Scientific Report 2013

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1 Scientific Report 2013

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3 Scientific Report 2013

4 Cover image by Massimo Degano (see Biocrystallography Unit, page 151, figure 22): Active site of the IAGNH enzyme from T. brucei bound to a nanomolar inhibitor. Knowledge of the active site cavity features (green transparent surface) allows the modification of the compound (yellow sticks) to enhance its activity. Some of the images in this book has been published in scientific papers: Figure 2, p. 16: Modified from: Leukemia: 2013; 27(11): doi: /leu Figure 6, p. 50: Modified from: J. Clin. Invest. [published online ahead of print June 17, 2014] doi: /jci74664 Figure 8, p. 55: Modified from: Neurobiol. Aging: 2013; 34(11): e13-e18 doi: /j.neurobiolaging Figure 9, p. 57: Neuropsychopharmacology: 2013; 38(2): doi: /npp Figure 15, p. 88: J. Transl. Med Dec 13;11:310 doi: / Figure 20, p. 125: J. Allergy Clin. Immunol.: 2014; 133(3): e10 doi: /j.jaci Figure 34, p. 199: Cover image in: Tissue Engineering - Part A: 2014; 20(5-6) Figure 36, p. 216: FEBS J.: 2014; 281(1): doi: /febs Figure 37, p. 217: Curr. Biol.: 2014; 24(4): doi: /j.cub Figure 40A, p. 230: Modified from: Mol. Cell. Biol.: 2013; 33(18): doi: /MCB Figure 43, p. 251: Neurology: 2013; 81(2): doi: /WNL.0b013e31829a33f8 Figure 46, p. 263: Proteomics: 2013; 94: doi: /j.jprot Edited by the San Raffaele Library Layout project by Rolando Cassinari Cover design by the San Raffaele Marketing, Fundraising & Communication Office Printed by Grafiche Parole Nuove, Brugherio

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7 INDEX INTRODUCTION IX Scientific Directors' Introduction XII A short visual history of the Institute XX San Raffaele Scientific Retreat 2013 XXI 2013 Seminars and lectures XXIV DIVISION OF MOLECULAR ONCOLOGY 5 Introduction by the Directors 11 Research Units Lymphoid malignancies Unit 12 Biology of multiple myeloma 12 Cell activation and signalling 13 Tumour microenvironment 13 Immuno-biotherapy of melanoma and solid tumors Unit 14 Cancer gene therapy 15 B-cell neoplasia Unit 15 Functional genomics of cancer Unit 16 Lymphoid organ development Unit 17 Molecular histology and cell growth Unit 18 Preclinical models of cancer Unit 18 Tumor biology and vascular targeting Unit 19 Clinical Research Units Digestive and pancreatico-biliary endoscopy Unit 20 Endosonography: diagnostic and therapeutic endoscopic ultrasound 20 Gastrointestinal surgical oncology Unit 21 Head and neck oncology Unit 21 Multidisciplinary group for thoracic surgical oncology 22 Oncogenesis in liver neoplasms Unit 23 Pancreatic cancer Unit: biology and new therapeutic approaches 23 Pathology Unit 24 Clinical lymphoid malignancies 24 Gynecologic oncology 25 Medical oncology Unit - Clinical trials 26 Medical oncology Unit - Phase I and lung cancer clinical trials 26 Onco-hematology 27 Urological Research Institute (URI) 28 Introduction by the Director 28 Research Units Urological pre-clinical research Unit 29 Functional urology 29 Clinical Research Units Prostate cancer 30 Bladder cancer Unit 30 Renal cancer Unit 31 Sexual medicine Unit 31 Selected publications 32 Selected publications, URI 33 DIVISION OF NEUROSCIENCE 37 Introduction by the Directors 44 Research Units Neuropsychopharmacology Unit 45 Rett syndrome research group 46 Cell adhesion Unit 46 Cellular neurophysiology Unit 47 Developmental neurogenetics Unit 48 Neurobiology of learning Unit 49 Proteomics of iron metabolism Unit 49 Stem cells and neurogenesis Unit 50 Molecular genetics of mental retardation Unit 51 Clinical Research Units Acute brain protection, Acute post-operative pain, Drugs and central nervous system Unit 52 Cognitive neuroscience Unit 52 Experimental neurosurgery Unit 52 Eye repair Unit 53 Functional neuroradiology Unit 54 In vivo Human molecular and structural neuroimaging Unit 55 Neuroothology Unit 56 Psychiatry and clinical psychobiology 56 Sleep medicine 57 Clinical psychology 58 Motor function rehabilitation 59 Institute of Experimental Neurology (INSPE) 60 Introduction by the Director 60 Research Units 61 Experimental neuropathology 61 Experimental neurophysiology 61 Molecular genetics of behaviour 62 Neuromuscular repair 62 Neuroimmunology Unit 63 Clinical neuroimmunology 64 Immunobiology of neurological disorders 65 Neuroimaging research Unit 66 Neuroimaging of CNS white matter 66 Human inherited neuropathies Unit 67 Axo-glia interactions Unit 68 Clinical Research Units Inflammatory CNS disorders Unit 69 V

8 INDEX Cerebrovascular disorders 69 Memory disorders 70 Movement disorders 70 Neuromuscular disorders 71 Paroxysmal events 71 Selected publications 72 Selected publications, INSPE 73 DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES 81 Introduction by the Directors 85 Research Units Coagulation and platelet biology Unit 86 Cardiodiabetes & core Lab 87 Complications of diabetes 87 Metabolism, nutrigenomics and cell differentiation 88 Bone metabolism Unit 89 Coagulation service & thrombosis research Unit 89 Pediatric endocrinology research 90 Clinical Research Units Diabetes and endocrinology Unit 91 Cardio-metabolism and clinical trials 91 Fetal-maternal medicine 92 Clinical pediatric endocrinology 92 Diabetes and metabolic diseases in children and adolescents 93 Neonatology 93 Structural heart disease Unit 94 Cardiopulmonary clinical physiology Unit 95 Cardiovascular interventions Unit 95 Center for arrhythmia research 96 Echocardiography Unit 96 Ischaemic heart disease, heart failure and echocardiography Unit 97 Organ protection in critically ill patients, Advanced cardiac failure and mechanical supports Unit 98 Strategic research on heart failure Unit 99 Study and treatment of aortic disease Unit 99 Vision first Unit 100 Selected publications 101 DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY 107 IIntroduction by the Directors 112 Research Units Angiogenesis and tumor targeting Unit 113 Functional genetics of muscle regeneration 113 Neural stem cell biology 114 Autoimmunity & vascular inflammation Unit 114 Innate immunity and tissue remodelling 115 Experimental hematology Unit 116 Gene expression and muscular dystrophy Unit 117 Leukemia immunotherapy Unit 118 Molecular and functional immunogenetics Unit 118 Clinical Research Units Hematology and hematopoietic stem cell transplantation Unit 119 Immunohematology and transfusion medicine Unit 119 The San Raffaele-Telethon Institute for Gene Therapy (HSR-TIGET) 120 Introduction by the Director 120 Research Units Gene transfer technologies and new gene therapy strategies Unit 121 Gene/Neural stem cell therapy for lysosomal storage diseases 121 Gene therapy for WASP/Omenn Unit 122 Gene transfer into stem cells Unit 122 Hematopoietic stem cell based gene therapy for the treatment of lysosomal storage disorders Unit 123 Immunological tolerance Unit 123 Genetic autoimmune diseases 124 Pathogenesis and therapy of ADA-SCID Unit 125 Safety of gene therapy and insertional mutagenesis Unit 126 Tolerogenic dendritic cells Unit 126 Clinical Research Units PCRU - Gene therapy for Wiskott-Aldrich Syndrome 127 PCRU - ADA gene transfer into hematopoietic stem cells for the treatment of ADA-SCID 127 PCRU - Clinical trial of gene therapy in metachromatic leukodystrophy 128 Selected publications 129 Selected publications, HSR-TIGET 130 DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES 139 Introduction by the Directors 146 Research Units Immunopathology Unit 147 Cellular and molecular allergology 147 Human virology 148

9 INDEX Protein engineering and therapeutics 148 γδ T cells in innate and adaptive immunity 149 Immunobiology of HIV 150 AIDS immunopathogenesis Unit 150 Biocrystallography Unit 151 Cellular immunology Unit 152 Dynamics of immune responses Unit 152 Emerging bacterial pathogens Unit 153 Experimental immunology Unit 154 Infection and cystic fibrosis Unit 154 Leukocyte biology Unit 155 Lymphocyte activation Unit 156 Tumor immunology Unit 156 Viral evolution and transmission Unit 157 Viral pathogens and biosafety Unit 158 Clinical Research Units Management and antiretroviral treatment of HIV infection 159 Neurovirology 159 Study and treatment of hepatotropic viruses related diseases 160 Vaccine and immunotherapy 161 Clinical immunopathology and advanced medical therapeutics Unit 161 Clinical transplant Unit 162 Pancreatic tumors Unit: immunotherapy and β cell function substitution 162 Gynecological cancers immunology 163 Immunology in liver neoplasms 163 Obesity and bariatric surgery 164 Clinical hepato-gastroenterology 164 Digestive pathophysiology 165 Diabetes Research Institute (DRI) 166 Introduction by the Directors 166 Research Units Experimental diabetes 167 β cell biology Unit 167 Immune-mediated diseases Unit: from pathogenesis to treatment 168 Clinical Research Units Prevention in Type 1 diabetes Unit 169 Epidemiology & data management 169 Islet transplantation 169 Childhood diabetes 170 Selected publications 171 Selected publications, DRI 172 DIVISION OF GENETICS AND CELL BIOLOGY 183 Introduction by the Directors 186 Research Units Protein transport and secretion Unit 187 Age related diseases 188 Molecular immunology 188 Chromatin dynamics Unit 189 In vivo Chromatin and transcription 190 Molecular dynamics of the nucleus 191 Biology of myelin Unit 191 Biomolecular mass spectrometry Unit 192 European Institute for Research in Cystic Fibrosis (IERFC) 192 Genetics of common disorders Unit 193 Intracellular signaling pathways Unit 193 Molecular basis of polycystic kidney disease Unit 194 NeuroGlia Unit 194 Regulation of iron metabolism Unit 196 Molecular genetics of renal disorders Unit 196 Clinical Research Units Dento-facial histopathology Unit 197 Genomics of renal diseases and hypertension Unit 197 Reproductive sciences Lab 198 Tissue engineering and biomaterials 199 Selected publications 201 CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS 211 Introduction by the Directors 213 Research Units Neurogenomics Unit 214 Genome function Unit 215 Biomolecular NMR Laboratory 215 Genomic Unit for the diagnosis of human pathologies 216 Organelle biogenesis and motility Unit 217 Proteome biochemistry Unit 218 Selected publications 219 EXPERIMENTAL IMAGING CENTER 225 Introduction by the Directors 228 Research Units Advanced fluorescence microscopy and nanoscopy research Unit 229 Dynamic fluorescence spectroscopy in biomedicine 230 Mouse functional genetics Unit 231 Clinical Research Units VII

10 INDEX Clinical and experimental radiology Unit 232 High technology in radiation therapy Unit 232 Medical physics Unit 233 Molecular imaging Unit 233 Neuroradiology research group 234 Service Units ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center 235 Intravital microscopy 236 Preclinical MRI and US facility 237 Pre-clinical PET facility 238 Selected publications 239 RESEARCH PROGRAMMES 243 Brain Regeneration using medical Devices, Gene vectors and stem cells (BRIDGE) 243 Program in Immunology and Bio-immunotherapy of Cancer (PIBIC) 245 Islet Trasplantation Program (ITP) 247 Human Brain Invivo Mapping with neuroimaging (BRAINMAP) 249 Bone Physiopathology Program (BoNetwork) 252 Correlates of HIV-Associated Immune Response Modulation program (CHARM) 254 Microenvironment and Genes in Cancers of the Blood (MAGIC) 256 FACILITIES 259 CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis 260 FRACTAL, Flow cytometry Resource, Advanced Cytometry Technical Applications Laboratory 261 CERMAC, Centre of Excellence of High Field Magnetic Resonance 262 ProMiFa, Protein Microsequencing Facility 262 Mouse histopathology 263 THE ETHICS COMMITTEE 266 THE CLINICAL DEPARTMENTS 269 Cardio-thoracic-vascular Department 271 Selected publications 274 Department of general and specialistic surgery 276 Selected publications 279 Head and neck Department 280 Selected publications 282 Department of infectious diseases 284 Selected publications 286 Maternal and child health Department 287 Selected publications 289 Department of internal and specialistic medicine 291 Selected publications 292 Department of clinical neuroscience 294 Selected publications 297 Department of neurology 299 Selected publications 300 Department of onco-haematology 301 Selected publications 302 Department of medical oncology 304 Selected publications 305 Department of radiology 307 Selected publications 309 Department of urology 310 Selected publications 312 CLINICAL SERVICES 313 Pathology 315 Nuclear medicine 316 Radiotherapy 316 Laboratory medicine 317 Immunohematology and transfusion medicine service 317 Emergency medicine 318 General intensive care 318 General anaesthesia and neurointensive care Unit 319 Selected publications 320 WHO Collaborating Centre for Integrated Laboratory Strengthening on Tuberculosis, WHO Supranational Reference Laboratory and ESCMID collaborative Centre 324 PUBLICATIONS 325 List of 2013 publications 327

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13 SAN RAFFAELE SCIENTIFIC INSTITUTE Scientific Director: Francesco Montorsi*, since September 2013 Deputy Scientific Director: Luca G. Guidotti, since September 2013 Scientific Director: Maria Grazia Roncarolo*, until September 2013 * Professor at: Università Vita-Salute San Raffaele XI

14 INTRODUCTION Scientific Directors Introduction The San Raffaele Scientific Institute (SRSI) gathers basic, translational and clinical research activities conducted within Ospedale San Raffaele (OSR) and Fondazione Centro San Raffaele (FCSR). OSR is a forprofit organization that is governed by Prof. Gabriele Pelissero (President) and Dr. Nicola Bedin (CEO); FCSR is a non-profit entity headed by Prof. Giuseppe Banfi (General Director) was a year of high scientific productivity for SRSI. Indeed, SRSI scientific productivity continued its upward trend as per i) quantity and quality of publications, ii) total impact factor and iii) number of clinical trials. All of this reflects the dedication and the excellence of our scientists and clinical investigators, who continue to be highly recognized at the national and international level was also a year in which the SRSI governance was re-organized: on September 15th, Prof. Francesco Montorsi was appointed as the new Scientific Director (in place of Prof. Maria Grazia Roncarolo) and Prof. Luca G. Guidotti was appointed as Deputy Scientific Director. Research Divisions and Centers During 2013, SRSI has maintained its previous research organization. Six Research Divisions and two Research Centers provide critical mass and synergy in existing areas of excellence. RESEARCH DIVISIONS Director Associate Director Molecular Oncology Federico Caligaris-Cappio Giorgio Parmiani Neuroscience Gianvito Martino Flavia Valtorta Regenerative Medicine, Stem Cells Luigi Naldini Fabio Ciceri and Gene Therapy Immunology, Transplantation Ruggero Pardi/ Adriano Lazzarin and Infectious Diseases Luca G. Guidotti Genetics and Cell Biology Roberto Sitia Marco E. Bianchi Metabolic and Cardiovascular Sciences Ottavio Alfieri and Emanuele Bosi (Co-directors); Zaverio Ruggeri (Coordinator for Basic Research) RESEARCH CENTERS Director Co-Director Experimental Imaging Carlo Tacchetti Alessandro Del Maschio Translational Genomics and Bioinformatics Giorgio Casari Elia Stupka Research Institutes Four internal Research Institutes continue to focus on specific and coherent research themes RESEARCH INSTITUTE San Raffaele Telethon Institute for Gene Therapy (TIGET) Institute for Experimental Neurology (INSPE) Diabetes Research Institute (DRI) Urological Research Institute (URI) Director Luigi Naldini Giancarlo Comi Emanuele Bosi Francesco Montorsi (ad interim)

15 INTRODUCTION The San Raffaele Telethon Institute for Gene Therapy (TIGET), a joint venture with the Telethon Foundation, is an internationally renowned center pioneering cell and gene therapy in genetic diseases. The Institute for Experimental Neurology (INSPE), based on an agreement with Merck-Serono, constitutes one of the major European Institutes primarily dedicated to translational research in neuroscience. The Diabetes Research Institute (DRI) is part of the International DRI Federation (an organization that includes 12 other DRIs around the world) and mainly promotes basic and clinical research on Type 1 Diabetes (T1D). The Urological Research Institute (URI) is an internationally recognized center carrying out basic and clinical research in oncological and non-oncological diseases of the genito-urinary tract. Research Programs Research Programs represent strategic projects focused on specific scientific goals. During 2013, seven Research Programs have remained active at SRSI, and they relate to dedicated areas in the fields of Neuroscience, Oncology, Immunology, Metabolic or Infectious Diseases. Research Programs Head Brain Regeneration using medical Devises, Gene vectors Head: and stem cells (BRIDGE) Gianvito Martino (ad interim) Deputy Head: Luigi Naldini (ad interim) Program in Immunology and Bio-immunotherapy of Cancer (PIBIC) Co-Heads: Paolo Dellabona Giorgio Parmiani Pancreatic Islet Trasplantation Co-Heads: Lorenzo Piemonti Paola Maffi Human Brain In vivo Mapping with neuroimaging (BRAINMAP) Head: Massimo Filippi Deputy Head: Andrea Falini Bone Physiopathology Program (BoNetwork) Co-Heads: Roberto Sitia Enrico Gherlone Correlates of HIV-Associated Immune Response Modulation (CHARM) Co-Heads: Paola Cinque Guido Poli Microenvironment and Genes in Cancers of the Blood (MAGIC) Co-Heads: Paolo Ghia Giovanni Tonon XIII

16 INTRODUCTION Scientific Directors Introduction Institutional Facilities Traditionally, strategic investments in facilities and technological platforms have been a top priority at SRSI. As such, SRSI continue to offer state-of-the art services covering different research areas. Eight Institutional Facilities are operational at SRSI, including proteomics, flow cytometry, conditional mutagenesis, mouse histopathology, high field magnetic resonance, light and electron microscopy and statistics. Facility Scientific Manager Supervisor Promifa Angela Bachi/ Annapaola Andolfo Facility Manager Marco E. Bianchi Fractal Alessio Palini Chiara Villa Head of Facility Experimental models Luca G. Guidotti Enzo Oriani Facility Manager of diseases Cfcm Marco E. Bianchi Lorenza Ronfani Facility Manager Mhp Claudio Doglioni Francesca Sanvito Facility Manager Alembic Fabio Grohovaz Fabio Grohovaz Head of Facility Cermac Enrico Smeraldi Andrea Falini Head of Facility Cussb Clelia Di Serio Clelia Di Serio Head of Facility Human resources at SRSI As of December 2013 over 1,640 individuals - distributed throughout the 6 Research Divisions, the 2 Research Centers and the 8 Institutional Facilities - have been working at SRSI: 964 people, including scientists, technicians, postdoctoral fellows, PhD students and undergraduate students, have been working on preclinical and translational research; 665 people, including physicians, research nurses, residents and clinical fellows have been working on clinical research projects; 25 people, including heads of facility, lab managers, research associates and technicians have been working in Institutional Facilities. Highlights of scientific activities in 2013 News from Basic Research A study published in Science reports encouraging results using lentivirus gene therapy to treat the fatal genetic disorder Metachromatic Leukodystrophy (MLD) that lacks any effective treatments. Hematopoietic stem cells were collected from children with the most severe variant of MLD, exposed to a lentiviral vector expressing the corrective gene and re-injected in the patients after a short course of chemotherapy. Almost two years after treatment, sustained engraftment of gene corrected stem cells and prevention of neurological disease manifestation or progression were observed (Biffi et al., Science 2013; 341, ). A parallel study published in Science reports promising results of gene therapy in Wiskott-Aldrich syndrome (WAS), a genetic disorder characterized by thrombocytopenia and immune deficiency. Three patients received infusion of autologous hematopoietic stem/progenitor cell, transduced with a lentiviral vector encoding WAS, following reduced chemotherapy conditioning. Molecular studies showed high level engraftment of gene corrected stem cells (25-50%) with multilineage hematopoiesis and a safe profile of vector integration. Gene therapy resulted in improved platelet counts with decreased bleeding,

17 INTRODUCTION improved immune functions and reduced infections (Aiuti et al., Science 2013; 34, ). A study published in Nature Immunology disclosed an essential function of autophagy in the immune system. Autophagy ensures sustainable antibody production through selective digestion of the plasma cell secretory compartment. Moreover, autophagy is required for the maintenance of memory plasma cells in bone marrow. This study furthers our understanding of immunity and offers a framework for identifying new targets against multiple myeloma, the cancer of plasma cells (Pengo et al., Nat Immunol. 2013; 14: ). A study published in Nature Medicine demonstrated that a common variant in the promoter of the UMOD gene encoding uromodulin, the most abundant protein in urine, triggers a cascade of events that end up in hypertension and signs of chronic kidney disease. This study expands our knowledge on the complex mechanisms that determine hypertension and chronic kidney disease and it shows how genetic information could be exploited for personalized medicine (Trudu et al., Nat Med. 2013; 19: ). A study published in Nature Medicine described a new set of surface markers (CD49b and lymphocyte activation gene 3) enabling the identification and isolation of a particularly important subset of human and mouse CD4+ T regulatory cells (Tr1 cells). The discovery makes it feasible to track Tr1 cells in vivo and to purify Tr1 cells for cell therapy approaches aimed at inducing or restoring tolerance in subjects with immune-mediated diseases (Gagliani et al., Nat Med. 2013; 19: ). A study published in Nature Medicine shed new light in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common genetic disorder characterized by bilateral renal cyst formation. This work showed that the epithelia lining the cysts have an aberrant glucose metabolism, characterized by anaerobic glycolysis. Glucose deprivation impairs their growth and survival. A glucose analogue, 2-Deoxy-D-Glucose, administered to murine models of PKD effectively retarded disease progression, providing a proof-of-concept for the use of this molecule as a safe therapeutical approach (Rowe et al., Nat Med. 2013; 19: ). A study published in Nature Methods utilized a novel and highly mutagenic lentiviral vector to uncover genes that are involved in hepatocellular carcinoma (HCC) development. Four cancer genes were identified and validated as altered genes in HCC samples isolated from patients. This innovative approach should help identify new prognostic markers and new therapeutic targets for this and perhaps other relevant human cancers (Ranzani et al., Nat Methods 2013; 10: ). A study published in Immunity identified specific multipotent mesodermal precursors that give rise to different stromal cell subsets of the spleen and support injury-induced regeneration. These results begin to define the cellular mechanisms responsible for the generation of stromal diversity in secondary lymphoid organs and for the remodeling of lymphoid tissue (Castagnaro et al. Immunity: 2013; 38: ). News from Translational and Clinical Research The vibrant interaction between basic research and clinical areas represents one of the greatest values of SRSI and, undoubtedly, this is the peculiarity that makes the Institute so unique. In the various chapters included in this scientific report one can follow in detail the lines of research developed in all the laboratories and clinical units of the hospital and understand the deepest sense of their value. All major areas in medicine and biology, which are actively developed at SRSI, are covered by translational and clinical research projects. As mentioned above, top-level research was conducted in the pediatric arena with gene therapy-based approaches for MLD and WAS. A new paradigm of treatment with excellent results in terms of efficacy, safety and tolerability was developed. XV

18 INTRODUCTION Scientific Directors Introduction The area of oncology brought in a large number of state-of- the-art areas of research including oncohematology, cancers of the genito-urinary tract, breast cancer and cancers of the digestive system. Namely, genomics of chronic lymphocytic leukemia, pancreatic islet auto-transplantation for pancreatic cancer, innovative medical treatment for breast cancer, prognostic factors and multimodal therapy for prostate cancer, the relationship between inflammation-immunity and cancer are only a few of the many topics that were protagonists of our research. Radiology and Nuclear Medicine contributed significantly in the areas of central nervous system disease, oncology in almost all systems, cardiovascular medicine. Laboratory medicine was able to produce top-level research in many areas including pharmacotherapy of venous thromboembolism and management of infections. Neuroscience confirmed its leadership with a large number of different research projects in MR imaging, management of sleep disorders, multiple sclerosis and genomics, management of degenerative disease of the central nervous system, use of stem cells for different conditions including eye disease. Cardiovascular research was significant in many areas including percutaneous vs. open surgical management of coronary artery disease and valve disease, pathophysiology of ischemic heart disease, hypertension and heart failure, and management of arrhythmias. Diabetes has remained a historically proven area of major scientific research, and contributions in the field of pancreatic islet transplantation and pharmacotherapy for type 2 Diabetes have been substantial. Last but not least in the area of dentistry research of substantial interest was led in many areas. It is expected that both translational and clinical research will continue to flourish in the coming years.

19 INTRODUCTION Scientific productivity in 2013 In 2013 the number of SRSI scientific publications and the total impact factor continued to rise, as compared to data from previous years. The total number of scientific publications was 1,142, with a total Impact Factor of 6, (Figure 1). In 2013 more than to 10% of all SRSI publications were in top-level scientific journals (Impact Factor over 10, Figure 2). Based on these results, SRSI has been recognized - once more - as the most highly ranked Italian IRCCS (among the 47 Italian IRCCS) in terms of scientific quality and scientific productivity. Figure 1. Publications and total Impact Factor of SRSI in the past 4 years 5, , , , ,107 1, (average IF: 5.558) 2011 (average IF: 5.798) 2012 (average IF: 5.527) 2013 * (average IF: 5.650) Total IF Publications * based upon IF 2012 Figure 2. % of SRSI publications sorted according to Impact Factor ranges 100% Percentage of publications 80% 60% 40% 20% 65.1% 65.3% 65.2% 61.0% 27.3% 28.6% 26.9% 24.2% 7.6% 10.4% 7.8% 10.6% 0% < Impact Factor ranges >_ Highlighting the notion that clinical research is a major strength at SRSI, the 2013 output in clinical trial activity was simply excellent. The Ethics Committee examined a total of 243 clinical protocols: 110 (45.3 %) sponsored by Pharmaceutical Companies, 72 (29.6%) SRSI investigator initiated trials and 61 (25.1%) no-profit groups sponsored trials (Figure 3). XVII

20 INTRODUCTION Scientific Directors Introduction Figure 3. Clinical trials evaluated by the OSR Ethics Committee in 2013 Clinical trials evaluated by EC, (29.6%) 110 (45.3%) 61 (25.1%) Biotechnology Transfer Activity in 2013 The Office of Biotechnology Transfer (OBT) acts as the interface between SRSI and the business community. Its mission is to generate value from know-how, intellectual property, technologies and research facilities. In the last 10 years of activity OBT obtained the following results: 368 sponsored research or industrial collaboration contracts with about 130 biotech/pharmaceutical companies were successfully finalized; 68 licenses/options and evaluation agreements with industrial partners were executed; 135 patent families (patented technologies) were filed; 47 patent families (corresponding to a total of 221 patents and patent applications) are alive as of December Funding for research activities As in the past, the Ministry of Health structural funds (Ricerca Corrente) contributed significantly to the 2013 total research revenues of SRSI. Important research revenues were also obtained from external grants, which were assigned through internationally recognized peer-reviewed processes. Below is a list of the most representative funding agencies and of their contribution to SRSI (both OSR and FCSR) in 2013.

21 INTRODUCTION Contributions from Main Funding Agencies YEAR 2013 data in Ricerca Finalizzata (Ministry of Health) 6,095,030 AIRC (Italian Association for Cancer Research) 4,513,590 EU (European Union) Other Private Funding Agencies 1,206,305 Telethon Foundation 1,205,492 ISS (Italian National Institute of Health) 977,431 Armenise Harvard Foundation 603,521 Lombardy Region 546,556 MIUR (Ministry of Education, University and Research) 382,215 JDRF (Juvenile Diabetes Research Foundation) 290,962 FISM (Italian Federation for Multiple Sclerosis) 265,220 AICR (Association for International Cancer Research) 185,365 WHO (World Health Organization) 157,526 INAIL (National institute for insurance against industrial injuries) 124,186 Conclusions and future perspectives The 2013 Scientific Report of SRSI clearly shows that research in all its forms is lively and vibrant. We would like to take this opportunity to thank Prof. Maria Grazia Roncarolo who acted as Scientific Director until September 2013 and who was instrumental in the organization of the various Research Divisions, Institutes and Centers. This structure is currently being revamped in order to improve the workflow of research but the overall skeleton, being robust and efficient, will be maintained. At present the team of the Scientific Directorate has expanded to include Prof. Giuseppe Banfi, General Director of Fondazione Centro San Raffaele (FCSR) and Dr. Anna Flavia d Amelio Einaudi as representative of the CEO of OSR. The first objective of this new team is to serve the scientific community in order to facilitate the every day work of all scientists and clinicians involved in research activities. Creating liaisons among different groups to foster the development of new research projects, helping the process of grant writing, facilitating the entrance of students as active participants in prestigious research groups, supporting educational programs for all those involved in research, also represent targets that we want to hit. We are convinced that the quality of health care provided to patients is better in hospitals where research is actively practiced; curing our patients remain our first goal. Francesco Montorsi Scientific Director Luca G. Guidotti Deputy Scientific Director XIX