trial for a severe form of primary immunodeficiency (ADA-SCID) has provided the most successful demonstration today that gene transfer into human hematopoietic stem cells can result in long-term correction of disease with an excellent safety record. DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 85 Research Units GENE TRANSFER TECHNOLOGIES AND NEW GENE THERAPY STRATEGIES UNIT Our laboratory has long been at the forefront of the development of experimental gene transfer and has exploited the new technologies to gain novel insights into fundamental biological processes of high relevance for molecular medicine, such as stem cell activity and angiogenesis. Recently, we pioneered two new strategies to improve gene transfer: regulating transgene expression by exploiting cellular microRNAs and targeting integration by designer Zinc finger nucleases. The application of microRNA regulation to vector design has provided a new experimental strategy in which transgene expression can be made specifically responsive to the cell lineage and differentiation stage of the target cell. By using this approach, we could overcome the immunological barriers to stable gene transfer, a major hurdle to successful gene therapy, and establish long-term correction of hemophilia in mouse models. We have also recently extended these studies to develop a platform for knockingdown microRNA activity in vivo and investigating their function. We have also demonstrated the use of engineered Zinc-finger nucleases to target vector integration and edit the human genome. This proof-of-principle study has opened the way to correct, rather than replace genes. We are now investigating the microRNA network regulating hematopoiesis and exploiting the new knowledge to develop vectors with stringently controlled expression throughout the hematopoietic lineages. We are developing Zinc finger nuclease-based vectors that insert the transgene with high efficiency and specificity either downstream to its own endogenous promoter or into a safe genomic harbor that allows for robust expression without interference on the neighboring genes. By combining these strategies we will provide radically improved gene transfer platforms. Furthermore, we will exploit these technologies for the generation and genetic correction of induced pluripotent stem cells, providing a potentially unlimited source of patient-derived vector free gene corrected multipotent stem cells for future applications of regenerative medicine. Luigi Naldini GENE/NEURAL STEM CELL THERAPY FOR LYSOSOMAL STORAGE DISEASES Our main goal is to develop novel combined gene- and neural stem cell (NSC)-based approaches to treat Leukodystrophies and GM2-gangliosidosis, a group of lysosomal storage disorders (LSD) with CNS involvement. In order to exploit the therapeutic potentials of NSCs we want to study their biology in both physiological and pathological conditions. Our research activity can be divided as follows: • Functional characterization of NSCs in LSD animal models. On NSC cell lines derived from disease animal models and from the WT counterpart we investigate: i) the impact of the genetic defect on stem cell functional parameters; ii) the efficiency of lentiviral-mediated gene-correction; iii) the potential toxicity due to metabolite accumulation and/or protein over-expression. We established optimal conditions for successful reconstitution of enzyme activity in NSCs and their progeny while preserving their biological features. We have also described a disease-dependent proliferation defect in the precursor cell population residing in the CNS neurogenic niches. • Gene/NSC-based therapy. We use WT or enzyme-deficient LV-gene corrected NSCs for heterologous or autologous transplantation, respectively, in different experimental settings. We are currently optimizing transplantation protocols trying to clarify to which extent exogenous NSCs may contribute to delay/prevent/arrest the progressive and widespread demyelination/neurodegeneration typical of these diseases, also giving information on the potential advantage of genetically-modified NSCs on their wt counterpart. 86 - SAN RAFFAELE SCIENTIFIC INSTITUTE • Lentiviral (LV)-mediated multiple gene delivery strategy. Our goal is to combine intracranial and systemic LV delivery performed in neonatal mice to achieve sustained production and widespread distribution of the deficient enzymes in the CNS, PNS and viscera starting from the early days after birth. This gene delivery approach might be coupled to an anti-inflammatory treatment able to modulate the progressive neuroinflammation that concurs to the progression of pathology. We are evaluating the safety and the efficacy of the procedures, also assessing whether their combination might have additive or synergistic effects, eventually resulting in improved pathology and function as well as in prolonged lifespan. Angela Gritti HEMATOPOIETIC STEM CELL BASED GENE THERAPY FOR THE TREATMENT OF LYSOSOMAL STORAGE DISORDERS In most Lysosomal Storage Disorders (LSD) hematopoietic stem cell (HSC) transplantation is not or poorly effective. HSC gene therapy could ameliorate the outcome of allogeneic transplant and thus provide an expectation of efficacious treatment for these LSD. HSC can be genetically modified to express supra-normal levels of the therapeutic enzyme, and become a quantitatively more effective source of functional enzyme than normal donor’s cells. Moreover, autologous HSC are immediately available, thus saving precious time in rapidly progressing forms, and, when employed in a transplant setting, significantly reduce transplant-related morbidity and mortality. We are thus implementing an innovative approach based on the transplantation of autologous, gene corrected HSC for the treatment of severe LSD lacking efficacious and safe therapeutic opportunities. To this goal, we exploit the unique features of lentiviral vectors (LV), which are prime candidates for HSC gene transfer. By using LV for HSC gene correction, we proved the therapeutic potential of HSC gene therapy in the murine model of metachromatic leukodystrophy (MLD), a severe dysmyelinating LSD. Based on the results obtained in the preclinical model and on an extensive safety study, HSC gene therapy for MLD is now entering clinical testing. The same approach has been applied with success to the murine model of type 1 Mucopolysaccharidosis (MPS1), a LSD characterized by visceral organ, skeleton and nervous system involvement. Thus, MPS1 may become a second target for translating this approach into clinical testing. In the case of globoid cell leukodystrophy (GLD) or Krabbe disease, we recently demonstrated that the disease-causing enzyme (GALC) could not be over-expressed in HSC since it causes an unbalance in the content of bioactive sphingolipids tightly controlling HSC survival. Interestingly, when using a LV in which GALC expression is regulated by an HSCspecific microRNA we could obtain safe HSC transduction, GALC over-expression in the transduced HSC progeny, and significant phenotypic amelioration in mice transplanted with the transduced HSC. Therefore, an advanced LV design allows rendering HSC gene therapy a safe and efficacious approach to be further developed also for the treatment of GLD. Alessandra Biffi SAFETY OF GENE THERAPY AND INSERTIONAL MUTAGENESIS Our group is focused on 2 main research areas: A) studying and improving the safety of vector integration B) vector-based oncogene tagging for the discovery of cancer genes in hematopoietic and solid tissues. A)We dissected the contribution of vector design and viral Integration Site Selection (ISS) to oncogenesis using an in vivo genotoxicity assay based on transplantation of vector-treated tumor prone Cdkn2a-/- mouse Hematopoietic Stem/Progenitor Cells (HSPCs). By swapping genetic elements between γ-Retroviral Vectors ( γ-RV) and Lentiviral Vectors (LV), we demonstrated that transcriptionally active Long Terminal Repeats (LTRs) are crucial determinants of genotoxicity even when reconstituted in LV, and that self-inactivating (SIN) LTRs enhance the safety of γ-RV. The ISS and the position of enhancer/promoter elements within the vector modulate vector genotoxicity to a previously unappreciated extent. Because LV has a safer ISS and a SIN LTR design, it may represent the first choice among currently available integrative vectors. These data have been recently published in Journal of Clinical Investigation (Montini, Cesana et al., JCI. 2009 Apr;119(4):964-75). We will DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 87 test additional genetic elements to improve the safety of gene therapy vectors in alternative in vivo models to assay residual vector genotoxicity. B) We used a new LV with LTRs carrying enhancers capable to activate neighboring genes upon integration and exploited its broader tissue tropism and high in vivo transduction efficiency to mutagenize the murine liver. We tested this genotoxic LV (gLV) on mouse models of Cdkn2a or Pten deficiency, whose mutations are relevant in human hepatocellular carcinoma (HCC), and wild type mice. This gLV was able to induce HCCs in the different mouse models while none was found in untreated controls. Vector integrations studies on the HCCs led to the identification of novel liver cancer genes. This project could open new avenues in unraveling synergistic interactions between cancer genes and in the discovery of early diagnostic markers and pharmacological targets for the effective diagnosis and treatment of HCC and solid tumors in general. The data obtained are now being submitted to a high ranking journal. Eugenio Montini GENE TRANSFER INTO STEM CELLS UNIT Gene therapy for β-thalassemia Thalassemias are globally the most common monogenic disorders, affecting thousands of newborn annually. Patients affected by the most severe form of β-thalassemia is characterized by a profound anemia that leads to death unless treated with regular blood transfusions. So far, allogeneic bone marrow transplantation from HLAmatched donors represents the only curative treatment, although limited to patients with compatible donors. For patients lacking a donor, autologous transplantation of genetically corrected HSCs offers the promise of a definitive cure. Therefore, a relevant issue is to demonstrate feasibility, safety and therapeutic efficacy of gene transfer in pre-clinical models and patients’ cells. We developed a β-globin-expressing lentiviral vector (GLOBE) able to sustain long-term correction of thalassemia in the murine preclinical model (Miccio et al. PNAS, 2008). To move forward with clinical translation, the therapeutic efficacy of GLOBE was tested in the context of human cells. From the collaboration with PSIEP the availability of samples from a large population of patients allowed us to perform analyses with statistically significant numbers. No difference in the yield and clonogenic potential of CD34+ cells was found between normal and thalassemic samples (n=29). We transduced BM-derived CD34+ cells (n=16) at high efficiency (37-95%, mean: 62%), leading to normal levels of HbA in culture and BFU-Es. Following pre-activation by cytokines, we monitored changes in committed progenitors and global gene expression profile. To assess the risk of integration in potentially dangerous genes, we sequenced and mapped the GLOBE integration sites in the genome of thalassemic CD34+ cells. Analysis of integration events showed preference for intragenic regions, without hot spots in protoncogenes, tumor-supressor or cell cycle related genes. Cross-annotating the expression category for flanking host genes revealed that GLOBE preferentially lays into proximity of expressed genes. The genotoxic potential of LCR-containing globin vectors in perturbing the expression of hit genes or flanking the integration site will be tested in human erythroid cells. Overall, these results provide evidence of efficacy and safety for the use of GLOBE in a clinical setting. Giuliana Ferrari IMMUNOLOGICAL TOLERANCE UNIT The induction of immunological tolerance in allogeneic hematopoietic stem cell (HSC) or solid organ transplantation, autoimmune diseases, and gene therapy remains an important yet elusive goal for immunologists. We focused our studies on CD4+ regulatory T (Tr) cells, which actively control immune responses. CD4+ Tr cells have been classified based on their ontogenesis: nTr (CD4+CD25+FOXP3+) cells generated in the thymus, and Tr1 cells induced in the periphery upon chronic antigen (Ag) stimulation in the presence of IL-10. nTr suppress effector T cells via a yet to be clarified mechanism which requires cell-cell contact whereas Tr1 cells (IL10++, TGF-β+, IFN-γlow, IL-2-, IL-17-, IL-4-, IL-5+) suppress through a cytokine dependent mechanism. We are exploring and developing different strategies to promote and maintain tolerance via Tr cells: a) the in vivo induction of Tr cells using novel therapeutic approaches, b) adoptive cell therapy with in vitro expansion/induc- 88 - SAN RAFFAELE SCIENTIFIC INSTITUTE tion of Tr cells, and c) adoptive cell therapy with effector T cells converted into Tr cells by gene transfer with FOXP3 or IL-10. In a model of pancreatic islet transplantation, we demonstrated that treatment with an IL-10-based protocol efficiently promoted tolerance in vivo via the induction of both nTr and Tr1 cells. Furthermore, adoptive transfer of allo-Ag specific but not polyclonal Tr1 cells endorsed long term tolerance, indicating that therapeutic efficacy of Tr1 cells is highly dependent on their Ag-specificity. In a model of gene therapy, we showed that incorporation of target sequences for the hematopoietic-specific micro-RNA, miR-142, into an antigen-encoding transgene (Tg), avoids Tg expression from APC, and promotes Tg-specific tolerance via the induction of Agspecific Tr cells. To generate Tr cells in vitro suitable for cell therapy, we developed protocols for both selective expansion of CD4+CD25+FOXP3+ T cells using rapamycin and induction of allo-specific Tr1 cells using either exogenous IL-10 or a population of tolerogenic DC, called DC-10. In patients with mixed chimerism after allogeneic hematopoietic stem cells we demonstrated that tolerance correlated with a high frequencies of alloantigen specific Tr1 cells. Based on all these data, we are conducting a clinical trial in patients receiving haplo-identical HSC-transplant using allo-specific Tr cells induced in vitro with exogenous IL-10, with the aim to demonstrate that cellular therapy with Tr cells is safe, can provide immune-reconstitution, and decreases graft versus host disease severity. These novel approaches represent the first step towards the definition of new therapeutic protocols for suppressing pathology and restoring peripheral tolerance in immune-mediated diseases. Maria Grazia Roncarolo FROM FOXP3 MUTATION TO IPEX SYNDROME IPEX syndrome as a paradigm of monogenic autoimmune disease: genotype/phenotype correlation, immune pathogenic mechanisms and novel therapeutic options Immune dysregulation, Polyendocrinopathy, Enteropathy, X?linked (IPEX) syndrome is due to mutations of FOXP3 gene, the transcription factor driving the differentiation and function of regulatory T (Treg) cells. The disease is characterized by early onset refractory and life threatening enteropathy, eczema, elevated IgE levels and Type I diabetes. Within the Italian Study Group of IPEX (www.ipexconsortium.org), to date the disease has been carefully analysed in 14 unrelated affected males with different mutations. We observed that similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity; in addition, FOXP3 expression did not correlate with disease severity. Genetic analysis of FOXP3 mutations should always be performed to ensure an accurate diagnosis and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX. Since IPEX patients have both impaired suppressive function by nTreg and defective Th1 cytokine production by effector T (Teff) cells, studies aimed at understanding the respective contribution of nTreg and Teff cells in the pathogenesis of IPEX are currently ongoing. We have recently demonstrated that in carrier mothers of FOXP3 mutations only the nTreg cells bearing the active wt allele of FOXP3 are selected to give rise to a normal Treg cell population, suggesting that the active mutFOXP3 allele might not interfere with an overall normal Teff cell differentiation. At present, immunosuppressive drugs can only partially control the clinical manifestations and haematopoietic stem cell transplantation (HSCT) is the only definitive cure, but it is accessible for a limited number of patients. Results of FOXP3 gene transfer into conventional Teff cells demonstrated that suppressive capacity is conferred to human T cells upon high and stable lentiviral mediated FOXP3 expression even in the presence of FOXP3 mutations. Therefore, gene transfer might represent an alternative strategy to restore tolerance in IPEX patients. Results obtained from this study will provide new insights into the biology of immune regulation, and will pave the way for expert diagnosis and more rationale therapeutic approaches not only for IPEX but also for other autoimmune pathologies. Rosa Bacchetta DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 89 TOLEROGENIC DENDRITIC CELLS Further characterization of the mechanisms of adaptive type 1 regulatory T (Tr1) cell induction via tolerogenic dendritic cells and function Type 1 regulatory T cells (Tr1) are a subset of regulatory T cells that is induced in the periphery in the presence of IL-10, produces high levels of interleukin-10 (IL-10) and suppresses effector T cells via a cytokine-dependent mechanism. IL-10 is essential not only for suppression mediated by Tr1 cells, but also for their differentiation in vitro and in vivo. However, little is known on the molecular mechanisms underneath the IL-10-mediated induction of Tr1 cells. We characterize a novel subset of human DC, termed DC-10, present in vivo and inducible in vitro in the presence of IL-10. DC-10 secrete high levels of IL-10 and IL-6, but low IL-12 and TNF-α, are CD14brightCD16+CD11c+CD11b+HLA-DR+CD83+CD1a-CD1c-, express CD40, CD80, and CD86, but not CD68 and M-DC8. DC-10 express high levels of the tolerogenic molecules immunoglobulin-like transcript(ILT)2, ILT3, ILT4, and HLA-G1. DC-10 are potent inducers of allo-specific IL-10-producing Tr1 cells in vitro.DC-10 promote induction of Tr1 cells through the IL-10-dependent ILT4/HLA-G pathway. Therefore, DC-10 represent a newly identified subset of human tolerogenic DC with unique cytokine production profile characterized by a high ratio of IL-10/IL-12 production, that express ILT4 and HLA-G1, and induce Tr1 cells via the IL-10-dependent ILT4/HLA-G1 interaction. Recently perforin and granzyme B have been involved in the immunosuppressive mechanism of Tr1-like cells generated by activation of naive CD4+ T cells with CD3/CD46 cross-linking. To exploit whether bone fide Tr1 cells utilize granzyme B to suppress immune responses, we examined expression, release, and function of granzyme B in Tr1 cell lines and clones. Tr1 cell lines were differentiated in the presence of IL-10 and IFN-α with a system of artificial APC and Tr1 cell clones were isolated from peripheral blood of normal donors. Tr1 cell lines and clones express and secrete high level of granzyme B and specifically lyse antigen-presenting cells. Our findings demonstrate that granzyme B together with perforin plays an important role in the modulation of immune-responses mediated by Tr1 cells. Overall, these studies further advance our knowledge on induction of tolerance by Tr1 cells via tolerogenic DC. Silvia Gregori PATHOGENESIS AND THERAPY OF ADA-SCID UNIT Pathogenesis of ADA-SCID and its correction by gene therapy Adenosine (ADA)-deficient SCID is a primary immunodeficiency characterized by an altered purine metabolism leading to impaired immune function and organ alterations. Our studies are aimed at investigating the molecular and cellular mechanisms linking the purine metabolism disorder to the immune and non immune alterations of the disease and to assess their correction by gene therapy. We found that both intracellular and extracellular adenosine-mediated signalling cooperate in inducing the severe T-cell dysfunction of ADA-SCID patients. Two lines of research are currently ongoing in ADA-KO mice and humans to study the mechanisms causing immune dysregulation in ADA deficiency. Our preliminary results showed an altered thymic structure in untreated mice and the development of autoimmune manifestations in mice treated with enzyme replacement therapy. Since bone and hematopoietic defects are commonly observed in ADA-SCID, we have studied the effects of the altered ADA metabolism on bone and stromal cells. We found that ADA-KO mice show a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced RANKL/OPG axis, causing decreased osteoclastogenesis, and of a low bone formation rate due to deficient osteoblast function. Furthermore, the bone marrow microenvironment of ADA-KO mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-KO neonatal mice with lentiviral-mediated gene therapy resulted in full recovery of the altered bone parameters, similarly to bone marrow transplant. Thus, ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. Studies on vector integrations are providing crucial information on vector biology, the dynamics of genetically modified cells, and the safety of gene therapy. Specifically, gene expression studies at bulk and clonal level 90 - SAN RAFFAELE SCIENTIFIC INSTITUTE have confirmed that integration of retroviral vectors induce minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy. Our findings are providing new insights into the pathogenesis of the ADA-SCID and will contribute to the design of better therapeutic approaches. Alessandro Aiuti GENE THERAPY FOR WASP/OMENN Characterization of hematopoietic and immune defects & gene therapy preclinical studies Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by severe hemorrhages, recurrent infections, increased lymphomas and autoimmune manifestations. As an alternative treatment to allogeneic HSC transplantation, we have developed a gene therapy (GT) approach based on lentiviral vector containing the WAS promoter/cDNA sequences. We demonstrated that this vector allows WASP expression to physiological levels in T cells and led to correction of cytokine production and proliferation. In the WAS-/- mouse model, infusion of in vitro HSC transduced led to WASP expression in multiple hematopoietic lineages, including T cells, B cells and platelets. During this last year, we have completed the preclinical evaluation of efficacy and safety of in vitro GT with HSC in was-/- mice, by the generation of a large cohort of GT treated mice using low (10-20) and high MOI (200). We took advantage of CD45.1-CD45.2 mismatched transplantation to determine donor engraftment by means of FACS analysis. Treated mice were followed for 12 months. Levels of engraftment in the low MOI group were >90% in total bone marrow (BM) cells and in T cells purified from the spleen, while those in control groups lin—wt and lin—was-/- were >80%. In the high MOI group, the average T cell engraftment was 86% and 69% in the lin—was-/- group. In the other cell types tested, full donor engraftment was observed. Efficacy of GT was evaluated by assessing the persistence of engraftment of WASP-expressing cells, and the long-term correction of T cell function. In the low MOI group, BM cells contained a median of 1 VCN, while splenic T cells had a median value of 2.2. As expected, total BM and T cells of mice belonging to the high MOI group contained a higher VCN: 2.5 and 4, respectively. Taken together, these data demonstrated that engraftment of lentiviral-vector transduced lin- cells persisted for 12 months, and suggested that a selective growth advantage was taking place in T cells. Importantly, no tumours derived from donor origin were observed in GT treated mice.In parallel, we have characterized iNKT cell defect in the absence of WASp. We demonstrated that was-/- iNKT cells are functionally impaired contributing to the pathogenesis of WAS. Anna Villa Clinical Research Units PEDIATRIC CLINICAL RESEARCH UNIT - GENE THERAPY FOR WISKOTT-ALDRICH SYNDROME Clinical trial of gene therapy for Wiskott-Aldrich Syndrome Wiskott-Aldrich Syndrome (WAS) is a rare genetic disease characterized by multiple haematopoietic cellular defects, including thrombocytopenia, decreased capacity to control infections, autoimmune manifestations, and susceptibility to develop cancer. Transplantation of haematopoietic stem cell (HSC) from HLA-identical donors provides a complete cure for this disease but is not available for all patients and is still associated with risks of complications. For this reason, gene therapy with autologous HSC could represent a valid alternative approach, potentially applicable to all patients. DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 91 We have developed and tested a lentiviral vector containing the WAS cDNA/promoter sequences (w1.6W). GMP grade, highly purified vector lots have been produced in large scale for clinical use. We have completed the preclinical studies showing that the GMP grade vector can efficiently transduce CD34+ HSC from normal donors and patients leading to restoration of WASP expression in the absence of toxicity. Transplant of transduced CD34+ cells into the Rag2-/-/ γ-chain-/ murine model showed that HSC were able to normally differentiate in various haematopoietic lineages, containing the normal WASp gene. These data, combined with the results form the preclinical studies in the mouse model demonstrating the long-term safety and efficacy in vivo, provide the necessary preclinical basis for the implementation of a gene therapy trial. We are now implementing a phase I/II clinical trial based on infusion of CD34+ HSC transduced with the w1.6W vector, combined to a reduced intensity conditioning. The regimen is designed to allow a competitive advantage to gene corrected HSC and mature lymphocytes and deplete potentially autoreactive cells, while providing less toxicity than current preparatory schemes used in HSC transplant. The clinical trial is aimed at investigating: 1) the safety of the procedure and of the use of lentiviral vectors; 2) the in vivo long-term engraftment and expression of vector-derived WASP; 3) the ability of gene corrected cells to restore immune functions and increase platelet counts. If successful this study will provide key results on the safety and efficacy of gene therapy for WAS. Maria Grazia Roncarolo PEDIATRIC CLINICAL RESEARCH UNIT - ADA GENE TRANSFER INTO HEMATOPOIETIC STEM CELLS FOR THE TREATMENT OF ADA-SCID SCID due to adenosine deaminase (ADA)-deficiency is a fatal congenital disorder of the immune system associated with systemic toxicity. In the absence of an HLA-matched sibling donor, hematopoietic stem cell (HSC) transplant from alternative donors is still affected by high morbidity and mortality, while enzyme replacement therapy (PEG-ADA) fails often to sustain adequate immune reconstitution. Our approach is based on gene transfer into bone marrow CD34+ HSC combined to a nonmyeloablative chemotherapy prior to cell reinfusion. Fifteen ADA-SCID children hae been treated according to this experimental protocol, enrolled in 3 different clinical trials. No toxicity or adverse events related to gene transfer have been observed after gene therapy. The reduced dose of busulfan induced a transient myelosuppression, which was sufficient to achieve long-term engraftment of gene corrected HSC, differentiating into myeloid and lymphoid cells. The dose of CD34+ cells infused and the efficiency of gene transfer were shown to be critical factors in determining a higher proportion of gene corrected myeloid cells engrafting in patient. Molecular analysis revealed a polyclonal profile of vector integrations, reflecting the preference for retroviral vector at the time of transduction in CD34+ cells, and without in vivo bias for potentially dangerous genes. ADA expression persisted long-term, resulting in efficient systemic detoxification. Immunological studies showed a progressive recovery in T-cell count and normalization of immune functions; in the 6 patients in whom IVIg replacement was discontinued, antigen-specific antibody responses were demonstrated after exposure to vaccine or viral antigens. Effective protection from infections and improvement in patients’ physical development led to a normal life style. All patients are alive and 13 remain off PEG-ADA, with the longest follow up at >8 years after gene therapy. In conclusion, these studies have provided evidence that HSC gene transfer is a safe and efficacious therapy for ADASCID, resulting in correction of both the immunological and metabolic defects. These results have opened a new perspective for the cure of other life-threatening diseases using gene therapy combined to a conditioning regimen. Alessandro Aiuti Figure 13. Schema of ADA-SCID gene therapy 92 - SAN RAFFAELE SCIENTIFIC INSTITUTE PEDIATRIC CLINICAL RESEARCH UNIT - CLINICAL TRIAL OF GENE THERAPY IN METACHROMATIC LEUKODYSTROPHY A natural history study for defining clinical trial design in hematopoietic stem cell gene therapy for metachromatic leukodystrophy Metachromatic Leukodystrophy (MLD) is a rare demyelinating lysosomal storage disease caused by deficiency in arylsulfatase A (ARSA) activity. It is characterized by signs and symptoms of involvement of central and peripheral nervous systems (CNS and PNS) with variable onset and severe prognosis in the majority of cases. Since no effective treatment is currently available, we are developing a gene therapy approach with hematopoietic stem cells (HSC) engineered to over-express the ARSA gene. In the last six years we have studied the natural history of MLD on a cohort of 27 patients, to collect information for the clinical translation of the gene therapy approach. We demonstrated a precise genotype-phenotype correlation, confirming that patients carrying at least one severe mutation of the ARSA gene have an early disease onset (late infantile and early juvenile) and a rapid and homogenous clinical progression, while patients with two mild mutations have a late onset (late juvenile and adult) and are characterized by stability of the disease and significant heterogeneity in their clinical presentation. According to these findings, early onset patients represent the best candidates for our novel treatment having a favourable risk-benefit ratio, given their severe disease, and being more informative due to their homogenous phenotype and evolution. Indeed, in late onset patients, it would be difficult discriminating between the potential clinical benefit and the natural benign course of the disease. Moreover, this study allowed us to validate clinical (Gross Motor Function Measure, GMFM) and instrumental (brain Magnetic Resonance, MR; ElectroNeuroGraphic recordings, ENG) tests to monitor disease progression. Based on this information, we defined as efficacy end-points for the upcoming trial the stability or reduced progression of the motor impairment, as assessed by the GMFM scoring, and of demyelination in the CNS and PNS, assessed by brain MR and ENG, respectively, in comparison to control untreated subjects. GMP-grade lentiviral vectors encoding the therapeutic ARSA gene were produced and are currently being validated for clinical use. We foresee to start recruiting patients fro the trial at the beginning of 2010. Maria Sessa DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 93 Functional genetics of muscle regeneration Gene expression and muscular dystrophy Unit Neural stem cell biology Experimental hematology Unit 94 - SAN RAFFAELE SCIENTIFIC INSTITUTE PSIEP - Strategic Program of Pediatric Immunohematology Gene transfer into stem cells Unit Tolerogenic dendritic cells DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 95 DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES Director: Ruggero Pardi* Associate Director: Adriano Lazzarin* Research Units Leukocyte biology Unit HEAD OF UNIT: Ruggero Pardi* RESEARCHER: Monica Fabbri POST-DOCTORAL FELLOWS: Lorenzo Bombardelli, Raffaella Molteni, Martina Panattoni** PHD STUDENTS: Antonella Giammarresi**, Carolina Lage Crespo**, Anna Lukacs**, Michela Palmisano, Michol Savio** TECHNICIAN: Barbara Clissi Cellular and molecular allergology GROUP LEADER: Samuele E. Burastero PHD STUDENT: Mona-Rita Yacoub** TECHNICIAN: Daniela Breda Human virology GROUP LEADER: Mauro S. Malnati RESEARCHER: Silvia Heltai PHD STUDENT: Lia Vassena** FELLOWS: Giulia Cassina, Emanuela De Martino TECHNICIAN: Francesca Sironi Infection and cystic fibrosis GROUP LEADER: Alessandra Bragonzi POST-DOCTORAL FELLOW: Cristina Cigana PHD STUDENTS: Irene Bianconi, Nicola Ivan Lorè, Moira Paroni Protein engineering and therapeutics GROUP LEADER: Luca Vangelista POST-DOCTORAL FELLOW: Massimiliano Secchi γδ T cells in innate and adaptive immunity RESEARCHER: Maria Raffaella Zocchi Infectious diseases Unit HEAD OF UNIT: Adriano Lazzarin* Immunobiology of HIV GROUP LEADER: Lucia Lopalco PHD STUDENTS: Lorenzo Diomede, Maria Luisa Visciano** FELLOW: Valentina Merati TECHNICIAN: Claudia Pastori Immunological diagnostics of tuberculosis GROUP LEADER: Claudio Fortis FELLOW: Manuela Ratti 96 - SAN RAFFAELE SCIENTIFIC INSTITUTE AIDS immunopathogenesis Unit HEAD OF UNIT: Guido Poli* RESEARCHER: Massimo Alfano PHD STUDENTS: Luca Cassetta, Giulia Della Chiara, Samanta Mariani TECHNICIAN: Chiara Rizzi Biocrystallography Unit HEAD OF UNIT: Massimo Degano POST-DOCTORAL FELLOWS: Beatrice Alfieri, Fabrizio Gangemi PHD STUDENTS: Claudia Minici, Stefano Vavassori** FELLOW: Francesca Giannese TECHNICIAN: Paola Tornaghi Cellular immunology Unit HEAD OF UNIT: Matteo Bellone PHD STUDENTS: Elena Jachetti**, Alessia Ricupito**, Nicolò Rigamonti** TECHNICIAN: Matteo Grioni Emerging bacterial pathogens Unit HEAD OF UNIT: Daniela Maria Cirillo PHD STUDENT: Paolo Miotto FELLOWS: Rossella Baldan, Emanuele Borroni, Antonella Tuscano, Diego Zallocco Experimental immunology Unit HEAD OF UNIT: Paolo Dellabona RESEARCHERS: Giulia Casorati, Claudia De Lalla PHD STUDENTS: Virginia Cecconi**, Maya Fedeli**, Marco Lepore, Anna Napoletano, Elena Tonti FELLOW: Sara Del Mare TECHNICIANS: Marta Delogu, Claudio Garavaglia Immunopathology Unit HEAD OF UNIT: Luca G. Guidotti RESEARCHER: Giovanni Sitia POST-DOCTORAL FELLOW: Lara Ravanetti PHD STUDENT: Matteo Iannacone TECHNICIAN: Marta Mainetti Lymphocyte activation Unit HEAD OF UNIT: Anna Mondino POST-DOCTORAL FELLOWS: Chaitanya Ekkirala, Rodrigo Hess Michelini PHD STUDENTS: Teresa Manzo**, Romana Tomasoni** TECHNICIAN: Veronica Basso Tumor immunology Unit HEAD OF UNIT: Maria Pia Protti RESEARCHER: Lucia De Monte POST-DOCTORAL FELLOW: Giulia Di Lullo PHD STUDENTS: Samantha Seresini, Elena Tassi FELLOW: Donato Calabrese TECHNICIAN: Giuseppe Consogno Viral evolution and transmission Unit HEAD OF UNIT: Gabriella Scarlatti POST-DOCTORAL FELLOW: Mariangela Cavarelli PHD STUDENTS: Miriam Baroni, Stefania Dispinseri, Lara Mainetti FELLOWS: Priscilla Biswas, Chiara Foglieni, Stefania Sala TECHNICIAN: Angela Pastore DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 97 Viral pathogens and biosafety Unit HEAD OF UNIT: Elisa Vicenzi POST-DOCTORAL FELLOW: Anna Kajaste-Rudnitski PHD STUDENT: Tiziana Coradin FELLOW: Cinzia Pultrone TECHNICIAN: Silvia Ghezzi Clinical Research Units Infectious diseases Unit HEAD OF UNIT: Adriano Lazzarin* Management and antiretroviral treatment of HIV infection CLINICAL GROUP LEADER: Antonella Castagna PHYSICIAN: Nicola Gianotti FELLOWS: Francesca Cossarini, Vincenzo Spagnuolo STATISTICIAN: Laura Galli TECHNICIAN: Andrea Galli Neurovirology CLINICAL GROUP LEADER: Paola Cinque PHYSICIANS: Simona Bossolasco, Annamaria Pazzi POST-DOCTORAL FELLOWS: Roberta Formicola, Anna Granata, Manuela Testa TECHNICIAN: Arabella Bestetti Study and treatment of hepatotropic viruses related diseases CLINICAL GROUP LEADER: Caterina Uberti Foppa RESEARCHER: Giulia Morsica POST-DOCTORAL FELLOWS: Sabrina Bagaglio, Giulia Gallotta, Hamid Ibrahim Hasson FELLOW: Lucy Porrino Vaccine and immunotherapy CLINICAL GROUP LEADER: Giuseppe Tambussi PHYSICIANS: Silvia Nozza, Cecilia Pizzocolo FELLOW: Manuela Pogliaghi TECHNICIAN: Andrea Galli Clinical immunopathology and advanced medical therapeutics Unit HEAD OF UNIT: Maria Grazia Sabbadini* PHYSICIANS: Elena Baldissera, Enrica P. Bozzolo, Giselda Colombo, Lorenzo Dagna, Massimo Memoli, Luisa Praderio, Moreno Tresoldi POST-DOCTORAL FELLOWS: Patrizia Tanina Aiello, Stefano Franchini FELLOWS: Fulvio Salvo, Mirta Tiraboschi Clinical transplant Unit HEAD OF UNIT: Antonio Secchi* PHYSICIANS: Rossana Caldara, Francesca De Taddeo, Chiara Gremizzi, Rosa Pedale POST-DOCTORAL FELLOWS: Alessandra Petrelli, Andrea Vergani Gynecological cancers immunology HEAD OF UNIT: Augusto Ferrari* CLINICAL GROUP LEADER: Massimo Origoni* PHYSICIAN: Luigi Caputo RESIDENTS: Francesca Occhi, Chiara Stefani 98 - SAN RAFFAELE SCIENTIFIC INSTITUTE Immunology in liver neoplasms HEAD OF UNIT: Gianfranco Ferla* CLINICAL GROUP LEADER: Luca Aldrighetti PHYSICIANS: Marco Catena, Renato Finazzi RESIDENT: Carlo Pulitanò Obesity RESEARCHER: Michele Paganelli Pancreatic tumors: immunotherapy and β-cell function substitution HEAD OF UNIT: Valerio Di Carlo* CLINICAL GROUP LEADER: Alessandro Zerbi PHYSICIANS: Marco Braga*, Marco Stella RESIDENTS: Vanessa Capitanio, Giovanni Capretti, Federica Merlini Gastroenterology Unit Head of Unit: Pier Alberto Testoni* Clinical hepato-gastroenterology RESEARCHER: Mario Guslandi Digestive pathophysiology RESEARCHER: Sandro Passaretti Transplant surgery HEAD OF UNIT: Carlo Staudacher* RESEARCHER: Carlo Socci DRI, Diabetes Research Institute Director: Luca G. Guidotti Associate Director: Emanuele Bosi* Research Units Immune tolerance GROUP LEADER: Manuela Battaglia PHD STUDENTS: Alessandra Ferraro, Nicola Gagliani FELLOW: Andrea Valle TECHNICIANS: Tatiana Jofra, Angela Stabilini Experimental diabetes GROUP LEADER: Marika Falcone POST-DOCTORAL FELLOW: Ester Badami PHD STUDENT: Simone Caielli FELLOWS: Caterina Di Pietro, Carlo Ruberto TECHNICIAN: Alessandra Caputo β cell biology GROUP LEADER: Lorenzo Piemonti POST-DOCTORAL FELLOW: Leda Racanicchi PHD STUDENT: Valeria Sordi FELLOWS: Elisa Cantarelli, Erica Dugani DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 99 Cell imaging HEAD OF UNIT: Alessandro Del Maschio* GROUP LEADER: Maria Luisa Malosio FELLOW: Cristina Brigatti Clinical Research Units Islet transplantation HEAD OF UNIT: Antonio Secchi* CLINICAL GROUP LEADER: Paola Maffi BIOLOGIST: Paola Magistretti Prevention in Type 1 diabetes HEAD OF UNIT: Emanuele Bosi* CLINICAL GROUP LEADER: Luca Falqui PHYSICIANS: Matteo Rocco Pastore, Sabina Martinenghi RESIDENT: Laura Molteni RESEARCH NURSE: Pauline Grogan Epidemiology & data management RESEARCHER: Marina Scavini Childhood diabetes HEAD OF UNIT: Giuseppe Chiumello* RESEARCHER: Riccardo Bonfanti Islet processing activity SUPERVISOR: Lorenzo Piemonti RESEARCHER: Rita Nano FELLOWS: Raffaella Melzi, Alessia Mercalli * Professor at: Università Vita-Salute San Raffaele ** Università Vita-Salute San Raffaele 100 - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Directors The Division of Immunology, Transplantation and Infectious Diseases (DITID) stems from a deeply integrated area of Institutional research at the San Raffaele, dating back to the inception of DIBIT and constituting the scientific core of areas of intense clinical investigation, which include, but are not limited to, cancer, type 1 diabetes, allergy, cell and solid organ transplantation and HIV infection. Although the contribution of a normal or deranged immune response to the pathoRuggero Pardi genesis of the above conditions is highly diversified, common themes emerge, thus justifying the creation of a scientific and cultural environment where pre-clinical models, technology platforms and specific know-how pertinent to immunology can be optimized to achieve critical mass, to develop higher education programs and to promote innovative research outcomes, both in preclinical research and in the clinical settings. Based on these premises, the comprehensive goal and unifying mission of the DITID is to harness the immune response for the benefit of patients. To this aim, the DITID will foster research efforts and development of new technologies aimed at dissecting the Adriano Lazzarin mechanisms underlying the immune response to infectious agents, cancer- and transplantation-associated antigens, as well as the dysregulation of the mechanisms involved in peripheral tolerance to self-antigens. Validation of these basic discoveries will require standardization of pre-clinical models and extensive analysis of human immune cells and tissues. The most promising findings will be translated into proof-of-concept designs for phase I/II clinical trials. To achieve its goals, the DITID has structured selected research activities into a limited set of Research Programs, aimed at fostering interdisciplinary research and strong integration of pre-clinical and clinical investigations. The Islet Transplantation Program (ITP) aims at achieving long-lasting insulin independence in patients with type 1 diabetes (T1D) undergoing portal vein islet transplantation. Recognized experts in islet transplantation, immunological tolerance, liver immunopathology and non-invasive imaging have been brought together to address and modify innate and adaptive immune responses to islet transplants that together prevent lifelong persistence of functional islets within the liver, as well as to identify potentially novel and safer implantation sites. The Program of Immunology and Immuno-biotherapy of Cancer (PIBIC) is promoted jointly by the DITID and the Division of Molecular Oncology. The major goals of the PIBIC are twofold: i. a deeper understanding of the mechanisms underlying the tumor/immune system interactions; and ii. the provision of new immunotherapy strategies that are rationally designed to increase significantly the therapeutic efficacy of the current ones. A third Program soon to be launched stems from the recognition of a critical mass of basic and applied investigators already ongoing in this Division and in the Department of Infectious and Tropical Diseases on the role of CCR5 and its ligands in HIV infection and related clinical entities. The Program is named Correlates of HIV-associated Immune Response Modulation (CHARM). General goals of CHARM are the investigation and exploitation of the role of CCR5 and its natural or chemical ligands in HIV infection and in infection-related inflammation. DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 101 Research Units LEUKOCYTE BIOLOGY UNIT Adhesion receptor signaling and dynamics in leukocyte migration, proliferation and survival Most somatic cells require adhesion to substrate for progression through the cell cycle and the onset of DNA replication in response to growth factors. This phenomenon is known as “anchorage-dependence” (AD), and is thought to be largely dependent on active signaling by surface integrins. AD is lost at an early stage in neoplastic transformation. We have identified a multimolecular protein complex, the COP9 signalosome (CSN), which appears to act as a point of convergence of signals originated from adhesion receptors and conveyed to the nucleus via post-translational modifications of selected transcription factors involved in cell proliferation, differentiation and the adaptive response to stress. We are investigating this novel signaling axis within the context of normal developmental processes (e.g. liver regeneration, see Figure) and in neoplastic transformation. To this aim we have generated conditional knockout mice in which the catalytic subunit of the CSN has been genetically inactivated in various tissues (T cells, macrophages, hepatocytes). We also investigate adhesion receptor dynamics in cell migration: in primary neutrophils, we have shown that unengaged αL/β2 integrin (LFA-1) is internalized and rapidly recycled upon chemoattractant stimulation via a clathrin-independent, cholesterol-sensitive pathway involving dynamic partitioning into detergent-resistant membranes (DRMs). DRM-associated endocytosis allows efficient retrieval of integrins, as they detach from their ligands, followed by polarized recycling to areas of the plasma membrane, such as lamellipodia, where they establish new adhesive interactions and promote outside-in signaling events. More recently, we unveiled a novel role of β-arrestins in regulating the activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in β-arrestin knockout mice with in vitro studies in engineered cellular models we show that membrane-recruited β-arrestin-2 is required for the onset and maintenance of shear stress-resistant leukocyte adhesion mediated by both β-1 and β-2 integrins. Ruggero Pardi Figure 14. CSN5 expressing clones of hepatocytes emerge in conditionally deleted CN5 knock-out regenerating liver parenchyma 102 - SAN RAFFAELE SCIENTIFIC INSTITUTE CELLULAR AND MOLECULAR ALLERGOLOGY Recombinant allergens are entering clinical practice as highly performing diagnostic tools and demonstrated efficacy and safety in controlled clinical trials. Recombinant allergens can be mutated to reduce their allergenicity, i.e., IgE binding, while fully maintaining T-cell stimulatory potential, which is mandatory for the success of immunotherapy. Modified, allergens with reduced allergenicity are referred to as “allergoids”. Conventional strategies to generate allergoids include extended deletions of B-cell epitopes and multiple mutations of the allergen. Alternatively, we are investigating the possibility to destroy crucial B cell epitopes with a single mutation approach. We propose to verify whether structurally-guided point mutations represent a successful strategy in the design of modified allergens for immunotherapy, as opposed to standard approaches implying more radical molecular modifications. We have been working in the last year on the model of the Mus m 1 major mouse allergen, belonging to the lipocalin protein family. We found that Tyr120 is particularly important for the overall stability of this protein. Mutations at the level of this residue appear primarily responsible for alterations in the H-bonds network that stabilizes this molecule and provide striking conformational modifications of the global protein architecture, as assessed by NMR. We will investigate whether and to what extent this approach is capable of significantly impairing allergen recognition by IgE from mouse-allergic patients, and its impact on T-cell epitopes. We are also interested to verify whether this strategy can be applied to recombinant panallergens. Panallergens, such as profilins, are promising tools to vaccinate a relevant proportion of allergic subjects who are presently orphans of a specific immunotherapy. We demonstrated that profilins play a crucial role in the epitope spreading of the immune response in polysensitized individuals, who represent approximately one third of allergic individuals. A specific vaccination with immunogens clinically “easy to handle” due to low allergenicity could bring about a favorable interference in this process for a large proportion of allergic individuals. Samuele E. Burastero HUMAN VIROLOGY Background The failure of anti HIV-1 vaccine strategy based on the exclusive induction of a broad T-cell response against structural antigens suggests that the most effective defence against HIV-1 transmission might require the combination of HIV-1-specific T-cell responses and anti-HIV-specific antibody (Ab) responses. Our unit is mainly involved in two projects focussed on the development of an effective anti HIV-1 vaccine studying, on one side, the distinctive features of the T-cell mediated immune response towards structural and regulatory HIV-1 encoded antigens in particular cohorts of HIV-1 infected individuals who survive for long time without sign of immune deterioration (LTNP) and/or naturally control viral replication below the level of detection of the clinical lab tests (Elite controllers = EC). On the other side, we are conducting a deep characterization of the HIV1 Envelope protein gp120 aiming to individuate key structural modifications to render the gp120 an useful immunogen. Indeed, monomeric gp120 Env fails to induce NAbs, whereas NAbs have the unique ability to bind to the gp120 Env trimer. Moreover, relevant epitopes of this oligomeric structure are shielded by the variable loops that we are removing/modifying from the gp120 scaffolds of two selected HIV-1 strains: the CCR5 dependent strain BaL and the R5X4 strain US077. Main results obtained in 2008 A strong polyepitopic response against the HIV-1 encoded antigen Tat is the hallmark of EC individuals showing, in addition a peculiar restriction towards particular regions of the protein that are never or rarely seen by patients belonging to other cohorts of HIV-1 infected individuals. On the contrary, in LTNP the major feature of the T-cell mediated immune response is represented by a distinctive population of TEMRA CD8 cells secreting Mip-1â representing a specific immunological marker of natural protection from HIV-1 disease progression.Regarding the second project the functional analysis of the gp160 proteins expressed in vaccinia virus vectors demonstrates that the deletion of the V1 region is well tolerated by both gp160 scaffolds with preserved function. On the contrary deletion of the V2 region reduced fusion and modify the recognition of mAbs directed against CD4 induced epitopes. Mauro S. Malnati DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 103 INFECTION AND CYSTIC FIBROSIS Pseudomonas aeruginosa-host interactions in Cystic Fibrosis: implications for pathogenesis and therapy Persistent bacterial infections involving Pseudomonas aeruginosa pose serious problems for human health including Cystic Fibrosis (CF) patients. After causing an initial acute disease state, which is kept in check by an adaptive immune response, Pseudomonas aeruginosa establishes persistent infection and colonize the host by evading immune surveillance. The goal of our program is to elucidate cellular and molecular mechanisms that are involved in the host-pathogen interactions during persistent infection with the aim of devising new therapeutic approaches to treat respiratory infections. • • Cellular and molecular mechanisms involved in P. aeruginosa-host pathogen interactions. We selected strains from CF patients, which carried the same clonal lineage from the onset of colonization over many years. Genotypic analysis showed genome rearrangements, uptake or loss of genomic islands and acquisition of pathoadaptive mutations. Virulence of early and late CF isolates was assessed by monitoring acute mortality versus survival, and P. aeruginosa persistence versus clearance in mice of different genetic backgrounds, including CF. We found that chronic infection is established with pathogenic variants distinguished by initially acquired strains and attenuated in causing acute mortality. Of particular interest is the finding that P. aeruginosa virulence factors are modified or selected against during chronic infection. In particular, changes in P. aeruginosa PAMPs lead to escape host innate immune system and endorse pathogenesis. Our findings emphasize studies to define novel virulence determinants in adapted P. aeruginosa population and to identify novel targets which may lead to improved antimicrobial therapy strategies. Evaluation of novel molecules for treating respiratory infection and inflammation. Our group has established and characterized a mouse model for airway chronic infection with opportunistic P. aeruginosa and collected unique reagents such as highly virulent CF-related pathogens. Based on this expertise, we have established the Cystic Fibrosis Animal Core Facility (CFaCore) to support investigations on candidate therapeutic molecules and to favor the translation of basic research projects into pre-clinical applications. Alessandra Bragonzi PROTEIN ENGINEERING AND THERAPEUTICS Research in our laboratory focuses on molding protein design, engineering and expression strategies into novel therapeutic interventions. Two major fields are being exploited. The chemokine-chemokine receptor axis is one of them. Main efforts are devoted to HIV-1 entry inhibitors based on engineered derivatives of RANTES and other CCR5-binding chemokines, in an attempt to create CCR5 antagonists with potent anti-HIV-1 activity. Both full-length RANTES mutants and short peptides are presently being developed as CCR5-antagonist anti-HIV-1 mucosal microbicides. In perspective, AIDS prevention by microbicides represents an alternative as well as a complement to an HIV-1 vaccine. The ‘live microbicides’ field is a particularly promising and innovative approach based on the engineering of human commensal bacteria, such as lactobacilli, to produce antiHIV-1 protein therapeutics, a field in which we are involved and committed. A further aspect of HIV-1 entry inhibitor development consists in the possible combination of different lead compounds. Both full-length and short peptide RANTES derivatives presented full additivity or even slight synergism when tested in vitro in combination with different HIV-1 inhibitors. In a second research area, we are trying to couple structure-function knowledge on IgE and its receptors to the benefit of human health. In this view, we devise IgE engineering in an attempt to combat both allergic manifestations as well as cancer. Interestingly, in a research program codirected with Prof. Antonio Siccardi, we found that IgE is a potent adjuvant in anti-tumor vaccination and Fc ε RI, the high affinity receptor for IgE, the key mediator of the IgE anti-tumor effect. We are now evolving this system by recruiting also membrane-bound IgE variants and safe recombinant viral vectors. We engineered a recombinant MVA (modified vaccinia virus Ankara) to express a truncated version of human membrane IgE capable to bind and activate human Fc ε RI. This system, that includes the use of transgenic mice expressing the human receptor, has the advantage of being safe and close to the clinics. Luca Vangelista 104 - SAN RAFFAELE SCIENTIFIC INSTITUTE Figure 15. The “live microbicide” concept represented by an engineered lactobacillus secreting RANTES that diffuses and blocks cellular CCR5 at mucosal sites γδ T CELLS IN INNATE AND ADAPTIVE IMMUNITY Involvement of γδ T cells in host defense against infections and lymphomas Circulating Vδ2 T lymphocytes are involved in the response to mycobacterial infections and EBV, while Vδ1 T cells, resident in mucosal-associated lymphoid tissues, contribute to the immunity against L. monocytogenes and CMV. Vδ2 T lymphocytes recognize non-peptidic phosphorylated metabolites of isoprenoid biosynthesis, expressed by mycobacteria, while Vδ1 T cells interact with stress-induced MHC-related antigens (MIC-A, MIC-B) and with the UL-16 binding proteins (ULBPs), receptors for the UL-16 protein produced by CMV-infected cells. Vδ1 T lymphocytes are increased in HIV-1 infected patients and we showed that this is related to chemokine receptor expression and chemokine response. In these patients ex-vivo isolated Vδ1 T cells express cytoplasmic interferon (IFN)-γ and interleukin (IL)-17. These cells proliferate and produce IFN-γ and IL-17 in response to C. albicans, while Vδ2 T cells respond to mycobacterial or phosphate antigens. The IFN-γ/IL-17 double producer γδ T cells express the Th17 RORC and the Th1 TXB21 transcription factors, bear the CD27 memory T cell marker, the CCR7 homing receptor, the chemokine receptors CCR4+ and CCR6+ and the CD161 molecule, that mediates transendothelial migration and marker of Th17 cells (Blood 2009, in press). We also found that circulating Vδ1 T lymphocytes are increased in patients with CLL and non Hodgkin NHL, where they can proliferate, produce TNF-α or IFN-γ in response to autologous cells, provided they express MIC-A or ULBPs, and in NHL also IL-4 (Blood 2007, 109:2078-2085). These ligands can be up-regulated both in vitro and in vivo by the use of all-trans-retinoic acid or sodium valproate (Leukemia 2009, 23:642-648). Of note, the number of circulating Vδ1 T cells in CLL and of IL-4 producing Vδ1 T lymphocytes infiltrating the lymph nodes in NHL correlates with disease stage and progression. Thus, specifically equipped circulating memory γδ T cell populations seem to be expanded in different pathological conditions, being preferentially Th1/Th17 or Th2, probably depending on the antigen(s) encountered in the microenvironment of lymphoid tissues undergoing infections, chronic inflammation, or lymphoid malignant transformation. Maria Raffaella Zocchi DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 105 IMMUNOBIOLOGY OF HIV HIV-specific mucosal immunty involved in HIV exposure/infection Since HIV-1 is sexually transmitted, the genital mucosa represents the main site for initial host-virus contact, although the role of oral mucosa is not jet clarified. We studied the humoral immune responses at both genital, oral and systemic levels of HIV-exposed but uninfected individuals (ESN) adults and in samples from seronegative babies born from Subtype C infected mothers, which represents a relevant issue in order to better understand biological mechanisms involved in natural resistance to HIV infection. We also determined whether oral HIV-1 exposure incites a persistent systemic anti-HIV-1 response in ESN of discordant couples of men who have sex with men (MSM), and whether this response correlates with exposure to HIV as measured by viral load in the HIV-positive partners. Orally exposed uninfected MSM can mount neutralizing anti HIV-1 activity in plasma, mediated primarily by IgA1. This activity correlates with the viral load in HIV-positive partners. Moreover, we found IgA1 to CCR5 in a subset of HIV seropositive subjects who did not progress toward disease. In this study we will focus on immuno and virologic characterization of such HIV blocking antibodies. We also analyzed cord blood from 37 seronegative babies born from HIV-seronegative mothers and plasma from the mothers. We found high titers of IgG directed against one region within the HR1 portion of gp41 but not against MPER (region recognized by 2F5 and 4E10 which are two broad neautralizing antibodies) in seropositive mothers, although high levels of IgG antibodies against both of these two regions of gp41 were found in their neonates. A specific neutralizing activity was found in a large number of exposed but uninfected babies and in their mothers. Preliminary data indicate a positive correlation between neutralizing antibodies and two regions of gp41 such as a domain within the α helic region and a second domain overlapping with 2F5 epitope but not with 4E10 epitope. The characterization of mucosal immune system in HIV infection could give us a key to better understand the mechanisms of viral transmission. Our findings may be relevant in the design of an HIV vaccine able to protect from HIV-1 Subtype C strains. Lucia Lopalco IMMUNOLOGICAL DIAGNOSTICS OF TUBERCULOSIS A flow cytometric assay for discriminating active from latent Mycobacterium tuberculosis infection The WHO estimated that one-third of the world’s population harbours Mycobacterium tuberculosis (Mtb) in an asymptomatic, latent form but retains a lifelong risk of future disease. We have recently validated an in-house ELISpot-IFN-γ assay based on a restricted pool of highly selected peptides derived from MTb-specific proteins (here defined MTP). The test resulted highly specific (87%) and sensitive (93%) for detecting MTb infection. However, actually no tests are able to discriminate active from LTBI. The possibility to identify specific T cell subsets and different patterns of T cell memory responses by means of a selected panel of surface and intracellular markers makes flow cytometry an invaluable tool for discriminating active from LTBI as recently suggested by several animal models of infection characterised by a rapid clearance or persistence of the pathogen. We have conducted a preliminary flow cytometric analysis on active Mtb-infected and LTBI subjects (all with a positive ELISpot-IFN-γ MTP-specific response) using a panel of 4 mAbs against surface (CD4 and CD45RA) and intracytoplasmic (IFN-γ and IL-2) markers. Cryopreserved PBMC were stimulated 6h with the pool of MTP plus a costimulatory signal (anti-CD28/-CD49d mAbs); after 1h Brefeldin A was added. As negative control unstimulated cells, and as positive control cells stimulated with PMA/Ionomycin were used. The analysis was performed first gating on CD4+ T lymphocytes then on either CD45RA+ or CD45RA- subsets. Within each subset, the frequency of single positive (IFN-γ+ or IL-2+) or double positive (IFN-γ+/IL-2+) cells was determined and the ratio MTP-stimulated/unstimulated (S/US) cells calculated. While CD4+CD45RA- single or double positive T cells were present in both active and LTBI subjects, a significant increase of CD4+CD45RA+ double positive cells in LTBI vs. active MTb-infected subjects was observed. We calculated the Area Under the Curve (AUC)=0.7 (CI 95% 0.503-0.897) and the best cut off point to discriminate active from LTBI. When the cut off S/US cells <1.5, sensitivity= 87% and specificity= 50%. Two observation could be extrapolated from 106 - SAN RAFFAELE SCIENTIFIC INSTITUTE these results: first, when the cut off >1.5 is highly probable that the subject have a LTBI; second two subgroups of LTBI subjects are recognized, and probably only those with the higher cut off could harbour replicating mycobacteria so representing real latently MTb-infected persons. Claudio Fortis AIDS IMMUNOPATHOGENESIS UNIT Immunopathogenesis of HIV infection Central theme of our Unit is the regulation of HIV replication by exogenous host factors, primarily of immunological nature. In this scenario, we have been focusing our research primarily on the 4 topics listed below. I. Molecular pathogenesis of HIV infection, with specific regard to the role of the JAK/STAT signaling pathway, and of STAT5 in particular, in HIV replication. This project is the development of our paper published in 2007 (A. Crotti et al. Blood) in which we demonstrate a direct and functional binding of STAT5 and of its naturally C-terminus truncated variant STAT5∆ to the HIV-1 LTR. In addition, we are pursuing the characterization of a transcriptome derived from primary CD4+ T cells infected with either a CCR5-using (R5) vs. a CXCR4-dependent (X4) HIV infection. II. Role of macrophage polarization in HIV infection. This project explores the potential role of M1 vs. M2 polarization of monocyte-derived macrophages (MDM) infected in vitro with R5 HIV-1 in terms of virus replication. We have observed that both M1 and M2 polarized MDM support less efficiently virus multiplication, although with differences in terms of potency (M1>M2), duration (M2>M1) of the effect and mechanism of action (M1: pre-integration; M2: post-integration). III. Role of cell adhesion in controlling HIV replication. Based on our published papers on the inhibitory effect of urokinase-type plasminogen activator (uPA), we are addressing the role of static adhesion and of integrin-dependent signaling in impeding the release of mature virions from intra-cellular compartments from infected MDM and related cell lines. IV. Genetic studies in HIV long-term nonprogressors (LTNP). Within a EC-funded consortium (“GISHEAL”), headed by Guido Poli, we are performing genome-wide association studies (GWAS) using an ILLUMINA platform to identify candidate alleles associated with the LTNP condition. The preliminary analysis encourages this approach. Guido Poli BIOCRYSTALLOGRAPHY UNIT Structural approaches against cancer, immune-mediated, and infectious diseases In the post-genomic era, a considerable effort is put in the identification of target genes whose activity is relevant for human disease. The crystal structure of the macromolecule encoded by the gene is crucial information that provides an invaluable basis for the rational design of compounds that may selectively bind to the gene product, and specifically interfere with its activity. Our unit focuses on the determination of the three-dimensional structure of proteins and protein-ligand complexes using X-ray crystallography. Our interest range from enzymes crucial for the survival of pathogens that are causative agents of infectious diseases, to proteins involved in the pathogenesis of neoplasies, and immune systems receptors. We recently demonstrated that a Staphylococcal enzyme with nucleoside hydrolase activity plays a crucial role in the uptake pathway of components for the biosynthesis of NAD+. Since S. aureus is NAD-autotrophic, this enzyme is a highly amenable target for a completely new class of antibacterial compounds. We crystallized and determined the structure of the staphylococcal NH enzymes, both unliganded and in complex with a newly identified micromolar inhibitor. These compounds are effective in reducing bacterial growth in culture, and are currently being tested in animal models of infection. The same family of enzymes is of central importance in the purine-auxotrophic Trypanosomes, causative DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 107 agents of Chagas’ disease and sleeping sickness in humans. NHs bear the burden of providing the building blocks of DNA, RNA, and cofactors in these organism, and are hence obvious yet overlooked targets for drug design. We determined the crystal structures of the three NHs from T. brucei brucei, differing in specificity, and engineered isozyme-specific compounds that display sub-nanomolar affinities and are strong candidates as antitrypanosomal lead compounds. We also developed, based on functional information from NH structure, a synthetic enzyme that activates a lowly toxic antineoplastic prodrug, and greatly augments its efficacy in killing cancer cells. Ongoing experiments in models in vivo demonstrate that large tumor masses can be dramatically reduced with this gene-prodrug therapy. Massimo Degano CELLULAR IMMUNOLOGY UNIT Our major goal is to achieve a deeper understanding of the molecular events regulating the interactions among transformed cells, their surrounding stroma and the immune system during the different phases of tumor development and progression. This knowledge is then implemented to identify means whereby induce in vivo a therapeutic tumor-specific immune response. These tasks require investigation into reliable animal models that truthfully reflect the human pathology. Monitoring the immune response against the tumor associated antigen Tag in the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, a primary model of prostate cancer (PC), we have found that spontaneous tumor development and progression associates with the induction of a progressive state of selective immune tolerance to Tag. Indeed, tumor-bearing mice still harbor Tag-specific T lymphocytes that no longer respond to a specific vaccination. So far, none of the best-characterized mechanisms of tumor escape [i.e. regulatory T cells (Treg), myeloid derived suppressor cells (MDSC), and inhibitory enzymes] although existing in tumor-bearing TRAMP mice, appeared to be relevant for the induction of Tag-tolerance. Indeed, neither depletion/impairment of Treg by monoclonal antibodies or cyclophosphamyde, inhibition of MDSC function by arginase and iNOS inhibitors, nor inhibition of IDO allowed rescue of Tag-specific T cells and/or delay in tumor progression. In parallel, we are investigating an original therapeutic approach that combines chemotherapy and immunotherapy with molecules able to affect tumor vessels. This approach aims at improving penetration of conventional doses of chemotherapeutic drugs in tumors, favoring their local anti-tumor and immune adjuvant effects. However, it can also be exploited to reduce the dose of chemotherapeutic drugs and their toxicity, including that against cells of the immune system, with potential additive and synergistic effects. We recently showed that pre-treatment with NGR-TNF-α, a TNF-α derivative able to target tumor vessels and alter vessel permeability, increases the penetration and the efficacy of doxorubicin in pre-clinical models of PC. Matteo Bellone EMERGING BACTERIAL PATHOGENS UNIT Pathogenesis and epidemiological control of drug resistant bacterial pathogens of community and nosocomial origin 1) Tuberculosis (TB): from public health to basic and applied research. We target some of the research priority areas in the TB field: new diagnostics tools for accurate and rapid DRTB diagnosis and markers of virulence for a potential vaccine strategy. We established a European consortium with extensive experience in basic and clinical research relating to MDR-TB, TB control and epidemiology. TBPAN-NET and TM-REST FP7grants sustain this project. Part of this activity is integrated with the activities of our HSR-WHO TB Supranational laboratory. We used our MDR-TB strains collection for the development of an automated innovative platform for MDRTB diagnosis. 108 - SAN RAFFAELE SCIENTIFIC INSTITUTE An efficient innate immune response is crucial in the natural resistance against MTB. We established an in vitro model for MTB infection in human macrophages for studying the gene regulatory events associated with host-pathogen interaction by the analysis of small RNAs induced in both macrophages and bacteria. We used a bioinformatics approach to identify one hundred putative sRNAs candidates in M.tuberculosis. sRNA fraction from the pathogenic M. tuberculosis H37Rv and the avirulent strain M.bovis BCG were sequenced. 2) Molecular epidemiology and virulence factors characterization of nosocomial multidrug resistant microorganisms. Global epidemiology of S.aureus methicillin-resistant (MRSA) is constantly evolving and the community-acquired (CA) highly virulent US300-ST8 MRSA clone is the predominant MRSA clone in the US. In Europe several clones CA-MRSA are emerging. Studying 350 MRSA strains since 2005 we have identified: 1) a significant shift over the years from clones bearing the scc mecI to clones with scc mec IV; 2) two predominant clones, ST22 (EMRSA15) and HSR1 (Italian); 3) toxigenic US300 related strains causing severe infections. We are investigating the expression of virulence determinants in the identified clones. C.difficile associated-colitis is increasing in nosocomial settings and highly virulent strains are spreading worldwide. We characterized 130 C.difficile strains positive for tcdA/tcdB, 40/130 harbouring cdtA/B as additional virulence factor. We are now investigating the presence of mutations in the tcdC gene, coding for the negative regulator of toxinA/B. Daniela Maria Cirillo EXPERIMENTAL IMMUNOLOGY UNIT Investigating the T cell response specific for tumor-specific peptide or lipid antigens 1. Investigating the development and function of T cells that recognize self-lipid antigens presented by CD1 molecules. We study two types of CD1-restricted T cells. First, the invariant (i)NKT cells, which are a distinct lineage of T lymphocytes with innate effector functions, whose development relies on a unique genetic program. Our data support a critical role of miRNAs in the physiology of iNKT cells. Furthermore, we have found that iNKT cells sustain antibody response to vaccine models by licensing APCs and facilitating the induction of Th cells. Finally, we have obtained evidence both in man and mouse that the presence of iNKT cells plays a protective role against cancer. We are interested also in a second type of CD1 restricted T cells, which recognise self-lipid antigens presented by CD1a, b, c. We are testing the hypothesis that lipids synthesised by malignant cells may stimulate this CD1-restricted T cell response. We have identified a set of self-lipids extracted from leukemia cells that stimulate CD1-restricted T cells. 2. Discovery of unique tumor antigens and characterization of the specific T cell responses. We are testing the hypothesis that somatic mutations in selected colon cancer genes (CAN-genes) generate strongly immunogenic antigens and specific immune responses in patients. We have started the identification of the somatic mutations in 40 CAN-genes by massive parallel sequencing from several CRC specimens. Furthermore, we have shown that it is possible to substantially improve HLA-DR tetramer technology to help identifying tumor antigen-specific T cells by optimizing peptide binding registers Paolo Dellabona DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 109 IMMUNOPATHOLOGY UNIT Host-Virus interactions in the pathogenesis of viral hepatitis and viral hemorrhagic fevers The hepatitis B virus (HBV) and hepatitis C virus (HCV) are noncytopathic viruses causing acute and chronic hepatitis of variable duration and severity. Over 700 million people worldwide are chronically infected by these viruses and about 2 million of them die each year from the complications (i.e. cirrhosis and hepatocellular carcinoma, HCC) of these infections. The main objective of our research is to define the cellular and molecular mechanisms responsible for viral clearance and disease pathogenesis during HBV or HCV infection with the expectation that our results will help to devise new therapeutic approaches to prevent and cure these diseases. Our hepatitis program takes advantage of infected patients, unique mouse models of infection and new technological advances in the field of live imaging, tackling a number of unresolved issues that comprise the means by which virus-specific T cells traffic and recognize viral antigens within the liver and how such processes are affected by the anatomical and hemodynamical changes that characterize the complications of chronic HBV infection. Having recently described a novel role for platelets in the pathogenesis of viral hepatitis (i.e. activated platelets contribute promote the recruitment of virus-specific T cells into the liver), we are also currently dissecting the molecular basis of platelet/CTL interactions and the impact that pharmacologic inhibition of platelet activation may have on the severity of immune-mediated chronic liver injury and HCC development. In related studies aimed at testing the role of platelets in the pathogenesis of viral hemorrhagic fevers, we found that mice infected with different isolates of hemorrhagic arenaviruses develop a mild hemorrhagic anemia, which becomes severe and eventually lethal in animals depleted of platelets or lacking integrin β-3. Lethal hemorrhagic anemia is mediated by virus-induced interferon (IFN)- α/β that causes platelet dysfunction, mucocutaneous blood loss and suppression of erythropoiesis. Further, platelet-depleted mice fail to mount an efficient T cell response and do not clear the virus. These studies indicate that IFN- α/β is required and sufficient to cause the platelet dysfunction and the mechanism of this action is currently under investigation. Luca G. Guidotti LYMPHOCYTE ACTIVATION UNIT Understanding the cellular and molecular events underlying T-cell dependent immunity and tolerance Our research activity is centered on the characterization of the cellular and molecular events underlying protective immunity and tolerance. In particular we are interested in defining CD4+ T lymphocytes activation, proliferation, and differentiation as these cells orchestrate immune responses against pathogens and tumors. To characterize the relative contribution of TCR/CD28 and cytokine-mediated events to T helper cell clonal expansion and differentiation, we are studying antigen- induced responses in primary T cells by biochemical and molecular biology assays coupled to single cell flow cytometry analysis. At present we are focusing on mTOR-mediated signaling controlling cell growth and transcription of cytokine genes important for cell polarization. The in vitro studies are coupled to the in vivo analysis of antigen-specific T cells. We have developed a number of mouse models where to track antigen-specific CD4+ and CD8+ T cells in lymphoid and non-lymphoid tissues by flow cytometry and immunohistochemestry. These models allowed the study of the dynamic interaction between developing tumors and adaptive immune responses and the definition of active and adoptive immunotherapy strategies able to overcome mechanism of central and peripheral tolerance. In collaboration with the group of M. Bellone we are also investigating the contribution of minor histocompatibility antigen-restricted T cells to protective anti-tumor immunity in the context of allotransplantation. Finally, in collaboration with I. De Curtis and M. L. Feltri we are also studying the impact of a dysfunctional nervous system development on the acquisition and maintenance of immunocompetence. Future challenges will involve the definition of in vitro strategies able to modulate T cell function and allowing the generation of defined lymphocyte population capable of transferring protective immunity of tolerance upon in vivo infusion. Anna Mondino 110 - SAN RAFFAELE SCIENTIFIC INSTITUTE TUMOR IMMUNOLOGY UNIT Role of tumor antigen specific CD4+ T cells in tumor regression and promotion Animal models have shown that CD4+ T cells play a role in anti-tumor immunity by licensing dendritic cells to fully activate CD8+ T cells in the lymphnodes and indirectly by cytokines release at the tumor site. To address the role of tumor antigen specific CD4+ T cells in the human system we first set a strategy to identify tumor peptides recognized by CD4+ T cells and second we used those peptides to study the quantity and quality of the spontaneous tumor specific CD4+ T cell immunity in neoplastic patients. The models used are cervical and pancreatic cancer. Cervical lesions are associated with infection by HPV, mostly genotypes 16 and 18. Development of different grade HPV-16+ cervical intraepithelial neoplasia (CIN) to cervical cancer has been associated with impaired CD4+ T cell immunity against early antigens. We focus on HPV-18 and in patients with high-grade CIN undergoing conization. We found that HPV-18 E6 and E7 specific CD4+ T cells are present in 50% of patients, irrespective of the presence of HPV-18 in their lesions. Importantly, a robust Th1/Th2 immune response against E7 but not E6 was associated with the HPV-18- status. On the contrary, when the patients were divided based on their clinical outcome after surgery, a robust Th1/Th2 immune response against E6 but not against E7 correlated with lack of relapse. Our data demonstrate that, at difference with HPV-16, HPV-18 is immunogenic and suggest different roles for anti-E6 and E7 CD4+ T cells in anti-viral and anti-tumor immunity. Pancreatic cancer (PC) is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which favors rapid tumor progression. We evaluated the extent of cancer immune-surveillance and immune-suppression in PC patients by comparing the anti-tumor (antiCEA) and anti-viral CD4+ T cell immunity. We found that PC patients have a Th2 skew in the anti-CEA but not in the anti-viral CD4+ T cell immunity, demonstrating that Th2 immune-deviation in PC is not generalized but tumor related and possibly due to factor(s) present at the tumor site. In agreement, immunohistochemical analysis showed the presence of a predominant GATA-3+ tumor lymphoid infiltrate, supporting a Th2 skew also at the tumor site. Maria Pia Protti VIRAL EVOLUTION AND TRANSMISSION UNIT Antigenic and phenotypic characterisation of HIV-1 variants in transmission and disease progression as target for vaccine development Production of an broad neutralizing antibody (Nab) against multiple HIV-1 variants is a desired characteristic for HIV vaccines. Some HIV-1 variants are able to elicit a strong humoral virus-specific, broad Nab response, providing fundamental proof-of-principle that such a response can be elicited in vivo, and thus these same variants may elicit a potent response again if formulated into an appropriate vaccine. We showed that viruses with a more flexible use of the CCR5 as coreceptor (called R5broad) and a high resistance to the natural ligand RANTES, are predictive of immunological failure in the infected newborn. Progression of disease is accompanied with an evolution of the virus to a more complex and flexible CCR5 usage. However, individuals who do control the disease progression (Long-term non progressors) and/or control naturally the virus (Elite controllers) have particularly slow replicating viruses which retain the specificity for the wild-type coreceptor only (R5narrow). These data demonstrate the high degree of variability within R5 viruses, and the need to confine R5 evolution to prevent disease progression. The development of a Nab response against the transmitted virus can appear as early as 6 months post-infection in adults and children, and persist throughout the disease progression. A Nab response is detectable in slow but not rapid progressing children. Nab against virus variants newly arising during disease are characteristic of immune escape. The specificity of binding of these antibodies as well as the genetic patterns of immune escape are ongoing research. In this regard we are also investigating the role of the intestinal mucosa, the main portal of entry of HIV-1 via all routes of transmission, and the site of major immune subversion early after infection, which can give us important information on which B and T cell responses HIV-1 is targeting. Our results support the hypothesis that dendritic cells mediate HIV-1 transmission from the lumen through the intestinal mucosa with a process DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 111 similar to bacterial sampling via a virus envelope-mediated mechanism. Understanding the cellular cross-talk and the type of immune responses promoted, will provide useful information on how to achieve an efficient anti-HIV immune responses in vivo. Gabriella Scarlatti VIRAL PATHOGENS AND BIOSAFETY UNIT Human Immunodeficiency Virus (HIV): virus-host interactions, SARS coronavirus (SARS-CoV) pathogenesis and Influenza viruses HIV. We have been studying HIV-infected individuals who naturally control HIV-1 infection maintaining a healthy clinical state without the use of antiretroviral drugs (defined as LTNP). Among the nine HIV genes, the integrity, variability and function of nef and vif accessory genes have been analyzed in LTNP. Since in vitro studies have shown that these two and most of HIV genes exploit and manipulate cell host proteins, we are currently concentrating on host cell factors that restrict HIV infection. In particular, we are interested in the role of the member 22 of the TRIparite Motif protein family (TRIM22) on HIV replication. Previous observations have shown that overexpression of TRIM22 restricts HIV in vitro infection. We have identified a model of U937 cell subclones in which TRIM22 endogenous expression correlates with poor HIV replication. Current studies are ongoing to define the precise mechanism of TRIM22 restriction. SARS-CoV is the etiological agent of the Severe Acute Respiratory Syndrome (SARS). Although the virus primarily infects the lungs, however, SARS-CoV causes a systemic infection since the virus has been found in blood, urine and stool. We have been particularly interested in the kidney tropism of the virus and identified human kidney cell lines that support SARS-CoV persistent infection. Such an infection leads to viral adaptation sustained by the emergence of a single point mutation in the viral membrane glycoprotein that increases SARSCoV replication in vitro and contributes to enhance its cytopathicity in a mouse model of SARS-CoV infection. Influenza viruses. A currently believed dogma assesses that avian influenza viruses of H5, H7 and H9 subtypes have the potential to be passed from animals, whether domesticated or wild, to humans. In contrast, H1 and H3 subtypes are devoid of such danger since the human population is endowed with cross-neutralizing antibodies raised during seasonal infection and/or vaccination. By screening a panel of sera obtained from health care workers who have responded to the seasonal influenza vaccine, we have demonstrated that humans do not have cross-reacting antibodies against contemporary avian viruses raising concerns on future pandemic influenza. Elisa Vicenzi Clinical Research Units NEUROVIROLOGY Viral infections of the Central Nervous System (CNS): HIV infection of the CNS and Progressive Multifocal Leukoencephalopathy (PML) The importance of HIV CNS infection in the current era of suppressive antiretroviral treatment is related to the role of the CNS as virus reservoir and the concern that its chronic infection may cause cognitive problems over a time frame of years that need be distiguished from other forms of cognitive impairment not related to HIV. Within an international 4-part ‘cerebospinal fluid (CSF) consortium’, which collects and studies biomarkers of HIV CNS infection, we have recently identified and validated the neurofilament light chain (NFL) and 112 - SAN RAFFAELE SCIENTIFIC INSTITUTE the soluble amyloid precursor proteins (sAPPa, sAPPb) as sensitive and specific markers of HIV-associated dementia (HAD) that differentiate this form from other forms of dementia. Also, we have investigated the role of the urokinase system in HAD and found that the soluble urokinase receptor (suPAR) is overexpressed in CSF and brain tissue of patients with HAD and that its CSF expression is highly correlated to intrathecal HIV replication, immune activation, and the above markers of neuronal damage, suggesting that suPAR might also play a role in mediating HIV-induced neurotoxicity. PML is a progressive demyelinating disease caused by JCV infection of oligodendrocytes. It is not known why, when and where JCV reactivates in certain patients with compromised immunity causing PML. We have sequenced the JCV non coding control region (NCCR), which enabled to identify identically highly ‘rearranged’ sequences in CSF and plasma pairs, but not in urine, from the majority of PML patients, suggesting that JCV might either reactivate in the CNS or in peripheral sites. By sequencing the viral capsid protein-1 (VP1) coding gene we identified point mutations in both CSF and plasma, but not in urine, of PML patients, corresponding to aminacid substitutions at critical sites for JCV binding to sialic acid residues of the cell receptor, suggesting that, during reactivation, the virus may acquire adaptive mutations associated with increased neurotropism. Preliminary results by the IFN-γ Elispot assay also showed that some of these PML-specific substitutions also involve epitopes specifically recognised by JCV-specific T-cells. Paola Cinque VACCINE AND IMMUNOTHERAPY Immunotherapy of HIV infection HIV infection is characterized by depletion of CD4 T cells and altered immune function, leading to severe immune deficiency. Mechanisms leading to this T-cell depletion are not completely understood. Potent antiretroviral therapy restores T-cell counts and improves prognosis. For many years, the use of recombinant interleukin-2 (IL-2) in HIV-infected individuals has been explored. The results of the two large clinical endpoint studies of IL-2 (SILCAAT and ESPRIT) the results of SILCAAT and ESPRIT indicate that IL-2 offers no clinical benefit compared to ART alone. Whether these findings are relevant to other immunotherapies, such as IL-7, is uncertain. The precise role of the immune system in the pathogenesis of HIV infection may benefit from a re-evaluation as a consequence of these results. These data indicate that all CD4+ subsets may not be equal with respect to host defence and suggests that refinements in CD4+ measurements might improve the prognostic and/or surrogate marker value of T cell subset determinations. Apart from antiviral therapy for the infection, immunotherapies such as interleukin-7 (IL-7) that influence Tcell homeostatic mechanisms are undergoing clinical evaluation. Because of its pleiotropic effects on developing and mature T cells, IL-7 may help to restore immune function during HIV infection. Numerous recent findings highlight the importance of IL-7 pathway impairment in the pathogenesis of HIV infection. Notably, IL-7 levels increased with advancing CD4 T-cell lymphopenia, whereas IL-77 receptor expression is downregulated mainly on CD8 T cells. The clinical research activity of Vaccine and Immunotherapy Research Center is currently focused on the conduction of multicentric, internantional phase I clinical trials employing IL-7 as immunotherapy on HIV positive patients with poor CD4 recovery under conventional antiretroviral therapy. GiuseppeTambussi CLINICAL IMMUNOPATHOLOGY AND ADVANCED MEDICAL THERAPEUTICS UNIT The main interest of our group is the study of the immunological features of systemic inflammatory diseases. In particular we focus on the identification of new diagnostic and predictive markers of disease and disease activity, and on the understanding of the pathogenic mechanisms underlying such diseases, also in order to find DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 113 more effective and less toxic therapeutic strategies. We are specifically interested in: • the pathogenesis of the prototypic systemic autoimmune disease, Systemic Lupus Erythematosus, with particular regards to the processes leading to kidney damage and pregnancy complications; • the role of neuroendocrine mediators in vessel inflammation. In particular, we are carrying out a rather comprehensive analysis of the factors underlying the enhanced cardiovascular risk of patients with sustained systemic inflammation; • the immunopathogenesis of scleroderma and possible novel therapies for it; • novel approaches in diagnosing and treating systemic vasculitides; • the cytokine and chemokine network underlying the recruitment and activation of cells in systemic histiocytoses; • the mechanisms of actions of biological agents used for the treatment of immune-mediated diseases (cytokines & anti-cytokines, monoclonal antibodies). The research work is carried out in tight collaboration with the activities of the Unit of Internal Medicine and Clinical Immunology, which encompasses a clinical ward with 43 beds for inpatients, a Center for Allergy, dedicated outpatient clinics for Rheumatology, Clinical Immunology, Autoimmunity and Pregnancy, and Medical Hepatology. The staff comprises 18 staff physicians and 7 fellows from the Residency Programs in Allergy and Clinical Immunology and in Emergency Medicine of the Vita-Salute San Raffaele University. Maria Grazia Sabbadini CLINICAL TRANSPLANT UNIT Impact of Pancreas transplantation on diabetic nephropathy Diabetic nephropathy in its early stage is frequently observed in type 1 diabetic patient undergoing pancreas transplantation alone. The beneficial effect of tight blood glucose control achieved with pancreas transplantation can be counterbalanced by the use of nephrotoxic agents, such as Calcineurin inhibitor. The aim of the study is to compare the impact of isolated pancreas transplantation on patient survival and diabetic nephropathy compared to an optimized exogenous insulin therapeutic regimen in type-1 diabetic patients with fragile metabolic control Metabolic impact of portal venous drainage in pancreas transplantation The veins of a transplanted pancreas are usually anastomozed to the external iliac vein of the recipient, leading to peripheral insulin secretion, while in physiological setting insulin is secreted within the portal system. This leads to peripheral hyperinsulinization, a condition that was reported to be atherogenic. Pancreas transplantation can be performed with portal venous drainage, but requires a more complicated surgical procedure. Furthermore portal drainage of the transplanted pancreas was considered less immunogenic than systemic drainage. The aim of this study is to evaluate the endocrine-metabolic impact and rate of rejection of portal venous drainage in patients undergoing pancreas transplantation, compared to systemic venous drainage. Open-label single center study comparing the efficacy and safety of tacrolimus vs cyclosporin in simultaneous kidney-pancras transplantation. The aim of the study is to evaluate the impact on patient survival, graft survival, rate of rejection, rate of complications and metabolic control of Cyclosporin vs Tacrolimus in kidney-pancreas transplantation. All patients receive concomitant rATG induction therapy, MMF and short-term corticosteroids. Neurophysiological study of the impact of pancreatic islet transplantation on diabetic neuropathy in uremic type 1 diabetic kidney transplanted patients The aim is to evaluate whether pancreas transplantation may help stabilising polyneuropathy in type 1 diabetic patients undergoing kidney transplantation, and to assess reliability of nerve conduction tests for longitudinal monitoring of neuropathy. Antonio Secchi 114 - SAN RAFFAELE SCIENTIFIC INSTITUTE GYNECOLOGICAL CANCERS IMMUNOLOGY Cervical cancer is the second most common cancer among women worldwide, accounting for 11.7% of the total cancer burden. There is indisputable evidence that cervical cancer is related to persistent infection of Human Papillomavirus (HPV). Using sensitive Polymerase Chain Reaction (PCR) techniques, HPV-DNA is detected in almost 100% of invasive cervical cancers. Actually HPV is the most prevalent sexually transmitted disease; approximately 80% of sexually active women have been in contact with genital HPVs. Human Papillomaviruses consist of over 100 identified genotypes showing different tissue tropism and association with specific disease manifestations. Of the 15 types of High-Risk (HR) HPVs, the most predominant are HPV-16 and HPV-18, which are found in 40-60% and 10-20% of uterine cervix invasive cancers, respectively. The highest prevalence of HPV-induced cervical pre-neoplastic changes occurs in the third decade, while the mean age of invasive carcinoma occurs in the middle of the sixth decade, suggesting a prolonged latent phase of genital infection before the onset of malignant disease. Cancers caused by a viral agent are unique in that they are related to the host immunity. In the immunocompetent host, it has been demonstrated that HPV infection is usually transient, with a median duration of 8 months. Seventy percent (70%) of women clear a new HPV infection within 12 months and 91% clear it within 24 months, leading to frequent spontaneous resolution of early dysplastic changes. Immunocompromised patients present some problems to clear HPV infections, presumably due to an impaired ability to clear virus. We previously reported that anti-HPV-18 E6 CD4+ T cells are present, although at variable extent, in 100% of patients with high-grade HPV-18 expressing cervical lesions but also in 50% of patients, independently of the HPV type carried. These results indicated that HPV-18 E6 is very immunogenic and suggested that all responsive patients, irrespective of the HPV expressed, had encountered the HPV-18 and cleared the infection. We found that, although E7 specific CD4+ T cells were present in all women, a robust Th1/Th2 type response was associated with the HPV-18 negative status, suggesting that indeed these patients might have cleared the virus. In agreement with this hypothesis, we found a strong anti-E7 CD4+ T cell immunity also in 20% of normal donors without evidence of disease. On the contrary, anti-E6 CD4+ T cell immunity did not discriminate between HPV-18 positive and negative patients. When the patients, independently of the genotype carried, were divided based on their clinical outcome after surgery, a robust Th1/Th2 type response against E6 but not against E7 correlated with lack of relapse. Collectively, our data strongly suggest a different role for anti-HPV18 E6 and -E7 CD4+ T cells in anti-viral immunity. Massimo Origoni IMMUNOLOGY IN LIVER NEOPLASMS Evaluation of stress response in laparoscopic liver surgery: a prospective study of inflammatory profile, coagulation, homeostasis, and clinical outcome The aim of this prospective study is to perform a case-matched analysis to investigate the short term outcome in patients undergoing laparoscopic and open liver resections, in particular in terms of clinical outcome, inflammatory profile and coagulation homeostasis. Thirty-two (=32) patients undergoing elective hepatic resections have been enrolled in the study. Sixteen (=16) patients were non randomly assigned to the laparoscopic approach (LPS group), while the further 16 to the traditional open procedure (LPT group). The two groups were matched for the extent of resection, and then for further parameters such as age, gender, preoperative liver function, tumor histology and size, and ASA score. We collected information about several indicators of postoperative clinical outcome, such as operating time, intraoperative blood losses and blood transfusions, tumor exposure at the transection surface and minimal surgical margin, hospital stay and overall morbidity rate, postoperative analgesic therapy, mobilization recovery time and fasting duration.. We obtained plasmatic samples (collected preoperatively, in 1st, 2nd and 5th postoperative day) for the liver function assessment, measuring the Aspartate Aminotranspherase (AST), Alanina Aminotranspherase (ALT) and Total Bilirubin (BIL) levels. Moreover, we determined the serum levels of white blood cells count (WBC), C-reactive protein (CRP), Interleukin-6 (IL-6) and Tumor Necrosis Factor (TNF) as markers of the inflammatory surgical stress response. Finally, we evaluated the coagulation homeostasis measuring the serum levels of several parameters, such as DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 115 prothrombin time (PT ratio), platelets count (PLT), fibrinogen (FG), antithrombin III (ATIII) and fibrin Ddimer (XDP).Postoperative plasma levels of AST, ALT, WBC, CRP, IL-6, PT and XDP, along with blood losses, blood transfusions rate, analgesic therapy amount, fasting duration, mobilization recovery time and overall morbidity showed a lower rise in LPS group compared to LPT group. The decrease of PLT, ATIII and FG levels was lower in LPS group than in LPT group. The laparoscopic technique for hepatic resections results in improved clinical outcome, lower inflammatory stress response and lower coagulation alterations. Luca Aldrighetti OBESITY Laparoscopic gastric banding for morbid obesity Laparoscopic adjustable gastric banding (LAGB) is performed in case of primary obesity with Body Mass Index (BMI) >40 or BMI >35 with concomitant serious medical obesity-related conditions, unresponsive to dietary treatment. Preoperative evaluation included screening for endocrine disease, endoscopic and radiological study of the upper digestive tract and ultrasound study of the upper abdomen. Between June 1996 and December 2008, 336 patients (58 males/278 females, ranging 18-65 years) received LAGB. Mean body weight was 116.1 ± 18.7 Kg (range 90-195 Kg), with a BMI ranging between 35 and 65.7 (mean 43.2 ± 5.9). The laparoscopic procedure was completed in 327 patients (97.3 %). Eight cases (2.4%) had to be converted to the laparotomic procedure either because of hepatomegaly (1 case) or because of gastric lesion during the laparoscopic approach (7 cases). In one patient the procedure was performed with open technique together with ventral hernia repair. Michele Paganelli PANCREATIC TUMORS: IMMUNOTHERAPY AND β CELL FUNCTION SUBSTITUTION The Unit of Pancreatic and Endocrine Surgery during 2008 has focused its clinical research on pancreatic tumors. Surgical procedures performed by the Unit represent the source of data and material necessary for every type of investigation and research. During 2008, 168 pancreatic resections have been performed, represented in details by: 94 pancreatoduodenectomy, 60 distal pancreatectomy, 9 enucleation, 5 total pancreatectomy. In 162 cases (96.4%) resection was performed for a tumor: histology was ductal carcinoma in 98 cases, endocrine tumor in 23 cases, cystic tumor in 16, ampullary tumor in 13, distal bile duct in 8, metastasis in 4 (in 3 cases from a renal cancer, in 1 case from a melanoma). In cooperation with the group of tumor immunology, we recruited 26 patients with pancreatic ductal carcinoma undergoing resection, in which a peripheral blood sample (about 60 ml) was obtained before surgery, to isolate T cells (CD4) and to assess their reaction to antigenic peptides. In these patents specimens of tumor tissue and lymph nodes were also obtained, to test the ability of activated lymphocytes to recognize specific tumor antigens. The main clinical research evaluated different techniques to manage pancreatic stump after pancreatoduodenectomy. Among the 94 pancreatoduodenectomy performed, in 20 cases the pancreatic stump was at highrisk for fistula, i.e. with soft parenchyma and/or non-dilated duct (1-3 mm). In these patients two techniques were applied: A. standard reconstruction (pancreatic, biliary and duodenal anastomosis on the same loop) (8 patients); B. pancreatico-jejunostomy on a separate Roux-en-Y loop with external Wirsung stenting (12 patients). Pancreatic fistula rate was 62.5% in group A, 66.6% in group B (p=0.3). The severity of fistula was measured by the fistula-related mortality and relaparotomy rates: they were 0% and 25% in group A; 8.3% and 8.3% in group B (not significant reduction, due to the poor number of cases). The Roux-en-Y anastomosis with external Wirsung stenting may then reduce, but not avoid, the dramatic sequelae of an anastomotic leak. We are planning a study to prospectively compare this type of reconstruction with pancreatic stump removal (i.e. total pancreatectomy) combined with islets autotransplantation. Alessandro Zerbi 116 - SAN RAFFAELE SCIENTIFIC INSTITUTE CLINICAL HEPATO-GASTROENTEROLOGY Manipulation of the gut microbiota in the management of chronic intestinal disorders The role of the gut microbiota in promoting and maintaining intestinal inflammation is now well recognized. Antibiotics such as ciprofloxacin and metronidazole can be effectively employed in the treatment of inflammatory bowel disease, but side effects are common. Either non-adsorbable antibiotics such as rifaximin or probiotics can represent a safer alternative. Probiotics have been tested in the treatment of ulcerative colitis and Crohn’s disease (both in the acute phase and in the maintenance of remission) with variable but promising results. The choice of the specific probiotic agent to is a critical point because the mechanism of action of the various Lactobacillus strains, Bifidobacteria or yeasts such as Saccharomyces boulardii is quite different. To further our previous published experience in this area, we are currently evaluating the precise role of single probiotic agents, probiotic mixtures and rifaximin in the acute and chronic treatment of chronic intestinal disorders both of overt inflammatory nature (ulcerative colitis and Crohn’s disease) and where microscopic inflammation has a recognized pathogenetic role (microscopic colitis, irritable bowel syndrome). Moreover, in co-operation with the recently established Probiotic Club ( a multidisciplinary national society including gastroenterologists, paediatricians and microbiologists) we are endeavouring to identify and develop proper study protocols in order to evaluate the efficacy of probiotic agents in clinical trials carried out according to a correct methodology able to generate sound evidence-based data. Mario Guslandi DIGESTIVE PATHOPHYSIOLOGY 1) Evaluation of new approaches for endoscopic fundoplication in patients with gastro-esophageal reflux evaluating symptoms, quality of life and gastroesophageal refluxes, measured by manometry and esophageal pH-impedence. 2) Evaluation of new techniques for the study of esophageal motility such as high resolution manometry (HRM) and their application in a clinical setting. 3) Surgical operation proposed for haemorrhoids induces a reduction of rectal distensibility that could be responsible for symptoms of rectal urgency referred by some patients. We are investigating the effect on rectal physiology (rectal motor and sensory response to distension) of the surgery for haemorrhoids. 4) Previous studies have demonstrated that patients subjected to rectal resection for neoplasia developed symptoms of rectal urgency reducing their quality of life. We are evaluating symptoms, quality of life, and rectal sensory and motor function, as measured by electronic barostat, before and after surgical operation with or without radiotherapy. Sandro Passaretti TRANSPLANT SURGERY The Area of Transplant Surgery focused its clinical research on Simultaneous Pancreas and Kidney Transplantation and Pancreas Alone Transplantation in IDDM patients regarding the following three fields: a) effect of pancreatic transplantation with portal delivery of insulin secretion; b) effect of immunosuppressive protocols on pancreas alone transplantation; c) efficacy of pancreas from pediatric donors tu cure diabetes. a) 25 patients underwent to pancreas transplantation with portal delivery of insulin secretion. Survival DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 117 b) c) of the pancreas was 82% and 63% at 1 and 5 years, respectively. Homa B% values which represent insulin delivery and insulin sensitivity recipients was no significantly differente between patients with portal drainage transplant and normal individuals. From 2004 38 Pancreas transplantation alone have been performed; All of them received the whole organ with enteric diversion of exocrine secretion, 8 with portal-venous and 20 with systemic-venous graft drainage. Two regimens of immunosuppressive therapywere used: in 2004 it was prednisone, mycophenolate mofetil, ATG (Anti-thymocyte globulin) and cyclosporine A, while from 2005 to 2009 was prednisone, mycophenolate mofetil, ATG and tacrolimus. Cyclosporine A group included nine patients while tacrolimus group included nineteen. 1 year graft survival was 55% in the cyclosporine A group while it was 80,7% in the tacrolimus group (p 0.12); after 5 years, graft survival was 33% in the cyclosporine A group and 72,7% in the tacrolimus group (p 0.062). Pediatric donors could represent a novel source available for pancreas transplantation. From 2006 13 IDDM patients received pancreas transplants from pediatric donors (age between 12 and 17 years). After 1 year, patients survival rate is 92%, while pancreas graft survival is 61,5%, 40% for portal and 75% for systemic drainage. 2 patients with portal drainage developed graft thrombosis and one interrupted immunosuppressive therapy because of the onset of Moskowitz syndrome. 1 year after the operation mean HgbA1 was 4,9 (range 4,6 to 5,4) %; during OGTT mean basal glucose was 81,9mg/dl and mean basal insulin was 9,1 µU/ml, at 120 minutes mean glucose was 88,3mg/dl and mean insulin was 42,4 µU/ml. Carlo Socci DIABETES RESEARCH INSTITUTE (DRI) Director: Luca G. Guidotti Associate Director: Emanuele Bosi* Introduction by the Directors Type 1 diabetes (T1D) is the most frequent chronic disease of childhood and adolescence in developed countries and its incidence is steadily increasing. T1D results from the body’s inability to produce insulin, a hormone that is needed to convert glucose into energy and regulate metabolism. The cause of insulin deficiency is the immune-mediated destruction of insulin producing β-cells located within the islets of the pancreas. The cellular and molecular determinants mediating this autoimmune process are still largely unknown. Luca G. Guidotti Over the last 3 decades T1D has been one of the most relevant single areas of interest for patient care and research at the San Raffaele Scientific Institute. With the objective of reinforcing and expanding its commitment on diabetes research and care, in late 2007 a specialized and independent Research 118 - SAN RAFFAELE SCIENTIFIC INSTITUTE Institute entirely devoted to T1D, denominated Diabetes Research Institute (HSRDRI), was launched at San Raffaele. HSR-DRI is part of the International DRI federation (DRI-NET), which includes 12 other DRI’s around the world. HSR-DRI has an Executive Committee (Maria Grazia Roncarolo, Emanuele Bosi, Luca G. Guidotti, Alessandro Del Maschio, Antonio Secchi) and a Scientific Advisory Board (Guido Pozza, Camillo Ricordi, Giuseppe Chiumello, Massimo Trucco) and is composed of five Units of Basic Research and four Groups of Clinical Research. Emanuele Bosi The Institute collaborates with nine groups of Basic Research (E. Bonifacio, Uni-Dresden; M. Von Herrath, Uni-San Diego; M. Atkinson, Uni-Gainesville; P. Fiorina, Harvard; S. Gregori, Tiget; R. Bacchetta, Tiget; G. Zerbini, M. Lorenzi, V. Lampasona, HSR), six external Units of Clinical Research (C. Ricordi, Miami; A. Ziegler, Uni-Munchen; F. Bertuzzi, Niguarda, Milan; PM. Piatti, G. Perseghin; M. Venturini HSR) and three external Cores (L. Monti, HSR; E. Bazzigaluppi, Laboraf; A. Sanna, LaboRaf), which closely interact with HSR-DRI scientists and actively contribute to the scientific progress of the Institute. The overall objective of HSR-DRI is to prevent and cure T1D. To achieve this objective, two specific programs are pursued, both of which take advantage of patients and animal models: Prediction and prevention of T1D: this program aims to define mechanisms of induction and perpetuation of autoimmunity and at developing strategies for halting/reverting the progression to T1D. β cell replacement and cell therapy in T1D: this program aims to develop novel immune tolerance-inducing, immunosuppression-lightening and islet-regeneration therapies to prolong the survival of native and/or transplanted β cells. Research Units IMMUNE TOLERANCE Immunological tolerance in autoimmune type 1 diabetes: from problems toward solutions Aims: Type-1 diabetes (T1D) is a chronic disorder mediated by self reactive cells that invade the pancreas and destroy the insulin-producing cells. Peripheral tolerance results from a fine tuned balance between autoreactive T cells and regulatory T cells (Tregs). Our goals are to: (i) characterize the immune responses occurring in the target organ of T1D patients; (ii) define new clinical grade protocols for the expansion of human Tregs; and (iii) identify new therapies for establishing tolerance in pre-clinical animal models of T1D. Achievements: (i) Pancreatic lymph nodes (PLN) were collected from T1D patients who underwent pancreas transplantation. These samples were characterized phenotypically by flow cytometry and functionally by in vitro cultures. Phenotypical analysis revealed that, on the contrary to what observed in the periphery, Tregs are significantly reduced in PLN of T1D patients as compared to that of controls. In addition, increased memory T and B cells in PLN of T1D patients were observed as compared to those of controls. (ii) We previously demonstrated that rapamycin selectively spares Tregs while impedes the expansion of effector T cells. New studies have now delineated a good manufacturing practice (GMP) protocol for rapamycin-based human Tregs expan- DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 119 sion. Finally, (iii) we took advantage of the NOD mouse, a preclinical model for T1D, to test whether rapamycin, which prevent T1D in NOD mice, could increase the therapeutic effectiveness of anti-CD3 in T1D treatment. To evaluate this possibility, anti-CD3 was administered to diabetic NOD mice alone or together with rapamycin. Surprisingly, the addition of rapamycin to anti-CD3 blocked its ability to effectively reverse disease in NOD mice. Conclusions: (i) The target organ of T1D patients has an altered balance between effector and regulatory T cells which might be the cause for autoimmune disease development. (ii) The definition of a GMP grade protocol for Treg expansion opens new interesting therapeutic possibilities for the treatment of T-cell mediated diseases. (iii) The unexpected role of rapamycin on anti-CD3 therapy poses caution in combinational therapies but can also shed light onto the mechanisms by which anti-CD3 affords its therapeutic benefit. Manuela Battaglia EXPERIMENTAL DIABETES Innate immune regulation in Type 1 Diabetes Autoimmune disease results from the interplay between environmental and genetic factors. Inherited susceptibility to autoimmune disease such as Type 1 Diabetes (T1D) is related to defects of immune regulatory pathways whose function is to avoid or limit the activation of self-reactive T lymphocytes. It recently emerged that innate immune cells such as dendritic cells, mast cells and natural killer T cells play a central role for self/nonself discrimination and for prevention of autoimmunity. During infections they recognize “danger” and contribute to the immune responses for the clearance of pathogens. In the steady state those innate cells are crucial to maintain peripheral tolerance and prevent autoimmune diseases such as T1D. Our objective is to determine whether a defect of those innate immune cells underlies the pathogenesis of autoimmune diabetes in mice and humans and to restore those immune regulatory pathways for prevention of T1D. We demonstrated that those cells play an important immune regulatory role in the pathogenesis of autoimmune diabetes and that their functional defects are found in mice and humans affected by autoimmune diabetes. Specifically, we found that dendritic cells of diabetic NOD mice or patients affected by T1D lacked their capacity to induce the differentiation of regulatory T cells including invariant NKT cells (Baev D.V. et al. J Immun 2008) and peripheral differentiation of FoxP3+CD25+CD4+ Treg cells in the gut (Badami E. et al. manuscript in preparation). In addition, we found that mast cells of NOD mice fail to acquire a tolerogenic IL-10-secreting phenotype and contribute to the pathogenesis of autoimmune diabetes with an overly inflammatory phenotype (Gri G. et al. manuscript in preparation). Our future goal is to develop molecular and cellular to restore the immune regulatory function of innate cells and to restore immune tolerance against islet antigens in pre-clinical models of T1D. On the other hand, we aim to assess whether those defects of immune regulation are present in T1D patients and their “at risk” relatives. Our final goal is to demonstrate that functional impairment of innate immune regulation is involved in the pathogenesis of human T1D and can be corrected to prevent and/or cure autoimmune diabetes. Marika Falcone β CELL BIOLOGY β cell replacing in diabetes Background and unsolved issues. In principle, treatment for type-1 diabetes and many cases of type-2 diabetes, lies in the possibility of finding a β cell mass replacement capable of performing two essential functions: assessing blood sugar levels and secreting appropriate levels of insulin in the vascular bed. Our project focuses on creating conditions that favour 120 - SAN RAFFAELE SCIENTIFIC INSTITUTE β cell expansion and survival in transplanted and native environments Currently, the only available clinical therapy capable of restoring β cell mass in diabetic patients is the allogeneic/autologous transplantation of β cells. Despite advances in recent years the somatic cell therapy is still problematic Starting hypothesis and main results. The somatic cell therapy for T1D is a great platform to address mechanistic questions regarding type-1 diabetes. In the last years we were able to study the impact of β cell challenge to the immune status of the patient and the efficacy of immunotherapeutics and their ability to control allogeneic and autoimmune responses. The results of these studies demonstrate (i) that survival of both syngeneic and allogeneic islet grafts in the liver is sub-optimal, (ii) that inflammatory reaction play a relevant role for the survival and function of islets after transplantation, (iii) that the actual immunosuppressive regimens do not control efficiently both allogeneic and autoimmune response. Conclusions and future plans. To obtain the long term replacement of β cells in patients with diabetes we propose to: (I) study bone marrow as site for islet transplantation, (II) develop novel islet survival strategies by modulating inflammation specifically inhibiting pathways involving CCL2 or IL-8, (III) Improve islet transplantation outcome by cotransplantation of islets and feeder cells using mesenchymal stem cells, (IV) determine mechanisms of islet autoantigen immunization and destruction (V) to identify a renewable source of cells to be used to increase the transplantable β cell mass. Lorenzo Piemonti Figure 16. Histological appearance (10x) of C57BL/6 mouse femur 12 month after intra bone islet syngeneic transplantation. Upper panel: Hematoxylin & Eosin staining: B= bone, BM= bone marrow. Lower panel: immunoistochemistry image shows insulin staining (red). Scale bar 100 µm CELL IMAGING Improving the procedure for detection of intrahepatic transplanted islets by Magnetic Resonance Imaging Background and unresolved issues Islet transplantation is an effective therapy for restoring normoglycemia in type-1 diabetes, but long-term islet graft function is achieved only in a minority of cases. Developing a reliable, non-invasive imaging modality to trace over time the fate of islets transplanted within the liver would help the interpretation of functional parameters monitored in the periphery. Starting hypothesis and main results Non-invasive magnetic resonance imaging of pancreatic islets is an attractive option for the “real-time” monitoring of graft evolution. So far, previous studies have been performed in the absence of a standardized labeling procedure and, besides a human feasibility study in patients, the effectiveness and safety of various labeling approaches were tested only with high field small bore magnets (4.7T). We have now addressed: a.) standardization and reproducibility of a procedure for the labeling of human islets with the clinically-approved contrast agent Endorem®, b.) safety aspects of labeling related to inflammation, c.) quality of imaging both at 7T and 1.5T. We have highlighted that the ratio of Endorem®/islet is crucial for reproducible labeling and demonstrated that labeled islets are neither inflamed nor more susceptible to inflammatory insults than unlabeled ones. We DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 121 also successfully compared, at 1.5T and 7.0T magnetic fields, transplanted animals up to 143 days after intrahepatic infusion (Figure 17; Malosio et al. 2009 AJT, in press). Conclusions and future plans The results of this work have been important for the development of a standardized clinical protocol allowing non-invasive imaging of transplanted islets in humans, that has been recently approved by the ethical committee. Future plans will include to perform the clinical protocol and to understand the quantitative potential of MRI in islet transplantation. Furthermore our wish is to develop novel imaging approaches for monitoring the endogenous islet mass and the inflammatory processes taking place in diabetes. Maria Luisa Malosio A B C D st. s.c. E F K 600 Labeled Unlabeled 500 mg/dl 400 300 200 100 0 0 20 40 60 80 100 120 Days after transplant G s.c. H I J st. Figure 17. In vivo magnetic resonance imaging of transplanted islets at 1.5 and 7.0 T Magnetic resonance transverse sections of liver regions (7.0T, panels A-E; 1.5T, panels F-J) of mice transplanted with either unlabeled islets (E, F) or labeled islets (A-D; G-J) at 48 h (A), 9 days (G), 20 days (B), 35 days (H), 57 days (C), 65 days (I), 105 days (D) and 142 days (J). Images in panels A-D and G-J at different time points were obtained from the same subject analyzed both at 1.5 and 7.0 T. Red circles and arrows highlight hypointense regions associated with the presence of Endorem®-labeled islets; st = stomach, s.c. = spinal cord. Panel K: non-fasting blood glycemia of animals transplanted with labeled or unlabeled islets measured weekly after transplantation (n=4). Clinical Research Units ISLET TRANSPLANTATION The clinical Islet Transplantation Program included the following lines of research: 1) study of the effect of exenatide on the transplanted islet dysfunction. Three patients, who previously received islet transplant alone achieving long lasting insulin independence, were enrolled when early signs of islet dysfunction arose: they received exenatide, they were evaluated monthly for metabolic control, every 3 months for insulin response to stimuli (i.v arginine; oral glucose). The scheduled duration of treatment is 1 year. One patient dropped out because of exenatide side effects; two patients are still in follow-up. 2) pilot clinical trial, started in 2007, based on the development of new immunosuppressive regimen accomodating T regulatory cells expansion, avoiding daclizumab and calcineurin inhibitors. This study is part of a multicenter trial in collaboration with the European Consortium for Islet Transplantation (ECIT). 5 infusions were performed in three patients with type 1 diabetes in agreement with the inclusion criteria; after completion of transplants one patient became insulin independent and one patient had partial function; one patient, not completed, had early failure, probably because of acute rejection. 3) study of the effect of islet transplantation alone in patients with type 1 diabetes on long-term diabetes complications: early retinopathy (ophthalmologist assessment, doppler ultrasound of the retinal vein and retinal central artery, OCT); neuropathy (measurement of nerve conduction velocity); carotid artery disease (Doppler ultrasound of the carotid arteries). These parameters have been evaluated yearly; data will be processed after 5 years follow-up. 4) prospective study of kidney function and incidence of cancer in patients with type 1 diabetes who received islet transplant alone. 122 - SAN RAFFAELE SCIENTIFIC INSTITUTE 5) commitment in the Collaborative Islet Transplant Registry, supported by USA National Institute of Health and JDRF. 6) evaluation of the safety and efficacy of pancreatic islet autotransplantation with completion pancreatectomy in the management of patients with high risk for pancreaticojejunostomy after Whipple Resection. One patient received islet autotransplant, with normalization of metabolic control in presence of few units of exogenous insulin. Paola Maffi PREVENTION IN TYPE 1 DIABETES This research program encompasses all studies aiming at the definition of pathogenetic mechanisms of induction and perpetuation of autoimmunity in humans and the identification of strategies for halting or reverting the progression to clinically overt type 1 diabetes. In 2002, with the support of the Juvenile Diabetes Research Foundation (JDRF), a Clinical Center infrastructure has been created at San Raffaele to host a TrialNet Center. TrialNet is a NIH-supported network of clinical centres, investigators and core support facilities in the US and Canada, United Kingdom, Italy, Germany, Finland and Australia. The goals of TrialNet programs are to: further define epidemiology, natural history and risk factors of type 1 diabetes; support the development and implementation of clinical trials of agents to slow the progression of type 1 diabetes in new-onset patients, and delaying or preventing the emergence of type 1 diabetes in individuals found to be at risk of the disease. Recently completed studies at the San Raffaele Centre include: the metabolic assessment of residual insulin secretion in patients with type 1 diabetes and the Mycophenolate/Daclizumab clinical trial in recent onset patients; ongoing studies include: the natural history of development of type 1 diabetes; studies under implementation include: Oral Insulin for the prevention of diabetes in relatives at risk. An additional focus of the Clinical centre is the creation and expansion of a wide network of affiliate and satellite centres throughout Italy to support the enrolment into all the TrialNet studies. Based on the same JDRF-funded infrastructure, other clinical trials, in addition to those performed within TrialNet, are expected to be developed in the future, possibly including also phase I/proof-of-concept studies. Emanuele Bosi EPIDEMIOLOGY & DATA MANAGEMENT The mission of the Epidemiology and Data Management Core is to provide methodological support to investigator-initiated clinical research projects within the Department of Immunology, Transplantation and Infectious Diseases with special regards to those within the Diabetes Research Institute (DRI). Priority of this core are the translational research projects developed within the San Raffaele Scientific Institute. The Epidemiology and Data Management Core is currently providing support to four major projects within the Diabetes Research Institute, all conducted within the Islet Transplant Program: a) a clinical trial testing safety, feasibility and efficacy of an immunesuppressive regimen that is compatible with the use of T regulatory cells to induce immune tolerance. This study is part of a multicenter trial in collaboration with the European Consortium for Islet Transplantation (ECIT); b) a pilot trial testing feasibility, safety and efficacy of the bone marrow as an alternative site for islet cell transplant in patients with type 1 diabetes following the encouraging experience in animal models; c) a randomized clinical trial to assess whether total pancreatectomy with islet autotransplantation is a superior alternative to pancreaticoduodenectomy in patients at very high-risk of complications of the pancreatic anastomosis (soft pancreas and pancreatic duct diameter <3 mm). This project is conducted in collaboration with the University of Pisa; d) a longitudinal study to identify and characterize the organ donor “inflammatory signature” and the potential for this “inflammatory signature” to predict graft outcome. The study is conducted in collaboration with the Nord Italian Transplant program (NITp) and will involve over 1000 cadaveric organ donors and 2000 organ recipients over the area served by NITp. Marina Scavini DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 123 CHILDHOOD DIABETES The aim of the unit is to do clinical research in children with type 1 diabetes. We follow in our out-patients unit more than 700 children and we have 80-100 new cases of disease each year. We have two main lines of research: 1) Study of etiopathogenesis of new cases of insulin dependent diabetes in childhood. We try to define using immunology and genetics all new cases of diabetes. In this way we define type 1 a in 96% of patients (at least 1 of 5 antibodies for diabetes). We were able to identify 2 cases of genetic diabetes due to a mutation of insulin gene. We published our results in Diabetes Care 2009,32;123-125 and Diabetic Medicine 2009,26;660-661. 2) Studies of intervention in patients at onset of disease. At the moment we are part of a study of phase 3 using vaccination with GAD-alum in order to reduce the β cell distruction after the clinical diagnosis, sponsored by Dyamid. We screened 4 patients and we started the treatment in 2 patients. Moreover we are part of a study who planned to use Metformine in diabetes at onset in order to reduce immune destruction of β cells and we collaborate to a study of primary prevention in children with high genetic risk of diabetes (Prepoint) and we submit as soon as possible to IRB of HSR. We actively participate to the Diabetes in Children group of SIEDP/ISPED and we collaborated in different multicenter studies: Twins study, Vipkids, etc Riccardo Bonfanti ISLET PROCESSING ACTIVITY Islet Processing Facility (IPF) of San Raffaele Scientific Institute was established as the Unit devoted to islet of Langerhans isolation from human pancreas. IPF mission is to provide isolated human islets for transplantation in type 1 diabetic patients as stated on the Italian organ and tissues transplant regulation. Islets available for transplantation means that they have been determined to meet all release specifications and to be suitable for utilization. At this purpose, IPF organized management with the target of ensuring that human islets have the quality required for transplantation in humans. Human islet preparations not suitable for transplant in patients can be used as a mean to drive the isolation procedures improvement, engraftment and its outcome, according to the local ethical committee decisions. Moreover the Milan Centre belongs to an European Consortium (ECIT) supported by JDRF, that distribute final islet preparation not suitable for transplant, with the aim to improve the research activities in diabetes. Together with the human islet transplantation program, the center has developed all the in vivo and in vitro experimental models for islet studies: 1) production of islet from mice, rats and pig 2) islet transplantation in mouse and rat (liver, kidney capsule) including metabolic follow up (ie IVGTT, OGTT) and morphologic study (i.e. immunohistochemistry, immunofluorescence, confocal microscopy) 3) islet culture in vitro 4) islet function in vitro (stimulation in static incubation or dynamic perfusion). Different studies are currently in progress with the aim to increase the effectiveness in times of the transplant, to achieve the immunological tolerance, define the best culture condition in terms of recovery before the transplant, and improve the islet transplant program with the stem cell base therapy. Rita Nano Figure 18. Human Islet after isolation before infusion in man 124 - SAN RAFFAELE SCIENTIFIC INSTITUTE Protein engineering and therapeutics Leukocyte biology Unit AIDS immunopathogenesis Unit Human virology Viral evolution and transmission Unit Biocrystallography Unit DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 125 Emerging bacterial pathogens Unit Viral pathogens and biosafety Unit Lymphocyte activation Unit Immune tolerance Neurovirology 126 - SAN RAFFAELE SCIENTIFIC INSTITUTE Experimental diabetes Cell imaging β cell biology Islet processing activity DIVISION OF GENETICS AND CELL BIOLOGY - 127 DIVISION OF GENETICS AND CELL BIOLOGY Director: Roberto Sitia* Associate Director: Marco E. Bianchi* Research Units Protein transport and secretion Unit HEAD OF UNIT: Roberto Sitia* RESEARCHERS: Tiziana Anelli, Ester Zito POST-DOCTORAL FELLOWS: Jose Garcia-Manteiga, Eva Margittai** PHD STUDENT: Margherita Cortini** FELLOWS: Milena Bertolotti, Giada Bianchi, Riccardo Ronzoni TECHNICIANS: Claudio Fagioli, Elena Pasqualetto Age related diseases GROUP LEADER: Simone Cenci PHD STUDENTS: Elisa Benasciutti, Laura Oliva** FELLOW: Niccolò Pengo** TECHNICIAN: Elisabetta Mariani Molecular immunology GROUP LEADER: Antonio Siccardi FELLOWS: Rita Nunzia Fucci, Elisa Nigro TECHNICIAN: Elisa Soprana Chromatin dynamics Unit HEAD OF UNIT: Marco E. Bianchi* POST-DOCTORAL FELLOWS: Roberta Palumbo, Angela Raucci PHD STUDENTS: Antonella Antonelli, Barbara Lanfranchi**, Jaron Liu, Tobias Pusterla FELLOWS: Lisa Trisciuoglio, Luca Sessa TECHNICIANS: Francesco De Marchis, Alessandro Catucci In vivo Chromatin and transcription GROUP LEADER: Alessandra Agresti PHD STUDENT: Barbara Celona Biology of myelin Unit HEAD OF UNIT: Lawrence Wrabetz POST-DOCTORAL FELLOWS: Maurizio D’Antonio, Pietro Fratta PHD STUDENTS: Nicolò Musner**, Francesca Ornaghi**, Elisa Tinelli**, Domenica Vizzuso** TECHNICIANS: Cinzia Ferri, Paola Saveri Biomolecular mass spectrometry Unit HEAD OF UNIT: Angela Bachi POST-DOCTORAL FELLOWS: Alfonsina D’Amato, Vittoria Matafora, Federico Torta PHD STUDENTS: Umberto Restuccia, Vera Usuelli FELLOW: Santosh Anand TECHNICIAN: Angela Cattaneo 128 - SAN RAFFAELE SCIENTIFIC INSTITUTE Gene expression Unit HEAD OF UNIT: Fulvio Mavilio RESEARCHERS: Maria Pannese, Alessandra Recchia POST-DOCTORAL FELLOW: Claudia Cattoglio PHD STUDENT: Valentina Poletti** FELLOWS: Alessandro Bertolo, Simona Capossela TECHNICIAN: Serenella Sartori Genetics of common disorder Unit HEAD OF UNIT: Daniela Toniolo RESEARCHER: Silvia Bione POST-DOCTORAL FELLOW: Giorgio Pistis PHD STUDENT: Tanguy Corre** FELLOWS: Ivan Buetti, Salvatore Carrabino, Corrado Masciullo, Alessandra Sirri TECHNICIANS: Cinzia Sala, Fiammetta Viganò Molecular basis of polycystic kidney disease Unit (Dulbecco Telethon Institute) HEAD OF UNIT: Alessandra Boletta POST-DOCTORAL FELLOWS: Isaline Rowe, Claas Wodarczyk PHD STUDENT: Maddalena Castelli** FELLOW: Monika Pema TECHNICIANS: Marco Chiaravalli, Gianfranco Distefano Molecular genetics Unit HEAD OF UNIT: Francesco Blasi* RESEARCHER: Daniela Talarico POST-DOCTORAL FELLOW: Silvia D’Alessio PHD STUDENTS: Patrizia Marzorati, Silvia Mori FELLOWS: Ambra Crippa, Laura Gerasi TECHNICIAN: Massimo Resnati Molecular dynamics of the nucleus GROUP LEADER: Massimo Crippa POST-DOCTORAL FELLOWS: Carmelo Ferrai, Nicola Micali PHD STUDENT: Monika Wozinska** FELLOWS: Matteo Marinelli, Andrea Boni NeuroGlia Unit HEAD OF UNIT: Maria Laura Feltri POST-DOCTORAL FELLOWS: Silvia Bogni, Ernesto Pavoni PHD STUDENTS: Cristina Colombelli, Marta Pellegatta** FELLOW: Monica Ghidinelli TECHNICIANS: Stefania Saccucci, Desirée Zambroni Regulation of iron metabolism Unit HEAD OF UNIT: Clara Camaschella* POST-DOCTORAL FELLOW: Laura Silvestri PHD STUDENTS: Antonella Nai, Alessia Pagani RESIDENT: Erika Poggiali Molecular genetics of renal disorders Unit (Dulbecco Telethon Institute) GROUP LEADER: Luca Rampoldi POST-DOCTORAL FELLOW: Céline Schaeffer PHD STUDENT: Ilenia Bernascone** FELLOWS: Simone Perucca, Elisa Zanella DIVISION OF GENETICS AND CELL BIOLOGY - 129 Clinical Research Units Dento-facial histopathology Unit HEAD OF UNIT: Enrico Gherlone* PHYSICIANS: Paolo Capparé, Carlo Alberto Cortella, Roberto Crespi, Massimo Pasi, Raffaele Vinci Genomics of renal diseases and hypertension Unit HEAD OF UNIT: Paolo Manunta* CLINICAL GROUP LEADER: Donatella Spotti RESEARCHER: Laura Zagato PHYSICIANS: Teresa Arcidiacono, Chiara Lanzani, Luisa Persichini, Maria Teresa Sciarrone Alibrandi, Giuseppe Vezzoli RESIDENTS: Giovanna Bonavida, Lino Merlino, Marialuisa Querques, Francesco Rainone, Marco Simonini FELLOWS: Lorena Citterio, Simona Delli Carpini, Elisabetta Messaggio TECHNICIAN: Nunzia Casamassima Tissue engineering and biomaterials HEAD OF UNIT: Gianfranco Fraschini* CLINICAL GROUP LEADER: Giuseppe M. Peretti PHYSICIAN: Corrado Sosio RESIDENTS: Laura Mangiavini, Alessandro Pozzi, Celeste Scotti POST-DOCTORAL FELLOW: Daniela Deponti FELLOW: Rosa Ballis * Professor at: Università Vita-Salute San Raffaele ** Università Vita-Salute San Raffaele 130 - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Directors The Division of Genetics and Cell Biology (DGCB) consists of 14 basic and 3 clinical research groups, totaling over 140 staff. It occupies laboratory space in Dibit 1 and 2 buildings. Mission - DGCB aims at the mechanistic comprehension of biological phenomena to acquire basic knowledge and fuel translational and clinical research with novel concepts, tools and protocols. Understanding Physiology and Pathology in cellular and molecular terms is fundamental to cure disease and create novel bio-technologies. Scientific training is another DGCB priority. Roberto Sitia Organization - Scientists are free to engage in competitive research projects: they are encouraged to join forces, data and equipment so as to foster synergies. Areas of particular strength include bone and cartilage physiopathology, the physiopathology of stress responses and conformational diseases, chromatin dynamics and epigenetics, cell polarity, and the genetics of complex disorders. DGCB staff are engaged in inter-Divisional Research Programs and Institutional Facilities. Goals - Biology is becoming more and more a hard science. Surprising disMarco E. Bianchi coveries are still made of course, but there is little doubt that quantitative aspects are now essential. This is especially true for an Institute like ours, which expects basic and clinical research to synergistically flourish. In strict collaboration with the Center of Genomics, BioInformatics and BioStatistics, DGCB develops state of the art technological platforms for the scientific community. DGCB aims at providing clinical sciences with novel concepts and protocols and develops robust cellular and animal models for their testing. As important is reverse translation, where the detailed analysis of cohorts of patients can unravel physiological mechanisms. Identifying mutational hotspots in patients, for instance, sheds light on the structure and function of the normal product. The iterative process of translation is a key asset for DGCB. Training opportunities - DGCB hosts both PhD and PostDoctoral training programs, where positions are offered on a competitive basis for a minimum of 3 and 2 years, respectively. DIVISION OF GENETICS AND CELL BIOLOGY - 131 Research Units PROTEIN TRANSPORT AND SECRETION UNIT Our Unit is exploring the processes of oxidative folding, quality control and degradation of proteins - antibodies in particular - in the early secretory compartment. Solving the structure of ERp44 revealed a novel mechanism that regulates the binding and release of this chaperone to its client proteins (Wang et al., 2008; Fraldi et al., 2008). ERp44 interacts also with ERGIC-53, and Ero1 and plays a key role in IgM polymerization. With Ero1, it also regulates IP3R1 channels (Bergamelli et al., submitted), thus integrating redox and calcium homeostasis/signaling (Anelli & Sitia, 2008). By manipulating the expression of these molecules we were able to modulate the rate and extent of intracellular protein aggregation (Ronzoni et al., unpublished). These results have profound implications in the pathogenesis of ER storage disorders and other protein conformational diseases. The lab analyses also the mechanisms that orchestrate the architectural (de novo biogenesis of the secretory apparatus) and functional (onset of Ig secretion and eventually apoptosis) changes during B lymphocyte-plasma cell differentiation. Our observation that proteasomal capacity declines in parallel to the massive increase in antibody production explains in part the exquisite sensitivity of normal and malignant plasma cells to proteasome inhibitors (Nerini et al., 2008; Cascio et al., 2008). Indeed, the proteasomal load vs capacity ratio correlates with drug sensitivity and can hence provide a useful clinical indicator (Bianchi et al., 2009). The possibility of modulating ER proteostasis and stress could offer new therapeutic strategies not only in ER storage and conformational diseases, but also in myeloma and other types of cancer. Roberto Sitia AGE RELATED DISEASES We explore the basic cell biology of normal and malignant plasma cells, with implications for Ab responses and Multiple Myeloma (MM, 2% of all cancer deaths). Our discovery that differentiating plasma cells decrease proteasome activity and suffer from proteotoxic stress (Cenci et al, 2006) provided us with a unique biological model linking protein synthesis to death, with key immune and oncological implications, like the potential exploitation of proteasome inhibitors (PI) as humoral immunosuppressants in vivo (Cascio et al, 2008). Hence, our research activity aims at: understanding how plasma cells cope with stress and proteasomal overload, investigating the mysterious mechanisms regulating mammalian proteasome biogenesis; exploiting proteotoxicity to identify novel targets against plasma cell cancers. Along these lines, we found that plasma cells deploy autophagy with potent regulatory effects on lifespan and Ig secretion (Pengo et al, manuscript in preparation). In MM, proteasome expression and functional workload are key determinants of apoptotic sensitivity to PI, providing potential molecular targets and prognostic indicators (Bianchi et al, 2009). Moreover, we are demonstrating an adaptive role for autophagy in MM (Fontana et al, unpublished). Parallel in vivo studies on the molecular mechanisms driving the differentiation of osteoclasts, unique boneresorbing cells, are unveiling novel links between adaptive immunity and bone biology, of potential therapeutic interest against bone-wasting conditions (Cenci et al, 2003; Benasciutti et al, manuscript in preparation). Given the vicious connection between MM and bone cells, this model will be of use to better understand the MM environment. Simone Cenci 132 - SAN RAFFAELE SCIENTIFIC INSTITUTE MOLECULAR IMMUNOLOGY Two main projects are pursued. 1) Construction of recombinant poxviruses. We developed novel methods that allow an extremely rapid production of recombinant poxviruses (MVA and FPV). An interesting side product was the description of the sequence of homologous recombination events that lead to the formation of markerless recombinants (Di Lullo et al., 2009a; Di Lullo et al., 2009b, submitted). Moreover, the parallel construction of MVA and FPV recombinants (that are not immunologically cross-reactive) allows an efficient prime/boost strategy. The technology has led to the production of a number of recombinants with potential applications in various fields of veterinary and human medicine, notably in tumor and influenza vaccines (human, avian, swine). 2) Exploiting the adjuvant role of membrane IgE in cell vaccines. Owing to interactions between membrane IgE with specific receptors located on effector cells in a form of intercellular synapsis (Vangelista et al., 2005), tumor cells bearing membrane IgE are better vaccines than control cells (Reali et al., 2001). The adjuvanticity is dependent upon the interaction with Fc-epsilion RI receptor bearing cell (as demonstrated in knock-out mice). The adjuvant effect of human membrane IgE is demostrable also in mice which express only the human receptor (Nigro et al., 2009, submitted). Double-recombinant MVA expressing membrane IgE and any other antigen have allowed to extend the adjuvant effect to all sorts of vaccines. Antonio Siccardi CHROMATIN DYNAMICS UNIT Our group studies chromatin organization and function, and in particular the role of one protein, High Mobility Group Box 1 (HMGB1). The state of chromatin determines how specific genes are expressed by different cells in the same organism (that contain the same genome). Moreover, differentiated cells maintain their identity over time, and stem cells maintain their plasticity. When they fail in this, they can become tumors, or simply start performing erratically (degenerative diseases of various kinds). We are also very interested in a remarkable property of HMGB1. This nuclear protein can be leaked out of necrotic cells and signal traumatic tissue damage, triggering inflammation, cell proliferation and migration, innate and adaptive immune responses, angiogenesis and eventually tissue repair. The connection between chromatin status in apoptosis and tissue repair is a particular focus of our group. During 2008 we investigated the role of HMGB1 in muscle and skin repair, and during ischemia-reperfusion in the heart. We have also continued to investigate the signalling pathway of extracellular HMGB1: we showed that the RAGE receptor is expressed at extremely low level in most cells, in part because it is constitutively cleaved by the membrane-associated protease ADAM10. We also found that HMGB1 that remains tightly attached to nucleosomes originating from apoptotic cells can trigger inflammation and dendritic cell activation by interacting with the TLR2 receptor. As a consequence, autoantibodies are produced against histones and DNA, which is a hallmark of autoimmune diseases. In fact, HMGB1-nucleosome complexes have been found in the blood of patients with systemic lupus erythematosus (SLE), where they can play a role in the pathogenesis. The Group led by Alessandra Agresti has built and tested a computational model of the activation of NF-κB, the transcription factor responsible for most inflammatory responses. They have also shown that the systems oscillates in living cells, and that the oscillations are required for specific gene expression programs. Marco E. Bianchi DIVISION OF GENETICS AND CELL BIOLOGY - 133 Figure 19. Real time monitoring of GFP-p65 using GFP knock-in MEF and live cell microscopy allows accurate quantification of single cell dynamics of endogenous p65. (A) The population average time course of nuclear NF-kB (red) can show strongly damped oscillation even when the individual cells (black, 20 out of 1000 shown) have sustained oscillatory dynamics. Thousand hypothetical sine waves were generated to have a period slightly varying from 2 hours (15% S.D. in cycle frequency) and linearly decreasing amplitude. The late peaks become unsynchronized, making the average profile appear constant. (B) The knock-in mice have the endogenous p65 locus replaced by GFP-p65 and have wild-type phenotype. (C) A typical time series of a single living cell treated with 10 ng/ml TNF-a and imaged overnight. The low GFP level required special image acquisition setup. The quantification of the GFP intensity data is shown in the time course plot in (D). (D) The time lapse image analysis procedure is shown schematically. The nuclear:total ratio of GFP-p65 plotted is for the cell in (C), where the labeled arrows correspond to the images. The ratio was obtained as the mean nuclear intensity divided by mean cellular intensity. The periodogram on right has a single sharp peak and indicates that the estimated period is ~ 1.5 hours for this cell. IN VIVO CHROMATIN AND TRANSCRIPTION Sustained oscillations in NF-κB produce differential gene regulation Inducible transcription factors, like the inflammatory NF-κB family, activate the expression of genes that provide feedback loops upon their own signalling pathways. These feedback loops also create the potential for NFκB to oscillate between cytoplasm and nucleus over hours. However, oscillations of endogenous NF-κB have not been clearly described in living cells and the functional significance of such oscillations is unknown. Are they a mere side effect of the pathway settling back to the basal state, or are periodic cycles required for proper gene expression programs? We used an NF-κB/p65-GFP knock-in system and time-lapse microscopy in living cells to demonstrate that oscillations of p65 were sustained, with several cycles of transient nuclear translocation after TNF-α stimulation. NF-κB ability to interact with the genome in vivo remained functional, from early to late cycles. Mathematical modeling and computational simulations predicted that two different system perturbations would abolish oscillations, constrain p65 in the nucleus and result in opposite functional consequences of p65 activity. In vivo experiments confirmed model predictions: both perturbations abolished oscillations, but had opposite effects on p65 genome-scanning activities. Consistent with the hypothesis that dynamic patterns in the oscillations of NF-κB activity encode specific cellular signaling information, we found that expression of NF-κB target genes is either inhibited or profoundly enhanced when NF-κB oscillations are manipulated. Moreover, some genes are transcribed only after the second cycle of NF-κB activation, indicating that NF-κB activates transcription according to the persistence of the inflammatory signal. We propose that “classical negative feedback” in the NF-κB pathway does not simply function to terminate signaling, but enables repeated sampling of the environment thanks the oscillatory dynamics it creates. In this way, NF-κB signaling can orchestrate optimal transcriptional responses, some of which are immediate whereas others are tuned to occur only after prolonged stimulation. Alessandra Agresti 134 - SAN RAFFAELE SCIENTIFIC INSTITUTE BIOLOGY OF MYELIN UNIT Genesis and maintenance of myelin We have a long-standing interest in myelin, the sheath that enwraps larger axons in both the central (CNS) and peripheral nervous system (PNS) to permit rapid conduction of impulses and guarantee axonal health. We have explored the role of axonal signals, adhesion and transcriptional regulation in myelination. In particular, we have exploited inherited neuropathies, which reveal important determinants of myelin formation. More recently, we have produced/studied seven mouse models of Myelin Protein Zero (MPZ) neuropathies that cause widely varying neuropathy phenotypes in patients. Mice overexpressing wildtype P0 develop a congenital hypomyelination; mice expressing P0 with a myc-epitope tag at the amino terminus unexpectedly model two more severe subtypes of CMT1B neuropathy; and mice expressing P0 with any of five known human MPZ mutations model CMT1B or Congenital Hypomyelination Neuropathy. We validated these preclinical models (Figure shows onion bulbs and demyelination in peripheral nerve of MPZS63del mice), confirmed that the mutations operate through gain of function, and showed that the mutant proteins have their ‘toxic’ effect from various locations in the Schwann cell, many times away from myelin itself. For example, in MpzS63del mice, we have identified endoplasmic reticulum retention of the mutant P0 and activation of protein quality control pathways in myelinating Schwann cells of peripheral nerve. Our recent data suggest that protein quality control unintentionally alters translation of myelin proteins or impairs proteasome degradation of myelin proteins, thereby impairing myelin stability in CMT nerves. Another mutant P0 protein, P0Q215X, may be mistrafficked to the surface of Schwann cells where it may interfere with appropriate signals from its extracellular matrix. Finally, P0S63C may form disulfide bonded dimers in trans in the myelin sheath, altering the fluidity of the myelin sheath. These continuing studies reveal both the pathogenesis of neuropathy, and biological clues about the normal genesis and maintenance of myelin. Lawrence Wrabetz Figure 20. Onion bulbs and demyelination in peripheral nerve of MPZS63del mice BIOMOLECULAR MASS SPECTROMETRY UNIT Our group is mainly interested in the development and application of sensitive and specific methods for protein identification and microcharacterization. We are developing novel approaches that can be applied to the proteome analysis of cells under physiological and pathological states. During 2008 we investigated different protein post-translational modifications. In particular, to gain insights into the interconnection of the SUMO and the ubiquitin-proteasome pathway, we have studied, by a SILAC based quantitative approach, the effect of proteasome inhibition on SUMO-conjugated proteins. 193 potential DIVISION OF GENETICS AND CELL BIOLOGY - 135 SUMO-1 substrates were identified, 78 of which are upregulated upon proteasome inhibition. Among these, Histone H1, Histone H3 and p160 myb binding protein 1A have been further characterized as novel SUMO-1 substrates. The analysis of the nature of the SUMO-1 targets identified strongly indicates that sumoylation regulates the maintenance of nucleolar integrity acting in coordination with the ubiquitin-proteasome system. As part of the study of phosphorylation in cells and as a methodological approach to improve the selective enrichment of phosphorylated peptides, a new MALDI target was built, called T-plate, produced by exploiting pulsed laser deposition (PLD) of a nanostructured titanium dioxide thin film onto a standard stainless steel plate (in collaboration with Dr. Casari at Politecnico di Milano). This new active surface is able to bind and enrich phosphopeptides from complex mixtures and make them detectable for a standard MALDI-MS or MS/MS analysis. The compatibility with a MALDI-TOF/TOF instrument could open the perspective of using it for the identification of phosphosites in complex biological samples while its ability to retain also other kind of phosphorylated biomolecules could open a new way of studying phospholipids. Another PTM that we tried to characterize is S-nitrosylation which is induced by Nitric oxide (NO) on specific cysteine residues. This route is dynamically regulated and is known to be part of the redox signaling pathway. We have developed a specific MS-based method for the characterization of S-nitrosylated residues and applied it to several cellular and animal models. Angela Bachi Figure 21. MS/MS spectrum acquired on a LTQ-Orbitrap GENE EXPRESSION UNIT The molecular basis of the interactions between retroviruses and mammalian genomes is poorly understood. We investigate the genetic and viral determinants of target site selection of MLV- and HIV-derived retroviral vectors in human hematopoietic cells. Retroviral integrations are mapped on the human genome, comparatively analyzed, and correlated with the activity of genes located around insertion sites. The genetic and epigenetic features of the chromatin regions preferentially targeted by retroviruses are determined in different cell types. By a combination of genomic, bioinformatic and biochemical techniques, we study the role of transcriptional regulatory elements and transcriptional complexes in targeting viral pre-integration complexes to specific chromatin regions. We showed that MLV, but not HIV vectors integrate in genomic regions enriched in cell-type specific subsets of transcription factor binding sites. The MLV integrase and LTR enhancer are the viral determinants of this selection. This study suggests that transcription factors binding the LTR enhancer may synergize with the integrase in tethering retroviral pre-integration complexes to transcriptionally active regulatory regions. These data indicate that γ-retroviruses and lentiviruses have evolved different strategies to interact with the host cell chromatin, with important implications for the biosafety of viral vectors in clinical applications. Control of translation plays a critical role in development, growth, and differentiation. In eukaryotes this process is mainly regulated at the level of the initiation step. Wbscr1 encodes for eIF4H, a positive regulator of 136 - SAN RAFFAELE SCIENTIFIC INSTITUTE protein synthesis at the initiation level. The human homolog is on chromosome 7, in a region commonly deleted in patients affected by Williams-Beuren Syndrome. We have generated mutant mice for Wbscr1. The null mice are characterized by dwarfism, reduced fertility and an impairment of sensorimotor coordination, as in WBS patients. To identify genes regulated at translational level by Wbscr1 we are performing microarray profiling on total and polysomal mRNAs from MEF and liver of wild type and null mice. These data will be a starting point to clarify the functions of this gene in physiology and pathology Fulvio Mavilio GENETICS OF COMMON DISORDERS UNIT Genetics of complex disorders One of the projects of the Unit is the study of the genetics Premature Ovarian Failure (POF) and of age of menopause, complex traits that have become relevant due to the postponement of first child bearing occurring in most countries and the consequent infertility problems. The research involves the study of genetic association of DNA variants in candidate genes identified by us as well as genome wide association studies in a large cohort of women presenting POF collected over the years with the collaboration of clinicians and patients associations in Italy. Two genes have been recently identified and replication of the associations as well as functional studies are ongoing to confirm their involvement in ovarian function, to elucidate their role and to identify the causative variants. The study also involves the analysis of a genetically isolated population living in a geographically isolated valley in the Apennine, Val Borbera, whose inhabitants live in 7 villages. We have collected clinical and family data of 1800 people representing about 60% of the resident population and a large genealogical tree has been constructed to establish all the family relationships going back to the 1600. Epidemiological and genetic data analysis is ongoing on fertility traits as well on many other traits representing risk factors for complex disorders. From the data collected we have the possibility to study hematological, endocrinological, cardiovascular traits, food preferences and cognitive functions by studying the whole set of variation as well as by selecting peopled presenting extreme values. Such phenotypes may be caused by rare variants present in the general populations, but that could be identified more easily or exclusively in such special populations. Daniela Toniolo MOLECULAR BASIS OF POLYCYSTIC KIDNEY DISEASE UNIT Unraveling the function of Polycystin-1, the protein most commonly altered in Polycystic Kidney Diseases The nephron is the filtering unit of the kidney and is formed by the glomerulus and the renal tubule. The diameter of the tubule needs to be tightly controlled for its proper function. Polycystic Kidney Diseases (PKD) are a class of pathologies characterized by abnormally enlarged tubules, eventually causing renal failure. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of PKD and a very frequent genetic disease affecting 1:1000. ADPKD is caused by mutations in either the PKD1 (in 85% of cases) or the PKD2 genes (in 15%) encoding for Polycystin-1 (PC-1), a large plasma membrane receptor, and Polycystin-2 (PC-2), a calcium channel, respectively. Our major interest is on studying the normal function of PC-1. In the past we had found that PC-1 is a multi-tasking receptor involved in regulating several signaling cascades. PC-1 induces cell-cycle arrest in the G0/G1 phase of the cell cycle and concomitantly resistance to apoptosis. More recently, using a series of loss and gain of function in vitro models we have shown that PC-1 controls cell growth (size) in addition to and independently of its action on proliferation. PC-1 achieves this effect by inhibiting the mTORC1 pathway by cross-talking with Tsc2 and controlling its ERKs-dependent phosphorylation. Next, we have generated a conditional Pkd1 line and crossed it with a kidney- specific Cre line, resulting in massive renal cystogenesis. Biochemical analysis confirmed upregulation of the mTORC1 cascade in polycystic kidneys through an ERKs-dependent, Akt-independent mechanism. Our data show that PC-1 inhibits the DIVISION OF GENETICS AND CELL BIOLOGY - 137 mTORC1 pathway and that lack of PC-1 results in upregulation of the cascade in PKD via an unusual mechanism. We are currently investigating further the molecular details of this and the significance of PC-1/Tsc2 cross-talk in vivo using a series of animal models. Alessandra Boletta MOLECULAR GENETICS UNIT Prep1 Structure and Function. Prep1 is an homeodomain transcription factor essential for mouse development. We have studied its function in thymus demonstrating its role in the early T cells differentiation (Penkov et al, PLOS One, 2008) and in the musckle, demonstrating that it is required for regulating insulin sensitivity (Oriente et al, Mol Cell Biol, 2008). At the molecular level, we ha investigated the mechanism through which the lack of Prep1 induces apoptosis. Prep1 is a direct regulator of Bcl-xL. In the absence of Prep1, Bcl-xL mRNA and protein is reduced and this induced mitochondrial potential anomalies and apoptosis (Micali et al, Mol Cell Biol, 2009). Moreover we have identified a nover cytoplasmic role of Prep1. In fact, by interacting with 4EHP ribosomal protein, Prep1 inhibits the translation of the HoxB4 mRNA which results in major anomalies in the structure and function of the mouse oocytes. Finally, we have demonstrated that actin polymerization is required for transcription of the HoxB genes, through an interaction with Prep1 (Ferrai et al, Mol Biol Cell, 2009, in press). Urokinase receptor (uPAR) structure and function. We have analyzed the lipid composition of the membrane microdomains that contain uPAR and shown that this is dependent on the binding of its ligand, uPA (Cortese et al., PLOS One, 2008). At the functional level, we have studied the uPAR Ko mkice and demonstrated that they have a defective would healing. This is due to to the abdence of activation of the EGF receptor and to the inability to deposit laminin (D’Alessio et al., J Cell Sci, 2009). Finally, we have examined the role of uPAR in quiescent and mobilized hematopoietic stem cells. We find that uPAR is essential in both stem cells maintenance and homeostasis. This appears to be due to an interaction between uPAR and the integrin α4β1, that together constitute a retaining signal for hematopoietic stem cells (Tjwa et al, J Clin Inv, 2009). Francesco Blasi MOLECULAR DYNAMICS OF THE NUCLEUS In 2008 laboratory activities focused on two major topics: 1) the role of the TALE transcription factor Prep1 in development and pathology and 2) the relationship between the genomic component (DNA) of the cell nucleus and non-genomic (protein) components from the structural and functional standpoint. 1) By using hypomorphic Prep1i/i mutant mice we have shown that the homeobox-containing transcription factor Prep1 is involved in apoptosis by directly modulating mitochondrial homeostasis through the transcriptional control of the endogenous levels of the antiapoptotic Bcl-XL mRNA and protein, providing a possible explanation for the general organ hypoplasia and the small size of Prep1i/i embryos and mice (collaboration with Prof. F. Blasi, Università Vita-Salute S. Raffaele). We also nearly completed studies on the role of Prep1 in Down Syndrome. We find that overexpression of Prep1 (located on human chromosome 21, in the region relevant for DS) in fibroblasts from DS patients alters their homeostasis and it may be a relevant therapeutic target for DS-associated diseases. 2) Our studies on the molecular dynamics of the nucleus allowing transcription to take place led us to identify novel nuclear structures associated with yet untranscribed genes. They oscillate between an inactive and an active state through small modification of their protein component, allowing a rapid and efficient transcriptional response of the genes associated with them. We have also contributed to establish a major role for actin in the transcriptional activation of the Hox-B gene cluster in mouse cells (collaboration with Prof. F. Blasi). 138 - SAN RAFFAELE SCIENTIFIC INSTITUTE We investigated the role of unconventional Myosin VI in the onset and development of prostate cancer. We find that the depletion of myosin VI by RNA interference in an androgen-insensitive, prostate cancer cell line (PC3) affects their growth and invasiveness. This, in turn, affects the onset and development of tumors in mice subcutaneously injected with these cells. We continued our investigation on the nuclear role of myosin VI by studying the nucleo-cytoplasmic shuttling of the protein by live cell microscopy and by exploring myosin VI-associated nuclear and cytoplasmic protein complexes by proteomics. Massimo Crippa NEUROGLIA UNIT Laminin receptors in nerve development and hereditary diseases Schwann cells myelinate peripheral nerves, and contribute to neuronal development, differentiation, integrity and regeneration. Laminins and their receptors are required for many of these functions, and mutations in genes coding for laminins or components of laminin receptor complexes cause hereditary neuropathies (Merosin Deficient Congenital Muscular Dystrophy 1A, CMD1A and Charcot-Marie-Tooth 4F). One of the processes affected in the absence of laminins in CMD1A is axonal sorting, the process by which large axons to be myelinated are segregated by a single Schwann cell. We have used the Cre/LoxP system to identify laminins and a β1 integrin as the receptors that allow Schwann cells to sort axons. This year we have determined that another receptor, dystroglycan, is required, and β1 integrin pair with two different α integrins to mediate sorting. All these are laminin receptors, so experiments are underway to determine if they bind to different laminins present in the Schwann cell basal lamina, and if they activate different signaling pathways. One signaling pathways that we had identified is the small RhoGTPase Rac1. We are using primary co-coltures of sensory neurons and Schwann cells to identify Rac1 effectors relevant to myelination. It is known that neuropathies due to laminin deficiency also have abnormal folding of myelin and short myelin segments (internodes). This in turn leads to myelin instability and reduced nerve conduction velocity. We have shown that this is due to lack of adhesion to α6β4 integrin and dystroglycan, as mice lacking both of these receptors develop myelin instability causing an age-dependent acute demyelination. Also, we showed that short internodes correlate with lack of proper compartmentalization of the myelin fiber, caused by abnormal linkage between laminin 211, dystroglycan, dystrophin-related-protein2, and periaxin (mutated in Charcot-Marie-Tooth 4F). We also showed that glycosylation of dystroglycan is required for this linkage to form (Court et al. J. Neuroscience 2009). Similar abnormalities are found in CMD1A patients. Thus, laminin receptors have important and diverse function in peripheral nerves, which are relevant to the pathogenesis of neuromuscular diseases. Maria Laura Feltri Figure 22. Compartments in the outer cytoplasm of myelinated peripheral nerve fibers are stained for f-actin (red), tubulin (blue) and dystrophin-related-protein 2 (DRP2, green). Wild type mice show fibers (top four) with small Cajal-bands containing tubulin and f-actin separated by large DRP2 apposition, in contrast in the absence of dystroglycan this cytoskeletal organization is disrupted (bottom four fibers). DIVISION OF GENETICS AND CELL BIOLOGY - 139 REGULATION OF IRON METABOLISM UNIT The aim of our research is to investigate how the liver peptide hepcidin regulates systemic iron availability, as a background to understand the molecular pathogenesis of genetic iron disorders leading to both iron deficiency and overload. Hepcidin is upregulated in iron overload by a bone morphogenetic protein (BMP) - SMAD dependent pathway that uses the hemochromatosis protein hemojuvelin as coreceptor. Hepcidin expression is also increased in inflammation by an IL-6-STAT3-dependent pathway. Hepcidin expression is suppressed in iron deficiency/hypoxia by several partially unexplored mechanisms. Recent genetic evidence indicates that the liver serine protease matriptase-2, encoded by TMPRSS6, is a powerful hepcidin inhibitor, since TMPRSS6 inactivation leads to low iron absorption and iron deficiency due to high hepcidin levels in both mice and humans. However, the protease substrate and the molecular mechanism of hepcidin downregulation remained unknown. We have shown that matriptase-2 cleaves hemojuvelin through its proteolytic processing on plasma membrane and that this cleavage is suppressed in TMPRSS6 mutants lacking or mutated in the serine protease domain. Matriptase-2 knock down by morpholino oligos causes anemia with high hepcidin levels in zebrafish embryos, whereas the expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and indirectly its interaction with hemojuvelin. Matriptase-2 lacking the protease domain is still able to interact with hemojuvelin strengthening that the interaction occurs through its ectodomain. Our findings indicate that suppression of the BMP stimulatory pathway is essential for hepcidin inhibition and suggest that this pathway requiring hemojuvelin as coreceptor is the main iron-dependent pathway of hepcidin regulation. These results are of relevance to understand the molecular pathogenesis and to implement innovative treatments for the two opposite disorders of iron metabolism: hemochromatosis and iron refractory iron deficiency anemia (IRIDA). Clara Camaschella Figure 23. Control of iron homeostasis by hepcidin in mammals (Camaschella C., Nat Genet 2009) MOLECULAR GENETICS OF RENAL DISORDERS UNIT Cellular and animal models for the identification of the pathogenetic mechanisms in uromodulin-associated renal cystic disorders Medullary cystic kidney disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) are autosomal dominant kidney diseases characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN are caused by mutations in the uromodulin gene, UMOD (Hart et al., 2002). Uromodulin is exclusively expressed by epithelial cells of the thick ascending limb of the loop of Henle and by distal convoluted tubules and it is released in the urine through a conserved proteolytic cleavage (Santam- 140 - SAN RAFFAELE SCIENTIFIC INSTITUTE brogio et al., 2008). Its biological function is still not fully understood. Studies on umod knock-out mice demonstrated that it has a protective role against urinary tract infections (Bates et al., 2004) and calcium oxalate crystals-induced urothelial damage (Mo et al., 2004). To date, more than 50 UMOD mutations have been reported in MCKD/FJHN patients. All but three (in-frame deletions) are missense changes likely leading to protein misfolding. Indeed, the presence of uromodulin aggregates within the cytoplasm of tubular cells has been reported in kidney biopsies of MCKD/FJHN patients (Dahan et al., 2003; Rampoldi et al., 2003). Our research interest is to understand the mechanisms of pathogenesis in MCKD/FJHN and to gain insights into uromodulin biology. Through studies in transfected cells we demonstrated that mutations in uromodulin lead to ER retention of mutant protein (Rampoldi et al., 2003; Bernascone et al., 2006). We are currently investigating both in in vitro and in vivo models the molecular pathways that are activated upon uromodulin intracellular retention and aggregation. We also focused our studies on the molecular mechanisms that regulate uromodulin polymerization. We recently identified two motifs whose mutations lead to premature intracellular polymerisation of a soluble uromodulin isoform demonstrating the inhibitory role of these sequences for protein assembly. Proteolytic cleavage separating one of the two motifs from the mature monomer is necessary to release the inhibitory function and allow protein polymerisation (Schaeffer et al., 2009). Luca Rampoldi Clinical Research Units DENTO-FACIAL HISTOPATHOLOGY UNIT We assessed the biological features and clinical applications of bone substitutes in grafting procedures and dental devices to allow implant-proshtodontics oral rehabilitations in edentulous patients. Firstly, we analyzed magnesium-enriched hydroxyapatite (MHA) and calcium sulfate (CS) in clinical studies by radiological, histological and histomorphometric examinations (percentages of mean vital bone, connective tissue and residual grafting material). In 45 postextractions sockets, radiographic examination revealed a greater reduction of alveolar ridge in the CS group then MHA one, histologic examination showed more bone formation and faster resorption in CS group and more residual implant material in MHA group (see figure). Both biomaterials, in particular MHA, demonstrated bone regeneration features to allow predictable implant positioning and oral rehabilitations. Thus, we applied these findings in testing ‘platform switching’ dental implants, reporting high-predictable results in 45 patients. Furthermore, MHA is widely used in preimplant oral surgery as a bone substitute because of its osteoconductive ability. So far, evaluation of clinical outcome and histomorphometrical parameters are the only ways to demonstrate successful engraftment, but a pre-clinical indicator of successful bone regeneration would be precious for both clinical and biotechnological purposes (e.g. biomaterial validation). So, we developed an alternative technological platform based on ex vivo osteoblast expansion and highly sensitive gene expression profiling by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In 25 bone specimens obtained from 15 patients, we demonstrated that gene expression profiling of an array of osteoblast specific genes is effective in certifying osteoblast identity and function in the bone tissue regenerated by the engrafted MHA. These findings provide the framework to develop a strategy to test the osteoinductive capacity of a given biomaterial at the biomolecular level. Enrico Gherlone DIVISION OF GENETICS AND CELL BIOLOGY - 141 Figure 24. Histological section from bone obtained 3 months postgrafting, with presence of osteons and numerous connective tissue spaces (CT) and vital bone (VB) in contact with MHA particles (GM) GENOMICS OF RENAL DISEASES AND HYPERTENSION UNIT Genomics and pharmacogenomics of complex renal diseases Calcium kidney stone disease is a complex disorder due to nutritional and genetic alterations. Calcium sensing receptor rs7652589 and rs1501899 polymorphisms were associated with stones in patients with primary hyperparathyroidism (n=296), a finding previously observed in idiopathic stone formers. The nutritional analysis in stone formers identified high sodium and fructose intake as a risk factor for the stone production. A GWA study carried out on salt-sensitivity of never treated hypertensive patients allowed to discover: i. 76 intragenic and 154 flanking “top” SNPs (p≤10-4) detecting loci related to cytoskeleton rearrangement (DAAM2, RHOC), ion transport (SLC24A3, KCNMB4) and vasoconstriction (BDKRB2, PRKG1); ii. “candidate” SNPs (p≤10-3) located in SLC8A1, SLC12A3, PKD2, UMOD and ADRB2 genes. Analysis of genetic profile would predict sodium-sensitive hypertension susceptibility. Response to ?-blocker therapy is variable among hypertensive patients. A number of sympathetic nervous system genes have been explored for this variability such as ?1-adrenergic receptor gene (ADR?1). We investigated the relationship between dipping and non-dipping nocturnal pattern. Patients undergone a 24-h ambulatory BP monitoring and the acute salt load test, received ?-blocker (Atenolol or Nebivolol) for 2 months. Carriers of wild-type Arg389Gly ADRB1 genotype resulted dipper, salt-resistant and responsive to ?-blockers. Salt sensitivity test together with ADR?1 genotype can predict the best responders to ?-blocker therapy. In the OASIS trial (Ouabain Adducin Specific Intervention with Sodium in hypertension), we analyzed the response to PST2238 drug (rostafuroxin) according to candidate genes involved in Adducin-Ouabain pathway. The end point was the difference in SBP office after five weeks of therapy. No difference between placebo and 2238 effect was found. However a greater response to 2238 has been showed in patients carrying a LSS2 mutation. In patients carrying specific genotypic combinations the relative risk to be responder to rostafuroxin was 18.84 (p model <0.001). PST2238 is an effective anti-hypertensive drug only in selected patients that can be identified by genotyping for candidate genes. Paolo Manunta TISSUE ENGINEERING AND BIOMATERIALS Tissue engineering and analysis for cartilage, meniscus and tendon tissue One of the goals of our research is the development of an engineered osteochondral composite for the repair of the cartilage lesion. In our studies, we focused on engineering in vitro a biphasic composite made of cellular fibrin glue and an osteo-bio-compatible scaffold. Our studies have demonstrated a gross a stable integration between the two components and a cartilage-like quality of the newly formed matrix. In collaboration with other laboratories, we are also testing different biomaterials as scaffold for the reparative cells. We are also started a series of experiments with the attempt of characterizing the meniscal cells having the ultimate goal of developing an engineered meniscal substitute. We have demonstrated the presence of at least three cell lines within the meniscus tissue. We have recently started a series of experiments with the goal of create a tissue engineered tendon. Tendons 142 - SAN RAFFAELE SCIENTIFIC INSTITUTE do not repair spontaneously in the acute or chronic ruptures. We believe that a tendon engineered in vitro with a biological scaffold seeded with autologous fibroblasts could represent an important solution. As possible cell source we have tested tendon, ligament, and derma. We have also started a series of tests for the creation a lesion model in the rabbit patellar tendon. This would allow to test in vivo the efficacy of the engineered tendon for repairing lesion defect in vivo. In collaboration with the Politecnico di Milano, we have started a series of studies on the analysis of the biomechanical properties of normal and osteoarthritic articular cartilage, including the permeability, which is a crucial property for the functionality of this tissue. Recently we have started a series of studies on cartilage at the early stage of osteoarthrosis. This would allow understanding the correlation between the macroscopic appearance of the degenerative process in articular cartilage and the decrease of biomechanical properties of the tissue. Giuseppe M. Peretti DIVISION OF GENETICS AND CELL BIOLOGY - 143 Molecular immunology Protein transport and secretion Unit Biology of myelin Unit Age related diseases Chromatin dynamics Unit 144 - SAN RAFFAELE SCIENTIFIC INSTITUTE Regulation of iron metabolism Unit Genetics of common disorder Unit NeuroGlia Unit Molecular genetics of renal disorders Unit Tissue engineering and biomaterials Molecular basis of polycystic kidney disease Unit CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS - 145 CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS Director: Giorgio Casari * Research Units Neurogenomics Unit HEAD OF UNIT: Giorgio Casari* RESEARCHER: Giovanni Lavorgna POST-DOCTORAL FELLOW: Francesca Maltecca, Riccardo Vago PHD STUDENTS: Laura Cassina, Loredana Leo**, Michela Riba FELLOWS: Laura Corti, Sara Cottonaro TECHNICIANS: Maurizio De Fusco, Celia Pardini Theoretical Biology GROUP LEADER: Riccardo Fesce Biogenesis and motility of secretory organelles Unit HEAD OF UNIT: Maria Vittoria Schiaffino POST-DOCTORAL FELLOWS: Rosa Lucia D’Ambrosio, Tiziana Daniele, Ilaria Palmisano PHD STUDENT: Angela Palmigiano** Genomic Unit for the diagnosis of human pathologies HEAD OF UNIT: Maurizio Ferrari* RESEARCHERS: Annapaola Andolfo, Sara Benedetti, Paola Carrera, Laura Cremonesi, Isabella Fermo, Vito Lampasona FELLOWS: Stefania Battistella, Sara Bonalumi, Viviana Bornaghi, Angela Brisci**, Francesca Bruno, Emanuela Castiglioni, Vincenza Causarano, Chiara Di Resta, Alessandra Foglio, Silvia Galbiati, Cristina Montrasio, Elena Sommariva, Stefania Stenirri, Chiara Redaelli, Daniele Zeni Proteome biochemistry Unit HEAD OF UNIT: Massimo Alessio POST-DOCTORAL FELLOWS: Barbara Comuzzi, Valeria Corti PHD STUDENTS: Carlo Vittorio Cannistraci, Stefano Olivieri** FELLOW: Sara D’Annibale TECHNICIAN: Antonio Conti Biomolecular NMR laboratory (Dulbecco Telethon Institute) GROUP LEADER: Giovanna Musco POST-DOCTORAL FELLOWS: Massimiliano Gaetani, Michela Ghitti, Silvia Mari, Luca Mollica, Andrea Spitaleri PHD STUDENTS: Francesca Chignola, Dmitrios Spiliotoupulos, Chiara Zucchelli FELLOW: Valeria Mannella * Professor at: Università Vita-Salute San Raffaele ** Università Vita-Salute San Raffaele 146 - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Director After the completion of the human genome sequence, and as well many other model organism genomes, we entered a sort of new deal in life sciences taking advantage of innovative powerful technologies, such as deep sequencing, total gene expression, protein mass spectrometry and molecular NMR and of recently discovered or rediscovered phenomena, such as microRNAs, epigenetic regulation, abundant untranslated transcripts, posttranslational modifications. All these cooked together with powerful algorithms aimed at detecting functional relations among genes, proteins, pathways, disease conditions. The Center for Genomics, Bioinformatics and Biostatistics originates as an institutional initiative and follows this track. Giorgio Casari The CGBB actually bases on two components: research groups with established biological expertise already present in the institute and computational and system biology scientists, who are partly to be recruited. We reckon to complete this phase within the next few months. Notwithstanding, we are setting up platforms for Gene expression, Genetic analysis, Deep sequencing, Computational biology thanks to internal and external collaborations. A proteomics service is also being activated for the institute community. The Center is being located in the core of Dibit2, the “Basilica” central building on a 1500 sq.m. area and includes, at present, 52 researchers. CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS - 147 Research Units NEUROGENOMICS UNIT A single protein complex for two diseases. The case of the mitochondrial metalloprotease m-AAA Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin/AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m-AAA proteases. These complexes exert protein quality control on mitochondrial proteins and are players in the regulation of mitochondrial fusion and fission. When mutated, both proteins cause diseases: paraplegin mutations are responsible for hereditary spastic paraplegia (HSP), while AFG3L2 mutations are associated to spinocerebellar ataxia type 28 (SCA28). At present, the study of murine mutants are opening the way for the comprehension of the pathogenetic mechanisms leading to these degenerative forms, which substantially differ for the neuronal targets, such as the motoneuron (HSP) and Purkinje cell (SCA28). PINK1, the mitochondrial kinase associated to Parkinson’s disease Although familiar forms of PD are rare, the identification of genes responsible for Mendelian forms of PD has contributed crucial information on the molecular mechanism of the disease. Mutations of PINK1, a serthreo mitochondrial kinase, are responsible for a juvenile recessive form of PD. We demonstrated that mutant variants display a reduced autophosphorylation activity, which is regulated by the carboxy-terminus moiety of the protein. At present, the project is focusing on the physiologic role of PINK1 and on the identification of natural substrate and interactors, which associate PINK1 to autophagy. Na,K ATPase and hemiplegic migraine Migraine is a common chronic recurrent disease characterized by disabling headache attacks, which can be associated to additional symptoms, such as aura. We demonstrated that familiar hemiplegic migraine type 2 (FHM2) is due to ATP1A2 gene mutations. In vitro models suggest a loss of function effect of the mutants showing a reduced resting potential and increased excitability, associated to cortical spreading depression, the neuronal correlate of aura. The project focuses on the molecular mechanism at the basis of the facilitated cortical spreading depression in FHM knockin and conditional knockout murine models. Giorgio Casari Figure 25. Fusion and fission dance THEORETICAL BIOLOGY Research activity is aimed at developing original approaches to data analysis, simulation and modelling. Such approaches are to be applied in particular to the study of synaptic function. During the last year two projects have undergone significant progress: 1) We have almost completed the set up of a system for simultaneous acquisition of extracellular electrophysiological signals from a microelectrode array (MEA), with the associated procedures of data/signal analysis, to study the connectivity and plasticity (short term recruitment and fatigue, long-term potentiation, LTP and de- 148 - SAN RAFFAELE SCIENTIFIC INSTITUTE pression, LTD) in cultured hippocampal neurons or in hippocampus slices from adult animals. The cultures are used to characterise the role of specific proteins in synaptic function (the first target will be synapsin I, a protein involved in synaptic vesicle availability for transmitter release), by comparing cultures from wild-type and knock-out animals (collaboration with prof. Valtorta’s lab – San Raffaele Scientific Institute). As tissue slices make it possible to study hippocampal connectivity and plasticity at late postnatal developmental stages, this second approach will be employed to study the acute and chronic action of psychoactive drugs on hippocampal function, and its possible residual alterations in adults exposed to psychoactive drugs during adolescence (collaboration with prof. Parolaro’s lab, Insubria University). 2) Our competence in signal/data analysis and mathematical modeling has been exploited in a collaborative effort with the groups of prof. Sacchi and prof. Rossi in Ferrara University: • we have studied the bioelectrical properties of the orthosympathetic neuron in the rat superior cervical ganglion and observed the contribution of a little known chloride conductance to underthreshold behavior of the neuron, to its excitability properties and to the ionic selectivity of the nicotinic acetylcholine receptor channel. • an original signal analysis software has been developed to quantify synaptic activity at the cytoneural junction of frog labyrinth, and has been employed to study the effects of exposure to simulated micro-gravity conditions on labyrinthine function; quantal release and spike generation were observed to be markedly compromised. Riccardo Fesce BIOGENESIS AND MOTILITY OF SECRETORY ORGANELLES UNIT The ocular albinism type 1 protein (OA1), an intracellular G protein-coupled receptor, regulates organelle biogenesis and motility in pigment cells We are focused into the study of secretory organelle biogenesis and transport in mammalian cells as alteration of these processes represents an important cause of human disease. Our experimental model is ocular albinism type 1, an X-linked disorder characterized by severe reduction of visual acuity, nystagmus, strabismus, photophobia, retinal hypopigmentation, foveal hypoplasia and misrouting of the optic tracts. The protein product of the ocular albinism gene, named OA1, is a pigment cell-specific membrane glycoprotein, displaying structural and functional features of G protein-coupled receptors (GPCRs), yet exclusively localized to intracellular organelles, i. e. lysosomes and melanosomes. Although the precise signaling pathway activated by OA1 remains unknown, the presence of giant melanosomes (macromelanosomes) in the skin and eyes of patients with ocular albinism suggests that this receptor is implicated in the biogenesis of melanosomes. In order to unravel the downstream pathway of OA1, we generated melanocyte cultures from an Oa1-KO mouse model. We found that, in addition to a reduced number of melanosomes and to the presence of giant melanosomes, Oa1-KO melanocytes display an abnormal distribution of the organelles toward the cell periphery. The same phenotype was observed in the retina, at developmental stages relevant for the development of the optic system, yet preceding the formation of macromelanosomes. Time-lapse video microscopy and organelle tracking analyses showed that Oa1-KO melanosomes display a defective motility along microtubules, but only in the presence of an intact actin cytoskeleton. Thus, OA1 appears to facilitate melanosome motility along tubulin versus actin filaments and could co-ordinate the maturation of melanosomes with their transport toward the cell periphery. These findings imply a novel interpretation of the role of OA1 in pigment cells and suggest that ocular albinism results from a different pathogenetic mechanism than previously thought, based on the disruption of an organelle-autonomous signaling pathway implicated in the regulation of both membrane traffic and transport. Maria Vittoria Schiaffino CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS - 149 GENOMIC UNIT FOR THE DIAGNOSIS OF HUMAN PATHOLOGIES The Genomic group applied advanced methodologies to molecular analysis of genes involved in several pathologies, including neurologic and neuromuscular disorders, arhythmogenic disorders, pediatric surfactant deficiency, macular degeneration, neurodegeneration, iron metabolism disorders, polycystic kidney disease, and myeloproliferative disorders. This led to the identification of a variety of known and new sequence variations and made possible a genotype-phenotype correlation with particular respect in the field of both monogenic and multifactorial traits. In addition, we performed case-control association and pharmaco-genetic studies to correlate genome variation to disease predisposition and drug response. We also developed new genotyping devices and methodologies, such as GS-FLX parallel pyrosequencing on amplicon pools, high throughput SNP analysis, automation of genotyping process, microchip electrophoresis with dual color single-photon avalanche diodes, ligation detection reaction on copolymer-coated glass slides, PNA-mediated enriched PCR for noninvasive prenatal diagnosis of beta-thalassemia, and new microarray substrates for high sensitive genotyping of minority mutated alleles. In the frame of the International Human Variome Project (HVP) and the Human Genome Variation Society (HGVS) we are involved in creation and maintenance of Locus Specific Data Bases and Clinical-Molecular Data Bases aimed to realize an accurate documentation of genome variants related to disease. Our Clinical Proteomics group is working out strategies for biomarker discovery in different pathologies: prostate cancer, laminopathies, type-1 diabetes-related nephropathy. Our approach consists of identification of differentially expressed proteins by means of 2D-electrophoresis, image analysis and mass spectrometry, in order to clarify molecular mechanisms of pathogenesis, indicate diagnostic tools or therapeutic targets to develop. Diagnostics of autoimmunity is largely based on measurements of disease associated circulating autoantibodies. In our immunoassay development laboratory novel assays were introduced based on recombinant autoantigens including those for autoantibodies to the type 1 diabetes autoantigen ZnT8 and to the neuromyelitis optica autoantigen AQP4. Maurizio Ferrari PROTEOME BIOCHEMISTRY UNIT Differential proteomics profile analysis ONCO-PROTEOMICS Serological Proteome Analysis (SERPA) of colorectal carcinoma: Immunologic tolerance to self-components is broken in pathologic conditions such as cancer. In this project we performed a screening of the colorectal tumor proteoma by exploiting auto-antibodies contained in the sera of patients to identify colon specific tumoral antigens. Tumour-specific immunoreactive proteins have been found, the analysis demonstrated a modification in antigen recognition by patients B cells as a function of colon cancer progression. Characterization of Mena breast carcinoma antigen: Human Mena, is an antigen overexpressed in breast cancer playing a role in the control of cell motility and adhesion regulating the actin cytoskeleton. By 2D-electrophoresis we identified different Mena isoforms generated by alternative splicing and/or by different protein post translational modifications. Mena phosphorylation has been detected as consequence of EGF treatment of breast carcinoma cell lines and both its overexpression and phosphorylation lead to increase p42/44 MAPK activation and cell proliferation. NEURO-PROTEOMICS Protein pattern changes in cerebrospinal fluid (CSF) of neurodegenerative diseases: CSF being in contact with the brain contains proteins released directly from the central nervous system following pathological conditions, thus CSF analysis is very important to understand the pathological processes and for diagnostic purpose. We successfully applied differential expression proteomics analysis to CSF of patients with Amyotrophic Lateral Sclerosis compared to healthy subjects finding that ceruloplasmin protein is expression was increased in ALS patients and that in particular an asialo-ceruloplasmin isoforms was increased. We are currently working on CSF from patients affected by and Parkinson’s Disease. Proteins involved in the 150 - SAN RAFFAELE SCIENTIFIC INSTITUTE regulation of redox balance that might be a target of oxidative stress damage have been found differentially expressed showing also different post-translational modifications. We also developed computational tools based on linear and non-linear dimensional reduction approaches followed by automatic clustering evaluation for the analysis of 2DE imagines aimed at the patients clustering and classification. Massimo Alessio BIOMOLECULAR NMR LABORATORY We study the structure and dynamics of biomolecular complexes in solution by NMR spectroscopy in combination with a wide range of biochemical, biophysical and computational techniques.Our activity is focused on two main projects: 1) Structural characterization of the interaction of small drugs with extracellular cellular receptors; and 2) Structural and dynamic characterization of novel chromatin-interacting modules. 1. Integrin aVb3 is involved in many biological processes such as angiogenesis, inflammation, and cancer. aVb3 exerts its role interacting with proteins containing an RGD motif. Recent drug design research has therefore focused on the development of RGD-containing ligands for medical applications. A. Corti has recently shown that the isoDGR motif can compete with RGD in the binding to aVb3. By means of docking approaches and molecular simulations we have characterized the interaction isoDGR-aVb3. Using ligand-based NMR techniques we are characterizing the interactions of a small library of RGD derived ligands with surface receptors localized on living cells (in collaboration with Molmed) 2. Methylation of lysine residues on histone H3 tails regulates transcription. A recent addition to the list of known methylated histone binding modules is the PHD finger. AIRE protein contains two PHD fingers and mutations in AIRE gene cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells where it promotes the expression of tissue-specific antigens. The mechanism by which AIRE controls gene expression is currently unknown and the function of its domains, in particular of its PHD fingers is still elusive. We have characterized the three-dimensional structure of AIREPDH1 in complex with H3Keme0 (in collaboration with P-Peterson,T artu- University) providing a new link between the status of histone modifications and the regulation of tissue-specific antigen expression in thymus. The group collaborates to other projects aiming to characterize at molecular levels a) the interactions of the protein HMGB1 with CpG rich oligonucleotides (M.Bianchi) and b) the interaction between PKD1 and NPHP1, two protein involved in renal genetic diseases (A. Boletta) Giovanna Musco Figure 26. Solution structure of AIREPHD1 in complex with H3K4me0. Surface plot of the lowest energy complex structure. Cyan-dashed lines represent intermolecular hydrogen bonds. Colour coding: pink, AIRE-PHD1; blue, H3K4me0; orange, protein residues forming specific polar contacts with H3K4me0; green, protein residues forming hydrophobic contacts with H3K3me0 CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS - 151 Neurogenomics Unit Neurogenomics UnitProteome biochemistry Unit Biomolecular NMR laboratory CENTER FOR IMAGING - 153 CENTER FOR IMAGING Clinical Research Units Clinical and experimental radiology Unit HEAD OF UNIT: Alessandro Del Maschio* PHYSICIANS: Francesco De Cobelli, Pietro Panizza, Massimo Venturini CONSULTANTS: Antonio Esposito, Claudio Losio TECHNICIAN: Tamara Canu High technology in radiation therapy Unit HEAD OF UNIT: Nadia Di Muzio PHYSICIANS: Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Italo Dell’Oca, Andrei Fodor, Micaela Motta, Marcella Pasetti, Paolo Passoni, Lara Rigoni, Stefano Schipani RESIDENTS: Mariangela Caimi, Aniko Maria Deli, Najla Slim TECHNICIANS: Laura Longoni, Simone Selli. Molecular imaging Unit HEAD OF UNIT: Luigi Gianolli PHYSICIANS: Elena Busnardo, Carla Canevari, Federico Fallanca, Claudio Landoni, Patrizia Magnani, Maria Cristina Messa, Andrea Panzacchi, Maria Picchio, Ana Maria Samanes Gajate, Pietro Spagnolo, Paola Todeschini RESEARCHERS: Sara Belloli, Valentino Bettinardi, Assunta Carpinelli, Isabella Castiglioni, Maria Carla Gilardi, Mario Matarrese, Maria Grazia Minotti, Rosa Maria Moresco, Marco Rigamonti, Paola Scifo, Sergio Todde POST-DOCTORAL FELLOWS: Ioana Florea, Manuela Giglio, Valeria Masiello PHD STUDENTS: Francesca Gallivanone, Cristina Monterisi, Eugenio Rapisarda TECHNICIANS: Antonia Compierchio, Andrea Fabro, Paola Lanzoni, Carlo Pizzamiglio, Pasquale Simonelli, Stefano Stucchi, Francesco Sudati, Elia Anna Turolla, Mauro Vaghi Neuroradiology research group HEAD OF UNIT: Giuseppe Scotti* CLINICAL GROUP LEADER: Letterio Salvatore Politi PHYSICIANS: Simonetta Gerevini, Claudio Righi, Franco Simionato, Francesco Scomazzoni FELLOW: Sara Pizzi * Professor at: Università Vita-Salute San Raffaele 154 - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction Clinical Imaging including Radiology (Conventional Radiology / CR, Ultrasound / US, Computed Tomography / CT, Magnetic Resonance Imaging, / MRI, Diagnostic and Interventional Angiography / DSA), Neuroradiology (as above), Nuclear Medicine (Conventional Scintigraphy, Single Photon Emission Tomography / SPECT, Positron Emission Tomography / PET) is probably the most complete and reliable method to explore the human body in order to establish disease prediction/prevention and/or diagnosis. Clinical Imaging is closely related to clinical, biochemical and histopathological data. Clinical Imaging provides morphological, structural and metabolic information to confirm clinical assumptions and to solve differential diagnoses. Moreover, Clinical Imaging is highly relevant to validate results from clinical trials and it is often considered the standard of reference for phase I-II-III-IV clinical trials. Today it is possible to apply these technologies to pre-clinical animal studies and indeed Experimental Imaging is becoming instrumental for translational research. The Imaging Center is comprehensive of a complete set of Clinical Imaging and Experimental Imaging techniques. The Experimental Imaging Center includes: • MR imaging / spectroscopy, 7 Tesla, small bore, for animal studies (mouse, rat, rabbit) • Micro CT • Micro PET • Optical Imaging / O.I. (infrared waves / fluorescence) • Microscopic Ultrasound Imaging • In vivo microscopy: Single photon, double-photon These technologies have been applied to the following research fields: Macroscopic imaging (organs & tissues), Cell imaging (aggregations of cells and single cells), Molecular Imaging and Spectroscopy imaging (characterization of molecular metabolic processes). In addition, the Imaging Center is dedicating resources to the technological progress and development of original models. CENTER FOR IMAGING - 155 Clinical Research Units CLINICAL AND EXPERIMENTAL RADIOLOGY UNIT The main research projects of the Clinical and Experimental Radiology Unit encompass: 1) Cardiac magnetic resonance (CMR) Imaging and Spectroscopy and cardiac Computed Tomography (CT). We are developing different lines of research: the first is on characterization of different causes of cardiomyopathy using the gadolinium delayed-enhanced CMR technique; the second line is on evaluation of ventricular function and energy metabolism in different conditions such as different type of exercise training, obesity and fatty liver or insulin-resistance; the third line consists in the evaluation of the accuracy of CT in excluding the disease in patients with suspected CAD. 2) Diffusion-weighted Magnetic Resonance Imaging. Non-invasive differential diagnosis of pancreatic disease and breast lesions is a major challenge. We demonstrated that DWI provides quantitative and qualitative evaluation of pancreatic and breast focal lesions, helping to differentiate between malignant and non-malignant lesions; moreover, DWI allows early information about patient’s response to chemotherapy. 3) Development of clinical trials with new contrast agents. In the last year clinical trials mainly on different contrast media have been conducted in evaluation of breast lesions, cardiac diseases, coronary disease and Takayasu’s arteritis. 4) Cellular and molecular imaging. A non-invasive MR based method for in-vivo cellular tracking has been developed and applied to follow the dendritic cells (DCs) in tumor bearing mice, allowing to investigate the critical aspects of DCs migration to establish an immune mediated cancer therapy. A similar approach for cells labeling and imaging was also used to follow the pancreatic islets fate, after their transplantation in mouse model of type 1 diabetes. 5) Pancreatic cancer’s imaging. In the last year we focused our research on the evaluation of endocrine tumors and periampullary tumors performing a prospective study using Color-Doppler Ultrasound, Endoscopicultrasonography and MDCT in evaluation of vascular invasion. 6) Implementation of radiotherapy planning by new imaging-techniques. Our aim has been to use different techniques such as MRI and 4D-CT to improve target volume definition in prostate cancer and in pancreatic ductal adenocarcinoma. Alessandro Del Maschio HIGH TECHNOLOGY IN RADIATION THERAPY UNIT Our scientific activity in 2008 was focused mainly on the following areas: prostate, rectal, pancreatic, lung, head and neck and central nervous system neoplasms. Prostate cancer: 1) Phase I-II study comparing a short course adjuvant tomotherapy (1 month) VS conventional radiation therapy (2 months) in terms of acute and late genito urinary (GU) and gastrointestinal (GI) toxicity and biochemical control. 2) Phase I-II study of radical hypofractionated RT with tomotherapy assessing acute and late GU and GI toxicity and biochemical control. 3) Investigation of the role of dose in post-operative setting, leading to the first mono institutional analysis indicating a clinical benefit from doses ≥ 70 Gy in the early adjuvant setting. 4) Study of dose escalation on dominant intraprostatic lesion individuated by means of MRI in order to definitively eradicate prostate cancer. 156 - SAN RAFFAELE SCIENTIFIC INSTITUTE Rectal and Pancreatic Cancer: 1) A dosimetric study of comparison between 4D-CT vs standard technique and between tomotherapy vs 3D-CRT. 2) A Phase I study of tomotherapy in combination with capecitabine. Rectal cancer: A Phase II study of preoperative tomotherapy in combination with oxaliplatin and 5-FU in rectal cancer. Lung: Hypofractionated tomotherapy treatments in early and advanced stage NSCLC with various radiation dose delivery regimens utilizing PET/CT for planning and CT/SPECT for evaluation of lung perfusion in order to reduce radiation toxicity to the lung. Head and Neck: Study of moderate hypofractionation radiation therapy in adjuvant and radical treatment by means of simoultaneous integrated boost technique utilizing MRI and PET/CT for improved definition of tumors, organs at risk and more radioresistent tumor subvolumes on which to implement dose escalation. CNS: 1) study of hypofractionated tomotherapy treatment vs. γ knife radiosurgery for benign neoplasms (meningioma; pituitary adenoma). 2) EORTC trial on low grade gliomas standard radiotherapy alone vs. chemiotherapy alone. 3) Study of tomotherapy treatment for large skull base meningiomas not suitable for γ knife or surgery in terms of acute a subacute side effects and disease control. Nadia Di Muzio MOLECULAR IMAGING UNIT Main research activities are focused on: 1) Radiochemistry, 2) Technological developments, 3) Preclinical Imaging, 4) Clinical Imaging in Oncology, 5) Clinical Imaging in Neuropharmacology, and 6) Clinical Imaging in Cardiovascular Disease. 1) Radiolabeling of ligands for in vivo PET imaging: a) an activated microglia linked Translocator Protein ligand: 19F-VC701; b) a β amyloid complex ligand: 11C-PIB and c) a marker for cardiac sympathetic nervous system: 11C-HED. d) In addition, the development of new tools for in vivo detection of angiogenesis and hypoxia and of an automatic system for the production of radiolabeled metals, such as 64/60 Cupper and 110 Indium are still ongoing. 2) Development of novel methods of image acquisition, processing and analysis: a) respiratory gating technique (4D PET/CT) to improve PET image quality and to optimize RT target volume definition, by accounting for respiratory movements; b) a web service based on GRID technology for statistical analysis of PET and SPECT neurological studies, to support the diagnostic confidence level. 3) Preclinical imaging activities for: a) pharmacological evaluation of ligands for in vivo hypoxia detection in rodent models of cancer, b) potential use of 18F-FDG for imaging inflammation in a mouse model of lung injury and c) biological characterization of models of neurodegenerative and neoplastic diseases. CENTER FOR IMAGING - 157 4) Evaluation of PET/CT in staging and re-staging different neoplastic diseases, by using 18F-FDG and 11CCholine. In particular, it has been established that PSA serum levels and anti-androgenic therapy are, respectively, positive and negative predictors of prostate 11C-Choline uptake. 5) Clinical Imaging in Neuropharmacology was dedicated to the development of methods for the in vivo quantification of brain inflammation and to the study of the neurobiology of human behaviour, and in particular of the involvement of mu opiate receptors in the hedonic component of obesity. 6) Clinical Imaging in cardiovascular disease was dedicated to cardiac fusion imaging (SPECT and 64-MDCT): clinical feasibility in patients risk stratification, and to the validation of a new MDCT acquisition protocol with a dramatic reduction of radiation exposure without compromising image quality. Luigi Gianolli NEURORADIOLOGY RESEARCH GROUP The research activity of the Neuroradiology Research Unit is focused on 2 main areas: 1) Preclinical studies: using a human-grade 3 Tesla Magnetic Resonance Imaging (MRI) apparatus equipped with a mouse-dedicated coil we evaluated and quantified structural changes in the brains of murine models of several neurological pathologies, such as inherited or acquired demyelinating disorders and brain tumors. Further, with the aim of tracking somatic stem cells (SC) upon transplantation or within gene therapy applications, we explored several cell labelling strategies based on superparamagnetic iron oxides particles and on different MR reporter genes, allowing iron accumulation within cells. Lentiviral vectors (LV) carrying the cDNA of the human tyrosinase, intracellular H-ferritin, L-ferritin and a mutated form of the latter were produced and employed for transducing cell lines, neural and hematopoietic SC (HSC), and for in vivo gene expression studies. Interestingly, when transduced HSC were trasplanted into recipient mice after bone marrow ablation, a signal change was observed in repopulated tissues. LV were also directly injected in the hippocampus of mice that underwent serial MRI examinations. Signal change due to gene expression was detectable in vivo in the relevant areas from 2 to 15 weeks from the time of injection. Overall these data indicate that expression of tyrosinase and ferritin enables efficient cellular marking for MR localization studies and represent a promising strategy for in vivo long term monitoring of the fate of SC and their progeny. 2) Clinical studies: conventional and advanced MRI studies were performed on patients carrying, orbital lesions, such as orbital adnexal lymphomas of thyroid associated orbitopathy, progressive multifocal leukoencephalopathy or HIV- positive patients affected by central nervous system immuno-reconstitution inflammatory syndrome. Diffusion weighted imaging, proton MR spectroscopy and diffusion tensor imaging techniques were employed and their clinical usefulness in suggesting correct diagnosis and assessing response to therapy was determined. Further, we investigated the potential of MRI in depicting and quantifying peripheral nervous system inflammatory and post-traumatic lesions. Letterio Salvatore Politi FACILITIES - 159 FACILITIES ALEMBIC , Advanced Light and Electron Microscopy BioImaging Center HEAD OF UNIT: Fabio Grohovaz* RESEARCHER: Maria Carla Panzeri FELLOW: Miriam Ascagni TECHNICIANS: Cesare Covino, Andrea Menegon CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis HEAD OF UNIT: Marco E. Bianchi* FELLOWS: Elisa Allievi, Ivana Benzoni, Rosanna Rinaldi TECHNICIANS: Maria Luisa Pintonello, Lorenza Ronfani FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications Laboratory HEAD OF UNIT: Alessio Palini BIOLOGIST: Chiara Villa TECHNICIAN: Emanuele Canonico CERMAC, Centre of Excellence of High Field Magnetic Resonance HEAD OF UNIT: Giuseppe Scotti* PHYSICIAN: Valeria Blasi RESIDENTS: Antonella Castellano, Elisa Scola POST-DOCTORAL FELLOWS: Monia Cabinio, Sara Cirillo, Roberta Longaretti, Silvia Polverigiani PHD STUDENT: Paolo Vezzulli FELLOW: Paola Scifo TECHNICIAN: Antonella Iadanza Mouse histopathology HEAD OF UNIT: Claudio Doglioni* GROUP LEADER: Francesca Sanvito TECHNICIAN: Martina Rocchi * Professor at: Università Vita-Salute San Raffaele 160 - SAN RAFFAELE SCIENTIFIC INSTITUTE ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center Alembic is a resource for the scientific community by providing both access to sophisticated imaging techniques and innovation through the efforts of a small staff. The facility is designed to accommodate researchers by providing instrumentation and instructing them in the most effective use of it, so that they may perform experiments independently. This is particularly true for access to optical microscopes for which those interested are required to attend a course taught by the Alembic staff before being authorized to use the instrumentation. The research activity of the staff also promotes technical updates on a regular basis to keep the local facility on the forefront of available technology. In the course of the years, several new technologies have been integrated into Alembic and new ones are being developed. There is also an area in which the staff develops new methodologies and conducts research on techniques with significant potential to enhance bioimaging research. These activities converge within two main directions: • Use of voltage sensitive dyes - integration of optical recordings with a multi electrode system to monitor membrane potential changes in complex neuronal networks (in collaboration with Politecnico di Milano and San Raffaele Units); use in drug discovery screening (in collaboration with Optotec); • Imaging of luminescence signals - set up of conditions for the in vitro and in vivo imaging (in collaboration with San Raffaele Units and Axxam); evaluation of new photon counting detectors (SPAD, in collaboration with Politecnico di Milano). Main instrumentations at Alembic are: LIGHT MICROSCOPY • Leica TCS SP2 Laser Scanning Confocal • BioRad MRC 1024 Laser Scanning Confocal • Perkin Elmer UltraVIEW ERS Spinning Disk Confocal • Widefield Imaging Setup for time-lapse imaging • AIS2 automatic Microinjection/Imaging setup • ∆Vision RT Deconvolution System • Zeiss Axioplan2 with AxioCam MRc • GElifesciences IN Cell Analyzer 1000 for high throughput/high content screening ELECTRON MICROSCOPY • TEM LEO 912AB with energy filter for microanalysis • TEM Zeiss EM900 Our numbers in 2008 are: 561 registered users (292 active), 95 persons attending theorical/practical courses; about 6000 hours of independent microscopes use. Web: www.sanraffaele.org/research/alembic Fabio Grohovaz CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis Transgenic and knock-out mice are widely used in the research because of their high impact in the understanding of the proteins functional role and because constitute models to study genetic diseases. The San Raffaele-Telethon Core Facility for Conditional Mutagenesis (CFCM) is operative from 1999. During this time CFCM provided to the Scientific Community more than 280 murine models. CFCM performs pronuclear injections and lentiviral infections to generate transgenic mice, offers the electroporation of Embryonic Stem cells and the blastocysts injection of recombinant clones. Moreover, CFCM carries out rederivation of mice via embryo transfer. In addition, CFCM helps Researchers to plan experiments, to manipulate and genotype mice. From 1999 to now the number of services offered by CFCM duplicate. FACILITIES - 161 In the last year CFCM introduced two services: the screening of resistant clones by Southern Blotting to identify gene targeted clones and the production of lentiviral vectors to generate transgenic mice via oocytes infections. Very important, CFCM is offering now the Embryo Cryopreservation. This is a basic service because Researchers spent time and moneys to maintain murine lines not necessary for their current studies. Moreover, these murine lines occupy precious space in the Animal House. More information can be found at the site http://www.sanraffaele.org/CFCMn.html Marco E. Bianchi FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications Laboratory The Flow cytometry Resource and Analytical Cytology Technical Applications Laboratory is a core facility that offers state-of-the-art instrumentation and analysis techniques to the scientific community. Flow cytometry is an evolving field; it is continually being re-discovered by young scientists who approach this technology to answer a multitude of questions in their discovery work. Cytometrists continue to find and develop new applications. So wide ranging is the applicability of this technology that practitioners may include, in addition to biologists, physicians, microbiologists, marine biologists, veterinarians and research chemists to name a few. Verifiable results can easily be obtained for such applications as Immunophenotyping, Cell division and Apoptosis, Cell activation, Intracellular pH shifts, Phagocytosis, Oxidative burst and many more. In addition to the analytical capabilities of this technique, the core facility offers assisted cell Sorting services for characterizing, separating and purifying populations of particles as diverse as beads, bacteria, micro-particles, cells and chromosomes. In 2008 the facility supported over 350 Researchers, performed more than 1400 cell sorts and logged over 9000 hours of analytical instrument time. Alessio Palini CERMAC, Centre of Excellence of High Field Magnetic Resonance CERMAC is a Centre of Excellence financed by an original grant of the ministry of Education and Ministry of health. Different research groups have access to the centre and perform studies independently financed. The core facility available is a 3Tesla magnet with post processing hardware and software facilities for advanced morphological and functional studies of the Central Nervous System. The following research groups have access and develop their projects within the centre: Neuroradiology, Nuclear Medicine, Neurology, Psychiatry, Radiology, Cognitive neurosciences. In 2008, 20 papers have been published in indexed journals. The main fields of research are devoted to: • Development and validation of MR advanced techniques and dedicated post-processing programs • Application of conventional and advanced techniques in the study of the normal brain: • Brain maturation in premature and terms neonates • Aging • Brain functions in paediatric and adult population (perception of music and sounds, language, memory and other cognitive functions) • Motor system function including mirror neurons system • Application of conventional and advanced techniques in the study of the diseased brain: • Brain inflammatory diseases, with a special focus on Multiple Sclerosis • Mood disorders and other psychiatric diseases like schizophrenia 162 - SAN RAFFAELE SCIENTIFIC INSTITUTE • • • Neuro-oncology (diffusion tensor imaging and tractography in brain tumors) Vascular diseases Degenerative diseases Giuseppe Scotti MOUSE HISTOPATHOLOGY The principal aim of the Rodent Histopathology Unit is to support, complement and favour the advancement of scientific projects, by providing conventional morphological analysis and immunophenotyping. The facility is located in the Department of Pathology and offers the technical and the interpretative experience for the analysis of tissues from animal models, evaluating the best histological or immunocytochemical procedures, based on the expected results. The services provided include: A) macroscopic examination including perfusion and necroscopy B) microscopic analysis • paraffin embedding and inclusion • microtome sectioning and standard HE staining • special histochemical staining (Perls, PAS, Masson, Gomori stain…) • frozen tissues and cryostatic section preparation • immunohistochemistry (commercial antibody and • cytospin and paraffin cytoblock • final report C) image analysis The role of pathology in the field of experimental studies on laboratory animal is of interest for: • identification and evaluation of experimentally induced lesions • setting of animal models of human diseases • efficacy and safety studies • phenotyping of transgenic mice To date multiple collaborations within our Institute have been settled in order to analyze the morphological and immunophenotipical patterns of murine models of diseases, treated with different therapeutic approaches and to analyze the efficacy of genic therapy and safety of the use of viral vectors. Francesca Sanvito FACILITIES - 163 CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis CLINICAL DEPARTMENTS - 165 THE CLINICAL DEPARTMENTS The following staffs are officially approved 166 - SAN RAFFAELE SCIENTIFIC INSTITUTE DEPARTMENT OF ARRHYTHMOLOGY Head of Department: Carlo Pappone DEPARTMENT AREA COORDINATOR: Vincenzo Santinelli Electrophysiology and cardiac pacing HEAD OF UNIT: Carlo Pappone RESEARCHER:Vincenzo Santinelli PHYSICIANS: Giuseppe Augello, Cristiano Ciaccio, Simone Gulletta, Patrizio Mazzone, Gabriele Paglino, Alessia Pappone, Simone Sala, Andreina Santagostino, Nicoleta Sora, Pasquale Vergara, Gabriele Vicedomini RESIDENTS: Francesco Arioli, Maria Avitabile, Giuseppe Ciconte, Amarild Cuko, Enrico Frigoli, Emma Gelera, Alessandra Marzi, Rita Naio, Andrea Radinovic, Stefania Sacchi, Massimo Saviano, Roberto Spoladore BIO ENGINEERS: Simonetta Crisà, Giorgio Maida FELLOWS: Ombretta Osnago, Francesca Zuffada In the Arrhythmology Department, which has both clinical and invasive autonomy, all types of cardiac arrhythmias and associated diseases are treated and most of them are definitively cured by catheter ablation. The most important clinical activities are as follows: • Ablation of Atrial Fibrillation • Electric treatment of Heart Failure • Device implantation (Pacemakers, ICD, Biventricular pacing) • Treatment of inherited arrhythmias (Brugada syndrome, long QT syndrome, Arrhythmogenic Right Ventricular Carlo Pappone Dysplasia, etc.) • Robotic remote approach for ablation of supraventricular tachyarrhythmias, including WPW syndrome • Robotic remote approach for the identification of the best site and lead positioning within coronary sinus during Biventricular implantation in patients with Heart Failure • Diagnostic and Therapeutic Telemedicine (home ECG and remote device monitoring and interrogation) • Recently, in the Department of Arrhythmology has been set up a clinical-electrophysiology training center, the Academy of Arrhythmology, where foreign physicians come to learn and discuss procedures in real-time. Another area of research is the development of new technologies for catheter design (tip-irrigated, flexible or stiff catheters) and new software for real-time accurate 3D anatomical reconstruction of cardiac chambers for atrial fibrillation ablation. The Arrhythmology Department also cooperates with international biotechnology laboratories, and with the Miami University in both clinical and scientific field. In addition, the Arrhythmology Department is involved in writing several textbook chapters. Carlo Pappone CLINICAL DEPARTMENTS - 167 CARDIO-THORACIC-VASCULAR DEPARTMENT Head of Department: Ottavio Alfieri* DEPARTMENT AREA COORDINATORS: Stefano Benussi, Renata Clotilde Castellano, Domenico Cianflone*, Guglielmo Cornero, Stefano Gerosa, Giovanni La Canna, Silvio Magrin, Giovanni Marino, Enrico Maria Marone, Germano Melissano, Stefano Moriggia, Carlopietro Voci* Cardiac surgery HEAD OF UNIT: Ottavio Alfieri* CLINICAL UNIT LEADERS: Michele De Bonis, Francesco Maisano, Alessandra Rossodivita CLINICAL UNIT COORDINATOR: Alessandro Castiglioni PHYSICIANS: Irina Arendar, Stefano Benussi, Andrea Blasio, David Ferrara, Andrea Fumero, Andrea Galanti, Antonio Grimaldi, Giuseppe Iaci, Giovanni Laino, Elisabetta Lapenna, Stefano Moriggia, Simona Nascimbene, Maria Grazia Pala, Alessandro Verzini RESIDENTS: Maria Chiara Calabrese, Micaela Cioni, Egidio Collu, Paolo Denti, Enrica Dorigo, Andrea Giacomini, Mario Manca, Maurizio Taramasso, Giorgio Viganò FELLOWS: Andrea Guidotti, Ylenia Privitera, Davide Schiavi Cardiac ultrasound imaging HEAD OF UNIT: Giovanni La Canna Cardiovascular rehabilitation and prevention HEAD OF UNIT: Domenico Cianflone* CLINICAL UNIT LEADER: Carlo Meloni Physician: Alice Calabrese Cath Lab HEAD OF UNIT: Antonio Colombo CLINICAL UNIT LEADERS: Mauro Carlino, Matteo Montorfano PHYSICIANS: Alfredo Castelli, Alaide Chieffo, Iassen Michev RESIDENTS: Raffaele Lacquaniti, Marco Mussardo FELLOWS: Marta Bande, Cosmo Godino, Alfonso Ielasi, Azeem Mohamed Latib, Valeria Magni TECHNICIANS: Gianfranco Accarino, Raimondo Bellanca, Salvatore Cannavale, Andrea Di Marco, Fanny Lavazza, Matteo Longoni, Davide Maccagni, Massimo Angelo Messa, Marcello Murino, Vittorio Romano, Mario Squilla Clinical cardiology HEAD OF UNIT: Alberto Margonato CLINICAL UNIT LEADERS: Fabrizio Bonetti, Alberto Cappelletti, Andrea Conversano, Gabriele Fragasso, Andrea Macchi, Michele Oppizzi PHYSICIANS: Eustachio Agricola, Fabio Buzzetti, Chiara Camesasca, Cristina Canciani, Stefano Gerosa, Alessandra Mailhac, Cinzia Nitti, Alessandra Pancaldi, Marco Papa, Cristina Pedrigi, Patrizia Puccetti, Carmen Silipigni Coronary Care Unit (CCU) HEAD OF UNIT: Alberto Margonato CLINICAL UNIT LEADERS: Carlo Ballarotto, Giuseppe Pizzetti PHYSICIANS: Giorgio Bassanelli, Luca Falqui Functional Rehabilitation HEAD OF UNIT: Alessandra Raschi 168 - SAN RAFFAELE SCIENTIFIC INSTITUTE Intensive Care Unit (ICU) and Post Operatory Care Unit (POCU) HEAD OF UNIT: Alberto Zangrillo* CLINICAL UNIT LEADERS: Giovanni Landoni, Giovanni Marino CLINICAL UNIT COORDINATORS: Antonella Crescenti, Andrea Carozzo, Jaques Ntzepa Batonga, Rossana Fiori PHYSICIANS: Elena Bignami, Tiziana Bove, Maria Grazia Calabrò, Giuseppina Maria Casiraghi, Remo Daniel Covello, Monica De Luca, Greta Fano, Annalisa Franco, Chiara Gerli, Roberta Mennella, Fabrizio Monaco, Massimiliano Nuzzi, Federico Pappalardo, Tiziana Quattrocchi, Dino Rapati, Anna Mara Scandroglio Thoracic surgery HEAD OF UNIT: Piero Zannini* CLINICAL UNIT LEADERS: Giulio Melloni, Giampiero Negri* CLINICAL UNIT COORDINATOR: Angelo Carretta PHYSICIANS: Paola Ciriaco, Armando Puglisi, Carlopietro Voci* RESIDENTS: Alessandro Bandiera, Michele Giovanardi, Annamaria Gremmo, Piergiorgio Muriana, Stefano Sestini Vascular surgery HEAD OF UNIT: Roberto Chiesa* CLINICAL UNIT LEADER: Efrem Civilini CLINICAL UNIT COORDINATOR: Renata Clotilde Castellano PHYSICIANS: Domenico Astore, Laura Dordoni, Gloria Esposito, Enrico Maria Marone, Massimiliano Marrocco-Trischitta, Germano Melissano, Yamume Tshomba * Professor at: Università Vita-Salute San Raffaele The clinical activity of the Department is devoted to the diagnosis and treatment of cardiac, thoracic and vascular disease. In 2008, new techniques and technologies have been introduced to offer to the patients the entire spectrum of the therapy options in a multidisciplinary environment. Patients centered care is the philosophy behind the daily clinical practice. The interaction among different specialists (anesthesiologists, cardiovascular and thoracic surgeons, interventional and clinical cardiologists) is favored by the contiguity of the areas devoted to surgery, cath lab procedures and intensive care. Patients with acute disease coming on emergency basis as well as patients with chronic diseases admitted electively are submitted to diagnostic investigation, treatment, an then rehabilitation Ottavio Alfieri if needed. A well structured rehabilitation program is available providing complete recovery even for the sickest patients. An active outpatient clinic is functioning for new referrals and follow-up. In regard to cardiac diseases, the main pathologies are ischemic and valvular heart diseases, which are treated either with catheter based interventions or minimally invasive procedures or conventional surgery. Grown-up patients with congenital heart disease have been increasing recently. A large number of patients with major aortic and vascular pathologies are also increasingly referred as well as patients with complex oncological problems of the thoracic organs. During the year 2008, transcatheter aortic valve implantation has been widely introduced to treat inoperable or high risk patients with severe aortic stenosis and today the largest experience in Italy has been accumulated in this field by our multidisciplinary team. CLINICAL DEPARTMENTS - 169 The percutaneous treatment of mitral insufficiency has been also initiated in patients with heart failure and our series represents one of the very first in Europe. Innovative modalities of medical treatment for patients with congestive heart failure have been recently introduced, particularly in the field of improvement of cardiac metabolism, achieving a significant increase of survival/quality of life as compared to figures reported in the literature. A structurized program for the treatment of patients with end-stage heart failure has been developed. Aim of the program is to provide a comprehensive treatment for the failing heart, including mechanical circulatory support (short and long term) in different clinical settings: post cardiotomy cardiogenic shock, acute myocardial infarction, bridge to transplant, destination therapy. Also treatment of acute hypoxia and ARDS by ECMO is now offered as a life-saving procedure. A wide spectrum of aortic pathologies, including aneurysms, dissection, traumatic injuries, coarctation etc., are treated using both conventional and endovascular approaches. For high risk patients with complex aortic arch and thoracoabdominal pathology, hybrid open and endovascular strategies are selectively performed, and endovascular branch-technology is currently under evaluation. Both open and endovascular procedures are also used for carotid and lower limb revascularization. A great recent achievement in thoracic surgery has been the treatment of lung cancer in patients with emphysema. The respiratory impairment due to this disease used to be a surgical contraindication in the past. Today different strategies have been introduced in our Department to extend surgical indication in lung cancer including parenchyma-sparing bronchoplasty techniques, lung volume reduction surgery and bronchoscopic lung volume reduction. Finally, in 2008, 3-D echocardiography has been introduced as a routine imaging modality to assess patients with structural heart disease, with considerable enhancement of diagnostic capabilities. Ottavio Alfieri 170 - SAN RAFFAELE SCIENTIFIC INSTITUTE DEPARTMENT OF GENERAL AND SPECIALISTIC SURGERY Head of Department: Carlo Staudacher* DEPARTMENT AREA COORDINATORS: Marco Braga*, Carlo Castoldi, Renato Castoldi, Francesco Deni, Renato Finazzi, Emiliano Giorgi, Gilberto Mari, Michele Paganelli, Danilo Parolini, Sandro Passaretti, Carlo Socci, Marco Stella, Walter Zuliani Gastroenterologic surgery HEAD OF UNIT: Carlo Staudacher* CLINICAL UNIT LEADERS: Saverio Di Palo, Elena Orsenigo CLINICAL UNIT COORDINATORS: Paolo Aldo Raul Baccari, Paola De Nardi PHYSICIANS: Renato Castoldi, Andrea Marco Tamburini, Andrea Vignali, Walter Zuliani RESIDENTS: Michele Carvello, Tiziana Casiraghi, Carmen Forestieri, Francesco Luparini, Alessio Mocci, Danilo Parolini, Carlo Socci,Valentina Tomajer, Roberta Varale TECHNICIAN: Alessandra Castiglioni General and pancreatic surgery HEAD OF UNIT: Valerio Di Carlo* CLINICAL UNIT LEADERS: Marco Braga*, Marco Cristallo, Alessandro Zerbi PHYSICIANS: Gianpaolo Balzano, Enrico Fiacco, Marco Stella RESEARCHER: Lorenzo Piemonti RESIDENTS: Vanessa Capitanio, Giovanni Capretti, Federica Merlini, Federica Milani, Cristina Ridolfi, Simone Squillante FELLOWS: Alessia Mercalli, Valeria Sordi Hepatobiliary and week surgery HEAD OF UNIT: Gianfranco Ferla* CLINICAL UNIT LEADERS: Luca Aldrighetti, Edoardo Beretta, Alberto Marassi PHYSICIANS: Marco Catena, Enrico Fiacco, Renato Finazzi, Gilberto Mari, Mvunde Mukenge, Michele Paganelli CONSULTANT: Veronica Zuber RESIDENTS: Matteo Frasson, Cristina Gilardini, Eleonora Guzzetti, Ines Mulas, Carlo Pulitanò Orthopaedics HEAD OF UNIT: Gianfranco Fraschini* CLINICAL UNIT LEADERS: Francesco Camnasio, Maurizio De Pellegrin, Giuseppe Gioia, Crispino Grispigni, Eliseo Mainetti RESEARCHER: Giuseppe M. Peretti PHYSICIANS: Arianna Banfi, Carlo Castoldi, Pietro Ciampi, Alessandro De Ponti, Dario Fracassetti, Davide Mandelli, Gianluigi Moro, Paola Rivoltini, Paolo Sirtori, Corrado Sosio, Matteo Vitali, Umberto Mezzadri RESIDENTS: Niky Mancini, Laura Mangiavini, Celeste Scotti POST-DOCTORAL FELLOW: Daniela Deponti Gastroenterology-Endoscopy HEAD OF UNIT: Pier Alberto Testoni* CLINICAL UNIT LEADERS: Paolo Giorgio Arcidiacono, Mario Guslandi, Sandro Passaretti PHYSICIANS: Silvia Carrara, Lorella Fanti, Alberto Mariani, Edi Viale FELLOWS: Cinzia Boemo, Antonella Giussani, Chiara Notaristefano, Cristian Vailati CONSULTANTS: Maura Corsetti, Gianni Mezzi, Cristina Ogliari, Maria Chiara Petrone Anaesthesiology and resuscitation HEAD OF UNIT: Luigi Beretta* CLINICAL UNIT COORDINATORS: Massimo Agostoni, Eleonora Colnaghi, Laura Comotti, Carla Martani, Valeria Perotti, Roberto Valeri, Giovanna Valentini General intensive care HEAD OF UNIT: Alberto Zangrillo* CLINICAL UNIT LEADER: Sergio Colombo CLINICAL DEPARTMENTS - 171 The Department of Surgery and Specialized Units encompasses Upper Gastrointestinal Surgery, Colorectal Surgery, Pancreas Surgery, Breast Unit, Hepatobiliary Unit, Bariatric Surgery, Lymphatic Surgery, Endocrine Surgery, General Surgery, Transplantation, Gastroenterology and Endoscopy, Orthopedic Surgery, Anesthesiology, and Intensive Care Unit. The Department has three core missions: excellent clinical care, outstanding research productivity and the delivery of state of the art educational programs. The Upper Gastrointestinal Surgery Unit has a dedicated program in treating cancers and benign diseases of the upper gastrointestinal tract. Patients are treated by a multidisciplinary team of experts. A research program is ongoing for sentinel node identification in early cancer stage and neoadiuvant chemotherapy and HIPEC in the advanced ones. The activity volume is very high. The Colorectal Surgery Unit offers the most advanced surgical and minimally inCarlo Staudacher vasive options not only to eradicate the disease, but also to preserve patients’ ability to normal function. The team includes specialists in colorectal surgery, in hepatobiliary surgery (for patients with liver metastasis) radiotherapist and medical oncologist . This is a high volume Unit. The Pancreatic Surgery Unit has one of the highest pancreatic surgery volume in Europe. In 2008, 168 pancreatic resections have been performed: 94 pancreatoduodenectomy, 60 left pancreatectomy, 9 enucleation, 5 total pancreatectomy. The Breast Unit applies the International Standard of excellence stated by EUSOMA (European Society of Mastology). In the Hepatobiliary Surgery Unit the activities are mainly focused on hepatobiliary tumors and chronic liver diseases, including primary and metastastic liver tumors, benign and malignant diseases of the biliary tract, acute and chronic hepatitis. Concerning the hepatic surgery the Unit is a high-volume unit for liver resections, performing 150-170 liver resection/year. A clinical program of laparoscopic liver surgery has been started on January 2007. Data regarding the Bariatric Surgery Unit included a successful activity in the past years. The current program foresees an activity increase, with special interest to the obese diabetic patient. Lymphatic Surgery: the primary and secondary lymphoedema surgical therapy finds in the lympho-venous anastomosis, as well as in the lymphatic grafting the more reliable procedures. The Section of Endocrine Surgery treats endocrine tumors in children and adults. Surgeons working in this section apply the state-of-the-art technology, including minimally invasive parathyroid surgery with intraoperative parathyroid (PTH) assay determination , and laparoscopic adrenalectomy. The Area of Transplant Surgery focused its clinical activity on Simultaneous Pancreas and Kidney Transplantation and Pancreas Alone Transplantation in IDDM patients. There is also a program regarding islet transplantation. The clinical activity of the Division of Gastroenterology and Gastrointestinal Endoscopy includes four main sections: clinical gastroenterology and hepatology, gastrointestinal and pancreatico-biliary endoscopy, ultrasound endoscopy, and digestive motility. In the year 2008, 14,400 endoscopic procedures have been performed. In the 2009 about 15,700 procedures are expected. The Division of Orthopedic Surgery cares for all injuries and diseases of the musculoskeletal system. The Division provides subspecialty clinics in the specific areas of major joint reconstruction, sports medicine, pediatric orthopedics, foot, hand, spine, trauma, oncology, reconstructive microsurgery, and rehabilitation. The Anesthesiology and Intensive Care Unit reflects the comprehensive effort of a team of anesthesia physicians, nurses, and staff to advanced patient care. Pre-admission diagnosis and staging program is ongoing in order to decrease hospital stay. Carlo Staudacher 172 - SAN RAFFAELE SCIENTIFIC INSTITUTE HEAD AND NECK DEPARTMENT Head of Department: Giuseppe Scotti* DEPARTMENT AREA COORDINATOR: Antonio dell’Acqua, Andrea Falini, Marco Gemma, Susanna Piccoli, Sandra Pieralli, Claudio Righi, Francesco Scomazzoni Neuroradiology HEAD OF UNIT: Giuseppe Scotti* CLINICAL UNIT LEADERS: Nicoletta Anzalone, Cristina Baldoli, Andrea Falini, Franco Simionato PHYSICIANS: Simonetta Gerevini, Sandra Pieralli, Letterio Salvatore Politi, Silvia Pontesilli, Claudio Righi, Francesco Scomazzoni, Roberta Scotti, Paolo Vezzulli Head and neck anaesthesia and neurointensive care HEAD OF UNIT: Luigi Beretta* CLINICAL UNIT LEADERS: Silvano Cozzi, Cristina Mattioli PHYSICIANS: Antonio Dell’Acqua, Fabio Bernasconi, Maria Rosa Calvi, Marco Cerri, Antonella Cipriani, Assunta De Vitis, Cristina Frascoli, Marco Gemma, Luigi Gioia, Elisabetta Grandi, Maurizio Mungo, Susanna Piccoli, Alfredo Ravizza, Luisa Sacchi Ophthalmology HEAD OF UNIT: Paolo Rama CLINICAL UNIT LEADERS: Francesco Fasce CLINICAL AREA COORDINATORS: Gianluigi Bolognesi, Luisa Pierro PHYSICIANS: Nicola Baccelli, Paolo Bettin, Stefania Bianchi Marzoli, Elena Bruschi, Gabriella Cammarata, Roberto Carassa, Stefano Ciaccia, Carlo Ciampi, Paola Ciasca, Marco Codenotti, Annalisa Colucci, Umberto De Benedetto, Federico Di Matteo, Federica Ferrario, Marina Fiori, Maddalena Forti, Marco Gagliardi, Matteo Ghidoni, Silvia Giatsidis, Antonio Giordano Resti, Lauretta Guarisco, Chiara Insacco, Ugo Introini, Rosangela Lattanzio, Francesca Legorini, Francesco Loperfido, Gisella Maestranzi, Abu Amria Majed, Angela Malegori, Maria Pia Manitto, Elena Mantovani, Elisabetta Martina, Stanislav Matuska, Paolo Mauceri, Lisa Melzi, Elisabetta Miserocchi, Giulio Modorati, Veronica Odazio, Giorgio Paganoni, Flavio Paratore, Matteo Prati, Andrea Ramoni, Laura Regali, Carmen Rojo, Michela Rossi, Fabrizio Scotti, Marco Setaccioli, Alessandra Spinelli, Monica Stoppani, Gemma Tremolada, Maurizia Viganò TECHNICIANS: Giorgio Alto, Adriana Angiolini, Alessio Buzzotta, Enrico Delfino, Elisa Restelli, Antonella Ribecca Otorhinolaryngology HEAD OF UNIT: Mario Bussi* PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Lucia Oriella Piccioni, Matteo Trimarchi CONSULTANTS: Fabrizio Ferrario, Andrea Muzza, Francesca Palonta, Rosaria Taverna, Roberto Teggi RESIDENTS: Chiara Bellini, Beatrice Fabiano, Pietro Limardo, Paola Recanati SPEECH THERAPISTS: Daniela Gherner, Barbara Ramella TECHNICIAN: Federica Mores Neurosurgery HEAD OF UNIT: Pietro Mortini* CLINICAL UNIT LEADERS: Stefania Acerno, Camillo Ferrari Da Passano, Alberto Franzin, Marco Losa, Carlo Mandelli, Piero Picozzi PHYSICIANS: Lina Raffaella Barzaghi, Nicola Boari, Lorenzo Gioia, Silvia Snider, Micol Valle CONSULTANTS: Luca Attuati, Marzia Medone, Paola Castellazzi * Professor at: Università Vita-Salute San Raffaele CLINICAL DEPARTMENTS - 173 Giuseppe Scotti The clinical activity of the Head and Neck department includes diagnosis and treatment of diseases of the central nervous system, peripheral nervous system, eye, ear, nose and throat diseases. The Department has a total of 103 beds, of which 6 in the neurointensive care unit, 49 in neurosurgery, 26 in ophthalmology and 22 in the ENT unit. The people involved in the Department activity are 280, of which 100 physicians. In 2008, 4363 surgical procedures have been performed (1736 ophthalmology; 931 ENT; 1696 neurosurgery). Intensive care admissions: 300. Anaesthesiological procedures for surgery or sedations, in children and adults: about 4.000. Gamma knife treatments: 615. Neuroradiological examinations: 38.000. Endovascular neuroradiological treatments: 70. The Head and Neck Department is composed by five units: Neurosurgery Unit Neurosurgical procedures are performed in adult and paediatric age, with main interest in brain tumors, base of the skull and pituitary tumors, spine surgery, peripheral nervous system, stereotactic and functional neurosurgery. The unit is responsible for the gamma knife activity. Otolaryngology and ENT Main fields of activity are oncological surgery of larynx, mouth and throat, Vertigo and imbalance disturbances, otosurgery. Phoniatric rehabilitation. Neurointensive care Every year 300 patients are admitted, 50% from the Emergency Department (severe head injury, stroke and subarachnoid haemorrhage) and 50% from the Neurosurgery Unit (tumor, vascular). 20 patients with brain death are treated and 12 of them become organ donors. The Anaesthesia Group provide for general anaesthesia in neurosurgical, interventional neuroradiology, ENT and ophthalmic surgery for approximately 3000 cases per year and for conscious sedations in children and adults (1000 cases per year) submitted to diagnostic or therapeutic procedures. Ophthalmology Ophthalmology Unit has 53 medical doctors divided into 13 sub-Units which include Cornea and Ocular Surface, General Ophthalmology, Glaucoma, Neuro-Ophthalmology, Oculoplastics and Orbit, Oncology, Cataract Surgery, Out-patient Cataract Surgery, Pediatrics Genetics and Strabismus, Surgical and Medical Retina, and Uveitis. Neuroradiology The Dept is equipped with three 1.5T MR systems, one 3T System (CERMAC), two CT scanners (64 and 16 slices respectively), an angio suite biplane rotational, a digital xray conventional system. Both diagnostic and interventional procedures are performed, in adult and paediatric age. Giuseppe Scotti 174 - SAN RAFFAELE SCIENTIFIC INSTITUTE DEPARTMENT OF INFECTIOUS DISEASES Head of Department: Adriano Lazzarin* DEPARTMENT AREA COORDINATORS: Nicola Gianotti, Paolo Scarpellini Infectious diseases HEAD OF UNIT: Adriano Lazzarin* CLINICAL UNIT LEADERS: Antonella Castagna, Massimo Cernuschi, Paolo Scarpellini, Giuseppe Tambussi, Caterina Uberti-Foppa PHYSICIANS: Paola Cinque, Fulvio Crippa, Anna Danise, Luca Fumagalli, Nicola Gianotti, Monica Guffanti, Myriam Maillard RESEARCHERS: Alberto Beretta, Claudio Fortis, Laura Galli, Lucia Lopalco, Giulia Morsica, Claudia Pastori CONSULTANTS: Priscilla Biswas, Simona Bossolasco, Giuliana Fusetti, Giovanni Gaiera, Andrea Galli, Clara Ronchetti, Vega Rusconi, Flavia Salmaso, Stefania Salpietro FELLOWS: Sabrina Bagaglio, Francesca Cossarini, Giulia Gallotta, Hamid Ibrahim Hasson, Silvia Nozza, Annamaria Pazzi, Deborah Ratti, Gianluca Semeraro, Alessandro Soria, Vincenzo Spagnuolo, Chiara Tassan Din, Simon Tiberi, Giovanna Travi, Francesca Visco TECHNICIAN: Arabella Bestetti * Professor at: Università Vita-Salute San Raffaele The general aim of the Department of Infectious Diseases is to maintain and improve excellence in the management of infectious diseases. The Department activity is organized in five Functional Units (ordinary admission, HIV-infected outpatient ambulatory, infectivology service at San Raffaele main building, experimental therapies, day-hospital plus gastroenterological fibroscopy and tropical diseases) and two Coordination Areas (quality and information technology). In particular, the Department aims at optimizing treatment of HIV infection by clinical trials and data analyses, infectious Adriano Lazzarin diseases other than HIV, including tropical diseases, central nervous system infections and hepatitis, hospital-acquired infections, and opportunistic infections in the immune deficient host. In this view, two Clinical Trial Units have been set up and collaborations with basic research laboratories are continuously sought. Also, a clinical database has been implemented, which allows patients’ clinical data gathered during everyday activity to be used for clinical research and to be timely available for matching laboratory findings with clinical findings. The Department includes three ordinary admission units, with 34 beds cumulatively (one unit with 10 beds is currently borrowed from the Neurology Department), one day-hospital unit with six beds, and nine ambulatory rooms. The staff amounts to 57 people (27 medical doctors, 22 ward nurses, three study nurses, three study coordinators, one data manager, and one statistician). About 3500 outpatients with HIV infection (80% on treatment with antiretroviral drugs) are currently followed-up, each of them attending about four visits per year. During 2008, 35 clinical trials were ongoing at the Department, including phase II and III clinical trials. Research collaborations with European and NIH academic initiatives are also well established, particularly in the field of HIV infection: the Department is member of the following study groups: Italian Cohort of Antiretroviral Naïve patients (ICONA), EUROSIDA (both of them taking part in the inter- CLINICAL DEPARTMENTS - 175 continental Data Collection on Adverse events of Anti-HIV Drugs - D:A:D: study group), European AIDS Treatment Network (NEAT), and COHERE. The ongoing clinical research lines include: the development of new drugs against HIV, new approaches to the treatment of HIV infection (including vaccines and immune-based therapies), the pathogenesis of HIV drug-resistance, HIV encephalopathy, metabolic disorders and cardiovascular complications of HIV disease, co-infection with HIV and hepatitis viruses, new strategies for the management of patients with highly drug-resistant HIV infection, central nervous system involvement, metabolic complications, and co-infection with hepatitis viruses. With regard to HIV treatment, the Department is also collaborating with the Regione Lombardia in order to investigate strategies aimed at reducing health costs without jeopardizing treatment efficacy. Moreover, though the analysis of data from more than 7000 HIV-infected patients recorded in its clinical database, prognostic factors of HIV disease are continuously studied and the results are transferred into clinical practice. The Department is also involved in the research of new diagnostic tools for the management of viral diseases different from HIV, particularly those affecting the central nervous system. It also tightly collaborates with the Comitato per le Infezioni Ospedaliere in order to survey, lower the incidence and improve the management of hospital-acquired infections, as well as with the transplantations units for the prevention and treatment of opportunistic infections in patients with treatment-related immune deficiencies. In this context, it is committed to the development and implementation of guidelines able to assist each other Department in the management of infectious diseases. Furthermore, the Department participates in national initiatives aimed at studying and preventing the widespread of emerging and re-emerging diseases, such as tropical diseases and tuberculosis. In this context it is also involved in projects aimed at improving the cures in low-income countries, in collaboration with AISPO. Due to its high ranking in the management of HIV infection, the Department organizes many residential stages in this field for doctors coming from all over Italy. Adriano Lazzarin 176 - SAN RAFFAELE SCIENTIFIC INSTITUTE MATERNAL AND CHILD HEALTH DEPARTMENT Head of Department: Giuseppe Chiumello* DEPARTMENT AREA COORDINATORS: Alessandro Aiuti, Ferdinando Bombelli, Riccardo Bonfanti, Guido Candotti, Moreno Dindelli, Stefano Ferrari, Maria Pia Guarneri, Stefania Luchini, Massimo Origoni* Pediatrics and neonatology HEAD OF UNIT: Giuseppe Chiumello* CLINICAL UNIT LEADERS: Graziano Barera, Franco Meschi, Gianni Russo, Giovanna Weber* PHYSICIANS: Riccardo Bonfanti, Laura Bosio, Stefania Di Candia, Margherita Franco, Maria Pia Guarneri, Karen Marenzi, Marta Odoni, Antonella Poloniato, Gabriella Pozzobon, Rosanna Rovelli, Paola Sgaramella, Maria Cristina Vigone, Matteo Viscardi RESEARCHER: Stefano Mora RESIDENTS: Valentina Biffi, Maddalena Bove, Maria Francesca Brambillasca, Giuseppe Cannalire, Valeria Cerioni, Ilaria Colombo, Francesca Cortinovis, Stefania Ferrari, Matilde Ferrario, Gisella Garbetta, Alessandra Giardelli, Stefano Giardino, Cristina Lui, Emilio Palumbo, Barbara Parma, Arianna Passoni, Alessandra Perduca, Maria Antonietta Piscopo, Marco Pitea, Andrea Rigamonti, Elisa Rizzato, Elisa Letizia Sabbioni, Raed Suliman Salmi Selmi, Paola Sogno Valin, Maria Cristina Villa FELLOWS: Maria Puzzovio, Ilaria Zamproni Gynaecology and obstetrics HEAD OF UNIT: Augusto Ferrari* CLINICAL UNIT LEADERS: Claudio Brigante, Maria Teresa Castiglioni, Enrico Conti, Giorgia Mangili, Daniele Spagnolo, Luca Valsecchi, Riccardo Viganò CLINICAL UNIT COORDINATOR: Francesco Fusi PHYSICIANS: Ferdinando Bombelli, Guido Candotti, Anna Cardani, Gabriella Colombo, Moreno Dindelli, Davide Ferrari, Stefano Ferrari, Luca Gandini, Elisabetta Garavaglia, Stefania Luchini, Guido Marelli, Elena Marsiglio, Micaela Petrone, Maria Teresa Potenza, Emanuela Rabaiotti, Susanna Rosa, Maddalena Smid RESEARCHER: Massimo Origoni* CONSULTANTS: Giada Almirante, Luigi Caputo, Paolo Cavoretto, Raffaella Chionna, Patrizia De Marzi, Rossana Favia, Susanna Filippis, Paolo Giardina, Michela Molgora, Nicoletta Panacci, Enrico Papaleo, Massimo Pileri, Simone Rofena RESIDENTS: Francesca Di Sebastiano, Dania Gambini, Cinzia Gentile, Serena Montoli, Federica Pasi, Paola Persico, Serena Pirola, Chiara Stefani Pediatric immuno-hematology Unit HEAD OF UNIT: Maria Grazia Roncarolo* CLINICAL UNIT LEADER: Sarah Marktel PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Alessandra Biffi, Barbara Cappelli, Robert Chiesa RESIDENTS: Erika Biral, Costanza Evangelio, Valentina Finizio, Marco Fossati, Ilaria Frugnoli, Anna Noè CHARGE NURSE: Clara Soliman RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi * Professor at: Università Vita-Salute San Raffaele The obstetrical outpatient management focuses on the clinical control of physiological and pathological pregnancies, with particular attention to gestational and pre-gestational diabetes, hypertension, autoimmune diseases, thrombophilia and recurrent abortion. In 2008, 3300 outpatient evaluations have been performed. A complementary first and second level ultrasound service and prenatal diagnosis is available, with nearly 3600 examinations performed in 2008. The obstetrical inpatient activities are mostly dedicated to delivery assistance (in 2008, 1910 deliveries) of which 66% are vaginal deliveries and 34% CLINICAL DEPARTMENTS - 177 caesarean sections. The obstetrical admissions for medical complications of pregnancy represent less than 10% of total admissions underlining the predominant outpatient management of high risk pregnancies. Other activities include Day surgery procedures, conservative and demolitive laparotomy, laparoscopy, vaginal surgery, and surgical treatment of urogenital prolapse and stress incontinence. Diagnosis, radical surgery, and chemotherapy for genital tumors, treatment for trophoblastic diseases, and diagnostic/operative hysteroscopy are also performed. Infertile couples are managed with the most advanced treatments and assisted reproduction techniques such as intra uterine inseminaGiuseppe Chiumello tion (IUI), in vitro fertilization & embryo transfer (IVF), and intra cytoplasmic sperm Injection (ICSI) with fresh or frozen-thawed ejaculated semen or spermatozoa from surgically retrieved testicles. The activities concerning pediatric emergencies mainly involve general pediatric diseases. Particular attention is also given to the collaboration with the family paediatrician. Neonatal care is inspired by the most modern criteria of assistance for healthy newborns, and particular importance is given to the relationship between the mother and the newborn. Specialized assistance is provided to both premature and unhealthy newborns. Approximately 700 patients with congenital hypothyroidism are followed by an integrated multidisciplinary approach involving the pediatric endocrinologist and neuropsychologist. More than 750 cases of Type 1 Diabetes Mellitus are currently followed and 80 patients are newly diagnosed each year, representing one of the broadest case records in Italy and Europe. Particular focus is given to diabetes self-management education. A global therapeutic approach is followed in collaboration with psychologists and social workers, also involving family and school environments. The management of Willi-Prader Syndrome involves a medical-psychological evaluation, close relationship with the family and motor-skills intervention, all of which have determined improvements in the prognosis of this disease. The case records of children with genital ambiguity is the greatest in Italy, and its management includes a collaboration with surgeons and psychologists. The number of patients with GH disorders under growth hormone treatment is one of the greatest in Italy. Other main fields are bone diseases and hyperinsulinemic hypoglicemia. The department closely cooperates with parent associations which actively participate in organizing support and educational activities. The field of immunohematology is dedicated to the diagnosis and cure of children with immunological, hematological diseases and other genetic disorders. In this context children are offered in addition to standard care also experimental therapeutic options, among these cellular therapy and gene therapy. From 2005 in partnership with the Mediterranean Institute of Hematology, programs for research, diagnosis and cure of blood disorders in patients from Mediterranean countries have been developed. This partnership allowed 64 children affected by beta thalassemia from Syria, Lebanon, Palestine, Iraq, Jordan and Egypt to receive allogeneic bone marrow transplantation. The clinical activity of HSR-TIGET with focus on the pathogenesis and therapy for genetic diseases, with particular regards to primary immunodeficiencies and autoimmune diseases with known or unknown genetic defects are being hosted. Clinical studies for gene therapy of pediatric genetic diseases are ongoing (ADA-SCID) or in preparation (Wiskott-Aldrich Syndrome, Metachromatic Leukodystrophy, Thalassemia). Finally, a cell therapy clinical study for Duchenne muscular dystrophy is being implemented. Giuseppe Chiumello 178 - SAN RAFFAELE SCIENTIFIC INSTITUTE DEPARTMENT OF INTERNAL AND SPECIALISTIC MEDICINE Head of Department: Emanuele Bosi* DEPARTMENT AREA COORDINATORS: Giselda Colombo, Matteo Rocco Pastore, Moreno Tresoldi General medicine, diabetes, endocrinology and metabolic diseases HEAD OF UNIT: Emanuele Bosi* CLINICAL UNIT LEADERS: Luca Falqui, Gabriella Galimberti, Roberto Lanzi, Matteo Rocco Pastore, Piermarco Piatti CLINICAL UNIT COORDINATOR: Marco Federico Manzoni PHYSICIANS: Alberto Davalli, Sabina Martinenghi (till July), Maria Grazia Perfetti, Alessandro Saibene, Maurizio Storti RESIDENTS: Chiara Cappelletti, Valentina Crippa, Valentina Doria, Ilaria Formenti, Manuela Fortunato, Giulia Franchi, Claudia Guerra, Andrea Laurenzi, Pietro Lucotti, Sara Madaschi, Laura Molteni, Francesca Perticone, Cecilia Piani, Elena Peretti, Maria Grazia Radaelli, Alessandro Rossini, Annachiara Uccellatore NUTRITIONIST: Monica Marchi Clinical transplantation HEAD OF UNIT: Antonio Secchi* CLINICAL UNIT LEADERS: Rossana Caldara, Paola Maffi PHYSICIANS: Sabina Martinenghi (from July) CONSULTANTS: Francesca De Taddeo, Chiara Gremizzi, Rosa Pedale RESIDENTS: Alessandra Petrelli, Andrea Vergani General medicine, clinical immunology and rheumatology HEAD OF UNIT: Maria Grazia Sabbadini* CLINICAL UNIT LEADERS: Giselda Colombo, Luisa Praderio, Moreno Tresoldi PHYSICIANS: Enrica P. Bozzolo, Lorenzo Dagna, Massimo Memoli, Chiara Salmaggi, Nicoletta Saporiti, Raffaella Scotti, Magda Vecellio CONSULTANTS: Elena Baldissera, Teresa D’Aliberti, Stefano Franchini, Mona-Rita Yacoub, Patrizia Tanina Aiello RESIDENTS: Mattia Baldini, Emmanuel della Torre, Barbara Guglielmi, Alessandro Marinosci, Francesca Motta, Fulvio Salvo, Mirta Tiraboschi Nephrology and dialysis HEAD OF UNIT: Donatella Spotti CLINICAL UNIT LEADERS: Giorgio Slaviero, Giuseppe Vezzoli PHYSICIANS: : Teresa Arcidiacono, Chiara Lanzani, Marco Melandri, Luisa Persichini, Rita Quartagno, Maria Teresa Sciarrone Alibrandi, Paola Stella RESIDENTS: Giovanna Bonavida, Maria Bracale, Vera Paloschi, Marialuisa Querques, Francesco Rainone, Marco Simonini, Cristina Tantardini * Professor at: Università Vita-Salute San Raffaele CLINICAL DEPARTMENTS - 179 The Department of Internal Medicine is composed of four inpatient Clinical Units and many Outpatient Clinics and Services covering General Medicine and the medical specialties of Allergology, Clinical Immunology, Clinical Transplantation, Diabetes, Dialysis, Endocrinology, Hypertension, Metabolic Diseases, Nephrology, Nutrition and Rheumatology. Moreover, the Department of Internal Medicine works in close interaction with the Emergency Department, representing the main structure for hospitalization of patients presenting at the Emergency Medicine. Within the Department, physicians, nurses, technicians, students and volunteers are Emanuele Bosi dedicated to the compassionate practice of medicine, with a continuum of care encompassing preventive medicine, acute care, palliative therapies and rehabilitation. The objective of the Department is to integrate clinical care, research and education with the aim of assisting patients at the best of current medical knowledge and technological expertise. Integration between clinical care and research is a general theme across the Department, with some important projects of translational medicine in the fields of islet transplantation and immunotherapies of type 1 diabetes and other autoimmune diseases. The Department is embedded in a remarkable clinical and scientific environment at San Raffaele, which offers unique opportunities for interdisciplinary collaboration and translational research. The Department of Internal Medicine offers a complete range of teaching for students at the Medical School and hosts the Post Graduate Medical Schools of Allergology and Clinical Immunology, Endocrinology, Nephrology and Emergency Medicine. The scientific production by physicians and clinical investigators from the Department is remarkable, with internationally recognized areas of excellence in clinical immunology, diabetes and metabolism, hypertension, islet and pancreas transplantation. Emanuele Bosi 180 - SAN RAFFAELE SCIENTIFIC INSTITUTE DEPARTMENT OF CLINICAL NEUROSCIENCE Head of Department: Enrico Smeraldi* DEPARTMENT AREA COORDINATORS: Barbara Barbini, Francesco Benedetti, Maria Cristina Cavallini, Andrea Fossati*, Ernestina Politi, Paolo Ronchi General psychiatry HEAD OF UNIT: Enrico Smeraldi* CLINICAL UNIT LEADERS: Roberto Cavallaro, Marco Locatelli PHYSICIANS: Sara Angelone, Laura Bianchi, Mirella Brunetta, Michele Cucchi, Ernestina Politi, Adriana Pontiggia, Paolo Ronchi, Laura Sforzini, Francesca Siliprandi RESIDENTS: Marta Bosia, Eugenia Fauci, Chiara Insacco, Laura Liperi, Fausto Panigada, Chiara Ruffini TECHNICIANS: Simona Anselmetti, Margherita Bechi, Elena Ermoli, Francesco Fresi, Alessia Santoro Clinical health psychology HEAD OF UNIT: Lucio Sarno* PSYCHOLOGISTS: Valentina Di Mattei, Claudia Finocchiaro, Samantha Gabrielli, Serena Giuliani, Carola Iris Ferrari, Rita Milesi, Chiara Motta, Liliana Novella, Valentina Nuzzaci, Gianluca Palermo, Valeria Pezzani, Alissia Pistarà, Alessandra Pradella, Maria Monica Ratti, Camilla Testa, Laura Tirloni, Silvana Villa RESIDENTS: Stefano Clerici Clinical psychology and psychotherapy HEAD OF UNIT: Cesare Maffei* CLINICAL UNIT LEADERS: Mariagrazia Movalli, Laura Vanzulli CLINICAL UNIT COORDINATOR: Raffaele Visintini PHYSICIANS: Marco Battaglia*, Andrea Fossati* CONSULTANTS: Francesca Biondini, Serena Borroni, Raffaella Braga, Valentina Bregani, Paola Broggi, Elena Campanini, Ilaria Carretta, Paolo Casati, Elisabetta Cattaneo, Rosaria Devoti, Michela Donini, Marina Fiore, Sara Gaietta, Salvatore La Viola, Gema Moelia Moreno Granados, Anna Ogliari*, Alessandro Pieri, Sergio Premoli, Roberto Vanni, Daniele Villa RESIDENTS: Ilaria Aina, Roberta Alesiani, Silvia Boccalon, Alessandra Bosaia, Naima Coppolino, Cinzia Facchi, Maria Chiara Fiorin§, Gianluca Franciosi, Roberta Gallese, Laura Giarolli, Valeria Parlatini, Paola Pesenti Gritti§, Caterina Antonia Eloisa Rocco di Torrepadula, Erica Rossi, Chiara Spatola§, Martina Testa, Annalisa Zanoni § External residents Eating disorders HEAD OF UNIT: Laura Bellodi* CLINICAL UNIT LEADERS: Stefano Erzegovesi, Giampaolo Perna CLINICAL UNIT COORDINATORS: Marco Catalano, Giuseppina Diaferia, Paolo Cavedini PHYSICIANS: Cinzia Arancio, Silvia Cocchi, Daniela Di Molfetta, Angela Gabriele RESEARCHERS: Angelo Bertani, Daniela Caldirola, Maria Cristina Cavallini RESIDENT: Claudia Zorzi FELLOWS: Clementina Baraldi, Elisa Galimberti, Monica Piccinni, Giuliana Salomoni Mood disorders HEAD OF UNIT: Cristina Colombo CLINICAL UNIT LEADERS: Linda Franchini, Adelio Lucca, Raffaella Zanardi PHYSICIANS: Barbara Barbini, Francesco Benedetti, Fanny Bongiorno, Euridice Campori, Mara Cigala Fulgosi, Sara Dallaspezia, Danilo Dotoli, David Rossini CLINICAL DEPARTMENTS - 181 Neurology HEAD OF UNIT: Stefano F. Cappa* CLINICAL UNIT LEADER: Sandro Iannaccone CLINICAL UNIT COORDINATOR: Marco Zucconi PHYSICIANS: Luca Bernasconi, Maria Cristina Giusti, Valeria Golzi, Alessandra Marcone, Barbara Sferrazza, Michele Zamboni RESEARCHERS: Jubin Abutalebi*, Nicola Canessa, Eleonora Catricalà, Pasquale Della Rosa PSYCHOLOGISTS: Valentina Esposito, Paola Frasson, Elena Farina, Valeria Ginex * Professor at: Università Vita-Salute San Raffaele The first and main committment of the Department is to define and to develop a common guideline for the clinical approach to the different aspects of behavioural disorders, according to the funding principles of our Institution, in order to overcome the strict meaning of each symptom, to adequately consider the nature and the whole of the individual suffering. Enrico Smeraldi The public psychiatric structure is based on the model of Mental Health Department (DSM). Our department, in its psychiatric and psychological component, is based on long term therapeutical assistance, hence resembling DSM and their mode of function, but it differs from DSM in its objectives. In DSM, the main aim is to take care of the mental health of a community (differently defined) and it must be addressed to it in terms of prevention too. Treating patients in SPDC and CPS is a newly introduced option which can be considered also as a therapy in social environment (= territory, in the language of social psychiatry), that will be useful and produce mental health. On the other hand, the activity of our Department is mainly focused on the individual suffering and is addressed to the patient: the possible interest for the environment in which he lives or for his relationships is only aimed at improving assistance and theraeutical approach to the patient, who freely chooses our structure instead of the public one, even if located in his territory. The relationship between these two types of Psychiatric Departments has not yet been established and we are trying to find a different model of assistance according to the psychopathological “quality” of each disease. Another innovative feature is to put together in the same Department cognitive neurology and psychiatry, since behavioural disorders are frequent and common and the same therapeutical principles can be applied. In 2008, the number of patients discharged from the Department has been 3.111, with a mean hospital stay of 19,1 days and a subsequent employment rate of 91,72%. As regards the outpatient activity, the final balance 2008 was 70.381 consults, corresponding to a turnover of eur 2.981.836,00 Moreover, the activity of the Daily Center has to be considered: 456 consults, for a turnover of eur 55.719,00 The profit and loss statement of the Department realizes a total turnover of 18.676.000 with a first contribution margin of 29,64 and a gross margin of 42,32. Enrico Smeraldi 182 - SAN RAFFAELE SCIENTIFIC INSTITUTE DEPARTMENT OF NEUROLOGY Head of Department: Giancarlo Comi* CLINICAL UNIT LEADERS: Mauro Comola, Ubaldo Del Carro, Vittorio Martinelli, Fabio Minicucci DISEASE UNIT COORDINATORS: Bruno Colombo, Raffaella Fazio, Giuseppe Magnani, Paolo Marchettini, Vittorio Martinelli, Maria Antonietta Volontè, Maria Sessa, Giulio Truci, Letizia Leocani PHYSICIANS: Stefano Amadio, Francesco Corea, Giovanna Franca Fanelli, Roberta Guerriero, Fabio Formaglio, Silvia Mammi, Filippo Martinelli-Boneschi, Stefania Medaglini, Lucia Moiola, Antonella Poggi, Mariaemma Rodegher, Paolo Rossi, Luisa Roveri, Marina Scarlato RESIDENTS: Martina Absinta, Marco Bacigaluppi, Beatrice Benedetti, Mariangela Bianco, Sebastiano Bucello, Calogera Butera, Francesca Caso, Daniela Ceppi, Federica Cerri, Raffaella Chieffo, Dacia Dalla Libera, Donatella De Feo, Luisa De Toni Franceschini, Francesca Fumagalli, Sebastiano Galantucci, Chiara Ghidinelli, Elda Judica, Sara La Gioia, Ignazio Diego Lopez, Maria Merello, Giulia Pavan, Elisabetta Stefania Perego, Luca Peruzzotti Jametti, Francesco Peschechera, Annalisa Rizzo, Eliana Schiatti, Francesca Spagnolo, Laura Straffi, Habtom Tesfaghebriel, Daniela Ungaro, Chiara Vismara * Professor at: Università Vita-Salute San Raffaele The Department of Neurology consists of the Neurology Unit (45 beds), the Neurorehabilitation Unit (42 beds), the laboratory of Clinical Neurophysiology and the Neuropsychology Service. The out patient area, day hospital service and the Centres for Epilepsy, Multiple Sclerosis, Headache, Pain, ALS and Multiple Sclerosis are the other activity characterising the Department. Clinical activities are organized in disease units in order to provide patients an integrated assistance going from the diagnostic aspects Giancarlo Comi to the advanced therapeutic interventions, including rehabilitation. The Department of Neurology is mostly qualified for advanced treatment strategies in inflammatory diseases of the Central and Peripheral Nervous System, stroke, neurodegenerative disorders, acting in strict interaction with the Institute of Experimental Neurology. A large number of phase I-IV clinical trials performed in co-operation with pharmaceutical industries and generated by the Department itself make it possible to provide patients with more advanced therapeutic strategies. Points of excellence of the clinical research are etiologic and symptomatic treatment of multiple sclerosis, epidemiological studies on multiple sclerosis, and the evaluation of the disease pathogenesis and pathophysiology. Ischemic stroke researches are focused on the risk factors for the occurrence in young adults and on the organisational aspect of the early intervention. Studies on dementia are conducted in co-operation with Imaging and clinical neurophysiology laboratories and aims to define biomarkers specific for dementia subtypes and to assess the risk for evolution to Alzheimer Disease in patients with minimal cognitive impairment. In Amyotrophic Lateral Sclerosis the contribution of instrumental test to the early diagnosis, the characterisation of cognitive dysfunction, the assessment of the value of new treatments are the key research activities. The recovery medicine is one of the more recent area of research activated in the Department, because of the possibility to follow neurological dysfunctions due to acute central nervous system lesions, from the onset to the recovery phase. The impact of various therapeutic strategies to enhance recovery, the functional and molecular bases underlying brain plasticity after acute damage with imaging and neurophysiological examinations are deeply investigated. Giancarlo Comi CLINICAL DEPARTMENTS - 183 DEPARTMENT OF ONCOLOGY Head of Department: Federico Caligaris-Cappio* DEPARTMENT AREA COORDINATORS: Gianni Bordogna, Gianfranco Ciboddo, Consuelo Corti, Andrès Jose Maria Ferreri, Michele Reni Internal medicine HEAD OF UNIT: Federico Caligaris-Cappio* CLINICAL UNIT LEADERS: Marco Foppoli, Giovanna Petrella CLINICAL UNIT COORDINATOR: Aurelio Vicari PHYSICIANS: Gianfranco Ciboddo, Giovanni Citterio, Manuela Pacchioni RESIDENTS: Giovanni Donadoni, Giada Licata, Chiara Miggiano, Federica Pozzi, Gilda Rossoni, Irene Vandoni, Chiara Francesca Verona, Angela Zanoni Haematology and bone marrow transplantation HEAD OF UNIT: Fabio Ciceri CLINICAL UNIT LEADERS: Massimo Bernardi, Consuelo Corti, Jacopo Peccatori PHYSICIANS: Andrea Assanelli, Lionello Camba, Matteo Carrabba, Elena Guggiari, Francesca Lunghi, Magda Marcatti, Maria Teresa Lupo Stanghellini Medical oncology HEAD OF UNIT: Eugenio Villa CLINICAL UNIT LEADERS: Daniela Aldrighetti, Monica Ronzoni PHYSICIANS: Gianni Bordogna, Andrés Jose Maria Ferreri, Vanesa Gregorc, Elena Mazza, Michele Reni, Giordano Pietro Vitali, Patrizia Zucchinelli CONSULTANTS: Carmen Belli, Stefano Cereda, Monica Giovannini, Vincenzo Ricci, Alessia Rognone, Maria Grazia Viganò Nuclear medicine HEAD OF UNIT: Luigi Gianolli CLINICAL UNIT COORDINATOR: Daniela Perani* RESEARCHERS: Sara Belloli, Valentino Bettinardi, Assunta Carpinelli, Isabella Castiglioni, Elisa Galli, Maria Carla Gilardi, Adelmo Grimaldi, Valeria Masiello,Mario Matarrese, Maria Grazia Minotti, Rosa Maria Moresco, Maria Picchio, Marco Rigamonti, Annarita Savi, Paola Scifo, Marco Tettamanti, Sergio Todde, Elia Anna Turolla PHYSICIANS: Carla Canevari, Flaviano Dosio, Federico Fallanca, Claudio Landoni, Patrizia Magnani, Ursola Pajoro, Andrea Panzacchi, Gino Pepe, Ana Maria Samanes Gajate, Paola Todeschini, Giovanna Vanoli CONSULTANTS: Mark Anthony Aquilina, Elena Busnardo, Rosella Collivasone, Giampiero Giovacchini, Pietro Spagnolo RESIDENTS: Cinzia Crivellaro, Giuseppe Di Pisa, Anna Giudice, Rita Garcia Parra, Paola Mapelli, Annalisa Pepe, Maria Antonia Rimicci, Elena Spinapolice, Vincenzo Tripoli FELLOWS: Manuela Giglio, Eugenio Rapisarda PHD STUDENTS: Francesca Gallivanone, Cristina Monterisi TECHNICIANS: Matteo Barbagli, Luca Brioschi, Maurizio Carenzi, Patrizia Cerè, Antonia Compierchio, Paola Cordisco, Valeria Crippa, Silvia Debbia, Andrea Fabro, Davide Gatti, Vincenzo Giori, Paola Lanzoni, Stefania Longari, Claudia Francesca Maddé, Claudio Mannu, Raffaele Menichini, Felice Neutro, Giacomo Orlandi, Massimiliano Papagni, Jacopo Perego, Carlo Pizzamiglio, Riccardo Rigamonti, Sabrina Riolo, Silvana Romano, Simone Rossi, Lucia Rozza, Pasquale Simonelli, Stefano Stucchi, Francesco Sudati, Mauro Vaghi, Raffaele Vannulli Radiotherapy HEAD OF UNIT: Nadia Di Muzio CLINICAL UNIT LEADER: Angelo Bolognesi PHYSICIANS: Fodor Andrei, Saverio Beatrice, Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Italo Dell’Oca, Micaela Motta, Marcella Pasetti, Paolo Passoni, Stefano Schipani RESIDENT: Filippo Alongi TECHNICIANS: Fabio Baratto, Nietta Barricella, Roberta Bin, Rita Calaciura, Alessandro Capelli, Alberta De Leonardis, Letizia Erre, Caterina Fiordelisi, Laura Longoni, Marilena Martulano, Lidio Palumbo, Diana Parutto, Vincenzo Sacco, Giovannella Salvadori, Andrea Sbalchiero, Simone Selli, Antonella Soccio, Marco Spagnuolo, Alessandro Tavilla * Professor at: Università Vita-Salute San Raffaele 184 - SAN RAFFAELE SCIENTIFIC INSTITUTE The general aims of the Department of Oncology are the optimization of care and the acceleration of cure. The specific aims are: 1) to rationalize clinical activity with the purpose of maintaining/reaching the state of the art in all the different types of cancer; 2) to improve logistic and organization thereby ameliorating the arrangement of patient care; 3) to expand and strengthen research in the field of oncology with the instruments of Translational Research and an interdisciplinary approach: this aim foresees the establishment of a Clinical Trial Unit essentially devoted to Phase I and Phase II clinical trials; 4) to join efforts with the Division of Molecular OncolFederico Caligaris-Cappio ogy to create a network organization, multidisciplinary teams and defined programmes for different tumours. The Department includes the Division of Medicine 1Q, the Division of Hematology and Bone Marrow Transplantation, the Unit of Medical Oncology, the Unit of Radiotherapy and the Unit of Nuclear Medicine. The number of beds is 63, the personnel amounts to 193 people; there are both a management coordinator and a nurse coordinator. In the year 2008 the overall number of cancer patients the Department has taken care of, including both patients admitted to the wards as well as patients followed in the Day Hospital or as outpatients, is about 4500. The Department cultural organization follows the Disease Unit model and is based upon a fruitful interaction with other Departments involved in the field of Oncology such as the Departments of Surgery, Head and Neck and Imaging. The active Disease Units are Lymphoid, Lung, Pancreas, Breast, Head and Neck, GastroIntestinal, Melanoma, NeuroOncology, Genito-Urinary and Gynecological Oncology. In 2008 the Departmental Area of Lymphoid Tumors has been established with 25 ongoing clinical trials (HSR is the coordinating center of 11). In the same year the Bone Marrow Transplantation Unit has ranked among the firsts in Italy as for the number of allogeneic transplantations performed. Overall in the year 2008 more than 50 clinical trials have been at hand including numerous Phase I and Phase II trials. Blood, lung, pancreas and brain tumors are the Areas where the Department is especially active, not to mention the urological cancers in collaboration with the Department of Urology. The Department has become member of the European Organization of Cancer Centers (OECI), the Southern Europe for New Drugs Organization (SENDO), the Swiss Group for Clinical Cancer Research (SAKK), the CLL US/Europe Alliance Organization (driven by the MD Anderson Cancer Center) and is also member of the Network Italiano BioImmunoterapia dei Tumori (NIBIT) and of the Italian Melanoma Intergroup. The currently ongoing research takes advantage of basic, translational and clinical research projects. We are building up teams of laboratory-based and clinical investigators with the aim of defining molecular endpoints in clinical material and use them to develop studies on the pathobiology and pathogenesis of specific tumors and to organize pilot studies and investigator-driven clinical trials. On these basis the currently ongoing projects can be summarized under three main headings: 1) Molecular mechanisms of disease, one example being the notion that a number of infectious agents are associated with the development of specific types of cancer; 2) New diagnostic and prognostic approaches to define new tools and new biologically-based prognostic and predictive markers, one example being the validation of a number of new markers with proteomic technologies; 3) New treatment strategies to develop new approaches and novel treatments by increasing Phase I and I-II studies and by clinically translating the results of HSRbased preclinical investigations, examples being immunotherapy, anti-angiogenesis-based treatments and the use of tomotherapy in specific types of cancer. Federico Caligaris-Cappio CLINICAL DEPARTMENTS - 185 DEPARTMENT OF RADIOLOGY Head of Department: Alessandro Del Maschio* DEPARTMENT AREA COORDINATORS: Francesco De Cobelli, Maurizia Del Maschio, Roberto Nicoletti, Pierluigi Paesano Radiology HSR HEAD OF UNIT: Alessandro del Maschio* CLINICAL UNIT LEADERS: Francesco De Cobelli, Maurizia Del Maschio, Roberto Nicoletti, Pierluigi Paesano, Pietro Panizza, Massimo Venturini PHYSICIANS: Laura Brasca, Stefano Cappio, Giulia Maria Crespi, Angela De Gaspari, Elda Garuti, Domenico Ghio, Simone Gusmini, Carlo Martinenghi, Renata Mellone, Maria Grazia Rodighiero, Marco Salvioni, Simona Irma Tacchini, Roberto Varagona CONSULTANTS: Marina Benveniste, Roberta Carpanelli, Elena Contrino, Antonio Esposito, Claudio Losio Radiology HSRT HEAD OF UNIT: Giuseppe Balconi CLINICAL UNIT LEADER: Gianpiero Cardone PHYSICIANS: Francesca Di Sebastiano, Rossana Favia, Cristiana Iabichino, Roberto Lanzi, Paolo Mandelli TECHNICIANS: Cecilia Bertocchi, Enza Galvano, Caterina Parolo, Alessandra Poggi, Maria Pia Rapallo, Stefano Rovani * Professor at: Università Vita-Salute San Raffaele The Global Activity of the Clinical Department of radiology includes 166.137, diagnostic and interventional procedures (including emergency) per year. The Department includes six sections: 1. Conventional and Digital Radiology 2. Breast Imaging 3. Ultrasound 4. Computed Tomography 5. Magnetic Resonance Imaging and Spectroscopy 6. Diagnostic and Interventional Radiology/Angiography Alessandro Del Maschio Moreover we developed many collaborations with internal and external groups, in particular: • with the Section of Nutrition/Metabolism and the Faculty of Exercise Sciences, Università degli Studi di Milano with Prof. Perseghin and Prof. Luzi it has been developed a tight cooperation on Magnetic resonance spectroscopy of the heart and of the liver in order to evaluate the functional and metabolic effects of physical exercise and pathological conditions such as diabetes, obesity or cardiomyopathies; • with the group of Prof. Manfredi, a non-invasive MR based method for in-vivo cellular tracking has been developed and applied to follow the dendritic cells (DCs) in tumor bearing mice, allowing to investigate the critical aspects of DCs migration to establish an immune mediated cancer therapy; • with the group of Dr. Malosio in the setting of the DRI, a similar approach for cells labelling and imaging was also used to follow the pancreatic islets fate, after their transplantation in mouse model of type 1 diabetes; 186 - SAN RAFFAELE SCIENTIFIC INSTITUTE • with the Unit of Radiation Therapy and Medical Physics of Dr. Di Muzio and Dr. Calandrino we sought to implement the radiotherapy planning by new imaging-techniques. We have use different imaging technique as MRI and contrast enhanced 4D-CT to improve target volume definition in prostate cancer and in pancreatic ductal adenocarcinoma; • with the Transplant Unit of Prof. Secchi and Dr. Maffi we studied the metabolic effects in type 1 diabetic patients who have undergone kidney or combined kidney-pancreas transplantation or islet-transplantation with different imaging or spectroscopic approaches. • with the Department of Mechanics, Politecnico di Torino, with the Department of Bioengineering, Politecnico di Milano, with the Istituto di Bioimmagini e Fisiologia Molecolare, Research National Council, Milan in order to develop a method for quantifying helical flow in vivo employing time-resolved cine phase contrast magnetic resonance imaging to obtain the complete spatio-temporal description of the three-dimensional pulsatile blood flow patterns in aorta. Alessandro Del Maschio CLINICAL DEPARTMENTS - 187 DEPARTMENT OF UROLOGY Head of Department: Patrizio Rigatti* DEPARTMENT AREA COORDINATORS: Roberto Bertini, Luigi Broglia, Andrea Cestari, Valerio Di Girolamo, Francesco Montorsi*, Luciano Nava,Vincenzo Scattoni Urology HSR HEAD OF UNIT: Patrizio Rigatti* CLINICAL UNIT COORDINATORS: Roberto Bertini, Renzo Colombo, Andrea Salonia PHYSICIANS: Alberto Briganti, Lina Bua, Andrea Gallina, Massimo Ghezzi, Caterina Lania, Arianna Lesma, Marco Raber, Marco Roscigno, Vincenzo Scattoni, Nazareno Suardi,Giuseppe Zanni RESIDENTS: Abdollah Firas, Diego Angiolilli, Marco Bianchi, Tommaso Camerota, Umberto Capitanio, Dario Di Trapani, Matteo Ferrari, Andrea Gallina, Salvatore Grimaldi, Carmen Maccagnano, Federico Pellucchi, Giovanni Petralia, Lorenzo Rocchini, Antonino Saccà, Francesco Sozzi, Elena Strada, Manuela Tutolo Urological endoscopy service and day surgery HEAD OF UNIT: Valerio Di Girolamo Strategic program for Urology HEAD OF UNIT: Francesco Montorsi* Urology HSRT HEAD OF UNIT: Giorgio Guazzoni* CLINICAL UNIT LEADERS: Piera Bellinzoni, Luciano Nava PHYSICIANS: Luigi Broglia, Antonia Centemero, Andrea Cestari, Andrea Losa, Tommaso Maga CONSULTANTS: Nicolò Maria Buffi, Fabio Fabbri, Lorenzo Rigatti, Mattia Sangalli, Emanuele Scapaticci, Matteo Zanoni RESIDENT: Giovanni Lughezzani The Department of Urology, Vita-Salute San Raffaele, Milan, headed by Professor Patrizio Rigatti, represents one of the most important International institutions for the diagnosis and the treatment of urological malignancies. The Department takes account weekly of 25 operating rooms, serving 110 beds for ordinary recovery. Every year, about 1000, 500 and 250 surgeries are performed for prostate, bladder and kidney cancer, respectively. The clinical investigations performed in the last years leaded to the publication of 571 scientific contributions for a overall citation index of 5503 with a significant boost in the last three years (citation index last three years: 2262; h index 37) [Source SCOPUS January 2009]. Every year, the Department substantially contributes with a significant numPatrizio Rigatti ber of accepted abstracts to the most important international and national meetings. The main research areas consist of prostate cancer, kidney cancer, bladder cancer, infertility and andrology, female sexual medicine, benign prostatic hyperplasia. The clinical research relied on analyses of clinical, pathological and follow-up prospectively collected data regarding thousands of patients treated at San Raffaele Hospital. The records are collected within specific databases developed in the last years. Patrizio Rigatti 188 - SAN RAFFAELE SCIENTIFIC INSTITUTE CLINICAL SERVICES Medical physics HEAD OF UNIT: Riccardo Calandrino PHYSICISTS: Sara Broggi, Giovanni Mauro Cattaneo, Antonella Del Vecchio, Claudio Fiorino, Barbara Longobardi, Paola Mangili, Lucia Perna, Patrizia Signorotto RESEARCHER: Antonello Spinelli FELLOWS: Angelo Maggio, Veronica Ardu Pathology HEAD OF UNIT: Claudio Doglioni* CLINICAL UNIT COORDINATORS: Gianluigi Arrigoni, Massimo Freschi, Maurilio Ponzoni, Isabella Sassi, Gianluca Taccagni, Maria Rosa Terreni PHYSICIANS: Luca Albarello, Giacomo Dell’Antonio, Nathalie Rizzo RESEARCHER: Francesca Sanvito CONSULTANTS: Anna Cremonini, Graziana Famoso BIOLOGISTS: Mariagiulia Cangi, Lorenza Pecciarini POST-DOCTORAL FELLOWS: Greta Grassini, Ilenia Papa TECHNICIANS: Mara Bertolazzi, Marina Brambilla, Roberta Brambilla, Roberto Cairella, Diana Ciscato, Elena Dal Cin, Stefania Demasi, Barbara Di Ruvo, Patrizia Ferrari, Marilena Flore, Franco Galli, Stefano Grassi, Camilla Lambiente, Anna Mauri, Martina Rocchi, Graziella Santambrogio, Carlo Silva, Anna Talarico CYTOTECHNOLOGISTS: Teresa Carbone, Miriam Cosciotti, Grazia Lamonaca, Giulio Legnani, Franca Toffolo Laboratory medicine HEADS OF DIVISION: Ferruccio Ceriotti, Massimo Clementi*, Fernanda Dorigatti, Maurizio Ferrari* HEADS OF UNIT: Armando D’Angelo(#), Alberto Sanna CLINICAL UNIT LEADERS: Paola Cichero, Stefania Del Rosso, Fulvio Ferrara, Anna Maria Girardi, Massimo Locatelli, Cristina Ossi, Marina Pontillo, Sara Racca, Armando Soldarini, Laura Soldini, Silvana Viganò D’Angelo PHYSICIANS: Enzo Boeri, Luciano Crippa, Rita Daverio, Annalisa Fattorini, Nicasio Mancini, Andrea Motta, Maria Grazia Patricelli, Serena Rolla, Loredana Tomassini, Mladen Trbos. BIOLOGISTS: Elena Bazzigaluppi, Silvia Carletti Anna Carobene, Carlo Alberto Ferrero, Rossella Ieri, Rosanna Latino, Marcello Marinelli, Gabriella Passerini, Elisabetta Pattarini, Flavia Piccini, Barbara Maria Pirola, Laura Seghezzi, Barbara Sioli, Ivana Spiga, Annunziata Spina, Monica Zanussi BIOENGINEER: Davide Alessio CONSULTANTS: Pierangelo Bonini*, Emanuele Bosi*(#), Roberto Burioni*, Orsetta Zuffardi* RESEARCHERS: Paola Carrera(*), Laura Cremonesi(*), Patrizia Della Valle(#), Isabella Fermo(*), Vito Lampasona(*), Annapaola Andolfo(*) RESEARCH FELLOWS: Marco Bianchi, Luca Bolzoni, Sara Bonalumi(*), Angela Brisci(*), Francesca Bruno(*), Filippo Canducci, Davide Carcione, Emanuela Castiglioni(*), Vincenza Causarano(*), Alessio Colombo, Donata De Marco, Roberta Diotti, Silvia Galbiati(*), Stefano Gerola(*), Nadia Ghidoli, Nicola Maganetti, Maria Chiara Marinozzi, Angelica Morandi, Marco Nalin, Fabio Perotti, Nicola Perrelli, Sabina Piccinini, Monica Ramponi, Monica Sassi, Riccardo Serafin, Elena Sommariva(*), Stefania Stenirri(*), Sauro Vicini, David Williams. TECHNICIANS: Rose Mary Carletti(*), Cinzia Magagnotti(*), Michela Sanpaolo, Francesca Sanpietro(#), Nadia Soriani(*). (*) reporting to the CENTER FOR GENOMICS, BIOINFORMATICS, AND BIOSTATISTICS (#) reporting to the DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES Service of immunohematology and transfusion medicine HEAD OF UNIT: Silvano Rossini CLINICAL UNIT LEADERS: Lorena Barzizza, Laura Bellio PHYSICIANS: Cinzia Bargiggia, Alketa Bolentini, Katharina Fleischhauer, Salvatore Gattillo, Lucia Malabarba, Lilian Romero, Paola Ronchi BIOLOGISTS: Lia Parma, Oriana Perini, Cristina Tresoldi, Elisabetta Zino CHEMIST: Benedetta Mazzi TECHNICIANS: Daniela Ceresa, Silvia Corno, Luigi D’Amato, Stefania Dell’Orco, Giuseppe Di Leo, Dina Di Sciacca, Alessandra Galli, Emanuela Grioni, Maria Antonia Introini, Giuseppina Marabelli, Ilaria Mazzi, Gabriella Salomoni, Massimo Sacconi, Elisabetta Sironi, Serenesse Tomasi, Gabriele Torriani, Federica Valtorta, Matilde Zambelli, Paola Zappalalio CLINICAL DEPARTMENTS - 189 Emergency medicine HEAD OF UNIT: Michele Carlucci DIRECTOR OF EMERGENCY MEDICINE PROGRAM: Marzia Spessot CLINICAL UNIT COORDINATORS: Anna Borri, Roberto Faccincani, Maria Vittoria Lavorato, Federica Mariani PHYSICIANS: Aldo Beneduce, Pietro Bisagni, Giuseppe Capasso, Barbara Demarchi, Laura Ferrario, Federico Furlan, Giulia Gallotta, Elisa Gatti, Francesca Gavazzi, Simona Mauri, Enrico Ortolano, Annamaria Pazzi, Simona Rocchetti, Maria Vittoria Taglietti, Luca Tomaello, Valentina Tomajer RESIDENTS: Chiara Cappelletti, Federica Dilani, Carmen Forestieri, Manuela Fortunato, Matteo Frasson, Francesca Luisi, Francesco Luparini, Alessandro Marinosci, Federica Merlini, Alessandro Rossini, Simone Squillante, Roberta Varale, Veronica Zuber General intensive care HEAD OF UNIT: Alberto Zangrillo* CLINICAL UNIT COORDINATORS: Gabriele Cornaggia, Paolo Silvani Anesthesia and resuscitation HEAD OF UNIT: Luigi Beretta* CLINICAL UNIT COORDINATORS: Massimo Caldi, Daniela Giudici * Professor at: Università Vita-Salute San Raffaele 190 - SAN RAFFAELE SCIENTIFIC INSTITUTE MEDICAL PHYSICS A) Advantages of using a Helical Tomotherapy (HT): planning comparisons vs other radiotherapy (RT) delivery modalities HT is an innovative solution in RT that offers advantages in creating deep dose gradients between planning target volume (PTV) and organs at risk (OARs). Main results: • In case of prostate, head-neck and lung diseases significant advantages of using HT both in PTV coverage and in OARs sparing. • In case of prostate, HT and intensity-modulated arc therapy have been compared. The two modalities are similar with a slightly better PTV coverage obtained with HT. • For nasopharynx cancer, HT was compared with intensity-modulated proton therapy. Both modalities guarantee an excellent PTV coverage and sparing of the OARs in the high-to-medium dose range. B) Modeling toxicity in RT by correlating clinical data with dose-volume parameters (DVHs) Individual 3D DVHs may be used to model the clinically reported effects in order to define quantitative estimators of toxicity after RT. A number of investigations have been conducted on patients (PTs) treated at our and other Institutions. Important results were found for: • late rectal bleeding and acute bowel toxicity. • correlation between DVH, genes involved in DNA repair and late rectal bleeding in PTs treated for prostate cancer. • preliminary results concerning hypofractionated clinical protocols with HT in pelvis diseases. C) Treatment planning optimization by means of integrated imaging modalities The availability of multi-modal images allows: 1) a more accurate definition of the real extension of neoplastic disease and the definition of “metabolic” tumor maps; 2) a better visualization of OARs; 3) the evaluation of breathing related tumor/organ mobility; 4) the analysis of geometric uncertainties by means of daily MVCT. A number of investigations have been conducted evaluating the impact of multi-modal approach in treatment planning optimization for malignancies of different anatomical districts. D) Methods for risk evaluation in workers in Medical Cyclotron Facilities Two main items have been investigated: • the contamination of the exhausted air from the hot cells dedicated to the synthesis of PET radiopharmaceuticals. • the risk evaluation and the doses due to internal contamination. Riccardo Calandrino PATHOLOGY The Unit of Anatomy Pathology is a Clinical Service that provides surgical pathology and cytopathology activity, intraoperative consultations, post-mortem examination to the San Raffaele Hospital, performing gross and microscopic examination and interpretation of tissue specimens that include biopsies and surgical excisions. Activity Our Unit evaluated approximately 25.000 surgical and 24.000 cytologic specimens in 2008. The diversity of the specimen material reflects the specialized medical and surgical practice of San Raffaele Hospital. Pathologists with particular interest and expertise in various pathology areas (e.g., hematopathology, uropathology, neuropathology, gynecologic pathology, etc.) interpret and signout the cases that fall into the subspecialty categories. This approach ensures excellent diagnostic interpretations, enhancing collaboration with the large variety of specialized clinical services present in San Raffaele Hospital. A broad, continuously updated, array of specialized techniques is available to complement routine morphologic examination, including an ever-expanding menu of immunohistochemical stains, immunofluorescence studies, molecular pathology analyses, cell cultures, karyotyping of solid tumors and molecular cytogenetic techniques. Claudio Doglioni CLINICAL DEPARTMENTS - 191 LABORATORY MEDICINE Standardization in clinical chemistry. Two types of activities were running: the definition of reference intervals for several quantities (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatinine) and the implementation of reference methods to be applied to set target values to control materials for external quality assessment schemes and to validate and certify other field methods and routine laboratories. Microbiology and Virology. Several research lines both in microbiology and in virology. Microbiology: resistance and susceptibility to antibiotics and antifungal of bacteria and fungi; molecular diagnosis of sepsis. Virology: viruses involved in respiratory syndromes (Coronavirus, respiratory syncytial virus and viruses identified recently in infants with acute respiratory disease); molecular epidemiology and pathogenic potential of human papillomavirus; perspectives and opportunities of novel antiviral treatments targeting virus fitness; Hepatitis C virus: utilization of neutralizing human monoclonal antibodies as anti-HCV drugs; cross-reacting and neutralizing human monoclonal antibody directed against the HCV\E2 protein; Hepatitis C virus (HCV)-driven stimulation of subfamily-restricted natural IgM antibodies in mixed cryoglobulinemia; HIV-1 replication capacity and genotype changes in patients undergoing treatment interruption or lamivudine monotherapy; AntiHIV-1 Response Elicited in Rabbits by Anti-Idiotype Monoclonal Antibodies mimicking the CD4-Binding Site. Fernanda Dorigatti SERVICE OF IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE The Hospital San Raffaele (HSR) Immunohematology and Transfusion Medicine Service (ITMS) provides clinical services to support HSR patients in need of blood component therapy, cellular therapy, therapeutic apheresis, and specialized laboratory diagnostics. In addition, it collects and prepares the blood components and cellular therapy products used in patient care at the HSR, maintains an accredited Immunohematology Reference Lab, and runs a training program in Blood Banking. We strive for sustained excellence using our talents as innovators, inventors, investigators, and instructors to advance safe and effective transfusion practices, to train the leaders of tomorrow’s science, and to deliver the services and products that make creative clinical research possible. An RFID project is underway with the goal of increasing safety by implementing radiofrequency identification technology in the daily management of transfusions and transfusion products. This system is a model for process traceability from donor to patient, for automation in the identification of patients, blood units and/or cellular products. Our Mission: The mission of the San Raffaele Immunohematology and Transfusion Medicine Service is to provide high quality patient care and hospital services in support of HSR clinical research programs, to pursue research that contributes to our knowledge and practice of transfusion medicine and related technologies, and to provide advanced training in transfusion medicine. Our Goals: • To provide outstanding clinical, consultative, laboratory, and blood component manufacturing services to HSR Clinical patients or other Institutions in a way that: a) maintains the highest standards for safety and quality, b) meets the needs of the Institute for unique services and innovative approaches, and c) assures optimal utilization of resources. • To advance the practice of transfusion medicine by: a) improving the effectiveness of standard blood components, b) exploring new approaches to the use of standard components, and c) developing new cellular components, techniques, and technologies to support novel therapeutic strategies. • To improve blood safety by: a) reducing the risk of transfusion-transmitted infections, and b) minimizing non-infectious, transfusion-associated adverse reactions. • To advance the science of transfusion medicine by: a) sustaining active, innovative research programs, b) communicating new knowledge gained through research, and c) training others to carry on the pursuit of innovative research and leading edge clinical care. Silvano Rossini 192 - SAN RAFFAELE SCIENTIFIC INSTITUTE EMERGENCY MEDICINE In 2008 the Emergency Department of San Raffaele Hospital provided care for 61.809 patients. 807 of the patients triaged were given red code (that is, to be seen immediately in the resuscitation area). 8967 cases were given yellow code (that is, to be seen within 30 minutes of arrival). The largest amount of them (49.138 ) were given lower priority (green code, that means they had to be seen within 1 hour of arrival). Only 2897 (%) were given a white code (that is, patients whose conditions are not true emergencies). In 2008 we have seen 20.494 patients with medical problems, 16.812 with surgical problems and 11832 with minor trauma. 6878 children have been treated in the pediatric area. In the dedicated area for obstetrics 5835 women received treatment. 9944 patients, after initial evaluation, were admitted to different wards for further investigations and treatments. In 2008, 600 patients received surgery in the Emergency Room. Major trauma (patients with multiple injuries) is treated by a trauma team who have been trained using the principles taught in the internationally recognized Advanced Trauma Life Support course. Medical emergencies are treated as taught in the Advanced Life Support and Trauma Advanced Life Support courses. Some members of the Emergency Room staff are ALS and ATLS Instructors and such courses are regularly held in Hospital every year. Staff members received Emergency Medicine Up-to date meetings every two weeks. Università Vita e Salute medical students are trained on application of classical emergency medicine principals in a humanistic and supportive patient environment. In 2008 physicians attended the following meetings and courses: Trauma: Update and organization (Bologna, February ); 27° Congresso nazionale ACOI, (Bergamo, May); Trauma Update: Morbidity and mortality on Trauma patients (Milano, May ); Trauma Update: Il trauma grave:the days after (Rome, September); Trauma Update. Il sistema trauma: imparare dall’errore (Cesena, November ); VI Congresso nazionale SIMEU (Rimini, November); Benchmarking in Pronto Soccorso: SIMEU Lombardia (Milan, November); Antibiotici ed antifungini per le infezioni gravi (Pisa, November); XXXVI Congresso nazionale SICUT (Bari, December); Trauma Update: Incidenti stradali: dalla prevenzione alla riabilitazione (Milan, December) Michele Carlucci GENERAL INTENSIVE CARE In 2008 our General ICU admitted 491 patients, half of them for postoperative monitoring after major elective surgery. The occupational rate was 95%. We’re currently changing our admission strategy, improving the early postoperative care in the recovery room, in order to guarantee the care for hospital and territorial emergencies. In 2008 the principal critical illnesses admitted to our unit included: Trauma patients (traffic and work accidents accounting for 20% of all intensive treatments) as 2nd level hospital in Milan county. Respiratory failure (40% of intensive treatments). Primary and secondary ARDS (acute respiratory distress syndrome) are evolutions of pneumonia or systemic sepsis, especially in immune-compromised patients such as after transplantation. Cardiovascular failure or multiple organ dysfunctions (20%). Patients rescued from cardiac arrest or with severe cardiac congestive failure. Septic shock (10%), a dreadful complication after major surgery or transplantation. In our general ICU can provide a wide range of therapeutic options for the above cited pathologies, following updated international guidelines: the newest strategies in mechanical ventilation including extracorporeal life support; updated antibiotic therapy; hypothermic therapy after cardiac arrest; developments in continuous renal replacement therapy. Staff was trained to the use of echography in ICU. We also managed hospital emergencies 24 hours a day through the “medical emergency team” (MET) com- CLINICAL DEPARTMENTS - 193 posed by anesthesiologists working both in operating theatre and ICU. MET provides adult and pediatric anesthesia (in a dedicated operatory room) and critical care for non-cardiosurgical emergencies, for the Casualty Department and for critical patients treated outside the Intensive Care Units. This kind of organization allows MET to perform safely a non invasive ventilation treatment for mild or chronic respiratory failure in non intensive areas. Day shift is covered by two anesthesiologists with the supervision of a coordinator. Night shift is covered by two anesthesiologists with a supervision of a senior consultant on call. Alberto Zangrillo ANAESTHESIA AND NEUROINTENSIVE CARE UNIT Neurointensive Care is a 6 beds unit. 300 patients are admitted every year, 50% from the Casualty Department (severe head injury, stroke and subarachnoid haemorrhage) and 50% from the Neurosurgery Unit (tumor, vascular). 20 patients with brain death are treated and 12 of them become organ donors. The Head and Neck Anaesthesia Staff provides for general anaesthesia in neurosurgical, interventional neuroradiology, ENT and ophthalmic surgery for approximately 3000 cases per year and for conscious sedations in children and adults (1000 cases per year) submitted to diagnostic or therapeutic procedures in Neuroradiology. The General Anaesthesia Staff provides for anaesthesia in the Surgical Department (Gastroenterology, Haepatology, Endocrine, Pancreatic), Orthopaedics, Obstetrics and Gynaecology, Plastic Surgery (approximately 20.000 cases/per year). Outside the O.R. sedation and anaesthesia are performed for diagnostic and therapeutic interventions in Gastroenterology. A staff is dedicated to the treatment of the postoperative acute pain and chronical neoplastic pain (“Hospital without Pain” Committee). Luigi Beretta Medical physics PUBLICATIONS - 195 PUBLICATIONS PUBLICATIONS - 197 BEST PAPERS 2008 1. Gandin, V; Miluzio, A; Barbieri, AM; Beugnet, A; Kiyokawa, H; Marchisio, PC; Biffo, S. Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation. Nature: 2008; 455(7213): 684-688 - Article IF 2008: 31,434 2. Comi, G; Pulizzi, A; Rovaris, M; Abramsky, O; Arbizu, T; Boiko, A; Gold, R; Havrdova, E; Komoly, S; Selmaj, K; Sharrack, B; Filippi, M. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet: 2008; 371(9630): 2085-2092 - Article IF 2008: 28,409 3. Gargioli, C; Coletta, M; De Grandis, F; Cannata, SM; Cossu, G. PlGF-MMP-9-expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle. Nat.Med.: 2008; 14(9): 973-978 - Article IF 2008: 27,553 4. De Palma, M; Mazzieri, R; Politi, LS; Pucci, F; Zonari, E; Sitia, G; Mazzoleni, S; Moi, D; Venneri, MA; Indraccolo, S; Falini, A; Guidotti, LG; Galli, R; Naldini, L. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell: 2008; 14(4): 299-311 - Article IF 2008: 24,962 5. Ferreri, AJM; Dognini, GP; Govi, S; Crocchiolo, R; Bouzani, M; Bollinger, CR; D’Incan, M; Delaporte, E; Hamadani, M; Jardin, F; Martusewicz-Boros, M; Montanari, M; Szomor, A; Zucca, E; Cavalli, F; Ponzoni, M. Can rituximab change the usually dismal prognosis of patients with intravascular large B-cell lymphoma? J. Clin. Oncol.: 2008; 26(31): 5134 - 5136 - Letter IF 2008: 17,157 6. Caligaris-Cappio, F; Ghia, P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J. Clin. Oncol.: 2008; 26(27): 4497-4503 - Article IF 2008: 17,157 7. Malnati, MS; Scarlatti, G; Gatto, F; Salvatori, F; Cassina, G; Rutigliano, T; Volpi, R; Lusso, P. A universal real-time PCR assay for the quantification of group-M HIV-1 proviral load. Nat. Protoc.: 2008; 3(7): 1240 - 1248 Article IF 2008: 16,821 8. Monti, P; Scirpoli, M; Maffi, P; Ghidoli, N; De Taddeo, F; Bertuzzi, F; Piemonti, L; Falcone, M; Secchi, A; Bonifacio, E. 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Prevention of cardiac surgery-associated acute kidney injury. Int. J. Artif. Organs: 2008; 31(2): 179-189 - Review IF 2008: 1,299 P.708. Lapenna, E; De Bonis, M; Sorrentino, F; La Canna, G; Grimaldi, A; Torracca, L; Maisano, F; Alfieri, O. Commissural closure for the treatment of commissural mitral valve prolapse or flail. J. Heart Valve Dis.: 2008; 17(3): 261-266 - Article IF 2008: 1,112 P.709. Scotti, C; Camnasio, F; Rizzo, N; Fontana, F; De Cobelli, F; Peretti, GM; Fraschini, G. Mammary-type myofibroblastoma of popliteal fossa. Skeletal Radiol.: 2008; 37(6): 549-553 - Case Report IF 2008: 1,085 P.710. Mosam, A; Hurkchand, HP; Cassol, E; Page, T; Cassol, S; Bodasing, U; Aboobaker, J; Dawood, H; Friedland, GH; Coovadia, HM. Characteristics of HIV-1-associated Kaposi’s sarcoma among women and men in South Africa. Int. J. STD AIDS: 2008; 19(6): 400 - 405 - Article IF 2008: 1,075 P.711. Perego, GB; Landolina, M; Vergara, G; Lunati, M; Zanotto, G; Pappone, A; Lonardi, G; Speca, G; Iacopino, S; Varbaro, A; Sarkar, S; Hettrick, DA; Denaro, A. Implantable CRT device diagnostics identify patients with increased risk for heart failure hospitalization. J. Interv. Card. Electrophysiol.: 2008; 23(3): 235-242 - Article IF 2008: 1,075 PUBLICATIONS - 229 P.712. Miserocchi, E; Modorati, G; Rama, P. Effective treatment with topical cyclosporine of a child with steroid-dependent interstitial keratitis. Eur. J. Ophthalmol.: 2008; 18(5): 816-818 Article IF 2008: 1,010 P.713. Milani, P; Pierro, L; Scialdone, A. OCT-guided photodynamic therapy for angiographic occult CNV in pathologic myopia. Eur. J. Ophthalmol.: 2008; 18(5): 837-840 - Article IF 2008: 1,010 P.714. Roasio, A; Lobreglio, R; Santin, A; Landoni, G; Verdecchia, C. Fenoldopam Reduces the Incidence of Renal Replacement Therapy After Cardiac Surgery. J. Cardiothorac. Vasc. Anesth.: 2008; 22(1): 23-26 - Article IF 2008: 0,994 P.715. Landoni, G; Zangrillo, A; Fochi, O; Maj, G; Scandroglio, AM; Morelli, A; Tritapepe, L; Montorfano, M; Colombo, A. Cardiac Protection With Volatile Anesthetics in Stenting Procedures. J. Cardiothorac. Vasc. Anesth.: 2008; 22(4): 543 - 547 Article IF 2008: 0,994 P.716. Casati, V; Barbato, L; D’Angelo, A; Masotti, C; Nocera, G; Grasso, MA; Porta, A; Guerra, F. Complex Cardiac Surgery in Jehovah’s Witnesses With Chronic Renal Failure. J. Cardiothorac. Vasc. Anesth.: 2008; 22(3): 453-454 - Article IF 2008: 0,994 P.717. Landoni, G; Biondi-Zoccai, GGL; Marino, G; Bove, T; Fochi, O; Maj, G; Calabro, MG; Sheiban, I; Tumlin, JA; Ranucci, M; Zangrillo, A. Fenoldopam Reduces the Need for Renal Replacement Therapy and In-Hospital Death in Cardiovascular Surgery: A Meta-Analysis. J. Cardiothorac. Vasc. Anesth.: 2008; 22(1): 27-33 - Article IF 2008: 0,994 P.718. Porter, CR; Suardi, N; Kodama, K; Capitanio, U; Gibbons, RP; Correa, R; Jeldres, C; Perrotte, P; Montorsi, F; Karakiewicz, PI. A nomogram predicting metastatic progression after radical prostatectomy. Int. J. Urol.: 2008; 15(10): 889-894 Article IF 2008: 0,982 P.719. Sardanelli, F; Bacigalupo, L; Carbonaro, L; Esseridou, A; Giuseppetti, GM; Panizza, P; Lattanzio, V; Del Maschio, A. What is the sensitivity of mammography and dynamic MR imaging for DCIS if the whole-breast histopathology is used as a reference standard? £Radiol. Med.: 2008; 113(3): 439-451 - Article IF 2008: 0,955 P.720. Sardanelli, F; Giuseppetti, GM; Canavese, G; Cataliotti, L; Corcione, S; Cossu, E; Federico, M; Marotti, L; Martincich, L; Panizza, P; Podo, F; Rosselli Del Turco, M; Zuiani, C; Alfano, C; Bazzocchi, M; Belli, P; Bianchi, S; Cilotti, A; Calabrese, M; Carbonaro, L; Cortesi, L; Di Maggio, C; Del Maschio, A; Esseridou, A; Fausto, A; Gennaro, M; Girometti, R; Ienzi, R; Luini, A; Manoukian, S; Morassutt, S; Morrone, D; Nori, J; Orlacchio, A; Pane, F; Panzarola, P; Ponzone, R; Simonetti, G; Torricelli, P; Valeri, G. Indications for breast magnetic resonance imaging. Consensus Document “Attualita` in Senologia”, Florence 2007. Radiol. Med.: 2008; 113: 1085-1095 - Article IF 2008: 0,955 P.721. Gianotti, N; Maillard, M; Gaiera, G; Bestetti, A; Cernuschi, M; De Bona, A; Lazzarin, A; Cinque, P; Bossolasco, S. Leishmania infection can hamper immune recovery in virologically suppressed HIV-infected patients. New Microbiol.: 2008; : 435-438 - Short Communication IF 2008: 0,912 P.722. Menegazzi, P; Reho, E; Ulivi, M; Varnier, OE; Lillo, FB; Tagliaferro, L. Rapid and accurate quantification of different HCV genotypes by LightCycler Real Time PCR and direct se- quencing of HCV amplicons. New Microbiol.: 2008; 31(2): 181-187 - Article IF 2008: 0,912 P.723. Miotto, P; Piana, F; Migliori, GB; Cirillo, DM. Evaluation of the GenoCard as a tool for transport and storage of samples for tuberculosis molecular drug susceptibility testing. New Microbiol.: 2008; 31(1): 147-150 - Article IF 2008: 0,912 P.724. Tete, S; Mastrangelo, F; Scioletti, AP; Tranasi, M; Raicu, F; Paolantonio, M; Stuppia, L; Vinci, R; Gherlone, E; Ciampoli, C; Sberna, MT; Conti, P. Microarray expression profiling of human dental pulp from single subject. Clin. Invest. Med.: 2008; 31(2): E55-E61 - Article IF 2008: 0,905 P.725. Giammusso, B; Colpi, GM; Cormio, L; Ludovico, G; Soli, M; Ponchietti, R; Montorsi, F; Panzironi, C; Guastella, B. An open-label, randomized, flexible-dose, crossover study to assess the comparative efficacy and safety of sildenafil citrate and apomorphine hydrochloride in men with erectile dysfunction. Urol. Int.: 2008; 81(4): 409-415 - Article IF 2008: 0,891 P.726. Vezzoni, L; Parmiani, G. Limitations of the cancer stem cell theory. Cytotechnology: 2008; 58(1): 3-9 - Article IF 2008: 0,875 P.727. Melissano, G; Venturini, M; Baccellieri, D; Calliari, F; Del Maschio, A; Chiesa, R. Distal embolization and proximal stentgraft deployment: A dual approach to endovascular treatment of ruptured superior gluteal artery aneurysm. Tex. Heart Inst. J.: 2008; 35(1): 50-53 - Article IF 2008: 0,873 P.728. Chiesa, R; Melissano, G; Civilini, E; Bertoglio, L; Setacci, F; Baccellieri, D. Giant aneurysm: 25 Years after patch aortoplasty for aortic coarctation. Tex. Heart Inst. J.: 2008; 35(2): 220 221 - Article IF 2008: 0,873 P.729. Marioni, G; Gaio, E; Giacomelli, L; Bertolin, A; D’Alessandro, E; Stramare, R; Facco, E; Staffieri, A; Blandamura, S. MASPIN subcellular localization and expression in oral cavity squamous cell carcinoma. Eur. Arch. Oto-Rhino-Laryn.: 2008; 265(SUPPL. 1): - - Conference Paper IF 2008: 0,843 P.730. Pech, O; Petrone, MC; Manner, H; Rabenstein, T; May, A; Pohl, J; Ell, C. One-step chromoendoscopy and structure enhancement using balsamic vinegar for screening of Barrett’s esophagus. Acta Gastro-Enterol. Belg.: 2008; 71(2): 243-245 Article IF 2008: 0,832 P.731. Teggi, R; Ceserani, N; Lira Luce, F; Lazzarin, A; Bussi, M. Otoneurological findings in human immunodeficiency virus positive patients. J. Laryngol. Otol.: 2008; 122(12): 1289-1294 - Article IF 2008: 0,796 P.732. Maio, M; Fonsatti, E; Burigo, A; Parmiani, G. The Italian Network for Tumor Biotherapy (NIBIT). Sharing visions, goals and efforts at European level. Suppl. Tumori: 2008; 94(2): 179181 - Conference Paper IF 2008: 0,791 P.733. Alongi, F; Di Muzio, N; Motta, M; Broggi, S; De Martin, E; Bolognesi, A; Cattaneo, M; Calandrino, R; Fazio, F. Adenoid cystic carcinoma of trachea treated with adjuvant hypofractionated tomotherapy. Case report and literature review. Suppl. Tumori: 2008; 94(1): 121-125 - Case Reports IF 2008: 0,791 P.734. Ludovini, V; Pistola, L; Gregorc, V; Floriani, I; Rulli, E; Di Carlo, L; Semeraro, A; Daddi, G; Darwish, S; Stocchi, L; Tofanetti, FR; Bellezza, G; Sidoni, A; Tognellini, R; Crino, L; Tonato, M. Biological markers and DNA flow cytometric analysis in radically resected patients with non-small cell lung cancer. A 230 - SAN RAFFAELE SCIENTIFIC INSTITUTE study of the perugia multidisciplinary team for thoracic tumors. Suppl. Tumori: 2008; 94(3): 398 - 405 - Article IF 2008: 0,791 P.735. Labanca, M; Azzola, F; Vinci, R; Rodella, LF. Piezoelectric surgery: Twenty years of use. Br. J. Oral Maxillofac. Surg.: 2008; 46(4): 265-269 - Article IF 2008: 0,787 P.736. Gerevini, S; Mandelli, C; Cadioli, M; Scotti, G. Diagnostic value and surgical implications of the magnetic resonance imaging in the management of adult patients with brachial plexus pathologies. Surg. Radiol. Anat.: 2008; 30(2): 91-101 - Article IF 2008: 0,782 P.737. Chiaroni, D; Chiesa, V; De Massis, A; Frattini, F. The knowledge-bridging role of Technical and Scientific Services in knowledge-intensive industries. Int. J. Technol. Manage.: 2008; 41(3-4): 249-272 - Article IF 2008: 0,526 P.738. Chiesa, R; Melissano, G; Bertoglio, L; Campos Moraes Amato, A; Tshomba, Y; Civilini, E; Calliari, FM; Marone, EM. The risk of spinal cord ischemia during thoracic aorta endografting. Acta Chir. Belg.: 2008; 108(5): 492 - 502 - Article IF 2008: 0,474 P.739. Mandelli, C; Porras, L; Lopez-Sanchez, C; Sicuri, GM; Lomonaco, I; Garcia-Martinez, V. The partial labyrinthectomy petrous apicectomy approach to petroclival meningiomas. A quantitative anatomic comparison with other approaches to the same region. Neurocirugia: 2008; 19(2): 133 - 142 - Article IF 2008: 0,277 P.740. Miniussi, C; Cappa, SF; Cohen, LG; Floel, A; Fregni, F; Nitsche, MA; Oliveri, M; Pascual-Leone, A; Paulus, W; Priori, A; Walsh, V. Efficacy of repetitive transcranial magnetic stimulation/transcranial direct current stimulation in cognitive neurorehabilitation. Brain Stimul.: 2008; 1(4): 326-336 - Review IF 2008: Indexed by JCR 2008 AUTHOR INDEX - 231 AUTHOR INDEX A Abdollah, Firas 187 P255 Absinta, Martina 27, 182 P131 Abutalebi, Jubin 24, 181 P617, P685 Accarino, Gianfranco 167 Acerno, Stefania 172 Agosta, Chiara 25 Agosta, Federica 27 P216, P217, P218, P416, P428, P429, P514, P563, P608, P624, P631 Agostoni, Massimo 170 Agresti, Alessandra 127, 133 Agricola, Eustachio 55, 167 P466, P467, P468, P639 Aiello, Patrizia Tanina 97, 178 Aina, Ilaria 25, 180 Aiuti, Alessandro 72, 73, 74, 90, 91, 176 P47, P186, P518 Albarello, Luca 188 P95, P104, P178, P179, P181, P447 Alberigo, Giada 73 Albieri, Ilaria 23 Aldrighetti, Daniela 4, 183 Aldrighetti, Luca 98, 115, 170 P320, P355, P377, P542, P570, P588, P589 Alemanno, Federica 24 Alesiani, Roberta 25, 180 Alessio, Davide 188 Alessio, Massimo 145, 150 P167, P222, P497, P605, P679 Alfano, Massimo 96 P185, P210 Alfieri, Beatrice 96 Alfieri, Ottavio 55, 66, 167, 169 P27, P77, P197, P198, P383, P396, P426, P438, P472, P530, P611, P613, P614, P615, P708 Allievi, Elisa 159 Almirante, Giada 176 Alongi, Filippo 183 P302, P305, P357, P511, P625, P733 Alto, Giorgio 24, 172 Amadio, Stefano 27, 182 P325, P449, P559, P575 Amato, Ninfa Amendola, Mario 26 72 P199 Ammirati, Enrico 55 P135 Anand, Santosh 127 Andolfi, Grazia 73 P186 Andolfo, Annapaola 145, 188 P482 Andrei, Fodor 183 Anelli, Tiziana 127 P83, P116 Angelone, Sara 25, 180 Angiolilli, Diego 187 Angiolini, Adriana 172 Annoni, Andrea 73 Anselmetti, Simona 25, 180 P700 Antonelli, Antonella 127 P120 Anzalone, Nicoletta 24, 172 P264, P509, P583 Apollonio, Benedetta 1 P53 Aquilina, Mark 183 Anthony Arancio, Cinzia 25, 180 Arcidiacono, Paolo 3, 15, 170 Giorgio P178, P179, P180, P552, P626, P657 Arcidiacono, Teresa 129, 178 Ardu, Veronica 188 Arendar, Irina 167 Arioli, Francesco 166 P339, P464, P592 Arrigoni, Gianluigi 188 P143, P273, P532 Ascagni, Miriam 159 Asperti, Claudia 23 Assanelli, Andrea 72, 183 P571, P634, P636 Astore, Domenico 168 Astro, Veronica 23 Attuati, Luca 24, 172 Augello, Giuseppe 55, 166 Avitabile, Maria 166 Azzoni, Emanuele 71 232 - SAN RAFFAELE SCIENTIFIC INSTITUTE B Baccari, Paolo Aldo Raul Baccelli, Nicola Bacchetta, Rosa 3, 170 172 72, 73, 88, 176 P37, P48, P63, P199, P450, P518 Bacchi, Fabrizio XI Bachi, Angela 127, 135 P36, P207, P208, P221, P222, P315, P316, P374, P481, P497, P535, P545 Bacigaluppi, Marco 26, 182 P582, P655 Badaloni, Aurora 23 Badami, Ester 98 Bagaglio, Sabrina 97, 174 Balconi, Giuseppe 185 Baldan, Rossella 96 P483, P484 Baldelli, Sara 72 Baldini, Mattia 178 Baldissera, Elena 97, 178 Baldoli, Cristina 24, 172 P449 Ballarotto, Carlo 167 Ballis, Rosa 129 Balzano, Gianpaolo 3, 170 P35, P288, P375, P657 Bande, Marta 54, 167 Bandiera, Alessandro 3, 168 P537 Banfi, Arianna 170 Banfi, Michela 55 P135 Baraldi, Clementina 180 Baratto, Fabio 183 Barbagli, Matteo 183 Barbini, Barbara 25, 180 P343, P539, P703 Barcella, Valeria 27 Barera, Graziano 54, 62, 176 P281 Bargiggia, Cinzia 188 Barili, Valeria 23 Baroni, Miriam 96 Barricella, Nietta 183 Barzaghi, Lina 24, 172 Raffaella P620 Barzizza, Lorena 188 Bassanelli, Giorgio 167 P339, P592 Basso, Veronica 96 P23, P94 Battaglia, Manuela 98, 119 P8, P450 Battaglia, Marco 180 P661 Battistella, Stefania Bazzigaluppi, Elena Beatrice, Saverio Bechi, Margherita Belfiore, Marcello Bellanca, Raimondo Bellani, Serena Belli, Carmen Bellini, Chiara Bellinzoni, Piera Bellio, Laura Bellodi, Laura Belloli, Sara Bellomo, Daniela Bellone, Matteo Belloni, Daniela Belloni, Ilaria Benasciutti, Elisa Bencardino, Katia Benedetti, Beatrice Benedetti, Francesco Benedetti, Sara Benedetti, Sara Benedicenti, Fabrizio Benedini, Stefano Beneduce, Aldo Alberto Benussi, Stefano Benveniste, Marina Benzoni, Ivana Berardi, Genoveffa Beretta, Alberto Beretta, Edoardo Beretta, Luigi Bergamante, Valentina Bergamaschi, Andrea Bergami, Alessandra Bernardi, Massimo Bernardi, Rosa 145 P231 188 183 25, 180 P700 23 167 23 4, 183 P413 3, 172 P658 187 72, 188 25, 180 P220, P425, P441 153, 183 P317 XI 96, 107 P62, P91, P279, P471 1 55 127 4 27, 182 25, 39, 180 P343, P379, P452, P533, P539, P688, P703 71 145 P371 73 53 P404, P405, P597 189 P288, P375 55, 167 P198, P426, P472, P529, P614, P615 185 159 153, 183 174 170 P704 24, 36, 170, 172, 189, 193 P275, P583 74 26 P68, P497 26 P325, P326 3, 183 P46, P48, P81, P634 1, 10 P113 AUTHOR INDEX - 233 Bernascone, Ilenia 128 P535 Bernasconi, 25 Alessandro P343, P379, P539, P688, P703 Bernasconi, Fabio 172 Bernasconi, Luca 181 P434 Bertani, Angelo 180 Bertilaccio, Maria 1 Teresa Sabrina P91, P471 Bertini, Diego Maria XI Bertini, Roberto 4, 187 P143, P150, P162, P568, P602 Bertocchi, Cecilia 185 Bertoglio, Luca 55 P390, P473, P477, P728, P738 Bertolazzi, Mara 188 Bertolo, Alessandro 128 Bertolotti, Milena 127 Bestetti, Arabella 97, 174 P721 Bettegazzi, Barbara 23 Bettin, Paolo 24, 172 Bettinardi, Valentino 153, 183 P322, P361 Beugnet, Anne 2 P7 Biagetti, Raffaella XI Bianchi Marzoli, 24, 172 Stefania P620 Bianchi, Giada 127 Bianchi, Laura 25, 180 Bianchi, Marco 4, 187 Bianchi, Marco 188 Bianchi, Marco E. 127, 130, 132, 159, 161 P24, P26, P120, P187, P265, P616 Bianchi, Veronica 24 Bianco, Mariangela 26, 182 Bianconi, Irene 95 Biasco, Luca 73 Biffi, Alessandra 73, 74, 86, 176 P382, P417, P449 Biffi, Valentina 176 Biffo, Stefano 2, 13 P7, P111, P344 Bignami, Elena 55, 168 P272, P676 Bin, Roberta 183 Biondini, Francesca 180 Bione, Silvia 128 P107, P196 Biral, Erika 72, 176 P418 Bisagni, Pietro 189 Biswas, Priscilla 96, 174 P185 Biziato, Daniela Bizzozero, Laura Blasi, Francesco Blasi, Valeria Blasio, Andrea Boari, Nicola Boccalatte, Francesco Boccalon, Silvia Boemo, Cinzia Boeri, Enzo Bogni, Silvia Bolentini, Alketa Boletta, Alessandra Bolino, Alessandra Bolis, Annalisa Bolognesi, Angelo Bolognesi, Gianluigi Bolzoni, Luca Bombardelli, Lorenzo Bombelli, Ferdinando Bombelli, Giovanna Bonalumi, Sara Bonavida, Giovanna Bondanza, Attilio Bondardo, Flavia Bondi, Stefano Bonetti, Fabrizio Bonfanti, Riccardo Bongiorno, Fanny Boni, Andrea Bonini, Chiara Bonini, Pierangelo Bordogna, Gianni Bornaghi, Viviana Borri, Anna Borroni, Barbara Borroni, Emanuele Borroni, Serena Bortolanza, Sergia Bosaia, Alessandra 72 72 128, 137 P389, P414 24, 159 P213, P229 167 24, 172 P280 72 25, 180 3, 170 P178, P179 188 P558 128 188 128, 137 27, 47 P122 27 183 P327, P625, P733 172 188 95 176 P186 XI 145, 188 P371 129, 178 72 P48 55 3, 172 167 99, 123, 176 P63 180 128 72, 81 P48, P81, P342, P386, P622 188 P256, P648 183 145 189 P375 25 P121, P124, P205, P278, P587 96 25, 180 P629 71 25, 180 234 - SAN RAFFAELE SCIENTIFIC INSTITUTE Bosi, Emanuele 53, 54, 61, 98, 99, 117, 122, 178, 179, 188 P141, P256, P383, P488, P504, P647, P681 Bosia, Marta 25, 180 Bosio, Laura 176 Bossolasco, Simona 97, 174 P572, P721 Bosticardo, Marita 73 Bosurgi, Lidia 71 P44 Botti, Francesca 23 Botti, Renato XXI, XXII Bove, Maddalena 176 Bove, Tiziana 55, 168 P707, P717 Bozzolo, Enrica P. 97, 178 Bracale, Maria 178 Braga, Marco 98, 170 P222, P288, P538, P541 Braga, Raffaella 180 Bragonzi, Alessandra 95, 103 P299, P351, P399 Brambilla, Elena 26 P68, P325, P326 Brambilla, Marina 188 Brambilla, Riccardo 26, 43 Brambilla, Roberta 188 Brambillasca, Maria 176 Francesca Brasca, Laura 185 Breda, Daniela 95 Bregani, Valentina 180 P682 Brendolan, Andrea 1, 10 Brigante, Claudio 176 Briganti, Alberto 4, 187 P34, P142, P144, P146, P149, P150, P151, P158, P162, P251, P253, P267, P367, P522, P526, P637, P665 Brigatti, Cristina 99 P174 Brigida, Immacolata 73 Brina, Daniela 2 Brioschi, Luca 183 Brisci, Angela 145, 188 P51 Broccoli, Vania 24, 35 P31, P58, P90, P98 Broggi, Paola 180 Broggi, Sara 188 P302, P303, P305, P357, P359, P360, P511, P733 Broglia, Luigi 187 Brunelli, Silvia 71, 77 P89, P340, P440 Brunetta, Mirella 180 Bruno Ventre, Marta Bruno, Francesca Bruschi, Elena Bua, Lina Bucello, Sebastiano 3 145, 188 172 187 27, 182 P432 Buetti, Ivan 128 Buffi, Nicolò Maria 4, 187 Buffo, Paola 25 Buono, Roberta 72 Burastero, Samuele E. 95, 102 P442, P544 Burioni, Roberto 188 P118, P260, P263, P610 Busnardo, Elena 153, 183 Bussi, Mario 3, 16, 25, 39, 172 P658, P702, P731 Butera, Calogera 27, 182 P559 Butti, Erica 26 P325, P326 Buzzetti, Fabio 55, 167 Buzzotta, Alessio 24, 172 C Cabianca, Daphne Cabinio, Monia Cabrini, Luca 71 24, 159 55 P140, P670 Caielli, Simone 98 P189 Caimi, Mariangela 153 Caiolfa, Valeria R. 1, 9 P74, P482 Cairella, Roberto 188 Calabrese, Alice 167 Calabrese, Donato 96 Calabrese, Giovanna 23 Calabrese, Maria 167 Chiara Calabrò, Maria 168 Grazia P717 Calaciura, Rita 183 Calamita, Piera 24 Calandrino, Riccardo 188, 190 P302, P303, P305, P357, P359, P360, P511, P733 Calbi, Valeri 72 Caldara, Rossana 97, 178 P141 Caldi, Massimo 189 Caldirola, Daniela 180 Caligaris-Cappio, 1, 3, 5, 7, 183, 184 Federico P18, P50, P53, P54, P57, P82, P287, P328, P634 AUTHOR INDEX - 235 Callegaro, Luciano 74, 176 P518 Calliari, Fabio 55 Massimo P391, P473, P727, P738 Calori, Giliola XI P398, P464 Calvi, Maria Rosa 24, 172 P583 Camaschella, Clara 128, 139 P22, P52, P190, P193, P194, P195, P196, P274, P329, P353 Camba, Lionello 183 Cambiaghi, Marco 26 Camerota, Tommaso 187 Camesasca, Chiara 167 Cammarata, Gabriella 172 Camnasio, Francesco 170 P709 Campana, Lara 71 P44 Campanella, 23 Alessandro Campanini, Elena 180 Campori, Euridice 180 P343 Canciani, Cristina 167 Candotti, Guido 176 Canducci, Filippo 188 P261, P555 Canessa, Nicola 24, 181 P566 Canevari, Carla 153, 183 P634 Cangi, Maria Giulia 188 P170, P285, P294, P295 Cannalire, Giuseppe 176 Cannavale, Salvatore 167 Cannistraci, Carlo 145 Vittorio P497 Canonico, Emanuele 159 Cantarelli, Elisa 98 Cantore, Alessio 72 Canu, Tamara 153 P42, P187, P486 Capasso, Giuseppe 189 P381 Capelletti, Alberto 55 Capelli, Alessandro 183 Capitanio, Umberto 4, 187 P149, P150, P151, P153, P159, P162, P257, P269, P293, P525, P527, P568, P601, P603, P718 Capitanio, Vanessa 98, 170 Capobianco, Annalisa 71 P187, P307, P394 Capossela, Simona 128 Capotondo, Alessia 73 Cappa, Stefano F. 24, 37, 181 P121, P125, P203, P214, P233, P480, P508, P513, P515, P516, P517, P566, P679, P698, P700, P740 Capparé, Paolo 129 Cappellari, Ornella 71 Cappelletti, Alberto 167 Cappelletti, Chiara 54, 178, 189 P681 Cappelli, Barbara 72, 176 P418, P652 Cappio, Stefano 185 P361 Capretti, Giovanni 98, 170 Caputo, Alessandra 98 Caputo, Luigi 97, 176 Carassa, Roberto 172 P446 Carbone, Teresa 188 Carcione, Davide 188 Cardani, Anna 176 Cardone, Gianpiero 185 Carenzi, Maurizio 183 Carletti, Rose Mary 188 Carletti, Silvia 188 Carlino, Mauro 54, 167 P347, P372, P464, P600 Carlucci, Michele 189, 192 Carlucci, Silvia 53 Carobene, Anna 188 Carozzo, Andrea 168 Carpanelli, Roberta 185 Carpinelli, Assunta 25, 153, 183 P220, P292 Carrabba, Matteo 3, 183 Carrabino, Salvatore 128 P351 Carrara, Silvia 3, 170 P178, P179, P180 Carrera, Paola 145, 188 P81, P117, P133, P371, P681 Carretta, Angelo 3, 168 P537 Carretta, Ilaria 180 Carvello, Michele 3, 170 Casamassima, Nunzia 129 P270, P271, P463 Casari, Giorgio 145, 146, 147 P100, P383, P393, P478, P643 Casati, Paolo 180 Casiraghi, Giuseppina 55, 168 Maria Casiraghi, Miriam 74, 176 Casiraghi, Tiziana 170 Caso, Francesca 27, 182 Casorati, Giulia 96 P23, P186, P387, P443 236 - SAN RAFFAELE SCIENTIFIC INSTITUTE Cassella, Patrizia Cassetta, Luca 27 96 P576 Cassina, Giulia 95 P20 Cassina, Laura 145 P100, P383 Castagna, Antonella 97, 174 P345, P556, P558 Castagnaro, Laura 1 Castellano, Antonella 24, 159 P213 Castellano, Renata 55, 167, 168 Clotilde Castellazzi, Paola 24, 172 Castelli, Alfredo 54, 167 Castelli, Maddalena 128 Castiglioni, Alessandra 3, 71, 170 Castiglioni, Alessandro 167 Castiglioni, Emanuela 145, 188 Castiglioni, Isabella 25, 153, 183 Castiglioni, Maria 54, 63, 176 Teresa Castoldi, Carlo 170 Castoldi, Renato 170 Casucci, Monica 72 Catalano, Marco 25, 180 Catena, Marco 98, 170 P377, P542, P570, P588 Catenaccio, Barbara 55 Catricalà, Eleonora 24, 181 Cattaneo, Angela 127 P207, P221, P535 Cattaneo, Elisabetta 180 P682 Cattaneo, Giovanni 188 Mauro P303, P358, P359, P360, P361, P511 Cattoglio, Claudia 128 P204 Catucci, Alessandro 127 Catucci, Marco 73 Caumo, Andrea 53 P106, P404 Causarano, Vincenza 145, 188 Cavallaro, Roberto 25, 180 P700 Cavallini, Maria 25, 180 Cristina Cavarelli, Mariangela 96 P556 Cavazzin, Chiara 73 Cavedini, Paolo 25, 180 Cavoretto, Paolo 54, 176 P415 Ceccarelli, Antonella 27 P127, P215, P219, P430, P564 Cecconi, Virginia Celona, Barbara Cenci, Simone Centemero, Antonia Ceppi, Daniela Cera, Michela Cerè, Patrizia Cereda, Stefano Ceresa, Daniela Cerioni, Valeria Ceriotti, Ferruccio Cernuschi, Massimo Cerri, Federica Cerri, Marco Cesana, Daniela Cesani, Martina Cestari, Andrea Chiara, Anna Chiaravalli, Marco Chieffo, Alaide Chieffo, Raffaella Chiesa, Robert Chiesa, Roberto Chignola, Francesca Chionna, Raffaella Chiumello, Giuseppe Ciaccia, Stefano Ciaccio, Cristiano Ciampi, Carlo Ciampi, Pietro Cianflone, Domenico Ciasca, Paola Ciboddo, Gianfranco Ciceri, Fabio Cichero, Paola Ciconte, Giuseppe 96 P443 127 127, 131 187 27, 182 55 P373, P574 183 4, 183 P510, P657 188 P650 176 188 P230, P232 174 P721 26, 182 P129, P559 172 73 73, 74 P382, P449 4, 187 P143, P637 153, 183 128 54, 167 P40, P347, P348, P372, P373, P465 26, 182 72, 176 P418 55, 67, 168 P143, P258, P390, P391, P422, P473, P477, P727, P728, P738 145 P114 176 53, 54, 99, 176, 177 P63 172 166 24, 172 170 55, 64, 167 P135, P574 172 183 3, 18, 71, 72, 75, 82, 183 P17, P48, P49, P81, P331, P342, P386, P418, P419, P610, P622, P634 188 P483 55, 166 P338 AUTHOR INDEX - 237 Cigala Fulgosi, Mara 25, 180 P343, P539 Cigana, Cristina 95 Cino, Ilaria 54 Cinque, Paola 97, 112, 174 P572, P721 Cioni, Micaela 167 P614 Cipriani, Antonella 172 Ciriaco, Paola 3, 168 P532, P537 Cirillo, Daniela Maria 96, 108 P84, P234, P235, P370, P483, P484, P585, P590, P591, P723 Cirillo, Sara 159 Ciscato, Diana 188 Citterio, Giovanni 183 Citterio, Lorena 129 P270, P271, P383, P463 Civilini, Efrem 55, 168 P477, P728, P738 Clementi, Emilio 72, 80 P323, P340, P439, P474 Clementi, Massimo 188 P118, P260, P261, P263, P407, P495, P555, P558, P610 Clerici, Daniela 72 P610, P634 Clerici, Stefano 180 Clissi, Barbara 95 Cocchi, Federica 25 Cocchi, Silvia 180 Codazzi, Franca 23 P479 Codella, Roberto 53 Codenotti, Marco 24, 172 Colasante, Gaia 24 P98 Coli, Stefano 55 P396 Collivasone, Rosella 183 Collu, Egidio 167 Colnaghi, Eleonora 170 Colombelli, Cristina 128 P97 Colombo, Alessio 188 P371 Colombo, Antonio 54, 64, 167 P38, P39, P40, P41, P78, P79, P282, P347, P348, P349, P372, P373, P383, P465, P494, P531, P598, P599, P600, P715 Colombo, Barbara 2 P279 Colombo, Bruno 27, 182 P219, P392, P434, P689, P692 Colombo, Cristina Colombo, Gabriella Colombo, Giselda Colombo, Ilaria Colombo, Renzo Colombo, Sergio Coltella, Nadia Colucci, Annalisa Comi, Giancarlo Comola, Mauro Comotti, Laura Compierchio, Antonia Comuzzi, Barbara Consalez, Gian Giacomo Consogno, Giuseppe Consonni, Alessandra Consonni, Monica 25, 180 P343, P379, P533, P539, P703 176 97, 178 P65 176 4, 187 P150, P151, P162, P602 55, 170 P483, P670 1 24, 172 26, 41, 182 P12, P68, P122, P126, P127, P128, P129, P131, P134, P166, P206, P215, P219, P250, P325, P326, P363, P392, P429, P430, P432, P449, P559, P562, P564, P579, P687, P689, P691, P692, P693 182 P559 170 P588 153, 183 145 23, 32 P406, P475 96 23 24 P480 Conti, Antonio 145 P605, P679 Conti, Enrico 176 Conti, Valentina 71 Contrino, Elena 185 Conversano, Andrea 55, 167 Coppi, Giovanni 55 Coppolino, Naima 25, 180 Coradin, Tiziana 97 P298 Corbetta, Sara 23 P453 Cordisco, Paola 183 Corea, Francesco 27, 182 P166 Corna, Gianfranca 71 Cornaggia, Gabriele 189 Cornero, Guglielmo 167 Corno, Daniela 71 Corno, Laura 55 Corno, Silvia 188 Corre, Tanguy 128 Corsetti, Maura 170 P540 Corsin, Patrizia 54 238 - SAN RAFFAELE SCIENTIFIC INSTITUTE Cortella, Carlo Alberto Corti, Angelo Corti, Consuelo Corti, Laura Corti, Valeria Cortini, Margherita Cortinovis, Francesca Cosciotti, Miriam Cossarini, Francesca Cossetti, Chiara Cossu, Giulio Costa, Sabrina Cottonaro, Sara Cottone, Lucia Covarello, Diego Covello, Remo Daniel Coviello, Silvia Covino, Cesare Cozzarini, Cesare Cozzi, Anna Cozzi, Silvano Cremona, Ottavio Cremonesi, Laura Cremonini, Anna Crescenti, Antonella Crespi, Giulia Maria Crespi, Roberto Crippa, Ambra Crippa, Fulvio Crippa, Luca Crippa, Luciano Crippa, Massimo Crippa, Valentina Crippa, Valeria Crisà, Simonetta Cristallo, Marco Cristell, Nicole Crivellaro, Cinzia Crivello, Pietro Croci, Laura Crotta, Alessandro Cucchi, Michele 129 Cuko, Amarild 2, 14 P55, P62, P92, P236, P279, P471 3, 183 145 145 P497 127 176 188 97, 174 26 71, 75, 76 P13, P19, P33, P89, P90, P200, P520 53 P504 145 71 71 P89 55, 168 P676, P677 27 159 153, 183 P145, P162, P302, P305, P322, P357, P511, P625 23 172 2, 13 P71 145, 188 P51, P119, P191, P231, P371, P376, P411, P412, P551, P646 188 168 185 129 128 174 2 P92 53, 188 128, 138 54, 178 183 166 170 55 P347 183 71 23 P406, P475 3 180 Curci, Francesco Curnis, Flavio Cursi, Marco Cusimano, Melania 166 P592 XI 2 P55, P92, P236, P279 26 P432 26 D D’Adamo, Patrizia 24, 34 P196, P453 23 P324 128 178 127 188 145 D’Alessandro, Rosalba D’Alessio, Silvia D’Aliberti, Teresa D’Amato, Alfonsina D’Amato, Luigi D’Ambrosio, Rosa Lucia D’Angelo, Armando 53, 59, 188 P192, P716 D’Annibale, Sara 145 D’Antoni, Angela 26 D’Antonio, Maurizio 127 P32 D’Isa, Raffaele 26 Dacci, Patrizia 26 P122 Dagklis, Antonis 1 P54 Dagna, Lorenzo 97, 178 Dal Cin, Elena 188 P170, P294 Dall’Occhio, Luca 27 Dalla Libera, Dacia 26, 182 Dallaspezia, Sara 25, 180 P343, P379, P539 Daneri, Riccarda XI Daniele, Tiziana 145 Danise, Anna 174 P558 Davalli, Alberto 54, 178 Daverio, Rita 188 P256 De Benedetto, 24, 172 Umberto De Bonis, Michele 55, 167 P197, P530, P612, P613, P708 De Cesare, Stefania 71 De Cobelli, 153, 185 Francesco P42, P187, P486, P709 De Curtis, Ivan 23, 30 P453, P498 De Feo, Donatella 182 AUTHOR INDEX - 239 De Fusco, Maurizio 145 P643 De Gaspari, Angela 185 De Lalla, Claudia 96 P186 De Leonardis, Alberta 183 De Luca, Monica 168 P676 De Marchis, 127 Francesco P24 De Marco, Donata 188 P260, P610 De Martino, 95 Emanuela De Marzi, Patrizia 4, 176 P283, P489 De Monte, Lucia 96 P222, P679 De Nardi, Paola 3, 170 P540 De Palma, Clara 72 P323, P474 De Palma, Michele 72, 81 P14 De Pellegrin, 26, 170 Maurizio P674 De Ponti, Alessandro 170 De Santis, Lucia 54 P350 De Taddeo, 97, 178 Francesca P21 De Toni Franceschini, 27, 182 Luisa De Vitis, Assunta 24, 172 Debbia, Silvia 183 Degano, Massimo 96, 107 P116, P424 Deidda Vigoriti, 71 Vivian Del Carro, Ubaldo 27, 49, 182 P32, P97, P325, P449, P575 Del Mare, Sara 96 P443 Del Maschio, 99, 153, 155, 185, 186 Alessandro P42, P187, P361, P486, P680, P719, P720, P727 Del Maschio, 185 Maurizia Del Rosso, Stefania 188 Del Vecchio, 188 Antonella P359 Delai, Stefania 73 Delfino, Enrico 172 Deli, Aniko Maria 153 Dell’Acqua, Antonio 172 P141 Dell’Antonio, Giacomo Dell’Oca, Italo 188 P502 153, 183 P303, P360 Dell’Orco, Stefania 188 Della Chiara, Giulia 96 Della Rosa, Pasquale 24, 181 P203, P214 Della Torre, 178 Emmanuel Della Valle, Patrizia 53, 188 P395, P630 Dellabona, Paolo 96, 108 P186, P222, P443 Dellavalle, Arianna 71 P89 Delli Carpini, Simona 129 P102, P270, P702 Delogu, Marta 96 Demarchi, Barbara 189 Demasi, Stefania 188 Deni, Francesco 170 Denti, Paolo 167 Deponti, Daniela 129, 170 Devoti, Rosaria 180 Di Candia, Stefania 54, 176 Di Carlo, Valerio 3, 18, 98, 170 P35, P95, P288, P375, P541, P549, P657 Di Girolamo, Valerio 187 P150, P158 Di Leo, Giuseppe 188 Di Leo, Milena 3 Di Lullo, Giulia 96 Di Marco, Andrea 167 Di Mattei, Valentina 180 P698 Di Matteo, Federico 24, 172 Di Molfetta, Daniela 180 Di Muzio, Nadia 153, 156, 183 P302, P303, P305, P357, P360, P361, P511, P625, P733 Di Nunzio, Sara 73 P450 Di Palo, Saverio 3, 170 P447 Di Pietro, Caterina 98 Di Pisa, Giuseppe 183 Di Resta, Chiara 145 Di Ruvo, Barbara 188 Di Sciacca, Dina 188 Di Sebastiano, 176, 185 Francesca Di Stefano, Bruno 24 Di Tomaso, Tiziano 2 Di Trapani, Dario 187 Diaferia, Giuseppina 180 240 - SAN RAFFAELE SCIENTIFIC INSTITUTE Diaz, Jordie Dilani, Federica Dina, Giorgia 71 189 26 P97, P122 Dindelli, Moreno 176 Diomede, Lorenzo 95 Diotti, Roberta 188 P260, P263, P610 Dispinseri, Stefania 96 Distefano, Gianfranco 128 Doglioni, Claudio 159, 188, 190 P23, P63, P91, P95, P170, P178, P179, P187, P222, P273, P285, P286, P294, P295, P321, P447, P571 Donadoni, Giovanni 183 Dondossola, Eleonora 2 Donini, Annalisa 53 Donini, Michela 180 Dordoni, Laura 55, 168 Doria, Valentina 54, 178 Dorigatti, Fernanda 188, 191 Dorigo, Enrica 167 P426, P614 Dosio, Flaviano 183 Dotoli, Danilo 25, 180 Draghici, Elena 73 Dugani, Erica 98 Durante, Alessandro 55 E Ekkirala, Chaitanya Ermoli, Elena Erre, Letizia Erzegovesi, Stefano Esposito, Antonio Esposito, Federica Esposito, Gloria Esposito, Marianna Esposito, Valentina Evangelio, Costanza 96 180 P700 183 25, 180 P441 153, 185 P42, P187, P211, P486 27 55, 168 26 P325 181 176 P418 F Fabbri, Fabio Fabbri, Monica Fabiano, Beatrice Fabro, Andrea 187 P256 95 P101 3, 172 P658 153, 183 P317 Facchi, Cinzia Facchini, Alberto Faccincani, Roberto Faccio, Lucia Fagioli, Claudio Falcone, Marika Falcone, Sestina Falini, Andrea Fallanca, Federico Falqui, Luca Falqui, Luca Famoso, Graziana Fanelli, Giovanna Franca Fano, Greta Fanti, Lorella Fanto, Manolis Farina, Elena 25, 180 55 189 XI 127 P346 98, 119 P21, P189, P436 72 P323 24, 38, 172 P14, P127, P213, P214, P215, P229, P379, P392, P642, P699 153, 183 P331 99, 178 167 188 P571 27, 182 168 3, 170 24, 34 181 P642 Fasano, Stefania 26 Fasce, Francesco 172 Fattorini, Annalisa 53, 188 Fauci, Eugenia 25, 180 Favia, Rossana 176, 185 Fazi, Claudia 1 P54 Fazio, Raffaella 27, 50, 182 P122, P559 Fedeli, Maya 96 Feltri, Maria Laura 128, 138 P32, P73, P97, P226 Ferenderes, Federica 1 Ferini-Strambi, Luigi 25, 40 P30, P332, P334, P378, P429, P444, P445, P454, P455, P694, P706 Ferla, Gianfranco 3, 17, 98, 170 P355, P377, P542, P570, P588 Fermo, Isabella 145, 188 P277, P488 Ferrai, Carmelo 128 P98 Ferrara, David 167 Ferrara, Fulvio 188 Ferrari Da Passano, 172 Camillo Ferrari, Angela 54 Ferrari, Augusto 4, 54, 97, 176 P191 Ferrari, Carola Iris 180 Ferrari, Davide 176 AUTHOR INDEX - 241 Ferrari, Giuliana 73, 87 P70, P115 Ferrari, Matteo 187 Ferrari, Maurizio 145, 149, 188 P51, P81, P119, P191, P231, P371, P411, P412, P646, P681 Ferrari, Patrizia 188 Ferrari, Stefania 176 Ferrari, Stefano 176 P327 Ferrarini, Marina 1, 8 P56, P185, P328 Ferrario, Fabrizio 25, 172 Ferrario, Federica 172 Ferrario, Laura 189 Ferrario, Matilde 176 Ferraro, Alessandra 98 Ferreri, Andrès Jose 3, 19, 183 Maria P16, P76, P170, P285, P286, P295, P309, P310, P311, P313, P327, P571, P634, P635, P636 Ferrero, Carlo Alberto 188 Ferrero, Elisabetta 1, 11 P92, P396 Ferri, Cinzia 127 Ferro, Mattia 23 Ferron, Simona 2 Ferrua, Francesca 74 Fesce, Riccardo 145, 148 Fiacco, Enrico 170 Filippi, Massimo 27, 46 P12, P28, P59, P60, P123, P126, P127, P130, P131, P206, P212, P215, P216, P217, P218, P219, P250, P334, P392, P416, P428, P429, P430, P433, P514, P534, P562, P563, P564, P577, P581, P608, P631, P695, P696, P697, P701 Filippis, Susanna 176 Finazzi, Renato 98, 170 P239, P570 Finizio, Valentina 176 Finocchiaro, Claudia 180 Fiordelisi, Caterina 183 Fiore, Marina 180 Fiori, Marina 172 Fiori, Rossana 168 P418 Fiorin, Maria Chiara 180 Fiorino, Claudio 188 P301, P302, P303, P304, P305, P357, P358, P360, P511 Fleischhauer, 71, 78, 188 Katharina P48, P81 Flore, Marilena 188 Florea, Ioana 153 Fodor, Andrei 153 Foglieni, Chiara 96 P135, P396 Foglio, Alessandra 145 Fontana, Barbara 53 P504 Fontana, Raffaella 2 Foppoli, Marco 183 P76 Forestieri, Carmen 170, 189 Formaglio, Fabio 27, 182 Formenti, Ilaria 54, 178 Formicola, Roberta 97 Fornasiero, Eugenio 23 Forti, Maddalena 172 Fortis, Claudio 95, 106, 174 Fortunato, Manuela 54, 178, 189 Fossati, Andrea 25, 180 P629 Fossati, Marco 176 Fracassetti, Dario 170 Fragasso, Enrico 27 Fragasso, Gabriele 55, 167 P339, P464, P468, P592 Franchi, Giulia 178 P493, P681 Franchini, Linda 25, 180 Franchini, Stefano 97, 178 Franciosi, Gianluca 25, 180 Franco, Annalisa 168 Franco, Margherita 176 François, Stephanie 71 Franzin, Alberto 24, 172 P175 Franzoni, Irene 55 Fraschini, Gianfranco 129, 170 P709 Frascoli, Cristina 172 P583 Frasson, Matteo 170, 189 P222, P541 Frasson, Paola 181 Fratta, Pietro 127 Frenquelli, Michela 1 P53 Freschi, Massimo 188 P91, P151, P162, P322, P365, P471 Fresi, Francesco 25, 180 P452 Frigoli, Enrico 166 Frugnoli, Ilaria 176 P418 Fucci, Rita Nunzia 127 Fumagalli, Francesca 27, 74, 182 P449 Fumagalli, Luca 174 Fumero, Andrea 167 P614 242 - SAN RAFFAELE SCIENTIFIC INSTITUTE Furlan, Federico Furlan, Roberto Fusetti, Giuliana Fusi, Francesco 189 26, 45 P325, P326, P401, P431, P621, P690 174 54, 63, 176 P350 G Gabellini, Daniela Gabellini, Davide Gabriele, Angela Gabrielli, Samantha Gaetani, Massimiliano Gagliani, Nicola Gagliardi, Filippo Gagliardi, Marco Gaiera, Giovanni Gaietta, Sara Galanti, Andrea Galantucci, Sebastiano Galbiati, Silvia 53 71, 78 180 180 145 P114 98 24 24, 172 174 P572, P721 180 167 P614 27, 182 145, 188 P191, P412 Galimberti, Elisa 180 Galimberti, Gabriella 54, 178 Gallese, Roberta 25, 180 Galli, Alessandra 188 Galli, Andrea 97, 174 P557 Galli, Elisa 183 Galli, Franco 188 Galli, Laura 97, 174 P558 Galli, Rossella 71, 79 P14 Galliani, Alberto XXI Gallina, Andrea 4, 187 P144, P150, P151, P158, P162, P251, P255, P256, P293, P522, P526, P637, P638 Gallivanone, 153, 183 Francesca Gallo, Simone 2 Gallotta, Giulia 97, 174, 189 Galluccio, Elena 53 P383, P488, P504 Galvano, Enza 185 Gambaro, Margherita XXI Gambini, Dania 176 Gandini, Luca 176 Gangemi, Fabrizio 96 Garavaglia, Claudio 96 Garavaglia, Elisabetta 4, 176 P415 Garbetta, Gisella 176 Garcia-Manteiga, Jose 127 Gardini, Chiara 55 Garibotto, Valentina 25 P121, P125, P205, P220, P278, P292, P454 Garuti, Elda 185 Gasparri, Anna 2 P92, P279 Gatti, Davide 183 Gatti, Elisa 189 P488 Gatti, Roberto 25, 40 P427 Gattillo, Salvatore 188 Gavazzi, Francesca 189 Gavina, Manuela 23 Gazzetta, Paolo 3 Gelera, Emma 166 Gemma, Marco 24, 172 Genovese, Pietro 72 Genovese, Silvia 53 Gentile, Cinzia 4, 176 P415, P489 Gentner, Bernhard R. 72 Gerasi, Laura 128 Gerevini, Simonetta 153, 172 P449, P736 Gerli, Chiara 168 Gerola, Stefano 188 Gerosa, Stefano 55, 167 P464 Gherlone, Enrico 129, 140 P506, P507, P724 Gherner, Daniela 3, 172 Ghezzi, Massimo 187 Ghezzi, Silvia 97 P261, P298 Ghia, Paolo 1, 8 P18, P53, P54, P57, P80, P248 Ghidinelli, Chiara 27, 182 Ghidinelli, Monica 128 Ghidoli, Nadia 188 P21, P260, P610 Ghidoni, Matteo 172 Ghio, Domenico 185 P87 Ghirardelli, Luca 3 Ghitti, Michela 145 Giacomini, Andrea 167 Giammarresi, 95 Antonella Giannandrea, Maila 24 Giannelli, Serena 24 AUTHOR INDEX - 243 Giannese, Francesca 96 P424 Gianolli, Luigi 153, 157, 183 P331, P464, P574, P634 Gianotti, Nicola 97, 174 P557, P558, P572, P721 Giardelli, Alessandra 176 Giardina, Paolo 176 Giardino, Stefano 176 Giarolli, Laura 25, 180 Giatsidis, Silvia 24, 172 Giglio, Fabio 3 Giglio, Manuela 153, 183 Gilardi, Maria Carla 153, 183 P361 Gilardini, Cristina 170 Ginex, Valeria 181 P125 Gioia, Giuseppe 170 Gioia, Lorenzo 172 P175 Gioia, Luigi 172 Giordano, Leone 3, 172 Giorgi, Emiliano 170 Giori, Vincenzo 183 Giovacchini, 183 Giampiero P146, P322, P331, P451 Giovanardi, Michele 3, 168 Giovannini, Monica 4, 183 P413 Girardi, Anna Maria 188 Gismano, Elena 54 Giudice, Anna 183 Giudici, Daniela 189 Giuliani, Serena 180 Giussani, Antonella 3, 170 Giusti, Maria Cristina 24, 181 Giusto, Elena 26 Godino, Cosmo 54, 167 P135, P347, P372, P373, P574, P600 Godio, Cristina 71 Golzi, Valeria 181 Gonzalez-Rosa, Javier 26 Govi, Silvia 3 P16, P636 Granata, Anna 97 Grandi, Elisabetta 172 Grassi, Stefano 188 P170, P294 Grassini, Greta 3, 188 Greco, Raffaella 72 Gregorc, Vanesa 4, 21, 183 P87, P413, P734 Gregori, Silvia 73, 89 P37, P291 Gremizzi, Chiara 97, 178 Gremmo, Annamaria 3, 168 Grimaldi, Adelmo Grimaldi, Antonio Grimaldi, Salvatore Grioni, Emanuela Grioni, Matteo Grispigni, Crispino Gritti, Angela Grogan, Pauline Grohovaz, Fabio Grosso, Stefano Guarisco, Lauretta Guarneri, Maria Pia Guarnerio, Ylenia Guazzoni, Giorgio Guerra, Claudia Guerriero, Roberta Guffanti, Monica Guggiari, Elena Guglielmi, Barbara Guidotti, Andrea Guidotti, Luca G. Gulletta, Simone Guslandi, Mario Gusmini, Simone Guzzetti, Eleonora Guzzoni, Samantha 183 167 P530, P613, P708 187 188 96 P91, P471 170 73, 86 P86 99 23, 31, 159, 160 P423, P479 2 P344 172 176 1 P94 4, 187 P143, P144, P150, P154, P162, P251, P305, P357, P365, P637 178 27, 182 174 P572 3, 183 178 55, 167 96, 98, 109, 117 P14, P69 166 P338 98, 116, 170 P462, P633, P675 185 P361, P680 3, 170 P355, P377, P542, P570, P588 26 H Hasson, Hamid Ibrahim Hellriegel, Christian Heltai, Silvia Hess-Michelini, Rodrigo Hidetoshi, Hoshia 97, 174 P345 1 95 96 P91 71 I Iabichino, Cristiana Iaci, Giuseppe Iadanza, Antonella 185 167 24, 159 P264, P509 244 - SAN RAFFAELE SCIENTIFIC INSTITUTE Iannaccone, Sandro 24, 181 P454, P480, P605, P679 Iannacone, Matteo 96 P69 Ianniello, Margherita XI Ianzano, Dina 55 Ielasi, Alfonso 54, 167 P78 Ierardi, Rossella 73 Ieri, Rossella 188 Indrigo, Marzia 26 Innocenzi, Anna 71 Insacco, Chiara 172 Insacco, Chiara 180 Introini, Maria 188 Antonia Introini, Ugo 24, 172 Inuggi, Alberto 26 J Jachetti, Elena Jofra Hernandez, Raisa Jofra, Tatiana Judica, Elda 96 P91, P279, P471 73 98 27, 182 P126, P416, P430, P564 K Kahlberg, Andrea Kajaste-Rudnitski, Anna Kusamura, Shigeki 55 P422, P473 97 P298, P461 3 L La Canna, Giovanni 167 P530, P531, P613, P708 La Gioia, Sara 27, 182 La Marca, Rosa 27 La Viola, Salvatore 180 Lacerenza, Marco 24 Lacquaniti, Raffaele 54, 167 Lage Crespo, Carolina 95 Laino, Giovanni 167 Lambiente, Camilla 188 Lamonaca, Grazia 188 Lampasona, Vito Landoni, Claudio Landoni, Giovanni Landsberger, Nicoletta Lanfranchi, Barbara Lania, Caterina Lanzani, Chiara 145, 188 P173, P621 153, 183 P574, P634 55, 168 P140, P272, P402, P669, P671, P676, P677, P714, P715, P717 24 127 187 129, 178 P102, P271, P702 Lanzi, Roberto 185 Lanzi, Roberto 54, 178 P488 Lanzoni, Paola 153, 183 Lapenna, Elisabetta 167 P530, P602, P613, P708 Laterza, Cecilia 26 Latib, Azeem 54, 167 Mohamed P38, P78, P282, P347, P372, P373, P494, P599, P600 Latino, Rosanna 188 Lattanzi, Annalisa 73 Lattanzio, Rosangela 24, 172 Lattuada, Guido 53 P42 Laurenzi, Andrea 54, 178 Lavazza, Fanny 167 Lavorato, Maria 189 Vittoria Lavorgna, Giovanni 145 P321 Lazzarin, Adriano 95, 97, 100, 174, 175 P1, P4, P5, P185, P239, P242, P244, P247, P318, P319, P345, P354, P556, P557, P558, P572, P573, P597, P721, P731 Legnani, Giulio 188 Legorini, Francesca 172 Lenti, Elisa 1 Leo, Loredana 145 Leocani, Letizia 26, 43, 182 P692, P693 Leporati, Ennio 53 Lepore, Marco 96 Lesma, Arianna 187 Levi, Sonia 23, 33 P519 Licata, Giada 183 Lidonnici, Maria Rosa 73 Limardo, Pietro 3, 172 Liperi, Laura 25, 180 Lira Luce, Francesca 3, 172 P731 Liu, Jaron 127 AUTHOR INDEX - 245 Locatelli, Marco Locatelli, Massimo Locatelli, Simona Locci, Michela Logaldo, Davide Lombardo, Angelo L. Longaretti, Roberta Longari, Stefania Longo, Alessandro Longobardi, Barbara 25, 180 188 XI 73 55 72 159 183 XXI 188 P359 Longoni, Giulia 27 Longoni, Laura 153, 183 Longoni, Matteo 167 Lopalco, Lucia 95, 105, 174 P442 Lopalco, Sara 24 Loperfido, Francesco 172 Lopez, Ignazio Diego 26, 182 Lorè, Nicola Ivan 95 Lorenzetti, Isabella 26 P122 Lorenzi, Cristina 25 P343, P379, P533 Lorenzi, Mara 53 Lorusso, Anna 23 Losa, Andrea 187 Losa, Marco 24, 172 P175, P488, P620 Losio, Claudio 153, 185 Lucca, Adelio 25, 180 Luchini, Stefania 176 Lucotti, Pietro 54, 178 P383, P488, P504, P647 Lughezzani, Giovanni 4, 187 Lui, Cristina 176 Luisi, Francesca 189 Lukacs, Anna 95 Lunghi, Francesca 3, 183 P634 Luparini, Francesco 3, 170, 189 Lupo Stanghellini, 72, 183 Maria Teresa P48, P49, P81, P634 Luzi, Livio 53, 57 P42, P106, P404, P405, P458, P460, P597 M Maccagnano, Carmen 187 P255 Maccagni, Davide 167 Maccalli, Cristina 2 P168, P491 Macchi, Andrea 55, 167 Macco, Romina Madaschi, Sara Maddé, Claudia Francesca Maderna, Claudio Maestranzi, Gisella Maestroni, Anna Maestroni, Silvia Maffei, Cesare 23 P479 54, 178 183 73 24, 172 53 53 25, 40, 180 P682 Maffi, Paola 99, 122, 178 P21, P106, P405 Maga, Tommaso 187 P365 Magagnotti, Cinzia 188 Maganetti, Nicola 188 Maggio, Angelo 188 Maggioni, Daniela 2 Magistretti, Paola 99 Magnani, Chiara 73 Magnani, Giuseppe 27, 49, 182 P448 Magnani, Patrizia 153, 183 Magnani, Zulma 72 Magni, Valeria 54, 167 Magnoni, Marco 55 Magri, Laura 71 Magrin, Silvio 167 Maida, Giorgio 55, 166 Mailhac, Alessandra 167 Maillard, Myriam 174 P271, P721 Mainetti, Eliseo 170 Mainetti, Lara 96 Mainetti, Marta 96 Maiorino, Chiara 26 Maisano, Francesco 55, 167 P77, P396, P466, P530, P531, P611, P613, P639, P708 Maj, Giulia 55 P140, P272, P715, P717 Majed, Abu Amria 172 Malabarba, Lucia 188 P295 Malaguti, Alessia 25 P703 Malato, Simona 3 Malegori, Angela 172 Malgaroli, Antonio 23, 33 P316, P497 Malnati, Mauro S. 95, 102 P20 Malosio, Maria Luisa 99, 121 P95, P174, P324 Maltecca, Francesca 145 P100 246 - SAN RAFFAELE SCIENTIFIC INSTITUTE Mammi, Silvia Manca, Mario Mancini, Nicasio 27, 182 167 188 P118, P260, P263, P483, P610 Mancini, Niky 170 Manconi, Mauro 25 P334, P378, P429, P445, P454 Mandelli, Carlo 24, 172 P736, P739 Mandelli, Davide 170 Mandelli, Giacomo 73 Mandelli, Maria Rosa XI Mandelli, Paolo 185 Manenti, Rosa 24 P214, P508, P515 Manfredi, Angelo A. 71, 79 P24, P45, P135, P187, P307, P340, P394, P439 Mangiavini, Laura 129, 170 Mangili, Giorgia 4, 19, 176 P25, P283, P415, P489 Mangili, Paola 188 P305, P511 Manitto, Maria Pia 24, 172 P646 Mannella, Valeria 145 Mannu, Claudio 183 Mantovani, Elena 24, 172 Manunta, Paolo 129, 141 P102, P249, P271, P463, P702 Manzo, Teresa 96 Manzoni, Marco 54, 178 Federico P681 Mapelli, Paola 183 Mappa, Silvia 3 Marabelli, 188 Giuseppina Marangoni, Francesco 73 Maranta, Francesco 55 Marassi, Alberto 170 Marcatti, Magda 3, 183 Marchettini, Paolo 27, 182 Marchi, Monica 54, 178 Marchisio, Pier Carlo 2 P7, P344 Marcone, Alessandra 24, 181 P125, P454, P516, P517, P698 Marelli, Guido 176 Marenzi, Karen 54, 176 Margittai, Eva 127 Margonato, Alberto 55, 65, 167 P339, P464, P466, P468, P574, P592, P639 Mari, Gilberto 170 Mari, Silvia 145 P236 Mariani, Alberto 3, 170 P103, P550, P627 Mariani, Elisabetta 127 Mariani, Federica 189 Mariani, Samanta 96 Marinaro, Cinzia 26 Marinelli, Marcello 188 Marinelli, Matteo 128 Marino, Elena 25 P539 Marino, Giovanni 55, 167, 168 P677, P717 Marinosci, Alessandro 178, 189 Marinozzi, Maria 188 Chiara P555 Marktel, Sarah 72, 176 P418, P419 Marone, Enrico Maria 55, 167, 168 P143, P258, P390, P391, P422, P738 Marrella, Veronica 73 P43, P61 Marrocco-Trischitta, 55, 168 Massimiliano P422, P473 Marsiglio, Elena 176 Martani, Carla 170 Martina, Elisabetta 172 Martinelli, Vittorio 27, 48, 182 P126, P206, P219, P430, P432, P434, P564 Martinelli-Boneschi, 27, 182 Filippo P202, P432, P434, P487 Martinenghi, Carlo 185 P680 Martinenghi, Sabina 99, 178 Martino, Gianvito 23, 26, 28, 44 P67, P68, P325, P326, P400, P401, P432, P578, P582 Martulano, Marilena 183 Marzi, Alessandra 166 Marzorati, Patrizia 128 Masciullo, Corrado 128 Masiello, Valeria 153, 183 Masperi, Carla XXI Masserdotti, Giacomo 23 Mastaglio, Sara 72 P622 Matafora, Vittoria 127 P424 Matarrese, Mario 25, 153, 183 P220, P317 Mattarucchi, Roberta 3, 72 Mattioli, Cristina 172 Matuska, Stanislav 172 Mauceri, Paolo 172 Maugeri, Norma 55, 71 P595 AUTHOR INDEX - 247 Mauri, Anna Mauri, Simona Mavilio, Fulvio 188 189 128, 136 P115, P325, P326 Mazza, Elena 4, 183 P308, P510, P657 Mazzavillani, Monica 55 Mazzi, Benedetta 188 P48, P81, P650 Mazzi, Ilaria 188 Mazzieri, Roberta 72 P14 Mazzoleni, Stefania 71 P14 Mazzone, Patrizio 166 P338 Mazzuconi, Roberts XXI P483 Meani, Alessandro 27 Medaglini, Stefania 27, 182 Medone, Marzia 24, 172 Meini, Maria 2 Alessandra Melandri, Marco 178 P249 Meldolesi, Jacopo 23, 31 P72, P174, P177, P324 Melissano, Germano 55, 167, 168 P390, P473, P477, P727, P728, P738 Mellone, Renata 185 P486 Melloni, Giulio 3, 168 P537 Meloni, Carlo 167 Melzi, Lisa 24, 172 Melzi, Raffaella 99 Memoli, Massimo 97, 178 Menegon, Andrea 159 Menichini, Raffaele 183 Mennella, Roberta 168 Merati, Valentina 95 Mercalli, Alessia 99, 170 P141 Merello, Maria 182 Merlini, Federica 98, 170, 189 Merlino, Lino 129 Meschi, Franco 54, 62, 176 P63 Messa, Maria Cristina 153 P322, P451, P574 Messa, Massimo 167 Angelo Messaggio, Elisabetta 129 Messina, Graziella 71 P90, P200 Mezzadri, Umberto 170 Mezzi, Gianni Micali, Nicola Micheletti, Luisa Michev, Iassen Miggiano, Chiara Mignogna, Giovanna Milani, Davide Milani, Federica Milesi, Rita Miluzio, Annarita Minici, Claudia Minicucci, Fabio Minotti, Maria Grazia Miotto, Paolo Misci, Paolo Miserocchi, Elisabetta Mizzi, Anna Maria Mocci, Alessio Modorati, Giulio Moi, Davide Moiola, Lucia Molgora, Michela Mollica, Luca Molteni, Laura Molteni, Raffaella Monaco, Fabrizio Monari, Marta Mondino, Anna Monello, Alberto Monno, Antonella Montanaro, Claudio Monterisi, Cristina Montesano, Anna Monteverde, Stefania Monti, Alberto Monti, Giacomo Monti, Lucilla D. Montini, Eugenio Montoli, Serena Montorfano, Matteo 3, 170 P182 128 23 54, 167 183 53 24 3, 170 180 2 P7 96 P424 27, 50, 182 25, 153, 183 96 P370, P723 27 24, 172 P712 55 3, 170 24, 172 P712 72 P14 27, 182 P128, P131, P432 54, 176 145 P114, P616 99, 178 95 168 23 96, 109 P23, P62, P94, P386 55 71 P187, P394 55 153, 183 53 71 P90 27 55 53, 59 P105, P120, P383, P488, P504, P647 73, 87 P23 4, 176 P283 54, 167 P347, P372, P531, P715 248 - SAN RAFFAELE SCIENTIFIC INSTITUTE Montorsi, Francesco 4, 21, 187 P34, P142, P143, P144, P146, P150, P151, P152, P157, P158, P159, P162, P164, P165, P169, P251, P252, P253, P255, P256, P257, P258, P267, P268, P269, P293, P357, P365, P366, P367, P369, P501, P522, P524, P525, P526, P527, P528, P568, P594, P601, P628, P637, P638, P664, P718, P725 Montrasio, Cristina 145 P371 Mora, Stefano 53, 60, 176 P296, P619 Morandi, Angelica 188 Moreno Granados, 180 Gema Moelia Mores, Federica 172 Moresco, Rosa Maria 25, 153, 183 P220, P292, P317 Mori, Silvia 128 Moriggia, Stefano 167 Moro, Andrea 24 P214 Moro, Gianluigi 53, 170 P512 Morsica, Giulia 97, 174 Mortini, Pietro 24, 37, 172 P175, P280, P571, P620 Motta, Andrea 188 Motta, Chiara 180 Motta, Francesca 178 Motta, Micaela 153, 183 P625, P733 Movalli, Mariagrazia 25, 180 Mrak, Emanuela 53 Mukenge, Mvunde 3, 170 Mulas, Ines 170 Mungo, Maurizio 172 Muriana, Piergiorgio 168 Murino, Marcello 167 Musco, Giovanna 145, 150 P114, P236, P616 Musner, Nicolò 127 Mussardo, Marco 54, 167 Muzio, Luca 26 P68 Muzio, Marta 1, 9 P53 Muzza, Andrea 172 N Nai, Antonella Naio, Rita 128 P22, P195 166 Naldini, Luigi Nalin, Marco Nano, Rita 71, 72, 84, 85 P14, P86, P199 188 99, 123 P106, P384 96 24 Napoletano, Anna Napoletano, Francesco Nascimbene, Simona 167 P426, P614 Nassif, Reem 55 Natali Sora, Maria 27 Grazia Nava, Luciano 4, 187 P365 Negri, Anna XI Negri, Giampiero 3, 168 Negri, Giulio XI Negro, Aurora 2 P306 Neri, Margherita 73 P86 Neutro, Felice 183 Nicoletti, Roberto 185 P657, P680 Nifosi, Jacopo 3 Nigro, Annamaria 26 Nigro, Elisa 127 Nisoli, Ilaria 24 Nitti, Cinzia 167 Noè, Anna 176 P418 Notaristefano, Chiara 3, 170 Novella, Liliana 180 P698 Noviello, Maddalena 72 Nozza, Silvia 97, 174 Ntoufa, Stavroula 1 Ntzepa Batonga, 168 Jaques Nuzzaci, Valentina 180 Nuzzaco, Grazia 27 Nuzzi, Massimiliano 168 P272 O Occhi, Francesca Occhi, Simona Odazio, Veronica Odoni, Marta Ogliari, Anna Ogliari, Cristina 97 P350 24 P97 172 176 180 P661 170 AUTHOR INDEX - 249 Oldani, Alessandro Oliva, Laura Olivieri, Stefano Oppizzi, Michele Orellana, Daniel Origoni, Massimo Orlandi, Giacomo Ornaghi, Francesca Orsenigo, Elena Ortolano, Enrico Osnago, Ombretta Ossi, Cristina Ottolina, Jessica 25 P378 127 145 P222, P384, P679 55, 167 P466, P468, P639 26 97, 114, 176 183 127 3, 170 P447 189 P375 166 188 P297, P483 4 P Pacchioni, Manuela 183 Padovani, Alessandro 25 P121, P124, P205, P278, P587 Paesano, Pierluigi 185 Paganelli, Michele 3, 98, 115, 170 Pagani, Alessia 128 P22, P52, P195 Pagani, Elisabetta 27 P206, P215, P216, P219, P392, P701 Paganoni, Giorgio 172 Paglino, Gabriele 166 P338 Pajoro, Ursola 183 Pala, Maria Grazia 167 Pala, Mauro 71 Palermo, Gianluca 180 Palini, Alessio 159, 161 P48, P81 Palmigiano, Angela 145 P108 Palmisano, Ilaria 145 P108 Palmisano, Michela 95 Palonta, Francesca 172 Paloschi, Vera 178 Palumbo, Emilio 176 Palumbo, Lidio 183 Palumbo, Roberta 127 P265 Panacci, Nicoletta 54, 176 Panattoni, Martina 95 P23 Pancaldi, Alessandra 167 Panigada, Fausto 25, 180 Panizza, Pietro 153, 185 P719, P720 Pannese, Maria 128 Panzacchi, Andrea 153, 183 P220, P292 Panzeri, Maria Carla 159 Papa, Ilenia 188 Papa, Marco 167 Papagni, Massimiliano 183 Papale, Alessandro 26 Papaleo, Enrico 54, 176 P350 Pappalardo, Federico 55, 168 P272, P671 Pappone, Alessia 55, 166 P711 Pappone, Carlo 55, 166 P338, P341, P606, P673 Paratore, Flavio 172 Pardi, Ruggero 95, 100, 101 P23, P110 Pardini, Celia 145 Paris, Simona 23 Parlatini, Valeria 25, 180 Parma, Barbara 176 Parma, Lia 188 Parmiani, Giorgio 1, 2, 5, 11 P88, P168, P388, P490, P726, P732 Parolini, Danilo 170 Parolo, Caterina 185 Paroni, Moira 95 P299, P399 Parra, Rita Garcia 183 Parutto, Diana 183 Pasetti, Marcella 153, 183 P360 Pasi, Federica 54, 176 P191 Pasi, Massimo 129 Pasqualetto, Elena 127 Passaretti, Sandro 98, 116, 170 P540, P554 Passarin, Olga 24 Passerini, Gabriella 188 Passerini, Laura 73 P63, P450 Passoni, Arianna 176 Passoni, Paolo 153, 183 P361, P657 Pastore, Angela 96 Pastore, Matteo 99, 178 Rocco Pastori, Claudia 95, 174 Patricelli, Maria 188 Grazia P659 Pattarini, Elisabetta 188 Pavan, Giulia 27, 182 250 - SAN RAFFAELE SCIENTIFIC INSTITUTE Pavani, Giulia Pavoni, Ernesto Pazzi, Annamaria Peccatori, Jacopo 53 128 97, 174, 189 72, 183 P48, P81, P634 Pecciarini, Lorenza 188 P170, P285, P294, P295 Pedale, Rosa 97, 178 Pedrigi, Cristina 167 Pelizzoni, Ilaria 23 P479 Pella, Francesca 4 Pellegatta, Marta 128 Pellucchi, Federico 187 P255 Pema, Monika 128 Pengo, Niccolò 127 Pennucci, Roberta 23 Pepe, Annalisa 183 Pepe, Gino 183 Perani, Daniela 25, 38, 183 P121, P124, P125, P205, P214, P220, P278, P292, P454, P480, P587 Perani, Laura 71 Perduca, Alessandra 176 Perego, Elisabetta 27, 182 Stefania Perego, Jacopo 183 Peretti, Elena 54, 178 Peretti, Giuseppe M. 129, 142, 170 P709 Perfetti, Maria Grazia 178 Perini, Oriana 188 Perlini, Laura 23 Perna, Giampaolo 25, 180 Perna, Lucia 188 P359, P360, P511 Perotti, Fabio 188 Perotti, Valeria 170 Perrelli, Nicola 188 Perrotta, Cristiana 72 P474 Perseghin, Gianluca 53, 58 P42, P172, P404, P486 Persichini, Luisa 129, 178 Persico, Paola 176 Perticone, Francesca 54, 178 Perucca, Simone 128 Peruzzotti Jametti, 26, 182 Luca Pesce, Elisa 2 Peschechera, 27, 182 Francesco Pesenti-Gritti, Paola 180 P661 Pessina, Annalisa 55 Pessina, Patrizia 71 Petralia, Giovanni 187 P143, P602 Petrella, Giovanna 183 Petrelli, Alessandra 97, 178 Petrolini, Melissa 27 Petrone, Maria Chiara 3, 170 P183, P184, P552, P626, P730 Petrone, Micaela 4, 176 P489 Pezzani, Valeria 180 Piani, Cecilia 54, 178 P681 Piantoni, Lara 27 Piatti, Piermarco 54, 61, 178 P138, P383, P488, P504, P647 Picchio, Maria 153, 183 P139, P146, P322 Piccini, Flavia 188 Piccinini, Sabina 188 Piccinni, Monica 180 Piccioni, Lucia Oriella 25, 172 Piccoli, Susanna 172 Picozzi, Paola 71 Picozzi, Piero 24, 172 P175, P668 Piemonti, Lorenzo 98, 99, 120, 170 P21, P95, P106, P141, P503 Pieralli, Sandra 172 P620 Pieri, Alessandro 180 Pierro, Luisa 24, 172 P713 Pievani, Michela 27 Pileri, Massimo 176 Pilla, Lorenzo 2 Pintonello, Maria 159 Luisa Pirola, Barbara Maria 188 Pirola, Serena 54, 176 Pirovano, Adele 25 P539 Pisani, Matteo 55 P466, P468, P639 Piscopo, Maria 176 Antonietta Pisoni, Serena 72 Pistarà, Alissia 180 Pistis, Giorgio 128 Pistocchi, Anna 71 Pistoni, Mariaelena 71 Pitea, Marco 176 Pizzamiglio, Carlo 153, 183 Pizzetti, Giuseppe 167 Pizzi, Sara 153 Pizzo, Riccardo XXI Pizzocolo, Cecilia 97 Plati, Tiziana 73, 74 AUTHOR INDEX - 251 Pluchino, Stefano Podini, Paola Poggi, Alessandra Poggi, Antonella Poggiali, Erika Pogliaghi, Manuela Poletti, Sara Poletti, Valentina Poli, Davide Poli, Guido Politi, Ernestina Politi, Letterio Salvatore Poloniato, Antonella Polverigiani, Silvia Pontesilli, Silvia Pontiggia, Adriana Pontillo, Marina Pontiroli, Barbara Ponzi, Elena Ponzoni, Maurilio Porrello, Emanuela Porrino, Lucy Potenza, Maria Teresa Pozzi, Alessandro Pozzi, Federica Pozzi, Paola Pozzobon, Gabriella Prada, Ilaria Pradella, Alessandra Praderio, Luisa Prati, Matteo Premoli, Sergio Previtali, Stefano C. Privitera, Daniela Privitera, Ylenia Prodi, Dionigio Protti, Maria Pia Provasi, Elena Psacharopulo, Daniele Puccetti, Patrizia Pucci, Ferdinando Puglisi, Armando 26, 45 P67, P68, P325, P578, P582, P641 23 P174, P324, P362 185 27, 182 128 97 25 P700 128 24 P492 96, 106 P210, P261, P298, P496 25, 180 153, 157, 172 P14, P286, P684 54, 176 159 24, 172 25, 180 P343, P703 188 P256 55 XI 188 P16, P70, P76, P129, P170, P273, P285, P286, P295, P327, P331, P571 26 P122 97 176 129 183 XI 54, 176 23 180 97, 178 172 180 26, 44 P97, P100, P122, P129, P448, P565 27 167 24 96, 110 P96, P222, P387 72 55 167 72 P14 3, 168 P537 Pulitanò, Carlo Pultrone, Cinzia Pusterla, Tobias Puzzovio, Maria 98, 170 P320, P355, P377, P542, P570, P588, P589 97 127 53, 176 Q Quartagno, Rita Quattrini, Angelo 178 26, 42 P32, P97, P100, P122, P129, P362, P502, P559 Quattrocchi, Tiziana 168 Querques, Marialuisa 129, 178 R Rabaiotti, Emanuela 4, 176 P415, P489 Raber, Marco 187 P158, P365 Racanicchi, Leda 98 Racca, Sara 188 Racchetti, Gabriella 23 P177 Raccosta, Laura 2 P306 Radaelli, Maria Grazia 54, 178 Radaelli, Marta 27 P432 Radinovic, Andrea 55, 166 P338, P341 Ragogna, Francesca 53 P42 Rainelli, Cristina 2 Rainone, Francesco 129, 178 Raiteri, Elisabetta 2 Rama, Paolo 24, 36, 172 P546, P547, P640, P660, P678, P712 Ramella, Barbara 3, 172 Ramoni, Andrea 24, 172 Rampoldi, Luca 128, 140 P535 Ramponi, Monica 188 Ranzani, Marco 73 Rapallo, Maria Pia 185 Rapati, Dino 168 Rapisarda, Eugenio 153, 183 Raschi, Alessandra 25, 167 Ratti, Deborah 174 P572 Ratti, Manuela 95 Ratti, Maria Monica 25, 180 Raucci, Angela 127 P120, P187 252 - SAN RAFFAELE SCIENTIFIC INSTITUTE Ravanetti, Lara Ravizza, Alfredo Rebagliati, Paola Recanati, Paola Recchia, Alessandra Redaelli, Chiara Regali, Laura Reiss, Laura Reni, Michele 96 172 XI 3, 172 128 145 24, 172 XI 4, 20, 183 P95, P308, P312, P314, P361, P510, P636, P657 Resnati, Massimo 128 P414 Restelli, Elisa 172 Resti, Antonio 172 Giordano P285, P286, P295 Restuccia, Umberto 127 P208 Riba, Michela 145 Ribecca, Antonella 172 Ricci, Vincenzo 183 Ricciardi, Sara 24 P58 Riccitelli, Gianna 27 P126 Ricupito, Alessia 96 Ridolfi, Cristina 3, 170 Rigamonti, Andrea 176 Rigamonti, Marco 153, 183 Rigamonti, Nicolò 96 Rigamonti, Riccardo 183 Rigatti, Lorenzo 187 Rigatti, Patrizio 4, 187 P34, P142, P143, P144, P146, P150, P151, P158, P162, P251, P255, P256, P258, P357, P365, P367, P526, P602, P637 Righi, Claudio 153, 172 P509 Rigoni, Lara 153 Rimicci, Maria 183 Antonia Rinaldi, Rosanna 159 Riolo, Sabrina 183 Ripamonti, Anna 73 Ripamonti, 23 Maddalena Riva, Elisabetta XI Riva, Marco 24 P365 Riva, Nilo 26 P122, P129, P559 Rivoltini, Paola 170 Rizzato, Elisa 176 Rizzi, Chiara 96 P185 Rizzo, Annalisa 182 P687 Rizzo, Nathalie 188 P586, P709 Rocca, Alda 24 Rocca, Maria Assunta 27, 46 P28, P127, P131, P215, P216, P218, P219, P250, P392, P416, P429, P514, P562, P563, P608, P696, P697 Rocchetti, Simona 189 P288 Rocchi, Martina 159, 188 Rocchini, Lorenzo 4, 187 P255 Rocco di Torrepadula, 25, 180 Caterina Antonia Eloisa Rodegher, 27, 182 Mariaemma P250, P432 Rodighiero, Maria 185 Grazia Rofena, Simone 54, 176 Rognone, Alessia 4, 183 Rojo, Carmen 172 Rolla, Serena 188 Roma, Andrea XXI Romano, Maria XXI Romano, Silvana 183 Romano, Vittorio 167 Romero, Lilian 188 Roncarolo, Maria XI, XII-XV, 72, 73, 74, 83, 88, 91, 176 Grazia P8, P37, P47, P48, P63, P199, P291, P418, P419, P449, P450, P518 Ronchetti, Clara 174 Ronchi, Paola 188 Ronchi, Paolo 180 Rondinelli, Beatrice 2 Ronfani, Lorenza 159 Ronzoni, Monica 4, 183 P284, P377 Ronzoni, Riccardo 127 P116 Rosa, Isabella 55 Rosa, Susanna 54, 176 Roscigno, Marco 4, 187 P143, P158, P162, P365, P602 Roselli, Emanuela 73 Anna Rossetti, Maura 73 Rossi, Claudia 73 P70 Rossi, Erica 25, 180 Rossi, Michela 172 Rossi, Paolo 27, 182 P580 Rossi, Simone 183 Rossini, Alessandro 54, 178, 189 AUTHOR INDEX - 253 Rossini, David Rossini, Silvano Rossodivita, Alessandra Rossoni, Gilda Rovani, Stefano Rovelli, Elisabetta Rovelli, Rosanna Rovere-Querini, Patrizia 180 P703 72, 82, 188, 191 P48, P81, P295 167 183 185 23 54, 176 71, 80 P24, P44, P45, P187, P307, P340, P394, P440 Roveri, Luisa 27, 182 Rowe, Isaline 128 Rozza, Lucia 183 Ruberto, Carlo 98 Rubinacci, Alessandro 53, 58 P409, P512 Ruffini, Chiara 25, 180 Ruffini, Francesca 26 Ruggeri, Annalisa 72 P330 Ruggeri, Laura 55 Ruggeri, Valentina 2 Rusconi, Vega 174 Russo, Alberto XXI Russo, Gianni 54, 176 Russo, Vincenzo 2, 12 P96, P306, P321, P490, P609 S Sabbadini, Maria 97, 113, 178 Grazia Sabbioni, Elisa Letizia 176 Saccà, Antonino 187 P144, P251, P258 Sacchi, Angelina 2 P92, P279 Sacchi, Luisa 172 Sacchi, Stefania 166 P338 Sacco, Vincenzo 183 Sacconi, Massimo 188 Saccucci, Stefania 128 Saccuman, Cristina 25 P203 Saibene, Alessandro 54, 178 Sala, Cinzia 128 P461 Sala, Simone 55, 166 P338 Sala, Stefania 27 P416 Sala, Stefania Salandini, Maria Chiara Salani, Giuliana 96 P556 3 26 P68 Salaris, Davide 55 Salerno, Anna 55 P339 Salmaggi, Chiara 178 Salmaso, Flavia 174 P572 Salomoni, Gabriella 188 Salomoni, Giuliana 180 Salonia, Andrea 4, 187 P144, P147, P148, P150, P151, P155, P158, P161, P251, P254, P255, P256, P357, P367, P526, P637 Salpietro, Stefania 174 Salvadori, Giovannella 183 Salvioni, Marco 185 Salvo, Fulvio 97, 178 Samanes Gajate, Ana 153, 183 Maria P451 Samarati, Maria XI Sammartino, XXI Piergiorgio Sampietro, Francesca 53 Sangalli, Mattia 187 P365 Sanna, Alberto XXI, 188 Sanpaolo, Michela 188 Sanpietro, Francesca 188 Santagostino, 166 Andreina Santagostino, Ilaria 3 Santambrogio, 188 Graziella P285 Santambrogio, Paolo 23 Santambrogio, Sara 73 P535 Santarella, Roberto XI Santinelli, Vincenzo 55, 68, 166 P338, P341 Santoro, Alessia 180 P284 Sanvito, Francesca 159, 162, 188 P23, P70, P187, P222, P384 Saporiti, Nicoletta 178 Sarno, Lucio 180 P698 Sartirana, Claudia 73 Sartori, Serenella 128 Sassi, Isabella 188 P283 Sassi, Monica 188 P260 254 - SAN RAFFAELE SCIENTIFIC INSTITUTE Sauer, Aisha Saveri, Paola Savi, Annarita Savi, Maurizio Saviano, Massimo Savio, Michol 73 127 183 XI 55, 166 95 P110 Sbalchiero, Andrea 183 Scandroglio, Anna 168 Mara P715 Scapaticci, Emanuele 4, 187 Scaramuzza, 73, 74 Samantha Scarfò, Lydia 1 Scarlato, Marina 26, 182 P122, P202 Scarlatti, Gabriella 96, 111 P20, P410, P470, P556 Scarpellini, Paolo 174 P483 Scattoni, Vincenzo 4, 187 P146, P151, P158, P162, P267, P322, P365 Scavini, Marina 99, 122 P141, P256 Schaeffer, Céline 128 Schiaffino, Maria 145, 148 Vittoria P108 Schiatti, Eliana 27, 182 Schiavi, Davide 167 Schipani, Stefano 153, 183 Schira, Giulia 72 Sciarrone Alibrandi, 129, 178 Maria Teresa Scielzo, Cristina 1 P53, P54, P57 Scifo, Paola 25, 153, 159, 183 P42, P203, P356 Sciorati, Clara 72 Scola, Elisa 24, 159 Scomazzoni, 153, 172 Francesco P264, P509 Scotti, Celeste 129, 170 P709 Scotti, Fabrizio 24, 172 Scotti, Giuseppe 153, 159, 162, 172, 173 P127, P213, P215, P264, P356, P379, P509, P642, P736 Scotti, Raffaella 178 Scotti, Roberta 24, 172 Secchi, Antonio 97, 99, 113, 178 P21, P106, P141, P405 Secchi, Massimiliano 95 P437 Seghezzi, Laura 188 Selleri, Silvia 73 Selli, Simone 153, 183 Selmi, Raed Suliman Salmi Semeraro, Gianluca Senesi, Pamela Serafin, Riccardo Serafini, Audrey Serafini, Giorgia Seresini, Samantha Sergi Sergi, Lucia Serra, Carlo Sessa, Alessandro 176 174 53 188 54 73 96 72 24 24 P31 Sessa, Giuseppina 23 Sessa, Luca 127 Sessa, Maria 27, 48, 74, 92, 182 P132, P417, P449, P686 Sestini, Stefano 3, 168 Setaccioli, Marco 24, 172 Setola, Emanuela 54 P383, P488, P504, P647 Sferrazza, Barbara 181 P480, P679 Sforzini, Laura 25, 180 Sgaramella, Paola 176 Sibilia, Mauro 27 Siccardi, Antonio 127, 132 Sigismondi, Cristina 4 Signorotto, Patrizia 188 Silipigni, Carmen 167 Siliprandi, Francesca 180 Silva, Carlo 188 Silvani, Paolo 55, 189 P276 Silvestri, Laura 128 P22, P52, P190, P195, P274 Simionato, Franco 153, 172 P509 Simonelli, Pasquale 153, 183 Simonetti, Giorgia 1 Simonini, Marco 129, 178 P102, P271 Sinem, Kara 26 Sioli, Barbara 188 Sioli, Fabrizio 55 Sironi, Elisabetta 188 P81 Sironi, Francesca 95 Sirri, Alessandra 128 Sirtori, Marcella 53 Sirtori, Paolo 170 Sitia, Giovanni 96 P14, P69 Sitia, Roberto 127, 130, 131 P83, P109, P116, P289, P328, P346 Sizzano, Federico 71 Slaviero, Giorgio 178 Slim, Najla 153 AUTHOR INDEX - 255 Smeraldi, Enrico 180, 181 P343, P379, P452, P533, P539, P700, P703 Smid, Maddalena 54, 176 P191 Snider, Silvia 24, 172 Socci, Carlo 98, 117, 170 P141 Soccio, Antonella 183 Sogno Valin, Paola 176 Soldarini, Armando 188 Soldini, Laura 188 Soliman, Clara 176 P418 Sommariva, Elena 145, 188 Soprana, Elisa 127 Sora, Nicoleta 55, 166 Sordi, Valeria 98, 170 P141, P503 Soria, Alessandro 174 P556 Soriani, Nadia 188 P119 Sosio, Corrado 129, 170 Sovena, Gloria 2 Sozzi, Francesco 187 Spada, Danilo 25 Spagnolo, Daniele 176 Spagnolo, Francesca 26, 182 Spagnolo, Pietro 153, 183 Spagnuolo, Marco 183 Spagnuolo, Vincenzo 97, 174 Spatola, Chiara 180 P661 Spelta, Sara 55 Spessot, Marzia 189 Spiga, Ivana 188 Spiliotoupulos, 145 Dmitrios Spina, Annunziata 188 Spinapolice, Elena 183 Spinelli, Alessandra 24, 172 Spinelli, Antonello 188 Spinelli, Maria 27 Carmela Spitaleri, Andrea 145 P236 Spoladore, Roberto 55, 166 P339, P592 Spotti, Donatella 129, 178 P249, P403 Spreafico, Anna 4 P87 Squadrito, Mario 72 Squilla, Mario 167 Squillante, Simone 170, 189 P540 Stabilini, Angela Staudacher, Carlo Stefani, Chiara Stefani, Rossella Stella, Marco Stella, Paola Stenirri, Stefania Stoppani, Monica Storti, Maurizio Strada, Elena Straffi, Laura Strauss, Laura Stucchi, Stefano Suardi, Nazareno Sudati, Francesco 98 3, 16, 98, 170, 171 P447, P540, P657 97, 176 XI, XVI-XVII 98, 170 178 P249, P271 145, 188 P371, P411, P646 172 178 187 P143, P602 26, 182 73 153, 183 4, 187 P143, P144, P150, P156, P252, P257, P259, P268, P269, P293, P367, P522, P523, P524, P526, P527, P638, P718 153, 183 P317 T Taccagni, Gianluca 188 P283, P327 Tacchini, Simona Irma 185 Taglietti, Maria 189 Vittoria Talarico, Anna 188 P294 Talarico, Daniela 128 Tambani, Laura 23 Tamburini, Andrea 3, 170 Marco Tambussi, Giuseppe 97, 112, 174 P241, P243 Tantardini, Cristina 178 P102, P271 Taramasso, Maurizio 167 Tarlasco, Camilla 55 Tassan Din, Chiara 174 Tassara, Michela 3 P634 Tassi, Elena 96 Taveggia, Carla 27, 47 P228 Taverna, Rosaria 172 Tavilla, Alessandro 183 Tedesco, Saverio 71 Teggi, Roberto 25, 172 P658, P702, P731 Tei, Laura XI 256 - SAN RAFFAELE SCIENTIFIC INSTITUTE Terreni, Maria Rosa Terruzzi, Ileana Tesfaghebriel, Habtom Testa, Camilla Testa, Manuela Testa, Martina Testoni, Pier Alberto 188 P571, P620 53 P404, P597 27, 182 180 97 25, 180 3, 15, 98, 170 P66, P103, P178, P179, P180, P182, P505, P540, P548, P550, P626, P627, P633 Testoni, Sabrina 3 Tettamanti, Andrea 25 Tettamanti, Marco 25, 183 P203, P214 Teuta, Domi 26 Tiberi, Simon 174 P558 Tiboni, Francesca 73 Tinelli, Elisa 127 P32 Tiraboschi, Mirta 97, 178 Tirloni, Laura 180 Todde, Sergio 153, 183 Todeschini, Paola 153, 183 Toffolo, Franca 188 Tomaello, Luca 189 Tomajer, Valentina 170, 189 P447 Tomasi, Serenesse 188 Tomasoni, Daniela 73 Tomasoni, Romana 96 Tomassini, Loredana 188 Toniolo, Daniela 128, 136 P54, P107, P196, P659 Tonlorenzi, Rossana 71 Tonon, Giovanni 2, 12 Tonti, Elena 96 Tornaghi, Paola 96 Torriani, Gabriele 188 Torta, Federico 127 P209, P316 Totaro, Antonio 23 Touvier, Thierry 71 Travi, Giovanna 174 Trbos, Mladen 188 Tremolada, Gemma 24, 53, 172 Tresoldi, Cristina 188 Tresoldi, Eleonora 73 Tresoldi, Moreno 97, 178 Trimarchi, Matteo 3, 172 P137 Trimarco, Amelia 27 Triolo, Daniela 26 P122, P362 Tripoli, Vincenzo Trisciuoglio, Lisa Truci, Giulio Tshomba, Yamume Tuoro, Antonio Turchiano, Giandomenico Turi, Stefano Turolla, Elia Anna Tuscano, Antonella Tutolo, Manuela 183 127 182 55, 168 P390, P391, P422, P738 3 71 55 153, 183 96 187 U Uberti-Foppa, Caterina Uccellatore, Annachiara Ugarte, Gonzalo Ungari, Silvia Ungaro, Daniela Ungaro, Federica Usuelli, Vera 97, 174 P247, P421 54, 178 71 73 27, 182 24 127 P316 V Vaccari, Ilaria Vaghi, Mauro Vago, Luca Vago, Riccardo Vailati, Cristian Valentini, Giovanna Valeri, Roberto Valle, Andrea Valle, Micol Valsasina, Paola Valsecchi, Luca Valtolina, Veronica Valtorta, Federica Valtorta, Flavia Vandoni, Irene Vangelista, Luca Vanni, Roberto Vannulli, Raffaele Vanoli, Giovanna Vanzulli, Laura Varagona, Roberto 27 153, 183 P317 72 P48, P81 145 3, 170 170 170 98 172 P175 27 P217, P416, P534, P631 54, 176 72 188 23, 28, 29 P98, P176, P456, P649 183 P53 95, 103 P437, P672 180 183 183 25, 180 185 AUTHOR INDEX - 257 Varale, Roberta Vassena, Lia Vavassori, Stefano 170, 189 95 96 P116 Vecellio, Magda 178 Velikova, Svetla 26 Venditti, Alessandra 72 Venneri, Mary Anna 72 P14 Venturini, Massimo 153, 185 P377, P727 Vergani, Andrea 97, 178 P385 Vergara, Pasquale 55, 166 Vermi, Anna Chiara 55 P135 Verona, Chiara 183 Francesca P327 Verzini, Alessandro 167 P530 Veschini, Lorenzo 1 Vezzoli, Giuseppe 129, 178 P368 Vezzoli, Michela 71 Vezzulli, Paolo 24, 159, 172 Viale, Edi 3, 170 P447, P505 Vicari, Aurelio 183 Vicedomini, Gabriele 166 P338 Vicenzi, Elisa 97, 111 P261, P298, P461, P576 Vicini, Sauro 188 Viganò D’Angelo, 53, 188 Silvana P192 Viganò, Fiammetta 128 P222 Viganò, Giorgio 167 Viganò, Maria Grazia 4, 183 P87 Viganò, Maurizia 172 Viganò, Riccardo 4, 176 P489 Vignali, Andrea 3, 170 P538, P541 Vigone, Maria 54, 176 Cristina P420 Villa, Anna 73, 90 P43, P61, P64 Villa, Chiara 159 Villa, Daniele 180 Villa, Eugenio 4, 183 P87, P377, P413 Villa, Isabella 53 P512 Villa, Maria Cristina 176 Villa, Silvana 180 Villa, Valentina Vinci, Raffaele 54 129 P724, P735 Vino, Arianna 3 Viscardi, Matteo 54, 176 P518 Visciano, Maria Luisa 95 Visco, Francesca 174 Visigalli, Ilaria 73 Visintini, Raffaele 25, 180 P242, P682 Vismara, Chiara 27, 182 Vitali, Giordano 4, 183 Pietro P377 Vitali, Matteo 170 Vizzuso, Domenica 127 Voci, Carlopietro 3, 167, 168 Volontè, Maria 27, 182 Antonietta Volta, Viviana 2 P344 Vuotto, Roberto 27 W Weber, Giovanna Williams, David Wodarczyk, Claas Wozinska, Monika Wrabetz, Lawrence 54, 61, 176 P420 188 128 128 127, 134 P32, P73, P97, P227, P499 Y Yacoub, Mona-Rita 95, 178 Z Zacchetti, Daniele Zagato, Laura Zallocco, Diego Zamai, Moreno Zambelli, Matilde Zamboni, Michele Zambroni, Desirée Zamproni, Ilaria Zanardi, Raffaella Zanella, Elisa 23 P479 129 P102, P702 96 1 P74, P482 188 24, 181 P454, P480 128 P97 53, 176 25, 180 P703 128 258 - SAN RAFFAELE SCIENTIFIC INSTITUTE Zangrillo, Alberto Zanni, Giuseppe Zannini, Piero Zanoni, Angela Zanoni, Annalisa Zanoni, Matteo Zanotti, Lucia Zanussi, Monica Zappalalio, Paola Zatti, Alessandra Zeni, Daniele Zerbi, Alessandro Zerbi, Valerio Zerbini, Gianpaolo Zimarino, Vincenzo 55, 66, 168, 170, 189, 193 P140, P272, P669, P671, P676, P677, P715, P717 187 P144, P251, P255, P256, P637 3, 17, 168 P532, P537 183 180 187 P365, P367 26 188 P81 188 2 145 98, 115, 170 P95, P288, P375, P549, P657 55 P614 53, 57 23 Zino, Elisabetta Zito, Ester Zito, Laura Zocchi, Maria Raffaella Zonari, Erika Zoppei, Gianna Zordan, Paola Zorzi, Claudia Zuber, Veronica Zucchelli, Chiara Zucchinelli, Patrizia Zucconi, Marco Zuffada, Francesca Zuffardi, Orsetta Zuliani, Walter 188 P48 127 P109 71 95, 104 P82 72 P14 XXI 23 P475 180 170, 189 145 183 25, 181 P333, P335, P378, P445, P454 166 188 P659 3, 170 P541 San Raffaele Scientific Institute Via Olgettina, 60 20132 Milano Tel. 0236431 www.sanraffaele.org