Annual Report 2010 NCMLS

Transcription

1 Annual Report 2010 NCMLS

2 Postal address 259 NCMLS P.O. Box HB Nijmegen The Netherlands Visiting address Geert Grooteplein GA Nijmegen T: +31 (0) F: +31 (0) E: I: Editing: Judith Burgers, Dr. Adrian Cohen Design: Final Design Front cover: Melanoma tumor cells and structures of the tumor microenvironment in vivo imaged by two-photon microscopy. Green: B16F10 melanoma cells expressing cytoplasmic E2-Crimson, orange: GFP expressing muscle fibers, red: blood vessels and phagocytic cells labeled with 70kDa Dextran-TM-rhodamine, grey: collagen fibers visualized by second harmonic generation, blue: nerve fiber and fat cells visualized by third harmonic generation. Image provided by Bettina Weigelin, Department of Cell Biology. Photography: Dr. Adrian Cohen, Theo Hafmans page Google-Kaartgegevens 2011 Google-Tele Atlas Printed by: Rikken Print 2 NCMLS

3 It is with great pleasure and honour that I introduce the NCMLS annual report Since 1 st September 2010, I have taken over the responsibility of Prof.dr. Carl Figdor as Scientific Director of NCMLS, who for Foreword It is with great pleasure and honour that I introduce the NCMLS annual report Since 1 st September 2010, I have taken over the responsibility of Prof.dr. Carl Figdor as Scientific Director of NCMLS, who for many years has been instrumental in the successes of the NCMLS institute. NCMLS is gaining in international visibility as evidenced by our increasing publications in top journals as well as external subsidies. Numerous large coordinator grants have been obtained by NCMLS researchers in 2010 and to mention them all here would be inappropriate. However, I would like to draw attention to the 22 million awarded by the EU for two European large-integrated systems biology projects, GENCODYS and SYSCILIA, coordinated by Prof.dr. Hans van Bokhoven and Dr. Ronald Roepman, respectively. Furthermore, 4.5 million was acquired in funding from NWO and ZonMW to set-up a Centre for Systems Biology and Bioenergetics (coordinator Prof.dr. Jan Smeitink, These successes confirm the importance of systems biology research in Nijmegen. Many researchers in 2010 have been successful in obtaining personal career development grants including prestigious NWO Veni, Vidi and Vici awards. The NCMLS remains committed to stimulating young researchers at every step of their career path and I would like to take this opportunity to wish all of them success in their projects. Other particular highlights for 2010 include our fourth international New Frontiers symposium that focussed on the molecular mechanisms of energy metabolism in health and disease. The symposium was organised together with the Institute for Genetic & Metabolic Disease (IGMD) and attracted over 300 people from across the globe to Nijmegen. In 2010 the tradition of PhD and post-doc retreats was also continued, each retreat allowing young researchers time to reflect on their research work, career ambitions and to network. In 2010, we embarked on two new initiatives, which will be continued in Firstly, a PhD recruitment initiative, Talent Event, in which a selected group of highly motivated and talented students were invited to NCMLS to get a first-hand impression of molecular life sciences research in Nijmegen. The best candidates returned home with an offer of a four-year fully-funded PhD position. Secondly, young researchers from foreign countries need to be able to integrate within Dutch culture and life-style and so with this thought in mind we organised a pilot course of Dutch language lessons. I would like to acknowledge the excellent work that Prof.dr. Frans Cremers has done for our international research master s program, Molecular Mechanisms of Disease (MMD). The quality of the students in this program remains very high and this was duly recognised by the recent re-accredidation of the program by the Dutch-Flemish accreditation authority (NVAO). For this we are very grateful and I wish Prof.dr. Roland Brock every success in his new role as Director. Whilst our annual report provides an opportunity to reflect on the achievements in the past year, it is also appropriate to consider the priorities for the forthcoming year. As mentioned above systems biology is an important area for further investment. Likewise, we are committed to chemical biology and strengthening our collaborative efforts with the Institute for Molecules and Materials (IMM), as well as building on our strengths in regenerative medicine. With an external site-visit planned, 2011 will be an important and stimulating year. The 2010 annual report focuses on some of the younger researchers within the various research themes of our centre and their contribution to the understanding of the molecular and cellular basis of disease. You will also find information about various NCMLS activities in 2010 as well as the NCMLS Graduate School. Wishing you an enjoyable read, Prof.dr. René Bindels Scientific Director NCMLS Annual Report 2010 René Bindels Foreword 3

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5 Table of contents Page Foreword 3 Nijmegen Centre for Molecular Life Sciences 7-24 Nijmegen Centre for Molecular Life Sciences 7-8 Mission 7 Introduction 7 Research and management organisation 8 Research 9-10 Research themes 9 Output 11 NCMLS & Selected Awards New Frontiers in Bioenergetics Symposium 15 NCMLS Activities PhD retreat 17 Post-doc retreat 17 NCMLS PhD recruitment initiative success 18 Dutch lessons for international students (NCMLeS) 18 Technology Platforms 20 The NCMLS as Graduate School Introduction 21 MSc Molecular Mechanisms of Disease 22 International PhD programme 23 NCMLS Members 24 NCMLS Committees 25 Selected Research Highlights NCMLS Theme 1: Infection, immunity and regenerative medicine Theme 1a Infection and autoimmunity 28 Theme 1b Immune regulation 33 Theme 1c Regenerative medicine & microenvironment 40 Theme 2: Cell metabolism, transport and motion Theme 2a Energy and redox metabolism 46 Theme 2b Membrane transport and cell dynamics 49 Theme 3: Cell growth and differentiation Theme 3a Genetic and epigenetic pathways of disease 54 Theme 3b Chemical and physical biology 61 Scientific Publications Annual Report 2010 Table of contents 5

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7 The NCMLS seeks to achieve greater insights into the complexity of living cells with the purpose of obtaining a multifaceted knowledge of both normal and pathological processes. The NCMLS will pursue its goals in the Nijmegen Centre for Molecular Life Sciences interests of curiosity driven research and education. The NCMLS aims to advance innovation in translational research based on the integration of diverse scientific expertise in molecular and medical sciences. Mission Understanding the cellular basis of disease The NCMLS seeks to achieve greater insights into the complexity of living cells with the purpose of obtaining a multifaceted knowledge of both normal and pathological processes. The NCMLS will pursue its goals in the interests of curiosity driven research and education. The NCMLS aims to advance innovation in translational research based on the integration of diverse scientific expertise in molecular and medical sciences. Introduction The NCMLS was first established in 1994 under the name Institute of Cellular Signalling (ICS), and subsequently in 1995 and again in 2000 recognised by the Royal Netherlands Academy of Arts and Sciences (KNAW) as a research school. In 2000 the name Nijmegen Centre for Molecular Life Science (NCMLS) was coined, the NCMLS and ICS organisations were merged and placed under a collegial board of directors to reflect a further integration of Nijmegen research themes and the multidisciplinary and translational research approach of the organisation. New approval for the new name and organisation for the NCMLS was obtained during the 2004 recognition-round by the KNAW. The research school continues to represent a growing research staff, both from the Radboud University Nijmegen Medical Centre (RUNMC) and the Faculty of Science, Mathematics and Computing Sciences (FNWI) at the Radboud University Nijmegen (RU). The NCMLS is a leading multidisciplinary research school within the domain of molecular mechanisms of disease and particularly in the fields of molecular medicine, cell biology and translational research. NCMLS aims to develop as a unique centre of excellence with innovative approaches to research and education. In order for the NCMLS to rank as one of the top European research institutes/graduate school, a competitive research environment should be created where quality and excellence are foremost considerations. By offering researchers a stimulating and challenging environment, NCMLS aims to foster talent and further increase international visibility. The major goal of the NCMLS is to generate basic knowledge in molecular medical research and to translate this knowledge into clinical applications, into the development of diagnostics and into the treatment of patients through translational research programmes. The multi-disciplinary approach to research in molecular life science is reflected both in its research themes and in the Master s and PhD programmes offered. As such, NCMLS provides a stimulating and challenging environment for young scientists to learn the vital skills necessary for an independent and productive career in science. The NCMLS Graduate School operates a two-year Research Masters M.Sc programme, Molecular Mechanisms of Disease, accredited by NVAO, the Dutch-Flemish accreditation organisation, which is a member of the European Consortium for Accreditation (ECA). The NCMLS also runs a nationally approved PhD research training programme which attracts an increasing number of foreign students to the institute. NCMLS researchers collaborate at local, national and international levels. The research school is allied with the Institute for Molecules and Materials (IMM) and the Donders Institute for Brain, Cognition and Behaviour (DI-BCB), providing a solid platform for integrating the chemical synthesis, nanoscience and neuroscience with molecular life sciences. Furthermore, incorporating the Centre for Molecular and Biomolecular Informatics (CMBI) within the NCMLS has strengthened the multidisciplinary approach to solving biomedical research problems. The NCMLS houses The Netherlands Bioinformatics Centre (NBIC) which aims to stimulate the development of bioinformatics in the Netherlands, further strengthening NCMLS links in bioinformatics. The NCMLS also has associations with the Dutch Programme for Tissue Engineering (DPTE) and the Netherlands Proteomics Centre. The NCMLS contributes to the Top-Institute Pharma and has several academic and industrial partners in this context. In addition, the NCMLS is actively involved in national programmes, such as the BioMedical Materials program (BMM), Centre for Societal Genomics (CSG), Center for Translational and Molecular Medicine, Netherlands Genomics Initiative (NGI), and international multipartner programmes such as EU FP6/7. Annual Report 2010 Nijmegen Centre for Molecular Life Sciences 7

8 The NCMLS seeks to achieve greater insights into the complexity of living cells with the purpose of obtaining a multifaceted knowledge of both normal and pathological processes. The NCMLS will pursue its goals Nijmegen in the Centre interests for of Molecular curiositylife driven Sciences research and education. The NCMLS aims to advance innovation in translational research based on the integration of diverse scientific expertise in molecular and medical sciences. Research and management organisation Research and education are focused along three main research themes in keeping with our mission towards Understanding the molecular basis of disease : (a) Infection, immunity & tissue regeneration; (b) Metabolism, transport & motion; and (c) Cell growth & differentiation. These themes are further divided into seven sub-themes. Group leaders are organised within these (sub)themes providing critical mass of expertise per subtheme and a visible structure for the institute on which to base science research and education policy. The Scientific Director of the NCMLS institute, Prof.dr. C. Figdor, consults with the Dean of the Medical Faculty (Prof.dr. Frans Corstens) and the Dean of the Science Faculty (Prof.dr. Jan Kuijpers) during regular meetings in which research and education policy is discussed in relation to Radboud University and its Medical Centre research strategies. With effect from 1 st September 2010, Prof.dr. René Bindels took over from Prof.dr. Carl Figdor as Scientific Director of the NCMLS. René Bindels is Professor of Physiology and Head of the Department of Physiology. He has won great accolades in the field of biomedical research and education. As Director René Bindels will follow in the footsteps of Prof. dr. Carl Figdor, who has had a considerable role in building NCMLS up, over the past ten years, to one of the most prestigious research institutes in the Netherlands. Carl Figdor is going to fully focus on his research activities and on the Wetenschapsknooppunt ( a project in which students from the elementary school receive an introduction to scientific research. The NCMLS Research Council meets monthly and is involved with all decisions and policy-making with respect to NCMLS research and education activities. The Research Council comprises representatives of the three research themes, representatives of the seven sub-themes and representatives from the various NCMLS Committees. A number of NCMLS Committees are established, each focusing on particular aspects of NCMLS research and education. All Committees report to the Research Council, directly or via the Scientific Manager. As of January 2011 the NCMLS Research Council will be reformed into a smaller NCMLS Management Team that will meet on a fortnightly basis. NCMLS Symposium New Frontiers, Bioenergetics: Live & Let Die (see page 15) 8 Nijmegen Centre for Molecular Life Sciences NCMLS

9 Within the NCMLS institute, all research and education is linked to the study of molecular life sciences Research in relation to disease. NCMLS focuses on three thematic research areas, which are further divided into sub-themes. Each Research themes Within the NCMLS institute, all research and education is linked to the study of molecular life sciences in relation to disease. NCMLS focuses on three thematic research areas, which are further divided into sub-themes. Each subtheme and theme is headed by a prominent NCMLS Principal Investigator. Theme 1 Theme 2 Theme 3 Infection, immunity and Cell metabolism, transport and motion Cell growth & differentiation regenerative medicine (Adema) (Wieringa) (van Bokhoven) 1a: Infection and autoimmunity (Schalkwijk) 2a: Energy and redox metabolism (Wieringa) 3a: Genetic and epigenetic pathways of disease 1b: Immune regulation (Adema) 2b: Membrane transport and cell dynamics (van Bokhoven) 1c: Regenerative medicine & microenvironment (Bindels) 3b: Chemical and physical biology (van Hest) (van Kuppevelt) Theme 1: Infection, immunity and regenerative medicine (Prof.dr. G. Adema) Infection and autoimmunity (Prof.dr. J. Schalkwijk) Immune regulation (Prof.dr. G. Adema) Regenerative medicine & microenvironment (Dr. A. van Kuppevelt) The immune system has the task of eliminating pathogens and eradicating arising tumours, while preventing auto-reactive responses harmful to the host. In keeping the balance of this dual task, a complex interplay between immune cells and tissue cells exist and many stimulatory and inhibitory circuits operate simultaneously. The functional outcome is further shaped by genetic and environmental factors, such as pathogens and tumours. Deregulation of this intricate balance is directly associated with human diseases, ranging from inflammatory and autoimmune disorders to cancer, infection and transplantation disorders. In every case, prolonged deregulation can initiate a cascade of events ultimately leading to tissue damage and destruction. Tissue engineering is a relatively new field of research aiming at repairing or replacing damaged tissues applying implantation of smart synthetic biomatrices or stem cells. Immune control is intrinsically involved in these processes to allow acceptance- and prevent immune attack of engineered tissues. The central questions in theme 1 are dealt with in a multi-disciplinary approach (from molecule-2-man) and aim to define the molecular basis of: (i) events that trigger or fuel immune-related disorders and infectious diseases (sub-theme 1a); (ii) immune regulatory circuits (sub-theme 1b); and (iii) tissue pathology and regeneration and stem cell behaviour and differentiation (sub-theme 1c). Insight into immune regulatory and differentiation pathways, and how they are deregulated in diseases, allows the design of novel treatments leading to a translational research aim of (iv) designing novel clinical applications in inflammatory and autoimmune diseases (e.g. SLE, rheumatoid arthritis, diabetes, psoriasis), infectious diseases (e.g. fungi, viruses), transplantation (e.g. stem cell, kidney), immunotherapy of cancer and tissue regeneration (sub - themes 1a/b/c). Annual Report 2010 Research 9

10 Within the NCMLS institute, all research and education is linked to the study of molecular life sciences Research in relation to disease. NCMLS focuses on three thematic research areas, which are further divided into sub-themes. Each Theme 2: Cell metabolism, transport and motion Energy and redox metabolism (Prof.dr. B. Wieringa) Membrane transport and cell dynamics (Prof.dr. R. Bindels) In depth knowledge of the behaviour and fate of macromolecules, metabolites and ions, and the different pathways for intermolecular relationships, is required because the genome only (read: transcriptome and proteome) has been a relatively poor source of explanation for the differences between cells or between healthy and sick people. Study of disease at the small molecule level but in the context of the macromolecular world of the cellular organelles, the intact cell, or organs and tissues in the entire organism is therefore a central theme in the theme 2 research programme of the NCMLS. Intrinsic genetic problems or extrinsic factors causing cellular energy deprivation, ion and metabolite and water transport failure, toxic accumulation of intermediates, or ischemia and anoxia caused by cerebro-vascular obstruction are underlying a broad range of diseases, including for example cancer, neuropathy and myopathy, degenerative disorders like Alzheimer s and Parkinson, ischemic/anoxic organ failure, exercise intolerance and fatigue or renal tubulopathy and retinopathy. Also for very frequent problems like obesity and diabetes type II and even aspects of ageing it is now well established that there is a direct connection to metabolism and molecular transport and motion. Within its research theme 2 the NCMLS bundles studies in two particular relevant and strongly overlapping areas (a) Energy and redox metabolism and (b) Membrane transport and cellular dynamics. Between these topics links exist at many levels. Metabolites like ATP and NAD(P)(H) produced by in key pathways like glycolysis and mitochondrial respiratory complexes are consumed as fuel or needed as co-factors for ion-transport ATPases or drug-transporters and the acto-myosin motor machinery involved in organelle dynamics and cell movements. Renal disease, cardiomyopathy and brain and muscle disorders have now been demonstrated to be caused by defects in the production or assembly of ATPases, water channels, or the mitochondrial machinery. Also sometimes defects in metabolic signalling are involved. The NCMLS already provides unique facilities and a strong combination of knowledge in medical, physical and chemical sciences to work in this molecule and disease area, with direct diagnostic and therapeutic relevance. Our future efforts will be directed to creating an even stronger focus on the particular fields of strength, with emphasis on renal disorders, mitochondrial medicine, muscle dystrophies, neurodegeneration and cancer, particularly in overlap with studies within Themes 1 and 3. Theme 3: Cell growth and differentiation Genetic and epigenetic pathways of disease (Prof.dr. H.van Bokhoven) Chemical and physical biology (Prof.dr. J. van Hest) The fate of all cells lies in the fine balance between growth and differentiation. If this balance is disturbed, uncontrolled growth and deregulated cellular development can lead to disease. Studying the processes that underlie growth and differentiation is pivotal to a basic understanding of the causes of many diseases and malfunctions. Multi-level analysis is used to study the functional blueprint of all cellular decisions, a functional genomics approach is pursued that ranges from deciphering the genome in terms of actively transcribed genes under defined cellular circumstances (such as normal differentiation versus unregulated proliferation) to specific disease-linked genomic studies. Since the single cell cannot be viewed in isolation from its cellular surrounding, decisions within the cell need to be linked to external cues and constraints, and the translation of this approach within cells is at the core of research on signalling networks. In order to understand the molecules that convey the information packaged in the functional genomic blueprint as well as the signals from the cellular outside world, it is also necessary to gain a better understanding of the protein structure and design of these molecules that finally convey the growth and differentiation decisions. Valuable insights can be gained from investigating a specific differentiation programme and neural development is studied as a special case. Our research activities aim to: Unravel the molecular basis of cell behavior, which emanates from genetic and epigenetic code contained in the nucleus in the context of health and disease (e.g. cancer, developmental disorders, mental handicap, cognitive impairments, neurodegenerative disorders and age-related bone diseases). Elucidate protein structure and protein-protein interactions within cellular signaling pathways that control cell proliferation and differentiation. Exploit the potential of molecular chemistry to modify, design and mimic proteins and their building blocks with the purpose to modulate and analyze their activities and properties in the cellular environment. 10 Research NCMLS

11 The output of an institute, measured in publications, prestigious awards, patent applications etc, is an Output important measure of the growth and performance of an institute. Furthermore, such information can be used to determine The output of an institute, measured in publications, prestigious awards, patent applications etc, is an important measure of the growth and performance of an institute. Furthermore, such information can be used to determine internal scientific policy, to facilitate comparisons with other similar research institutes and ultimately provide a source of quantitative information for institute evaluations. In recent years, NCMLS has been growing steadily with increasing numbers of yearly publications, from just under 500 in 2004 (not shown) to a steady state of +/-600 publications per year since 2006 (Source: Metis). Of course, the international relevance of these publications is also important and indeed may be quantitatively measured. All scientific journals have a so-called impact factor (Thomson Institute for Scientific Information), which is a measure of their international importance judged by a citation analysis of publications in the journal of interest. A number of journals were selected that have high impact factors and an analysis of the number of NCMLS publications per journal was conducted. Since 2006 there has been steady increase in the number of publications in these top journals demonstrating a continuing improvement in the external profile of NCMLS. The top three high-impact factor journal categories in 2010 for NCMLS publications were: Nature & Naturederived journals including Nature reviews, American Journal of Human Genetics and PloS. Publications within NCMLS are well distributed across the 7 different subthemes, ranging from 6% - 21% of the total NCMLS publications. Notably, Theme 1 contributes more than half of all publications, whilst Theme 2 and Theme 3 contribute approximately one fifth and one quarter of all publications, respectively. All publications can be found in our digital annual report NCMLS 2010 at Annual Report 2010 Output 11

12 The Veni, Vidi and Vici grants are awarded by the NWO as part of the Vernieuwingsimpuls (Renewal impulse) NCMLS and & Selected is supported Awardsby the Ministry of Science, Education and Culture (OCW), and the Royal Academy of Sciences and the Arts NCMLS Awards Joost Lesterhuis received the NCMLS award for best thesis 2010: Dendritic cells in cancer immunotherapy. Veronika te Boekhorst received the NCMLS award for best scientific report 2010: Control of cancer cell invasion and nuclear deformability by nuclear lamins. Selected Coordination grants 2010 More than 22 million was awarded by the EU for two European large-integrated systems biology projects. The GENCODYS project, coordinated by Prof.dr. Hans van Bokhoven, will explore the relationship between genes and cognitive disorders. The SYSCILIA project, coordinated by Dr. Ronald Roepman, plans to create an advanced computer model of the molecular machinery of the cilium. Prof.dr. Peter Hermans and Prof.dr. Han Zuilhof (Wageningen University) have received a FES project grant to develop an electronic platform for high throughput and real-time detection of biomarkers for inflammation. In the Centre for Systems Biology and Bioenergetics (CSBB) more than thirty-five research groups of the Radboud University Nijmegen Medical Centre and the Radboud University are working together to develop an innovative computer model that can accurately predict energy metabolism. The CSBB received a grant from NWO and ZonMw ( 4.5 million) for the initial development of in silico models that will integrate the available knowledge about the energy metabolism of the human muscle. This project is coordinated by Prof. Jan Smeitink. Prof.dr. Wout Feitz and Dr. Toin van Kuppevelt have been awarded a Pieken in de Delta grant of nearly 2.5 million to develop new regenerative urological products (NovioTissue). Dr. Frank van Kuppeveld has been awarded a grant for setting up a European Training Network on virus replication and antiviral drug development ( 5 million). The Dutch Kidney Foundation (DKF) awarded two grants ( 1.5 million each) to renal research consortia focusing on translational research. The first consortium is coordinated by Dr. Johan van der Vlag and will study the structure and function of the glomerular endothelial glycocalyx. The purpose of the second consortium, which includes Prof.dr. Luuk Hilbrands and Prof. Irma Joosten is to further improve the results of renal transplantation. Prof.dr. Robert Sauerwein was awarded 3 million to coordinate an EU FP7 grant: Clinical development of a Pfs48/45-based malaria transmission blocking vaccine. The four year project involving five international partners aims to optimise and up-scale production of PF10C-MBP, a transmission-blocking malaria vaccine (TBMV), leading to the release of clinical grade batches for human trials in Europe and subsequently in Africa. The Malaria Unit at the Radboud University Nijmegen Medical Centre represents a unique facility for culturing malaria parasites and breeding malaria (infected)-mosquitoes. The institute been world leader in production of different parasite lifecycle stages for more than two decades, distributing material and participating in many international studies while pursuing its own mission to develop new tools and strategies to eradicate malaria. CSBB group In this endeavor to further contribute to malaria control/research, a new extension of the malaria laboratories was opened on the 18th of May 2010 by Mr Thom C. de Graaf LLM, mayor of the city of Nijmegen in the presence of the chairman of the RUNMC board Drs E. Lohman. 12 NCMLS & Selected Awards NCMLS

13 The Veni, Vidi and Vici grants are awarded by the NWO as part of the Vernieuwingsimpuls (Renewal impulse) NCMLS and & Selected is supported Awardsby the Ministry of Science, Education and Culture (OCW), and the Royal Academy of Sciences and the Arts Selected personal grants 2010 TOP subsidy Horizon Award A TOP subsidy (ZonMw) was awarded to Prof.dr. Frans Cremers, Dr. Hannie Kremer and Dr. Anneke den Hollander to use a genomewide approach to search for novel sensory disease genes using consanguineous and non-consanguineous families. Dr. Richárd Bartfai - Massive parallel sequencing for extreme genomes. Dr. Ulrike Jacobi - A promoter resource to study the effect of genome duplication on regulatory sequences. Veni, Vidi & Vici Awards Prof.dr. Peter Friedl was awarded a Vici grant for research into the cancer invasion and metastasis. Prof.dr. Jan van Hest (IMM) was awarded a Vici grant for research into construction of hybrid polymer systems. Dr. Ronald van Rij - Functional genomics of antiviral defense in insects. Dr. Margit Schraders - The state-of-the art technology of next generation sequencing to identify the genes causing hereditary hearing loss. Prof.dr. Mihai Netea was awarded a Vici grant for the study of immunological memory (2009 round). Prof.dr. Hans Spelbrink was awarded a Vici grant for the study of mtdna nucleoids. EMBO long-term fellowship Dr. Karen Buysse obtained an EMBO long-term fellowship in order to perform post-doctoral research at the Molecular Genetics division of the Department of Human Genetics (Prof.dr. Hans van Bokhoven). Dr. Joost Martens was awarded a Vidi grant for the study of heritable epimutations. Dr. Bas Dutilh was awarded a Veni grant for the computational analysis of symbiosis. Dr. Mangala Srinivas was awarded a Veni grant for the development of novel cell therapy imaging tools. Dr. Rutger Vogel was awarded a Veni grant for research into the tumor invasion and metastasis. Dr. Emese Gazdag obtained an EMBO long-term fellowship in order to perform post-doctoral research at the Department of Molecular Biology (Dr. Gert-Jan Veenstra). Dr. Steffi Lehmann received an EMBO long-term fellowship to perform in vitro and in vivo experiments on the effect of hypoxia regulation of cancer invasion and metastasis (Prof. Peter Friedl). Dr. Anja Scholzen obtained an EMBO long-term fellowship in order to perform post-doctoral research at the Department of Medical Microbiology (Prof.dr. Robert Sauerwein). RUNMC tenure-track fellowship Dr. Marcel Coolen was awarded a tenure track fellowship for establishing a research line on human epigenetics. Dr. Jenny van der Wijst obtained an EMBO long-term fellowship in for a collaborative project between the MRC protein phosphorylation unit in Dundee (Prof.dr. Dario Alessie) and the department of Physiology (Prof.dr. René Bindels and Prof.dr. Joost Hoenderop). Dr. Nael Nadif Kasri was awarded a tenure track fellowship for establishing a research line on mental retardation. Annual Report 2010 NCMLS & Selected Awards 13

14 The Veni, Vidi and Vici grants are awarded by the NWO as part of the Vernieuwingsimpuls (Renewal impulse) NCMLS and & Selected is supported Awardsby the Ministry of Science, Education and Culture (OCW), and the Royal Academy of Sciences and the Arts Selected other awards Appointments Dr. Suzanne Heemskerk, Heleen Arts, Joris Robben, Kirsten Renkema and Angelique Rops have been awarded Kolff grants ( ,000 Euro) by the Dutch Kidney Foundation. Prof.dr. René Bindels has been appointed Scientific Director NCMLS Dr. Tom Nijenhuis received a Ruby Diabetes Research Grant from the Dutch Diabetes Research Foundation to investigate the role of TRPC6 in the pathogenesis of diabetic nephropathy (DNP). Dr. Timothy Radstake was awarded a research grant from the European League Against Rheumatism (EULAR) in an international project designed to identify molecular targets in systemic sclerosis. Prof.dr. Roland Brock has been appointed Director MMD Master s program Prof.dr. Robert Sauerwein received a grant from the ZonMw translational research programme to investigate whether co-administration of immune- modulating drugs can empower malaria immunization strategies. Dr. Christiane Trimpert was awarded a prestigious Marie-Curie fellowship (2 years) to perform post-doctoral research on aquaporin-2 water channels. Hans van Bokhoven, Peter Deen, Luuk Hilbrands, Joost Hoenderop and Nicoline Hoogerbrugge have been appointed to Professor. Selected Honours 2010 Dr. Rob Collin of the Departments of Human Genetics and Ophthalmology received the Retina Netherlands Career Development Award Dr. Roos Masereeuw has been awarded the Galenus Research Prize 2010 Drs. Jessica Nouws was awarded the Tweelingprijs by the Dutch Society of Paediatrics on behalf of the Maarten Kappelle Foundation for the best fundamental article on paediatrics published in a scientific journal in the period Prof. Peter Friedl has been appointed as consultant and Professor of Medicine at the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Dr. Ronald van Rij was awarded the Kluyver Award from the Netherlands Society for Microbiology (NVvM) in recognition of his outstanding contribution to microbiology. Dr. Ronald Roepman has received the European Vision Award 2010 from the European Vision Institute (EVI). 14 NCMLS & Selected Awards NCMLS

15 The NCMLS international New Frontiers symposium 2010, entitled, Bioenergetics: live and let die, New wasfrontiers held on in the 16th and Bioenergetics Symposium 17th November and, like previous years, attracted more than 300 visitors to the institute from The NCMLS international New Frontiers symposium 2010, entitled, Bioenergetics: live and let die, was held on the 16th and 17th November and, like previous years, attracted more than 300 visitors to the institute from across Europe, Asia and America. This years symposium was organized in collaboration with the Institute for Genetic and Metabolic Diseases (IGMD). During four sessions a large panel of internationally renowned scientists that have contributed significantly to the understanding of energy production in health and disease presented their latest research findings. (i) Bioenergetics: structure, function & regulation. The opening lecture by Immo Scheffler (Division of Biology, University of California, San Diego) introduced the role of ATP, the electron transport chain and the various complexes involved and presented his latest research into respiration-deficient mutant cells. Subsequently, Ulrich Brandt (Frankfurt University. Frankfurt, Germany) presented his recent work on deciphering the structure of mitochondrial complex I followed by Leo Nijtmans (RUNMC, Nijmegen, The Netherlands) on the assembly of human complex I (pathways, crucial steps and regulation). Vamsi Mootha (Massachusetts General Hospital, Boston, USA) described a mix of tandem mass spectrometry, large-scale GFP tagging, and computational analysis to systematically characterize the mitochondrial proteome and elucidate how these proteins go awry in mitochondrial disease. Anu Wartiovaara (Biomedicum Helsinki, University of Helsinki, Finland) described her omics approaches to reveal clues for mitochondrial disease diagnosis and pathogenesis. (ii) Pathobiology and treatment of mitochondrial disease. Doug Turnbull (Newcastle University, Newcastle upon Tyne, UK) gave an overview of the clinical features and strategies to combat mitochondrial DNA disorders. Massimo Zeviani (National Neurologic Institute C. Besta, Milan, Italy) discussed pathogenic mechanisms unraveled by new mitochondrial syndromes and Carlos Moraes (University of Miami Miller School of Medicine, Miami, USA) presented his research findings into OXPHOS dysfunction in the striatum. (iv) Energy & aging. The final session covered energy and aging and included talks from Anne Brunet (Stanford University School of Medicine, Stanford, USA), Linda Partridge (University College London, London, UK) and Nils Larsson (Max Planck Institute for Biology of Ageing, Cologne, Germany). The closing talk was by Brian Kennedy (University of Washington, Seattle, USA) on conserved pathways linking nutrient signaling to aging. Bloemendal Medal 2010 The Hans Bloemendal Medal for 2010 was awarded to Professor Bruce Spiegelman, in recognition of his groundbreaking studies in biomedical sciences, in particular those on transcriptional control of energy homeostasis. In more than 25 years at the Dana-Farber Cancer Institute and Harvard Medical School he has published over 230 research papers on fat cell development, regulation of glucose and lipid metabolism at the molecular, cellular and organismal level, as well as on gene control in cell differentiation and cancer. In 1994, in a landmark publication, Bruce Spiegelman and his research team identified the first master regulator of fat development: the nuclear receptor PPARγ. Subsequent studies dealt with the regulation of PPARγ pathways by ligands, coactivators and other transcription factors. More recently (2007), he has identified the zinc-finger protein, PRDM-16, as a master transcriptional regulator of brown fat cell development and differentiation. Combined with his outstanding studies on transcriptional control of mitochondrial energy metabolism through the PGC1 coactivator machinery it is evident that completely new avenues for the development of therapies for diabetes, obesity, muscular and neurodegenerative diseases have been opened up by these efforts. (iii) Energy & growth (dys)regulation. Doug Wallace (University of Pennsylvania, USA) discussed the mitochondrial-bioenergetic etiology of complex disease, followed by Eyal Gottlieb (Beatson Institute for Cancer Research, Cancer Research UK, Glasgow) about mitochondrial tumour suppressors. Paul Hwang (Translational Medicine Branch NHLBI- NIH, USA) discussed his work on p53 regulation of mitochondrial function and cell survival. This was followed by Bruce Spiegelman (Dana- Farber Cancer Institute, Boston, USA) who showed his latest data of the transcriptional pathways controlling energy expenditure through regulation of mitochondrial function. Lorenzo Galluzzi (Institut Gustave Roussy, Paris, France) presented work on Vitamin B6 metabolism affects CDDP (Cisplatin)-induced lung cancer cell death. Annual Report 2010 New Frontiers in Bioenergetics Symposium 15

16 16 NCMLS

17 The 16 th NCMLS PhD Retreat was held on 22 nd and 23 rd April 2010 at the congress centre Hof van Wageningen. NCMLS Activities Organi-sers 2010 were Maaike Luesink, Hanneke Wittgen and Renoud Marijnissen. The organising committee was pleased to PhD retreat The 16 th NCMLS PhD Retreat was held on 22 nd and 23 rd April 2010 at the congress centre Hof van Wageningen. Organisers were Maaike Luesink, Hanneke Wittgen and Renoud Marijnissen. The organising committee was pleased to welcome a record number of 132 participants from more than 28 different departments from both the Radboud University Nijmegen Medical Centre and the Faculty of Science of the Radboud University Nijmegen, reflecting the multidisciplinary nature of the PhD Retreat. The retreat aims to create a setting for young researchers to gather in an informal way and exchange their scientific knowledge. During the conference, 20 finishing PhD students gave an oral presentation about their scientific work; their results after four years of hard work. Furthermore, the other PhD students got the opportunity to present a poster to a small group of fellow PhD students. Thursday afternoon students could visiting the beautiful city centre of Wageningen while playing street golf. That evening, Prof. Dr. Elaine Dzierzak (Department of Cell Biology, Erasmus MC) gave an exciting lecture about hematopoietic stem cell development. To reward the best scientific work, Dr. Wilbert Boelens and Dr. Frank Wagener acted as members of the jury and selected the best lecture, poster and debater. They awarded the best lecture prize to Jayne Hehir-Kwa (Human Genetics) and the prize for the best poster was awarded to Hanka Venselaar (CMBI); The best debater award was granted to Renoud Marijnissen (Rheumatology). Post-doc retreat The purpose of the NLS-PP s (Nijmegen Life Sciences Post-doc Platform) Postdoc Retreat Signal your Network! (7-8 October 2010) in Lunteren was for 40 young scientists to discuss their science research, build new collaborations and reflect on their career ambitions. On the first day three speakers shared their experiences and thoughts on how to increase your chances of publishing your research in a high impact journal. In the afternoon, after a nice game of klootschieten, three successful academics told us about their grant applications. Besides the obvious importance of a good track record to succeed in science it is very important to find and keep your own balance in life. And above all: Be madly in love with science!. In the evening, a workshop on networking using social media such as LinkedIn showed that increasing and maintaining your network is also an important building block for your career. This workshop resulted in a number of new connections that were continued at the bar. The following day it was time to work on career development. An imagination exercise and a motivation game helped to answer the question What do I really want? At the end of the retreat everybody was able to use the information obtained on the first day to determine which step to take next on their career path to where they actually want to go. The NLS-PP is now online at and via LinkedIn ( PhD Retreat Post-doc Retreat Annual Report 2010 NCMLS Activities

18 NCMLS Graduate School offered the chance for a highly select group of students to visit the NCMLS NCMLS to get Activities a first-hand 2010 impression of molecular life sciences research in Nijmegen. Of the 12 short-listed international candi- NCMLS PhD recruitment initiative success NCMLS Graduate School offered the chance for a highly select group of students to visit the NCMLS to get a first-hand impression of molecular life sciences research in Nijmegen. Of the 12 short-listed international candidates invited to the NCMLS Talent Event held on 15th 17th September five were subsequently offered and accepted PhD positions. In a revised format to the previous Job Opportunity Market, NCMLS held the first ever Talent Event specifically aimed at recruiting new PhD students. The 2 1 / 2 day program allowed participants to visit departments of their choice, to engage in one-to-one discussions with group leaders and group members, as well as participate in organized lab tours. Candidates were also interviewed by a selection jury and gave 10 minute presentations to two departments of their choice. The pilot event exceeding all expectations and plans are underway for a second Talent Event in Dutch lessons for international students (NCMLeS) The NCMLS recruits many international and doctoral students from overseas. In order to increase integration into Dutch society, the NCMLS institute organized a pilot Dutch course for foreign students. The course covered basic Dutch and included language needed for doing the shopping, getting acquainted with people and travelling by public transport. Eventually, the students will be taught Dutch vocabulary closer to their own scientific research. The students participating in the course form a truly international group coming from all over the world, including Thailand, Peru, Portugal and China. Plans are underway for a second course in early Talent Event NCMLeS Dutch Course 18 NCMLS Activities 2010 NCMLS

19 Annual Report

20 Animal models are of great importance to molecular life scientists for biomedical research. The NCMLS Technology has excellent Platforms links to the Central Animal Facility (CDL) for expert advice and access to facilities for animal testing. Further- Research facilities available to members of NCMLS may be grouped in the following categories: Animal models Animal models are of great importance to molecular life scientists for biomedical research. The NCMLS has excellent links to the Central Animal Facility (CDL) for expert advice and access to facilities for animal testing. Furthermore, The 3V Research Centre, a new office of the CDL, provides service to scientists regarding alternatives to animal use (reduction, refinement and replacement). NCMLS has several diseaserelated models available, for example arthritis, cancer, kidney disease, tissue engineering, heart transplantation, neural disorders, metabolic disorders, osteoporosis, haematopoiesis, fungal and bacterial septicaemia and malaria (P. falciparum). Molecular imaging Imaging at the (sub)cellular level is an essential tool for molecular life scientists. The Microscopic Imaging Centre (MIC) at the NCMLS is a state-of-the-art facility for imaging of biological specimens utilizing light microscopy (bright-field, confocal and fluorescence), conventional scanning and transmission electron microscopy, and sophisticated digital imaging. The facility is available for researchers within and outside the NCMLS. NCMLS also offers access to other techniques such as, Atomic Force Microscopy Flow cytometry, FRET and FRAP. Access to magnetic resonance facilities for in vivo NMR and MRI of animals and humans (7 Tesla), as well as multi-photon microscopy, are also available. Collectively, these techniques form part of the molecule2man imaging platform. Translational research and cellular therapy A GMP facility with clean rooms is used for translational research e.g. immunotherapeutic cell therapy, stem cell transplantation and gene therapy. In November 1997 the Departments of Tumor Immunology, Medical Oncology and Haematology collectively initiated the application of dendritic cell-based anti-cancer vaccines in melanoma patients. To date, more than 250 patients have been treated with this experimental form of therapy. Genomics DNA sequencing as well as micro-array technology for gene expression profiling are rapidly becoming standard everyday laboratory tools. The Microarray Facility Nijmegen is one of the core facilities of the RUNMC. The Department of Human Genetics also harbours a sequencing facility and a genotyping facility. The facility is focusing on multiple applications such as expression profiling, genomic copy number profiling (array CGH) and high density SNP profiling. Next-generation Genome Sequencers (Roche 454 FLX Titanium and Solexa) are operational in the Departments of Human Genetics and of Molecular Biology. Proteomics The growing availability of genomic sequence information, together with improvements of protein characterisation by mass spectrometry, facilitates protein research enormously. To exploit these opportunities the Nijmegen Proteomics Facility (NPF) was established in The stateof-the-art proteomics facility offers fundamental technological tools in proteomics research and makes them available for academic and industrial researchers, both within and outside the Radboud University Nijmegen and Radboud University Nijmegen Medical Centre. Equipment available includes 2D-electrophoresis, SELDI-TOF and Mass spectrometry (MALDI-TOF, MALDI-LTQ and nano-lc LTQ-FT MS). Bioinformatics The CMBI is the Dutch national centre for computational molecular sciences and is housed on the groundfloor of the NCMLS research tower. The institute pursues a rigorous research programme with topics ranging from computational small-molecule chemistry to protein function prediction and the complete metabolism of a cell. The Centre s facilities, databases and software packages are available to external scientists and there is a helpdesk for scientists who use the service facility. Currently, the CMBI is primarily involved in bioinformatics research and in maintaining a data and software infrastructure to help scientists improve bioinformatics and/or computational small-molecule research. 20 Technology Platforms NCMLS

21 The Nijmegen Centre for Molecular Life Science (NCMLS) is the leading graduate school where The NCMLS students as Graduate follow a School tailormade research programmes shoulder to shoulder with professionals. NCMLS graduate school Introduction The Nijmegen Centre for Molecular Life Science (NCMLS) is the leading graduate school where students follow a tailor-made research programmes shoulder to shoulder with professionals. NCMLS graduate school offers career possibilities at all levels, from Masters students to PhD and beyond in the form of post-doctoral research positions and tenure-track positions. The regulation of cellular processes is crucial for human development, and maintenance of health throughout life. It is clear that cellular malfunction affects common multi-factorial diseases such as diabetes, immune and inflammatory disorders, renal disease, cardiovascular, metabolic and neurodegenerative diseases as well as obesity and certain forms of cancer. In the fight against such diseases, the NCMLS Graduate School which is part of Radboud University Nijmegen and Radboud University Nijmegen Medical Centre plays a key role. A major goal of the NCMLS is to translate basic knowledge generated from biomedical research into clinical application, in order to improve diagnostics and develop new treatments. All MSc and PhD students are registered junior members of the research school and have the corresponding responsibilities and privileges. Tailor-made tuition Students are guided throughout the practical training period by a supervisor and throughout the entire programme by a mentor, who stimulates them to explore your abilities and develop general research competencies, including reflection. Together with these coaches, students draw up a personal training and supervision plan. Such a broad and interdisciplinary approach to research is particularly important in the international scientific arena. Excellent career prospects There is considerable demand for specialists in fundamental molecular biology and cell biology as well as in its application to the treatment of diseases such as cancer, autoimmune and inflammatory disorders, and metabolic and neurodegenerative disorders. Our Research Master s MSc training enables students to move rapidly into an international PhD programme, giving them a more mature perspective and a broader range of experimental approaches than is possible within standard MSc programmes. They are also prepared for further training as a PhD-level researcher. Graduates are exempted from certain elements of the NCMLS PhD programme. For example, the graduate course is taught during the MSc phase and the main practical project can be incorporated into a PhD project. Education is focussed is on the domain of molecular life sciences related to disease and in particular in three main fields related to molecular medicine, cell biology and translational research. Programmes are aligned along the three research themes. Annual Report 2010 The NCMLS as Graduate School 21

22 The Nijmegen Centre for Molecular Life Science (NCMLS) is the leading graduate school where The students NCMLS as Graduate follow a School tailormade research programmes shoulder to shoulder with professionals. NCMLS graduate school MSc Molecular Mechanisms of Disease The NCMLS offers a high-quality Masters programme in Molecular Mechanisms of Disease (MMD), which is taught by top researchers and clinicians. A unique and challenging programme This ground-breaking programme translates disease-related basic research in cellular and molecular biology into clinical experimental research in patients. Designed to meet the needs of talented students with the drive, motivation and ambition to push forward their scientific careers, it represents a unique opportunity to develop a research project and build up an international research network. This extremely competitive programme provides a sound balance of theory and practice. We enrol just 24 students per year, each of whom is allocated a personal mentor. The selection of the top ten percent of students from all over the world results in an ambitious, highly-motivated group of students in an international atmosphere. The programme is intensive, but stimulating, with plenty of room for discussion and interaction. This selective approach guarantees excellence, especially during the research training periods. The programme offers a focused combination of didactic and practical components suited to optimally synthesize current discoveries, conceptual breakthroughs and technological advancement mandatory for the effective education of the new vanguard of multidisciplinary investigators. Currently, 21 students from 11 countries are enrolled in the programme. The MSc programme The 2-year Master s programme, which starts each September, is modular in structure and focuses on the three NCMLS research themes: Infection, immunity and regenerative medicine Metabolism, transport and motion Cell growth and differentiation Theoretical courses For each theme, one 4-week long module focuses on the core fundamental and translational research aspects of the field. These courses provide a solid basis of theoretical knowledge and expose students to translational research, which links basic science and the treatment of disease. The programme trains students not only in theoretical knowledge, but is also focused on important scientific skills such as academic writing, giving scientific presentations and writing grant applications. These skills offer our students head start in their scientific career. Research training periods The practical research skills are further developed in the two research training periods. The first research training is performed in the NCMLS. In the second year, students perform an international internship at renowned institutes which is concluded with a thesis. Table 1: Courses and study load of the Master s programme Molecular Mechanisms of Disease (1 EC = 28 hours of study, total programme is 120 EC) Year 1 Year 2 Introductory course (1.5 EC) Genomics and Statistics (4 EC) Excellence in communication (1.5 EC) International Master class (1.5 EC) Science and society (1.5 EC) Elective courses (9.5) Infection immunity and tissue repair (5.5 EC) Metabolism, transport and motion (5.5 EC) Cell growth and differentiation (5.5 EC) International Master classes (3 EC) Elective courses (2 EC) Research internship (34 EC) Research internship (45 EC) Career opportunities The MMD Master s programme provides students with the qualifications to enter an international PhD programme. Our graduate students distinguish themselves through their high knowledge level and independent working attitude. About 90% of them enter a PhD programme in Nijmegen or elsewhere in the world. PhD scholarships are available for the best MMD students who can apply for their self-written research-project within the NCMLS, thereby allowing them to actively shape their own career and future. Eight students graduated in 2008, four of which cum laude. Three of these students have started their PhD studies in the Nijmegen Centre for Molecular Life Sciences institute. Two students have started their PhD in international institutes (Cambridge and Stockholm). Three students have started research jobs in industry or at (international) universities. One of the highlights of the programme is a series of Master classes, which are given by leading authorities from renowned international institutes. These offer valuable insights both within and beyond your chosen specialist topics, explaining the current state of the art in important scientific areas. 22 The NCMLS as Graduate School NCMLS

23 The Nijmegen Centre for Molecular Life Science (NCMLS) is the leading graduate school where The NCMLS students as Graduate follow a School tailormade research programmes shoulder to shoulder with professionals. NCMLS graduate school International PhD programme The aim of the NCMLS PhD training programme is to provide PhD students with a multifaceted education in the field of Molecular Life Sciences. NCMLS PhD students are offered an interdisciplinary training programme, containing both general and elective components. The general components are followed by all students, whereas the elective components allow a section of the NCMLS training programme to be tailormade to complement the specific specialisation of the individual student. The training programme encourages both practical and theoretical participation in several NCMLS activities. Entrance requirements The training programme is accessible to PhD students from one of the research groups that are related to the graduate school. Students with a MSc degree, with a higher professional degree or with a similar degree from a foreign institute can enter the programme. Medicine, (Medical) Biology, Molecular Mechanisms of Disease, Chemistry, Physics, Mathematics, Computer Science and (Bio) Engineering are suitable preparatory fields of study. Because of the heterogeneity of the knowledge and interest of the students, a diverse education programme, in which many subjects will be taught, is provided. The NCMLS certificate Alongside practical training, PhD students are given the opportunity to broaden their skills through participation in specialised knowledge transfer courses. A certain number of courses are thought to be necessary in the development and education of each PhD student as independent researchers. Students that complete a full programme of NCMLS courses will be awarded with the NCMLS certificate. Annual Report 2010 The NCMLS as Graduate School 23

24 NCMLS Members I: Infection, immunity and regenerative II: Metabolism, transport and motion III: Cell growth and differentiation medicine Ia: Infection and autoimmunity IIa: Energy and redox metabolism IIIa: Genetics and epigenetic pathways (Schalkwijk) (Wieringa) of disease (van Bokhoven) Berden Jo 1a Wieringa* Bé 2a Bokhoven*, van Hans 3a Berg, van den Wim 1a Barentsz Jelle 2a Brunner Han 3a Galama Joep 1a Heerschap Arend 2a Coolen Marcel 3a Hermans Peter 1a Heuvel, van den Bert 2a Cremers Frans 3a Joosten Leo 1a Huynen Martijn 2a Geurts van Kessel Ad 3a Kullberg Bart Jan 1a Koopman Werner 2a Heesackers John 3a Kuppeveld, van Frank 1a Nijtmans Leo 2a Hollander, den Anneke 3a Loo, van de Fons 1a Smeitink Jan 2a Hoogerbrugge Nicoline 3a Meer, van der Jos 1a Smits Paul 2a Kremer Hannie 3a Melchers Willem 1a Spelbrink Peter 2a Krieken, van Han 3a Netea Mihai 1a Willems Peter 2a Logie Colin 3a Pruijn Ger 1a Martens Gerard 3a Radstake Tim 1a Roepman Ronald 3a Rij Ronald 1a Schalken Jack 3a Sauerwein Robert 1a Schenck Annette 3a Schalkwijk* Joost 1a Schoenmakers Eric 3a Verweij Paul 1a Stunnenberg Henk 3a Veenstra Gert Jan 3a Veltman Joris 3a Ib: Immune regulation (Adema) IIb: Membrane Transport and Cell IIIb: Chemical and physical biology Dynamics (Bindels) (van Hest) Adema* Gosse 1b Bindels* René 2b Delft, van Floris 3b Boerman Rolf 1b Deen Peter 2b Gielen Stan 3b Brock Roland 1b Drenth Joost 2b Hendriks Wiljan 3b Cambi Alessandra 1b Fransen Jack 2b Hest*, van Jan 3b Dolstra Harry 1b Hoenderop Joost 2b Huck Wilhelm 3b Figdor Carl 1b Knoers Nine 2b Leenders William 3b Friedl Peter 1b Koenderink Jan 2b Leeuwen, van Jeroen 3b Hilbrands Luuk 1b Kötter Rolf 2b Lubsen Lettie 3b Hoogerbrugge Peter 1b Masereeuw Roos 2b Nolte Roeland 3b Jansen Joop 1b Russel Frans 2b Rowan Alan 3b Joosten Irma 1b Rutjes Floris 3b Leeuwen, van Frank 1b Speller Sylvia 3b Oosterwijk Egbert 1b Theuvenet Lex 3b Punt Cees 1b Vriend Gert 3b Raymakers Reinier 1b Waal, de Rob 3b Reijden, van der Bert 1b Zoelen, van Joop 3b Vries, de Jolanda 1b Witte, de Theo 1b Zeeuwen Patrick 1b Ic: Regenerative medicine and microenvironment (van Kuppevelt) Buma Pieter 1c Jansen John 1c Feitz Wout 1c Kraan, van der Peter 1c Kuppevelt*, van Toin 1c Torensma Ruurd 1c Vlag, van der Johan 1c Walboomers Frank 1c Wesseling Pieter 1c Bold: theme leader; * subtheme leader Our people from Faculty of Science 24 NCMLS Members NCMLS

25 NCMLS Committees 1. NCMLS Research Council The NCMLS Research Council is involved in all decisions with respect to research and education activities within the NCMLS. The committee meets on a monthly basis and contains members representing the three research themes and sub-themes and/or play an active role in various NCMLS committees. Chairman: Prof.dr. Carl Figdor (<Sept 2010), Prof.dr. René Bindels (>Sept. 2010). 2. MMD Master s Educational Management Team The Educational Management Team ( Onderwijs management Team OMT ) is involved in the main aspects of the MSc MMD, such as the recruitment of students, budget planning and monitoring, mentorship assignments, initiation of new modules, selection of new Masterclass topics, and the evaluation of the courses. Chairman: Prof.dr. Frans Cremers (<Sept 2010), Prof.dr. Roland Brock (>Sept. 2010). 3. PhD Programme Committee This committee s primary role is the smooth running of the complete PhD programme, including the lectures for the 2 week introductory course, and approval of the individual PhD training programmes. The committee is responsible for the coordination of the student-mentor system, selects the lecturers for the graduate course, and regularly evaluates their performance. Furthermore, the committee organises an annual PhD conference and supervises the organisation (by PhD students) of 4-5 PhD workshops per annum. Chairman: Dr. Joop Jansen (<Sept 2010), Dr. Bert van der Reijden (>Sept. 2010). 4. Subsidy Review Committee This committee advises applicants (Master s, PhD students, post-docs etc) on grant applications provides concrete advice on how content and style may be improved to increase the likelihood of success. The Subsidy review Committee critically reviews pre-proposals for Veni, Vidi, Vici applications and KWF grants, and also provides interview training for students. Chairman: Dr. Gert-Jan Veenstra. 5. Seminars Committee This committee is responsible for the organization of NCMLS international seminars and Forum evenings. Chairman: Prof.dr. Hans van Bokhoven. Annual Report 2010 NCMLS Committees 25

26 26 NCMLS

27 Annual Report 2010 Theme 1 Infection, immunity and regenerative medicine

28 Systemic sclerosis (SSc) is a complex heterogeneous fibrosing autoimmune disorder with unknown pathogenesis. How the three Timothy Radstake major pathological Genetic fingerprinting in systemic sclerosis This work was published in: Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Radstake TR et al. Nat Genet 42: 426-9, Understanding systemic sclerosis by knowing its genetics Closing on the genetic and epigenetic background of systemic sclerosis Systemic sclerosis (SSc) is a complex heterogeneous fibrosing autoimmune disorder with unknown pathogenesis. How the three major pathological hallmarks of SSc, extensive fibrosis, and systemic vascular and immune dysfunction are interconnected is unknown. The lack of mechanistic understanding is limited in part due to inadequate animal models and clinically heterogeneous SSc patient populations. Based on the extent of cutaneous fibrosis, SSc is classified into two major subtypes namely limited cutaneous (lssc) and diffuse cutaneous SSc (dssc). Importantly, both SSc subtypes can be complicated by severe internal organ dysfunction. Pulmonary fibrosis and pulmonary arterial hypertension (PAH) are the two most feared complications now representing the major causes of mortality in patients with SSc. Since in many patients, particularly with dssc, the disease stabilizes or even regresses after several years, a major clinical challenge in SSc is assessing which patients have progressive disease. Thus, in addition to shedding light on pathogenic mechanisms in SSc, markers of the presence and progression of SSc clinical complications have potential utility as clinical biomarkers of disease activity. Based on the landmark observations by LeRoy et al. who identified increased collagen production by fibroblasts isolated from SSc skin and cultured in vitro, much of the research in SSc is focused on altered fibroblast biology. More recent studies, however, point to the importance of immune cells in SSc pathogenesis by the observation that plasmacytoid DCs, a rare dendritic cell subset, go awry. Strongly supporting this notion, recent genetic association studies revealed that the most highly associated susceptibility markers include the immune signaling genes Tbet, STAT4, IRF5, BLK and BANK1. Propelled by these observations we initiated an international consortium to collect DNA from a large set of well-documented SSc patients and geographically matched healthy individuals. In 2010, this resulted in the first Genome-wide scan perform in SSc. By analyzing data from 2296 SSc patients and 5171 healthy controls, we identified three novel genes that reach genome-wide significance namely CD247, Exoc2/IRF4 and CDH7 (figure 1). Next to that, the association of IRF5 and STAT4 with SSc susceptibility was firmly established. In a replication phase including 2753 independent SSc patients and 4569 healthy donors we firmly established CD247 as the novel gene for SSc (1). More recently, we re-analysed the GWAS data to study the genes possibly associated with SSc clinical phenotype. This resulted in the identification of IRF8, GRB10, RPL41/ESYT1 and SOX5 (figure 2) as genes associated with either limited or diffuse SSc (Gorlatov et al. Submitted 2011). Of high interest, from these risk genes, six are associated with the function of telomeres. We recently demonstrated that pdcs from SSc patients have a dramatically shortened telomere. Further research revealed that telomere function is also defective and the genes underlying this effect form a circuitry with the risk genes described here. In conclusion, much of our research is pointing towards a primary defect in pdcs in this condition. The manor challenge now is to unravel how the genes of interest are entangled in telomere dysfunction and aberrant pdc function. A better understanding would greatly enhance our understanding of the pathology of SSc and opens novel avenues to broaden our therapeutic armamentarium to treat this condition. Figure 1 Figure 2 28 Timothy Radstake Understanding systemic sclerosis by knowing its genetics NCMLS

29 Type 1 diabetes mellitus, is a chronic endocrine autoimmune disorder characterized by the progressive loss of insulin-producing β- Barbara Schulte cells. Genetic predispo- Type 1 Diabetes Regulation of (auto)immunity This work was published in: Phagocytosis of enterovirus-infected pancreatic beta-cells triggers innate immune responses in human dendritic cells. Schulte BM et al. Diabetes 59: , Understanding early events in autoimmune type 1 diabetes Responses of dendritic cells to enterovirus-infected pancreatic β-cells and the potential role of their interaction in type 1 diabetes development A Type 1 diabetes mellitus, is a chronic endocrine autoimmune disorder characterized by the progressive loss of insulin-producing β-cells. Genetic predisposition is a major risk factor for the acquisition of type 1 diabetes, yet also environmental factors are involved. Enteroviruses of the Human Enterovirus B (HEV-B) species of the Picornaviridae, such as coxsackievirus B (CVB) and echovirus (EV), have since long been associated with type 1 diabetes. Although these viruses are widespread and in general cause relative mild or asymptomatic infections, severe infections also occur where the virus can spread to secondary target organs such as the pancreas, brain and heart. The development or acceleration of type 1 diabetes (and autoimmune disease in general) depends on the balance between autoreactive effector T cells and regulatory T cells. This balance is particularly influenced by dendritic cells (DCs). DCs are the professional antigenpresenting cells of the immune system and B play a decisive role in initiating immune responses and maintaining self tolerance. DCs continuously sample their microenvironment; they phagocytose pathogens or pathogen-associated products such as immune complexes, yet also apoptotic cells are taken up. This results in the induction of immunity against invading pathogens and tolerance to self-antigens, respectively. Induction of an immune response occurs when DCs detect pathogen-associated danger signals or pathogen-associated molecular patterns (PAMPs), through specialized receptors, known as pattern recognition receptors (PRRs). Among these PRRs are RIGlike helicases, such as RIG-I and Mda5, that sense viral RNA and subsequently initiate immune responses. We hypothesized that enterovirus-infected pancreatic β-cells can be engulfed by DCs, that subsequently start antiviral responses to fight the infection. However, since not only viral proteins, yet also self-proteins are present unwanted auto-immune responses may also be initiated. In the present study we aimed to investigate the interaction between enterovirus-infected human pancreatic islets and human DCs. We show that both mock- and CVB3-infected human pancreatic islets were efficiently phagocytosed by human DCs (Figure 1A). Phagocytosis of CVB3-infected, but not mock-infected human islets resulted in induction of interferon-stimulated genes (ISGs) in DCs, indicating activation of the innate immune response. Among the induced genes are RIG-I and Mda5 (Figure 1B). The observed innate antiviral responses were both RNA- and type I interferon (IFN)-dependent (Figure 1B). In conclusion, human DCs can phagocytose enterovirus-infected pancreatic β-cells and subsequently induce innate antiviral responses, such as induction of RLHs. These responses may have important consequences for immune homeostasis in vivo and may play a role in the etiology of type 1 diabetes. DC + hisl/mock DC + hisl/cvb3 Figure 1: Uptake of human pancreatic islets by human DCs results in upregulation of innate interferon-dependent gene expression. A) Depicted is a confocal staining of mock- or CVB3-infected human pancreatic islets (PKH-26 labeled, red) that were cocultured with human DCs (CD86 cell surface stain, green) which shows uptake of both mock- (hisl/mock) and CVB3- (hisl/cvb3) infected human islets. B) Western blot analysis of three interferon-stimulated genes revealed that poly I:C (positive control) and CVB-infected Min 6 cells (Min6/CVB) induce interferon-stimulated genes in an interferon-dependent manner (decreased induction in the presence of anti-interferons; + antiifn). Mock-infected Min6 cells did not induce any interferon-stimulated genes. Annual Report 2010 Barbara Schulte Understanding early events in autoimmune type 1 diabetes 29

30 Recent genetic studies on common inflammatory disorders such as eczema, psoriasis, asthma and Crohn s disease suggest that Patrick Zeeuwen perturbance of epithe- Cystatin M/E controls skin barrier function This work was published in: The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. Zeeuwen PL et al. FASEB J 24: , Understanding the role of proteases and protease-inhibitors in epidermal differentiation Recent genetic studies on common inflammatory disorders such as eczema, psoriasis, asthma and Crohn s disease suggest that perturbance of epithelial barrier function in skin, lung and gut plays a role in their disease mechanisms. Clearly, the translation of these insights to understand the pathogenesis of skin diseases, or to develop new therapies, requires a detailed knowledge of epidermal differentiation and stratum corneum homeostasis. We have recently uncovered a biochemical pathway that involves cystatin M/E as a central regulator of stratum corneum homeostasis. Cystatin M/E (CST6) is a nonredundant, epithelium-specific protease inhibitor with a presumed role in epidermal differentiation and tumor suppression (Figure 1). We have reported that cystatin M/E deficiency in Cst6 -/- mice causes neonatal lethality due to excessive transepidermal water loss. Biochemical evidence indicates that cystatin M/E controls the activity of several proteases and may indirectly regulate activity of epidermal transglutaminases, which are key enzymes in skin cornification. In this paper we describe the genetic approach that we have used to define the role of cystatin M/E in epithelial biology by identification of its target proteases and their downstream functions. Ablation of cathepsin L in a Cst6 -/- background (Cst6 -/- Ctsl -/- double knockout mice) restored viability and resulted in normalization of stratum corneum morphology. Ablation of legumain or transglutaminase-3 in Cst6 -/- mice, however, did not rescue the lethal phenotype. Intriguingly, both Cst6 -/- Ctsl -/- and Cst6 -/- Ctsl +/- mice were viable, but the absence of cystatin M/E caused scarring alopecia in adult animals. In the cornea of Cst6 -/- Ctsl +/- mice, we observed keratitis, hyperplasia and transition to a cornified epithelium. Evidence is provided that activation of cathepsin D and transglutaminase-1 are downstream events, dependent of cathepsin L activity. We conclude that a tightly regulated balance between cathepsin L and cystatin M/E is essential for tissue integrity in epidermis, hair follicles and corneal epithelium (Figure 2). We would also speculate that genetic alterations of the proteins in this newly discovered pathway may be considered as candidate genes for unresolved monogenic human skin disorders that show faulty cornification, desquamation, and/or hair follicle morphogenesis. Figure 1: Cystatin M/E expression in normal human skin. Formalin fixed section of normal human skin was stained by rabbit anti-cystatin M/E antiserum. Staining is limited to the stratum granulosum. Figure 2: A tentative model of the regulatory role of cystatin M/E in processes that control epidermal cornification and desquamation. Human cystatin M/E is an inhibitor of legumain (LGMN), cathepsin L (CTSL) and cathepsin V (CTSV). Inhibition of LGMN regulates the processing of (pro)-cathepsins. Inhibition of CTSV regulates desquamation, as CTSV is able to degrade (corneo)-desmosomal proteins like desmoglein-1, desmocollin-1, and corneodesmosin. Inhibition of human CTSL activity by cystatin M/E is thought to be important in the cornification process, as CTSL is the elusive processing and activating enzyme for transglutaminase-3 (TGM3). CTSL is also able to process cathepsin D (CTSD), which in turn can activate transglutaminase- 1 (TGM1). As CTSV is only expressed in humans (pale blue oval), murine CTSL probably controls the specific functional enzymatic activities of both human CTSL and CTSV. Solid lines represent biochemical functions that are known from literature (grey) or deduced from our studies (black). Dashed lines represent unknown functions. BM, basal membrane; SB, stratum basale; SS, stratum spinosum; SG, stratum granulosum; SC, stratum corneum. 30 Patrick Zeeuwen Understanding the role of proteases and protease-inhibitors in epidermal differentiation NCMLS

31 The incidence of obesity is reaching epidemic proportions worldwide. The rise in obese individuals worldwide is closely paralleled by a Rinke Stienstra rapid increase in the Obesity and insulin resistance This work was published in: The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Stienstra R et al. Cell Metab 12: , Understanding the inflammatory mechanism by which obesity promotes insulin resistance Activation of caspase-1 contributes to the development of obesity-induced insulin resistance The incidence of obesity is reaching epidemic proportions worldwide. The rise in obese individuals worldwide is closely paralleled by a rapid increase in the prevalence of type 2 diabetes. The development of obesity is accompanied by an enlargement of adipose tissue mass that promotes hypertrophy of adipocytes and infiltration of immune cells into the adipose tissue. Altogether, these alterations lead to a pro-inflammatory status of the adipose tissue characterized by an increased production of cytokines that have been shown to promote the development of systemic insulin resistance. For example, previous studies have demonstrated that elevated circulating levels of the pro-inflammatory cytokine Interleukin-1β (IL-1β) are predictive of type 2 diabetes. In order to become activated, pro-il-1β needs to be cleaved into its biologically active form by the cysteine protease caspase-1. Caspase- 1 is part of the innate immune system and is activated by both microbial and endogenous danger signals. Activity of caspase-1 itself is rigorously controlled by proteins of the NODlike family of receptors such as ASC, NLRP3 and IPAF, that form a protein platform called the inflammasome. Our study revealed that caspase-1 is present in both human and mouse white adipose tissue (Figure 1A) and its gene expression levels are enhanced during the differentiation of pre-adipocytes towards mature adipocytes. Moreover, the development of obesity and insulin resistance due to high fat diet (HFD) feeding stimulated caspase-1 gene expression levels in adipose tissue of obese animals compared to lean animals fed a low fat diet (LFD) (Figure 1B). In parallel, IL-1β concentrations in white adipose tissue of animals rendered obese by high fat diet feeding were enhanced (Figure 1C). To analyze the effects of caspase-1 on systemic insulin sensitivity, both wild-type and caspase-1-/- animals were tested in a hyperinsulinemic euglycemic clamp study. Mice deficient for caspase-1 appeared to be more insulin sensitive as compared to wild-type animals. In line with these results, NLRP3-/- animals displayed an enhancement in insulin sensitivity levels as well. Finally, blockage of caspase-1 activity by a specific inhibitor in obese and insulin resistant animals robustly improved insulin sensitivity (Figure 2A) and led to a significant reduction in bodyweight gain after 2 weeks of treatment compared to control animals (Figure 2C). Overall, our results demonstrate that the inflammasome/caspase-1 is activated in adipose tissue of obese animals an promotes the development of systemic insulin resistance. Therefore, caspase-1 inhibition may represent a novel therapeutic target in clinical conditions associated with obesity and insulin resistance. Figure 1: Caspase-1 is present in white adipose tissue (A) and activated in obese animals (B) paralleled by enhanced IL-1β levels within adipose tissue (C). Figure 2: Blockage of caspase-1 by treatment with a specific inhibitor improves insulin sensitivity (A) and limits weight gain (B) in obese and insulin resistant animals. Annual Report 2010 Rinke Stienstra Understanding the inflammatory mechanism by which obesity promotes insulin resistance 31

32 Chronic fatigue syndrome (CFS), also named myalgic encephalitis (ME), is characterized by disabling physical and Frank van Kuppeveld mental fatigue, lasting Role of a new retrovirus in chronic fatigue syndrome This work was published in: Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. van Kuppeveld FJ et al. BMJ 340: c1018, Understanding the possible involvement of a virus in CFS etiology Prevalence of xenotropic murine leukemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. Chronic fatigue syndrome (CFS), also named myalgic encephalitis (ME), is characterized by disabling physical and mental fatigue, lasting for at least 6 months, without an apparent physical cause. Although the aetiology is unknown and the illness may cover more than one entity, many have suggested a role for infectious agents. Indeed, the onset of CFS is often preceded by an acute flu-like illness or infectious mononucleosis, recovery of which is seemingly impaired. A role of chronic infection and changed immunity has been postulated. In a recent publication in Science [1], Lombardi et al. reported the detection of XMRV - a human gamma retrovirus that was first identified in tumour tissue of patients with prostate cancer - in peripheral blood mononuclear cells (PBMC) of CFS patients. In that study, XMRV was detected by PCR in 67% of patients (68 of 101 samples) and in 4% of healthy individuals (8 out of 213 samples). This report was considered a major scientific breakthrough and attracted a lot of attention. However, the paper fell short in the description of the patients: what was the nature of the cohort (there were indications that these samples were derived from a very specific cohort [2]) and how well were the controls matched? Considering the potentially great medical and social relevance of such a discovery, investigation of an independent cohort was necessary before a causal association regarding XMRV infection and the development of CFS was justified. In this study, we investigated the presence of XMRV in a well-established Dutch cohort of CFS patients using a real time PCR targeting the XMRV integrase gene and a nested PCR targeting the XMRV gag gene. Total nucleic acid was isolated from PBMC of 32 patients and 43 controls, subjected to copy DNA synthesis, and analysed by PCR. No XMRV sequences were detected in any of the patients or their controls in either of the assays, in which relevant positive and negative isolation controls and PCR controls were included (Fig. 1A). Spiking experiments showed that we were able to detect at least 10 copies of XMRV sequences per 10 5 peripheral blood mononuclear cells by real time PCR (Fig. 1B) as well as by nested PCR (not shown), demonstrating high sensitivity of both assays. In conclusion, this study failed to demonstrate the presence of XMRV in PBMC of CFS patients in a Dutch cohort. These data cast doubt on the claim that XMRV is associated with CFS. At the same time this paper was published, three other groups also failed to establish an association between XMRV and CFS, and accumulating evidence argues against a role of XMRV in CFS. 1. Lombardi V, Ruscetti F, Das Gupta J, Pfost M, Hagen K, Peterson D, Ruscetti S, Bagni R, Petrow-Sadowski C, Gold B, Dean M, Silverman R, Mikovits J Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326: Van der Meer J, Netea M, Galama J, van Kuppeveld F Comment on Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 328:825. Figure 1: (A) XMRV integrase real time PCR. PBMC of all 32 patients were negative, as were those of all 43 controls (not shown in this figure) and all negative controls. The positive control (22Rv1) yielded a crossing point value of ~23. (B) Sensitivity of the XMRV integrase real time PCR PBMC were spiked with a dilution series of XMRV integrase PCR product (calibrator) of known concentration (i.e copies per 10 6 cells). Nucleic acid was isolated and 1/10 th was analyzed by PCR (i.e copies per reaction). Except for the reaction programmed with 1 copy of the calibrator, all spikes were positive. The inlay shows that there is a linear relation between the number of spiked molecules and the crossing point value from 10 1 to 10 6 copies per reaction. 32 Frank van Kuppeveld Understanding the possible involvement of a virus in CFS etiology NCMLS

33 Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic disorders. The diverse Gorica Nikoloski malignancies are char- Myelodysplastic Syndromes This work was published in: Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nikoloski G et al. Nat Genet 42: 665-7, Understanding the genetic background of myelodysplastic syndromes Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic disorders. The diverse malignancies are characterised by malformation (dysplasia) of granulocytic, megakaryocytic and/or erythroid cells in the bone marrow, hyperplasia and elevated levels of apoptosis, resulting in one or more cytopenias. Subjects suffering from MDS show an increased propensity of developing AML. The individual disorders differ in the severity and number of displayed cytopenias and the chance of developing AML. Cure cannot be achieved in the majority of patients. Identification of the underlying genetic aberrations may promote proper classification of the different syndromes, prognostication and the development of targeted therapy. Conventional cytogenetic techniques detect large chromosomal aberrations only in 40-60% of MDS patients. To identify genes that are mutated in MDS, we applied single nucleotide polymorphism (SNP) arrays and Sanger sequence analysis on the genomic DNA of 102 subjects suffering from MDS. Previously, we described the discovery of frequent deletions and mutations (26%) of the TET2 gene on the 4q24 locus (S.M.C. Langemeijer et al, Nat. Genet. 41, (2009)), a chromosome that does not show deletions using conventional karyotyping. In the present study, we paid attention to chromosome 7 abnormalities,since 7/7q deletions are amongst the most common cytogenetic aberrations in MDS (10% of the cases). These abnormalities correlate with very poor prognosis, but the affected gene(s) remained unknown. SNP array analysis revealed chromosome 7 deletions in 14/102 subjects and loss of heterozygosity due to uniparental disomy (UPD) in two subjects (Figure 1a). One subject harboured a monoallelic microdeletion of 130 kb at 7q36.1. This region was shared by 13/14 subjects with deletions and by 2/2 subjects with UPD. It encompassed two genes, CUL1 and EZH2. Genomic sequence analysis of these genes on the remaining allele revealed a wild-type CUL1 sequence, while EZH2 contained a frameshift mutation in exon 7 (c.703delginsaa), resulting in a premature stop codon. This implied that no intact copy of EZH2 was left in the malignant bone marrow cells of this individual. The EZH2 gene encodes the histone methyltransferase that constitutes the catalytic unit of the Polycomb Repressive Complex 2 (PRC2). This complex initiates di- and trimethylation of lysine 27 of histone H3 (H3K27), an epigenetic modification associated with gene silencing. Thus far, EZH2 was considered to be an oncogene, since overexpression of EZH2 in several tumors has been reported. To assess the prevalence of EZH2 mutations in MDS, we sequenced the gene in a total of 126 MDS patients. Acquired mono- and bi-allelic EZH2 mutations were observed in 8/126 subjects (6,3%; Figure 1b). The catalytic SET domain of EZH2 was either altered or truncated in at least one allele in all affected subjects. Mutant RNA transcripts were absent or present at lower levels than wild-type transcripts, suggesting loss-of-function. In addition to the 8 subjects with EZH2 point mutations, the EZH2 locus at 7q36.1 was entirely deleted at one allele in 22 subjects by 7/7q (micro)deletions. Collectively, deletions and point mutations of EZH2 were present in 23% of the patients. Subjects carrying 7/7q deletions and/or EZH2 point mutations showed a significantly worse survival compared to patients without any EZH2 abnormalities. We conclude that EZH2 is targeted by (loss-of-function) deletions and mutations in MDS, raising the possibility that the protein acts as a tumor suppressor rather than an oncogene in hematopoietic cells. Figure 1: EZH2 is recurrently affected in MDS. Genomic aberrations of chromosome 7 detected in 102 individuals with MDS by high-resolution SNP arrays. Numbers on the right represent unique patient numbers. Two subjects carried large areas of UPD (blue bars), fourteen subjects carried deletions (red bars) and six showed duplications (green bars, asterisks represent four different subjects). Subject 87 showed a 130-kb microdeletion at 7q36.1, containing the CUL1 and EZH2 genes. CNA=Copy Number Alterations, UPD=Uniparental disomy. (b) Localization of ten different EZH2 point mutations found in 8/126 subjects with MDS. The ruler indicates amino acids. The catalytic SET domain, a C-rich domain and the two SANT domains are indicated. Annual Report 2010 Gorica Nikoloski Understanding the genetic background of myelodysplastic syndromes 33

34 Follicular lymphoma is a solid tumor originating in lymphoid tissues,characterized by uncontrolled proliferation of B cells. Bert van der Reijden Treatment modalities Circulating cells in lymphoma This work was published in: BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC phase III intergroup study. van Oers MH et al. J Clin Oncol 28: , Understanding the prognostic value of lymphoma cells in blood and bone marrow Malignant cells in bone marrow after treatment do not predict survival in follicular lymphoma Follicular lymphoma is a solid tumor originating in lymphoid tissues, characterized by uncontrolled proliferation of B cells. Treatment modalities nowadays include monoclonal antibodies directed against B cell surface markers (e.g. CD20) to trigger apoptosis of the malignant cells. In about 80% of follicular lymphoma cases the disease is characterized by a t(14;18) chromosomal translocation. This translocation fuses the promoter of the IgH gene on chromosome 14 to the anti-apoptotic Bcl2 gene on chromosome 18. As a consequence, Bcl2 is highly expressed resulting in disturbed apoptosis, one of the hallmarks of lymphoma. In many patients with follicular lymphoma, the malignant B cells are also present in their blood and bone marrow. Following effective treatment, the frequency of IgH-Bcl2 positive cells in peripheral blood and bone marrow may be reduced as well. The frequency of these tumor cells might be used as surrogate to determine the efficacy of treatment, i.e. reduction of the malignant cells in lymph nodes. However, controversy exists as to whether responses seen in blood and bone marrow do parallel those in lymph nodes. Some studies have found positive correlations whereas others were unable to see comparable responses. These discrepancies may have been caused by the low numbers of studied patients so far. To objectively study this issue in more detail, blood and bone marrow samples from patients with relapsed/resistant follicular lymphoma were prospectively collected before and after treatment in the framework of a large intercontinental clinical study (EORTC20981). Patients in this study received chemotherapy either with or without monoclonal antibody therapy for their relapsed /resistant disease. To monitor malignant cells in blood and bone marrow, an IgH-Bcl2 realtime PCR assay was developed that enabled quantitative detection of up to 1 malignant cell among 10,000 normal cells. A total of 792 blood and bone marrow samples from 238 patients collected in Belgium, Canada, England, Sweden, Australia, Sweden, Slovak Republic, Norway and The Netherlands were shipped to Nijmegen for central, blinded analysis. Statistical analyses were performed to compare whether measured frequencies of malignant cells correlated with clinical response. This showed that the levels of malignant cells in blood and bone marrow did not influence the initial quality of response to therapy. However, higher levels predicted a significantly shorter progression free survival (Figure 1). Unexpectedly, malignant cells in blood or bone marrow detected before subsequent courses of therapy were not predictive for further survival (Figure 2). These results indicate that responses seen in blood and bone marrow do not parallel those in affected lymph nodes. Since this is the largest study conducted on this subject so far and because the observed effects were independent of the two types of treatment given, these data indicate that measuring malignant cells in blood or bone marrow after treatment is not useful for decisions on subsequent therapy for patients with relapsed follicular lymphoma. Figure 1: IgH-Bcl2 cells in bone marrow before first randomization predict a shorter progression free survival (p=0.023). The observed effects were independent of the type of treatment. Treatment consisted of a chemotherapy regiment (CHOP) with or without monoclonal antibody treatment (Rituximab). Similar results were observed in blood. Figure 2: IgH-Bcl2 cells in bone marrow at the end of reduction treatment do not predict progression free survival (p=0.385). The observed effects were independent of the treatment arm (observation versus Rituximab maintenance). Similar results were observed in blood. 34 Bert van der Reijden Understanding the prognostic value of lymphoma cells in blood and bone marrow NCMLS

35 Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children. Although cure rates are approaching 80%, relapse and associated therapy Frank van Leeuwen resist- Glucocorticoid resistance in pediatric leukemia This work was published in: BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia. van Galen JC et al. Blood 115: , Understanding therapy resistance in pediatric Acute Lymphoblastic Leukemia (ALL) BTG1, a regulator of glucocorticoid responses in ALL Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children. Although cure rates are approaching 80%, relapse and associated therapy resistance hampers a further improvement in long-term survival. Synthetic glucocorticoids (GCs) are keystone drugs in the treatment of pediatric ALL, as they effectively induce apoptosis in leukemic blasts. GCs exert their effects by binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor and member of the nuclear receptor family. Activation of the GR by GCs leads to recruitment of GR into large transcription regulatory complexes that modulate expression of GC response genes, which leads to the induction of apoptosis in lymphoblasts. Resistance to GCs is a major clinical problem, predictive of poor therapy outcome. Despite intensive research, mechanisms of GC therapy resistance remain poorly understood. Mutations in the GR are rarely seen in (relapsed) ALL and it remains unclear to what extent differences in GR mrna expression affect therapy response in the patient. We have previously shown that that microdeletions affecting the B-cell translocation gene 1 (BTG1) gene occur in about 10% of pediatric pre-b ALL cases. BTG1 expression and function have been linked to the inhibition of cell growth and the induction of apoptosis in a variety of model systems. Moreover, the BTG1 mrna is upregulated in ALL cell lines as well as clinical ALL isolates in response to GC exposure. Importantly, BTG1 interacts with and regulates the activity of the arginine methyltransferase PRMT1, a coregulator of several nuclear receptors that acts by arginine methylation of histone tails. In this paper, we used RNA interference to explore a role for BTG1 in modulating GC therapy responses. Using a lentiviral vector we expressed shrnas targeting different areas of the BTG1 gene in RS4;11 pre-b ALL cells. With either of these shrna constructs, BTG1 mrna expression was reduced to less than 10% in comparison to cells expressing an shrna control. Whereas vector control cells were highly sensitive to prednisolone exposure, both BTG1 knockdown cell lines had become completely refractory to the cytotoxic effects of this drug (Figure 1). By microarray expression analysis comparing control cells with BTG1 knockdown cells, we showed that this acquired GC resistance is due to a near complete loss of GC-induced gene expression. Notably, expression of the GR itself was reduced more than 10-fold in the BTG1 knockdown cells relative to the control cells, implicating BTG1 in GR autoinduction (Figure 2). By chromatin immunoprecipitations using anti PRMT1 antibodies, we further demonstrated that PRMT1 is recruited to the GR gene promoter in a BTG1-dependent manner. Based on these findings we propose that BTG1, probably in association with the PRMT1, promotes GR-mediated gene expression, while loss of BTG1 contributes to GC resistance. This type of therapy resistance appears to involve both defective GR autoinduction as well as reduced activation of GR target genes (Figure 2). As GCbased therapies are used in a variety of medical conditions, a detailed understanding of these novel regulators of GR-mediated gene expression may provide more rational approaches to overcoming GC resistance in the patient. Figure 1: BTG1 expression is required for the induction of GCmediated cell death. Relative viability of RS4;11 control and BTG1 knockdown cell lines as determined by an MTS-based cytotoxicity assay following three days of exposure to prednisolone. Data represent means +/- SEM of triplicate experiments. Figure 2: Model explaining how BTG1 regulates expression of the GR and that of GR-target genes GC-induced activation of the GR enhances its expression (a phenomenon known as GR-autoinduction) as well as expression of GR-target genes. Loss of BTG1 expression prevents recruitment of the BTG1/PRMT1 complex to the GR, leading to a cessation of GR autoregulation and GR mediated gene expression Annual Report 2010 Frank van Leeuwen Understanding therapy resistance in pediatric Acute Lymphoblastic Leukemia (ALL) 35

36 Allogeneic hematopoietic stem cell transplantation is a very potent form of immunotherapy in patients with hematological malignancies, Willemijn Hobo like leukemia, lym- Cancer immunotherapy This work was published in: sirna silencing of PD-L1 and PD-L2 on dendritic cells augments expansion and function of minor histocompatibility antigen-specific CD8+ T cells. Hobo W et al. Blood 116: , Understanding how knockdown of inhibitory molecules can improve dendritic cell vaccines Allogeneic hematopoietic stem cell transplantation is a very potent form of immunotherapy in patients with hematological malignancies, like leukemia, lymphoma and myeloma. The therapeutic efficacy is mediated by donorderived cytotoxic T lymphocytes (CTL) which attack malignant cells of the recipient. This graft-versus-tumor (GVT) response is mainly dependent on recognition of recipient-specific minor histocompatibility antigens (MiHA) by the donor immune system. MiHA are peptides arising from genetic polymorphisms between recipients and donors. While some MiHA are predominantly expressed by malignant cells, others are also expressed by healthy tissues. The latter results in graft-versus-host-disease (GVHD), which is a common cause of morbidity and mortality in allosct patients. Therefore, it is desired to direct GVT immunity towards MiHA selectively expressed by malignant cells. The power of graft-versus-tumor (GVT) effect is best illustrated by the induction of clinical remission in relapsed myeloid leukemia following post-transplant infusion of T cells from the original stem cell donor. However, in time these alloreactive T cells do not always respond efficiently to recurring tumor cells and this failure may contribute to the occurrence of tumor relapses. Dendritic cell (DC)- based vaccination boosting MiHA-specific T cell immunity is an appealing strategy to prevent or counteract tumor recurrence, but improvement is necessary to increase the clinical benefit. PD-L1 and PD-L2 are co-inhibitory ligands, expressed by professional antigen-presenting cells, that engage to the co-inhibitory receptor PD-1, resulting in negative regulation of T cell cytokine production and proliferation. In the past few years, it has been demonstrated that the PD-1/PD-L pathway can be hijacked in chronic viral infections, solid tumors and chronic myeloid leukemia. Chronic stimulation of antigen-specific T cells in the presence of PD-1 signaling causes functional exhaustion of these cells. Interfering with the PD- 1/PD-L pathway would result in diminished T cell inhibition and, thereby, improve antigenspecific T cell responses (Figure 1A). In this study, we demonstrated that by knocking down PD-L1 and PD-L2 on monocytederived DC we could augment MiHA-specific T cell responses. We first identified small interfering RNAs (sirnas) that efficiently and specifically silenced PD-L1 and PD-L2 expression following electroporation of immature DC (Figure 1B). To investigate whether knockdown of PD-L1 and PD-L2 improved the stimulatory capacity of DC, we cultured mature PD-L knockdown DC with either allogeneic (primary response) or antigen-experienced (secondary response) T cells. This resulted in significant improvement of IFN-? and IL-2 production, and proliferation of the stimulated T cells. Furthermore, we demonstrated that PD-L gene-silenced DC show superior potential to expand PD-1-expressing MiHA-specific effector and memory T cells from leukemia patients shortly after DLI and later during relapse (Figure 1C). Together, these findings indicate that PD-L sirna-electroporated DC are attractive cells for improving the efficacy of MiHA-based DC vaccines to boost GVT immunity in SCT patients as well as antigen-loaded DC in cancer patients and chronic viral infections. Figure 1: PD-L knockdown DC boost the proliferative capacity of MiHA-specific CD8 + memory T cells. A) We hypothesize in our model, that by expressing the co-inhibitory ligand PD-L1 leukemia cells may impair PD-1 + MiHA-specific memory T cells. By silencing PD-L1 and PD-L2 on dendritic cell vaccines, the stimulatory potential of the DC increases and, thereby, revive functionally impaired CTLs to expand and regain effector functions. B) Immature DC were electroporated with PD-L1, PD-L2 or negative control sirna. After two days, PD-L expression was determined using flow cytometry. Both sirna duplexes efficiently and specifically down regulated PD-L expression (solid black lines) as compared to the negative control. C) To determine the effect of stimulation with MiHApresenting PD-L silenced DC on MiHA-specific T cell proliferation, we used cells of a leukemia patient containing 0.06% LRH-1-specific CD8 + memory T cells. Upon 3 weeks of consecutive stimulations, the expansion of LRH-1-specific CD8 + T cells was profoundly boosted by PD-L silenced DC compared to control DC. 36 Willemijn Hobo Understanding how knockdown of inhibitory molecules can improve dendritic cell vaccines NCMLS

37 Dendritic cells (DCs) are the most potent professional antigen-presenting cells of the immune system. Upon infection or inflammation, immature DCs are Gerty Schreibelt activated Cancer immunotherapy This work was published in: Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells. Schreibelt G et al. Blood 116: , Understanding dendritic cell-based vaccines Prophylactic vaccines as an alternative for synthetic TLR ligands to mature monocyte-derived Dendritic cells (DCs) are the most potent professional antigen-presenting cells of the immune system. Upon infection or inflammation, immature DCs are activated and differentiate into mature DCs that instruct and activate B and T lymphocytes, the mediators of adaptive immunity. Currently, DC-based immunotherapy is explored in clinical trials, predominantly in cancer patients. Over the last years vaccines consisting of autologous DCs loaded with tumor antigens have proven to be safe and capable of inducing tumor antigen-specific immune responses in a substantial part of vaccinated patients. However, clinical effectiveness is still low, underlining the necessity to further optimize different parameters, including DC maturation. It has been suggested that the current protocols used to generate mature DCs may not result in optimal T helper cell responses. To date, most clinical studies use a cocktail of proinflammatory cytokines for DC maturation. However, murine studies showed that only DCs matured in the presence of Toll-like receptor (TLR) ligands promotes optimal T cell help. TLR-mediated maturation of ex vivo-generated human DCs may thus improve immunological and clinical responses in DC vaccination of cancer patients. We recently demonstrated that a maturation cocktail combining TLR3 and TLR7/8 ligands yields DCs with high T cell stimulatory capacity. Unfortunately the limited availability of clinical grade TLR ligands significantly hampers the translation of these findings into DC-based vaccines for cancer patients. Therefore, we searched for an alternative maturation cocktail containing clinically applicable TLR-ligands. TLRs are pattern recognition receptors that sense microbial and viral products, such as viral double stranded RNA or bacterial cell wall components. Vaccines against infectious diseases frequently contain molecules derived from bacteria or viruses. These molecules may be recognized by pattern recognition receptors such as TLRs and may therefore be good candidates for stimulation of DCs. In this study we explored the use of 15 commercially available preventive vaccines as a possible source of TLR ligands. Four out of fifteen vaccines tested indeed contained TLR ligands. We found that a cocktail of the three vaccines BCG-SSI, Typhim and Influvac induced optimal DC maturation. DCs matured with this cocktail have a fully mature phenotype with high expression of costimulatory molecules and major histocompatibility molecules and secrete high levels of the proinflammatory cytokine IL-12, which is important to drive a T helper 1 response (figure). Our results indeed show that vaccine-matured DCs are potent inducers of T cell proliferation and T helper 1 polarization and, more importantly, are capable of inducing tumor antigen-specific effector T cells. Although vaccine-matured DC exhibit an impaired migratory capacity, this can be restored by addition of the prostaglandin PGE 2. Finally, in contrast to maturation with synthetically produced TLR3 ligands, DC maturation with vaccines is compatible with different antigen loading strategies, including RNA electroporation, which is favorable for clinical use, since RNA electroporation with tumor antigens results in presentation of multiple epitopes in both MHC class I and II. Our data thus identify a new clinical application for a mixture of commonly used preventive vaccines in the generation of clinical grade mature DC. Clinical studies are currently performed to investigate whether vaccine-matured DC improve anti-tumor responses in vivo. Figure 1: A) DCs matured with a cocktail of the vaccines BCG-SSI, Typhim and Influvac have a fully mature phenotype with high expression major histocompatibility complex molecules, costimulatory molecules CD80 en CD86 en the maturation marker CD83. B) DCs matured with the vaccine cocktail produce more IL-12 than immature DCs (imdc) or DCs matured with a commonly used cytokine cocktail consisting of IL-1β, IL-6, TNFα and PGE 2 (cdc). C) In mixed lymphocyte reaction, T cells produce more IFNg when cocultured with vaccine-matured DCs compared to cdc, indicating that vaccine-dcs induce a T helper 1 response. D) Vaccine-matured DCs induce tumor antigen (gp100)-specific granzyme B expression in naïve CD8+ T cells, indicating that vaccine-matured DCs are capable of activating cytotoxic T lymphocytes. Annual Report 2010 Gerty Schreibelt Understanding dendritic cell-based vaccines 37

38 The incidence of breast cancer is known to be affected by the hormonal milieu breast cells experience over time. Clinically and biochemically, there is a Marleen Ansems well- DC-SCRIPT This work was published in: DC-SCRIPT: nuclear receptor modulation and prognostic significance in primary breast cancer. Ansems M et al. J Natl Cancer Inst 102: 54-68, Understanding the role of the novel Nuclear Receptor coregulator DC-SCRIPT in breast cancer The incidence of breast cancer is known to be affected by the hormonal milieu breast cells experience over time. Clinically and biochemically, there is a well-recognized connection between hormone dependent nuclear receptors (NR) function and breast cancer development. NRs are intracellular receptors that execute a transcriptional program upon binding to hormones (e.g. estrogens, corticosteroids and androgens), vitamins (e.g. vitamin A and D) and metabolites (e.g. fatty acids, eicosanoid derivatives and oxidized lipids). In this study we have identified DC-SCRIPT (Dendritic Cell-Specific transcript) as a novel coregulator of different subclasses of NRs. DC-SCRIPT is a 744 amino acid protein, originally identified in a unique immune cell subset, the antigen presenting dendritic cells. The protein of DC-SCRIPT consists of an amino-terminal proline-rich domain, 11 C 2 H 2 - type Zinc fingers, and a C-terminal acidic region. The acidic region of DC-SCRIPT contains both a functional binding motif for the co-repressor protein CtBP and a LxxLL nuclear receptor (NR) interaction motif. We found that DC-SCRIPT could interact with the type I NRs, ER (Estrogen Receptor) and PR (Progesterone Receptor), but also with the type II NRs, the RXR (retinoid X receptor) heterodimers RAR (retinoic acid receptor alpha) and PPARγ (peroxisome proliferator activated receptor gamma). Ligands for the type I NRs, ER and PR, are often associated with the initiation and progression of breast cancer and are well known for their proliferative effect on breast cancer cells. Antiestrogen therapy with tamoxifen has been applied successfully in the treatment of breast cancer patients. In contrast to the type I NRs, the type II NRs RAR/RXR and PPAR/RXR, play a predominantly antitumorigenic role in human breast cancer by inhibiting cell growth and inducing apoptosis. Interestingly, our data demonstrated that DC- SCRIPT expression opposingly modulated transcription mediated by type I and type II NRs. It inhibited the activity of the primarily pro-proliferative type I NRs; in contrast the transcriptional activities of the mainly antiproliferative type II NRs were enhanced by DC- SCRIPT. As the NRs regulated by DC-SCRIPT have been associated with breast cancer we also investigated its expression in breast carcinoma tissue. Our data showed that ductal epithelial breast cells express DC-SCRIPT, breast tumors express lower levels of DC-SCRIPT than normal breast tissue from the same patient, and breast tumor cell lines do not express DC- SCRIPT mrna. Ectopic DC-SCRIPT expression in a breast cancer cell line inhibited breast carcinoma cell growth. Furthermore, quantification of DC-SCRIPT mrna expression in three cohorts of breast cancer patients revealed that DC-SCRIPT mrna expression is an independent prognostic factor for good survival in breast cancer patients with ER- and/or PRpositive tumors (figure 1). All together the data revealed that DC-SCRIPT is a unique coregulator of NRs that exhibits distinct effects on type I and type II NR mediated transcription and represents a factor with strong prognostic value in breast cancer (figure 2). Moreover, it suggests that DC- SCRIPT can act as a tumor suppressor in breast cancer development and may be an attractive target for NR coregulator specific therapy for either breast cancer prevention or adjuvant therapy. Figure 1: DC-SCRIPT) expression as aprognostic marker in ER/PR positive breast cancer. Kaplan Meier analysis of disease-free interval according to DC-SCRIPT mrna expression in tumors from patients with ERand PR-positive tumors (n = 65). Patients with high DC- SCRIPT expression were compared with patients with lower DC-SCRIPT expression. P value is two-sided (Cox proportional hazards tests). Figure 2: Balance of nuclear receptor function by DC-SCRIPT expression in breast cancer. Hypothesized model of DC-SCRIPT function in ER/PR positive breast epithelial cells. DC-SCRIPT represses the activity of the pro-tumourigenic type I NR ERα and PR and conversely enhances the anti-tumourigenic type II NR PPARγ and RARα, thereby actively regulating the NR balance. During malignant transformation and tumour progression, higher DC-SCRIPT expression leads to a more balanced NR function resulting in a better prognosis, whereas low expression of DC-SCRIPT results in an imbalance in NR function and to a bad prognosis. 38 Marleen Ansems Understanding the role of the novel Nuclear Receptor coregulator DC-SCRIPT in breast cancer NCMLS

39 Cell migration is a complex and heterogeneous process executed by all nucleated cell types at a given time window of their development. Cell Peter Friedl migration Tuning cell migration This work was published in: Plasticity of cell migration: a multiscale tuning model. Friedl P & Wolf K. J Cell Biol 188: 11-9, Understanding the diversity of cell movements in different contexts: Plasticity of cell migration a multi-scale tuning model Cell migration is a complex and heterogeneous process executed by all nucleated cell types at a given time window of their development. Cell migration underlies tissue formation, maintenance and regeneration as well as pathological conditions such as cancer invasion. How a certain cell type migrates ( migration mode ) was originally classified based on the cell morphology and pattern during migration (Fig. 1). As main categories, cell move either individually (amoeboid or mesenchymal) or collectively (cohesive multicellular units). In recent years, this terminology was extended to include additional parameters, such as structural and molecular determinants of both tissue environment and cells, including adhesion receptor function, cytoskeletal organization and the function of matrix-degrading enzymes. Albeit not all molecular determinants of each migration mode are fully understood, some key parameters have been identified as checkpoints that either maintain a given migration type, or, by increase or decrease of strength, initiate transitions. We here developed a multi-parameter tuning model to describe how dimension, density, orientation and stiffness of the extracellular matrix together with cell determinants - including cell-cell and cell-matrix adhesion, cytoskeletal polarity and stiffness, traction force, and pericellular proteolysis - interdependently control migration mode and efficiency (Fig. 2). Most determinants of cell migration are assumed to be tunable and thereby control the migration mode and efficiency in a continuous rather than a discrete on or off manner. By increasing or decreasing their input, they tune how moving cells polarize and engage with encountered tissue substrate. Each parameter is experimentally testable individually, however in most cases is interconnected with others. Because all parameters act concurrently, but at different strength, each parameter profile then impacts the type of migration (Fig. 2, colored lines indicate approximated parameter profiles of selected migration modes). Consequently, modulation by increasing or decreasing the magnitude of any parameter may alter the migration mode. The format of the tuning model mimics the popular display of a graphic equalizer, which is integral to modern media display programs (e.g. Windows Media Player or QuickTime); the graphic interface serves to adjust the intensity of different wave lengths of the phono output independently to modify the sound profile. The tuning model may be helpful to understand and experimentally test the adaptability of cell movement and its consequences for tissue formation and remodeling, particularly in morphogenesis and cancer metastasis. The model may further be a useful starting point for computational modelling of cell migration in different contexts. Future wet-lab and computational studies will have not only to integrate other tissue types, include novel, or exclude existing determinants for special migration modes and contexts, but also should take co-regulated synergistic or antagonistic multi-parameter modules into account. Figure 1: Cell morphologies, migration modes and transitions. Figure 2: Cell morphologies, migration modes and transitions. Annual Report 2010 Peter Friedl Understanding the diversity of cell movements in different contexts 39

40 In spina bifida the neural tube fails to close during embryonic development. Exposure of neural tissue to the amniotic fluid during Paul Geutjes pregnancy causes neu- Fetal therapies for congenital defects This work was published in: Intra-uterine tissue engineering of full-thickness skin defects in a fetal sheep model. Hosper NA et al. Biomaterials 31: , Understanding the role of growth factors in fetal skin regeneration Coverage of fetal skin defects with a collagen biomatrix loaded with growth factors in a sheep model In spina bifida the neural tube fails to close during embryonic development. Exposure of neural tissue to the amniotic fluid during pregnancy causes neural damage. For most patients this means live long disability. Current treatment consists of surgical closure of the defect after birth, in order to prevent infection and further damage. Early fetal therapy, or fetal skin closure, may diminish the amniotic fluid related damage. Tissue engineering is a rapidly growing interdisciplinary field which aims to repair, replace and enhance the biological function of diseased tissue. Ideally, a scaffold attracts distinct cells from the surrounding tissue that eventually synthesize tissue-specific extra cellular matrix (ECM). This approach may introduce alternative strategies for the treatment of congenital defects, such as spina bifida. In this study we investigated whether so called smart scaffolds can be used to treat full-thickness fetal skin defects to facilitate epidermal overgrowth and dermal repair. These are highly porous biodegradable collagen scaffolds (figure 1) which are loaded with a complex sugar molecule (heparin) and heparin binding growth factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). We emphasized that a combination of these growth factors enhances angiogenesis and accelerate epithelialization. Scaffolds with and without growth factors were evaluated in surgically created skin defects on the back of fetal lambs, which were macroscopically and histologically examined in time. On macroscopic level we found that wound contraction was mainly present in the uncovered defects, partially present in the standard scaffold, and almost no wound contraction occurred in growth factor loaded scaffold (figure 2). This effect can be explained by the FGF-2 expression in the scaffold, since FGF-2 can inhibit and reverse the differentiation of fibroblasts to myofibroblasts. It is highly important that wound contraction and scar formation will be minimized, as the fetus grows. One other basic process which is of importance for the remodeling of the biomaterial is angiogenesis. Blood vessels are essential in enabling cell migration and supplying sufficient oxygen and nutrition inside the scaffold. Both VEGF and FGF-2 can promote angiogenesis and this combination has been shown to have synergistic effects on neovascularisation. Particular in the growth factor loaded scaffold, excessive formation of capillaries was observed 8 weeks post surgery (figure 3). This indicates that a smart material has the ability to stimulate these key processes even without the addition of cells at the time of implantation. A highly interesting observation in this study was the formation of new hair follicles in the regenerated area of the growth factor loaded material (figure 4). Regeneration of these specialized structures indicates an enhanced functional healing. These newly formed hair follicles were less mature than the hair follicles in the unwounded skin, indicating that the follicles had not migrated from the wound edges. In conclusion, coverage of fetal skin defects with a VEGF and FGF-2 loaded collagen scaffold resulted in less wound contraction, improved angiogenesis and keratinocyt ingrowth. This scaffold can be useful in coverage of fetal spina bifida defects and may improve neonatal outcome. Figure 1: Macroscopical and microscopical images of highly porous cross-linked collagen scaffold Figure 2: Macroscopical overview of wound healing after surgery at 93 days (2 weeks post surgery). Note the shape of contraction of the untreated lesion and the reddish appearance of the wound treated with the growth factor loaded scaffold (COL-HEP/VF). Figure 3: Vascularization. Collagen IV staining of skin defects 8 weeks after implantation. A) Defect treated with only collagen scaffold. B) Defect treated with growth factor loaded scaffold. Note the excessive formation of capillaries (B1). Original magnifications: 50 (A and B) and 200 (A1 and B1). Figure 4: Masson's trichrome staining of skin defects 8 wk after implantation. Defect treated with A) collagen scaffold B) growth factor loaded scaffold. Note hair follicle formation in the regenerated epidermis (B1). Black striped line is edge of defect; black dotted line is border between surrounding tissue and scaffold. E = epidermis, D = dermis, S = scaffold. Original magnifications: 50 (A and B) and 200 (A1-B2). 40 Paul Geutjes Understanding the role of growth factors in fetal skin regeneration NCMLS

41 The general aim of regenerative medicine is to restore organs after they have been damaged or lost. One approach to reach this Gerwen Lammers goal is to implant a Skin tissue engineering This work was published in: High density gene expression microarrays and gene ontology analysis for identifying processes in implanted tissue engineering constructs. Lammers G et al. Biomaterials 31: , Understanding biological processes in regenerating skin High density gene expression microarray and gene ontology analysis of implanted tissue engineering constructs The general aim of regenerative medicine is to restore organs after they have been damaged or lost. One approach to reach this goal is to implant a suitable scaffold at the site of injury, e.g. after skin wounding. In order to further understand the observed process of regeneration, it is important to identify biological processes that take place in tissue-engineered constructs. Currently, histological evaluation is one of the main methodologies to identify these processes. However, histology comes with a number of drawbacks including the subjectivity of the scoring process, the expertise required to link histological observations to biological processes, the use of relatively small tissue samples (with the risk of missing important data), and the time-consuming nature of the process. Gene expression microarrays may bypass some of these drawbacks. Using high density microarrays, virtually all known (and yet unknown) genes can be analysed in a single experiment. Sophisticated and user-friendly software to analyse the large amount of data is becoming available, and the knowledge on array analysis and biological interpretation is rapidly expanding, allowing objective highthroughput analysis. The technique requires no more than five days from RNA isolation to the identification of biological processes, and the computerised workflow enables an objective, unbiased analysis. We used a high density microarray-based approach to identify biological processes up/downregulated in vivo in a double-layered skin construct applied in a rat full-thickness wound model studying at various time points after implantation (Fig. 1). Results were compared to wound healing without construct, and a freely-available program (DAVID) was used to identify up/downregulated biological processes (gene ontology (GO)-terms). Conventional (immuno)histology was used to validate the biological processes identified (Fig. 2 shows an example). Results indicated that microarray analysis may provide a valuable, fast and unbiased tool to evaluate the in vivo performance of tissue-engineered constructs. However, challenges remain e.g. with regards to the development of specific GOterms and annotation of the (rat) genome. Figure 1: Schematic overview of the complete procedure for the identification of biological processes occurring in vivo in constructs used for tissue engineering. In short, mrna was isolated from tissue samples and processed for hybridisation on rat exon arrays. The amount of hybridised RNA, reflecting the amount of specific mrna s, was compared between groups, resulting in lists with up- and downregulated genes. Lists were uploaded in the DAVID functional annotation tool and the enrichment in biological process gene ontology (GO) terms was analysed. Up/downregulated biological processes were validated by conventional histology. The minimal time required for each step is indicated on the right. 1 Randomise/balance samples when multiple runs are necessary; TD Tissue-dependent; T7 = T7 promoter. Picture of microarray is courtesy of Affymetrix. Figure 2: Lists of downregulated genes were significantly enriched for gene ontology terms like striated muscle contraction and muscle development, depicted here for construct day 112. (B-C) Downregulation (absence) of these processes was confirmed by immunostaining for muscle-specific desmin. (B) Construct day 112 showed no staining, while (C) a clear brown-stained muscle layer (the rodent panniculus carnosis) was visible in normal skin. Bar is 100 µm. Annual Report 2010 Gerwen Lammers Understanding biological processes in regenerating skin 41

42 Bones provide structural support to the body, organizing its components in space, protecting vital organs, and transmitting muscle Ljupcho Prodanov forces from one part of Cell mechanics This work was published in: The interaction between nanoscale surface features and mechanical loading and its effect on osteoblast-like cells behavior. Prodanov L et al. Biomaterials 31: , Understanding the sensitivity of the cells The interaction between bone cells and their dynamic environment Bones provide structural support to the body, organizing its components in space, protecting vital organs, and transmitting muscle forces from one part of the body to another. The buildup of the bone macro morphology, as well as the internal orientation of the collagen filaments, are adjusted in shape and orientation according to the principle direction of load. In order to achieve and maintain such proper architecture, bone cells receive environmental information in the form of (1) signaling molecules (growth factors, hormones), (2) mechanical stimuli arising from naturally occurring processes like fluid flow, compression, deformation and gravity, and (3) size, shape, and stiffness patterns recognized from the molecules composing the extracellular matrix (ECM). Thus, cellular processes are not influenced by a single parameter, but by multiple parameters acting simultaneously. Current designs for mechano-biological models, usually chose single-parameter approaches, which are atypical for the living organism, and to better understand cell behavior, new multi-factorial models need to be devolved. In the current study, our hypothesis was that using a nano-textured surface representing the structural component of the ECM, and mechanical loading representing the body s movement, we can develop a multi-factorial model in which both parameters truly interact. Secondly, we hypothesised that such a dual stimulation will show synergistic effects on cell behaviour in terms of cell attachment, ECM formation and osteoblast differentiation potential. In our study set up, primary bone marrow stromal cells were harvested from rat femura and differentiated towards an oseoblast phenotype in the presence of dexamethasone, a phosphate source, and ascorbic acid. Subsequently, the cells were seeded onto elastomer dishes. Mechanical stimulation was applied by discontinuous longitudinal stretch with a stretch magnitude of 8%, at a frequency of 1 Hz. The second parameter was the introduction of a specific nanometric texture on the surface of the elastomer substrate, consisting of a groove-ridge pattern of 300 nm wide and 60 nm deep. This pattern was applied in parallel direction to the direction of the stretch. The data of this study showed that on a planar control surface, cells always showed multipolar shapes with no evident distribution in orientation. On all textured substrates, an elongated cellular shape was induced, with all cells adjusting to a direction in parallel to the nano-grooves. When in both these situations mechanical loading was applied, cells changed their initial morphology and direction as shown in Figures 1 and 2. Most noticeably with a minimal deformation of 3%, the mechanical force was able to overrule the cue cells received from the surface patterning. Moreover the gene expression was altered in all three challenged conditions as compared to the smooth control. A significant synergistic effect in terms of gene expression for fibronectin and Cfba was observed when dual stimulation was used. The dual stimulation gave the highest gene expression profile. In conclusion, a first multi-factorial model was made, in which nano-scale structural and mechanical stimuli can truly interact. Furthermore, such dual stimulation can induce synergistic effects to the function of bone producing cells. Figure 1: Scanning electron micrographs of cells cultured at various conditions. Top left: random cell orientation on a control planar substrate without mechanical loading, top right: perpendicular cell orientation towards the direction of deformation. Bottom left: parallel cell orientation towards the texture on a substrate equipped with a nanometric groove pattern, bottom right: cell alignment to the substrate nanotopography is lost due to a stretch force. Green and red arrows indicate the direction of the stretch and grooves, respectively. Figure 2: Box-Whisker plot showing the cellular alignment. The median is marked in the box with red and the box-corners indicate the 25th to 75th percentiles. A median of 45 represents a totally random orientation. Cells subjected to a mechanical cue on a smooth surface showing gradual alignment in perpendicular direction to the stretch force, whereas cells on the texture are driven towards a parallel orientation. Note that cell alignment to the nanotextured substrate is lost due to the stretch force as depicted on the graphs above the plot. The p-value in the different groups was calculated against the smooth control (*= p<0.001), and each box in the plot represents ~ 200 cells. 42 Ljupcho Prodanov Understanding the sensitivity of the cells NCMLS

43 Heparan sulfate (HS) is a structurally complex polysaccharide that interacts with a broad spectrum of ligands and thereby is thought Nicole Smits to regulate a diverse Heparan Sulfate This work was published in: The heparan sulfate motif (GlcNS6S-IdoA2S)3, common in heparin, has a strict topography and is involved in cell behavior and disease. Smits NC et al. J Biol Chem 285: , Understanding Heparan Sulfate Sequences Linking Heparan Sulfate Motifs to Cell Behavior and Disease Heparan sulfate (HS) is a structurally complex polysaccharide that interacts with a broad spectrum of ligands and thereby is thought to regulate a diverse array of biological processes. The specificity of HS-ligand interactions is determined by the arrangement of sulfate groups on HS, which creates distinct binding motifs. Biologically important HS motifs are expected to exhibit regulated expression, yet little is known of the biologic roles of specific HS motifs. Progress in this field has been hampered by a lack of tools to identify and modulate the function of such structures. In particular, the extremely low immunogenicity of HS has limited the development of anti-hs antibodies. We have overcome this barrier by employing phage display technology, which allows for the generation of antibodies against self antigens, such as HS. Although it is increasingly recognized that a specific domain structure is responsible for HS modulation of biological activity, in only a few cases is there any structural information regarding monosaccharide sequences. Therefore, accelerating our understanding of structure-function relationships for HS requires the development of rapid yet thorough sequencing methodologies. In this study we report on the selection, characterization, and biological application of a novel phage display-derived antibody (NS4F5) that recognizes a highly regulated HS motif (HS NS4F5) that we have rigorously identified as (GlcNS6S-IdoA2S) 3, using octasaccharide libraries and modified heparins (GlcNS6S: N- and 6-O sulfated glucosamine; IdoA2S: 2-O sulfated iduronic acid). This is the first time recognition of a specific HS monosaccharide sequence by an antibody has been described. HS NS4F5 exhibits a very restricted distribution in HS in healthy adult tissues. To study the cell biological relevance of HS NS4F5, we used NS4F5 as a blocking agent to block HS NS4F5 engagement with natural ligands. Blocking the function of HS NS4F5 in vitro inhibits cell proliferation, sensitizes cells to apoptosis, but does not affect cell attachment to type I collagen. HS NS4F5 is highly expressed in endothelial cells activated with the cytokine TNF-α (Figure 1A). This indicates that HS NS4F5 is upregulated in activated endothelial cells and suggests that HS NS4F5 may regulate inflammatory processes. Indeed, treatment with the neutralizing antibody NS4F5 reduces the firm attachment of leukocytes to endothelial cells (Figure 1B). Thus, HS NS4F5 can be classified as a pro-inflammatory HS motif that enhances leukocyte:endothelial cell interactions and therefore may have therapeutic implications. HS NS4F5 is highly up-regulated in human ovarian cancer, whereas it is almost undetectable in normal ovarian epithelium. The use of HS NS4F5 as a biomarker of ovarian tumors is currently investigated. We further observed in mice the presence of HS NS4F5 in AA amyloid deposits with little or no reactivity in healthy, amyloid-free tissues (Figure 2). Using labeled NS4F5 antibodies, amyloid deposits could be visualized by single photon emission computed tomography. Thus, HS NS4F5 may be a key target for the development of novel therapeutic approaches for amyloid-associated disorders such as Alzheimer disease. Combined, our studies provide new insight into the distribution and function of a specific HS motif, HS NS4F5, and show that in addition to mediating cellular behavior it represents a novel biomarker of amyloid disease and possibly ovarian tumors. Taken together, the ability to identify specific HS structures with unique antibodies such as NS4F5 will accelerate our understanding of the relevance of polysaccharide structures to the regulation of biological functions. Figure 1: A, HS NS4F5 expression by HUVEC is increased after TNF-α activation. HS NS4F5 expression was measured by flow cytometry in non-activated and TNF-α activated HUVEC. Relative mean fluorescence intensity (MFI) is shown. MFI of non-activated HUVEC is set at 100. B, HS NS4F5 on activated HUVEC contributes to firm leukocyte adhesion. TNF-α activated HUVEC were co-incubated with labeled 32Dcl3 (leukocyte) cells and NS4F5 (or control antibody MPB49) and % inhibition of adhesion was calculated. Values are mean ± S.D. (n=5). *, p < Figure 2: Imaging, and co-localization of NS4F5 with AA amyloid deposits. 125 I-NS4F5 distribution was visualized in healthy (A) and amyloid-laden (B) mice by microspect imaging. 125 I-NS4F5 accumulated in amyloid deposits in liver (L), pancreas (or intestine, P/I) and kidney (RK). In amyloid-free mice, 125 I-NS4F5 was observed in the stomach (S) with some activity associated with renal clearance (RK). 125 I-NS4F5 uptake by hepatic amyloid deposits was confirmed microscopically, where Congophilic amyloid (C) was co-stained by black grains (D). No 125 I-NS4F5 accumulation was observed in healthy liver (E) (n=4). Annual Report 2010 Nicole Smits Understanding Heparan Sulfate Sequences 43

44 44 NCMLS

45 Annual Report 2010 Theme 2 Cell metabolism, transport and motion

46 The human body requires energy in the form of ATP. This highenergy coumpound is generated by stepwise breakdown of organic Jessica Nouws nutrients, like fatty Oxidative phosphorylation This work was published in: Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Nouws J et al. Cell Metab 12: , Understanding mitochondrial complex I deficiency The human body requires energy in the form of ATP. This high-energy coumpound is generated by stepwise breakdown of organic nutrients, like fatty acids and carbohydrates. Metabolic processes such as glycolysis, beta oxidation, and the krebs cycle produce NADH, which is the substrate for the final step in this process, the oxidative phosporylation (OXPHOS). Complex I is the first enzyme of the mitochondrial OXPHOS system. Defects in this enzyme can lead to a decreased ATP production and accumulation of toxic metabolites and reactive oxygen species. This typically leads to severe disorders with a very heterogeneous phenotype, an early onset, and a poor prognosis. To better understand the causes and consequences of a defective complex I, we study the assembly of this multisubunit enzyme and encountered a remarkable unexpected finding. We found that a protein that was proposed to play a role in the fatty acid oxidation, is involved in the biogenesis of complex I. Most of the complex I disorders can be explained by mutations in one of the 45 structural subunits, however fifty percent is still unaccounted for. This group is most likely explained by mutations in assembly factors, factors which aid the assembly of complex I. To find these unknown assembly factors, we performed co-purifications using two known assembly factors as a bait. Subsequent mass spectrometric analysis of the purified proteins led to the finding of a new unanticipated binding partner. This protein, ACAD9, was proposed to be active in mitochondrial fatty acid oxidation, more specifically the completion of the first step in the beta oxidation of long chain fatty acids. To explore its role in complex I biogenesis, we knocked down ACAD9 expression by RNA interference which resulted in a specific decrease of complex I level and activity, whereas fatty acid oxidation of long chain fatty acids appeared unaffected. This prompted us to screen complex I deficient patients for mutations in the ACAD9 gene. Excitingly we found two patients with different mutations in this gene. Mutation modeling revealed that these mutations in all probability have major structural consequences (figure 1). To determine whether these mutations were truly the causative mutations we performed complementation studies with RFP-tagged ACAD9, which resulted in a rescue of the complex I assembly defect. Moreover analysis of the oxidation of long chain fatty acids in patient material did not show a defect in this pathway. Phylogenetic analysis showed that ACAD9 is a very close family member of VLCAD, an established fatty acid oxidation enzyme. They share 65 percent amino acid homology, and the active sites in VLCAD responsible for the initial step in the fatty acid oxidation have been conserved in ACAD9. Alignment of multiple ACAD9 and VLCAD sequences highlights a stretch of about 35 amino acids that differ between the two proteins (figure 2). This stretch of amino acids may be responsible for the newly acquired function of ACAD9 in complex I assembly. In conclusion these results provide valuable insights into evolutionary adaptations. Most probably a relative recent gene duplication event has led to the occurrence of two proteins, which have diverted to functions in different, but related, metabolic pathways. Moreover this discovery has clinical implications, since complex I deficient patients now have to be screened for mutations in ACAD9. Figure 1: Characterization of the mutations. (A) Evolutionary conservation of the mutated amino acids. (B) Modeling of the location of the ACAD9 mutations found in the patients. Figure 2: Model of the ACAD9 dimer (green and blue). (A) Both monomers bind a FAD co-factor (yellow). The position in ACAD9 of the VLCAD-homologous active sites are indicated with red arrows. (B) The altered helices mapped on the dimer model. In light and dark red, indicative of moderate and strong structural differences between the ACAD9 model and VLCAD crystal structure. 46 Jessica Nouws Understanding mitochondrial complex I deficiency NCMLS

47 The energy which the cells of our body need, is produced in the form of ATP by a number of distinct cellular processes. The oxidative Saskia Hoefs phosphorylation Mitochondrial disorders This work was published in: NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease. Hoefs SJ et al. Eur J Hum Genet epub ahead of print, 2010 Dec 8. Understanding the cause of complex I deficiency The energy which the cells of our body need, is produced in the form of ATP by a number of distinct cellular processes. The oxidative phosphorylation (OXPHOS) system forms the final step in this energy production. It consists of five multi-protein assemblies, which are located in the mitochondrial inner membrane. Electrons from NADH and succinate are transported from complex to complex to the final acceptor molecular oxygen. Energy released with this transport is used to generate a proton gradient across the mitochondrial inner membrane, which will be used by complex V to produce ATP. Defects of the OXPHOS system belong to the most frequent inborn errors of metabolism and lead to a group of heterogeneous pathologies affecting different organs and tissues. The organs with the highest energy demand such as heart, brain, skeletal muscle tissue, and liver are the most affected organs. Complex I is the most frequently affected and disease presentation of isolated complex I deficiency often starts at birth or early childhood with mostly a fatal outcome. Complex I is the largest complex of the OXPHOS system, consisting of 45 subunits out of which seven are encoded by the mitochondrial DNA (mtdna). Owing to the bigenomic control of the OXPHOS system, mutations causing complex I deficiency can be found in either the mtdna or in genes encoded by the nuclear DNA. Previous studies identified pathogenic mutations in twelve structural complex I subunits and in nine assembly chaperones. However, for many patients the underlying genetic cause of the mitochondrial complex I deficiency has not been identified yet. We searched for the molecular defect causing the complex I deficiency by screening the entire mtdna, followed by screening the genes for all 38 nuclear-encoded subunits. Sequence analysis of the nuclear NDUFA10 gene demonstrated the presence of two heterozygous substitutions (Figure 1A) in a patient with Leigh syndrome who showed a complex I deficiency expressed in cultured fibroblasts and muscle tissue. The first substitution was found in exon 1, which disrupts the start codon methionine. The second mutation was found in exon 3, causing a substitution of amino acids. This mutation affects a highly conserved amino acid (Figure 1B). The father of the index patient was carrier of first and the mother of the second mutation. Both mutations were not present in 108 healthy controls. From these observations, we conclude that it is highly likely that both mutations are pathogenic. The effect of the mutations on the activity and amount of complex I was examined by performing BN-PAGE and SDS-PAGE analysis. Figure 2A shows a marked decrease of complex I activity and amount in patient fibroblasts compared with control cells. Figure 2B shows a clear decrease in the protein level of NDUFA10. Our finding of mutations in accessory subunit NDUFA10 emphasizes that disease-causing mutations are not restricted to a certain set of subunits and genetic screening should involve all subunits. Identifying new mutations causing complex I deficiency is important to improve genetic counseling and to get more insight in the function of complex I. Figure 1: Molecular analysis of the NDUFA10 gene. (A) Electrophergrams showing the wild-type sequence of NDUFA10 (top) and the nucleotide changes in fibroblasts of the patient (bottom). (B) Conservation of the altered amino acid in exon 3 is shown in Clustal W alignment. Figure 2: The mutations in NDUFA10 result in decreased activity and amount of complex I. (A) The complex I in-gel activity assay ((CI)-IGA) shows a decreased complex I activity. The amount of subunit NDUFA9 is also severely reduced, indicating a decreased amount of whole complex I. (B) The amount of NDUFA10 is decreased in patient fibroblasts. Annual Report 2010 Saskia Hoefs Understanding the cause of complex I deficiency 47

48 Mitochondria are direct descendants of a bacterial endosymbiont that found its way into a host cell. We know that the mitochondrion Radek Szklarczyk stems from a parasitic Mitochondrial proteome This work was published in: Mosaic origin of the mitochondrial proteome. Szklarczyk R & Huynen MA. Proteomics 10: , Understanding the evolution of the mitochondrial proteome Mitochondria are direct descendants of a bacterial endosymbiont that found its way into a host cell. We know that the mitochondrion stems from a parasitic alpha-proteobacteria, but the nature of the host cell that engulfed it is not well understood and still hotly debated. Only a small fraction of the current-day human mitochondrial proteome bears the phylogenetic footprint of alpha-proteobacteria (see Figure 1). Why some proteins were kept in the mitochondrion, while other were transferred other cellular compartments? And what new proteins arrived to the organelle? Following the endosymbiosis event, the mitochondrion underwent rapid changes culminating in highly reduced mitochondrial genomes and, often large, mitochondrial proteomes (1200 proteins in human). Unsurprisingly, also the mitochondrial proteome underwent large changes, with only 200 alpha-proteobacterial proteins in the human mitochondrial proteome (from more than 800 human alpha-proteobacterial genes in the nuclear genome). We also find that a large fraction (40%) of the mitochondrial proteome constitute proteins that were invented later in the evolution, in eukaryotes. These represent multiple membrane components of mitochondria, the interface that arose between the organelle and the rest of the cell. The loss of genes from mitochondria (and, concurrently, gain of new proteins) had to be accompanied by arising protein transport machinery of mitochondrial membranes. Some components of protein transport were inherited from the endosymbiont were they already played the role in membrane trasport (see Figure 2), but most of the transport proteins are eukaryotic inventions. A great majority of bacterial proteins left mitochondria, but which proteins stayed in this subcellular compartment? We noticed that protein complexes (mitochondrial ribosome, respiratory chain complexes) originate from the endosymbiont and were retained in mitochondria. They also grew larger (sometimes even twice) with novel eukaryotic proteins (see Figure 1B). In contrast, mitochondrial enzymes took very different paths in the evolution. They originate neither from the endosymbiont, nor they are specific to eukaryotes. Thus human mitochondrial enzymes constitute an evolutionary patchwork without a direct link to any specific phylogenetic clade. This parallels a trend observed in the evolution of genomes, and captured in so-called complexity hypothesis. Complexity hypothesis states that genes that encode components of larger molecular systems do not undergo horizontal gene transfer, while genes that work stand-alone are more prone to jump to other genomes and organisms in the course of evolution. We observe similar behaviour at the protein level, were proteins that are part of larger molecular systems do not change their subcellular compartments. We do not find alpha-proteobacterial protein complexes outside mitochondria, and coherently, we do not find non-alpha-proteobacterial complexes in mitochondria. Thus proteins that are a part of multi-subunit complexes do not change subcellular compartment in the course of evolution, even when their genes do. A B Figure 1: A) Mosaic evolutionary origin of the human mitochondrial proteome. Apart from the endosymbiotic and eukaryotic proteins, no other phylogenetic clade dominates the current-day mitochondrial proteome. B) Evolutionary origin of mitochondrial protein complexes (left) and enzymes (right). Figure 2: Conserved gene order in the neighborhood of TIMM44 orthologs across the a-proteobacteria lineage supports its function in protein export across the inner proteobacterial membrane. (a) SecB protein exporter, (b) FxsA inner membrane protein, (c) bacterial TIMM44, (d) Membrane-bound trans-glycosylase A. 48 Radek Szklarczyk Understanding the evolution of the mitochondrial proteome NCMLS

49 Overall maintenance of serum Mg 2+ concentration is essential for many cellular processes, including adequate function of neurological Jenny van de Wijst and cardiovascular sys- Mg 2+ homeostasis This work was published in: Effects of the EGFR inhibitor Erlotinib on magnesium handling. Dimke H et al. J Am Soc Nephrol 21: , Understanding the role of EGFR inhibitors in renal and systemic Mg 2+ handling Effects of Erlotinib on TRPM6 Overall maintenance of serum Mg 2+ concentration is essential for many cellular processes, including adequate function of neurological and cardiovascular systems. The kidney plays a key role in maintaining the Mg 2+ balance. The Transient Receptor Potential Melastatin subtype 6 (TRPM6) is expressed in kidney and colon and constitutes the gatekeeper and postulated rate-limiting entry step for active Mg 2+ (re-)absorption. The effect of epidermal growth factor (EGF) on Mg 2+ handling has been established. First, genetic linkage and sequence analysis implicated the pro-egf gene in isolated recessive renal hypomagnesemia. Second, application of EGF readily increases TRPM6 channel activity. Third, anti-cancer treatments with monoclonal antibodies (Cetuximab), an EGF receptor (EGFR)-targeting antibody, cause hypomagnesemia. Next to Cetuximab, patients suffering from cancer receive tyrosine kinase inhibitors, such as Erlotinib. At present, there are no published clinical reports detailing the potential effect of this inhibitor on systemic and renal Mg 2+ handling. Our study sought to ascertain whether Erlotinib alters Mg 2+ handling. C57BL/6 mice were injected intraperitoneally with a high dose of Erlotinib or vehicle for 23 days. Serum Mg 2+ concentration showed a significant decline in the Erlotinib-injected group, while no difference was observed in the urinary excretion of Mg 2+. Importantly, there was no change in the fractional excretion of Mg 2+. As mice injected with Erlotinib develop a modest reduction in serum Mg 2+, without a compensatory reduction in the fractional Mg 2+ excretion by the kidney, a possible effect could be on the expression level of TRPM6. Despite a significant decrease in renal TRPM6 mrna abundance, semi-quantitative comparison of TRPM6 immunofluorescence could not detect a difference in protein expression. These findings may be explained by the observation that TRPM6 is retained in endomembrane vesicles, leading to a decreased degradation of the protein. In fact, fluorescence recovery after photobleaching (FRAP) analysis (Fig. 1) support this observation, as we found that inhibition of Mg 2+ transport by Erlotinib is likely to occur via hampered TRPM6 routing, by preventing EGF-mediated changes in the mobile fraction of TRPM6 proteins. After application of Erlotinib, the EGF-stimulated fraction of TRPM6 channels becomes unresponsive. Furthermore, whole-cell patch clamp analysis in HEK293 cells shows that Erlotinib significantly inhibited EGF-stimulated TRPM6 channel activity. Though, individuals receiving a single standard dose of Erlotinib have a ~10 times lower circulating concentration than the mouse model. We tested whether this lower concentration would be able to block the effect of EGF on TRPM6 channel activity and could not detect any significant differences from EGFstimulated cells. These data indicate that Erlotinib treatment in human patients is unlikely to induce severe hypomagnesemia as observed with Cetuximab. Taken together, the current study is to our knowledge the first to delineate the effects of Erlotinib on Mg 2+ handling. Our findings suggest that Erlotinib can inhibit EGF-stimulated TRPM6 activity and consequently impair Mg 2+ reabsorption in the kidney. Additionally, it provides an explanation about why hypomagnesemia has not been correlated with Erlotinib treatment in patients, as has been observed with Cetuximab. However, it should be noted that Erlotinib has the potential to modulate renal and systemic Mg 2+ handling in vivo. Therefore, caution should be given when treating individuals prone to developing hypomagnesemia, and patients receiving combinational treatment with Mg 2+ lowering compounds. Figure 1: Fluorescence recovery after photobleaching (FRAP) analysis of EGF-stimulated changes in the mobile fraction of TRPM6. A special illumination step is used to perturb the steady-state fluorescence distribution within single HEK293 cells, expressing GFP-TRPM6. After this high intensity illumination has photobleached the fluorescent dye in a small selected region, surrounding molecules that are still fluorescent migrate into this blackened area recovering the fluorescence distribution. In this way, the trafficking of proteins to the plasma membrane can be measured by the time and amount of fluorescent recovery. The fluorescence recovery kinetics is plotted as a function of time. Cells pre-incubated with EGF (10 nm, min) have an increased mobility of GFP-TRPM6. Annual Report 2010 Jenny van de Wijst Understanding the role of EGFR inhibitors in renal and systemic Mg 2+ handling 49

50 The Transient Receptor Potential Vanilloid 5 (TRPV5) channel constitutes the luminal entry gate for active Ca 2+ reabsorption in the distal part of the Theun de Groot nephron. ProteinTransport This work was published in: The identification of Histidine 712 as a critical residue for constitutive TRPV5 internalization. de Groot T et al. J Biol Chem 285: , Understanding the regulation of the epithelial Ca 2+ channel TRPV5 Histidine 712 mediates constitutive TRPV5 internalization from the plasma membrane The Transient Receptor Potential Vanilloid 5 (TRPV5) channel constitutes the luminal entry gate for active Ca 2+ reabsorption in the distal part of the nephron. Active Ca 2+ reabsorption from the pro-urine into the blood determines the final amount of Ca 2+ excreted via the urine and is therefore highly regulated via tight control of TRPV5 activity. TRPV5 activity is determined by its single channel activity and its abundance at the plasma membrane (figure 1). Single channel activity is regulated via protein kinase A, Ca 2+, calmodulin and other factors. The plasma membrane abundance of TRPV5 is also controlled by various factors, including klotho, tissue kallikrein and alkaline ph. Although the molecular pathway, activated by these factors, is largely elucidated, the question remains how TRPV5 plasma membrane expression is regulated. To understand the mechanisms underlying an altered TRPV5 plasma membrane expression, the processes of exocytosis and endocytosis need to be precisely understood (figure 1). Our report reveals the role of the carboxy (C)- terminus in TRPV5 plasma membrane trafficking obtained via the generation of C-terminal TRPV5 deletion mutants. Fura-2 analysis of [Ca 2+ ] i of HEK293 cells expressing the TRPV5 C-terminal deletion mutants demonstrated that removal of amino acid histidine 712 (H712) elevated TRPV5 activity. Substitution of the positively charged H712 for a negative (H712D) or neutral (H712N) amino acid also stimulated TRPV5 activity. This critical role of H712 was confirmed by patch clamp analysis, which demonstrated increased Na + and Ca 2+ currents for TRPV5-H712D. Cell surface biotinylation studies revealed an enhanced cell surface presence of TRPV5-H712D as compared to wild-type (WT) TRPV5. This elevated plasma membrane expression was not due to the increased [Ca 2+ ] i, as a Ca2+-impermeable pore mutant TRPV5-H712D-D542A, which does exhibit Na+ currents, was also more abundant at the cell surface then TRPV5-WT- D542A. Interestingly, introduction of the D542A mutation further increased plasma membrane expression of both TRPV5-WT and TRPV5-H712D. This indicates that a high [Ca 2+ ] i as present in cells expressing TRPV5 hinders full plasma membrane accumulation to prevent excessive Ca 2+ influx. An internalization assay revealed a delayed cell surface retrieval for TRPV5-H712D. Significant internalization was observed after 30 min for both TRPV-WT and lesser extent TRPV5-H712D. In contrast, pilot experiments did not reveal any significant internalization of TRPV5-H712D after 5 min of internalization, while TRPV5-WT did. Thus, the increased plasma membrane expression of TRPV5-H712D is due to a delayed channel internalization from the plasma membrane. Protein internalization from the plasma membrane mainly takes place via two pathways, clathrin- and caveolin-mediated endocytosis. Several studies regarding TRPV5 plasma membrane internalization have been published over the last years. De Graaf et al. demonstrated the involvement of clathrinmediated endocytosis, while Cha et al. revealed a role for caveolae in TRPV5 endocytosis. Preliminary experiments using sucrose and filipin indicate that caveolae-mediated endocytosis of TRPV5-H712D is affected, rather than clathrin-mediated endocytosis of TRPV5. To establish the role of either internalization pathways on TRPV5 plasma membrane regulation in vivo, future research should make use of tissue expressing native TRPV5 channels. Figure 1: TRPV5 function and regulation in active renal Ca 2+ reabsorption After protein production and tetrameric assembly TRPV5 channels reach the plasma membrane, where they allow the influx of Ca 2+. Shortly after the arrival of TRPV5 at the plasma membrane, the channels are internalized via dynaminand clathrin-dependent processes. Internalized TRPV5 first appears in small vesicles after which they enter recycling endosomes or are degraded. By interaction with Rab11a proteins present in the recycling endosome, TRPV5 channels can reappear at the plasma membrane to undergo another round of Ca 2+ influx. 50 Theun de Groot Understanding the regulation of the epithelial Ca 2+ channel TRPV5 NCMLS

51 The drug efflux pump, P-glycoprotein (ABCB1/ P-gp) is present in excretory organs, including the kidney, where P-gp is Suzanne Heemskerk expressed in the renal NO renal drug transport regulation? This work was published in: Regulation of P-glycoprotein in renal proximal tubule epithelial cells by LPS and TNF-alpha. Heemskerk S et al. J Biomed Biotechnol 2010: , Understanding the regulation of renal drug transporters during inflammation At least two pathways regulate P-glycoprotein in renal proximal tubule cells during endotoxemia The drug efflux pump, P-glycoprotein (ABCB1/ P-gp) is present in excretory organs, including the kidney, where P-gp is expressed in the renal proximal tubule apical membrane. We recently found an up-regulation of P-gp in rat kidney during endotoxemia, signaled possibly by nitric oxide (NO) produced by renal inducible NO-synthase (inos). As the nuclear factor kappab (NF-κB) was previously shown to be involved in P-gp increase during renal toxicity, we hypothesized that the same signaling pathway is responsible for the up-regulation of P-gp in the kidney during endotoxemia and that NO is the central player in the field. To test this hypothesis, we used a spontaneously immortalized rat kidney proximal tubular cell line (GERP) and determined P-gp expression and activity after treating cells with endotoxin (lipopolysaccharide; LPS) or TNF-α. Exposing GERP cells to LPS or a combination of LPS and TNF-α resulted in an increase in inos gene and protein expression levels. In contrast, TNF-α alone did not have an effect on inos levels. Furthermore, P-gp gene and protein expressions were increased after TNF-α in the presence or absence of LPS, suggesting de novo P-gp synthesis. LPS alone did not alter the P-gp expression. The activity of P-gp was determined and found to be increased when cells were exposed to TNF-α alone or in combination with LPS. To determine the NOdependency of the P-gp up-regulation, GERP cells were co-treated with the NO scavenger, PTIO, or exposed to the NO donor, SNP. PTIO treatment only partially reversed the effect induced by TNF-α. In contrast, SNP did not increase P-gp protein expression neither its activity, suggesting that P-gp signaling by TNF-α is in a larger part NO-independent (Figure 1). LPS signals predominantly through toll-like receptor-4 (TLR-4) and TNF-α mediates its effect mainly by binding to TNFR1 and TNFR2. We found TNFR1 and TLR4 to be expressed in the GERP cell line, whereas TNFR2 expression could not be detected. We used inhibitors of and/or antibodies against TNFR1 and TLR4 to further unravel signaling to P-gp. Inhibition of TNFR1 could not prevent the up-regulation of the efflux pump by TNF-α, suggesting that although the receptor is expressed in GERP cells it may not be involved in P-gp regulation. On the other hand, the increased P-gp activity after exposure to TNF-α was reversed after exposure to antibodies against TLR-4. Furthermore, we found NF-κB to be involved in TNF-α stimulated regulation of P-gp, as inhibition of its nuclear translocation slightly reversed the increase in P-gp activity. Our findings indicate that at least two different pathways regulate P-gp in renal proximal tubule cells; one involving NO and an NOindependent pathway. The up-regulation of P-gp may be nephroprotective, as it serves to enhance efflux of accumulating metabolic wastes and toxicants during endotoxemia. Figure 1: Expression of inos and effect of NO on P-gp activity in GERP cells. (A) NOSII (inos) after exposure to 10 µg/ml LPS (closed bars), 10 ng/ml TNF-α (striped bars) or both (chequered bars). (B) inos protein (control; lanes 1 and 2) after exposure to LPS (lanes 3 and 4), TNF-α (lanes 5 and 6) or both (lanes 7 and 8). (C) P-gp transport activity after exposure to TNF-α or both LPS and TNF-α in combination with the NO-scavenger, PTIO, compared to control. (D) P-gp protein (control; lanes 1 and 2) and after exposure to SNP (lanes 3 and 4). (E) P-gp transport activity after exposure to SNP. Significance; *: P<0.05; **: P<0.01; ***: P< Figure 2: Scheme illustrating the proposed sequence of events by which inflammatory mediators increase P-gp-mediated transport. A). NO-dependent pathway after exposure to LPS directly or indirectly via TLR4. B). NO-independent pathway after exposure to TNF-α, involving activation of NF-κB inducing kinase (NIK) or IKKβ by TRAF2 or TLR4. TIR; toll-il-1r domain in TLR, LRR, leucine-rich repeats domain in TLR. Annual Report 2010 Suzanne Heemskerk Understanding the regulation of renal drug transporters during inflammation 51

52 In mammals, maintenance of a proper water balance is of vital importance and, therefore, is tightly regulated. Water is reabsorbed Michelle Boone from the pro-urine in Nephrogenic Diabetes Insipidus This work was published in: Effect of the cgmp pathway on AQP2 expression and translocation: potential implications for nephrogenic diabetes insipidus. Boone M et al. Nephrol Dial Transplant 25: 48-54, Understanding the role of the cgmp pathway in X-linked Nephrogenic Diabetes Insipidus - Effects of cgmp activation on Aquaporin-2 expression and translocation In mammals, maintenance of a proper water balance is of vital importance and, therefore, is tightly regulated. Water is reabsorbed from the pro-urine in the renal collecting duct, which is under control of the antidiuretic hormone arginine vasopressin (AVP). In states of dehydration or hypovolaemia, AVP binding to the vasopressin type 2 receptor (V2R) increases intracellular cyclic adenosine monophosphate (camp) levels, which activate protein kinase A (PKA), resulting in the phosphorylation of aquaporin-2 (AQP2) water channels. Consequently, AQP2-bearing vesicles translocate to and fuse with the apical membrane, rendering the membrane water permeable. Due to an osmotic gradient, water will then enter the cells via AQP2 and leave to the interstitium via AQP3 and AQP4, which are constitutively present in the basolateral membrane. Upon correction of hypovolaemia, AVP levels drop and AQP2 is retrieved from the apical membrane, resulting in reduced water reabsorption. In humans suffering from nephrogenic diabetes insipidus (NDI), the ability to reabsorb water and concentrate urine in response to AVP is severely disturbed. Congenital NDI can be caused by mutations in either the AQP2 gene or the AVPR2 gene. Mutations in the AVPR2 gene, which account for ~ 90% of inherited NDI cases, are inherited as an X- linked recessive trait. At present, several approaches are under development to find a treatment for NDI. One of these approaches for X-linked NDI is to bypass V2R and the camp activation pathway by the activation of the cgmp pathway. This approach is based on recent findings that AQP2 insertion could also be accomplished by the activation of the camp-independent and cgmp-dependent pathway. Nitric oxide donors and nitric oxide synthase substrate (L-arginine), as well as atrial natriuretic peptide (ANP), which increase cgmp levels, appeared to induce AQP2 translocation from intracellular vesicles to the apical membrane. In the absence of functional V2R, however, AQP2 expression levels are also reduced, because camp, generated through the activation of the V2R, stimulates AQP2 transcription through a camp-responsive element in its promoter. An important question thus was whether increased cgmp also leads to increased AQP2 transcription. In mouse cortical collecting duct cells (mpkccd), AVP increases endogenous AQP2 expression. Therefore, we used these cells to determine whether activation of the cgmpsignalling pathway not only induces AQP2 translocation, but also increases AQP2 expression. MpkCCD cells were incubated with ANP, L-arginine, and 8-Br-cGMP for 2 h and subjected to immunocytochemistry and cell surface biotinylation assays. ANP, L-arginine and 8-Br-cGMP induced the translocation of AQP2 in the mpkccd cells (Fig. 1). To test the effect of cgmp pathway activators on AQP2 expression, mpkccd cells were treated with ddavp, ANP and L-arginine for 4 days, or with 8-Br-cGMP for the last day. AQP2 protein levels were determined by immunoblotting. In contrast to ddavp, ANP, L-arginine and 8-BrcGMP did not increase the expression of AQP2 (Fig. 2). Our results suggest that while activators of the cgmp pathway are likely beneficial in the treatment of X-linked NDI, their ability to relieve NDI in the patients may be improved when combined with agents stimulating AQP2 expression. Figure 1: Effect of the activation of the cgmp pathway on translocation of AQP2 in the mpkccd cells. Confluent mpkccd monolayers were stimulated with 1 nm ddavp for 4 days, incubated with 1 µm V2R antagonist SR121463B for 4 h, and left untreated (a), or treated with 10 µm forskolin (b), 1 µm ANP (c), 10 mm L- arginine (d), or 100 µm 8-Br-cGMP (e) for 2 h. Cells were subjected to immunocytochemistry. Horizontal (XY) and vertical (XZ) confocal images are shown. Figure 2: Effect of the activation of the cgmp pathway on AQP2 expression in the mpkccd cells. Confluent mpkccd monolayers were left untreated, treated with 1 nm or 10 nm ddavp, or treated with 1 nm ddavp together with 1 µm ANP, 10 mm L-arginine (4 days) or 100 µm 8-Br-cGMP (1 day). Protein samples were immunoblotted for AQP2 and the blot was coomassie-stained to check for equal protein loading. The signals were scanned and the amount of AQP2 normalized for total protein amount was semiquantified in arbitrary units. Significant differences are indicated by asterisks. 52 Michelle Boone Understanding the role of the cgmp pathway in X-linked Nephrogenic Diabetes NCMLS

53 Annual Report 2010 Theme 3 Cell growth and differentiation

54 etinitis pigmentosa (RP) is a frequent cause of inherited blindness in the Netherlands and is characterized by progressive visual impairment, starting Rob Collin with Retinitis pigmentosa This work was published in: Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa. Bandah-Rozenfeld D*, Collin RWJ* et al. Am J Hum Genet 87: , *Both authors contributed equally. Understanding the genetics of inherited blindness Mutations in IMPG2 are causative for autosomal recessive retinitis pigmentosa Retinitis pigmentosa (RP) is a frequent cause of inherited blindness in the Netherlands and is characterized by progressive visual impairment, starting with night blindness and eventually resulting in complete vision loss. Genetically, RP is very heterogeneous, with over 40 genes identified to date in which mutations are causative for this disease. In the majority of cases, RP is inherited in an autosomal recessive (ar) manner, although autosomal dominant, X-linked and mitochondrial inheritance of RP is also observed. The majority of recessive RP genes have been identified using a positional cloning approach in large consanguineous families with multiple affected individuals. RP patients from these families often carry mutations homozygously, since their parents are first or second cousins. As a result, their homozygous regions (one of which contains the causative gene) are very large, up to 50 Mb or more. In previous studies, we have shown that in the Netherlands, a reasonable amount of recessive RP patients also carries their genetic defect in a homozygous state, presumably since their parents share a common ancestor who lived generations ago. As a result, not only the mutation but also a genomic region flanking the mutation will be homozygous, although these regions are expected to be much smaller compared to patients from consanguineous marriages. In one Dutch recessive RP family with three affected individuals, high-resolution homozygosity mapping using Affymetrix 5.0 SNP arrays revealed a 10-Mb genomic region that was homozygously shared by the affected individuals. Among the genes in this region was IMPG2, encoding interphotoreceptor matrix proteoglycan 2 that is expressed in the extracellular matrix surrounding the cone and rod photoreceptor cells of the retina. Sequence analysis of the proband resulted in the identification of a homozygous ~1.8 kb genomic deletion that contained exon 9 of IMPG2 (Figure 1A). As a consequence, the mutant protein lacks seven amino acids (Figure 1B) that are part of one of the predicted SEA domains that are thought to be involved in glycosylation (Figure 1C). Transient transfection experiments showed that a construct expressing the wild-type IMPG2 SEA domain was mainly present at the plasma membrane and in the ER, whereas the mutant counterpart that lacks the seven amino acids was partially retained in structures adjacent to the cell nucleus (Figure 2). Within our own cohort as well as those from collaborators within our European Retinal Disease Consortium, several recessive RP patients also carried homozygous regions encompassing IMPG2, and sequence analysis revealed six additional mutations in patients from the Netherlands (2), Italy (2) and Israel (2) (Figure 1C). Together, our data show that mutations in a gene encoding a component of the interphotoreceptor matrix are causative for RP, and stress the importance of this matrix for proper visual function. Figure 1: Mutation analysis and protein characteristics of IMPG2 A) Upper panel: PCR analysis of exon 9 of IMPG2 in the Dutch family W Exon 9 was not amplified in the three affected individuals. All relatives and their position in the pedigree are indicated above the electropherogram. Lower panel: after identification of the breakpoints of the genomic deletion, PCR primers were designed to amplify a product if the deletion is present. This breakpoint PCR shows a product in all three affected individuals and in the heterozygous carriers, i.e. both parents (I:1 and I:2) and one unaffected brother (II:3). B) Sequence analysis of IMPG2 mrna derived from EBV-transformed cultured lymphoblasts of individual II:1 and of an unrelated control. RT-PCR and subsequent analysis shows that, due to the presence of the genomic deletion, exon 9 of IMPG2 is absent in the mutant IMPG2 mrna. At the protein level, this is predicted to result in the absence of seven amino acids, i.e. RSPKEND. C) Graphical representation of the IMPG2 protein. Shown are the signal peptide, two SEA domains and two EGF-like domains in the large extracellular N-terminal part of the protein, and a transmembrane-spanning region. The positions of asparagine and threonine residues that are predicted to undergo N- or O-linked glycosylation, respectively, as well as the serine residues that may serve as core residues for the attachment of glycosaminoglycan side chains are indicated with symbols described in the figure. The positions of the mutations identified in this study are indicated with arrows. 54 Rob Collin Understanding the genetics of inherited blindness NCMLS

55 Cis-regulatory elements are required for proper gene regulation during embryonic development. Although the main stream genetic Evelyn Kouwenhoven studies are still focused Cis-regulatory elements in developmental disorders This work was published in: Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus. Kouwenhoven EN et al. PLoS Genet 6: e , Understanding non-coding regulatory elements in developmental disorders Disruption of a cis-regulatory element identified by a p63 binding site causes SHFM1 Cis-regulatory elements are required for proper gene regulation during embryonic development. Although the main stream genetic studies are still focused on the coding regions that occupy 2% of the genome, genetic variations in cis-regulatory elements located in the vast non-coding regions have become an emerging disease mechanism. So far evolutionary conservation has been used as a major tool to identify these regulatory elements. Our research paradigm is to identify disease-related regulatory elements with functional genomics profiling approaches. The transcription factor p63 is a master regulator in ectodermal development. Heterozygous mutations in p63 are associated with disorders of ectodermal origin manifesting defects in skin, limb and cleft lip/palate. There are also a large number of developmental disorders with unknown causes that resemble phenotypic features of p63-associated diseases. Therefore the identification of p63-responsive regulatory elements may assist to resolve the genetic basis of these p63-related disorders. Using genome-wide DNA-binding profiling with chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) in primary human keratinocytes, we identified a large number of p63 binding sites that serve as a catalogue of potential regulatory elements controlled by p63. Split hand/split foot malformation (SHFM), a disorder that can be caused by p63 mutations, is characterized by a deficiency of the central rays of the hands and feet, resulting in missing or malformed digits. Split Hand Foot Malformation 1 (SHFM1) has been linked to anomalies of genomic regions on chromosome 7 containing the DLX5 and DLX6 genes. Yet no mutations were found in these genes. Evidence suggested that these genes are controlled by a common regulatory element important for limb development. In a patient with SHFM, we identified a deletion on chromosome 7 that does not include the DLX5 and DLX6 genes (Figure 1). This observation suggested that disruption of regulatory elements that control expression of these genes might lead to the SHFM phenotype. We demonstrated by transient transfections and transgenesis in model systems that a p63 binding site (SHFM1-BS1) (Figure 1) functions as a p63- responsive regulatory element and regulates gene expression in the Apical Ectodermal Ridge (AER) of the developing limb, which is consistent with the expression pattern of endogenous zdlx5 and zdlx6 (Figure 2). Therefore disruption of the p63-responsive regulatory element is likely to be a novel disease mechanism for SHFM1. These data also show that p63 binding sites identified in HKCs can function as regulatory elements to control gene expression in embryonic limb development. In a separate report published in J. Clin. Invest. (Thomason et al., 2010) we also showed that a p63 binding site functions as a regulatory element to regulate IRF6 during palate development. Taken together, our study demonstrates that genome-wide DNAbinding of transcription factors provides a new tool to identify cis-regulatory elements involved in diseases. Figure 1: A screenshot of UCSC genome browser shows the p63 binding profile from two HKC cell lines (wt1 and wt2) with two p63 antibodies (4A4 and H129) near DLX5 and DLX6 on chromosome 7, showing the SHFM1-BS1 peak. Ultra-high Comparative Genomic Hybridization array analysis performed with DNA of a SHFM1 patient showed a chromosomal deletion of 880kb on chromosome 7 (the orange arrow) which includes DSS1, SLC25A13 and part of DYNC1I1 but not DLX5 and DLX6. A previously reported minimal deletion is marked with a black arrow. p63 binding sites identified in this ChIP-seq study are labeled in red. Figure 2: (A) SHFM1-BS1 drives gene expression (LacZ) specifically to the AER in mice. Mutations in the p63 binding motif in SHFM1-BS1 disrupted the specific expression pattern. (B) SHFM1-BS1 drives gene expression (GFP) specifically to the AER analysed by in situ hybridization in 48hpf zebrafish embryos and the expression pattern correlates with that of the endogenous zdlx5 and zdlx6. Annual Report 2010 Evelyn Kouwenhoven Understanding non-coding regulatory elements in developmental disorders 55

56 Schinzel-Giedion syndrome is a rare but highly recognizable syndrome characterized by severe mental retardation, distinctive Alexander Hoischen facial features, multiple Exome sequencing This work was published in: De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Hoischen A et al. Nat Genet 42: 483-5, Understanding rare mendelian disorders First dominant disease solved by exome sequencing: De novo mutations in SETBP1 cause Schinzel-Giedion syndrome Schinzel-Giedion syndrome is a rare but highly recognizable syndrome characterized by severe mental retardation, distinctive facial features, multiple congenital malformations and a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia. In almost all subjects, the disease phenotype occurs sporadically, suggesting that de novo dominant mutations in a single gene may be the underlying disease cause. Traditional disease-gene identification approaches have failed to identify the gene associated with this disease or those responsible for the majority of this class of rare sporadic disorders. In this publication we used a specific application of next generation sequencing called exome sequencing to identify the genetic cause of this dominant Mendelian disorder. We sequenced the exome, the protein-coding part of the genome, of four unrelated individuals with Schinzel-Giedion syndrome. Per individual on average 21,800 genetic variants were identified, including 5,351 non-synonymous changes. A number of prioritization steps were applied to reduce this number and to identify the potentially pathogenic mutations. A comparison with the NCBI dbsnp build 130 and in-house SNP data showed that >95% of all variants were known SNPs and cannot explain such a severe genetically dominant disease. After filtering these out we focused on the genes for which all four individuals carried variants and found that only two genes showed variants at different genomic positions, strengthening the likelihood that these variants are not novel SNPs. The best candidate gene was SETBP1, which encodes SET binding protein 1. All four variants in this gene were confirmed by Sanger sequencing. Moreover, DNA analysis of the unaffected parents showed that all mutations occurred de novo in the patients. In a next step, de novo SETBP1 mutations were identified in eight out of nine additional individuals with a clinical diagnosis of Schinzel-Giedion syndrome. None of the SETBP1 mutations were found in control individuals. Interestingly, all mutations occurred in a genomic stretch of only 11 nucleotides that are among the most highly evolutionary conserved positions in the human genome. There are two indications that the mutations seen here may either result in a gain-of-function effect. First, a gain-of-function mechanism has been described for other syndromes, that have very similar mutation clustering and also results in a gain-of-function effect. Second, the phenotype of individuals with partial chromosome 18q deletions which affect SETBP1 does not resemble Schinzel-Giedion syndrome. In conclusion, our study represents the first elucidation, of a dominant Mendelian disorder using exome sequencing, illustrating the potential of this technique for disease-gene identification. It is highly likely that the mutations examined here cause disease through either a dominant-negative or a gain-of-function effect. Exome sequencing is particularly useful for identifying these types of mutations for which no other genome-wide approach is applicable. De novo mutations may be a frequent cause of sporadic conditions with reduced fecundity, such as congenital malformations, mental retardation and psychiatric disorders. Figure 1: Identification of SETBP1 mutations in individuals with Schinzel-Giedion syndrome. Photos showing three of the four individuals for whom we performed exome sequencing (a). Note the characteristic facial features, prominent forehead, bi-temporal narrowing, midface retraction, hypertelorism, deep groove under the eyes, short upturned nose and low-set abnormal ears. We obtained written consent to publish photographs of all individuals shown. Evolutionary conservation of the SETBP1 region that harbors amino acid residues affected in Schinzel-Giedion syndrome (marked by asterisks above human protein sequence) (b). All affected residues (Asp868, Gly870 and Ile871) are completely conserved throughout evolution. Residues identical in all sequences are shown as black on a white background; different amino acids are shown as black on a gray background. Schematic overview of the SETBP1 protein (c). Known and predicted protein domains are shown in relation to the mutation cluster observed in 12 individuals with Schinzel-Giedion syndrome. Affected amino acid positions are marked with asterisks; each asterisk represents a single case. 56 Alexander Hoischen Understanding rare mendelian disorders NCMLS

57 Approximately 1 out of a 750 children is born with hearing impairment, which is caused by a genetic defect in over half of these cases. Margit Schraders The far majority of Hereditary Hearing Loss This work was published in: Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment. Schraders M et al. Am J Hum Genet 86: , Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. Schraders M et al. Am J Hum Genet 86:604-10, Mutations in TPRN cause a progressive form of autosomal recessive nonsyndromic hearing loss. Li Y et al. Am J Hum Genet 86:479-84, Understanding recessive nonsyndromic hearing impairment Approximately 1 out of a 750 children is born with hearing impairment, which is caused by a genetic defect in over half of these cases. The far majority of early-onset genetic deafness is recessively inherited, meaning that most deaf children have normally hearing parents. The genes known to be involved in autosomal recessive nonsyndromic hearing impairment (arnshi) have almost exclusively been identified using linkage analysis in large consanguineous families. In the Netherlands the GJB2 gene is involved in 10-20% of the cases. Further insight in the genes underlying arnshi in the Netherlands was extremely limited. The Dutch population is generally regarded to be a mixed population, however, based on demographics and molecular genetics knowledge it can be argued that this is only partially true. We therefore initiated a project in which homozygosity mapping was performed in ~80 Dutch arnshi families. The data indicated a large genetic heterogeneity for arnshi in the Dutch population, since only very few families shared homozygous regions. Interestingly, two families had an overlapping homozygous region of only 0.9 Mb within the previously described DFNB25 locus on chromosome 4. This 0.9 Mb interval contained the GRXCR1 gene which was an excellent candidate gene since the orthologous mouse gene was described to be mutated in the Pirouette (pi) mutant with hearing loss and circling behavior. Indeed, sequence analysis of the GRXCR1 gene demonstrated splice site mutations in the two Dutch families and a missense and nonsense mutation in two additional Pakistani families. A novel deafness locus was indicated by a homozygous region on chromosome 12 which was shared by two families, a non-consanguineous Dutch family and a consanguineous Moroccan family. All affected individuals shared a 3.17 Mb homozygous region harboring the human ortholog of the mouse Ptprq gene which is involved in deafness. Since the human PTPRQ gene was not completely annotated we characterized the gene and identified additional, alternatively spliced exons at the 5 end of the gene (Figure 1). Homozygous nonsense and missense mutations were found to underlie the deafness in the Dutch family and the Moroccan family, respectively. In both families, vestibular dysfunction was found to be associated with the deafness and the phenotype was milder in the family with the missense mutation. Our approach led to the identification of a third novel deafness gene, TRPN, and mutations in TMC1, a known arnshi gene. Characterization of the causative genetic defects is a prerequisite for adequate diagnostics and genetic counseling of patients and their families. More accurate information on prognosis can be provided based on the clinical outcome in patients with mutations in the same gene. At present we combine homozygosity mapping and next generation sequencing for deciphering the causes of recessive deafness in the Netherlands which will lead to the identification of more novel deafness genes and more insight in inner ear function. Figure 1: PTPRQ gene characterization and schematic representation of PTPRQ protein structure A) Schematic overview of the genomic organization of PTPRQ and alternative splicing (I-V). Also exon 49 was found to be alternatively spliced. The exons depicted in red indicate the open reading frame. B) Predictions of conserved domains of the identified alternatively spliced mrnas, as determined with the simple modular architecture research tool (SMART). Isoforms differ in the number of FN3 domains. The alternatively spliced exon 49 encodes part of the phosphatase domain. Annual Report 2010 Margit Schraders Understanding recessive nonsyndromic hearing impairment 57

58 Frank-Ter Haar syndrome (FTHS, MIM ), also known as Ter Haar syndrome, is an autosomal recessive disorder characterized by skeletal, Zafar Iqbal cardio- Podosomopathies This work was published in: Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome. Iqbal Z et al. Am J Hum Genet 86: , Homozygous TKS4 mutations affecting podosome function in Ter Haar syndrome Frank-Ter Haar syndrome (FTHS, MIM ), also known as Ter Haar syndrome, is an autosomal recessive disorder characterized by skeletal, cardiovascular and eye abnormalities, such as increased intra-ocular pressure, prominent eyes and hypertelorism. The patients with this condition usually die in their childhood due to heart defects, respiratory infections or unknown reasons. In the early 80 s, FTHS was described by the renowned pediatrician Ben Ter Haar from UMC St Radboud, Nijmegen. Ten years later Ben Hamel and Han Brunner saw a patient with same rare phenotype. This child appeared to be distantly related (separated by eight to ten generations) to the original family described by Ben ter Haar. This remarkable pedigree structure prompted us to localize the genetic defect by the powerful method of homozygosity mapping. We performed microarray-based homozygosity mapping in this family and another 11 apparently unrelated FTHS families with known or suspected consanguinity. A locus on chromosome 5q35.1 was identified for which patients from ten families shared homozygosity (Figure 1). For one family, a homozygous deletion mapped exactly to the smallest region of overlapping homozygosity, which contained a single gene, SH3PXD2B. This gene encodes the TKS4 protein, a PX and SH3 domain-containing adaptor protein and a known substrate for the oncogene Src. The TKS4 protein was recently shown to be involved in the formation of actin rich membrane protrusions called podosomes or invadopodia, which allow cells to shape their microenvironment by coordinating a variety of processes, such as pericellular proteolysis, cell-cell signaling and cell migration. Mutation analysis revealed five different homozygous mutations in SH3PXD2B in seven FTHS families. No SH3PXD2B mutations were detected in six other FTHS families, demonstrating genetic heterogeneity of this condition. Interestingly. However, dermal fibroblasts from one of the individuals without an SH3PXD2B mutation nevertheless expressed lower levels of the TKS4 protein, suggesting a common mechanism underlying disease causation. Mouse Tks4 is 87% identical to the human orthologue and has a similar domain structure. To gain more insight into the developmental processes in which Tks4 has a role, we performed crna in situ hybridization analysis. Spatio-temporally restricted Sh3pxd2b expression was observed at various embryonic development stages, in tissues that are affected in FTHS patients: heart, bone, and eye suggesting that it is required for the correct patterning and development of these organs. To get further knowledge into the disease mechanism, a knock out mouse model was generated and carefully investigated by our collaborators of the group of Sara Courtneidge (Burnham Institute, La Jolla). Mice lacking Tks4 show pronounced skeletal, eye and cardiac abnormalities and phenocopied the majority of the defects associated with FTHS. Our results establish a crucial role for Tks4 in bone, heart, and eye development, as well as a variety of other tissues. This is the first time that a developmental disorder is caused by the defect in podosomes. Further study on the role of podosomes may open a new horizon in identifying the genetic defects in related developmental disorders. Figure 1: Homozygosity mapping analysis. Schematic representation of the 5q35.1 region that is homozygous in 12 patients and homozygously deleted in family 7. The deletion was identified upon analysis of the 250K SNP array data using the CNAG algorithm, as visualized by the bottom diagram in which the deletion is encircled in blue. The overlap between the deletion and the smallest region of homozygosity harbors only a single gene, SH3PXD2B (grey shaded). 58 Zafar Iqbal Homozygous TKS4 mutations affecting podosome function in Ter Haar syndrome NCMLS

59 Acute promyelocytic leukemia is a distinctive subtype of acute myeloid leukemia (AML) that accounts for approximately 10% of Joost Martens all AML cases.the dis- Leukemia This work was published in: PML-RARalpha/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia. Martens JH et al. Cancer Cell 17: , Understanding the role of the PML-RARα oncofusion protein in Acute Promyelocytic Leukemia Acute promyelocytic leukemia is a distinctive subtype of acute myeloid leukemia (AML) that accounts for approximately 10% of all AML cases.the disease represents a highly malignant form of leukemia with high bleeding tendency and a fatal course of only few weeks. The main diagnostic feature of APL is an aberrant chromosomal translocation that juxtaposes the PML gene on chromosome 15 and the RARα gene on chromosome 17. The resultant chimeric protein, which is found in over 95% of human APLs, retains the DNA binding and ligand binding domains of RARα and the multimerization domain of PML. All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) are the two most important drugs in clinical use for the treatment of early diagnosed APL. Both ATRA and ATO degrade the PML-RARα fusion protein by acting on the RARα and PML moieties, respectively. ATRA mainly degrades the protein through proteosome mediated pathways and caspases, while the ATO induced degradation is initiated through sumoylation of the PML moiety. Many mechanisms have been proposed for PML-RARα function, including homodimerization, oligomerization, interaction with RXR, expanded DNA binding affinity and recruitment of a wide spectrum of epigenetic enzymes based on studying a few genomic regions, mostly the promoter of the RARβ gene. In this study, we set out to obtain a comprehensive genome-wide view of the molecular actions of the PML-RARα protein. Using genome-wide ChIP-seq analysis we identified high confidence PML-RARα binding sites in the leukemic model cell line NB4 and in primary blasts of two APL patients. We found colocalization of PML-RARα with RXR to the vast majority of these binding regions, including genes important in hematopoietic differentiation such as SPI1 (PU.1), GFI1 and RUNX1, ATRA binding proteins such as RARα and RARβ and many genes involved in epigenetic regulation. In addition, genome-wide epigenetic studies revealed that treatment with pharmacological doses of all-trans retinoic acid (ATRA) induces changes in H3 acetylation, but not H3K27me3, H3K9me3 or DNA methylation at the PML- RARα /RXR binding sites or at nearby target genes (Figure 1) suggesting that histone acetylation status is closely intertwined with oncofusion protein presence. In addition, we performed genome-wide profiling of RNAPII occupancy and defined nearly 2000 ATRA up (for example TGM2 in Figure 1) or down-regulated genes. To our surprise only 10% of both the up- as the down-regulated genes in all these studies were proximal to PML- RARα/RXR peaks, while the majority of ATRA affected genes where localized at greater distance from these binding sites. Together, our results suggest that PML- RARα/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for hematopoietic differentiation, RAR signaling and epigenetic control is crucial to the transforming potential of PML-RARα/RXR. Figure 1: ATRA induced transcriptional changes correlate with H3 acetylation changes at PML-RARα/RXR binding regions. Overview of ATRA induced expression of the TGM2 gene. In red the PML, in purple the RARα and in blue the RXR ChIP-seq data is plotted for proliferating NB4 cells. In green the RNAPII data is plotted for proliferating and 24 or 48 hours ATRA treated NB4 cells. For H3K9K14ac (pink), H3K27me3 (yellow), H3K9me3 (green) and DNAme (turquoise) the data is plotted both for proliferating and for 24 hours (H3K9K14ac, H3K9me3 and H3K27me3) or 48 hours (DNAme) ATRA treated NB4 cells. Annual Report 2010 Joost Martens Understanding the role of the PML-RARα oncofusion protein in Acute Promyelocytic Leukemia 59

60 Plasmodium falciparum is the unicellular parasitic organisms responsible for almost 1 million deaths annually. It causes malaria via Richard Bartfai invasion of human ery- Malaria epigenetics This work was published in: H2A.Z demarcates intergenic regions of the plasmodium falciparum epigenome that are dynamically marked by H3K9ac and H3K4me3. Bártfai R*, Hoeijmakers WA* et al. PLoS Pathog 6:e , *Both authors contributed equally. Understanding the Plasmodium falciparum epigenome stable H2A.Z and dynamic H3K4me3 and H3K9ac deposition during parasite development Plasmodium falciparum is the unicellular parasitic organisms responsible for almost 1 million deaths annually. It causes malaria via invasion of human erythrocytes, in which the parasite multiplies during an ~48 hour asexual reproductive cycle, meanwhile exploiting and remodeling the host red blood cell (RBC). This process demands the timely expression of distinct sets of proteins. Accordingly, a precise, well-timed program of gene expression is essential for parasite survival. Although some regulation takes place at the post-translational level, transcriptional and epigenetic processes play the most critical role in regulating gene expression. Epigenetic processes result in inherited changes in phenotype or gene expression, independent of changes in the underlying DNA sequence. This is mainly achieved by differential packaging of the DNA, which influences the DNA accessibility to a wide variety of effector proteins thereby regulating processes ranging from transcription initation to DNA replication. At the basis of this regulation lies the packaging material. Nucleosomes, the building blocks of chromatin, consist of 2 copies each of the 4 core histone proteins (H2A, H2B, H3 and H4), which can be substituted by different histone variants and/or post-translationally modified at their N-terminal tail. All these nucleosome varieties harbor distinct properties, provide a platform for recruitment of different effector protein complexes and ascertain that chromatin-associated processes take place at the right time and place. Although epigenetic regulation is indispensable for parasite survival and might provide a promising candidate for development of new anti-malarial drugs, little is known about epigenetic marking and the factors involved in writing and reading this Plasmodium histone code. With the genome-wide analysis of a few histone modifications/chromatin-associated proteins we have just begun to unveil the unique characteristics of the malaria epigenome. Previous studies uncovered that ~90% of the genome is in an open, euchromatic state (characterized by the trimethylation of lysine 4 on histone H3 (H3K4me3) and acetylation of lysine 9 on the same histone tail (H3K9ac)). H3K9me3-marked heterochromatic regions are confined to the chromosome ends and some intra-chromosomal islands and recognized by the effector protein heterochromatic protein 1 (PfHP1). Although H3K4me3 and H3K9ac generally associate with promoters of active genes, it was unclear whether this correlation was preserved in Plasmodium. Using state-of-the-art chromatin-immunoprecipitation followed by T7 linear amplification and Illumina sequencing (ChIP-seq), we reveal the genome-wide localization of two histone marks (H3K4me3, H3K9ac) and a histone variant (H2A.Z) at mononucleosomal resolution. Investigation at multiple stages during development of the parasite inside the human erythrocyte, in combination with transcription profiling (RNA-seq), allowed correlation of these epigenetic features to gene expression. We find that all 3 features are predominantly present in euchromatic intergenic regions of the P. falciparum genome, suggesting a possible interconnecting role in regulation of gene expression. H2A.Z levels appear to be largely invariable throughout intra-erythrocytic development (Figure 1) indicating a potential role in demarcating regulatory regions in the parasite genome. Contrary to this stable marking, H3K9ac and H3K4me3 placement /removal is dynamic, being transcription-coupled and stage-specific, respectively (Figure 1). In summary, our observations suggest that H2A.Z-containing nucleosomes might provide a platform for the dynamic recruitment of histone modifying enzymes. These dynamic marks might engage chromatin modifying and transcription initiating complexes to the right place at the right time, thereby supporting a tight control of gene expression during parasite development. Figure 1: 12 Groups of genes with different expression profiles were identified by k-means clustering of mrna expression patterns of euchromatic genes during P.falciparum intra-erythrocytic development and are displayed as a heat-map (left column). RNA expression was compared to marking of the intergenic region upstream of each gene and presented as heat-maps. This analysis unveiled stable H2A.Z-, transcription-coupled H3K9ac- and stage-specific H3K4me3-marking throughout RBC development (2 nd left, 2 nd right and right columns, respectively). (numbers next to each cluster indicate the percentage of genes belonging to that group, red = high signals/enrichment, green = low signals/depletion and hpi = hours post-invasion). 60 Richard Bartfai Understanding the Plasmodium falciparum epigenome NCMLS

61 Glycosylation of proteins represents a posttranslational modification that critically contributes to protein folding, conformation, stability, and Samuel Schmidt context- Simplified glycan labeling in living cells This work was published in: Readily accessible bicyclononynes for bioorthogonal labeling and threedimensional imaging of living cells. Dommerholt J*, Schmidt S* et al. Angew Chem Int Ed Engl 49: , *Both authors contributed equally. Understanding cancer invasion by simplified chemical glycan labeling of living cells Simplified chemical glycan labeling in living cells provides insight into cancer invasion Glycosylation of proteins represents a posttranslational modification that critically contributes to protein folding, conformation, stability, and context-dependent activity regulation. Protein-coupled sugar-moieties are diverse and include simple monosaccharides, linear glycosaminoglycans (GAGs) and complex branched aspargine-linked (N-linked) or serine/threonine (O-linked) oligosaccharides, all of which contribute to the structure and function of most eucaryotic proteins, including cell surface receptors and secreted proteins. Consequently, aberrant biochemical glycosylation of these proteins underlies various diseases such as autoimmune and storage diseases, diabetes and cancer. To gain insight into structure and dynamics of protein glycosylation it is thus important to identify the mechanistic contribution of glycans to cell homeostasis and disease. In contrast to protein function studies, which heavily employ fluorescent fusion proteins, no genetic approach is available to fluorescently label and visualize protein-coupled glycans. An alternative approach to study glycans in life sciences is the "chemical reporter strategy", which involves the two-stage labeling of biomolecules in living cells. First, a metabolic glycan precursor is generated in a 4-step process ("chemical reporter") (Fig. 1A). After metabolic incorporation of the sugar analogue into (protein-coupled) glycan backbones, the cells are treated in a second step with a labeled chemical probe (cyclononyne) that reacts bioorthogonally with the chemical reporter (Fig. 1B). The two-step bioorthogonal ligation procedure was developed by the group of Floris van Delft (IMM) and allowed the efficient, non-cytotoxic detection of cellsurface glycans. We applied the chemical reporter N-azidoacetylmannosamine to visualize sialic acid distribution and dynamics on metastatic MV3 melanoma cells during invasion through 3D fibrillar collagen lattices. For bioorthogonal ligation, bicyclo[6.1.0]nonyne (BCN) was used which combines high reactivity with good stability and no toxic side-effects towards living cells. By chemically connecting BCN to biotin, we labeled and visualized azido-conjugated cell-surface sialic acids on MV3 cells without negatively impacting cell viability and migration capabilities. At submicron resolution, sialic acids distributed towards filopodia at the leading edge, actin-rich contact sites to collagen fibers, and substantial glycan-rich deposits into the tissue matrix occurred at the trailing edge during forward movement (Fig. 1C). Thus, bioorthogonal labeling using BCN is a powerful tool to gain high-resolution insight into the expression, localization and molecular function of sialic acid in live-cell studies. This simplified chemical generation and universal applicability of BCN to different glycan types will open up unique opportunities for reagent-free functional characterization of a range of glycans with broad application range, including life sciences, diagnostics and material sciences. Figure 1: Priciple and application of glycan detection in living cells. (A) Synthesis and properties of BCN. (B) Principle of azide integration and fluorescence detection by bioorthogonal reaction with BCN in an intact cell. (C) Redistribution of sialic acid during melanoma cell invasion in 3D collagen lattice. Annual Report 2010 Samuel Schmidt Understanding cancer invasion by simplified chemical glycan labeling of living cells 61

62 Many diseases find their origin in the dysfunction or absence of enzymes inside cells. One way to treat patients affected by Wouter Verdurmen these diseases is Artificial organelles This work was published in: Cellular integration of an enzyme-loaded polymersome nanoreactor. van Dongen SF*, Verdurmen WPC* et al. Angew Chem Int Ed Engl 49: , *Both authors contributed equally. Understanding barriers to successful enzyme delivery therapy Cellular integration of enzyme-loaded nanoreactors Many diseases find their origin in the dysfunction or absence of enzymes inside cells. One way to treat patients affected by these diseases is through cellular enzyme delivery, a therapeutic modality which aims to deliver proteins produced in vitro to intracellular compartments such as lysosomes and mitochondria, or to the cytosol. Unfortunately, effectiveness is still limited, as many proteins suffer from poor in vivo stability. Moreover, efficient cellular uptake and directed intracellular trafficking are difficult to achieve. Therefore, a clear need exists for novel therapeutic platforms to treat cellular enzyme deficiencies. We developed a strategy for enzyme delivery inspired by the way compartmentalization works inside cells. Compartmentalization allows cells to exert tight spatial control over biochemical processes and organize reaction cascades. To mimic cellular compartmentalization, we generated polymersomes loaded with enzymes (nanoreactors; see figure 1). Polymersomes can be seen as spherical nanoparticles containing a bilayer architecture, similar to the one of a phospholipid membrane, formed by self-assembling amphiphilic block copolymers. Compared to liposomes, polymersomes show a greater stability, making them attractive candidates for intracellular targeting and maintenance of activity over an extended period of time. In our study, the average diameter of these nanoreactors was 114 nm, comparable to the size of many organelles in mammalian cells. To achieve cellular internalization of these artificial organelles, the cell-penetrating peptide Tat was attached to the surface through a highly chemoselective copper-free click reaction. Tat-functionalized polymersomes efficiently entered multiple cell types. A further investigation of the entry mechanism in HeLa cells showed that nanoreactors were mainly internalized via macropinocytosis, a type of fluid-phase endocytosis. To investigate the intracellular trafficking of nanoreactors, we analyzed their colocalization with lysotracker after a 4-hour incubation. An incomplete colocalization with lysotracker, a dye that stains acidic vesicles, indicates that the nanoreactors traffick only partially to acidic compartments. Next to internalization and trafficking of the nanoreactors, the cellular import of enzymes was also explored. Tat-modified nanoreactors containing horseradish peroxidase (HRP) protein were allowed to internalize into HeLa cells for 4 h. After washing away non-internalized nanoreactors, HRP activity was detected through the oxidation of the membrane permeable substrate 3,3,5,5 - tetramethylbenzidine which leads to formation of a colored precipitate. Activity of HRP protein encapsulated in Tat-polymersomes was maintained for much longer compared to reported activity periods for the free HRP (Figure 2). This study represents the first study in which enzyme-filled nanoreactors were delivered to cells without an intrinsically high phagocytic activity. As such, the results present a significant step towards the development of a functional artificial organelle as a treatment modality for enzyme deficiencies. The next step will be the import of enzymes to counter oxidative stress in cells with metabolic defects. Figure 1: Schematic view of the synthesis of Tat-modified nanoreactors. The polymer on the left indicates polystyrene 40 -block-poly[l-isocyanoalanine(2-thiophen-3-ylethyl)amide] 50 (PS-PIAT); the polymer on the right indicates 10 % polystyrene-block- poly(ethylene glycol)-tat (PS-PEG-Tat). THF, Tetrahydrofuran. Figure 2: Activity of horseradish peroxidase (HRP)-loaded nanoreactors inside cells. A) The activity of HRP protein encapsulated in Tat-polymersomes can be easily followed through crystal formation of the blue-colored oxidation product of 3,3,5,5 -tetramethylbenzidine. The image was acquired by transmission light microscopy using a digital camera. The scale bar corresponds to 30 µm. B) The activity of HRP protein encapsulated in Tatpolymersomes is maintained for substantial periods in HeLa cells after a 4 h incubation. 4 Hours after removal of non-internalized nanoreactors, activity was still 75 %. After 16 hours, 42 % of the activity remained. 62 Wouter Verdurmen Understanding barriers to successful enzyme delivery therapy NCMLS

63 All cells contain an extensive network of chaperones which aids in the folding of the primary peptide chain, the refolding of unfolding Lonneke Heldens proteins and the Heat shock proteins This work was published in: Co-chaperones are limiting in a depleted chaperone network. Heldens L et al. Cell Mol Life Sci 67: , Understanding ageing Co-chaperones are limiting in a depleted chaperone network All cells contain an extensive network of chaperones which aids in the folding of the primary peptide chain, the refolding of unfolding proteins and the removal of misfolded proteins and thus maintains proteostasis. Two of the major nodes in the network are the Hsp70 and Hsp90 folding machines. At the core of these machines are Hsp90 and Hsp70, the proteins that promote folding; the activity and substrate specificity is controlled by a number of co-factors and co-chaperones. For Hsp70 it is the DNAJ (Hsp40) proteins that determine substrate specificity. DNAJs also stimulate ATP hydrolysis by Hsp70. The chaperoning capacity of the cell is enhanced by additional chaperone synthesis as part of a proteotoxic stress response. That an increase in chaperones is required to combat proteotoxic stress suggests that under normal conditions the chaperone capacity of a cell is limiting. Cytoplasmic proteotoxic stress signals to the transcription factor heat shock factor 1 (HSF1), which then activates the transcription of a number of genes encoding a variety of chaperones, the so-called heat shock response. With age, the quality of the heat shock response diminishes due to a reduction in the affinity of HSF1 for its cognate DNA element (the heat shock element). Ageing-related failure of HSF1 will weaken the chaperone network, thus increasing the susceptibility to protein folding disease. Moreover, with accumulating evidence showing that HSF1 also regulates gene expression under non-stress conditions, its decline may already cause phenotypic defects in the absence of exogenous stress. To probe the limiting nodes in the chaperoning network, we expressed a dominant negative mutant of HSF1 (dnhsf1) to inhibit HSF1 activity. As expected, a number of chaperone and co-chaperone genes were downregulated by dnhsf1. To pinpoint the critical nodes of the chaperoning network, we used the glucorticoid response. Maturation of the steroid hormone receptor is known to be controlled by both the Hsp70 and the Hsp90 folding machinery (Figure 1) and augmenting the chaperone network by either stress or expression of a constitutively active HSF1 mutant potentiates the glucocorticoid response. Glucocorticoid signalling was severely impaired by dnhsf1, but could be fully rescued by expression of DNAJA1 or DNAJB1, and partially by p23 or ST13. Expression of Hsp70 had no effect while Hsp90 even inhibited (Figure 2). Our results suggest that the DNAJ co-chaperones in particular are limiting in the chaperoning network. Figure 1: Multiple roles for (co)chaperones in steroid hormone receptor signaling. The nascent chain of the glucocorticoid receptor (GR) is delivered to Hsp70 by DNAJs. DNAJs facilitate hydrolysis of ADP to ATP which results in changes in the confirmation of the GR accomplished by Hsp70. The folded GR with low affinity is then delivered to the Hsp90 complex to enable hormone binding. Other chaperones and co-chaperones possibly present in mature complexes were omitted for clarity. Modified from Grad I. and Picard D. (2007). Figure 2: Glucocorticoid response. Glucocorticoid signalling in HEK293 cells was severely impaired by dnhsf1, but could be fully rescued by expression of DNAJA1 or DNAJB1.The bars correspond to the activity of the glucocorticoidresponsive promoter in the presence of dexamethasone compared to the activity in untreated cells, which was set at 100%. Annual Report 2010 Lonneke Heldens Understanding ageing 63

64 The metabolism of all classes of RNAs is characterized by their synthesis, maturation and degradation. A key player in the latter two Raymond Staals processes is the exo- RNA Degradation This work was published in: Dis3-like 1: a novel exoribonuclease associated with the human exosome. Staals RH et al. EMBO J 29: , Understanding RNA degradation pathways in the cytoplasm Identification and characterization of a novel exosome-associated nuclease The metabolism of all classes of RNAs is characterized by their synthesis, maturation and degradation. A key player in the latter two processes is the exosome, an evolutionaryconserved, donut-shaped protein complex with 3 5 exoribonuclease activity (Figure 1). The exosome was originally identified in yeast as the enzyme responsible for the maturation of the 3 end of the 5.8S ribosomal RNA, but later it became clear that the exosome is involved in many processes in which RNAs are truncated from the 3 end or degraded in a 3 5 fashion. Most RNAs will encounter the exosome somewhere in their lifecycle. Nevertheless, our knowledge on the mechanism of action of the exosome is still poor. In eukaryotic cells, the core of the exosome complex was demonstrated to be enzymatically inactive, suggesting that other, auxiliary proteins are required for its 3 5 exoribonuclease activity. Two of such proteins have been identified in yeast: yrrp6 and ydis3, which belong to the RNase D and RNase R family of hydrolytic exonucleases respectively. Human homologues of these proteins were identified, but only PM/Scl-100 (homologue of yrrp6) appeared to associate stably with the exosome core. Since PM/Scl-100 is a predominantly nuclear protein, the question remained which protein(s) contribute to the cytoplasmic activities of the exosome. To identify exosome-associated proteins, exosomes were isolated from human cells by immunoaffinity purification. Subsequently, the isolated proteins were size-separated and analysed by nano-hplc mass spectrometry. The results showed that all exosome core components as well as PM/Scl-100 were present in the immunoaffinity-purified material. In addition, we identified a protein homologous to the previously identified yeast and human Dis3 proteins, which was designated human Dis3-like exoribonuclease 1 (hdis3l1). After confirmation of the interaction between this novel exoribonuclease and the exosome core by co-immunoprecipitation experiments, we addressed the biological function(s) of hdis3l1. By knocking-down the levels of hdis3l1 in human cells by RNA interference and by studying single amino acid substitution mutants, we demonstrated that hdis3l1 indeed functions as a 3 5 exoribonuclease. In addition, immunofluorescence experiments showed that hdis3l1 is predominantly localized in the cytoplasm, which suggested that hdis3l1 associates exclusively with cytoplasmic exosomes and most likely has a function in cytoplasmic RNA maturation or degradation. Among the many different RNAs that reside in the cytoplasm, and thus might be substrates for (exosome-associated) hdis3l1, are the ribosomal RNAs. In contrast to their synthesis and maturation, not much is known about their degradation, which most likely occurs in the cytoplasm. By using a highly sensitive reverse transcriptase-polymerase chain reaction procedure we, in collaboration with the group of Prof. Gadi Schuster (Technion, Haifa, Israel), were able to detect cytoplasmic rrna degradation intermediates that were extended at their 3 ends by adenosine-rich tails. These tails are most likely added to these intermediates to facilitate their degradation by the exosome (Figure 2). This was the first time that experimental evidence was obtained for a polyadenylation-mediated RNA degradation pathway operating in the cytoplasm of mammalian cells. To identify the exoribonuclease involved in the degradation of these molecules the levels of several exoribonucleases were down-regulated and the effects on the accumulation of tailed rrna degradation intermediates were studied. The results showed that a reduction of hdis3l1 led to strongly elevated levels of these tailed RNA molecules, indicating that hdis3l1 plays an important role in cytoplasmic rrna decay. Tailing of the substrate RNAs may be required for leading the 3 end of the relatively unstructured homopolymeric tails through the central channel of the exosome core to the catalytic site of the exosome-associated hdis3l1. Figure 1: The human exosome. Schematic illustration of the human exosome core complex, showing the donut-shaped ring structure and the relative position of the different subunits. A: top view; B: side view, including the tentative position of the associated hdis3l1 protein. Figure 2: Polyadenylation-stimulated 3 5 degradation of RNA. Model for the role of adenosine-rich tailing of RNAs during their degradation. First, the RNA is cleaved (step 2), after which the newly formed 3 end will be polyadenylated (step 3). The resulting tail will subsequently recruit the exosome and possibly other factors, which will degrade the RNA (step 4). 64 Raymond Staals Understanding RNA degradation pathways in the cytoplasm NCMLS

65 Scientific publications 2010 Annual Report

66 Scientific publications 2010 Aartsen, W.M., Cleef, K.W.R. van, Pellissier, L.P., Hoek, R.M., Vos, R.M., Blits, B., Ehlert, E.M., Balaggan, K.S., Ali, R.R., Verhaagen, J. & Wijnholds, J. (2010). GFAP-driven GFP expression in activated mouse Muller glial cells aligning retinal blood vessels following intravitreal injection of AAV2/6 vectors. PLoS ONE, 5(8), e N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Albrecht, B., Brouwer, A.P.M. de, Lefeber, D.J., Cremer, K., Hausser, I., Rossen, N., Wortmann, S.B., Wevers, R.A., Kornak, U. & Morava, E. (2010). MACS syndrome: A combined collagen and elastin disorder due to abnormal Golgi trafficking. American Journal of Medical Genetics Part A, 152A(11), DCN 2 - Lab LGEM, DCN 3 - Neurology, IGMD 3 - Hum Gen, IGMD 4 - Lab LGEM, IGMD 4 - Paediatrics, NCMLS 3A - Hum Gen - Aldarriaga Fernandez, I.C. S, Mei, H.C. van der, Metzger, S., Grainger, D.W., Engelsman, A.F., Nejadnik, M.R. & Busscher, H.J. (2010). In vitro and in vivo comparisons of staphylococcal biofilm formation on a cross-linked poly(ethylene glycol)-based polymer coating. Acta Biomaterialia, 6(3), NCMLS 1C - Dentistry - Alizadeh, B.Z., Broen, J., Rueda, B., Hesselstrand, R., Wuttge, D., Simeon, C., Ortego-Centeno, N., Gonzalez-Gay, M.A., Pros, A., Herrick, A., Worthington, J., Denton, C., Fonseca, C., Riemekasten, G., Vonk, M.C., Hoogen, F. Van Den, Guiducci, S., Matucci-Cerinic, M., Scorza, R., Beretta, L., Airo, P., Coenen, M., Martin, J., Koeleman, B.P. & Radstake, T.R.D.J. (2010). Functional variants of Fc gamma receptor (FCGR2A) and FCGR3A are not associated with susceptibility to systemic sclerosis in a large European Study (EUSTAR). Journal of Rheumatology, 37(8), IGMD 3 - Hum Gen, N4i 4 - Rheumatology, NCEBP 1 - Hum Gen, NCMLS 1A - Rheumatology - Aller, E., Jaijo, T., Wijk, E. van, Ebermann, I., Kersten, F., Garcia-Garcia, G., Voesenek, K., Aparisi, M.J., Hoefsloot, L., Cremers, C., Diaz-Llopis, M., Pennings, R., Bolz, H.J., Kremer, J.M.J. & Millan, J.M. (2010). Sequence variants of the DFNB31 gene among Usher syndrome patients of diverse origin. Molecular Vision, 16, DCN 2 - Hum Gen, DCN 2 - Ophthalmology, DCN 2 - Otorhinolaryn, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology, NCMLS 3A - Otorhinolaryn - Alons, K., Berge, S.J., Rieu, P.N.M.A. & Meijer, G.J. (2010). [Treatment of macroglossia due to acromegaly]. Nederlands Tijdschrift voor Tandheelkunde, 117(6), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Amadori, S., Suciu, S., Selleslag, D., Stasi, R., Alimena, G., Baila, L., Rizzoli, V., Borlenghi, E., Gaidano, G., Magro, D., Torelli, G., Muus, P., Venditti, A., Cacciola, E., Lauria, F, Vignetti, M. & Witte, T.J.M. de (2010). Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19). British Journal of Haematology, 149(3), NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Tumorimmunology - Anitei, M., Stange, C., Parshina, I., Baust, T., Schenck, A., Raposo, G., Kirchhausen, T. & Hoflack, B. (2010). Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signalling during clathrin-ap-1-coated carrier biogenesis at the TGN. Nature Cell Biology, 12(4), DCN 2 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Ansems, M., Hontelez, S., Karthaus, N., Span, P.N. & Adema, G.J. (2010). Crosstalk and DC-SCRIPT: Expanding nuclear receptor modulation. Biochimica et Biophysica Acta, 1806(2), NCMLS 1B - Tumorimmunology, ONCOL 3 - Rad Oncol - Wetensch. publ. refereed (artikel - letter to the editor) Ansems, M., Hontelez, S., Looman, M.W.G., Karthaus, N., Bult, P., Bonenkamp, J.J., Jansen, J.H., Sweep, F.C., Span, P.N. & Adema, G.J. (2010). DC- SCRIPT: nuclear receptor modulation and prognostic significance in primary breast cancer. Journal of the National Cancer Institute, 102(1), NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Lab LH, ONCOL 3 - Pathology, ONCOL 3 - Rad Oncol, ONCOL 5 - Lab LGEM, ONCOL 5 - Surgery - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Antoniou, A.C., Wang, X., Fredericksen, Z., McGuffog, L., Tarrell, R., Sinilnikova, O.M., Healey, S., Morrison, J., Kartsonaki, C., Lesnick, T., Ghoussaini, M., Barrowdale, D., Peock, S., Cook, M., Oliver, C., Frost, D., Eccles, D., Evans, D.G., Eeles, R., Izatt, L., Chu, C., Douglas, F., Paterson, J., Stoppa-Lyonnet, D., Houdayer, C., Mazoyer, S., Giraud, S., Lasset, C., Remenieras, A., Caron, O., Hardouin, A., Berthet, P., Hogervorst, F.B.L., Rookus, M.A., Jager, A., Ouweland, A.M.W. van den, Hoogerbrugge, N., Luijt, R.B. van der, Meijers-Heijboer, H., Gomez Garcia, E.B., Devilee, P., Vreeswijk, M.P., Lubinski, J., Jakubowska, A., Gronwald, J., Huzarski, T., Byrski, T., Gorski, B., Cybulski, C., Spurdle, A.B., Holland, H., Goldgar, D.E., John, E.M., Hopper, J.L., Southey, M.C., Buys, S.S., Daly, M.B., Terry, M.B., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Preisler-Adams, S., Arnold, N., Niederacher, D., Sutter, C., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Blum, J.L., Piedmonte, M., Rodriguez, G.C., Wakeley, K., Boggess, J.F., Basil, J., Blank, S.V., Friedman, E., Kaufman, B., Laitman, Y., Milgrom, R., Andrulis, I.L., Glendon, G., Ozcelik, H., Kirchhoff, T., Vijai, J., Gaudet, M.M., Altshuler, D., Guiducci, C., Loman, N., Harbst, K., Rantala, J., Ehrencrona, H., Gerdes, A.M., Thomassen, M., Sunde, L., Peterlongo, P., Manoukian, S., Bonanni, B. & Viel, A. (2010). A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nature Genetics, 42(10), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Arendrup, M.C., Mavridou, E., Mortensen, K.L., Snelders, E., Frimodt-Moller, N., Khan, H., Melchers, W.J.G. & Verweij, P.E. (2010). Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence. PLoS ONE, 5(4), e N4i 2 - Med Microbiol, NCMLS 1A - Med Microbiol - Arisan, V., Anil, A., Wolke, J.G.C. & Ozer, K. (2010). The effect of injectable calcium phosphate cement on bone anchorage of titanium implants: an experimental feasibility study in dogs. International Journal of Oral and Maxillofacial Surgery, 39(5), NCMLS 1C - Dentistry - Arntz, O.J., Geurts, J., Veenbergen, S., Bennink, M.B., Brand, B.T. van den, Abdollahi-Roodsaz, S., Berg, W.B. van den & Loo, F.A.J. van de (2010). A crucial role for tumor necrosis factor receptor 1 in synovial lining cells and the reticuloendothelial system in mediating experimental arthritis. Arthritis Research & Therapy, 12(2), R61. - N4i 4 - Rheumatology, NCMLS 1A - Rheumatology, NCMLS 1B - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, J.M.J., McEntagart, M.E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., Schlotter-Weigel, B., Senderek, J., Krebs, A., Dick, K.J., Petty, R., Longman, C., Anderson, N.E., Padberg, G.W.A.M., Schelhaas, H.J., Ravenswaaij-Arts, C.M.A. van, Pieber, T.R., Crosby, A.H. & Guelly, C. (2010). Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nature Genetics, 42(2), DCN 2 - Hum Gen, DCN 2 - Neurology, DCN 2 - Otorhinolaryn, NCMLS 3A - Hum Gen, NCMLS 3A - Otorhinolaryn - Avila-Fernandez, A., Cantalapiedra, D., Aller, E., Vallespin, E., Aguirre-Lamban, J., Blanco-Kelly, F., Corton, M., Riveiro-Alvarez, R., Allikmets, R., Trujillo-Tiebas, M.J., Millan, J.M., Cremers, F.P.M. & Ayuso, C. (2010). Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray. Molecular Vision, 16, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) 66 Scientific publications 2010 NCMLS

67 Ayub, H., Khan, M.I., Micheal, S., Akhtar, F., Ajmal, M., Shafique, S., Ali, S.H., Hollander, A.I. den, Ahmed, A. & Qamar, R. (2010). Association of enos and HSP70 gene polymorphisms with glaucoma in Pakistani cohorts. Molecular Vision, 16, IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Azam, M., Collin, R.W.J., Shah, S.T., Shah, A.A., Khan, M.I., Hussain, A., Sadeque, A., Strom, T.M., Thiadens, A.A.H.J., Roosing, S., Hollander, A.I. den, Cremers, F.P.M. & Qamar, R. (2010). Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia. Molecular Vision, 16, IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor) Bakema, J.E., Hiemstra, I.H., Bakker, J., Haij, S. de, Kok, Y., Adema, G., Egmond, M. van, Coffer, P.J., Winkel, J.G.J. van de & Leusen, J.H. (2010). c-jun activating binding protein 1 binds to the IgA receptor and modulates protein levels of FcalphaRI and FcRgamma-chain. European Journal of Immunology, 40(7), NCMLS 1B - Tumorimmunology - Baker, D.J. & Deursen, J.M.A. van (2010). Chromosome missegregation causes colon cancer by APC loss of heterozygosity. Cell Cycle, 9(9), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Balemans, M.C.M., Huibers, M.M., Eikelenboom, N.W., Kuipers, A.J., Summeren, R.C. van, Pijpers, M.M., Tachibana, M., Shinkai, Y., Bokhoven, J.H.L.M. van & Zee, C.E.E.M. van der (2010). Reduced exploration, increased anxiety, and altered social behavior: Autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice. Behavioural Brain Research, 208(1), DCN 2 - Cell Biology, DCN 2 - Hum Gen, NCMLS 2A - Cell Biology, NCMLS 3A - Hum Gen - Bandah-Rozenfeld, D., Collin, R.W.J., Banin, E., Born, L.I. van den, Coene, K.L.M., Siemiatkowska, A.M., Zelinger, L., Khan, M.I., Lefeber, D.J., Erdinest, I., Testa, F., Simonelli, F., Voesenek, K., Blokland, E.A.W., Strom, T.M., Klaver, C.C., Qamar, R., Banfi, S., Cremers, F.P.M., Sharon, D. & Hollander, A.I. den (2010). Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa. American Journal of Human Genetics, 87(2), DCN 3 - Neurology, IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, IGMD 4 - Lab LGEM, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Bandah-Rozenfeld, D., Littink, K.W., Ben-Yosef, T., Strom, T.M., Chowers, I., Collin, R.W.J., Hollander, A.I. den, Born, L.I. van den, Zonneveld, M.N., Merin, S., Banin, E., Cremers, F.P.M. & Sharon, D. (2010). Novel null mutations in the EYS gene are a frequent cause of autosomal recessive retinitis pigmentosa in the Israeli population. Investigative Ophthalmology & Visual Science, 51(9), IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Barkhuysen, R., Meijer, G.J., Soehardi, A., Merkx, M.A.W., Borstlap, W.A., Berge, S.J., Bronkhorst, E.M. & Hoppenreijs, T.J.M. (2010). The effect of a single dose of bupivacaine on donor site pain after anterior iliac crest bone harvesting. International Journal of Oral and Maxillofacial Surgery, 39(3), NCMLS 1C - Dentistry, ONCOL 3 - Oral Maxillo - Bart, M.J., Gent, M. van, Heide, H.G. van der, Boekhorst, J., Hermans, P.W.M., Parkhill, J. & Mooi, F.R. (2010). Comparative genomics of prevaccination and modern Bordetella pertussis strains. BMC Genomics, 11, N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Bart, M.J., Gent, M. van, Heide, H.G. van der, Boekhorst, J., Hermans, P.W.M., Parkhill, J. & Mooi, F.R. (2010). Comparative genomics of prevaccination and modern Bordetella pertussis strains. BMC Genomics, 11, NCMLS 2A - Lab LGEM - Wetensch. publ. refereed (artikel - letter to the editor) Bauland, C.G., Smit, J.M., Bartelink, L.R., Zondervan, H.A. & Spauwen, P.H.M. (2010). Hemangioma in the newborn: increased incidence after chorionic villus sampling. Prenatal Diagnosis, 30(10), NCMLS 1C - Plastic Surgery - Wetensch. publ. refereed (artikel - letter to the editor) Bavel, C.C.A.W. van, Dieker, J.W.C., Tamboer, W.P.M., Vlag, J. van der & Berden, J.H.M. (2010). Lupus-derived monoclonal autoantibodies against apoptotic chromatin recognize acetylated conformational epitopes. Molecular Immunology, 48(1-3), N4i 4 - Nephrology, NCMLS 1C - Nephrology - Bayjanov, J.R., Siezen, R.J. & Hijum, S.A.F.T. van (2010). PanCGHweb: a web tool for genotype calling in pangenome CGH data. Bioinformatics, 26(9), NCMLS 2A - CMBI - Bayley, J.P.M., Kunst, H.P.M., Cascon, A., Sampietro, M.L., Gaal, J., Korpershoek, E., Hinojar-Gutierrez, A., Timmers, H.J.L.M., Hoefsloot, L.H., Hermsen, M.A., Suarez, C., Hussain, A.K., Vriends, A.H., Hes, F.J., Jansen, J.C., Tops, C.M., Corssmit, E.P., Knijff, P. de, Lenders, J.W.M., Cremers, C.W.R.J., Devilee, P., Dinjens, W.N., Krijger, R.R. de & Robledo, M. (2010). SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncology, 11(4), DCN 2 - Otorhinolaryn, IGMD 3 - Hum Gen, IGMD 6 - Endocrinology, NCEBP 6 - Gen Int Med, NCMLS 3A - Otorhinolaryn - Becker, S.T., Douglas, T., Acil, Y., Seitz, H., Sivananthan, S., Wiltfang, J. & Warnke, P.H. (2010). Biocompatibility of individually designed scaffolds with human periosteum for use in tissue engineering. Journal of Materials Science-Materials in Medicine, 21(4), NCMLS 1C - Dentistry - Beekhuizen, H.J. van, Joosten, I., Lotgering, F.K., Bulten, J. & Kempen, L.C.L.T. van (2010). Natural killer cells and HLA-G expression in the basal decidua of human placenta adhesiva. Placenta, 31(12), N4i 4 - Lab LMI, NCMLS 1B - Lab LMI, ONCOL 3 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Belletti, B., Pellizzari, I., Berton, S., Fabris, L., Wolf, K. van der, Lovat, F., Schiappacassi, M., D Andrea, S., Nicoloso, M.S., Lovisa, S., Sonego, M., Defilippi, P., Vecchione, A., Colombatti, A., Friedl, P.H.A. & Baldassarre, G. (2010). p27kip1 controls cell morphology and motility by regulating microtubule-dependent lipid raft recycling. Molecular and Cellular Biology, 30(9), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Berende, A., Oosting, M., Kullberg, B.J., Netea, M.G. & Joosten, L.A.B. (2010). Activation of innate host defense mechanisms by Borrelia. European Cytokine Network, 21(1), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Berendsen, A.D., Smit, T.H., Schoenmaker, T., Walboomers, X.F., Harris, S.E., Everts, V. & Bronckers, A.L. (2010). Inorganic phosphate stimulates DMP1 expression in human periodontal ligament fibroblasts embedded in three-dimensional collagen gels. Cells Tissues Organs, 192(2), NCMLS 1C - Dentistry - Bergboer, J.G.M., Zeeuwen, P.L.J.M. & Schalkwijk, J. (2010). Pathogenesis of atopic dermatitis and psoriasis: focus on the epidermal differentiation complex. The open Dermatology Journal, 4, N4i 1 NCMLS 1A - DERMATOL - Bergboer, J.G.M., Zeeuwen, P.L.J.M., Irvine, A.D., Weidinger, S., Giardina, E., Novelli, G., Heijer, M. den, Rodriguez, E., Illig, T., Riveira-Munoz, E., Campbell, L.E., Tyson, J., Dannhauser, E.N., O Regan, G.M., Galli, E., Klopp, N., Koppelman, G.H., Novak, N., Estivill, X., McLean, W.H.I., Postma, D.S., Armour, J.A. & Schalkwijk, J. (2010). Deletion of Late Cornified Envelope 3B and 3C genes is not associated with atopic dermatitis. Journal of Investigative Dermatology, 130(8), IGMD 6 - Endocrinology, N4i 1 - Dermatology, NCEBP 1 - EBH, NCMLS 1A - Dermatology - Berk, L.C.J. van den, Jansen, B.J.H., Siebers-Vermeulen, K.G.C., Roelofs, H., Figdor, C.G., Adema, G.J. & Torensma, R. (2010). Mesenchymal stem cells respond to TNF but do not produce TNF. Journal of Leukocyte Biology, 87(2), NCMLS 1C - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Annual Report 2010 Scientific publications

68 Bhansing, K.J., Bon, L. van, Janssen, M. & Radstake, T.R.D.J. (2010). Gout: a clinical syndrome illustrated and discussed. Netherlands Journal of Medicine, 68(9), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Bindels, R.J.M. (2010) Homer W. Smith Award: Minerals in motion: from new ion transporters to new concepts. Journal of the American Society of Nephrology, 21(8), IGMD 9 - Physiology, NCMLS 2B - Physiology - Biswal, B.B., Mennes, M., Zuo, X.N., Gohel, S., Kelly, C., Smith, S.M., Beckmann, C.F., Adelstein, J.S., Buckner, R.L., Colcombe, S., Dogonowski, A.M., Ernst, M., Fair, D., Hampson, M., Hoptman, M.J., Hyde, J.S., Kiviniemi, V.J., Kotter, R., Li, S.J., Lin, C.P., Lowe, M.J., Mackay, C., Madden, D.J., Madsen, K.H., Margulies, D.S., Mayberg, H.S., McMahon, K., Monk, C.S., Mostofsky, S.H., Nagel, B.J., Pekar, J.J., Peltier, S.J., Petersen, S.E., Riedl, V., Rombouts, S.A., Rypma, B., Schlaggar, B.L., Schmidt, S., Seidler, R.D., Siegle, G.J., Sorg, C., Teng, G.J., Veijola, J., Villringer, A., Walter, M., Wang, L., Weng, X.C., Whitfield-Gabrieli, S., Williamson, P., Windischberger, C., Zang, Y.F., Zhang, H.Y., Castellanos, F.X. & Milham, M.P. (2010). Toward discovery science of human brain function. Proc Natl Acad Sci U S A, 107(10), DCN 3 - CNS, NCMLS 2B - CNS - Bloembergen, T.G., Gerretzen, J., Wouters, H.J.P., Gloerich, J., Wessels, H.J., Dael, M.F.P. van, Heuvel, L.P.W.J. van den, Eilers, P.H., Buydens, L.M.C. & Wehrens, R. (2010). Improved parametric time warping for proteomics. Chemometrics & Intelligent Laboratory Systems, 104(1), IGMD 9 - Paediatrics, NCMLS 2A - Paediatrics, RU SCI IMM AC - Bloembergen, T.G., Gerretzen, J., Wouters, H.J.P., Gloerich, J., Wessels, H.J., van Dael, M., van den Heuvel, L.P., Eilers, P.H., Buydens, L.M.C. & Wehrens, H.R.M.J. (2010). Improved Parametric time warping for proteomics. Chemometrics & Intelligent Laboratory Systems, 104(1), IGMD 9 - Lab LGEM, NCMLS 2A - Lab LGEM, RU SCI IMM AC - Blom, A.B., Lent, P.L.E.M. van, Kraan, P.M. van der & Berg, W.B. van den (2010). To seek shelter from the WNT in osteoarthritis? WNT-signaling as a target for osteoarthritis therapy. Current Drug Targets, 11(5), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor) Bokhoven, J.H.L.M. van & Kramer, J.M. (2010). Disruption of the epigenetic code: an emerging mechanism in mental retardation. Neurobiology of Disease, 39(1), DCN 2 - Hum Gen, NCMLS 3A - Hum Gen - Boleij, A., Roelofs, R., Schaeps, R.M.J., Schulin, T., Glaser, P., Swinkels, D.W., Kato, I. & Tjalsma, H. (2010). Increased exposure to bacterial antigen RpL7/L12 in early stage colorectal cancer patients. Cancer, 116(17), N4i 1 - Lab LGEM, N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol, ONCOL 5 - Lab LGEM - Bon, B.W.M. van, Koolen, D.A., Brueton, L., McMullan, D., Lichtenbelt, K.D., Ades, L.C., Peters, G., Gibson, K., Moloney, S., Novara, F., Pramparo, T., Bernardina, B. Dalla, Zoccante, L., Balottin, U., Piazza, F., Pecile, V., Gasparini, P., Guerci, V., Kets, M., Pfundt, R., Brouwer, A.P.M. de, Veltman, J.A., Leeuw, N. de, Wilson, M., Antony, J., Reitano, S., Luciano, D., Fichera, M., Romano, C, Brunner, H.G., Zuffardi, O. & Vries, B.B. de (2010). The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. European Journal of Human Genetics, 18(2), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Bondeson, J., Blom, A.B., Wainwright, S., Hughes, C., Caterson, B. & Berg, W.B. van den (2010). The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis and Rheumatism, 62(3), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Bongio, M., Beucken, J.J.J.P van den, Leeuwenburgh, S.C.G. & Jansen, J.A. (2010). Development of bone substitute materials: from biocompatible to instructive. Journal of Materials Chemistry, 20(40), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Bontkes, H.J., Moreno, M., Hangalapura, B., Lindenberg, J.J., Groot, J. de, Lougheed, S., Vliet, H.J. van der, Eertwegh, A.J. van den, Gruijl, T.D. de, Blomberg, B.M.E. von & Scheper, R.J. (2010). Attenuation of invariant natural killer T-cell anergy induction through intradermal delivery of alphagalactosylceramide. Clinical Immunology, 136(3), NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Wetensch. publ. refereed (artikel - letter to the editor) Boone, M., Kortenoeven, M.L.A., Robben, J.H. & Deen, P.M.T. (2010). Effect of the cgmp pathway on AQP2 expression and translocation: potential implications for nephrogenic diabetes insipidus. Nephrology Dialysis Transplantation, 25(1), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Boone, M., Mobasheri, A., Fenton, R.A., Balkom, B.W.M. van, Wismans, R., Zee, C.E.E.M. van der & Deen, P.M.T. (2010). The lysosomal trafficking regulator interacting protein-5 localizes mainly in epithelial cells. J Mol Histol, 41(1), DCN 2 - Cell Biology, IGMD 9 - Physiology, NCMLS 1C - Biochemistry, NCMLS 2A - Cell Biology, NCMLS 2B - Physiology - Borst, J.W., Willemse, M., Slijkhuis, R., Krogt, G. van der, Laptenok, S.P., Jalink, K., Wieringa, B. & Fransen, J.A.M. (2010). ATP changes the fluorescence lifetime of cyan fluorescent protein via an interaction with His148. PLoS ONE, 5(11), e IGMD 8 - Cell Biol, NCMLS 2A - Cell Biology - Bosman, G.J.C.G.M., Lasonder, E., Groenen-Dopp, Y.A., Willekens, F.L.A., Werre, J.M. & Novotny, V.M.J. (2010). Comparative proteomics of erythrocyte aging in vivo and in vitro. J Proteomics, 73(3), N4i 4 - Haematology, NCMLS 2A IGMD 8 - CMBI, NCMLS 3B - Biochemistry, ONCOL 5 - Haematology - Bosman, G.J.C.G.M., Stappers, M. & Novotny, V.M.J. (2010). Changes in band 3 structure as determinants of erythrocyte integrity during storage and survival after transfusion. Blood Transfus, 8 Suppl 3, s N4i 4 - Haematology, NCMLS 3B - Biochemistry, ONCOL 5 - Haematology - Bottema, R.W., Kerkhof, M. van de, Reijmerink, N.E., Koppelman, G.H., Thijs, C., Stelma, F.F., Smit, H.A., Brunekreef, B., Schayck, C.P. van & Postma, D.S. (2010). X-chromosome Forkhead Box P3 polymorphisms associate with atopy in girls in three Dutch birth cohorts. Allergy, 65(7), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Bottema, R.W., Postma, D.S., Reijmerink, N.E., Thijs, C., Stelma, F.F., Smit, H.A., Schayck, C.P. van, Brunekreef, B., Koppelman, G.H. & Kerkhof, M. van de (2010). Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE. European Respiratory Journal, 35(1), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Bousema, T., Drakeley, C., Gesase, S., Hashim, R., Magesa, S., Mosha, F., Otieno, S., Carneiro, I., Cox, J., Msuya, E., Kleinschmidt, I., Maxwell, C., Greenwood, B., Riley, E., Sauerwein, R.W., Chandramohan, D. & Gosling, R. (2010). Identification of hot spots of malaria transmission for targeted malaria control. Journal of Infectious Diseases, 201(11), N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Bousema, T., Okell, L., Shekalaghe, S., Griffin, J.T., Omar, S., Sawa, P., Sutherland, C., Sauerwein, R.W., Ghani, A.C. & Drakeley, C. (2010). Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malaria Journal, 9, N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Bousema, T., Roeffen, W., Meijerink, H., Mwerinde, H., Mwakalinga, S., Gemert, G.J.A. van, Vegte-Bolmer, M. van de, Mosha, F., Targett, G., Riley, E.M., Sauerwein, R.W. & Drakeley, C. (2010). The dynamics of naturally acquired immune responses to Plasmodium falciparum sexual stage antigens Pfs230 & Pfs48/45 in a low endemic area in Tanzania. PLoS ONE, 5(11), e N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - 68 Scientific publications 2010 NCMLS

69 Bralten, L.B., Gravendeel, A.M., Kloosterhof, N.K., Sacchetti, A., Vrijenhoek, T., Veltman, J.A., Bent, M.J. van den, Kros, J.M., Hoogenraad, C.C., Sillevis Smitt, P.A. & French, P.J. (2010). The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma. Oncogene, 29(46), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Brand, H.K., Hermans, P.W.M. & Groot, R. de (2010). Host biomarkers and paediatric infectious diseases: from molecular profiles to clinical application. Advances in Experimental Medicine and Biology (SCI), 659, N4i 1 - Lab LGEM, N4i 1 - Paediatrics, NCMLS 1A - Paediatrics, NCMLS 2A - Lab LGEM - Broek, R.W. Ten, Grefte, S. & den Hoff, J.W. Von (2010). Regulatory factors and cell populations involved in skeletal muscle regeneration. Journal of Cellular Physiology, 224(1), NCMLS 1C - Dentistry - Broen, J.C., Wolvers-Tettero, I.L.M., rts-van Bon, L. Geu, Vonk, M.C., Coenen, M.J.H., Lafyatis, R., Radstake, T.R.D.J. & Langerak, A.W. (2010). Skewed X chromosomal inactivation impacts T regulatory cell function in systemic sclerosis. Annals of the Rheumatic Diseases, 69(12), IGMD 3 - Hum Gen, N4i 4 - Rheumatology, NCEBP 1 - Hum Gen, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor) Brooijmans, R.J.W. & Siezen, R.J. (2010). Genomics of microalgae, fuel for the future? Microbial Biotechnology, 3(5), NCMLS 2A - CMBI - Brouwer, A.P.M. de, Bokhoven, J.H.L.M. van, Nabuurs, S.B., Arts, W.F.M., Christodoulou, J. & Duley, J. (2010). PRPS1 mutations: four distinct syndromes and potential treatment. American Journal of Human Genetics, 86(4), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, IGMD 9 - Physiology, NCMLS 2B - Physiology, NCMLS 3A - Hum Gen, NCMLS 3B - CMBI - Brouwers, M.M., Zanden, L.F.M. van der, Gier, R.P.E. de, Barten, E.J., Zielhuis, G.A., Feitz, W.F.J. & Roeleveld, N. (2010). Hypospadias: risk factor patterns and different phenotypes. BJU International, 105(2), IGMD 9 - EBH, NCEBP 12 - Hum Gen, NCEBP 2 - EBH, NCEBP 2 - Urology, NCMLS 1C - Urology - Bruggemann, R.J.M., Luin, M. van, Colbers, E.P.H., Dungen, M.W. van den, Pharo, C., Schouwenberg, B.J.J.W. & Burger, D.M. (2010). Effect of posaconazole on the pharmacokinetics of fosamprenavir and vice versa in healthy volunteers. Journal of Antimicrobial Chemotherapy, 65(10), N4i 2 - Clinical Pharmacy, N4i 3 - Clinical Pharmacy, N4i 3 - Pharm Tox, NCEBP 13 - Clinical Pharmacy, NCMLS 2B - Pharm Tox - Bruinsma, I.B., Riet, L. te, Gevers, T., Dam, G.B. ten, Kuppevelt, A.H.M.S.M. van, David, G., Kusters, B., Waal, R.M.W. de & Verbeek, M.M. (2010). Sulfation of heparan sulfate associated with amyloid-beta plaques in patients with Alzheimer s disease. Acta Neuropathologica, 119(2), DCN 2 - Lab LGEM, DCN 3 - Neurology, NCEBP, NCMLS 1C - Biochemistry, ONCOL 3 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor / Key publication RR) _ Buist, H.E., Burgsteden, J.A. van, Freidig, A.P., Maas, W.J. & Sandt, J.J. van de (2010). New in vitro dermal absorption database and the prediction of dermal absorption under finite conditions for risk assessment purposes. Regul Toxicol Pharmacol, 57(2-3), IGMD 9 - Physiology, NCMLS 2B - Physiology - Bult, P., Manders, P., Straatman, H.M.P.M., Tjan-Heijnen, V.C., Beex, L.V.A.M., Hendriks, J., Leer, J.W.H., Verbeek, A.L.M. & Holland, R. (2010). In primary breast cancer the mitotic activity yields similar prognostic information as the histological grade: a study with long-term follow-up. Breast Cancer Research and Treatment, 122(1), NCEBP 1 - EBH, NCEBP 2 - EBH, NCMLS 3B - Hum Gen, ONCOL 3 - Pathology, ONCOL 3 - Rad Oncol, ONCOL 5 - EBH - Burghout, P., Cron, L.E., Gradstedt, H., Quintero, B., Simonetti, E., Bijlsma, J.J., Bootsma, H.J. & Hermans, P.W.M. (2010). Carbonic anhydrase is essential for Streptococcus pneumoniae growth in environmental ambient air. Journal of Bacteriology, 192(15), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Buscher, A.K., Kranz, B., Buscher, R., Hildebrandt, F., Dworniczak, B., Pennekamp, P., Kuwertz-Broking, E., Wingen, A.M., John, U., Kemper, M., Monnens, L., Hoyer, P.F., Weber, S. & Konrad, M. (2010). Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol, 5(11), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Buschow, S.I. & Figdor, C.G. (2010). Dendritic cell subsets digested: RNA sensing makes the difference! Immunity, 32(2), NCMLS 1B - Tumorimmunology - Buschow, S.I., Balkom, B.W.M. van, Aalberts, M., Heck, A.J.R. van, Wauben, M. & Stoorvogel, W. (2010). MHC class II-associated proteins in B- cell exosomes and potential functional implications for exosome biogenesis. Immunol Cell Biol, 88(8), NCMLS 1B - Tumorimmunology - Buschow, S.I., Lasonder, E., Deutekom, H.W. van, Oud, M.M., Beltrame, L., Huynen, M.A., Vries, I.J.M. de, Figdor, C.G. & Cavalieri, D. (2010). Dominant processes during human dendritic cell maturation revealed by integration of proteome and transcriptome at the pathway level. Journal of Proteome Research, 9(4), IGMD 8 - CMBI, NCMLS 1B - Hum Gen, NCMLS 1B - Med Oncol, NCMLS 1B - Tumorimmunology, NCMLS 2A - CMBI - Cantagrel, V., Lefeber, D.J., Ng, B.G., Guan, Z., Silhavy, J.L., Bielas, S.L., Lehle, L., Hombauer, H., Adamowicz, M., Swiezewska, E., Brouwer, A.P.M. de, Blumel, P., Sykut-Cegielska, J., Houliston, S., Swistun, D., Ali, B.R., Dobyns, W.B., Babovic-Vuksanovic, D., Bokhoven, J.H.L.M. van, Wevers, R.A., Raetz, C.R., Freeze, H.H., Morava, E., Al-Gazali, L. & Gleeson, J.G. (2010). SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell, 142(2), DCN 2 - Hum Gen, DCN 2 - Lab LGEM, DCN 3 - Neurology, IGMD 3 - Hum Gen, IGMD 4 - Lab LGEM, IGMD 4 - Paediatrics, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCItijdschriften) Cao, G., Lee, K.P., Wijst, J. van der, Graaf, M. van der, Kemp, A. van der, Bindels, R.J.M. & Hoenderop, J.G.J. (2010). Methionine sulfoxide reductase B1 (MsrB1) recovers TRPM6 channel activity during oxidative stress. Journal of Biological Chemistry, 285(34), IGMD 9 - Physiology, NCMLS 2B - Physiology - Cavalieri, D., Rivero, D., Beltrame, L., Buschow, S.I., Calura, E., Rizzetto, L., Gessani, S., Gauzzi, M.C., Reith, W., Baur, A., Bonaiuti, R., Brandizi, M., Filippo, C. De, D Oro, U., Draghici, S., Dunand-Sauthier, I., Gatti, E., Granucci, F., Gundel, M., Kramer, M., Kuka, M., Lanyi, A., Melief, C.J., Montfoort, N. van, Ostuni, R., Pierre, P., Popovici, R., Rajnavolgyi, E., Schierer, S., Schuler, G., Soumelis, V., Splendiani, A., Stefanini, I., Torcia, M.G., Zanoni, I., Zollinger, R., Figdor, C.G. & Austyn, J.M. (2010). DC-ATLAS: a systems biology resource to dissect receptor specific signal transduction in dendritic cells. Immunome Res, 6, IGMD 2 - Gastroenterology, NCMLS 1B - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Caymaris, S., Bootsma, H.J., Martin, B., Hermans, P.W.M., Prudhomme, M. & Claverys, J.P. (2010). The global nutritional regulator CodY is an essential protein in the human pathogen Streptococcus pneumoniae. Molecular Microbiology, 78(2), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Chai, L.A., Netea, M.G., Teerenstra, S., Earnest, A., Vonk, A.G., Schlamm, H.T., Herbrecht, R., Troke, P.F. & Kullberg, B.J. (2010). Early proinflammatory cytokines and C-reactive protein trends as predictors of outcome in invasive Aspergillosis. Journal of Infectious Diseases, 202(9), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Annual Report 2010 Scientific publications

70 Chai, L.Y., Netea, M.G., Sugui, J., Vonk, A.G., Sande, W.W. van de, Warris, A., Kwon-Chung, K.J. & Kullberg, B.J. (2010). Aspergillus fumigatus conidial melanin modulates host cytokine response. Immunobiology, 215(11), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Chai, L.Y., Veerdonk, F. van de, Marijnissen, R.J., Cheng, S.C., Khoo, A.L., Hectors, M., Lagrou, K., Vonk, A.G., Maertens, J., Joosten, L.A.B., Kullberg, B.J. & Netea, M.G. (2010). Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity. Immunology, 130(1), N4i 2 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Gen Int Med, NCMLS 1A - Rheumatology - Chalandon, Y., Passweg, J.R., Schmid, C., Olavarria, E., Dazzi, F., Simula, M.P., Ljungman, P., Schattenberg, A., Witte, T.J.M. de, Lenhoff, S., Jacobs, P., Volin, L., Iacobelli, S., Finke, J., Niederwieser, D. & Guglielmi, C. (2010). Outcome of patients developing GVHD after DLI given to treat CML relapse: a study by the Chronic Leukemia Working Party of the EBMT. Bone Marrow Transplantation, 45(3), NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Tumorimmunology - Chen, G., Zou, X., Watanabe, H., Deursen, J.M.A. van & Shen, J. (2010). CREB binding protein is required for both short-term and long-term memory formation. Journal of Neuroscience, 30(39), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Wetensch. publ. refereed (artikel - letter to the editor) Chen, W., Ullmann, R., Langnick, C., Menzel, C., Wotschofsky, Z., Hu, H., Doring, A., Hu, Y., Kang, H., Tzschach, A., Hoeltzenbein, M., Neitzel, H., Markus, S., Wiedersberg, E., Kistner, G., Ravenswaaij-Arts, C.M.A. van, Kleefstra, T., Kalscheuer, V.M.M. & Ropers, H.H. (2010). Breakpoint analysis of balanced chromosome rearrangements by next-generation paired-end sequencing. European Journal of Human Genetics, 18(5), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Cheng, S.C., Chai, L.Y., Joosten, L.A.B., Vecchiarelli, A., Hube, B., Meer, J.W.M. van der, Kullberg, B.J. & Netea, M.G. (2010). Candida albicans releases soluble factors that potentiate cytokine production by human cells through a protease-activated receptor 1- and 2-independent pathway. Infection and Immunity, 78(1), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor) Cheng, S.C., Veerdonk, F. van de, Smeekens, S., Joosten, L.A.B., Meer, J.W.M. van der, Kullberg, B.J. & Netea, M.G. (2010). Candida albicans dampens host defense by downregulating IL-17 production. Journal of Immunology, 185(4), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Chisholm, S.A., Mouton, J.W., Lewis, D.A., Nichols, T., Ison, C.A. & Livermore, D.M. (2010). Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink? Journal of Antimicrobial Chemotherapy, 65(10), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Coenen, M.J.H., Enevold, C., Barrera, P., Schijvenaars, M.M.V.A.P., Toonen, E.J.M., Scheffer, H., Padyukov, L., Kastbom, A., Klareskog, L., Barton, A., Kievit, W., Rood, M.J., Jansen, T.L.Th.A., Swinkels, D.W., Riel, P.L.C.M. van, Franke, B., Bendtzen, K. & Radstake, T.R.D.J. (2010). Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome. PLoS ONE, 5(12), e DCN 1 - Psychiatry, DCN 2 - Hum Gen, IGMD 3 - Hum Gen, N4i 1 - Lab LGEM, N4i 4 - Rheumatology, NCEBP 1 - Hum Gen, NCEBP 2 - Rheumatology, NCEBP 5 - Rheumatology, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor) Cohen Stuart, J., Mouton, J.W., Diederen, B.M., Naiemi, N. Al, Thijsen, S., Vlaminckx, B.J., Fluit, A.C. & erstein-van Hall, M.A. Lev (2010). Evaluation of Etest to determine tigecycline MICs for Enterobacter species. Antimicrobial Agents and Chemotherapy, 54(6), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Collin, R.W.J., Safieh, C., Littink, K.W., Shalev, S.A., Garzozi, H.J., Rizel, L., Abbasi, A.H., Cremers, F.P.M., Hollander, A.I. den, Klevering, B.J. & Ben-Yosef, T. (2010). Mutations in C2ORF71 cause autosomal-recessive retinitis pigmentosa. American Journal of Human Genetics, 86(5), IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCEBP 2 - Human Genetics, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Constantinescu, P., Wang, B., Kovacevic, K., Jalilian, I., Bosman, G.J.C.G.M., Wiley, J.S. & Sluyter, R. (2010). P2X7 receptor activation induces cell death and microparticle release in murine erythroleukemia cells. Biochimica et Biophysica Acta, 1798(9), NCMLS 3B - Biochemistry - Coolen, M.W., Stirzaker, C., Song, J.Z., Statham, A.L., Kassir, Z., Moreno, C.S., Young, A.N., Varma, V., Speed, T.P., Cowley, M., Lacaze, P., Kaplan, W., Robinson, M.D. & Clark, S. J. (2010). Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nature Cell Biology, 12(3), NCMLS 3A - Hum Gen, RU SCI NCMLS MB - Creton, M., Cune, M., Verhoeven, W., Muradin, M., Wismeijer, D. & Meijer, G. (2010). Implant treatment in patients with severe hypodontia: a retrospective evaluation. Journal of Oral and Maxillofacial Surgery, 68(3), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Cruz, L.J., Tacken, P.J., Fokkink, R., Joosten, B., Stuart, M.C., Albericio, F., Torensma, R. & Figdor, C.G. (2010). Targeted PLGA nano- but not microparticles specifically deliver antigen to human dendritic cells via DC-SIGN in vitro. Journal of Controlled Release, 144(2), NCMLS 1B - Tumorimmunology - Cuijpers, M.L.H., Raymakers, R.A.P., Mackenzie, M.W., Witte, T.J.M. de & Swinkels, D.W. (2010). Recent advances in the understanding of iron overload in sideroblastic myelodysplastic syndrome. British Journal of Haematology, 149(3), IGMD 7 - Lab LGEM, NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology, ONCOL 5 - Haematology - Cuijpers, V.M.J.I., Walboomers, X.F. & Jansen, J.A. (2010). Three-dimensional localization of implanted biomaterials in anatomical and histological specimens using combined X-ray computed tomography and three-dimensional surface reconstruction: a technical note. Tissue Engineering Part C Methods, 16(1), NCMLS 1C - Dentistry - Davila, S., Wright, V.J., Khor, C.C., Sim, K.S., Binder, A., Breunis, W.B., Inwald, D., Nadel, S., Betts, H., Carrol, E.D., Groot, R. de, Hermans, P.W.M., Hazelzet, J., Emonts, M., Lim, C.C., Kuijpers, T.W., Martinon-Torres, F., Salas, A., Zenz, W., Levin, M. & Hibberd, M.L. (2010). Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nature Genetics, 42(9), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCItijdschriften) Dekker, N., Hermens, R.P.M.G., Elwyn, G., Weijden, T. van der, Nagengast, F.M., Duijvendijk, P. van, Salemink, S., Adang, E., Krieken, J.H.J.M. van, Ligtenberg, M.J.L. & Hoogerbrugge-van der Linden, N. (2010). Improving calculation, interpretation and communication of familial colorectal cancer risk: protocol for a randomized controlled trial. Implementation Science, 5, NCEBP 1 - Hum Gen, NCEBP 4 - IQ, NCMLS 3A - Hum Gen, ONCOL 1 - Gastroenterology, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology, ONCOL 4 - EBH, ONCOL 4 - Surgery - Deligny, A., Denys, A., Marcant, A., Melchior, A., Mazurier, J., Kuppevelt, A.H.M.S.M. van & Allain, F. (2010). Synthesis of heparan sulfate with cyclophilin B-binding properties is determined by cell type-specific expression of sulfotransferases. Journal of Biological Chemistry, 285(3), NCMLS 1C - Biochemistry - 70 Scientific publications 2010 NCMLS

71 Demir, K., Yntema, H.G., Altincik, A. & Bober, E. (2010). A mother and son with Noonan syndrome resulting from a PTPN11 mutation: first report of molecularly proven cases from Turkey. Turk J Pediatr, 52(3), NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Di, J., Yigit, R., Figdor, C.G., Duiveman- de Boer, T., Massuger, L.F.A.G. & Torensma, R. (2010). Expression compilation of several putative cancer stem cell markers by primary ovarian carcinoma. Journal of Cancer Therapy, NCMLS 1C - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Diamond, M.P., Wexner, S.D., dizereg, G.S., Korell, M., Zmora, O., Goor, H. van & Kamar, M. (2010). Adhesion prevention and reduction: current status and future recommendations of a multinational interdisciplinary consensus conference. Surgical Innovation, 17(3), NCMLS 1C - Surgery - Diavatopoulos, D.A., Short, K.R., Price, J.T., Wilksch, J.J., Brown, L.E., Briles, D.E., Strugnell, R.A. & Wijburg, O.L. (2010). Influenza A virus facilitates Streptococcus pneumoniae transmission and disease. FASEB Journal, 24(6), N4i 1 - Paediatrics, NCMLS 1A - Paediatrics - Dickinson, A.M., Pearce, K.F., Norden, J., O Brien, S.G., Holler, E., Bickeboller, H., Balavarca, Y., Rocha, V., Kolb, H.J., Hromadnikova, I., Sedlacek, P., Niederwieser, D., Brand, R., Ruutu, T., Apperley, J., Szydlo, R., Goulmy, E., Siegert, W., Witte, T.J.M. de & Gratwohl, A. (2010). Impact of genomic risk factors on outcome after hematopoietic stem cell transplantation for patients with chronic myeloid leukemia. Haematologica, 95(6), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Diepen, A. van, Brand, H.K., Sama, I., Lambooy, L.H.J., Heuvel, L.P.W.J. van den, Well, L. van der, Huynen, M., Osterhaus, A.D., Andeweg, A.C. & Hermans, P.W.M. (2010). Quantitative proteome profiling of respiratory virus-infected lung epithelial cells. J Proteomics, 73(9), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Dijk, M.R. van, Schaijk, B.C.L. van, Khan, S.M., Dooren, M.W. van, Ramesar, J., Kaczanowski, S., Gemert, G.J.A. van, Kroeze, H., Stunnenberg, H.G., Eling, W.M.C., Sauerwein, R.W., Waters, A.P. & Janse, C.J. (2010). Three members of the 6-cys protein family of Plasmodium play a role in gamete fertility. PLoS Pathogens, 6(4), e N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Dijkgraaf, I. & Boerman, O.C. (2010). Molecular imaging of angiogenesis with SPECT. European Journal of Nuclear Medicine and Molecular Imaging, 37 Suppl 1, S NCMLS 1B - Nuclear Med, ONCOL 3 - Nuclear Med - Dimke, H., Hoenderop, J.G.J. & Bindels, R.J.M. (2010). Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+. Clinical Science, 118(1), IGMD 9 - Physiology, NCMLS 2B - Physiology - Dimke, H., Wijst, J. van der, Alexander, T.R., Meijer, I.M.J., Mulder, G.M., Goor, H. van, Tejpar, S., Hoenderop, J.G.J. & Bindels, R.J.M. (2010). Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling. Journal of the American Society of Nephrology, 21(8), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Doceul, V., Hollinshead, M., Linden, L. van de & Smith, G.L. (2010). Repulsion of superinfecting virions: a mechanism for rapid virus spread. Science, 327(5967), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Doef, H.P. van der, Kokke, F.T., Beek, F.J., Woestenenk, J.W., Froeling, S.P. & Houwen, R.H.J. (2010). Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. Journal of Cystic Fibrosis, 9(1), NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Wetensch. publ. refereed (artikel - letter to the editor) Dolff, S., Berden, J.H.M. & Bijl, M. van der (2010). Treatment of lupus nephritis. Expert Rev Clin Immunol, 6(6), N4i 4 - Nephrology, NCMLS 1A - Nephrology - Dolker, N., Zachariae, U. & Grubmuller, H. (2010). Hydrophilic linkers and polar contacts affect aggregation of FG repeat peptides. Biophys J, 98(11), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Dommerholt, J., Schmidt, S., Temming, R., Hendriks, L.J., Rutjes, F.P.J.T., Hest, J.C. van, Lefeber, D.J., Friedl, P.H.A. & Delft, F.L. van (2010). Readily accessible bicyclononynes for bioorthogonal labeling and three-dimensional imaging of living cells. Angewandte Chemie-International Edition, 49(49), DCN 3 - Neurology, IGMD 4 - Lab LGEM, NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol, RU SCI IMM SOC - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Dongen, S.F. van, Verdurmen, W.P.I., Peters, R.J., Nolte, R.J.M., Brock, R.E. & Hest, J.C.M. van (2010). Cellular integration of an enzyme-loaded polymersome nanoreactor. Angewandte Chemie-International Edition, 49(40), NCMLS 3B - Biochemistry, RU SCI IMM BOC, RU SCI IMM POC - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Douglas, T., Liu, Q., Humpe, A., Wiltfang, J., Sivananthan, S. & Warnke, P.H. (2010). Novel ceramic bone replacement material CeraBall seeded with human mesenchymal stem cells. Clinical Oral Implants Research, 21(3), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Durante, M., Pignalosa, D., Jansen, J.A., Walboomers, X.F. & Ritter, S. (2010). Influence of nuclear geometry on the formation of genetic rearrangements in human cells. Radiation Research, 174(1), NCMLS 1C - Dentistry - Ecker, D. van den, Brand, M.A.M. van den, Bossinger, O., Mayatepek, E., Nijtmans, L.G.J. & Distelmaier, F. (2010). Blue native electrophoresis to study mitochondrial complex I in C. elegans. Analytical Biochemistry, 407(2), IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics - Egorova-Zachernyuk, T.A., Bosman, G.J.C.G.M., Degrip, W.J. & Shvets, V.I. (2010). Stable isotope labelling of human histamine receptor H1R: prospects for structure-based drug design. Dokl Biochem Biophys, 433, NCMLS 3B - Biochemistry - Wetensch. publ. refereed (artikel - letter to the editor) Eissens, D.N., Meer, A. van der, Cranenbroek, B. van, Preijers, F.W.M.B. & Joosten, I. (2010). Rapamycin and MPA, but not CsA, impair human NK cell cytotoxicity due to differential effects on NK cell phenotype. American Journal of Transplantation, 10(9), N4i 4 - Lab LMI, NCMLS 1B - Lab LH, NCMLS 1B - Lab LMI, ONCOL 3 - Lab LH - Eissens, D.N., Schaap, N.P.M., Preijers, F.W.M.B., Dolstra, H., Cranenbroek, B. van, Schattenberg, A.V.M.B., Joosten, I. & Meer, A. van der (2010). CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A. Leukemia, 24(3), N4i 4 - Lab LMI, NCMLS 1B - Haematology, NCMLS 1B - Lab LH, NCMLS 1B - Lab LMI, ONCOL 3 - Haematology, ONCOL 3 - Lab LH - Ejima, K., Shoda, M., Yagishita, D., Yashiro, B., Sato, T., Manaka, T. & Hagiwara, N. (2010). Silent obstruction of SVC with collateral circulation after cardioverter defibrillator implantation. Intern Med, 49(8), NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Eleveld-Trancikova, D., Sanecka, A., Hout-Kuijer, M.A. van, Looman, M.W.G., Hendriks, I.A., Jansen, B.J.H. & Adema, G.J. (2010). DC-STAMP interacts with ER-resident transcription factor LUMAN which becomes activated during DC maturation. Molecular Immunology, 47(11-12), NCMLS 1B - Tumorimmunology - Annual Report 2010 Scientific publications

72 Emonts, M., Vermont, C.L., Houwing-Duistermaat, J.J., Haralambous, E., ast-de Jongh, C.E. Ga, Hazelzet, J.A., Faust, S.N., Betts, H., Hermans, P.W.M., Levin, M. & Groot, R. de (2010). Polymorphisms in PARP, IL1B, IL4, IL10, C1INH, DEFB1, and DEFA4 in meningococcal disease in three populations. Shock, 34(1), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor) Engel, C., Versmold, B., Wappenschmidt, B., Simard, J., Easton, D.F., Peock, S., Cook, M., Oliver, C., Frost, D., Mayes, R., Evans, D.G., Eeles, R., Paterson, J., Brewer, C., Tollenaar, R.A.E.M., Hoogerbrugge, N., Ligtenberg, M.J.L., Ausems, M.G.E.M. & et. al.,. (2010). Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiology Biomarkers & Prevention, 19(11), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Engelsman, A.F., Saldarriaga-Fernandez, I.C., Nejadnik, M.R., Dam, G.M. van, Francis, K.P., Ploeg, R.J., Busscher, H.J. & Mei, H.C. van der (2010). The risk of biomaterial-associated infection after revision surgery due to an experimental primary implant infection. Biofouling, 26(7), NCMLS 1C - Dentistry - Escande, C., Chini, C.C., Nin, V., Dykhouse, K.M., Novak, C.M., Levine, J., Deursen, J.M.A. van, Gores, G.J., Chen, J., Lou, Z. & Chini, E.N. (2010). Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice. Journal of Clinical Investigation, 120(2), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Ettwig, K.F., Butler, M.K., Paslier, D. Le, Pelletier, E., Mangenot, S., Kuypers, M.M.M., Schreiber, F., Dutilh, B.E., Zedelius, J., Beer, D. de, Gloerich, J., Wessels, H., Alen, T. van, Luesken, F., Wu, M.L., Pas-Schoonen, K.T. Van de, Camp, H. den, Janssen-Megens, E.M., Francoijs, K.J., Stunnenberg, H., Weissenbach, J., Jetten, M.S.M. & Strous, M. (2010). Nitrite-driven anaerobic methane oxidation by oxygenic bacteria. Nature, 464(7288), IGMD 8 - CMBI, NCMLS 2A - CMBI, RU SCI IWWR EMB, RU SCI NCMLS MB - Wetensch. publ. refereed (artikel - letter to the editor / Key publication RR) Evers, A.W.M., Kleinpenning, M.M., Smits, T., Boezeman, J., Kerkhof, P.C.M. van de, Kraaimaat, F.W. & Gerritsen, M.J.P. (2010). Treatment nonadherence and long-term effects of narrowband UV-B therapy in patients with psoriasis. Archives of Dermatology, 146(2), N4i 1 - Dermatology, N4i 1 - Med Psychology, NCEBP 8 - Med Psychol, NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Wetensch. publ. refereed (artikel - letter to the editor) Faas, B.H.W., Burgt, C.J.A.M. van der, Kooper, A.J.A., Pfundt, R., Hehir, J.Y., Smits, A.P.T. & Leeuw, N. de (2010). Identification of clinically significant, submicroscopic chromosome alterations and UPD in fetuses with ultrasound anomalies using genome-wide 250k SNP array analysis. Journal of Medical Genetics, 47(9), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Ferre, S., Baldoli, E., Leidi, M. & Maier, J.A. (2010). Magnesium deficiency promotes a pro-atherogenic phenotype in cultured human endothelial cells via activation of NFkB. Biochimica et Biophysica Acta, 1802(11), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Ferwerda, G., Netea, M.G., Joosten, L.A.B., Meer, J.W.M. van der, Romani, L. & Kullberg, B.J. (2010). The role of Toll-like receptors and C-type lectins for vaccination against Candida albicans. Vaccine, 28(3), N4i 1 - Paediatrics, N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med, NCMLS 1A - Paediatrics - Figdor, C.G. & Spriel, A.B. van (2010). Fungal pattern-recognition receptors and tetraspanins: partners on antigen-presenting cells. Trends in Immunology, 31(3), NCMLS 1B - Tumorimmunology - Fischer, R., Hufnagel, H. & Brock, R. (2010). A doubly labeled penetratin analogue as a ratiometric sensor for intracellular proteolytic stability. Bioconjugate Chemistry, 21(1), NCMLS 3B - Biochemistry - Fitzgerald, R.C., Hardwick, R., Huntsman, D., Carneiro, F., Guilford, P., Blair, V., Chung, D.C., Norton, J., Ragunath, K., Krieken, J.H.J.M. van, Dwerryhouse, S. & Caldas, C. (2010). Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. Journal of Medical Genetics, 47(7), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 3 - Pathology - Forkink, M., Smeitink, J.A.M., Brock, R., Willems, P.H.G.M. & Koopman, W.J.H. (2010). Detection and manipulation of mitochondrial reactive oxygen species in mammalian cells. Biochimica et Biophysica Acta, 1797(6-7), IGMD 8 - Cell Biol, IGMD 8 - Paediatrics, NCMLS 2A - Biochemistry, NCMLS 2A - Cell Biology, NCMLS 3B - Biochemistry - Franke, B., Vasquez, A.A., Veltman, J.A., Brunner, H.G., Rijpkema, M.J.P. & Fernandez, G.S.E. (2010). Genetic variation in CACNA1C, a gene associated with bipolar disorder, influences brainstem rather than gray matter volume in healthy individuals. Biological Psychiatry, 68(6), DCN 1 - CNS, DCN 2 - CNS, DCN 2 - Hum Gen, DCN 2 - Psychiatry, IGMD 3 - Hum Gen, IGMD 3 - Psychiatry, NCMLS 3A - Hum Gen, RU FCDC 130 CN&M, RU FCDC 130 CN&M Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Franken, J.M., Hupkens, P. & Spauwen, P.H.M. (2010). The treatment of soft-tissue defects of the lower leg after a traumatic open tibial fracture. European Journal of Plastic Surgery, 33(3), NCMLS 1C - Plastic Surgery - Fransen, J.H., Vlag, J. van der, Ruben, J., Adema, G.J., Berden, J.H.M. & Hilbrands, L.B. (2010). The role of dendritic cells in the pathogenesis of systemic lupus erythematosus. Arthritis Research & Therapy, 12(2), N4i 4 - Nephrology, NCMLS 1B - Tumorimmunology, NCMLS 1C - Nephrology - Frencken, J.E.F.M. & Wolke, J.G.C. (2010). Clinical and SEM assessment of ART high-viscosity glass-ionomer sealants after 8-13 years in 4 teeth. Journal of Dentistry, 38(1), NCEBP 7 - Dentistry, NCMLS 1C - Dentistry - Friedl, P. & Zallen, J.A. (2010). Dynamics of cell-cell and cell-matrix interactions in morphogenesis, regeneration and cancer. Current Opinion in Cell Biology, 22(5), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Friedl, P.H.A. & Wolf, K. van der (2010). Plasticity of cell migration: a multiscale tuning model. Journal of Cell Biology, 188(1), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Friedl, P.H.A. (2010). To adhere or not to adhere? Nature Reviews Molecular Cell Biology, 11(1), 3. - NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Frijters, R., Fleuren, W., Toonen, E.J.M., Tuckermann, J.P., Reichardt, H.M., Maaden, H. van der, Elsas, A. van, Lierop, M.J.C. van, Dokter, W., Vlieg, J. de & Alkema, W. (2010). Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor. BMC Genomics, 11, NCMLS 3B - CMBI - Frijters, R., Vugt, M. De, Smeets, R., Schaik, R. van, Vlieg, J. de & Alkema, W. (2010). Literature mining for the discovery of hidden connections between drugs, genes and diseases. PLoS Computational Biology, 6(9). - NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Froehlich, M., Deen, P.M.T. & Klipp, E. (2010). A system biology approach: modeling of Aquaporin-2 trafficking. WSPC Proceedings. Genome Information, 24, IGMD 9 - Physiology, NCMLS 2B - Physiology - Galama, J.M.D. (2010). Epidemieën zijn moeilijk beheersbaar. Bijblijven, 7, N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Galama, J.M.D. (2010). Virus en evolutie. Nederlands Tijdschrift voor Geneeskunde, N4i 1 NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) 72 Scientific publications 2010 NCMLS

73 Galama, J.M.D., Bruisten, S.M., Vossen, A.C., Schuurman, R., Brandenburgh, A.H., Thjie, H.T. & Kaan, J.A. (2010). Is het tijdperk van de virologische weefselkweektechniek ten einde? Nederlands Tijdschrift voor Medische Microbiologie, 18, N4i 1 NCMLS 1A - Med Microbiol - Galen, J.C. van, Kuiper, R.P., Emst, J.E. van, Levers, M., Tijchon, E., Scheijen, B., Waanders, E., Reijmersdal, S.V. van, Gilissen, C., Geurts van Kessel, A.H.M., Hoogerbrugge, P.M. & Leeuwen, F.N. van (2010). BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia. Blood, 115(23), NCMLS 1B - Lab LGEM, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 3 - Hum Gen, ONCOL 3 - Lab LGEM, ONCOL 3 - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Garthoff, J.A., Heemskerk, S., Hempenius, R.A., Lina, B.A., Krul, C.A., Koeman, J.H. & Speijers, G.J. (2010). Safety evaluation of pectin-derived acidic oligosaccharides (paos): genotoxicity and sub-chronic studies. Regul Toxicol Pharmacol, 57(1), NCMLS 2B - Pharm Tox - Gartlan, K.H., Belz, G.T., Tarrant, J.M., Minigo, G., Katsara, M., Sheng, K.C., Sofi, M., Spriel, A.B. van, Apostolopoulos, V., Plebanski, M., Robb, L. & Wright, M.D. (2010). A complementary role for the tetraspanins CD37 and Tssc6 in cellular immunity. Journal of Immunology, 185(6), NCMLS 1B - Tumorimmunology - Gassling, V., Douglas, T., Warnke, P.H., Acil, Y., Wiltfang, J. & Becker, S.T. (2010). Platelet-rich fibrin membranes as scaffolds for periosteal tissue engineering. Clinical Oral Implants Research, 21(5), NCMLS 1C - Dentistry - Gaudet, M.M., Kirchhoff, T., Green, T., Vijai, J., Korn, J.M., Guiducci, C., Segre, A., McGee, K., McGuffog, L., Kartsonaki, C., Morrison, J., Healey, S., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Gauthier-Villars, M., Sobol, H., Longy, M., Frenay, I.H., Hogervorst, F.B.L., Rookus, M.A., Collee, J.M., Hoogerbrugge, N., Roozendaal, C.E.P. van, Ligtenberg, M.J.L. & et. al.,. (2010). Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genetics, 6(10), e e NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology - Genton, B., D Acremont, V., Lurati-Ruiz, F., Verhage, D., Audran, R., Hermsen, C., Wolters, L., Reymond, C., Spertini, F. & Sauerwein, R.W. (2010). Randomized double-blind controlled Phase I/IIa trial to assess the efficacy of malaria vaccine PfCS102 to protect against challenge with P. falciparum. Vaccine, 28(40), N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Gerkes, E.H., Kevie-Kersemaekers, A.M. van der, Yakin, M., Smeets, D.F.C.M. & Ravenswaaij-Arts, C.M.A. van (2010). The importance of chromosome studies in Roberts syndrome/sc phocomelia and other cohesinopathies. European Journal of Medical Genetics, 53(1), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Gerlach, N.L., Meijer, G.J., Maal, T.J.J., Mulder, J., Rangel, F.A., Borstlap, W.A. & Berge, S.J. (2010). Reproducibility of 3 different tracing methods based on cone beam computed tomography in determining the anatomical position of the mandibular canal. Journal of Oral and Maxillofacial Surgery, 68(4), NCEBP 2 - Dentistry, NCEBP 2 - Oral Maxillo, NCEBP 7 - Primary Health, NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Geurts van Kessel, A.H.M. (2010). The omics of cancer. Cancer Genetics and Cytogenetics, 203(1), NCMLS 3A - Hum Gen, ONCOL 3 - Hum Gen - Geutjes, P.J., Nillesen, S.T.M., Lammers, G., Daamen, W.F. & Kuppevelt, A.H.M.S.M. van (2010). Cloning, large-scale production, and purification of active dimeric rat vascular endothelial growth factor (rrvegf-164). Protein Expr Purif, 69(1), NCMLS 1C - Biochemistry - Wetensch. publ. refereed (artikel - letter to the editor) Geutjes, P.J., Vliet, J.A. van der, Faraj, K.A., Vries, N. de, Moerkerk, H.T.B. van, Wismans, R.G., Hendriks, T., Daamen, W.F. & Kuppevelt, A.H.M.S.M. van (2010). An animal model for femoral artery pseudoaneurysms. Journal of Vascular and Interventional Radiology, 21(7), NCMLS 1C - Biochemistry, NCMLS 1C - Surgery - Geutjes, P.J., Vliet, J.A. van der, Faraj, K.A., Vries, N. de, Moerkerk, H.T.B. van, Wismans, R.G., Hendriks, T., Daamen, W.F. & Kuppevelt, A.H.M.S.M. van (2010). Preparation and characterization of injectable fibrillar type I collagen and evaluation for pseudoaneurysm treatment in a pig model. Journal of Vascular Surgery, 52(5), NCMLS 1C - Biochemistry, NCMLS 1C - Surgery - Wetensch. publ. refereed (artikel - letter to the editor) Giannandrea, M., Bianchi, V., Mignogna, M.L., Sirri, A., Carrabino, S., D Elia, E., Vecellio, M., Russo, S., Cogliati, F., Larizza, L., Ropers, H.H., Tzschach, A., Kalscheuer, V., Oehl-Jaschkowitz, B., Skinner, C., Schwartz, C.E., Gecz, J., Esch, H. van, Raynaud, M., Chelly, J., Brouwer, A.P.M. de, Toniolo, D. & D Adamo, P. (2010). Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. American Journal of Human Genetics, 86(2), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Gilissen, C., Arts, H.H., Hoischen, A., Spruijt, L., Mans, D.A., Arts, P., Lier, B. van, Steehouwer, M., Reeuwijk, J. van, Kant, S.G., Roepman, R., Knoers, N.V.A.M., Veltman, J.A. & Brunner, H.G. (2010). Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. American Journal of Human Genetics, 87(3), IGMD 3 - Hum Gen, IGMD 9 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Gkioni, K., Leeuwenburgh, S.C.G., Douglas, T.E.L., Mikos, A.G. & Jansen, J.A. (2010). Mineralization of hydrogels for bone regeneration. Tissue Engineering Part B Reviews, 16(6), NCMLS 1C - Dentistry - Glasson, S.S., Chambers, M.G., Berg, W.B. van den & Little, C.B. (2010). The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis & Cartilage, 18 Suppl 3, S N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Glaudemans, B., Knoers, N.V.A.M., Hoenderop, J.G.J. & Bindels, R.J.M. (2010). New molecular players facilitating Mg(2+) reabsorption in the distal convoluted tubule. Kidney International, 77(1), IGMD 9 - Hum Gen, IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Glauner, H., Ruttekolk, I.R.R., Hansen, K., Steemers, B., Chung, Y.D., Becker, F., Hannus, S. & Brock, R. (2010). Simultaneous detection of intracellular target and off-target binding of small molecule cancer drugs at nanomolar concentrations. British Journal of Pharmacology, 160(4), NCMLS 3B - Biochemistry - Glind, G.J. van de, Gidding, C.E.M., Verlaat, C.M., Duthoi, K., Backx, A.P.C.M., Verweij, P.E. & Warris, A. (2010). Acute Cardiac Failure due to Intra-Atrial Mass Caused by Zygomycetes in an Immunocompromised Paediatric Patient. Case reports in medicine, 2010, N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol, ONCOL 4 - Paediatrics - Goh, B.T., Lee, S., Tideman, H., Jansen, J.A. & Stoelinga, P.J.W. (2010). Replacement of the condyle and ascending ramus by a modular endoprosthesis in Macaca fascicularis part 4: evaluation of the temporomandibular joints. Journal of Oral and Maxillofacial Surgery, 68(9), NCMLS 1C - Dentistry, ONCOL 3 - Oral Maxillo - Goh, B.T., Lee, S., Tideman, H., Stoelinga, P.J.W. & Jansen, J.A. (2010). Replacement of the condyle and ascending ramus by a modular endoprosthesis in Macaca fascicularis part 3: evaluation of peri-implant bone remodeling. Journal of Oral and Maxillofacial Surgery, 68(8), NCMLS 1C - Dentistry, ONCOL 3 - Oral Maxillo - Annual Report 2010 Scientific publications

74 Gorin, N.C., Labopin, M., Reiffers, J., Milpied, N., Blaise, D., Witz, F., Witte, T.J.M. de, Meloni, G., Attal, M., Bernal, T. & Rocha, V. (2010). Higher incidence of relapse in patients with acute myelocytic leukemia infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission. Blood, 116(17), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Gorska, K., Beyrath, J., Fournel, S., Guichard, G. & Winssinger, N. (2010). Ligand dimerization programmed by hybridization to study multimeric ligand-receptor interactions. Chemical Communications, 46(41), IGMD 8 - Pharm Tox, NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Gourh, P., Agarwal, S.K., Martin, E., Divecha, D., Rueda, B., Bunting, H., Assassi, S., Paz, G., Shete, S., McNearney, T., Draeger, H., Reveille, J.D., Radstake, T.R.D.J., Simeon, C.P., Rodriguez, L., Vicente, E., Gonzalez-Gay, M.A., Mayes, M.D., Tan, F.K., Martin, J. & Arnett, F.C. (2010). Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations. Journal of Autoimmunity, 34(2), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Graaf, M. van der, Tack, C.J.J., Haan, J.H.A. de, Klomp, D.W.J. & Heerschap, A. (2010). Magnetic resonance spectroscopy shows an inverse correlation between intramyocellular lipid content in human calf muscle and local glycogen synthesis rate. NMR in Biomedicine, 23(2), IGMD 1 - Paediatrics, IGMD 5 - Radiology, NCEBP 6 - Gen Int Med, NCMLS 2A - Radiology - Grefte, S., Kuijpers-Jagtman, A.M., Torensma, R. & den Hoff, J.W. Von (2010). Model for muscle regeneration around fibrotic lesions in recurrent strain injuries. Medicine and Science in Sports and Exercise, 42(4), NCMLS 1C - Dentistry, NCMLS 1C - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Grefte, S., Kuijpers-Jagtman, A.M., Torensma, R. & den Hoff, J.W. Von (2010). Skeletal muscle fibrosis: the effect of stromal-derived factor- 1α-loaded collagen scaffolds. Regenerative Medicine, 5(5), NCMLS 1C - Dentistry, NCMLS 1C - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Groot, T. de, Verkaart, S., Xi, Q., Bindels, R.J.M. & Hoenderop, J.G.J. (2010). The identification of Histidine 712 as a critical residue for constitutive TRPV5 internalization. Journal of Biological Chemistry, 285(37), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Gross, G., Snel, J., Boekhorst, J., Smits, M.P. & Kleerebezen, M. (2010). Biodiversity of mannose-specific adhesion in Lactobacillus plantarum revisted: strain-specific domain composition of the mannose-adhesion. Beneficial Microbes, 1(1), NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Guo, X., Park, H., Young, S., Kretlow, J.D., Beucken, J.J.J.P van den, Baggett, L.S., Tabata, Y., Kasper, F.K., Mikos, A.G. & Jansen, J.A. (2010). Repair of osteochondral defects with biodegradable hydrogel composites encapsulating marrow mesenchymal stem cells in a rabbit model. Acta Biomaterialia, 6(1), NCMLS 1C - Dentistry - Habraken, W.J.E.M., Liao, H.B., Zhang, Z., Wolke, J.G.C., Grijpma, D.W., Mikos, A.G., Feijen, J. & Jansen, J.A. (2010). In vivo degradation of calcium phosphate cement incorporated into biodegradable microspheres. Acta Biomaterialia, 6(6), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Hackanson, B., Abdelkarim, M., Jansen, J.H. & Lubbert, M. (2010). NHR4 domain mutations of ETO are probably very infrequent in AML1-ETO positive myeloid leukemia cells. Leukemia, 24(4), NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Wetensch. publ. refereed (artikel - letter to the editor) Hangalapura, B.N., Oosterhoff, D., Aggarwal, S., Wijnands, P.G.J.T.B., Ven, R. Van de, Santegoets, S.J., Tol, M.P. van den, Hooijberg, E., Pereboev, A., Eertwegh, A.J. van den, Curiel, D.T., Scheper, R.J. & Gruijl, T.D. de (2010). Selective transduction of dendritic cells in human lymph nodes and superior induction of high-avidity melanoma-reactive cytotoxic T cells by a CD40-targeted adenovirus. Journal of Immunotherapy, 33(7), NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Haren, F.M.P. van, Pickkers, P., Foudraine, N., Heemskerk, S., Sleigh, J. & Hoeven, J.G. van der (2010). The effects of methylene blue infusion on gastric tonometry and intestinal fatty acid binding protein levels in septic shock patients. Journal of Critical Care, 25(2), 358.e N4i 1 - Intensive Care, NCEBP 14 - Pharm Tox, NCMLS 2B - Pharm Tox - Hato, S.V., Sorgeloos, F., Ricour, C., Zoll, J., Melchers, W.J.G., Michiels, T. & Kuppeveld, F.J.M. van (2010). Differential IFN-alpha/beta production suppressing capacities of the leader proteins of mengovirus and foot-and-mouth disease virus. Cellular Microbiology, 12(3), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol, NCMLS 1B - Tumorimmunology - Heemskerk, S., Peters, J.G.P., Louisse, J., Sagar, S., Russel, F.G.M. & Masereeuw, R. (2010). Regulation of P-glycoprotein in renal proximal tubule epithelial cells by LPS and TNF-alpha. J Biomed Biotechnol, 2010, IGMD 9 - Pharm Tox, NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Hegmans, J.P., Veltman, J.D., Lambers, M.E., Vries, I.J.M. de, Figdor, C.G., Hendriks, R.W., Hoogsteden, H.C., Lambrecht, B.N. & Aerts, J.G. (2010). Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. American Journal of Respiratory and Critical Care Medicine, 181(12), NCMLS 1B - Tumorimmunology, ONCOL 3 - Med Oncol, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Hehir, J.Y., Wieskamp, N., Webber, C., Pfundt, R., Brunner, H.G., Gilissen, C., Vries, B.B. de, Ponting, C.P. & Veltman, J.A. (2010). Accurate distinction of pathogenic from benign CNVs in mental retardation. PLoS Computational Biology, 6(4), e IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Heide, H.J. van der, Kraan, P.M. van der, Rijnberg, W.J., Buma, P. & Schreurs, B.W. (2010). Elevated levels of numerous cytokines in drainage fluid after primary total hip arthroplasty. International Orthopaedics, 34(8), N4i 1 - Rheumatology, NCMLS 1C - Rheumatology - Heidt, S., Roelen, D.L., Eijsink, C., Eikmans, M., Kooten, C. van, Claas, F.H. & Mulder, A. (2010). Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clinical and Experimental Immunology, 159(2), N4i 4 - Lab LMI, NCMLS 1B - Lab LMI - Heinhuis, B., Koenders, M.M.J.F., Loo, F.A.J. van de, Lent, P.L.E.M. van, Kim, S.H., Dinarello, C.A., Joosten, L.A.B. & Berg, W.B. van den (2010). IL-32gamma and Streptococcus pyogenes cell wall fragments synergise for IL-1-dependent destructive arthritis via upregulation of TLR-2 and NOD2. Annals of the Rheumatic Diseases, 69(10), N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Gen Int Med, NCMLS 1A - Rheumatology - Hekkelman, M.L., Beek, T.A.H. te, Pettifer, S.R., Thorne, D., Attwood, T.K. & Vriend, G. (2010). WIWS: a protein structure bioinformatics Web service collection. Nucleic Acids Research, 38(Web Server issue), W NCMLS 3A - CMBI, NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Helden, S.F.G. van, Dries, K. van den, Oud, M.M., Raymakers, R.A.P., Netea, M.G., Leeuwen, F.N. van & Figdor, C.G. (2010). TLR4-mediated podosome loss discriminates gram-negative from gram-positive bacteria in their capacity to induce dendritic cell migration and maturation. Journal of Immunology, 184(3), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med, NCMLS 1B - Hum Gen, NCMLS 1B - Lab LGEM, NCMLS 1B - Tumorimmunology, ONCOL 3 - Lab LGEM, ONCOL 3 - Paediatrics - 74 Scientific publications 2010 NCMLS

75 Helfer, B.M., Balducci, A., Nelson, A.D., Janjic, J.M., Gil, R.R., Kalinski, P., Vries, I.J.M. de, Ahrens, E.T. & Mailliard, R.B. (2010). Functional assessment of human dendritic cells labeled for in vivo (19)F magnetic resonance imaging cell tracking. Cytotherapy, 12(2), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Hendriks, T., Bleichrodt, R.P., Lomme, R.M.L.M., Man, B.M. de, Goor, H. van & Buyne, O.R. (2010). Peritoneal cytokines predict mortality after surgical treatment of secondary peritonitis in the rat. Journal of the American College of Surgeons, 211(2), NCMLS 1C - Surgery - Henneke, M., Dreha-Kulaczewski, S., Brockmann, K., Graaf, M. van der, Willemsen, M.H., Engelke, U., Dechent, P., Heerschap, A., Helms, G., Wevers, R.A. & Gartner, J. (2010). In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiency. NMR in Biomedicine, 23(5), DCN 2 - Lab LGEM, DCN 3 - Neurology, IGMD 1 - Paediatrics, IGMD 3 - Lab LGEM, IGMD 3 - Radiology, NCMLS 2A - Radiology - Herda, L.R., Trimpert, C., Nauke, U., Landsberger, M., Hummel, A., Beug, D., Kieback, A., Dorr, M., Empen, K., Knebel, F., Ewert, R., Angelow, A., Hoffmann, W., Felix, S.B. & Staudt, A. (2010). Effects of immunoadsorption and subsequent immunoglobulin G substitution on cardiopulmonary exercise capacity in patients with dilated cardiomyopathy. American Heart Journal, 159(5), IGMD 9 - Physiology, NCMLS 2B - Physiology - Heskamp, S., Laarhoven, H.W.M. van, Molkenboer-Kuenen, J.D.M., Franssen, G.M., Versleijen-Jonkers, Y.M.H., Oyen, W.J., Graaf, W.T.A. van der & Boerman, O.C. (2010). ImmunoSPECT and immunopet of IGF-1R expression with the radiolabeled antibody R1507 in a triple-negative breast cancer model. Journal of Nuclear Medicine, 51(10), NCMLS 1B - Nuclear Med, ONCOL 3 - Nuclear Med, ONCOL 5 - Med Oncol - Hess, R., Douglas, T., Myers, K.A., Rentsch, B., Rentsch, C., Worch, H., Shrive, N.G., Hart, D.A. & Scharnweber, D. (2010). Hydrostatic pressure stimulation of human mesenchymal stem cells seeded on collagen-based artificial extracellular matrices. Journal of Biomechanical Engineering- Transactions of the ASME, 132(2), NCMLS 1C - Dentistry - Hessels, D., Gils, M.P.M.Q., Hooij, O. van, Jannink, S.A., Witjes, J.A., Verhaegh, G.W.C.T. & Schalken, J.A. (2010). Predictive value of PCA3 in urinary sediments in determining clinico-pathological characteristics of prostate cancer. Prostate, 70(1), NCEBP 1 - Urology, NCMLS 3A - Urology, ONCOL 3 - Urology, ONCOL 5 - Urology - Hijikata, A., Raju, R., Keerthikumar, S., Ramabadran, S., Balakrishnan, L., Ramadoss, S.K., Pandey, A., Mohan, S. & Ohara, O. (2010). Mutation@A Glance: an integrative web application for analysing mutations from human genetic diseases. DNA Research, 17(3), IGMD 8 - CMBI, NCMLS 2A - CMBI - Hildebrand, M.S., Gandolfo, L., Shearer, A.E., Webster, J.A., Jensen, M., Kimberling, W.J., Stephan, D., Huygen, P.L.M., Smith, R.J. & Bahlo, M. (2010). A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss. Laryngoscope, 120(12), DCN 2 - Otorhinolaryn, NCMLS 3A - Otorhinolaryn - Hildebrand, M.S., Kahrizi, K., Bromhead, C.J., Shearer, A.E., Webster, J.A., Khodaei, H., Abtahi, R., Bazazzadegan, N., Babanejad, M., Nikzat, N., Kimberling, W.J., Stephan, D., Huygen, P.L.M., Bahlo, M., Smith, R.J. & Najmabadi, H. (2010). Mutations in TMC1 are a common cause of DFNB7/11 hearing loss in the Iranian population. Annals of Otology Rhinology and Laryngology, 119(12), DCN 2 - Otorhinolaryn, NCMLS 3A - Otorhinolaryn - Hira, V., Sluijter, M., Goessens, W.H.F., Ott, A., Groot, R. de, Hermans, P.W.M. & Kornelisse, R.F. (2010). Coagulase-negative staphylococcal skin carriage among neonatal intensive care unit personnel: from population to infection. Journal of Clinical Microbiology, 48(11), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Hobo, W., Maas, F., Adisty, N., Witte, T.J.M. de, Schaap, N.P.M., Voort, R. & Dolstra, H. (2010). sirna silencing of PD-L1 and PD-L2 on dendritic cells augments expansion and function of minor histocompatibility antigen-specific CD8+ T cells. Blood, 116(22), NCMLS 1B - Haematology, NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Hoefs, S.J.G., Skjeldal, O.H., Rodenburg, R.J.T., Nedregaard, B., Kaauwen, E.P. van, Spiekerkotter, U., Kleist-Retzow, J.C. von, Smeitink, J.A.M., Nijtmans, L.G.J. & Heuvel, L.P.W.J. van den (2010). Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. Molecular Genetics and Metabolism, 100(3), IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, IGMD 9 - Paediatrics, NCMLS 2A - Lab LGEM - Hoff, A., Bagu, A.C., Andre, T., Roth, G., Wiesmuller, K.H., Guckel, B. & Brock, R. (2010). Peptide microarrays for the profiling of cytotoxic T-lymphocyte activity using minimum numbers of cells. Cancer Immunology Immunotherapy, 59(9), NCMLS 3B - Biochemistry - Hogewind, B.F.T., Mukhopadhyay, A., Theelen, T., Hollander, A.I. den & Hoyng, C.B. (2010). Variable clinical spectrum of the myocilin Gln368X mutation in a Dutch family with primary open angle glaucoma. Current Eye Research, 35(1), IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCEBP 2 - Human Genetics, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor) Hogewind, B.F.T., Pennings, R.J.E., Hol, F.A., Kunst, H.P.M., Hoefsloot, E.H., Cruysberg, J.R.M. & Cremers, C.W.R.J. (2010). Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1. Molecular Vision, 16, DCN 2 - Otorhinolaryn, IGMD 3 - Hum Gen, NCEBP 2 - Opthalmology, NCMLS 3A - Otorhinolaryn - Hoischen, A., Bon, B.W.M. van, Gilissen, C., Arts, P., Lier, B. van, Steehouwer, M., Vries, P. de, Reuver, R. de, Wieskamp, N., Mortier, G., Devriendt, K., Amorim, M.Z., Revencu, N., Kidd, A., Barbosa, M., Turner, A., Smith, J., Oley, C., Henderson, A., Hayes, I.M., Thompson, E.M., Brunner, H.G., Vries, B.B. de & Veltman, J.A. (2010). De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nature Genetics, 42(6), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Hoischen, A., Gilissen, C., Arts, P., Wieskamp, N., Vliet, W. van der, Vermeer, S., Steehouwer, M., Vries, P. de, Meijer, R., Seiqueros, J., Knoers, N.V.A.M., Buckley, M.F., Scheffer, H. & Veltman, J.A. (2010). Massively parallel sequencing of ataxia genes after array-based enrichment. Human Mutation, 31(4), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Hollander, A.I. den, Biyanwila, J., Kovach, P., Bardakjian, T., Traboulsi, E.I., Ragge, N.K., Schneider, A. & Malicki, J. (2010). Genetic defects of GDF6 in the zebrafish out of sight mutant and in human eye developmental anomalies. BMC Genet, 11, IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Hollander, A.I. den, Black, A., Bennett, J. & Cremers, F.P.M. (2010). Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies. Journal of Clinical Investigation, 120(9), IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Holle, N., Witte, T.J.M. de, Mandigers, C., Schaap, N. & Raymakers, R. (2010). Thalidomide and lenalidomide in primary myelofibrosis. Netherlands Journal of Medicine, 68(1), NCMLS 1B - Haematology, NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Tumorimmunology - Annual Report 2010 Scientific publications

76 Hoogen, M.W.F. van den & Hilbrands, L.B. (2010). Single-dose rituximab as induction in renal transplantation. Transplantation, 89(10), 1295; author reply N4i 4 - Nephrology, NCMLS 1B - Nephrology - Hosper, N.A., Eggink, A.J., Roelofs, L.A.J., Wijnen, R.M.H., Luyn, M.J.A. van, Bank, RA, Harmsen, M.C., Geutjes, P.J., Daamen, W.F., Kuppevelt, A.H.M.S.M. van, Tiemessen, D.M., Oosterwijk, E., Crevels, J.J., Blokx, W.A.M., Lotgering, F.K., Berg, P.P. van den & Feitz, W.F.J. (2010). Intra-uterine tissue engineering of full-thickness skin defects in a fetal sheep model. Biomaterials, 31(14), NCMLS 1C - Biochemistry, NCMLS 1C - Surgery, NCMLS 1C - Urology, ONCOL 3 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Hossain, M.M., Hosono-Fukao, T., Tang, R., Sugaya, N., Kuppevelt, A.H.M.S.M. van, Jenniskens, G.J., Kimata, K., Rosen, S.D. & Uchimura, K. (2010). Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88. Glycobiology, 20(2), NCMLS 1C - Biochemistry - Hosta-Rigau, L., Olmedo, I., Arbiol, J., Cruz, L.J., Kogan, M.J. & Albericio, F. (2010). Multifunctionalized gold nanoparticles with peptides targeted to gastrin-releasing peptide receptor of a tumor cell line. Bioconjugate Chemistry, 21(6), NCMLS 1B - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Houbraken, J., Verweij, P.E., Rijs, A.J.M.M., Borman, A.M. & Samson, R.A. (2010). Identification of Paecilomyces variotii in clinical samples and settings. Journal of Clinical Microbiology, 48(8), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Houweling, A.C., Mooij, Y.M. de, Burgt, C.J.A.M. van der, Yntema, H.G., Lachmeijer, A.M. & Go, A.T. (2010). Prenatal detection of Noonan syndrome by mutation analysis of the PTPN11 and the KRAS genes. Prenatal Diagnosis, 30(3), NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Hsu, N.Y., Ilnytska, O., Belov, G., Santiana, M., Chen, Y.H., Takvorian, P.M., Pau, C., Schaar, H. van der, Kaushik-Basu, N., Balla, T., Cameron, C.E., Ehrenfeld, E., Kuppeveld, F.J.M. van & Altan-Bonnet, N. (2010). Viral reorganization of the secretory pathway generates distinct organelles for RNA replication. Cell, 141(5), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Hsu, Y.J., Dimke, H., Hoenderop, J.G.J. & Bindels, R.J.M. (2010). Calcitonin-stimulated renal Ca2+ reabsorption occurs independently of TRPV5. Nephrology Dialysis Transplantation, 25(5), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Hsu, Y.J., Dimke, H., Schoeber, J.P.H., Hsu, S.C., Lin, S.H., Chu, P., Hoenderop, J.G.J. & Bindels, R.J.M. (2010). Testosterone increases urinary calcium excretion and inhibits expression of renal calcium transport proteins. Kidney International, 77(7), IGMD 9 - Pharm Tox, IGMD 9 - Physiology, NCMLS 2B - Pharm Tox, NCMLS 2B - Physiology - Huberts, D.H., Venselaar, H., Vriend, G., Veenhuis, M. & Klei, I.J. van der (2010). The moonlighting function of pyruvate carboxylase resides in the non-catalytic end of the TIM barrel. Biochimica et Biophysica Acta, 1803(9), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Huffmeier, U., Bergboer, J.G.M., Becker, T., Armour, J.A., Traupe, H., Estivill, X., Riveira-Munoz, E., Mossner, R., Reich, K., Kurrat, W., Wienker, T.F., Schalkwijk, J., Zeeuwen, P.L.J.M. & Reis, A. (2010). Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. Journal of Investigative Dermatology, 130(4), N4i 1 - Dermatology, NCMLS 1A - Dermatology - Wetensch. publ. refereed (artikel - letter to the editor) Huls, M., Schoeber, J.P.H., Verfaillie, C.M., Luttun, A., Ulloa-Montoya, F., Menke, A.L., Bolderen, L.R. van, Woestenenk, R.M., Merkx, G.F.M., Wetzels, J.F.M., Russel, F.G.M. & Masereeuw, R. (2010). Deficiency of either P-glycoprotein or breast cancer resistance protein protect against acute kidney injury. Cell Transplantation, 19(9), IGMD 3 - Hum Gen, IGMD 9 - Nephrology, IGMD 9 - Pharm Tox, NCMLS 1B - Lab LH, NCMLS 2B - Pharm Tox, ONCOL 3 - Lab LH - Hupkens, P., Loon, B. van, Lauret, G.J., Kooloos, J.G.M., Vehof, J.W., Hartman, E.H.M. & Spauwen, P.H.M. (2010). Anteromedial thigh flaps: an anatomical study to localize and classify anteromedial thigh perforators. Microsurgery, 30(1), DCN 2 NCEBP 3 - Anatomy, NCMLS 1C - Plastic Surgery - Hussain, S., Foreman, O., Perkins, S.L., Witzig, T.E., Miles, R.R., Deursen, J.M.A. van & Galardy, P.J. (2010). The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling. Leukemia, 24(9), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Huurne, M. ter, Figdor, C.G. & Torensma, R. (2010). Hematopoietic stem cells are coordinated by the molecular cues of the endosteal niche. Stem Cells and Development, 19(8), NCMLS 1C - Tumorimmunology - Ippagunta, S.K., Brand, D.D., Luo, J., Boyd, K.L., Calabrese, C., Stienstra, R., Veerdonk, F.L. van de, Netea, M.G., Joosten, L.A.B., Lamkanfi, M. & Kanneganti, T.D. (2010). Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis. Journal of Biological Chemistry, 285(16), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Ippel, J.H., Koutsopoulos, S., Nabuurs, S.M., Berkel, W.J. van, Oost, J. van der & Mierlo, C.P. van (2010). NMR characterization of a 264-residue hyperthermostable endo-beta-1,3-glucanase. Biochemical and Biophysical Research Communications, 391(1), IGMD 9 - Physiology, NCMLS 2B - Physiology - Iqbal, Z., Cejudo-Martin, P., Brouwer, A., Zwaag, B. van der, Ruiz-Lozano, P., Scimia, M.C., Lindsey, J.D., Weinreb, R., Albrecht, B., Megarbane, A., Alanay, Y., Ben-Neriah, Z., Amenduni, M., Artuso, R., Veltman, J.A., Beusekom, E. van, Oudakker, A., Millan, J.L., Hennekam, R., Hamel, B., Courtneidge, S.A. & Bokhoven, J.H.L.M. van (2010). Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome. American Journal of Human Genetics, 86(2), DCN 2 - CNS, DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Jacobs, J.F.M., Idema, A.J.S., Bol, K.F., Grotenhuis, J.A., Vries, I.J.M. de, Wesseling, P. & Adema, G.J. (2010). Prognostic significance and mechanism of Treg infiltration in human brain tumors. Journal of Neuroimmunology, 225(1-2), DCN 1 - Neurosurgery, DCN 3 - Neurology, N4i 4 - Lab LMI, NCMLS 1B - Lab LMI, NCMLS 1B - Med Oncol, NCMLS 1B - Tumorimmunology, ONCOL 3 - Neurosurgery, ONCOL 3 - Pathology, ONCOL 3 - Tumorimmunology - Jacobs, J.F.M., Joosten, I. & Klasen, I.S. (2010). Detecting only light chains, now what? Clinical Chemistry, 56(8), N4i 4 - Lab LMI, NCMLS 1B - Lab LMI, NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Jacobs, J.F.M., Punt, C.J.A., Lesterhuis, W.J., Sutmuller, R.P.M., Brouwer, H.M., Scharenborg, N.M., Klasen, I.S., Hilbrands, L.B., Figdor, C.G., Vries, I.J.M. de & Adema, G.J. (2010). Dendritic cell vaccination in combination with anti-cd25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clinical Cancer Research, 16(20), N4i 4 - Lab LMI, N4i 4 - Nephrology, NCMLS 1B - Lab LMI, NCMLS 1B - Nephrology, NCMLS 1B - Tumorimmunology, ONCOL 3 - Med Oncol, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) 76 Scientific publications 2010 NCMLS

77 Janse, F., Knauff, E.A., Niermeijer, M.F., Eijkemans, M.J., Laven, J.S.E., Lambalk, C.B., Fauser, B.C.J.M. & Goverde, A.J. (2010). Similar phenotype characteristics comparing familial and sporadic premature ovarian failure. Menopause-The Journal of the North American Menopause Society, 17(4), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Jansen, B.J.H., Gilissen, C., Roelofs, H., Schaap-Oziemlak, A., Veltman, J.A., Raymakers, R.A.P., Jansen, J.H., Kogler, G., Figdor, C.G., Torensma, R. & Adema, G.J. (2010). Functional differences between mesenchymal stem cell populations are reflected by their transcriptome. Stem Cells and Development, 19(4), NCMLS 1B - Haematology, NCMLS 1B - Lab LH, NCMLS 1C - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Lab LH - Jansen, E.J.S., Hafmans, T.G.M. & Martens, G.J. (2010). V-ATPase-mediated granular acidification is regulated by the V-ATPase accessory subunit Ac45 in POMC-producing cells. Molecular Biology of the Cell, 21(19), N4i 1 - Pulmonary Diseases, NCMLS 1C - Biochemistry - Jansen, J.H. & Langemeijer, S.M.C. (2010). The biological basis of MDS. European hematology association, education program book, NCMLS 1B ONCOL 3 - Lab LH - Jensen, L.R., Bartenschlager, H., Rujirabanjerd, S., Tzschach, A., Numann, A., Janecke, A.R., Sporle, R., Stricker, S., Raynaud, M., Nelson, J., Hackett, A., Fryns, J.P., Chelly, J., Brouwer, A.P.M. de, Hamel, B., Gecz, J., Ropers, H.H. & Kuss, A.W. (2010). A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C. Pathogenetics, 3(1), 2. - IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Ji, W., Yang, F., Beucken, J.J.J.P van den, Bian, Z., Fan, M., Chen, Z. & Jansen, J.A. (2010). Fibrous scaffolds loaded with protein prepared by blend or coaxial electrospinning. Acta Biomaterialia, 6(11), NCMLS 1C - Dentistry - Jin, F., Hamada, M., Malureanu, L., Jeganathan, K.B., Zhou, W., Morbeck, D.E. & Deursen, J.M.A. van (2010). Cdc20 is critical for meiosis I and fertility of female mice. PLoS Genetics, 6(9). - NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Joerink, M., Oortveld, M.A.W., Stenius, F., Rindsjo, E., Alm, J. & Scheynius, A. (2010). Lifestyle and parental allergen sensitization are reflected in the intrauterine environment at gene expression level. Allergy, 65(10), DCN 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Jong, H. de, Berlo, S.E., Hombrink, P., Otten, H.G., Eden, W. van, Lafeber, F.P.J.G., Heurkens, A.H.M., Bijlsma, J.W.J., Glant, T.T. & Prakken, B.J. (2010). Cartilage proteoglycan aggrecan epitopes induce proinflammatory autoreactive T-cell responses in rheumatoid arthritis and osteoarthritis. Annals of the Rheumatic Diseases, 69(1), IGMD 9 - Paediatrics, NCMLS 2A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor) Jonge, L.T. de, Ju, J., Leeuwenburgh, S.C.G., Yamagata, Y., Higuchi, T., Wolke, J.G.C., Inoue, K. & Jansen, J.A. (2010). A comparative study of two advanced spraying techniques for the desposition of biologically active enzyme coatings onto bone-substituting implants. Thin Solid Films, 518(19), NCMLS 1C - Dentistry - Jonge, L.T. de, Leeuwenburgh, S.C.G., Beucken, J.J.J.P van den, Riet, J. te, Daamen, W.F., Wolke, J.G.C., Scharnweber, D. & Jansen, J.A. (2010). The osteogenic effect of electrosprayed nanoscale collagen/calcium phosphate coatings on titanium. Biomaterials, 31(9), NCMLS 1B - Tumorimmunology, NCMLS 1C - Biochemistry, NCMLS 1C - Dentistry - Jonge, L.T. de, Leeuwenburgh, S.C.G., Beucken, J.J.J.P van den, Riet, J. te, Daamen, W.F., Wolke, J.G.C., Scharnweber, D. & Jansen, J.A. (2010). The osteogenic effect of electrosprayed nanoscale collagen/calcium phosphate coatings on titanium. Biomaterials, 31(9), NCMLS 1B - Tumorimmunology - Jongmans, M.C., Hoogerbrugge, P.M., Hilkens, L., Flucke, U., Burgt, I. van der, Noordam, K., Ruiterkamp-Versteeg, M., Yntema, H.G., Nillesen, W.M., Ligtenberg, M.J., Geurts van Kessel, A.H.M., Kuiper, R.P. & Hoogerbrugge, N. (2010). Noonan syndrome, the SOS1 gene and embryonal rhabdomyosarcoma. Genes Chromosomes & Cancer, 49(7), IGMD 6 - Paediatrics, NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Paediatrics, ONCOL 1 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Jongmans, M.C.J., Kuiper, R.P., Carmichael, C.L., Wilkins, E.J., Dors, N., Carmagnac, A., Schouten-van Meeteren, A.Y., Li, X., Stankovic, M., Kamping, E., Bengtsson, H., Schoenmakers, E.F.P.M., Geurts van Kessel, A.H.M., Hoogerbrugge, P.M., Hahn, C.N., Brons, P.P.T., Scott, H.S. & Hoogerbrugge-van der Linden, N. (2010). Novel RUNX1 mutations in familial platelet disorder with enhanced risk for acute myeloid leukemia: clues for improved identification of the FPD/AML syndrome. Leukemia, 24(1), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Jongmans, M.C.J., Pfundt, R.P., Hehir-Kwa, J.Y., Brunner, H.G. & Kerstjens-Frederikse, W.S. (2010). Choanal atresia, syngnathia, brachydactyly, mental retardation and short stature: an X-linked syndrome? Clinical Dysmorphology, 19(1), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Joost, K., Rodenburg, R., Piirsoo, A., Heuvel, B. van den, Zordania, R. & Ounap, K. (2010). A novel mutation in the SCO2 gene in a neonate with early-onset cardioencephalomyopathy. Pediatric Neurology, 42(3), IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - Lab LGEM - Joosten, L.A.B. (2010). Excessive interleukin-1 signaling determines the development of Th1 and Th17 responses in chronic inflammation. Arthritis and Rheumatism, 62(2), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Joosten, L.A.B., Netea, M.G., Mylona, E., Koenders, M.I., Malireddi, R.K., Oosting, M., Stienstra, R., Veerdonk, F.L. van de, Stalenhoef, A.F.H., Giamarellos-Bourboulis, E.J., Kanneganti, T.D. & Meer, J.W.M. van der (2010). Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1beta production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis and Rheumatism, 62(11), N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Gen Int Med, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor) Joosten, L.A.B., Veerdonk, F.L. van de, Vonk, A.G., Boerman, O.C., Keuter, M., Fantuzzi, G., Verschueren, I., Poll, T. van der, Dinarello, C.A., Kullberg, B.J., Meer, J.W.M. van der & Netea, M.G. (2010). Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1alpha, IL-1beta or IL-1 receptor type I. APMIS, 118(12), N4i 1 - Gen Int Med, N4i 1 - Nuclear Medicine, NCMLS 1A - Gen Int Med, NCMLS 1B - Nuclear Med - Junker, R., Manders, P.J.D., Wolke, J., Borisov, Y. & Jansen, J.A. (2010). Bone reaction adjacent to microplasma-sprayed CaP-coated oral implants subjected to occlusal load, an experimental study in the dog. Part I: short-term results. Clinical Oral Implants Research, 21(11), NCMLS 1C - Dentistry - Junker, R., Manders, P.J.D., Wolke, J., Borisov, Y. & Jansen, J.A. (2010). Bone-supportive behavior of microplasma-sprayed CaP-coated implants: mechanical and histological outcome in the goat. Clinical Oral Implants Research, 21(2), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Junker, R., Manders, P.J.D., Wolke, J., Borisov, Y., Braceras, I. & Jansen, J.A. (2010). Loaded microplasma-sprayed CaP-coated implants in vivo. Journal of Dental Research, 89(12), NCMLS 1C - Dentistry - Annual Report 2010 Scientific publications

78 Kaiser, M., Hilgetag, C.C. & Kotter, R. (2010). Hierarchy and dynamics of neural networks. Frontiers in Neuroinformatics, 4. - DCN 3 - CNS, NCMLS 2B - CNS - Kalff, K.M., Mouedden, M. El, Egmond, J. van, Veening, J., Joosten, L., Scheffer, G.J., Meert, T. & Vissers, K. (2010). Pre-treatment with capsaicin in a rat osteoarthritis model reduces the symptoms of pain and bone damage induced by monosodium iodoacetate. European Journal of Pharmacology, 641(2-3), DCN 1 - Anesthesiology, DCN 2 - Anatomy, N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCEBP 7 - Anesthesiology, NCMLS 1A - Rheumatology - Kampik, D., Ralla, B., Keller, S., Hirschberg, M., Friedl, P.H.A. & Geerling, G. (2010). Influence of corneal collagen crosslinking with riboflavin and ultraviolet-a irradiation on excimer laser surgery. Investigative Ophthalmology & Visual Science, 51(8), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Kamsteeg, M., Jansen, P.A.M., Vlijmen-Willems, I.M.J.J. van, Erp, P.E.J. van, Rodijk-Olthuis, D., Valk, P.G.M. van der, Feuth, T., Zeeuwen, P.L.J.M. & Schalkwijk, J. (2010). Molecular diagnostics of psoriasis, atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis. British Journal of Dermatology, 162(3), N4i 1 - Dermatology, NCEBP 1 - EBH, NCMLS 1A - Dermatology - Wetensch. publ. refereed (artikel - letter to the editor) Kan, H.E., Klomp, D.W.J., Wohlgemuth, M., Loosbroek-Wagemans, I. van, Engelen, B.G.M. van, Padberg, G.W.A.M. & Heerschap, A. (2010). Only fat infiltrated muscles in resting lower leg of FSHD patients show disturbed energy metabolism. NMR in Biomedicine, 23(6), DCN 2 - Neurology, IGMD 3 - Radiology, NCMLS 2A - Radiology - Kandasamy, K., Mohan, S.S., Raju, R., Keerthikumar, S., Kumar, G.S., Venugopal, A.K., Telikicherla, D., Navarro, J.D., Mathivanan, S., Pecquet, C., Gollapudi, S.K., Tattikota, S.G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H.K., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y.L., Rahiman, B.A., Prasad, T.S., Lin, J.X., Houtman, J.C., Desiderio, S., Renauld, J.C., Constantinescu, S.N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G.D., Sander, C., Leonard, W.J. & Pandey, A. (2010). NetPath: a public resource of curated signal transduction pathways. Genome Biology, 11(1), R3. - IGMD 8 - CMBI, NCMLS 2A - CMBI - Kashyap, M.K., Harsha, H., Renuse, S., Pawar, H., Sahasrabuddhe, N., Kim, M., Marimuthu, A., Keerthikumar, S., Muthusamy, B., Kandasamy, K., Subbannayya, Y., Prasad, T.S., Mahmood, R., Chaerkady, R., Meltzer, S.J., Kumar, R., Rustgi, A.K. & Pandey, A. (2010). SILAC-based quantitative proteomic approach to identify potential biomarkers from the esophageal squamous cell carcinoma secretome. Cancer Biology & Therapy, 10(8), IGMD 8 - CMBI, NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Kat Angelino, C.M. de, Raymakers, R., Teunesen, M.A., Jacobs, J.F.M. & Klasen, I.S. (2010). Overestimation of serum kappa free light chain concentration by immunonephelometry. Clinical Chemistry, 56(7), N4i 4 - Lab LMI, NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Keeney, M., Beucken, J.J.J.P van den, Kraan, P.M. van der, Jansen, J.A. & Pandit, A. (2010). The ability of a collagen/calcium phosphate scaffold to act as its own vector for gene delivery and to promote bone formation via transfection with VEGF(165). Biomaterials, 31(10), N4i 1 - Rheumatology, NCMLS 1C - Dentistry, NCMLS 1C - Rheumatology - Kersten, F.F.J., Wijk, E. van, Reeuwijk, J. van, Zwaag, B. van der, Marker, T., Peters, T.A., Katsanis, N., Wolfrum, U., Keunen, J.E.E., Roepman, R. & Kremer, J.M.J. (2010). Association of whirlin with Cav1.3 (alpha1d) channels in photoreceptors, defining a novel member of the usher protein network. Investigative Ophthalmology & Visual Science, 51(5), DCN 2 - Hum Gen, DCN 2 - Ophthalmology, DCN 2 - Otorhinolaryn, IGMD 9 - Hum Gen, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology, NCMLS 3A - Otorhinolaryn - Wetensch. publ. refereed (artikel - letter to the editor) Khalil, A.A. & Friedl, P.H.A. (2010). Determinants of leader cells in collective cell migration. Integr Biol (Camb), 2(11-12), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Khan, M.I., Collin, R.W.J., Arimadyo, K., Micheal, S., Azam, M., Qureshi, N., Faradz, S.M., Hollander, A.I. den, Qamar, R. & Cremers, F.P.M. (2010). Missense mutations at homologous positions in the fourth and fifth laminin A G-like domains of eyes shut homolog cause autosomal recessive retinitis pigmentosa. Molecular Vision, 16, IGMD 3 - Ophthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor) Khan, M.I., Micheal, S., Akhtar, F., Ahmed, W., Ijaz, B., Ahmed, A. & Qamar, R. (2010). The association of glutathione S-transferase GSTT1 and GSTM1 gene polymorphism with pseudoexfoliative glaucoma in a Pakistani population. Molecular Vision, 16, NCMLS 3A - Hum Gen - Khandanpour, C., Thiede, C., Valk, P.J., Sharif-Askari, E., Nuckel, H., Lohmann, D., Horsthemke, B., Siffert, W., Neubauer, A., Grzeschik, K.H., Bloomfield, C.D., Marcucci, G., Maharry, K., Slovak, M.L., Reijden, B.A. van der, Jansen, J.H., Schackert, H.K., Afshar, K., Schnittger, S., Peeters, J.K., Kroschinsky, F., Ehninger, G., Lowenberg, B., Duhrsen, U. & Moroy, T. (2010). A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia. Blood, 115(12), NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Wetensch. publ. refereed (artikel - letter to the editor) Khelashvili, G., Dorff, K., Shan, J., Camacho-Artacho, M., Skrabanek, L., Vroling, B., Bouvier, M., Devi, L.A., George, S.R., Javitch, J.A., Lohse, M.J., Milligan, G., Neubig, R.R., Palczewski, K., Parmentier, M., Pin, J.P., Vriend, G., Campagne, F. & Filizola, M. (2010). GPCR-OKB: the G Protein Coupled Receptor Oligomer Knowledge Base. Bioinformatics, 26(14), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Khwaja, S.S., Liu, H., Tong, C., Jin, F., Pear, W.S., Deursen, J.M.A. van & Bram, R.J. (2010). HIV-1 Rev-binding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice. Journal of Clinical Investigation, 120(7), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Kilsdonk, J.W.J. van, Bergers, M., Kempen, L.C.L.T. van, Schalkwijk, J. & Swart, G.W. (2010). Keratinocytes drive melanoma invasion in a reconstructed skin model. Melanoma Research, 20(5), NCMLS 1A - Dermatology, ONCOL 3 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Kilsdonk, J.W.J. van, Kempen, L.C.L.T. van, Muijen, G.N.P. van, Ruiter, D.J. & Swart, G.W. (2010). Soluble adhesion molecules in human cancers: sources and fates. European Journal of Cell Biology, 89(6), DCN 2 - Anatomy, NCMLS 1A - Dermatology, ONCOL 3 - Pathology - Kleefstra, T., Leeuw, N. de, Wolf, R., Nillesen, W.M., Schobers, G., Mieloo, H., Willemsen, M., Perrotta, C.S., Poddighe, P.J., Feenstra, I., Draaisma, J. & Ravenswaaij-Arts, C.M.A. van (2010). Phenotypic spectrum of 20 novel patients with molecularly defined supernumerary marker chromosomes 15 and a review of the literature. American Journal of Medical Genetics Part A, 152A(9), IGMD 3 - Hum Gen, IGMD 3 - Paediatrics, NCEBP 7 - Primary Health, NCMLS 3A - Hum Gen - Kleerebezem, M, Hols, P., Bernard, E., Rolain, T., Zhou, M., Siezen, R.J. & Bron, P.A. (2010). The extracellular biology of the lactobacilli. FEMS Microbiol Rev, 34(2), NCMLS 2A - CMBI - 78 Scientific publications 2010 NCMLS

79 279 Klijn, R.J., Meijer, G.J., Bronkhorst, E.M. & Jansen, J.A. (2010). A meta-analysis of histomorphometric results and graft healing time of various biomaterials compared to autologous bone used as sinus floor augmentation material in humans. Tissue Engineering Part B Reviews, 16(5), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry Klijn, R.J., Meijer, G.J., Bronkhorst, E.M. & Jansen, J.A. (2010). Sinus floor augmentation surgery using autologous bone grafts from various donor sites: a meta-analysis of the total bone volume. Tissue Engineering Part B Reviews, 16(3), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry Ko, B., Kamsteeg, E.J., Cooke, L.L., Moddes, L.N., Deen, P.M.T. & Hoover, R.S. (2010). RasGRP1 stimulation enhances ubiquitination and endocytosis of the sodium-chloride cotransporter. American Journal of Physiology-Renal Physiology, 299(2), F IGMD 9 - Physiology, NCMLS 2B - Hum Gen, NCMLS 2B - Physiology Koenderink, J.B., Kavishe, R.A., Rijpma, S.R. & Russel, F.G.M. (2010). The ABCs of multidrug resistance in malaria. Trends in Parasitology, 26(9), N4i 3 - Pharm Tox, NCMLS 2B - Pharm Tox Koenders, M.I. & Berg, W.B. van den (2010). Translational mini-review series on Th17 cells: are T helper 17 cells really pathogenic in autoimmunity? Clinical and Experimental Immunology, 159(2), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor) 284 Koenecke, C., Hertenstein, B., Schetelig, J., Biezen, A. van, Dammann, E., Gratwohl, A., Ganser, A., Schleuning, M., Bornhauser, M., Jacobsen, N., Kroger, N., Niederwieser, D., Witte, T.J.M. de & Ruutu, T. (2010). Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT. American Journal of Transplantation, 10(8), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology Koens, M.J.W., Faraj, K.A., Wismans, R.G., Vliet, J.A. van der, Krasznai, A.G., Cuijpers, V.M.J.I., Jansen, J.A., Daamen, W.F. & Kuppevelt, A.H.M.S.M. van (2010). Controlled fabrication of triple layered and molecularly defined collagen/elastin vascular grafts resembling the native blood vessel. Acta Biomaterialia, 6(12), NCMLS 1C - Biochemistry, NCMLS 1C - Dentistry, NCMLS 1C - Surgery - Wetensch. publ. refereed (artikel - letter to the editor) 286 Kogelenberg, M. van, Ghedia, S., McGillivray, G., Bruno, D., Leventer, R., Macdermot, K., Nelson, J., Nagarajan, L., Veltman, J.A., Brouwer, A.P.M. de, McKinlay Gardner, R.J., Bokhoven, J.H.L.M. van, Kirk, E.P. & Robertson, S.P. (2010). Periventricular heterotopia in common microdeletion syndromes. Mol Syndromol, 1(1), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) 287 Kone, A., Vegte-Bolmer, M. van de, Siebelink-Stoter, R., Gemert, G.J.A. van, Dara, A., Niangaly, H., Luty, A., Doumbo, O.K., Sauerwein, R.W. & Djimde, A.A. (2010). Sulfadoxine-pyrimethamine impairs Plasmodium falciparum gametocyte infectivity and Anopheles mosquito survival. International Journal for Parasitology, 40(10), N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) 288 Koning, H.D. de, Rodijk-Olthuis, D., Vlijmen-Willems, I.M.J.J. van, Joosten, L.A.B., Netea, M.G., Schalkwijk, J. & Zeeuwen, P.L.J.M. (2010). A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis. Journal of Investigative Dermatology, 130(11), N4i 1 - Dermatology, N4i 1 - Gen Int Med, NCMLS 1A - Dermatology, NCMLS 1A - Gen Int Med Koopman, W.J.H., Nijtmans, L.G.J., Dieteren, C.E.J., Roestenberg, P., Valsecchi, F., Smeitink, J.A.M. & Willems, P.H.G.M. (2010). Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation. Antioxid Redox Signal, 12(12), IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - Biochemistry, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Chen, S., Wassenhove-McCarthy, D., Yamaguchi, Y., Holzman, L., Kuppevelt, A.H.M.S.M. van, Orr, A.W., Funk, S., Woods, A. & McCarthy, K. (2010). Podocytes require the engagement of cell surface heparan sulfate proteoglycans for adhesion to extracellular matrices. Kidney International, 78(11), NCMLS 1C - Biochemistry Kourist, R., Jochens, H., Bartsch, S., Kuipers, R., Padhi, S.K., Gall, M., Bottcher, D., Joosten, HJ & Bornscheuer, U.T. (2010). The alpha/betahydrolase fold 3DM database (ABHDB) as a tool for protein engineering. Chembiochem, 11(12), NCMLS 3A - CMBI, NCMLS 3B - CMBI Kouwenhoven, E.N., Heeringen, S.J. van, Tena, J.J., Oti, M., Dutilh, B.E., Alonso, M.E., Calle-Mustienes, E. de la, Smeenk, L., Rinne, T., Parsaulian, L., Bolat, E., Jurgelenaite, R., Huynen, M.A., Hoischen, A., Veltman, J.A., Brunner, H.G., Roscioli, T., Oates, E., Wilson, M., Manzanares, M., Gomez-Skarmeta, J.L., Stunnenberg, H.G., Lohrum, M., Bokhoven, J.H.L.M. van & Zhou, H. (2010). Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus. PLoS Genetics, 6(8), e DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 2A IGMD 8 - CMBI, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) 292 Kouwenhoven, E.N., Heeringen, S.J. van, Tena, J.J., Oti, M.O., Dutilh, B.E., Eva Alonso, M., Calle-Mustienes, E. de la, Smeenk, L., Parsaulian, L., Bolat, E., Jurgelenaite, R., Huynen, M.A., Hoischen, A., Veltman, J.A., Brunner, H.G., Roscioli, T., Oates, E., Wilson, M., Manzanares, M., Gomez-Skarmeta, J.L., Stunnenberg, H.G., Lohrum, M.A.E., Bokhoven, J.H.L.M. van & Zhou, J.H. (2010). Genome-Wide Profiling of p63 DNA Binding Sites Identifies an Element that Regulates Gene Expression during Limb Development in the 7q21 SHFM1 Locus. PLoS Genetics, 6(8), e e IGMD 8 - CMBI, NCMLS 2A - CMBI, RU SCI ICIS IS, RU SCI NCMLS MB - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) 293 Kraan, P.M. van der (2010). Osteoarthritis and a high-fat diet: the full OA syndrome in a small animal model. Arthritis Research & Therapy, 12(4), N4i 1 - Rheumatology, NCMLS 1C - Rheumatology Kraan, P.M. van der, Blaney Davidson, E.N. & Berg, W.B. van den (2010). A role for age-related changes in TGFbeta signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Research & Therapy, 12(1), N4i 1 - Rheumatology, NCMLS 1C - Rheumatology Kraan, P.M. van der, Davidson, E.N. & Berg, W.B. van den (2010). Bone morphogenetic proteins and articular cartilage: To serve and protect or a wolf in sheep clothing s? Osteoarthritis & Cartilage, 18(6), N4i 1 - Rheumatology, NCMLS 1C - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor) 296 Kramer, M., Schulte, B.M., Eleveld-Trancikova, D., Hout-Kuijer, M. van, Toonen, L.W.J., Tel, J., Vries, I.J.M. de, Kuppeveld, F.J.M. van, Jansen, B.J.H. & Adema, G.J. (2010). Cross-talk between human dendritic cell subsets influences expression of RNA sensors and inhibits picornavirus infection. J Innate Immun, 2(4), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol, NCMLS 1B - Med Oncol, NCMLS 1B - Tumorimmunology Kretlow, J.D., Shi, M., Young, S., Spicer, P.P., Demian, N., Jansen, J.A., Wong, M.E., Kasper, F.K. & Mikos, A.G. (2010). Evaluation of soft tissue coverage over porous polymethylmethacrylate space maintainers within nonhealing alveolar bone defects. Tissue Engineering Part C Methods, 16(6), NCMLS 1C - Dentistry Kretlow, J.D., Spicer, P.P., Jansen, J.A., Vacanti, C.A., Kasper, F.K. & Mikos, A.G. (2010). Uncultured marrow mononuclear cells delivered within fibrin glue hydrogels to porous scaffolds enhance bone regeneration within critical-sized rat cranial defects. Tissue Engineering Part A, 16(12), NCMLS 1C - Dentistry - Annual Report 2010 Scientific publications

80 Kroese-Deutman, H.C., Wolke, J.G.C., Spauwen, P.H.M. & Jansen, J.A. (2010). Torque test measurement in segmental bone defects using porous calcium phosphate cement implants. Tissue Engineering Part C Methods, 16(5), NCMLS 1C - Dentistry, NCMLS 1C - Plastic Surgery - Kroger, N., Shimoni, A., Schilling, G., Schwerdtfeger, R., Bornhauser, M., Nagler, A., Zander, A.R., Heinzelmann, M., Brand, R., Gahrton, G., Morris, C., Niederwieser, D. & Witte, T.J.M. de (2010). Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. British Journal of Haematology, 148(2), NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Tumorimmunology - Kronke, G., Uderhardt, S., Kim, K.A., Stock, M., Scholtysek, C., Zaiss, M.M., Surmann-Schmitt, C., Luther, J., Katzenbeisser, J., David, J.P., Abdollahi-Roodsaz, S., Tran, K., Bright, J.M., Binnerts, M.E., Akhmetshina, A., Bohm, C., Distler, J.H., Joosten, L.A.B., Schett, G. & Abo, A. (2010). R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway. Arthritis and Rheumatism, 62(8), N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Krumnack, A., Reid, A.T., Wanke, E., Bezgin, G. & Kotter, R. (2010). Criteria for optimizing cortical hierarchies with continuous ranges. Frontiers in Neuroinformatics, 4, 7. - DCN 3 - CNS, NCMLS 2B - CNS - Kuiper, R.P., Hoogerbrugge, P.M. & Leeuwen, F.N. van (2010). Nieuwe genomische markers voor diagnostiek en behandeling van voorloper-b-cel acute lymfatische leukemie bij kinderen. Nederlands Tijdschrift voor Hematologie, 7, ONCOL 2 NCMLS 1B - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor) Kuiper, R.P., Waanders, E., Velden, V.H. van der, Reijmersdal, S.V. van, Venkatachalam, R., Scheijen, B., Sonneveld, E., Dongen, J.J.A.M. van, Veerman, A.J.P., Leeuwen, F.N. van, Geurts van Kessel, A.H.M. & Hoogerbrugge, P.M. (2010). IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia, 24(7), NCMLS 1B - Lab LGEM, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 3 - Hum Gen, ONCOL 3 - Lab LGEM, ONCOL 3 - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Kuipers, R., Bergh, T. van den, Joosten, HJ, Lekanne dit Deprez, R.H., Mannens, M.M.A.M. & Schaap, P.J. (2010). Novel tools for extraction and validation of disease-related mutations applied to Fabry disease. Human Mutation, 31(9), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Kuipers, R.K.P., Joosten, HJ, Berkel, W.J. van, Leferink, N.G., Rooijen, E., Ittmann, E., Zimmeren, F. van, Jochens, H., Bornscheuer, U., Vriend, G., Santos, V.A. dos & Schaap, P.J. (2010). 3DM: systematic analysis of heterogeneous superfamily data to discover protein functionalities. Proteins, 78(9), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Kumar, A., Duvvari, M.R., Prabhakaran, V.C., Shetty, J.S., Murthy, G.J. & Blanton, S.H. (2010). A homozygous mutation in LTBP2 causes isolated microspherophakia. Human Genetics, 128(4), IGMD 3 - Ophthalmology, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor) Kumpf, O., Giamarellos-Bourboulis, E.J., Koch, A., Hamann, L., Mouktaroudi, M., Oh, D.Y., Latz, E., Lorenz, E., Schwartz, D.A., Ferwerda, B., Routsi, C., Skalioti, C., Kullberg, B.J., Meer, J.W.M. van der, Schlag, P.M., Netea, M.G., Zacharowski, K. & Schumann, R.R. (2010). Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts. Critical Care, 14(3), R N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Kuppeveld, F.J.M. van, Jong, A.S. de, Lanke, K.H.W., Verhaegh, G.W.C.T., Melchers, W.J.G., Swanink, C.M.A., Bleijenberg, G., Netea, M.G., Galama, J.M.D. & Meer, J.W.M. van der (2010). Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. British Medical Journal, 340, c N4i 1 - Gen Int Med, N4i 1 - Med Microbiol, NCEBP 10 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Kurreeman, F.A., Goulielmos, G.N., Alizadeh, B.Z., Rueda, B., Houwing-Duistermaat, J., Sanchez, E., Bevova, M., Radstake, T.R.D.J., Vonk, M.C., Galanakis, E., Ortego, N., Verduyn, W., Zervou, M.I., Roep, B.O., Dema, B., Espino, L., Urcelay, E., Boumpas, D.T., Berg, L.H. van den, Wijmenga, C., Koeleman, B.P., Huizinga, T.W.J., Toes, R.E. & Martin, J. (2010). The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseases. Annals of the Rheumatic Diseases, 69(4), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor) Laarhoven, H.W.M. van, Philippens, M.E.P., Peeters, W.J.M., Rijken, P.F.J.W., Kogel, A.J. van der, Punt, C.J.A. & Heerschap, A. (2010). Assessment of Blood Hemodynamics by USPIO-Induced R(1) Changes in MRI of Murine Colon Carcinoma. Appl Magn Reson, 38(3), NCMLS 3B - Radiology, ONCOL 3 - Rad Oncol, ONCOL 3 - Radiology, ONCOL 5 - Med Oncol - Labar, B., Suciu, S., Willemze, R., Muus, P., Marie, J.P., Fillet, G., Berneman, Z., Jaksic, B., Feremans, W., Bron, D., Sinnige, H., Mistrik, M., Vreugdenhil, G., Bock, R. de, Nemet, D., Gilotay, C., Amadori, S. & Witte, T.J.M. de (2010). Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica, 95(9), NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Tumorimmunology, ONCOL 4 - Haematology - Lainez, S., Valente, P., Ontoria-Oviedo, I., Estevez-Herrera, J., Camprubi-Robles, M., Ferrer-Montiel, A. & Planells-Cases, R. (2010). GABAA receptor associated protein (GABARAP) modulates TRPV1 expression and channel function and desensitization. FASEB Journal, 24(6), IGMD 9 - Physiology, NCMLS 2B - Physiology - Lambeck, A.J.A., Nijman, H.W., Hoogeboom, B.N., Regts, J., Mare, A. de, Wilschut, J. & Daemen, T. (2010). Role of T cell competition in the induction of cytotoxic T lymphocyte activity during viral vector-based immunization regimens. Vaccine, 28(26), NCMLS 1B - Tumorimmunology - Lameris, A.L.L., Huybers, S., Burke, J.R., Monnens, L.A.H., Bindels, R.J.M. & Hoenderop, J.G.J. (2010). Involvement of claudin 3 and claudin 4 in idiopathic infantile hypercalcaemia: a novel hypothesis? Nephrology Dialysis Transplantation, 25(11), IGMD 9 - Physiology, NCMLS 2B - Physiology - Lamers, E., Horssen, R. van, Riet, J. te, Delft, F.C.M.J.M. van, Luttge, R., Walboomers, X.F. & Jansen, J.A. (2010). The influence of nanoscale topographical cues on initial osteoblast morphology and migration. Eur Cell Mater, 20, NCMLS 1B - Tumorimmunology, NCMLS 1C - Dentistry - Lamers, E., Walboomers, X.F., Domanski, M., Riet, J. te, Delft, F.C.M.J.M. van, Luttge, R., Winnubst, L.A.J.A., Gardeniers, H.J.G.E. & Jansen, J.A. (2010). The influence of nanoscale grooved substrates on osteoblast behavior and extracellular matrix deposition. Biomaterials, 31(12), NCMLS 1B - Tumorimmunology, NCMLS 1C - Dentistry - Lammens, C.R., Bleiker, E.M., Verhoef, S., Hes, F.J., Ausems, M.G., Majoor-Krakauer, D., Sijmons, R.H., Luijt, R.B. van der, Ouweland, A.M. van den, Os, T.A. Van, Hoogerbrugge, N., Gomez Garcia, E.B., Dommering, C.J., Gundy, C.M. & Aaronson, N.K. (2010). Psychosocial impact of Von Hippel-Lindau disease: levels and sources of distress. Clinical Genetics, 77(5), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol - 80 Scientific publications 2010 NCMLS

81 Lammers, G., Gilissen, C., Nillesen, S.T.M., Uijtdewilligen, P.J.E., Wismans, R.G., Veltman, J.A., Daamen, W.F. & Kuppevelt, A.H.M.S.M. van (2010). High density gene expression microarrays and gene ontology analysis for identifying processes in implanted tissue engineering constructs. Biomaterials, 31(32), IGMD 3 - Hum Gen, NCMLS 1C - Biochemistry, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Landsbergen, K.M., Prins, J.B., Kamm, Y.J.L., Brunner, H.G. & Hoogerbrugge-van der Linden, N. (2010). Female BRCA mutation carriers with a preference for prophylactic mastectomy are more likely to participate an educational-support group and to proceed with the preferred intervention within 2 years. Familial Cancer, 9(2), NCEBP 1 - Hum Gen, NCEBP 8 - Med Psychol, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 4 - Med Psychology - Langemeijer, S.M.C., Aslanyan, M.A. & Jansen, J.H. (2010). TETs mutaties in myeloide maligniteiten. Nederlands Tijdschrift voor Hematologie, 7(4), NCMLS 1B ONCOL 3 - Lab LH - Langereis, J.D., Raaijmakers, H.A., Ulfman, L.H. & Koenderman, L. (2010). Abrogation of NF-kappaB signaling in human neutrophils induces neutrophil survival through sustained p38-mapk activation. Journal of Leukocyte Biology, 88(4), N4i 1 - Paediatrics, NCMLS 1A - Paediatrics - Laumonnier, F., Shoubridge, C., Antar, C., Nguyen, L.S., Esch, H. van, Kleefstra, T., Briault, S., Fryns, J.P., Hamel, B., Chelly, J., Ropers, H.H., Ronce, N., Blesson, S., Moraine, C., Gecz, J. & Raynaud, M. (2010). Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism. Molecular Psychiatry, 15(7), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Laverman, P., McBride, W.J., Sharkey, R.M., Eek, A., Joosten, L., Oyen, W.J.G., Goldenberg, D.M. & Boerman, O.C. (2010). A novel facile method of labeling octreotide with (18)F-fluorine. Journal of Nuclear Medicine, 51(3), NCMLS 1B - Nuclear Med, ONCOL 3 - Nuclear Med - Leclercq, W.K., Keulers, B.J., Scheltinga, M.R.M., Spauwen, P.H.M. & Wilt, G.J. van der (2010). A review of surgical informed consent: past, present, and future. A quest to help patients make better decisions. World Journal of Surgery, 34(7), NCEBP 2 - EBH, NCMLS 1C - Plastic Surgery - Lee, K.P., Nair, A.V., Grimm, C, Zeeland, F. van, Heller, S., Bindels, R.J.M. & Hoenderop, J.G.J. (2010). A helix-breaking mutation in the epithelial Ca(2+) channel TRPV5 leads to reduced Ca(2+)-dependent inactivation. Cell Calcium, 48(5), IGMD 9 - Physiology, NCMLS 2B - Physiology - Leegaard, T.M., Bootsma, H.J., Caugant, D.A., Eleveld, M.J., Mannsaker, T., Froholm, L.O., Gaustad, P., Hoiby, E.A. & Hermans, P.W.M. (2010). Phenotypic and genomic characterization of pneumococcus-like streptococci isolated from HIV-seropositive patients. Microbiology, 156(Pt 3), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Leeuw, N. de, Bulk, S., Green, A., Jaeckle-Santos, L., Baker, L.A., Zinn, A.R., Kleefstra, T., Smagt, J.J. van der, Vianne Morgante, A.M., Vries, B.B. de, Bokhoven, J.H.L.M. van & Brouwer, A.P.M. de (2010). UBE2A deficiency syndrome: Mild to severe intellectual disability accompanied by seizures, absent speech, urogenital, and skin anomalies in male patients. American Journal of Medical Genetics Part A, 152A(12), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Leeuwen, E.J. van, Kuijpers-Jagtman, A.M., den Hoff, J.W. Von, Wagener, F.A.D.T.G. & Maltha, J.C. (2010). Rate of orthodontic tooth movement after changing the force magnitude: an experimental study in beagle dogs. Orthodontics & Craniofacial Research, 13(4), NCMLS 1C - Dentistry, NCMLS 2B - Pharm Tox - Leeuwenburgh, S.C.G., Ana, I.D. & Jansen, J.A. (2010). Sodium citrate as an effective dispersant for the synthesis of inorganic-organic composites with a nanodispersed mineral phase. Acta Biomaterialia, 6(3), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Leeuwenburgh, S.C.G., Jo, J., Wang, H., Yamamoto, M., Jansen, J.A. & Tabata, Y. (2010). Mineralization, biodegradation, and drug release behavior of gelatin/apatite composite microspheres for bone regeneration. Biomacromolecules, 11(10), NCMLS 1C - Dentistry - Lent, P.L.E.M. van, Grevers, L.C., Schelbergen, R., Blom, A., Geurts, J., Sloetjes, A., Vogl, T., Roth, J. & Berg, W.B. van den (2010). S100A8 causes a shift toward expression of activatory Fcgamma receptors on macrophages via toll-like receptor 4 and regulates Fcgamma receptor expression in synovium during chronic experimental arthritis. Arthritis and Rheumatism, 62(11), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Lesterhuis, W.J., Vries, I.J.M. de, Aarntzen, E.A., Boer, A. de, Scharenborg, N.M., Rakt, M. van de, Spronsen, D.J. van, Preijers, F.W.M.B., Figdor, C.G., Adema, G.J. & Punt, C.J.A. (2010). A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients. British Journal of Cancer, 103(9), NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Lab LH, ONCOL 3 - Med Oncol, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Lesterhuis, W.J., Vries, I.J.M. de, Schreibelt, G., Schuurhuis, D.H., Aarntzen, E.H.J.G., Boer, A. de, Scharenborg, N.M., Rakt, M. van de, Hesselink, E.J., Figdor, C.G., Adema, G.J. & Punt, C.J.A. (2010). Immunogenicity of Dendritic Cells Pulsed with CEA Peptide or Transfected with CEA mrna for Vaccination of Colorectal Cancer Patients. Anticancer Research, 30(12), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology, ONCOL 4 - Surgery - Levenga, H., Schaap, N., Maas, F., Esendam, B., Fredrix, H., Greupink-Draaisma, A., Witte, T.J.M. de, Dolstra, H. & Raymakers, R. (2010). Partial T cell-depleted allogeneic stem cell transplantation following reduced-intensity conditioning creates a platform for immunotherapy with donor lymphocyte infusion and recipient dendritic cell vaccination in multiple myeloma. Biol Blood Marrow Transplant, 16(3), NCMLS 1B - Haematology, NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Levtchenko, E., Schoeber, J. & Jaeken, J. (2010). Genetic disorders of renal phosphate transport. New England Journal of Medicine, 363(18), 1774; author reply IGMD 9 - Pharm Tox, NCMLS 2B - Pharm Tox - Levtchenko, E.N. & Monnens, L.A.H. (2010). Nephrogenic syndrome of inappropriate antidiuresis. Nephrology Dialysis Transplantation, 25(9), IGMD 9 - Physiology, NCMLS 2B - Physiology - Li, M., Fang, X., Baker, D.J., Guo, L., Gao, X., Wei, Z., Han, S., Deursen, J.M.A. van & Zhang, P. (2010). The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc Natl Acad Sci U S A, 107(32), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Wetensch. publ. refereed (artikel - letter to the editor) Li, Y., Pohl, E., Boulouiz, R., Schraders, M., Nurnberg, G., Charif, M., Admiraal, R.J.C., Ameln, S. von, Baessmann, I., Kandil, M., Veltman, J.A., Nurnberg, P., Kubisch, C., Barakat, A., Kremer, J.M.J. & Wollnik, B. (2010). Mutations in TPRN cause a progressive form of autosomal-recessive nonsyndromic hearing loss. American Journal of Human Genetics, 86(3), DCN 2 - Hum Gen, DCN 2 - Otorhinolaryn, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen, NCMLS 3A - Otorhinolaryn - Annual Report 2010 Scientific publications

82 Li, Z., Yubao, L., Yi, Z., Lan, W. & Jansen, J.A. (2010). In vitro and in vivo evaluation on the bioactivity of ZnO containing nano-hydroxyapatite/ chitosan cement. Journal of Biomedical Materials Research Part A, 93(1), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Lim, Z., Brand, R., Martino, R., Biezen, A. van, Finke, J., Bacigalupo, A., Beelen, D., Devergie, A., Alessandrino, E., Willemze, R., Ruutu, T., Boogaerts, M., Falda, M., Jouet, J.P., Niederwieser, D., Kroger, N., Mufti, G.J. & Witte, T.M. de (2010). Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. Journal of Clinical Oncology, 28(3), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Limbert, G., Lierde, C. van, Muraru, O.L., Walboomers, X.F., Frank, M., Hansson, S., Middleton, J. & Jaecques, S. (2010). Trabecular bone strains around a dental implant and associated micromotions a micro-ct-based three-dimensional finite element study. Journal of Biomechanics, 43(7), NCMLS 1C - Dentistry - Linden, L. van de, Schaar, H.M. van der, Lanke, K.H.W., Neyts, J. & Kuppeveld, F.J.M. van (2010). Differential effects of the putative GBF1 inhibitors Golgicide A and AG1478 on enterovirus replication. Journal of Virology, 84(15), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Linton, J.D., Holzhausen, L.C., Babai, N., Song, H., Miyagishima, K.J., Stearns, G.W., Lindsay, K., Wei, J., Chertov, A.O., Peters, T.A., Caffe, R., Pluk, W.L.L.P., Seeliger, M.W., Tanimoto, N., Fong, K., Bolton, L., Kuok, D.L., Sweet, I.R., Bartoletti, T.M., Radu, R.A., Travis, G.H., Zagotta, W.N., Townes-Anderson, E., Parker, E., Zee, C.E.E.M. van der, Sampath, A.P., Sokolov, M., Thoreson, W.B. & Hurley, J.B. (2010). Flow of energy in the outer retina in darkness and in light. Proc Natl Acad Sci U S A, 107(19), DCN 2 - Cell Biology, NCMLS 2A - Cell Biology, NCMLS 3A - Otorhinolaryn - Littink, K.W., Born, L.I. van den, Koenekoop, R.K., Collin, R.W.J., Zonneveld, M.N., Blokland, E.A.W., Khan, H., Theelen, T., Hoyng, C.B., Cremers, F.P.M., Hollander, A.I. den & Klevering, B.J. (2010). Mutations in the EYS gene account for approximately 5% of autosomal recessive retinitis pigmentosa and cause a fairly homogeneous phenotype. Ophthalmology, 117(10), , 2033.e IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCEBP 2 - Human Genetics, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor) Littink, K.W., Koenekoop, R.K., Born, L.I. van den, Collin, R.W.J., Moruz, L., Veltman, J.A., Roosing, S., Zonneveld, M.N., Omar, A., Darvish, M., Lopez, I., Kroes, H.Y., Genderen, M.M. van, Hoyng, C.B., Rohrschneider, K., Schooneveld, M.J. van, Cremers, F.P.M. & Hollander, A.I. den (2010). Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations. Investigative Ophthalmology & Visual Science, 51(11), IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCEBP 2 - Human Genetics, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Littink, K.W., Pott, J.W., Collin, R.W.J., Kroes, H.Y., Verheij, J.B., Blokland, E.A.W., Castro Miro, M. de, Hoyng, C.B., Klaver, C.C., Koenekoop, R.K., Rohrschneider, K., Cremers, F.P.M., Born, L.I. van den & Hollander, A.I. den (2010). A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype. Investigative Ophthalmology & Visual Science, 51(7), IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCEBP 2 - Human Genetics, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Liu, J., Bian, Z., Kuijpers-Jagtman, A.M. & den Hoff, J.W. Von (2010). Skin and oral mucosa equivalents: construction and performance. Orthodontics & Craniofacial Research, 13(1), NCMLS 1C - Dentistry - Liu, M., Bayjanov, J.R., Renckens, B., Nauta, A. & Siezen, R.J. (2010). The proteolytic system of lactic acid bacteria revisited: a genomic comparison. BMC Genomics, 11, NCMLS 2A - CMBI - Ljungman, P., Bregni, M., Brune, M., Cornelissen, J., Witte, T.J.M. de, Dini, G., Einsele, H., Gaspar, H.B., Gratwohl, A., Passweg, J., Peters, C., Rocha, V., Saccardi, R., Schouten, H., Sureda, A., Tichelli, A., Velardi, A. & Niederwieser, D. (2010). Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe Bone Marrow Transplantation, 45(2), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - llo Gonzalez, T. Be, Rivera-Olivero, I.A., Pocaterra, L., Spadola, E., Araque, M., Hermans, P.W.M. & Waard, J.H. de (2010). [Pneumococcal carriage in mothers and children of the Panare Amerindians from the State of Bolivar, Venezuela]. Rev Argent Microbiol, 42(1), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Lommel, M., Cirak, S., Willer, T., Hermann, R., Uyanik, G., Bokhoven, J.H.L.M. van, Korner, C., Voit, T., Baric, I., Hehr, U. & Strahl, S. (2010). Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies. Neurology, 74(2), DCN 2 - Hum Gen, NCMLS 3A - Hum Gen - Loo-Bouwman, C.A. Van, Naber, T.H., Breemen, R.B. van, Zhu, D., Dicke, H., Siebelink, E., Hulshof, P.J., Russel, F.G.M., Schaafsma, G. & West, C.E. (2010). Vitamin A equivalency and apparent absorption of beta-carotene in ileostomy subjects using a dual-isotope dilution technique. British Journal of Nutrition, 103(12), IGMD 2 - Gastroenterology, NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Loon, B. van, Maal, T.J.J., Plooij, J.M., Ingels, K.J.A.O., Borstlap, W.A., Kuijpers-Jagtman, A.M., Spauwen, P.H.M. & Berge, S.J. (2010). 3D Stereophotogrammetric assessment of pre- and postoperative volumetric changes in the cleft lip and palate nose. International Journal of Oral and Maxillofacial Surgery, 39(6), NCEBP 2 - Dentistry, NCEBP 2 - Oral Maxillo, NCEBP 2 - Otorhinolaryn, NCMLS 1C - Plastic Surgery - Los, E.L., Deen, P.M.T. & Robben, J.H. (2010). Potential of nonpeptide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus. Journal of Neuroendocrinology, 22(5), IGMD 9 - Physiology, NCMLS 2B - Physiology - Louie, C.M., Caridi, G., Lopes, V.S., Brancati, F., Kispert, A., Lancaster, M.A., Schlossman, A.M., Otto, E.A., Leitges, M., Grone, H.J., Lopez, I., Gudiseva, H.V., O Toole, J.F., Vallespin, E., Ayyagari, R., Ayuso, C., Cremers, F.P.M., Hollander, A.I. den, Koenekoop, R.K., Dallapiccola, B., Ghiggeri, G.M., Hildebrandt, F., Valente, E.M., Williams, D.S. & Gleeson, J.G. (2010). AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nature Genetics, 42(2), IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Luesink, M. & Jansen, J.H. (2010). Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia. British Journal of Haematology, 151(3), NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Lugtenberg, D., Zangrande-Vieira, L., Kirchhoff, M., Whibley, A.C., Oudakker, A.R., Kjaergaard, S., Vianna-Morgante, A.M., Kleefstra, T., Ruiter, E.M., Jehee, F.S., Ullmann, R., Schwartz, C.E., Stratton, M., Raymond, F.L., Veltman, J.A., Vrijenhoek, T., Pfundt, R., Schuurs-Hoeijmakers, J.H.M., Hehir, J.Y., Froyen, G., Chelly, J., Ropers, H.H., Moraine, C., Gecz, J., Knijnenburg, J., Kant, S.G., Hamel, B.C.J., Rosenberg, C., Bokhoven, J.H.L.M. van & Brouwer, A.P.M. de (2010). Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation. American Journal of Medical Genetics Part A, 152A(3), DCN 2 - CNS, DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - 82 Scientific publications 2010 NCMLS

83 Lumig, P.P.M. van, Lecluse, L.L., Driessen, R.J.B., Spuls, P.I., Boezeman, J.B.M., Kerkhof, P.C.M. van de & Jong, E.M.G.J. de (2010). Switching from etanercept to adalimumab is effective and safe: results in 30 patients with psoriasis with primary failure, secondary failure or intolerance to etanercept. British Journal of Dermatology, 163(4), N4i 1 - Dermatology, NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Maicas, N., Ferrandiz, M.L., Devesa, I., Motterlini, R., Koenders, M.I., Berg, W.B. van den & Alcaraz, M.J. (2010). The CO-releasing molecule CORM-3 protects against articular degradation in the K/BxN serum transfer arthritis model. European Journal of Pharmacology, 634(1-3), N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Mair, G.R., Lasonder, E., Garver, L.S., Franke-Fayard, B.M., Carret, C.K., Wiegant, J.C., Dirks, R.W., Dimopoulos, G., Janse, C.J. & Waters, A.P. (2010). Universal features of post-transcriptional gene regulation are critical for Plasmodium zygote development. PLoS Pathogens, 6(2), e IGMD 8 - CMBI, NCMLS 2A - CMBI - Malureanu, L., Jeganathan, K.B., Jin, F., Baker, D.J., Ree, J.H., Gullon, O., Chen, Z., Henley, J.R. & Deursen, J.M.A. van (2010). Cdc20 hypomorphic mice fail to counteract de novo synthesis of cyclin B1 in mitosis. Journal of Cell Biology, 191(2), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Martin, J.E., Alizadeh, B.Z., Gonzalez-Gay, M.A., Balsa, A., Pascual-Salcedo, D., Fernandez-Gutierrez, B., Raya, E., Franke, L., n t Slot, R. Va, Coenen, M.J.H., Riel, P. van, Radstake, T.R.D.J., Koeleman, B.P. & Martin, J. (2010). Identification of the oxidative stress-related gene MSRA as a rheumatoid arthritis susceptibility locus by genome-wide pathway analysis. Arthritis and Rheumatism, 62(11), IGMD 3 - Hum Gen, N4i 4 - Rheumatology, NCEBP 1 - Hum Gen, NCMLS 1A - Rheumatology - Martinelli, S., Luca, A. De, Stellacci, E., Rossi, C., Checquolo, S., Lepri, F., Caputo, V., Silvano, M., Buscherini, F., Consoli, F., Ferrara, G., Digilio, M.C., Cavaliere, M.L., Hagen, J.M. van, Zampino, G., Burgt, C.J.A.M. van der, Ferrero, G.B., Mazzanti, L., Screpanti, I., Yntema, H.G., Nillesen, W.M., Savarirayan, R., Zenker, M., Dallapiccola, B., Gelb, B.D. & Tartaglia, M. (2010). Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. American Journal of Human Genetics, 87(2), NCMLS 3A - Hum Gen - Masereeuw, R. & Russel, F.G.M. (2010). Therapeutic implications of renal anionic drug transporters. Pharmacology and Therapeutics, 126(2), IGMD 9 - Pharm Tox, NCMLS 2B - Pharm Tox - Mast, Q. de, Groot, P.G. de, Heerde, W.L. van, Roestenberg, M., Velzen, J.F. van, Verbruggen, B., Roest, M., McCall, M., Nieman, A.E., Westendorp, J., Syafruddin, D., Fijnheer, R., Dongen-Lases, E.C. van, Sauerwein, R.W. & Ven, A.J.A.M. van der (2010). Thrombocytopenia in early malaria is associated with GP1b shedding in absence of systemic platelet activation and consumptive coagulopathy. British Journal of Haematology, 151(5), N4i 3 - Gen Int Med, N4i 3 - Med Microbiol, NCEBP 14 - Lab LH, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Matthews, G.D., Gur, N., Koopman, W.J.H., Pines, O. & Vardimon, L. (2010). Weak mitochondrial targeting sequence determines tissue-specific subcellular localization of glutamine synthetase in liver and brain cells. Journal of Cell Science, 123(Pt 3), IGMD 8 - Cell Biol, NCMLS 2A - Biochemistry, NCMLS 2A - Cell Biology - Mavridou, E., Bruggemann, R.J.M., Melchers, W.J.G., Mouton, J.W. & Verweij, P.E. (2010). Efficacy of posaconazole against three clinical Aspergillus fumigatus isolates with mutations in the cyp51a gene. Antimicrobial Agents and Chemotherapy, 54(2), NCMLS 1A - Med Microbiol - Mavridou, E., Bruggemann, R.J.M., Melchers, W.J.G., Verweij, P.E. & Mouton, J.W. (2010). Impact of cyp51a mutations on the pharmacokinetic and pharmacodynamic properties of voriconazole in a murine model of disseminated aspergillosis. Antimicrobial Agents and Chemotherapy, 54(11), N4i 2 - Med Microbiol, NCMLS 1A - Med Microbiol - Maze, A., Boel, G., Zuniga, M., Bourand, A., Loux, V., Yebra, M.J., Monedero, V., Correia, K., Jacques, N., Beaufils, S., Poncet, S., Joyet, P., Milohanic, E., Casaregola, S., Auffray, Y., Perez-Martinez, G., Gibrat, J.F., Zagorec, M., Francke, C., Hartke, A. & Deutscher, J. (2010). Complete genome sequence of the probiotic Lactobacillus casei strain BL23. Journal of Bacteriology, 192(10), NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Mazzeu, J.F., Vianna-Morgante, A.M., Krepischi, A.C., Oudakker, A., Rosenberg, C., Szuhai, K., McGill, J., Maccraughan, J., Bokhoven, J.H.L.M. van & Brunner, H.G. (2010). Deletions encompassing 1q41q42.1 and clinical features of autosomal dominant Robinow syndrome. Clinical Genetics, 77(4), DCN 2 - CNS, DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - McCall, M.B.B. & Sauerwein, R.W. (2010). Interferon-gamma central mediator of protective immune responses against the pre-erythrocytic and blood stage of malaria. Journal of Leukocyte Biology, 88(6), N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) McCall, M.B.B., Ferwerda, B., Hopman, J., Ploemen, I., Maiga, B., Daou, M., Dolo, A., Hermsen, C.C., Doumbo, O.K., Bedu-Addo, G., Meer, J.W.M. van der, Troye-Blomberg, M., Ven, A.J.A.M. van der, Schumann, R.R., Sauerwein, R.W., Mockenhaupt, F.P. & Netea, M.G. (2010). Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations. European Cytokine Network, 21(2), N4i 1 - Gen Int Med, N4i 3 - Med Microbiol, NCMLS 1A - Gen Int Med, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) McCall, M.B.B., Hopman, J., Daou, M., Maiga, B., Dara, V., Ploemen, I., Nganou-Makamdop, K., Niangaly, A., Tolo, Y., Arama, C., Bousema, J.T., Meer, J.W.M. van der, Ven, A.J.A.M. van der, Troye-Blomberg, M., Dolo, A., Doumbo, O.K. & Sauerwein, R.W. (2010). Early interferon-gamma response against Plasmodium falciparum correlates with interethnic differences in susceptibility to parasitemia between sympatric Fulani and Dogon in Mali. Journal of Infectious Diseases, 201(1), N4i 3 - Gen Int Med, N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - McCall, M.B.B., Roestenberg, M., Ploemen, I., Teirlinck, A., Hopman, J., Mast, Q. de, Dolo, A., Doumbo, O.K., Luty, A., Ven, A.J.A.M. van der, Hermsen, C.C. & Sauerwein, R.W. (2010). Memory-like IFN-gamma response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum. European Journal of Immunology, 40(12), N4i 3 - Gen Int Med, N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - McKinney, C., Fanciulli, M., Merriman, M.E., Phipps-Green, A., Alizadeh, B.Z., Koeleman, B.P., Dalbeth, N., Gow, P.J., Harrison, A.A., Highton, J., Jones, P.B., Stamp, L.K., Steer, S., Barrera, P., Coenen, M.J.H., Franke, B., Riel, P.L.C.M. van, Vyse, T.J., Aitman, T.J., Radstake, T.R.D.J. & Merriman, T.R. (2010). Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples. Annals of the Rheumatic Diseases, 69(9), IGMD 3 - Hum Gen, IGMD 3 - Psychiatry, N4i 4 - Rheumatology, NCEBP 1 - Hum Gen, NCEBP 1 - Psychiatry, NCMLS 1A - Rheumatology - Medema, M.H., Zhou, M., Hijum, S.A.F.T. van, Gloerich, J., Wessels, H.J., Siezen, R.J. & Strous, M. (2010). A predicted physicochemically distinct sub-proteome associated with the intracellular organelle of the anammox bacterium Kuenenia stuttgartiensis. BMC Genomics, 11, IGMD 3 - Lab LGEM, NCMLS 2A - CMBI - Medendorp, K., Vreede, L., Groningen, J.J.M. van, Hetterschijt, L., Brugmans, L., Jansen, P.A.M., Hurk, W.H. van den, Bruijn, D.R.H. de & Geurts van Kessel, A.H.M. (2010). The mitotic arrest deficient protein MAD2B interacts with the clathrin light chain A during mitosis. PLoS ONE, 5(11), e NCMLS 3A - Hum Gen, ONCOL 3 - Hum Gen - Annual Report 2010 Scientific publications

84 Meer, J.W.M. van der, Netea, M.G., Galama, J.M.D. & Kuppeveld, F.J.M. van (2010). Comment on Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science, 328(5980), 825; author reply N4i 1 - Gen Int Med, N4i 1 - Med Microbiol, NCMLS 1A - Gen Int Med, NCMLS 1A - Med Microbiol - Meer, J.W.M. van der, Veerdonk, F.L. van de, Joosten, L.A.B., Kullberg, B.J. & Netea, M.G. (2010). Severe Candida spp. infections: new insights into natural immunity. International Journal of Antimicrobial Agents, 36 Suppl 2, S N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Meer, L.T. van der, Jansen, J.H. & Reijden, B.A. van der (2010). Gfi1 and Gfi1b: key regulators of hematopoiesis. Leukemia, 24(11), NCMLS 1B - Lab LGEM, NCMLS 1B - Lab LH, ONCOL 2 - Paediatrics, ONCOL 3 - Lab LGEM, ONCOL 3 - Lab LH - Wetensch. publ. refereed (artikel - letter to the editor) Meierjohann, S., Hufnagel, A., Wende, E., Kleinschmidt, M.A., Wolf, K. van der, Friedl, P.H.A., Gaubatz, S. & Schartl, M. (2010). MMP13 mediates cell cycle progression in melanocytes and melanoma cells: in vitro studies of migration and proliferation. Molecular Cancer, 9, NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Meijer, G.J., Dieleman, F.J., Berge, S.J. & Merkx, M.A.W. (2010). Removal of an oral squamous cell carcinoma including parts of osseointegrated implants in the marginal mandibulectomy. A case report. Oral and Maxillofacial Surgery, 14(4), NCMLS 1C - Dentistry, ONCOL 3 - Oral Maxillo - Meijerink, M., Hemert, S. van, Taverne, N., Wels, M., Vos, P., Bron, P.A., Savelkoul, H.F., Bilsen, J., Kleerebezem, M & Wells, J.M. (2010). Identification of genetic loci in Lactobacillus plantarum that modulate the immune response of dendritic cells using comparative genome hybridization. PLoS ONE, 5(5), e NCMLS 2A - CMBI - Meixenberger, K., Pache, F., Eitel, J., Schmeck, B., Hippenstiel, S., Slevogt, H., N Guessan, P., Witzenrath, M., Netea, M.G., Chakraborty, T., Suttorp, N. & Opitz, B. (2010). Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1beta, depending on listeriolysin O and NLRP3. Journal of Immunology, 184(2), N4i 1 - Gen Int Med, N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Melis, M., Swart, J., Visser, M. de, Berndsen, S.C., Koelewijn, S., Valkema, R., Boerman, O.C., Krenning, E.P. & Jong, M. de (2010). Dynamic and static small-animal SPECT in rats for monitoring renal function after 177Lu-labeled Tyr3-octreotate radionuclide therapy. Journal of Nuclear Medicine, 51(12), NCMLS 1B - Nuclear Med, ONCOL 3 - Nuclear Med - Melis, M., Vegt, E., Konijnenberg, M.W., Visser, M. de, Bijster, M., Vermeij, M., Krenning, E.P., Boerman, O.C. & Jong, M. de (2010). Nephrotoxicity in mice after repeated imaging using 111In-labeled peptides. Journal of Nuclear Medicine, 51(6), NCMLS 1B - Nuclear Med, ONCOL 3 - Nuclear Med - Michallet, M., Sobh, M., Milligan, D., Morisset, S., Niederwieser, D., Koza, V., Ruutu, T., Russell, N.H., Verdonck, L., Dhedin, N., Vitek, A., Boogaerts, M., Vindelov, L., Finke, J., Dubois, V., Biezen, A. van, Brand, R., Witte, T.J.M. de & Dreger, P. (2010). The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry. Leukemia, 24(10), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Middelbeek, J., Clark, K., Venselaar, H., Huynen, M.A. & Leeuwen, F.N. van (2010). The alpha-kinase family: an exceptional branch on the protein kinase tree. Cellular Molecular Life Science, 67(6), IGMD 8 - CMBI, NCMLS 1B - Lab LGEM, NCMLS 2A - CMBI, NCMLS 2A IGMD 8 - CMBI, NCMLS 3A - CMBI, NCMLS 3B - CMBI, ONCOL 3 - Lab LGEM, ONCOL 3 - Paediatrics - Mierlo, J.T. van, Cleef, K.W.R. van & Rij, R.P. van (2010). Small Silencing RNAs: Piecing Together a Viral Genome. Cell Host & Microbe, 7(2), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Mistry, A.S., Pham, Q.P., Schouten, C., Yeh, T., Christenson, E.M., Mikos, A.G. & Jansen, J.A. (2010). In vivo bone biocompatibility and degradation of porous fumarate-based polymer/alumoxane nanocomposites for bone tissue engineering. Journal of Biomedical Materials Research Part A, 92(2), NCMLS 1C - Dentistry - Mitsuishi, Y., Hasegawa, H., Matsuo, A., Araki, W., Suzuki, T., Tagami, S., Okochi, M., Takeda, M., Roepman, R. & Nishimura, M. (2010). Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein by binding to the presenilin complex. Journal of Biological Chemistry, 285(20), NCMLS 3A - Hum Gen - Mommers, M., Thijs, C., Stelma, F., Penders, J., Reimerink, J., Ree, R. van & Koopmans, M. (2010). Timing of infection and development of wheeze, eczema, and atopic sensitization during the first 2 yr of life: the KOALA Birth Cohort Study. Pediatric Allergy and Immunology, 21(6), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Monse, B., Heinrich-Weltzien, R., Benzian, H., Holmgren, C.J. & Palenstein Helderman, W.H. van (2010). PUFA an index of clinical consequences of untreated dental caries. Community Dentistry and Oral Epidemiology, 38(1), NCEBP 7 - Dentistry, NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Montezano, A.C., Zimmerman, D., Yusuf, H., Burger, D., Chignalia, A.Z., Wadhera, V., Leeuwen, F.N. van & Touyz, R.M. (2010). Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension, 56(3), NCMLS 1B - Lab LGEM, ONCOL 3 - Lab LGEM, ONCOL 3 - Paediatrics - Mooren, R.E.C.M., Dankers, A.C.A., Merkx, M.A.W., Bronkhorst, E.M., Jansen, J.A. & Stoelinga, P.J.W. (2010). The effect of platelet-rich plasma on early and late bone healing using a mixture of particulate autogenous cancellous bone and Bio-Oss: an experimental study in goats. International Journal of Oral and Maxillofacial Surgery, 39(4), NCMLS 2B - Pharm Tox, ONCOL 3 - Oral Maxillo - Wetensch. publ. refereed (artikel - letter to the editor) Mooren, R.E.C.M., Hendriks, E.J., Beucken, J.J.J.P van den, Merkx, M.A.W., Meijer, G.J., Jansen, J.A. & Stoelinga, P.J.W. (2010). The effect of platelet-rich plasma in vitro on primary cells: rat osteoblast-like cells and human endothelial cells. Tissue Engineering Part A, 16(10), NCMLS 1C - Dentistry - Mooren, R.E.C.M., Merkx, M.A.W., Kessler, P.A., Jansen, J.A. & Stoelinga, P.J.W. (2010). Reconstruction of the mandible using preshaped 2.3-mm titanium plates, autogenous cortical bone plates, particulate cancellous bone, and platelet-rich plasma: a retrospective analysis of 20 patients. Journal of Oral and Maxillofacial Surgery, 68(10), NCMLS 1C - Dentistry, ONCOL 3 - Oral Maxillo - Wetensch. publ. refereed (artikel - letter to the editor) Mora-Montes, H.M., Bates, S., Netea, M.G., Castillo, L., Brand, A., Buurman, E.T., Diaz-Jimenez, D.F., Jan Kullberg, B., Brown, A.J., Odds, F.C. & Gow, N.A. (2010). A multifunctional mannosyltransferase family in Candida albicans determines cell wall mannan structure and host-fungus interactions. Journal of Biological Chemistry, 285(16), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor) Morava, E., Wevers, R.A., Cantagrel, V., Hoefsloot, L.H., Al-Gazali, L., Schoots, J., Rooij, A. van, Huijben, K., Ravenswaaij-Arts, C.M.A. van, Jongmans, M.C.J., Sykut-Cegielska, J., Hoffmann, G.F., Bluemel, P., Adamowicz, M., Reeuwijk, J. van, Ng, B.G., Bergman, J.E., Bokhoven, J.H.L.M. van, Korner, C., Babovic-Vuksanovic, D., Willemsen, Marjolein, Gleeson, J.G., Lehle, L., Brouwer, A.P.M. de & Lefeber, D.J. (2010). A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain, 133(11), DCN 2 - Hum Gen, DCN 2 - Lab LGEM, DCN 3 - Neurology, IGMD 3 - Hum Gen, IGMD 3 - Paediatrics, IGMD 4 - Lab LGEM, NCMLS 3A - Hum Gen - 84 Scientific publications 2010 NCMLS

85 Moroso, V., Metselaar, H.J., Mancham, S., Tilanus, H.W., Eissens, D., Meer, A. van der, Laan, L.J. van der, Kuipers, E.J., Joosten, I. & Kwekkeboom, J. (2010). Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation. Liver Transplantation, 16(7), N4i 4 - Lab LMI, NCMLS 1B - Lab LMI - Morris, C., Drake, M., Apperley, J., Iacobelli, S., Biezen, A. van, Bjorkstrand, B., Goldschmidt, H., Harousseau, J.L., Morgan, G., Witte, T.J.M. de, Niederwieser, D. & Gahrton, G. (2010). Efficacy and outcome of autologous transplantation in rare myelomas. Haematologica, 95(12), NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Mukhopadhyay, A., Kramer, J.M., Merkx, G., Lugtenberg, D., Smeets, D.F.C.M., Oortveld, M.A.W., Blokland, E.A.W., Agrawal, J., Schenck, A., Bokhoven, J.H.L.M. van, Huys, E., Schoenmakers, E.F.P.M., Geurts van Kessel, A.H.M., Nouhuys, C.E. van & Cremers, F.P.M. (2010). CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation. Human Genetics, 128(3), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Mulders, S.A.M., Engelen, B.G.M. van, Wieringa, B. & Wansink, D.G. (2010). Molecular therapy in myotonic dystrophy: focus on RNA gain-offunction. Human Molecular Genetics, 19(R1), R DCN 2 - Neurology, IGMD 8 - Cell Biol, NCMLS 2A - Cell Biology - Wetensch. publ. refereed (artikel - letter to the editor) Muller, A.E., Mouton, J.W., Oostvogel, P.M., Dorr, P.J., Voskuyl, R.A., DeJongh, J., Steegers, E.A.P. & Danhof, M. (2010). Pharmacokinetics of clindamycin in pregnant women in the peripartum period. Antimicrobial Agents and Chemotherapy, 54(5), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Nabuurs, C., Huijbregts, B., Wieringa, B., Hilbers, C.W. & Heerschap, A. (2010). 31P saturation transfer spectroscopy predicts differential intracellular macromolecular association of ATP and ADP in skeletal muscle. Journal of Biological Chemistry, 285(51), IGMD 3 - Radiology, IGMD 8 - Cell Biol, NCMLS 2A - Cell Biology, NCMLS 2A - Radiology - Nabuurs, S.M. & Mierlo, C.P. van (2010). Interrupted hydrogen/deuterium exchange reveals the stable core of the remarkably helical molten globule of alpha-beta parallel protein flavodoxin. Journal of Biological Chemistry, 285(6), IGMD 9 - Physiology, NCMLS 2B - Physiology - Nabuurs, S.M., Kort, B.J. de, Westphal, A.H. & Mierlo, C.P. van (2010). Non-native hydrophobic interactions detected in unfolded apoflavodoxin by paramagnetic relaxation enhancement. Eur Biophys J, 39(4), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Nandoe Tewarie, R.D.S., Hurtado, A., Bartels, R.H.M.A., Grotenhuis, J.A. & Oudega, M. (2010). A clinical perspective of spinal cord injury. NeuroRehabilitation, 27(2), DCN 1 - Neurosurgery, NCMLS 1C - Neurosurgery - Nandoe Tewarie, R.D.S., Yu, J., Seidel, J., Rahiem, S.T., Hurtado, A., Tsui, B.M., Grotenhuis, J.A., Pomper, M.G. & Oudega, M. (2010). Positron emission tomography for serial imaging of the contused adult rat spinal cord. Mol Imaging, 9(2), DCN 1 - Neurosurgery, NCMLS 1C - Neurosurgery - Naranjo, S., Voesenek, K., Calle-Mustienes, E. de la, Robert-Moreno, A., Kokotas, H., Grigoriadou, M., Economides, J., Camp, G. van, Hilgert, N., Moreno, F., Alsina, B., Petersen, M.B., Kremer, J.M.J. & Gomez-Skarmeta, J.L. (2010). Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Human Genetics, 128(4), DCN 2 - Otorhinolaryn, NCMLS 3A - Otorhinolaryn - Forkink, M., Smeitink, J.A.M., Brock, R., Willems, P.H.G.M. & Koopman, W.J.H. (2010). Detection and manipulation of mitochondrial reactive oxygen species in mammalian cells. Biochimica et Biophysica Acta, 1797(6-7), IGMD 8 - Cell Biol, IGMD 8 - Paediatrics, NCMLS 2A - Biochemistry, NCMLS 2A - Cell Biology, NCMLS 3B - Biochemistry - Navis, A.C., Eijnden, M. van den, Schepens, J.T.G., ft van Huijsduijnen, R. Hoo, Wesseling, P. & Hendriks, W.J.A.J. (2010). Protein tyrosine phosphatases in glioma biology. Acta Neuropathologica, 119(2), DCN 3 - Cell Biology, NCMLS 3B - Cell Biology, ONCOL 3 - Pathology - Netea, M.G. & Joosten, L.A.B. (2010). A NOD for autophagy. Nature Medicine, 16(1), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Netea, M.G. & Kullberg, B.J. (2010). Epithelial sensing of fungal invasion. Cell Host & Microbe, 8(3), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Netea, M.G. & Marodi, L. (2010). Innate immune mechanisms for recognition and uptake of Candida species. Trends in Immunology, 31(9), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Netea, M.G., Gow, N.A., Joosten, L.A.B., Verschueren, I., Meer, J.W.M. van der & Kullberg, B.J. (2010). Variable recognition of Candida albicans strains by TLR4 and lectin recognition receptors. Medical Mycology, 48(7), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor) Netea, M.G., Kullberg, B.J. & Meer, J.W.M. van der (2010). Genomewide association study of leprosy. New England Journal of Medicine, 362(15), 1447; author reply N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Netea, M.G., Leij, F. van der, Drenth, J.P.H., Joosten, L.A.B., Morsche, R. te, Verweij, P., Jong, D. de, Kullberg, B.J. & Meer, J.W.M. van der (2010). Chronic yersiniosis due to defects in the TLR5 and NOD2 recognition pathways. Netherlands Journal of Medicine, 68(10), IGMD 2 - Gastroenterology, N4i 1 - Gen Int Med, N4i 1 - Med Microbiol, NCMLS 1A - Gen Int Med, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Netea, M.G., Simon, A., Veerdonk, F. van de, Kullberg, B.J., Meer, J.W.M. van der & Joosten, L.A.B. (2010). IL-1beta processing in host defense: beyond the inflammasomes. PLoS Pathogens, 6(2), e N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor) Nienhuijs, M.E.L., Walboomers, X.F., Briest, A., Merkx, M.A.W., Stoelinga, P.J.W. & Jansen, J.A. (2010). Healing of bone defects in the goat mandible, using COLLOSS E and beta-tricalciumphosphate. Journal of Biomedical Materials Research part B-Applied Biomaterials, 92(2), NCMLS 1C - Dentistry, ONCOL 3 - Oral Maxillo - Nijhuis, A.W.G., Leeuwenburgh, S.C.G. & Jansen, J.A. (2010). Wet-chemical deposition of functional coatings for bone implantology. Macromol Biosci, 10(11), NCMLS 1C - Dentistry - Nikoloski, G., Langemeijer, S.M.C., Kuiper, R.P., Knops, R., Massop, M., Tonnissen, E.R., Heijden, A. van der, Scheele, T.N., Vandenberghe, P., Witte, T.J.M. de, Reijden, B.A. van der & Jansen, J.H. (2010). Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nature Genetics, 42(8), NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Nikopoulos, K., Gilissen, C., Hoischen, A., Nouhuys, C.E. van, Boonstra, F.N., Blokland, E.A.W., Arts, P., Wieskamp, N., Strom, T.M., Ayuso, C., Tilanus, M.A.D., Bouwhuis, S., Mukhopadhyay, A., Scheffer, H., Hoefsloot, L.H., Veltman, J.A., Cremers, F.P.M. & Collin, R.W.J. (2010). Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. American Journal of Human Genetics, 86(2), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, IGMD 3 - Ophthalmology, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Annual Report 2010 Scientific publications

86 Nikopoulos, K., Venselaar, H., Collin, R.W.J., Riveiro-Alvarez, R., Boonstra, F.N., Hooymans, J.M., Mukhopadhyay, A., Shears, D., Bers, M. van, Wijs, I.J. de, Essen, A.J. van, Sijmons, R.H., Tilanus, M.A.D., Nouhuys, C.E. van, Ayuso, C., Hoefsloot, L.H. & Cremers, F.P.M. (2010). Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Human Mutation, 31(6), IGMD 3 - Ophthalmology, NCEBP 2 - Opthalmology, NCMLS 3A - CMBI, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology, NCMLS 3B - CMBI - Nooteboom, M., Johnson, R., Taylor, R.W., Wright, N.A., Lightowlers, R.N., Kirkwood, T.B., Mathers, J.C., Turnbull, D.M. & Greaves, L.C. (2010). Age-associated mitochondrial DNA mutations lead to small but significant changes in cell proliferation and apoptosis in human colonic crypts. Aging Cell, 9(1), NCMLS 2A - Biochemistry - Nossent, A.Y., Robben, J.H., Deen, P.M.T., Vos, H.L., Rosendaal, F.R., Doggen, C.J., Hansen, J.L., Sheikh, S.P., Bertina, R.M. & Eikenboom, J.C. (2010). Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels. Journal of Thrombosis and Haemostasis, 8(7), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Nouws, J., Nijtmans, L.G.J., Houten, S.M., Brand, M. van den, Huynen, M., Venselaar, H., Hoefs, S.J.G., Gloerich, J., Kronick, J., Hutchin, T., Willems, P., Rodenburg, R.J.T., Wanders, R., Heuvel, L.P.W.J. van den, Smeitink, J.A.M. & Vogel, R.O. (2010). Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metabolism, 12(3), IGMD 8 - CMBI, IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - Biochemistry, NCMLS 2A - CMBI, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Nuininga, J.E., Koens, M.J.W., Tiemessen, D.M., Oosterwijk, E., Daamen, W.F., Geutjes, P.J., Kuppevelt, A.H.M.S.M. van & Feitz, W.F.J. (2010). Urethral reconstruction of critical defects in rabbits using molecularly defined tubular type I collagen biomatrices: key issues in growth factor addition. Tissue Engineering Part A, 16(11), NCMLS 1C - Biochemistry, NCMLS 1C - Urology - Wetensch. publ. refereed (artikel - letter to the editor) O Connell, M., Burrows, N.P., Vlijmen-Willems, M.J. van, Clark, S.M. & Schalkwijk, J. (2010). Tenascin-X deficiency and Ehlers-Danlos syndrome: a case report and review of the literature. British Journal of Dermatology, 163(6), NCMLS 1A - Dermatology - Wetensch. publ. refereed (artikel - letter to the editor) Oers, M.H. van, Tonnissen, E., Glabbeke, M. van, Giurgea, L., Jansen, J.H., Klasa, R., Marcus, R.E., Wolf, M., Kimby, E., Vranovsky, A., Holte, H., Hagenbeek, A. & Reijden, B.A. van der (2010). BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC phase III intergroup study. Journal of Clinical Oncology, 28(13), NCMLS 1B - Lab LH, ONCOL 3 - Lab LH - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Olivier, J.D.A., Cools, A.R., Deen, P.M.T., Olivier, B. & Ellenbroek, A.A. (2010). Blockade of dopamine, but not noradrenaline, transporters produces hyperthermia in rats that lack serotonin transporters. European Journal of Pharmacology, 629(1-3), DCN 2 - CNS, IGMD 9 - Physiology, NCMLS 2B - Physiology - Oortgiesen, D.A.W., Meijer, G.J., Bronckers, A.L., Walboomers, X.F. & Jansen, J.A. (2010). Fenestration defects in the rabbit jaw: an inadequate model for studying periodontal regeneration. Tissue Engineering Part C Methods, 16(1), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Oostdijk, E.A., Smet, A.M. de, Blok, H.E., Thieme Groen, E.S., Asselt, G.J. van, Benus, R.F., Bernards, S.A., Frenay, I.H., Jansz, A.R., Jongh, B.M. de, Kaan, J.A., erstein-van Hall, M.A. Lev, Mascini, E.M., Pauw, W., Sturm, P.D.J., Thijsen, S.F., Kluytmans, J.A. & Bonten, M.J. (2010). Ecological effects of selective decontamination on resistant gram-negative bacterial colonization. American Journal of Respiratory and Critical Care Medicine, 181(5), N4i 1 - Intensive Care, N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Oosting, M., Berende, A., Sturm, P., Hofstede, H.J.M. ter, Jong, D.J. de, Kanneganti, T.D., Meer, J.W.M. van der, Kullberg, B.J., Netea, M.G. & Joosten, L.A.B. (2010). Recognition of Borrelia burgdorferi by NOD2 is central for the induction of an inflammatory reaction. Journal of Infectious Diseases, 201(12), N4i 1 - Gastroenterology, N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor) Ophof, R., Loo, L.M. van der, Maltha, J.C., Kuijpers-Jagtman, A.M. & den Hoff, J.W. Von (2010). Dentoalveolar development in beagle dogs after palatal repair with a dermal substitute. American Journal of Orthodontics and Dentofacial Orthopedics, 138(1), NCMLS 1C - Dentistry - O Toole, J.F., Liu, Y., Davis, E.E., Westlake, C.J., Attanasio, M., Otto, E.A., Seelow, D., Nurnberg, G., Becker, C., Nuutinen, M., Karppa, M., Ignatius, J., Uusimaa, J., Pakanen, S., Jaakkola, E., Heuvel, L.P.W.J. van den, Fehrenbach, H., Wiggins, R., Goyal, M., Zhou, W., Wolf, M.T., Wise, E., Helou, J., Allen, S.J., Murga-Zamalloa, C.A., Ashraf, S., Chaki, M., Heeringa, S., Chernin, G., Hoskins, B.E., Chaib, H., Gleeson, J., Kusakabe, T., Suzuki, T., Isaac, R.E., Quarmby, L.M., Tennant, B., Fujioka, H., Tuominen, H., Hassinen, I., Lohi, H., Houten, J.L. van, Rotig, A., Sayer, J.A., Rolinski, B., Freisinger, P., Madhavan, S.M., Herzer, M., Madignier, F., Prokisch, H., Nurnberg, P., Jackson, P.K., Khanna, H., Katsanis, N. & Hildebrandt, F. (2010). Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. Journal of Clinical Investigation, 120(3), IGMD 8 - Lab LGEM, IGMD 9 - Lab LGEM, IGMD 9 - Paediatrics, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics - Ott, M., Huls, M., Cornelius, M.G. & Fricker, G. (2010). St. John s Wort constituents modulate P-glycoprotein transport activity at the blood-brain barrier. Pharmaceutical Research, 27(5), NCMLS 2B - Pharm Tox - Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., Reeuwijk, J. van, Letteboer, S.J.F., Sang, L., Giles, R.H., Liu, Q., Coene, K.L.M., Estrada-Cuzcano, A., Collin, R.W.J., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermuller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nurnberg, G., Nurnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H. & Hildebrandt, F. (2010). Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nature Genetics, 42(10), IGMD 3 - Ophthalmology, IGMD 9 - Hum Gen, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor) Oude Lashof, A.M.L., Janssen, J.J.W.M., Meis, J.F.G.M., Warris, A., van t Wout, J.W., Natsch, S.S., van Zanten, A.R.H., Verweij, P.E. & Kullberg, B.J. (2010). SWAB-richtlijn voor de behandeling van invasieve schimmelinfecties. Nederlands Tijdschrift voor Medische Microbiologie, 18, N4i 1 NCMLS 1A - Med Microbiol - Ouedraogo, A.L., Bousema, T., Vlas, S.J. de, Cuzin-Ouattara, N., Verhave, J.P., Drakeley, C., Luty, A.J.F. & Sauerwein, R.W. (2010). The plasticity of Plasmodium falciparum gametocytaemia in relation to age in Burkina Faso. Malaria Journal, 9, N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - 86 Scientific publications 2010 NCMLS

87 Overbeek, L.I.H., Hermens, R.P.M.G., Krieken, J.H.J.M. van, Adang, E.M.M., Casparie, M., Nagengast, F.M., Ligtenberg, M.J.L. & Hoogerbrugge-van der Linden, N. (2010). Electronic reminders for pathologists promote recognition of patients at risk for Lynch syndrome: cluster-randomised controlled trial. Virchows Archiv, 456(6), IGMD 2 - Hum Genet, IGMD 3 - Hum Gen, NCEBP 1 - Hum Gen, NCEBP 4 - IQ, NCMLS 3A - Hum Gen, ONCOL 1 - Gastroenterology, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology, ONCOL 3 - Hum Gen, ONCOL 3 - Pathology, ONCOL 4 - EBH, ONCOL 5 - Surgery - Papadopoulos, A.I., Ferwerda, B., Antoniadou, A., Sakka, V., Galani, L., Kavatha, D., Panagopoulos, P., Poulakou, G., Kanellakopoulou, K., Meer, J.W.M. van der, Giamarellos-Bourboulis, E.J. & Netea, M.G. (2010). Association of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms with increased infection risk in patients with advanced HIV-1 infection. Clinical Infectious Diseases, 51(2), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Pavet, V., Beyrath, J., Pardin, C., Morizot, A., Lechner, M.C., Briand, J.P., Wendland, M., Maison, W., Fournel, S., Micheau, O., Guichard, G. & Gronemeyer, H. (2010). Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. Cancer Research, 70(3), IGMD 8 - Pharm Tox, NCMLS 2B - Pharm Tox - Person, A.D., Beiraghi, S., Sieben, C.M., Hermanson, S., Neumann, A.N., Robu, M.E., Schleiffarth, J.R., Billington CJ, J.r., Bokhoven, J.H.L.M. van, Hoogeboom, J.M., Mazzeu, J.F., Petryk, A., Schimmenti, L.A., Brunner, H.G., Ekker, S.C. & Lohr, J.L. (2010). WNT5A mutations in patients with autosomal dominant Robinow syndrome. Developmental Dynamics, 239(1), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Pettifer, S., Ison, J., Kalas, M., Thorne, D., McDermott, P., Jonassen, I., Liaquat, A., Fernandez, J.M., Rodriguez, J.M., Pisano, D.G., Blanchet, C, Uludag, M., Rice, P., Bartaseviciute, E., Rapacki, K., Hekkelman, M., Sand, O., Stockinger, H., Clegg, A.B., Bongcam-Rudloff, E., Salzemann, J., Breton, V., Attwood, T.K., Cameron, G. & Vriend, G. (2010). The EMBRACE web service collection. Nucleic Acids Research, 38 (Web Server issue), W NCMLS 3A - CMBI, NCMLS 3B - CMBI - Pfeiffer, M.J. & Schalken, J.A. (2010). Stem cell characteristics in prostate cancer cell lines. European Urology, 57(2), NCMLS 3A - Urology, ONCOL 3 - Urology, ONCOL 5 - Urology - Pfeiffer, M.J., Mulders, P.F.A. & Schalken, J.A. (2010). An in vitro model for preclinical testing of endocrine therapy combinations for prostate cancer. Prostate, 70(14), NCMLS 3A - Urology, ONCOL 3 - Urology, ONCOL 5 - Urology - Wetensch. publ. refereed (artikel - letter to the editor) Phylipsen, M., Prior, J.F., Lim, E., Lingam, N., Vogelaar, I.P., Giordano, P.C., Finlayson, J. & Harteveld, C.L. (2010). Thalassemia in Western Australia: 11 novel deletions characterized by Multiplex Ligation-dependent Probe Amplification. Blood Cells Molecules and Diseases, 44(3), NCMLS 3A - Hum Gen - Phylipsen, M., Vogelaar, I.P., Schaap, R.A., Arkesteijn, S.G., Boxma, G.L., Helden, W.C. van, Wildschut, I.C., Bruin-Roest, A.C. de, Giordano, P.C. & Harteveld, C.L. (2010). A new alpha(0)-thalassemia deletion found in a Dutch family ( (AW)). Blood Cells Molecules and Diseases, 45(2), NCMLS 3A - Hum Gen - Pietrella, D., Rachini, A., Pandey, N., Schild, L., Netea, M.G., Bistoni, F., Hube, B. & Vecchiarelli, A. (2010). The Inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity. Infection and Immunity, 78(11), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Pijl, B.J., Theelen, T., Tilanus, M.A.D., Rentenaar, R. & Crama, N. (2010). Acute endophthalmitis after cataract surgery: 250 consecutive cases treated at a tertiary referral center in the Netherlands. American Journal of Ophthalmology, 149(3), e N4i 1 - Med Microbiol, NCEBP 2 - Opthalmology, NCMLS 1A - Med Microbiol - Pijpe, A., Manders, P., Brohet, R.M., Collee, J.M., Verhoef, S., Vasen, H.F., Hoogerbrugge-van der Linden, N., Asperen, C.J. van, Dommering, C., Ausems, M.G.E.M., Aalfs, C.M., Gomez-Garcia, E.B., n t Veer, L.J. Va, Leeuwen, F.E. van & Rookus, M.A. (2010). Physical activity and the risk of breast cancer in BRCA1/2 mutation carriers. Breast Cancer Research and Treatment, 120(1), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol - Pijpe, A., Manders, P., Mulder, R.L., Leeuwen, F.E. van & Rookus, M.A. (2010). Reliability of self-reported diagnostic radiation history in BRCA1/2 mutation carriers. European Journal of Epidemiology, 25(2), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology - Pistorius, A.M.A., Luten, M., Bosman, G.J.C.G.M. & Degrip, W.J. (2010). A single assay for multiple storage-sensitive red blood cell characteristics by means of infrared spectroscopy. Transfusion, 50(2), NCMLS 3B - Biochemistry - Wetensch. publ. refereed (artikel - letter to the editor) Plantinga, T.S., Fransen, J., Takahashi, N., Stienstra, R., Riel, P.L.C.M. van, Berg, W.B. van den, Netea, M.G. & Joosten, L.A.B. (2010). Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis. Arthritis Research & Therapy, 12(1), R26. - IGMD 8 - Lab LGEM, N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCEBP 2 - Rheumatology, NCEBP 5 - Rheumatology, NCMLS 1A - Gen Int Med, NCMLS 1A - Rheumatology - Plantinga, T.S., Hamza, O.J., Willment, J.A., Ferwerda, B., Geer, N.M. van de, Verweij, P.E., Matee, M.I.N., Banahan, K., O Neill, L.A., Kullberg, B.J., Brown, G.D., Ven, A.J.A.M. van der & Netea, M.G. (2010). Genetic variation of innate immune genes in HIV-infected african patients with or without oropharyngeal candidiasis. JAIDS-Journal of Acquired Immune Deficiency Syndromes, 55(1), N4i 1 - Med Microbiol, N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med, NCMLS 1A - Med Microbiol - Ploussard, G., Haese, A., Poppel, H. van, Marberger, M., Stenzl, A., Mulders, P.F.A., Huland, H., Bastien, L., Abbou, C.C., Remzi, M., Tinzl, M., Feyerabend, S., Stillebroer, A.B., Gils, M.P.M.Q., Schalken, J.A. & Taille, A. De La (2010). The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free-to-total prostate-specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies? BJU International, 106(8), NCMLS 3A - Urology, ONCOL 3 - Urology, ONCOL 5 - Urology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Pohjoismaki, J.L., Holmes, J.B., Wood, S.R., Yang, M.Y., Yasukawa, T., Reyes, A., Bailey, L.J., Cluett, T.J., Goffart, S., Willcox, S., Rigby, R.E., Jackson, A.P., Spelbrink, J.N., Griffith, J.D., Crouch, R.J., Jacobs, H.T. & Holt, I.J. (2010). Mammalian mitochondrial DNA replication intermediates are essentially duplex but contain extensive tracts of RNA/DNA hybrid. Journal of Molecular Biology, 397(5), IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics - Polzer, K., Joosten, L., Gasser, J., Distler, J.H., Ruiz, G., Baum, W., Redlich, K., Bobacz, K., Smolen, J.S., Berg, W. van den, Schett, G. & Zwerina, J. (2010). Interleukin-1 is essential for systemic inflammatory bone loss. Annals of the Rheumatic Diseases, 69(1), N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Gen Int Med, NCMLS 1A - Rheumatology - Poole, R., Blake, S., Buschmann, M., Goldring, S., Laverty, S., Lockwood, S., Matyas, J., McDougall, J., Pritzker, K., Rudolphi, K., Berg, W. van den & Yaksh, T. (2010). Recommendations for the use of preclinical models in the study and treatment of osteoarthritis. Osteoarthritis & Cartilage, 18 Suppl 3, S N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Posma, L.A., Hendriks, T., Verhofstad, A.A.J., Man, B.M. de, Lomme, R.M.L.M. & Bleichrodt, R.P. (2010). Reduction of oxygenation and blood flow in pedicled bowel segments in the rat and its consequences for anastomotic healing. Diseases of the Colon & Rectum, 53(1), NCMLS 1C - Surgery - Annual Report 2010 Scientific publications

88 Post, R.S. van der, Kiemeney, L.A.L.M., Ligtenberg, M.J.L., Witjes, J.A., rgen-van de Kaa, C.A. Hulsbe, Bodmer, D., Schaap, L., Kets, C.M., Krieken, J.H.J.M. van & Hoogerbrugge-van der Linden, N. (2010). Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. Journal of Medical Genetics, 47(7), NCEBP 1 - Hum Gen, NCEBP 1 - Urology, NCEBP 2 - EBH, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology, ONCOL 1 - Urology, ONCOL 3 - Urology, ONCOL 5 - EBH - Wetensch. publ. refereed (artikel - letter to the editor) Prasad, T., Keerthikumar, S., Chaerkady, R., Kandasamy, K., Renuse, S., Marimutha, A., Venugopal, A., Thomas, J., Jacob, H., Goel, R., Pawar, H., Sahasrabuddhe, N., Krishna, V., Nair, B., Gucek, M., Cole, R., Ravikumar, R., Harsha, H. & Pandey, A. (2010). Comparative Proteomic Analysis of Candida albicans and Candida glabrata. Clinical Proteomics, 6(4), IGMD 8 - CMBI, NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Prodanov, L., Riet, J. te, Lamers, E., Domanski, M., Luttge, R., Loon, J.J.W.A. van, Jansen, J.A. & Walboomers, X.F. (2010). The interaction between nanoscale surface features and mechanical loading and its effect on osteoblast-like cells behavior. Biomaterials, 31(30), NCMLS 1B - Tumorimmunology, NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Raaijmakers, R., Gajjar, P., Schroder, C. & Nourse, P. (2010). Peritonitis in children on peritoneal dialysis in Cape Town, South Africa: epidemiology and risks. Pediatric Nephrology, 25(10), IGMD 9 - Paediatrics, NCMLS 2A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor) Radstake, T.R.D.J., Gorlova, O., Rueda, B., Martin, J.E., Alizadeh, B.Z., Palomino-Morales, R., Coenen, M.J.H., Vonk, M.C., Voskuyl, A.E., Schuerwegh, A.J., Broen, J.C., Riel, P.L.C.M. van, Slot, R. van t, Italiaander, A., Ophoff, R.A., Riemekasten, G., Hunzelmann, N., Simeon, C.P., Ortego-Centeno, N., Gonzalez-Gay, M.A., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Herrick, A., Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P., Westhovens, R., Kreuter, A., Kiener, H., Baere, E. de, Witte, T.J.M. de, Padykov, L., Klareskog, L., Beretta, L., Scorza, R., Lie, B.A., Hoffmann-Vold, A.M., Carreira, P., Varga, J., Hinchcliff, M., Gregersen, P.K., Lee, A.T., Ying, J., Han, Y., Weng, S.F., Amos, C.I., Wigley, F.M., Hummers, L., Nelson, J.L., Agarwal, S.K., Assassi, S., Gourh, P., Tan, F.K., Koeleman, B.P., Arnett, F.C., Martin, J. & Mayes, M.D. (2010). Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nature Genetics, 42(5), IGMD 3 - Hum Gen, N4i 4 - Rheumatology, NCEBP 1 - Hum Gen, NCEBP 2 - Rheumatology, NCEBP 5 - Rheumatology, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Rajagopalan, S., Moyle, M.W., Joosten, I. & Long, E.O. (2010). DNA-PKcs controls an endosomal signaling pathway for a proinflammatory response by natural killer cells. Sci Signal, 3(110), ra14. - N4i 4 - Lab LMI, NCMLS 1B - Lab LMI - Wetensch. publ. refereed (artikel - letter to the editor) Rao, P.N., Li, W., Vissers, L.E.L.M., Veltman, J.A. & Ophoff, R.A. (2010). Recurrent inversion events at 17q21.31 microdeletion locus are linked to the MAPT H2 haplotype. Cytogenetic and Genome Research, 129(4), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Ree, J.H., Jeganathan, K.B., Malureanu, L. & Deursen, J.M.A. van (2010). Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. Journal of Cell Biology, 188(1), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Reeuwijk, J. van, Olderode-Berends, M.J., Elzen, C. van den, Brouwer, O.F., Roscioli, T., Pampus, M.G. van, Scheffer, H., Brunner, H.G., Bokhoven, J.H.L.M. van & Hol, F.A. (2010). A homozygous FKRP start codon mutation is associated with Walker-Warburg syndrome, the severe end of the clinical spectrum. Clinical Genetics, 78(3), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Reichel, V., Klas, J., Fricker, G. & Masereeuw, R. (2010). Fluo-cAMP is transported by multidrug resistance-associated protein isoform 4 in rat choroid plexus. Journal of Neurochemistry, 115(1), NCMLS 2B - Pharm Tox - Reijden, B.A. van der, Massop, M., Simons, A., Witte, T.J.M. de, Breuning, M. & Jansen, J.H. (2010). The NDE1 gene is disrupted by the inv(16) in 90% of cases with CBFB-MYH11-positive acute myeloid leukemia. Leukemia, 24(4), NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Reijmerink, N.E., Bottema, R.W., Kerkhof, M. van de, Gerritsen, J., Stelma, F.F., Thijs, C., Schayck, C.P. van, Smit, H.A., Brunekreef, B., Koppelman, G.H. & Postma, D.S. (2010). TLR-related pathway analysis: novel gene-gene interactions in the development of asthma and atopy. Allergy, 65(2), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Richter, R., Rorbach, J., Pajak, A., Smith, P.M., Wessels, H.J., Huynen, M.A., Smeitink, J.A.M., Lightowlers, R.N. & Chrzanowska-Lightowlers, Z.M. (2010). A functional peptidyl-trna hydrolase, ICT1, has been recruited into the human mitochondrial ribosome. EMBO Journal, 29(6), IGMD 8 - CMBI, IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - CMBI - Riet, J. te, Smit, T., Gerritsen, J.W., Cambi, A., Elemans, J.A., Figdor, C.G. & Speller, S. (2010). Molecular friction as a tool to identify functionalized alkanethiols. Langmuir, 26(9), NCMLS 1B - Tumorimmunology - Rijkers, K., Mescheriakova, J., Majoie, M., Lemmens, E., Wijk, X. van, Philippens, M., Kranen-Mastenbroek, V. Van, Schijns, O., Vles, J. & Hoogland, G. (2010). Polymorphisms in CACNA1E and Camk2d are associated with seizure susceptibility of Sprague-Dawley rats. Epilepsy Research, 91(1), NCMLS 1C - Biochemistry - Ritfeld, G.J., Nandoe Tewarie, R.D.S., Rahiem, S.T., Hurtado, A., Roos, R.A., Grotenhuis, A. & Oudega, M. (2010). Reducing macrophages to improve bone marrow stromal cell survival in the contused spinal cord. Neuroreport, 21(3), DCN 1 - Neurosurgery, NCMLS 1C - Neurosurgery - Rizzetto, L., Kuka, M., Filippo, C. De, Cambi, A., Netea, M.G., Beltrame, L., Napolitani, G., Torcia, M.G., D Oro, U. & Cavalieri, D. (2010). Differential IL-17 production and mannan recognition contribute to fungal pathogenicity and commensalism. Journal of Immunology, 184(8), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med, NCMLS 1B - Tumorimmunology - Robert, G., Salagierski, M., Schalken, J.A. & Taille, A. De La (2010). [Inflammation and benign prostatic hyperplasia: cause or consequence?]. Progres en Urologie, 20(6), NCMLS 3A - Urology, ONCOL 3 - Urology, ONCOL 5 - Urology - Wetensch. publ. refereed (artikel - letter to the editor) Robinson, M.D., Stirzaker, C., Statham, A.L., Coolen, M.W., Song, J.Z., Nair, S.S., Strbenac, D., Speed, T.P. & Clark, S. J. (2010). Evaluation of affinity-based genome-wide DNA methylation data: effects of CpG density, amplification bias, and copy number variation. Genome Res, 20(12), NCMLS 3A - Hum Gen - Rodenhuis-Zybert, I.A., Schaar, H.M. van der, Silva Voorham, J.M. da, Ende-Metselaar, H. van der, Lei, H.Y., Wilschut, J. & Smit, J.M. (2010). Immature dengue virus: a veiled pathogen? PLoS Pathogens, 6(1), e N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Roosenburg, S., Laverman, P., Joosten, L., Eek, A., Oyen, W.J.G., Jong, M. de, Rutjes, F.P.J.T., Delft, F.L. van & Boerman, O.C. (2010). Stabilized (111)in-labeled scck8 analogues for targeting CCK2-receptor positive tumors: synthesis and evaluation. Bioconjugate Chemistry, 21(4), NCMLS 1B - Nuclear Med - 88 Scientific publications 2010 NCMLS

89 Rops, A.L., Figdor, C.G., Schaaf, A. van der, Tamboer, W.P.M., Bakker, M., Berden, J.H.M., Dijkman, H.B.P.M., Steenbergen, E.J., Vlag, J. van der & Spriel, A.B. van (2010). The tetraspanin CD37 protects against glomerular IgA deposition and renal pathology. American Journal of Pathology, 176(5), N4i 4 - Nephrology, NCMLS 1B - Tumorimmunology, NCMLS 1C - Nephrology, ONCOL 3 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Rostagno, P., Wolchinsky, Z., Vigano, A.M., Shivtiel, S., Zhou, H., Bokhoven, J.H.L.M. van, Ferone, G., Missero, C., Mantovani, R., Aberdam, D. & Virolle, T. (2010). Embryonic stem cells as an ectodermal cellular model of human p63-related dysplasia syndromes. Biochemical and Biophysical Research Communications, 395(1), DCN 2 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Ruijs, M.W., Verhoef, S., Rookus, M.A., Pruntel, R., Hout, A.H. van der, Hogervorst, F.B.L., Kluijt, I., Sijmons, R.H., Aalfs, C.M., Wagner, A., Ausems, M.G.E.M., Hoogerbrugge-van der Linden, N., Asperen, C.J. van, Gomez Garcia, E.B., Meijers-Heijboer, H., Kate, L.P. Ten, Menko, F.H. & Veer, L.J. van t (2010). TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. Journal of Medical Genetics, 47(6), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol - Ruiter, A. de, Bilt, A. van der, Meijer, G. & Koole, R. (2010). Orthodontic treatment results following grafting autologous mandibular bone to the alveolar cleft in patients with a complete unilateral cleft. Cleft Palate-Craniofacial Journal, 47(1), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Sagar, B., Marres, H.A.M. & Hartman, E.H.M. (2010). Hypopharyngeal reconstruction with an anterolateral thigh flap after laryngopharyngeal resection: results of a retrospective study on 20 patients. Journal of Plastic Reconstructive and Aesthetic Surgery, 63(6), NCMLS 1C - Plastic Surgery, ONCOL 3 - Otorhinolaryn - Salagierski, M., Verhaegh, G.W.C.T., Jannink, S.A., Smit, F.P., Hessels, D. & Schalken, J.A. (2010). Differential expression of PCA3 and its overlapping PRUNE2 transcript in prostate cancer. Prostate, 70(1), NCMLS 3A - Urology, ONCOL 3 - Urology, ONCOL 5 - Urology - Sama, I.E. & Huynen, M.A. (2010). Measuring the physical cohesiveness of proteins using physical interaction enrichment. Bioinformatics, 26(21), IGMD 8 - CMBI, NCMLS 2A - CMBI - Sambuughin, N., Yau, K.S., Olive, M., Duff, R.M., Bayarsaikhan, M., Lu, S., Gonzalez-Mera, L., Sivadorai, P., Nowak, K.J., Ravenscroft, G., Mastaglia, F.L., North, K.N., Ilkovski, B., Kremer, J.M.J., Lammens, M.M.Y., Engelen, B.G.M. van, Fabian, V., Lamont, P., Davis, M.R., Laing, N.G. & Goldfarb, L.G. (2010). Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. American Journal of Human Genetics, 87(6), DCN 1 - Pathology, DCN 2 - Neurology, DCN 2 - Otorhinolaryn, NCMLS 3A - Otorhinolaryn - Wetensch. publ. refereed (artikel - letter to the editor) Sanchez, C.J., Shivshankar, P., Stol, K., Trakhtenbroit, S., Sullam, P.M., Sauer, K., Hermans, P.W.M. & Orihuela, C.J. (2010). The pneumococcal serine-rich repeat protein is an intra-species bacterial adhesin that promotes bacterial aggregation in vivo and in biofilms. PLoS Pathogens, 6(8). - N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - San-Cristobal, P., Dimke, H., Hoenderop, J.G.J. & Bindels, R.J.M. (2010). Novel molecular pathways in renal Mg2+ transport: a guided tour along the nephron. Current Opinion in Nephrology and Hypertension, 19(5), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Sandoval, J., Pereda, J., Rodriguez, J.L., Escobar, J., Hidalgo, J., Joosten, L.A.B., Franco, L., Sastre, J. & Lopez-Rodas, G. (2010). Ordered transcriptional factor recruitment and epigenetic regulation of tnf-alpha in necrotizing acute pancreatitis. Cellular Molecular Life Science, 67(10), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Santegoets, Kim, Bon, L. van, Wenink, M.H. & Berg, W.B. van den (2010). Antigen-presenting cells and their Fcy and Toll-like receptors: Leading suspects in autoimmunity. The open Arthritis Journal, 3, NCMLS 1A - N4i 4 - Rheumatol - Wetensch. publ. refereed (artikel - letter to the editor) Sauerwein, R.W., Bijker, E.M. & Richie, T.L. (2010). Empowering malaria vaccination by drug administration. Current Opinion in Immunology, 22(3), N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Schaap-Oziemlak, A.M., Raymakers, R.A.P., Bergevoet, S.M., Gilissen, C., Jansen, B.J.H., Adema, G.J., Kogler, G., Sage, C. le, Agami, R., Reijden, B.A. van der & Jansen, J.H. (2010). MicroRNA hsa-mir-135b regulates mineralization in osteogenic differentiation of human unrestricted somatic stem cells. Stem Cells and Development, 19(6), NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Lab LH - Schaijk, B.C.L. van, Vos, M.W., Janse, C.J., Sauerwein, R.W. & Khan, S.M. (2010). Removal of heterologous sequences from Plasmodium falciparum mutants using FLPe-recombinase. PLoS ONE, 5(11), e N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Schmeits, P.C., Hermans, M.H., Geest-Daalderop, J.H. van, Poodt, J., Sauvage Nolting, P.R. de & Conemans, J.M. (2010). VKORC1 mutations in patients with partial resistance to phenprocoumon. British Journal of Haematology, 148(6), NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Schmid, F., Glaus, E., Cremers, F.P.M., Kloeckener-Gruissem, B., Berger, W. & Neidhardt, J. (2010). Mutation- and tissue-specific alterations of RPGR transcripts. Investigative Ophthalmology & Visual Science, 51(3), NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Schmidt, S. & Friedl, P.H.A. (2010). Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms. Cell and Tissue Research, 339(1), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Schoffelen, R., Graaf, W.T.A. van der, Franssen, G., Sharkey, R.M., Goldenberg, D.M., McBride, W.J., Rossi, E.A., Eek, A., Oyen, W.J.G. & Boerman, O.C. (2010). Pretargeted 177Lu radioimmunotherapy of carcinoembryonic antigen-expressing human colonic tumors in mice. Journal of Nuclear Medicine, 51(11), NCMLS 1B - Nuclear Med, ONCOL 3 - Med Oncol, ONCOL 3 - Nuclear Med - Wetensch. publ. refereed (artikel - letter to the editor) Schoffelen, R., Sharkey, R.M., Goldenberg, D.M., Franssen, G., McBride, W.J., Rossi, E.A., Chang, C.H., Laverman, P., Disselhorst, J.A., Eek, A., Graaf, W.T.A. van der, Oyen, W.J.G. & Boerman, O.C. (2010). Pretargeted immuno-positron emission tomography imaging of carcinoembryonic antigen-expressing tumors with a bispecific antibody and a 68Ga- and 18F-labeled hapten peptide in mice with human tumor xenografts. Molecular Cancer Therapeutics, 9(4), NCMLS 1B - Nuclear Med, ONCOL 3 - Med Oncol, ONCOL 3 - Nuclear Med - Wetensch. publ. refereed (artikel - letter to the editor) Schots, J.M., Fechner, M.R., Hoogbergen, M.M. & Tits, H.W.H.J. (2010). Malrotation of the McGhan Style 510 prosthesis. Plastic and Reconstructive Surgery, 126(1), NCMLS 1C - Plastic Surgery - Schouten, C., Beucken, J.J.J.P van den, Meijer, G.J., Sommerdijk, N.A., Spauwen, P.H.M. & Jansen, J.A. (2010). In vivo bioactivity of DNA-based coatings: an experimental study in rats. Journal of Biomedical Materials Research Part A, 92(3), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Annual Report 2010 Scientific publications

90 Schouten, C., Meijer, G.J., Beucken, J.J.J.P van den, Leeuwenburgh, S.C.G., Jonge, L.T. de, Wolke, J.G.C., Spauwen, P.H.M. & Jansen, J.A. (2010). In vivo bone response and mechanical evaluation of electrosprayed CaP nanoparticle coatings using the iliac crest of goats as an implantation model. Acta Biomaterialia, 6(6), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry, NCMLS 1C - Plastic Surgery - Wetensch. publ. refereed (artikel - letter to the editor) Schouten, C., Meijer, G.J., Beucken, J.J.J.P van den, Spauwen, P.H.M. & Jansen, J.A. (2010). A novel implantation model for evaluation of bone healing response to dental implants: the goat iliac crest. Clinical Oral Implants Research, 21(4), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry, NCMLS 1C - Plastic Surgery - Schraders, M., Lee, K., Oostrik, J., Huygen, P.L.M., Ali, G., Hoefsloot, L.H., Veltman, J.A., Cremers, F.P.M., Basit, S., Ansar, M., Cremers, C.W.R.J., Kunst, H.P.M., Ahmad, W., Admiraal, R.J.C., Leal, S.M. & Kremer, J.M.J. (2010). Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment. American Journal of Human Genetics, 86(2), DCN 2 - Otorhinolaryn, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen, NCMLS 3A - Otorhinolaryn - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Schraders, M., Oostrik, J., Huygen, P.L.M., Strom, T.M., Wijk, E. van, Kunst, H.P.M., Hoefsloot, L.H., Cremers, C.W.R.J., Admiraal, R.J.C. & Kremer, J.M.J. (2010). Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. American Journal of Human Genetics, 86(4), DCN 2 - Hum Gen, DCN 2 - Otorhinolaryn, IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen, NCMLS 3A - Otorhinolaryn - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Schreibelt, G., Benitez-Ribas, D., Schuurhuis, D., Lambeck, A.J.A., Hout-Kuijer, M. van, Schaft, N., Punt, C.J.A., Figdor, C.G., Adema, G.J. & Vries, I.J.M. de (2010). Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells. Blood, 116(4), NCMLS 1B - Med Oncol, NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Schreibelt, G., Tel, J., Sliepen, K.H., Benitez-Ribas, D., Figdor, C.G., Adema, G.J. & Vries, I.J.M. de (2010). Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunology Immunotherapy, 59(10), NCMLS 1B - Med Oncol, NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Schreinemacher, M.H., Broek, R.P. Ten, Bakkum, E.A., Goor, H. van & Bouvy, N.D. (2010). Adhesion awareness: a national survey of surgeons. World Journal of Surgery, 34(12), NCMLS 1C - Surgery - Schuemie, M.J., Kang, N., Hekkelman, M.L. & Kors, J.A. (2010). GeneE: gene and protein query expansion with disambiguation. Bioinformatics, 26(1), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Schulte, B.M., Bakkers, J., Lanke, K.H.W., Melchers, W.J.G., Westerlaken, C., Allebes, W., Aanstoot, H.J., Bruining, G.J., Adema, G.J., Kuppeveld, F.J.M. van & Galama, J.M.D. (2010). Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection. Viral Immunol, 23(1), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol, NCMLS 1B - Tumorimmunology - Schulte, B.M., Kramer, M., Ansems, M., Lanke, K.H.W., Doremalen, N. van, Piganelli, J.D., Bottino, R., Trucco, M., Galama, J.M.D., Adema, G.J. & Kuppeveld, F.J.M. van (2010). Phagocytosis of enterovirus-infected pancreatic beta-cells triggers innate immune responses in human dendritic cells. Diabetes, 59(5), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol, NCMLS 1B - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Schurch, A.C., Kremer, K., Daviena, O., Kiers, A., Boeree, M.J., Siezen, R.J. & Soolingen, D. van (2010). High-resolution typing by integration of genome sequencing data in a large tuberculosis cluster. Journal of Clinical Microbiology, 48(9), NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Schurch, A.C., Kremer, K., Kiers, A., Daviena, O., Boeree, M.J., Siezen, R.J., Smith, N.H. & Soolingen, D. van (2010). The tempo and mode of molecular evolution of Mycobacterium tuberculosis at patient-to-patient scale. Infect Genet Evol, 10(1), NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Schuwirth, L., Bosman, G., Henning, R.H., Rinkel, R. & Wenink, A.C. (2010). Collaboration on progress testing in medical schools in the Netherlands. Medical Teacher, 32(6), NCMLS 3B - Biochemistry - Shang, S., Yang, F., Cheng, X., Walboomers, X.F. & Jansen, J.A. (2010). The effect of electrospun fibre alignment on the behaviour of rat periodontal ligament cells. Eur Cell Mater, 19, NCMLS 1C - Dentistry - Shekalaghe, S.A., Braak, R. ter, Daou, M., Kavishe, R., Bijllaardt, W. van den, Bosch, S. van den, Koenderink, J.B., Luty, A.J.F., Whitty, C.J., Drakeley, C., Sauerwein, R.W. & Bousema, T. (2010). In Tanzania, hemolysis after a single dose of primaquine coadministered with an artemisinin is not restricted to glucose-6-phosphate dehydrogenase-deficient (G6PD A-) individuals. Antimicrobial Agents and Chemotherapy, 54(5), N4i 3 - Med Microbiol, N4i 3 - Pharm Tox, NCMLS 1A - Med Microbiol, NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Shi, X., Mierlo, J.T. van, French, A. & Elliott, R.M. (2010). Visualizing the replication cycle of bunyamwera orthobunyavirus expressing fluorescent protein-tagged Gc glycoprotein. Journal of Virology, 84(17), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Shoubridge, C., Tan, M.H., Fullston, T., Cloosterman, D., Coman, D., McGillivray, G., Mancini, G.M., Kleefstra, T. & Gecz, J. (2010). Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division. Pathogenetics, 3, 1. - IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Siemiatkowska, A., Bieniaszewska, M., Hellmann, A. & Limon, J. (2010). JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms. Leukemia Research, 34(3), IGMD 3 - Ophthalmology, NCMLS 3A - Ophthalmology - Wetensch. publ. refereed (artikel - letter to the editor) Sieuwerts, A.M., Ansems, M., Look, M.P., Span, P.N., Weerd, V. de, Galen, A. van, Foekens, J.A., Adema, G.J. & Martens, J.W. (2010). Clinical significance of the nuclear receptor co-regulator DC-SCRIPT in breast cancer: an independent retrospective validation study. Breast Cancer Research, 12(6), R103-R NCMLS 1B - Tumorimmunology, ONCOL 3 - Rad Oncol - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Siezen, R.J. & Hijum, S.A.F.T. van (2010). Genome (re-)annotation and open-source annotation pipelines. Microbial Biotechnology, 3(4), NCMLS 2A - CMBI - Siezen, R.J. & Wilson, G. (2010). Probiotics genomics. Microbial Biotechnology, 3(1), NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Siezen, R.J., Bayjanov, J., Renckens, B., Wels, M., Hijum, S.A.F.T. van, Molenaar, D & Hylckama Vlieg, J.E. van (2010). Complete genome sequence of Lactococcus lactis subsp. lactis KF147, a plant-associated lactic acid bacterium. Journal of Bacteriology, 192(10), NCMLS 2A - CMBI - Siezen, R.J., Tzeneva, V.A., Castioni, A., Wels, M., Phan, H.T., Rademaker, J.L., Starrenburg, M.J., Kleerebezem, M, Molenaar, D & Hylckama Vlieg, J.E. van (2010). Phenotypic and genomic diversity of Lactobacillus plantarum strains isolated from various environmental niches. Environmental Microbiology, 12(3), NCMLS 2A - CMBI - 90 Scientific publications 2010 NCMLS

91 Siezen, R.J., Wilson, G. & Todt, T. (2010). Prokaryotic whole-transcriptome analysis: deep sequencing and tiling arrays. Microbial Biotechnology, 3(2), NCMLS 2A - CMBI - Siller-Matula, J.M., Bayer, G., Bergmeister, H., Quehenberger, P., Petzelbauer, P., Friedl, P.H.A., Mesteri, I. & Jilma, B. (2010). An experimental model to study isolated effects of thrombin in vivo. Thrombosis Research, 126(5), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Wetensch. publ. refereed (artikel - letter to the editor) Silvestrini, F., Lasonder, E., Olivieri, A., Camarda, G., Schaijk, B. van, Sanchez, M., Younis Younis, S., Sauerwein, R.W. & Alano, P. (2010). Protein export marks the early phase of gametocytogenesis of the human malaria parasite Plasmodium falciparum. Molecular & Cellular Proteomics, 9(7), IGMD 8 - CMBI, N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol, NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Simoes, A.S., Sa-Leao, R., Eleveld, M.J., Tavares, D.A., Carrico, J.A., Bootsma, H.J. & Hermans, P.W.M. (2010). Highly penicillin-resistant multidrug-resistant pneumococcus-like strains colonizing children in Oeiras, Portugal: genomic characteristics and implications for surveillance. Journal of Clinical Microbiology, 48(1), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, N4i 4 - Paediatrics, NCMLS 1A - Paediatrics - Sitharaman, B., Zande, M. van der, Ananta, J.S., Shi, X., Veltien, A., Walboomers, X.F., Wilson, L.J., Mikos, A.G., Heerschap, A. & Jansen, J.A. (2010). Magnetic resonance imaging studies on gadonanotube-reinforced biodegradable polymer nanocomposites. Journal of Biomedical Materials Research Part A, 93(4), NCMLS 1C - Dentistry, NCMLS 1C - Radiology - Sluis, G.L. Van, Nieuwdorp, M., Kamphuisen, T.P.W., Vlag, J. van der, Noorden, C.J.F. van & Spek, C.A. (2010). A low molecular weight heparin inhibits experimental metastasis in mice independently of the endothelial glycocalyx. PLoS ONE, 5(6), e N4i 4 - Nephrology, NCMLS 1C - Nephrology - Smeekens, S.P., Veerdonk, F.L. van de, Meer, J.W.M. van der, Kullberg, B.J., Joosten, L.A.B. & Netea, M.G. (2010). The Candida Th17 response is dependent on mannan- and beta-glucan-induced prostaglandin E2. International Immunology, 22(11), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Smit, D.J., Luciano, M., Bartels, M., Beijsterveldt, C.E. van, Wright, M.J., Hansell, N.K., Brunner, H.G., ourgie-van Burk, G.F. Est, Geus, E.J. de, Martin, N.G. & Boomsma, D.I. (2010). Heritability of head size in dutch and Australian twin families at ages 0-50 years. Twin Research and Human Genetics, 13(4), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Smits, K.M., Schouten, L.J., Hudak, E., Verhage, B., Dijk, B.A. van, rgen-van de Kaa, C.A. Hulsbe, Goldbohm, R.A., Oosterwijk, E. & Brandt, P.A. van den (2010). Body mass index and von Hippel-Lindau gene mutations in clear-cell renal cancer: Results of the Netherlands Cohort Study on diet and cancer. Annals of Epidemiology, 20(5), NCMLS 3A - Urology, ONCOL 3 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Smits, N.C., Kurup, S., Rops, A.L., Dam, G.B. ten, Massuger, L.F.A.G., Hafmans, T., Turnbull, J.E., Spillmann, D., Li, J.P., Kennel, S.J., Wall, J.S., Shworak, N.W., Dekhuijzen, P.N.R., Vlag, J. van der & Kuppevelt, A.H.M.S.M. van (2010). The heparan sulfate motif (GlcNS6S-IdoA2S)3, common in heparin, has a strict topography and is involved in cell behavior and disease. Journal of Biological Chemistry, 285(52), N4i 4 - Nephrology, NCMLS 1C - Biochemistry, NCMLS 1C - Nephrology, NCMLS 1C - Obs Gyn - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Smits, N.C., Shworak, N.W., Dekhuijzen, P.N.R. & Kuppevelt, A.H.M.S.M. van (2010). Heparan sulfates in the lung: structure, diversity, and role in pulmonary emphysema. Anat Rec (Hoboken), 293(6), N4i 1 - Pulmonary Diseases, NCMLS 1C - Biochemistry - Wetensch. publ. refereed (artikel - letter to the editor) Smits, P., Mattijssen, S., Morava, E., Brand, M. van den, Brandt, F. van den, Wijburg, F., Pruijn, G.J.M., Smeitink, J.A.M., Nijtmans, L., Rodenburg, R. & Heuvel, L.P.W.J. van den (2010). Functional consequences of mitochondrial trna Trp and trna Arg mutations causing combined OXPHOS defects. European Journal of Human Genetics, 18(3), IGMD 8 - Lab LGEM, NCMLS 2A - Lab LGEM, RU SCI IMM BMC - Smits, P., Smeitink, J.A.M. & Heuvel, L.P.W.J. van den (2010). Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol, 2010, IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, IGMD 9 - Paediatrics, NCMLS 2A - Lab LGEM - Snelders, E., Karawajczyk, A., Schaftenaar, G., Verweij, P.E. & Melchers, W.J.G. (2010). Azole resistance profile of amino acid changes in Aspergillus fumigatus CYP51A based on protein homology modeling. Antimicrobial Agents and Chemotherapy, 54(6), N4i 2 - Med Microbiol, NCMLS 1A - Med Microbiol, NCMLS 3B - CMBI - Snijders, B.E., Stelma, F.F., Reijmerink, N.E., Thijs, C., Steege, G. van der, Damoiseaux, J.G., Brandt, P.A. van den, Ree, R. van, Postma, D.S. & Koppelman, G.H. (2010). CD14 polymorphisms in mother and infant, soluble CD14 in breast milk and atopy development in the infant (KOALA Study). Pediatric Allergy and Immunology, 21(3), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Spanedda, M.V., Heurtault, B., Weidner, S., Baehr, C., Boeglin, E., Beyrath, J., Milosevic, S., Bourel-Bonnet, L., Fournel, S. & Frisch, B. (2010). Novel powerful water-soluble lipid immunoadjuvants inducing mouse dendritic cell maturation and B cell proliferation using TLR2 pathway. Bioorganic & Medicinal Chemistry Letters, 20(6), IGMD 8 - Pharm Tox, NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Spanholtz, J., Tordoir, M., Eissens, D., Preijers, F., Meer, A. van der, Joosten, I., Schaap, N., Witte, T.M. de & Dolstra, H. (2010). High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS ONE, 5(2), e N4i 4 - Lab LMI, NCMLS 1B - Haematology, NCMLS 1B - Lab LH, NCMLS 1B - Lab LMI, NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Spath, M.A., Nillesen, W.N., Smits, A.P.T., Feuth, T.B., Braat, D.D.M., Geurts van Kessel, A.H.M. & Yntema, H.G. (2010). X chromosome inactivation does not define the development of premature ovarian failure in fragile X premutation carriers. American Journal of Medical Genetics Part A, 152A(2), IGMD 3 - Hum Gen, NCEBP 12 - Obs Gyn, NCMLS 3A - Hum Gen - Spelbrink, J.N. (2010). Functional organization of mammalian mitochondrial DNA in nucleoids: history, recent developments, and future challenges. IUBMB Life, 62(1), IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor) Spriel, A.B. van & Figdor, C.G. (2010). The role of tetraspanins in the pathogenesis of infectious diseases. Microbes and Infection, 12(2), NCMLS 1B - Tumorimmunology - Srinivas, M., Aarntzen, E.H.J.G., Bulte, J.W., Oyen, W.J.G., Heerschap, A., Vries, I.J.M. de & Figdor, C.G. (2010). Imaging of cellular therapies. Advanced Drug Delivery Reviews, 62(11), NCMLS 1B - Radiology, NCMLS 1B - Tumorimmunology, ONCOL 3 - Nuclear Med, ONCOL 3 - Radiology, ONCOL 3 - Tumorimmunology - Srinivas, M., Cruz, L.J., Bonetto, F., Heerschap, A., Figdor, C.G. & Vries, I.J.M. de (2010). Customizable, multi-functional fluorocarbon nanoparticles for quantitative in vivo imaging using 19F MRI and optical imaging. Biomaterials, 31(27), NCMLS 1B - Tumorimmunology, NCMLS 3B - Radiology, ONCOL 3 - Radiology, ONCOL 3 - Tumorimmunology - Annual Report 2010 Scientific publications

92 Srinivas, M., Heerschap, A., Ahrens, E.T., Figdor, C.G. & Vries, I.J.M. de (2010). (19)F MRI for quantitative in vivo cell tracking. Trends in Biotechnology, 28(7), NCMLS 1B - Radiology, NCMLS 1B - Tumorimmunology, ONCOL 3 - Radiology, ONCOL 3 - Tumorimmunology - Staals, R.H.J., Bronkhorst, A.W., Schilders, G., Slomovic, S., Schuster, G., Heck, A.J.R. van, Raijmakers, R. & Pruijn, G.J.M. (2010). Dis3-like 1: a novel exoribonuclease associated with the human exosome. EMBO Journal, 29(14), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol, RU SCI IMM BMC - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Stary, A., Wacker, S.J., Boukharta, L., Zachariae, U., Karimi-Nejad, Y., Aqvist, J., Vriend, G. & Groot, B.L. de (2010). Toward a consensus model of the HERG potassium channel. ChemMedChem, 5(3), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Statham, A.L., Strbenac, D., Coolen, M.W., Stirzaker, C., Clark, S. J. & Robinson, M.D. (2010). Repitools: an R package for the analysis of enrichment-based epigenomic data. Bioinformatics, 26(13), NCMLS 3A - Hum Gen - Staudt, A., Herda, L.R., Trimpert, C., Lubenow, L., Landsberger, M., Dorr, M., Hummel, A., Eckerle, L.G., Beug, D., Muller, C., Hoffmann, W., Weitmann, K., Klingel, K., Kandolf, R., Kroemer, H.K., Greinacher, A. & Felix, S.B. (2010). Fcgamma-receptor IIa polymorphism and the role of immunoadsorption in cardiac dysfunction in patients with dilated cardiomyopathy. Clinical Pharmacology & Therapeutics, 87(4), IGMD 9 - Physiology, NCMLS 2B - Physiology - Stienstra, R., Joosten, L.A.B., Koenen, T., Tits, B. van, Diepen, J.A. van, Berg, Sanne van den, Rensen, P.C., Voshol, P.J., Fantuzzi, G., Hijmans, A., Kersten, S., Muller, M., Berg, W.B. van den, Rooijen, N. van, Wabitsch, M., Kullberg, B.J., Meer, J.W.M. van der, Kanneganti, T., Tack, C.J.J. & Netea, M.G. (2010). The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metabolism, 12(6), IGMD 5 - Gen Int Med, N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Storim, J., Brocker, E.B. & Friedl, P.H.A. (2010). A dynamic immunological synapse mediates homeostatic TCR-dependent and -independent signaling. European Journal of Immunology, 40(10), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Wetensch. publ. refereed (artikel - letter to the editor) Strange, A., Capon, F., Spencer, C.C., Knight, J., Weale, M.E., Allen, M.H., Barton, A., Band, G., Bellenguez, C., Bergboer, J.G.M., Blackwell, J.M., Bramon, E., Bumpstead, S.J., Casas, J.P., Cork, M.J., Corvin, A., Deloukas, P., Dilthey, A., Duncanson, A., Edkins, S., Estivill, X., Fitzgerald, O., Freeman, C., Giardina, E., Gray, E., Hofer, A., Huffmeier, U., Hunt, S.E., Irvine, A.D., Jankowski, J., Kirby, B., Langford, C., Lascorz, J., Leman, J., Leslie, S., Mallbris, L., Markus, H.S., Mathew, C.G., McLean, W.H.I., McManus, R., Mossner, R., Moutsianas, L., Naluai, A.T., Nestle, F.O., Novelli, G., Onoufriadis, A., Palmer, C.N., Perricone, C., Pirinen, M., Plomin, R., Potter, S.C., Pujol, R.M., Rautanen, A., Riveira-Munoz, E., Ryan, A.W., Salmhofer, W., Samuelsson, L., Sawcer, S.J., Schalkwijk, J., Smith, C.H., Stahle, M., Su, Z., Tazi-Ahnini, R., Traupe, H., Viswanathan, A.C., Warren, R.B., Weger, W., Wolk, K., Wood, N., Worthington, J., Young, H.S., Zeeuwen, P.L.J.M., Hayday, A., Burden, A.D., Griffiths, C.E., Kere, J., Reis, A., McVean, G., Evans, D.M., Brown, M.A., Barker, J.N., Peltonen, L., Donnelly, P. & Trembath, R.C. (2010). A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature Genetics, 42(11), NCMLS 1A - Dermatology - Streijger, F., Scheenen, W.J., Luijtelaar, G. van, Oerlemans, F., Wieringa, B. & Zee, C.E.E.M. van der (2010). Complete brain-type creatine kinase deficiency in mice blocks seizure activity and affects intracellular calcium kinetics. Epilepsia, 51(1), DCN 2 - Cell Biology, NCMLS 2A - Cell Biology - Sturm, P.D.J., Bochum, E.T., Mook-Vermulst, S.V. van, Handgraaf, C., Klaassen, T. & Melchers, W.J.G. (2010). Prevalence, molecular characterization, and phenotypic confirmation of extended-spectrum beta-lactamases in Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca at the Radboud University Nijmegen Medical Centre in The Netherlands. Microbial Drug Resistance, 16(1), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Sun, Y., Almomani, R., Aten, E., Celli, J., Heijden, J. van der, Venselaar, H., Robertson, S.P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., Dunnen, J.T. den & Breuning, M.H. (2010). Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. American Journal of Human Genetics, 87(1), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Supali, T., Verweij, J.J., Wiria, A.E., Djuardi, Y., Hamid, F., Kaisar, M.M., Wammes, L.J., Lieshout, L. van, Luty, A.J.F., Sartono, E. & Yazdanbakhsh, M. (2010). Polyparasitism and its impact on the immune system. International Journal for Parasitology, 40(10), N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Szklarczyk, R. & Huynen, M.A. (2010). Mosaic origin of the mitochondrial proteome. Proteomics, 10(22), IGMD 8 - CMBI, NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Tabassum, A., Meijer, G.J., Wolke, J.G.C. & Jansen, J.A. (2010). Influence of surgical technique and surface roughness on the primary stability of an implant in artificial bone with different cortical thickness: a laboratory study. Clinical Oral Implants Research, 21(2), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Tabassum, A., Walboomers, X.F., Wolke, J.G.C., Meijer, G.J. & Jansen, J.A. (2010). Bone particles and the undersized surgical technique. Journal of Dental Research, 89(6), NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Tang, L., Bergevoet, S.M., Gilissen, C., Witte, T.J.M. de, Jansen, J.H., Reijden, B.A. van der & Raymakers, R.A.P. (2010). Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells. BMC Pharmacol, 10, NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Taranta, A., Wilmer, M.J.G., Heuvel, L.P.W.J. van den, Bencivenga, P., Bellomo, F., Levtchenko, E.N. & Emma, F. (2010). Analysis of CTNS gene transcripts in nephropathic cystinosis. Pediatric Nephrology, 25(7), IGMD 9 - Lab LGEM, IGMD 9 - Paediatrics, IGMD 9 - Pharm Tox, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics, NCMLS 2B - Pharm Tox - Tatrai, P., Egedi, K., Somoracz, A., Kuppevelt, A.H.M.S.M. van, Dam, G. Ten, Lyon, M., Deakin, J.A., Kiss, A., Schaff, Z. & Kovalszky, I. (2010). Quantitative and qualitative alterations of heparan sulfate in fibrogenic liver diseases and hepatocellular cancer. Journal of Histochemistry & Cytochemistry, 58(5), NCMLS 1C - Biochemistry - Tchkonia, T., Morbeck, D.E., Zglinicki, T. von, Deursen, J.M.A. van, Lustgarten, J., Scrable, H., Khosla, S., Jensen, M.D. & Kirkland, J.L. (2010). Fat tissue, aging, and cellular senescence. Aging Cell, 9(5), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Wetensch. publ. refereed (artikel - letter to the editor) Tejero, R., Bierbaum, S., Douglas, T., Reinstorf, A., Worch, H. & Scharnweber, D. (2010). Glucuronic acid and phosphoserine act as mineralization mediators of collagen I based biomimetic substrates. Journal of Materials Science-Materials in Medicine, 21(2), NCMLS 1C - Dentistry - Tel, J., Lambeck, A.J., Cruz, L.J., Tacken, P.J., Vries, I.J.M. de & Figdor, C.G. (2010). Human plasmacytoid dendritic cells phagocytose, process, and present exogenous particulate antigen. Journal of Immunology, 184(8), NCMLS 1B - Med Oncol, NCMLS 1B - Tumorimmunology, ONCOL 3 - Tumorimmunology - 92 Scientific publications 2010 NCMLS

93 Tendeloo, V.F. Van, Velde, A. van de, Driessche, A. Van, Cools, N., Anguille, S., Ladell, K., Gostick, E., Vermeulen, K., Pieters, K., Nijs, G., Stein, B., Smits, E.L., Schroyens, W.A., Gadisseur, A.P., Vrelust, I., Jorens, P.G., Goossens, H., Vries, I.J.M. de, Price, D.A., Oji, Y., Oka, Y., Sugiyama, H. & Berneman, Z.N. (2010). Induction of complete and molecular remissions in acute myeloid leukemia by Wilms tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A, 107(31), NCMLS 1B - Tumorimmunology, ONCOL 3 - Med Oncol, ONCOL 3 - Tumorimmunology - Thiadens, A.A.H.J., Roosing, S., Collin, R.W.J., Moll-Ramirez, N. van, Lith-Verhoeven, J.J. van, Schooneveld, M.J. van, Hollander, A.I. den, Born, L.I. van den, Hoyng, C.B., Cremers, F.P.M. & Klaver, C.C. (2010). Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy. Ophthalmology, 117(4), e1. - IGMD 3 - Ophthalmology, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen, NCMLS 3A - Ophthalmology - Thiadens, A.A.H.J., Somervuo, V., Born, L.I. van den, Roosing, S., Schooneveld, M.J. van, Kuijpers, R.W., Moll-Ramirez, N. van, Cremers, F.P.M., Hoyng, C.B. & Klaver, C.C. (2010). Progressive loss of cones in achromatopsia: an imaging study using spectral-domain optical coherence tomography. Investigative Ophthalmology & Visual Science, 51(11), IGMD 3 - Hum Gen, NCEBP 2 - Human Genetics, NCEBP 2 - Opthalmology, NCMLS 3A - Hum Gen - Thomason, H.A., Zhou, H., Kouwenhoven, E.N., Dotto, G.P., Restivo, G., Nguyen, B.C., Little, H., Dixon, M.J., Bokhoven, J.H.L.M. van & Dixon, J. (2010). Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice. Journal of Clinical Investigation, 120(5), DCN 2 - Hum Gen, NCMLS 3A - Hum Gen - Thomeer, H.G.X.M., Kunst, H.P.M. & Cremers, C.W.R.J. (2010). Isolated congenital stapes ankylosis: surgical results in a consecutive series of 39 ears. Annals of Otology Rhinology and Laryngology, 119(11), DCN 2 - Otorhinolaryn, NCMLS 3A - Otorhinolaryn - Wetensch. publ. refereed (artikel - letter to the editor) Tibussek, D., Schneider, D.T., Vandemeulebroecke, N., Turowski, B., Messing-Juenger, M., Willems, P.H.G.M., Mayatepek, E. & Distelmaier, F. (2010). Clinical spectrum of the pseudotumor cerebri complex in children. Childs Nervous System, 26(3), NCMLS 2A - Biochemistry - Timmer, N.M., Dijk, L. van, Zee, C.E.E.M. van der, Kiliaan, A., Waal, R.M.W. de & Verbeek, M.M. (2010). Enoxaparin treatment administered at both early and late stages of amyloid beta deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain A beta levels. Neurobiology of Disease, 40(1), DCN 2 - Anatomy, DCN 2 - CNS, DCN 2 - Cell Biology, DCN 2 - Lab LGEM, DCN 3 - Neurology, NCMLS 2A - Cell Biology, ONCOL 3 - Pathology - Timmer, N.M., Schirris, T.J.J., Bruinsma, I.B., Otte-Holler, I., Kuppevelt, A.H.M.S.M. van, Waal, R.M.W. de & Verbeek, M.M. (2010). Aggregation and cytotoxic properties towards cultured cerebrovascular cells of Dutch-mutated Abeta40 (DAbeta(1-40)) are modulated by sulfate moieties of heparin. Neurosci Res, 66(4), DCN 2 - Lab LGEM, DCN 3 - Neurology, NCMLS 1C - Biochemistry, NCMLS 2B - Pharm Tox, ONCOL 3 - Pathology - Toh, M.L., Gonzales, G., Koenders, M.I., Tournadre, A., Boyle, D., Lubberts, E., Zhou, Y., Firestein, G.S., Berg, W.B. van den & Miossec, P. (2010). Role of interleukin 17 in arthritis chronicity through survival of synoviocytes via regulation of synoviolin expression. PLoS ONE, 5(10), e N4i 4 - Rheumatology, NCMLS 1A - Rheumatology - Tonnaer, E.L.G.M., Peters, T.A. & Curfs, J.H.A.J. (2010). Neurofilament localization and phosphorylation in the developing inner ear of the rat. Hearing Research, 267(1-2), DCN 2 - Otorhinolaryn, NCMLS 3A - Otorhinolaryn - Trevelyan, A.J., Kirby, D.M., Smulders-Srinivasan, T.K., Nooteboom, M., Acin-Perez, R., Enriquez, J.A., Whittington, M.A., Lightowlers, R.N. & Turnbull, D.M. (2010). Mitochondrial DNA mutations affect calcium handling in differentiated neurons. Brain, 133(Pt 3), NCMLS 2A - Biochemistry - Trimpert, C., Herda, L.R., Eckerle, L.G., Pohle, S., Muller, C., Landsberger, M., Felix, S.B. & Staudt, A. (2010). Immunoadsorption in dilated cardiomyopathy: long-term reduction of cardiodepressant antibodies. European Journal of Clinical Investigation, 40(8), IGMD 9 - Physiology, NCMLS 2B - Physiology - Uchimura, K., Lemjabbar-Alaoui, H., Kuppevelt, A.H.M.S.M. van & Rosen, S.D. (2010). Use of a phage display antibody to measure the enzymatic activity of the Sulfs. Methods in Enzymology, 480, NCMLS 1C - Biochemistry - Valsecchi, F., Koopman, W.J.H., Manjeri, G.R., Rodenburg, R.J.T., Smeitink, J.A.M. & Willems, P.H.G.M. (2010). Complex I disorders: causes, mechanisms, and development of treatment strategies at the cellular level. Dev Disabil Res Rev, 16(2), IGMD 8 - Cell Biol, IGMD 8 - Lab LGEM, IGMD 8 - Paediatrics, NCMLS 2A - Biochemistry, NCMLS 2A - Cell Biology, NCMLS 2A - Lab LGEM - Wetensch. publ. refereed (artikel - letter to the editor) Vattemi, G., Gualandi, F., Oosterhof, A., Marini, M., Tonin, P., Rimessi, P., Neri, M., Guglielmi, V., Russignan, A., Poli, C., Kuppevelt, A.H.M.S.M. van, Ferlini, A. & Tomelleri, G. (2010). Brody disease: insights into biochemical features of SERCA1 and identification of a novel mutation. Journal of Neuropathology and Experimental Neurology, 69(3), NCMLS 1C - Biochemistry - Wetensch. publ. refereed (artikel - letter to the editor) Veenbergen, S., Smeets, R.L., Bennink, M.B., Arntz, O.J., Joosten, L.A.B., Berg, W.B. van den & Loo, F.A.J. van de (2010). The natural soluble form of IL-18 receptor beta exacerbates collagen-induced arthritis via modulation of T-cell immune responses. Annals of the Rheumatic Diseases, 69(1), N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Gen Int Med, NCMLS 1A - Rheumatology, NCMLS 1B - Tumorimmunology - Veerdonk, F.L. van de & Netea, M.G. (2010). Diversity: a hallmark of monocyte society. Immunity, 33(3), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Veerdonk, F.L. van de & Netea, M.G. (2010). T-cell Subsets and Antifungal Host Defenses. Current Fungal Infection Reports, 4(4), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Veerdonk, F.L. van de, Kullberg, B.J. & Netea, M.G. (2010). Pathogenesis of invasive candidiasis. Current Opinion in Critical Care, 16(5), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Veerdonk, F.L. van de, Kullberg, B.J., Verschueren, I.C., Hendriks, T., Meer, J.W.M. van der, Joosten, L.A.B. & Netea, M.G. (2010). Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure. Shock, 34(4), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med, NCMLS 1C - Surgery - Veerdonk, F.L. van de, Marijnissen, R., Joosten, L.A.B., Kullberg, B.J., Drenth, J.P.H., Netea, M.G. & Meer, J.W.M. van der (2010). Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency. Clinical and Experimental Immunology, 159(1), N4i 1 - Gastroenterology, N4i 1 - Gen Int Med, N4i 4 - Rheumatology, NCMLS 1A - Gen Int Med, NCMLS 1A - Rheumatology - Veerdonk, F.L. van de, Netea, M.G., Joosten, L.A.B., Meer, J.W.M. van der & Kullberg, B.J. (2010). Novel strategies for the prevention and treatment of Candida infections: the potential of immunotherapy. FEMS Microbiol Rev, 34(6), N4i 2 - Gen Int Med, NCMLS 1A - Gen Int Med - Annual Report 2010 Scientific publications

94 Veerdonk, F.L. van de, Smeekens, S.P., Joosten, L.A.B., Kullberg, B.J., Dinarello, C.A., Meer, J.W.M. van der & Netea, M.G. (2010). Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease. Proceedings of the National Academy of Science of the United States of America, 107(7), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Veerdonk, F.L. van de, Teirlinck, A.C., Kleinnijenhuis, J., Kullberg, B.J., Crevel, R. van, Meer, J.W.M. van der, Joosten, L.A.B. & Netea, M.G. (2010). Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1. Journal of Leukocyte Biology, 88(2), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Vegt, E. de, Jong, M. de, Wetzels, J.F.M., Masereeuw, R., Melis, M., Oyen, W.J.G., Gotthardt, M. & Boerman, O.C. (2010). Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention. Journal of Nuclear Medicine, 51(7), IGMD 9 - Nephrology, IGMD 9 - Pharm Tox, NCMLS 2B - Pharm Tox, ONCOL 3 - Nuclear Med - Wetensch. publ. refereed (artikel - letter to the editor) Velden, L.M. van der, Stapelbroek, J.M., Krieger, E., Berghe, P.V. van den, Berger, R., Verhulst, P.M., Holthuis, J.C., Houwen, R.H.J., Klomp, L.W. & Graaf, S.F. van de (2010). Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. Hepatology, 51(1), NCMLS 3A - CMBI, NCMLS 3B - CMBI, RU SCI NCMLS BI - Velden, W.J.F.M. van der, Plantinga, T.S., Feuth, T., Donnelly, J.P., Netea, M.G. & Blijlevens, N.M.A. (2010). The incidence of acute graft-versushost disease increases with Candida colonization depending the dectin-1 gene status. Clinical Immunology, 136(2), N4i 1 - Haematology, N4i 2 - Gen Int Med, N4i 2 - Haematology, NCMLS 1A - Gen Int Med, NCMLS 1B - Haematology, ONCOL 3 - Haematology, ONCOL 4 - Haematology - Veltman, J.A. & Brunner, H.G. (2010). Understanding variable expressivity in microdeletion syndromes. Nature Genetics, 42(3), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Ven, K.C.C. van der, Graaf, M. van der, Tack, C.J.J., Klomp, D.W.J., Heerschap, A. & Galan, B.E. de (2010). Optimized [1-(13)C]glucose infusion protocol for 13C magnetic resonance spectroscopy at 3T of human brain glucose metabolism under euglycemic and hypoglycemic conditions. Journal of Neuroscience Methods, 186(1), IGMD 1 - Paediatrics, IGMD 5 - Gen Int Med, IGMD 5 - Radiology, NCMLS 2A - Radiology - Venkatachalam, R., Ligtenberg, M.J.L., Hoogerbrugge, N., Schackert, H.K., Gorgens, H., Hahn, M.M., Kamping, E.J., Vreede, L., Hoenselaar, E., Looij, E. van de, Goossens, M., Churchman, M., Carvajal-Carmona, L., Tomlinson, I.P., Bruijn, D.R. de, Geurts van Kessel, A.H.M. & Kuiper, R.P. (2010). Germline epigenetic silencing of the tumor suppressor gene PTPRJ in early-onset familial colorectal cancer. Gastroenterology, 139(6), NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Venkatachalam, R., Ligtenberg, M.J.L., Hoogerbrugge-van der Linden, N., Bruijn, D.R.H. de, Kuiper, R.P. & Geurts van Kessel, A.H.M. (2010). The epigenetics of (hereditary) colorectal cancer. Cancer Genetics and Cytogenetics, 203(1), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology, ONCOL 3 - Hum Gen, ONCOL 3 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Venselaar, H., Beek, T.A.H. te, Kuipers, R.K.P., Hekkelman, M.L. & Vriend, G. (2010). Protein structure analysis of mutations causing inheritable diseases. An e-science approach with life scientist friendly interfaces. BMC Bioinformatics, 11, NCMLS 3A - CMBI, NCMLS 3B - CMBI - Venselaar, H., Joosten, R.P., Vroling, B., Baakman, C.A., Hekkelman, M.L., Krieger, E. & Vriend, G. (2010). Homology modelling and spectroscopy, a never-ending love story. Eur Biophys J, 39(4), NCMLS 3A - CMBI, NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Verdurmen, W.P.I., Thanos, M., Ruttekolk, I.R.R., Gulbins, E. & Brock, R. (2010). Cationic cell-penetrating peptides induce ceramide formation via acid sphingomyelinase: implications for uptake. Journal of Controlled Release, 147(2), NCMLS 3B - Biochemistry - Wetensch. publ. refereed (artikel - letter to the editor) Verhagen, L.M., Warris, A., Soolingen, D. van, Groot, R. de & Hermans, P.W.M. (2010). Human immunodeficiency virus and tuberculosis coinfection in children: challenges in diagnosis and treatment. Pediatric Infectious Disease Journal, 29(10), e N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Verhoeven, W.M.A., Kleefstra, T. & Egger, J.I. (2010). Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 153B(2), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Vermeer, S., Hoischen, A., Meijer, R.P., Gilissen, C., Neveling, K., Wieskamp, N., Brouwer, A., Koenig, M., Anheim, M., Assoum, M., Drouot, N., Todorovic, S., Milic-Rasic, V., Lochmuller, H., Stevanin, G., Goizet, C., David, A., Durr, A., Brice, A., Kremer, B., Warrenburg, B.P.C. van de, Schijvenaars, M.M.V.A.P., Heister, A., Kwint, M., Arts, P., Wijst, J. van der, Veltman, J., Kamsteeg, E.J., Scheffer, H. & Knoers, N. (2010). Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia. American Journal of Human Genetics, 87(6), DCN 2 - Hum Gen, DCN 2 - Neurology, IGMD 3 - Hum Gen, IGMD 9 - Physiology, NCMLS 2B - Physiology, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Versleijen, M.W.J., Roelofs, H.M.J., Morsche, R.H.M. te, Simonetti, E.R., Hermans, P.W.M. & Wanten, G.J.A. (2010). Parenteral lipids impair pneumococcal elimination by human neutrophils. European Journal of Clinical Investigation, 40(8), IGMD 2 - Gastroenterology, N4i 1 - Nuclear Medicine, N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics - Wetensch. publ. refereed (artikel - letter to the editor) Verstappen, J., Katsaros, C., Torensma, R. & den Hoff, J.W. Von (2010). Bone marrow-derived cells in palatal wound healing. Oral Diseases, 16(8), NCMLS 1C - Dentistry, NCMLS 1C - Tumorimmunology - Vinet, J., Jong, E.K. de, Boddeke, H.W., Stanulovic, V., Brouwer, N., Granic, I., Eisel, U.L., Liem, R.S. & Biber, K. (2010). Expression of CXCL10 in cultured cortical neurons. Journal of Neurochemistry, 112(3), DCN 2 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Vissers, L.E.L.M., Ligt, J. de, Gilissen, C., Janssen, I., Steehouwer, M., Vries, P. de, Lier, B. van, Arts, P., Wieskamp, N., Rosario, M. del, Bon, B.W.M. van, Hoischen, A., Vries, B.B. de, Brunner, H.G. & Veltman, J.A. (2010). A de novo paradigm for mental retardation. Nature Genetics, 42(12), IGMD 3 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Vissers, M., Stelma, F.F. & Koopmans, P.P. (2010). Could differential virological characteristics account for ongoing viral replication and insidious damage of the brain during HIV 1 infection of the central nervous system? Journal of Clinical Virology, 49(4), N4i 1 - Med Microbiol, N4i 1 - Paediatrics, N4i 3 - Gen Int Med, NCMLS 1A - Med Microbiol, NCMLS 1A - Paediatrics - Voigt, A., Bartel, K., Egerer, K., Trimpert, C., Feist, E., Gericke, C., Kandolf, R., Klingel, K., Kuckelkorn, U., Stangl, K., Felix, S.B., Baumann, G., Kloetzel, P.M. & Staudt, A. (2010). Humoral anti-proteasomal autoimmunity in dilated cardiomyopathy. Basic Research in Cardiology, 105(1), IGMD 9 - Physiology, NCMLS 2B - Physiology - 94 Scientific publications 2010 NCMLS

95 Voigt, A., Trimpert, C., Bartel, K., Egerer, K., Kuckelkorn, U., Feist, E., Gericke, C., Klingel, K., Kandolf, R., Felix, S.B., Baumann, G., Kloetzel, P.M., Stangl, K. & Staudt, A. (2010). Lack of evidence for a pathogenic role of proteasome-directed autoimmunity in dilated cardiomyopathy. Basic Research in Cardiology, 105(4), IGMD 9 - Physiology, NCMLS 2B - Physiology - Voort, R., Verweij, V., Witte, T.M. de, Lasonder, E., Adema, G.J. & Dolstra, H. (2010). An alternatively spliced CXCL16 isoform expressed by dendritic cells is a secreted chemoattractant for CXCR6+ cells. Journal of Leukocyte Biology, 87(6), IGMD 8 - CMBI, NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, NCMLS 2A - CMBI, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Vos, P.E., Jacobs, B., Andriessen, T.M.J.C., Lamers, K.J.B., Borm, G.F., Beems, T., Edwards, M., Rosmalen, C.F. & Vissers, J.L.M. (2010). GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology, 75(20), DCN 1 - Neurosurgery, DCN 3 - Neurology, NCEBP 2 - Surgery, NCMLS 1C - Neurosurgery - Vries, E. de, Stelma, F.F. & Boucher, C.A.B. (2010). Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. New England Journal of Medicine, 363(14), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Vries, S.P.W. de, Hijum, S.A.F.T. van, Schueler, W., Riesbeck, K., Hays, J.P., Hermans, P.W.M. & Bootsma, H.J. (2010). Genome analysis of Moraxella catarrhalis strain RH4, a human respiratory tract pathogen. Journal of Bacteriology, 192(14), N4i 1 - Paediatrics, N4i 1 NCMLS 1A - Lab LGEM, NCMLS 1A - Paediatrics, NCMLS 2A - CMBI - Vrieze, E. de, Metz, J.R., Hoff, J.W. Von den & Flik, G. (2010). ALP, TRacP and cathepsin K in elasmoid scales: a role in mineral metabolism. Journal of Applied Ichthyology, 26, NCMLS 1C - Dentistry, RU SCI IWWR OAP - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Waalboer, D.C.J., Leenders, S.H., Schulin-Casonato, T., Delft, F.L. van & Rutjes, F.P.J.T. (2010). Total synthesis and antibiotic activity of dehydrohomoplatencin. Chemistry, 16(37), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Waanders, E., Venselaar, H., Morsche, R.H.M. te, Koning, D.B. de, Kamath, P.S., Torres, V.E., Somlo, S. & Drenth, J.P.H. (2010). Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Clinical Genetics, 78(1), IGMD 2 - Gastroenterology, IGMD 2 - Hum Genet, NCMLS 3A - CMBI, NCMLS 3B - CMBI, ONCOL 3 - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Wagener, F.A.D.T.G., Scharstuhl, A., Tyrrell, R.M., den Hoff, J.W. Von, Jozkowicz, A., Dulak, J., Russel, F.G.M. & Kuijpers-Jagtman, A.M. (2010). The heme-heme oxygenase system in wound healing; implications for scar formation. Current Drug Targets, 11(12), NCMLS 1C - Dentistry, NCMLS 2B - Pharm Tox - Wallon, D., Guyant-Marechal, L., Laquerriere, A., Wevers, R.A., Martinaud, O., Kluijtmans, L.A.J., Yntema, H.G., Saugier-Veber, P. & Hannequin, D. (2010). Clinical imaging and neuropathological correlations in an unusual case of cerebrotendinous xanthomatosis. Clinical Neuropathology, 29(6), DCN 2 - Lab LGEM, DCN 3 - Neurology, IGMD 3 - Lab LGEM, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Wammes, L.J., Hamid, F., Wiria, A.E., Gier, B. de, Sartono, E., Maizels, R.M., Luty, A.J.F., Fillie, Y., Brice, G.T., Supali, T., Smits, H.H. & Yazdanbakhsh, M. (2010). Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum. European Journal of Immunology, 40(2), N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Wang, C.W., Mwakalinga, S.B., Sutherland, C.J., Schwank, S., Sharp, S., Hermsen, C.C., Sauerwein, R.W., Theander, T.G. & Lavstsen, T. (2010). Identification of a major rif transcript common to gametocytes and sporozoites of Plasmodium falciparum. Malaria Journal, 9, N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wang, X., Pankratz, V.S., Fredericksen, Z., Tarrell, R., Karaus, M., McGuffog, L., Pharaoh, P.D., Ponder, B.A.J., Dunning, A.M., Peock, S., Cook, M., Oliver, C., Frost, D., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Houdayer, C., Hogervorst, F.B.L., Hooning, M.J., Ligtenberg, M.J.L., Spurdle, A., Chenevix-Trench, G., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Singer, C.F., Gschwantler-Kaulich, D., Dressler, C., Fink, A., Szabo, C.I., Zikan, M., Foretova, L., Claes, K., Thomas, G., Hoover, R.N., Hunter, D.J., Chanock, S.J., Easton, D.F., Antoniou, A.C. & Couch, F.J. (2010). Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Human Molecular Genetics, 19(14), NCEBP 1 - Hum Gen, NCMLS 3A - Hum Gen, ONCOL 1 - Hum Gen, ONCOL 1 - Med Oncol, ONCOL 1 - Pathology - Wetensch. publ. refereed (artikel - letter to the editor) Warnke, P.H., Bolte, H., Schunemann, K., Nitsche, T., Sivananthan, S., Sherry, E., Douglas, T., Wiltfang, J. & Becker, S.T. (2010). Endocultivation: does delayed application of BMP improve intramuscular heterotopic bone formation? Journal of Cranio-Maxillofacial Surgery, 38(1), NCMLS 1C - Dentistry - Warnke, P.H., Seitz, H., Warnke, F., Becker, S.T., Sivananthan, S., Sherry, E., Liu, Q., Wiltfang, J. & Douglas, T. (2010). Ceramic scaffolds produced by computer-assisted 3D printing and sintering: characterization and biocompatibility investigations. Journal of Biomedical Materials Research part B-Applied Biomaterials, 93(1), NCMLS 1C - Dentistry - Warris, A., Onken, A., Gaustad, P., Janssen, W., Lee, H. van der, Verweij, P.E. & Abrahamsen, T.G. (2010). Point-of-use filtration method for the prevention of fungal contamination of hospital water. Journal of Hospital Infection, 76(1), N4i 1 - Med Microbiol, NCMLS 1A - Med Microbiol - Wassenberg, T., Willemsen, M.H., Geurtz, P.B., Lammens, M.M.Y., Verrijp, K., Wilmer, M., Lee, W.T., Wevers, R.A. & Verbeek, M.M. (2010). Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: the unsolved paradox. Molecular Genetics and Metabolism, 101(4), DCN 1 - Pathology, DCN 2 - Lab LGEM, DCN 3 - Neurology, IGMD 3 - Lab LGEM, IGMD 9 - Paediatrics, NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Wasylyk, C., Zambrano, A., Zhao, C., Brants, J., Abecassis, J., Schalken, J.A., Rogatsch, H., Schaefer, G., Pycha, A., Klocker, H. & Wasylyk, B. (2010). Tubulin tyrosine ligase like 12 links to prostate cancer through tubulin posttranslational modification and chromosome ploidy. International Journal of Cancer, 127(11), NCMLS 3A - Urology, ONCOL 3 - Urology, ONCOL 5 - Urology - Wetensch. publ. refereed (artikel - letter to the editor) Weigelin, B. & Friedl, P.H.A. (2010). A three-dimensional organotypic assay to measure target cell killing by cytotoxic T lymphocytes. Biochemical Pharmacology, 80(12), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Weijs, W.L.J., Siebers, T.J.H., Kuijpers-Jagtman, A.M., Berge, S.J., Meijer, G.J. & Borstlap, W.A. (2010). Early secondary closure of alveolar clefts with mandibular symphyseal bone grafts and beta-tri calcium phosphate (beta-tcp). International Journal of Oral and Maxillofacial Surgery, 39(5), NCEBP 2 - Dentistry, NCEBP 2 - Oral Maxillo, NCMLS 1C - Dentistry - Westenberg, M.A., Roerdink, J.B., Kuipers, O.P. & Hijum, S.A.F.T. van (2010). SpotXplore: a Cytoscape plugin for visual exploration of hotspot expression in gene regulatory networks. Bioinformatics, 26(22), NCMLS 2A - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Annual Report 2010 Scientific publications

96 Westra, D., Volokhina, E., Heijden, E. van der, Vos, A., Huigen, M., Jansen, J., Kaauwen, E. van, Velden, T. van der, Kar, N. van de & Heuvel, L.P.W.J. van den (2010). Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (ahus). Nephrology Dialysis Transplantation, 25(7), IGMD 9 - Lab LGEM, IGMD 9 - Paediatrics, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics - White, T.A., Johnson, T., Zarzhevsky, N., Tom, C., Delacroix, S., Holroyd, E.W., Maroney, S.A., Singh, R., Pan, S., Fay, W.P., Deursen, J.M.A. van, Mast, A.E., Sandhu, G.S. & Simari, R.D. (2010). Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis. Blood, 116(10), NCMLS 3A - Cell Biology, ONCOL 3 - Cell Biol - Wetensch. publ. refereed (artikel - letter to the editor) Wiedemann, D., Schneeberger, S., Friedl, P.H.A., Zacharowski, K., Wick, N., Boesch, F., Margreiter, R., Laufer, G., Petzelbauer, P. & Semsroth, S. (2010). The fibrin-derived peptide Bbeta(15-42) significantly attenuates ischemia-reperfusion injury in a cardiac transplant model. Transplantation, 89(7), NCMLS 1B - Cell Biol, ONCOL 3 - Cell Biol - Wijk, X.M.R. van, Oosterhof, A., Broek, S.A.M.W. van den, Griffioen, A.W., Dam, G.B. ten, Rutjes, F.P.J.T., Delft, F.L. van & Kuppevelt, A.H.M.S.M. van (2010). A 4-deoxy analogue of N-acetyl-D-glucosamine inhibits heparan sulphate expression and growth factor binding in vitro. Experimental Cell Research, 316(15), NCMLS 1C - Biochemistry, RU SCI IMM SOC - Wetensch. publ. refereed (artikel - letter to the editor) Wijnen, J.P., Graaf, M. van der, Scheenen, T.W.J., Klomp, D.W.J., Galan, B.E. de, Idema, A.J.S. & Heerschap, A. (2010). In vivo 13C magnetic resonance spectroscopy of a human brain tumor after application of 13C-1-enriched glucose. Magnetic Resonance Imaging, 28(5), DCN 1 - Neurosurgery, DCN 3 - Neurology, IGMD 1 - Paediatrics, NCMLS 2A - Radiology, NCMLS 3B - Neurosurgery, ONCOL 3 - Radiology - Wetensch. publ. refereed (artikel - letter to the editor) Wijnen, J.P., Scheenen, T.W.J., Klomp, D.W.J. & Heerschap, A. (2010). 31P magnetic resonance spectroscopic imaging with polarisation transfer of phosphomono- and diesters at 3 T in the human brain: relation with age and spatial differences. NMR in Biomedicine, 23(8), NCMLS 2A - Radiology, ONCOL 3 - Radiology - Wijst, J. van der, Glaudemans, B., Venselaar, H., Nair, A.V., Forst, A.L., Hoenderop, J.G.J. & Bindels, R.J.M. (2010). Functional analysis of the Kv1.1 N255D mutation associated with autosomal dominant hypomagnesemia. Journal of Biological Chemistry, 285(1), IGMD 8 - CMBI, IGMD 9 - Physiology, NCMLS 2A - CMBI, NCMLS 2B - Physiology, NCMLS 3A - CMBI, NCMLS 3B - CMBI - Wetensch. publ. refereed (artikel - letter to the editor) Wilbers, J., Idema, A. & Gijtenbeek, A. (2010). A bilateral foot drop due to neuroschistosomiasis. Journal of Neurology, 257(5), DCN 1 - Neurosurgery, DCN 3 - Neurology, NCMLS 1A - Neurosurgery - Wilch, E., Azaiez, H., Fisher, R.A., Elfenbein, J., Murgia, A., Birkenhager, R., Bolz, H., Silva-Costa, S.M. Da, Castillo, I. del, Haaf, T., Hoefsloot, L., Kremer, J.M.J., Kubisch, C., Marechal, C. Le, Pandya, A., Sartorato, E.L., Schneider, E., Camp, G. van, Wuyts, W., Smith, R.J. & Friderici, K.H. (2010). A novel DFNB1 deletion allele supports the existence of a distant cis-regulatory region that controls GJB2 and GJB6 expression. Clinical Genetics, 78(3), DCN 2 - Neurology, DCN 2 - Otorhinolaryn, IGMD 3 - Hum Gen, NCMLS 3A - Otorhinolaryn - Wetensch. publ. refereed (artikel - letter to the editor) Willems, M.C.M., Vliet, J.A. van der, Man, B.M. de, Laak, J.A.W.M. van der, Lomme, R.M.L.M. & Hendriks, T. (2010). Persistent effects of everolimus on strength of experimental wounds in intestine and fascia. Wound Repair and Regeneration, 18(1), NCMLS 1C - Surgery, ONCOL 3 - Pathology - Willemsen, M.H., Fernandez, B.A., Bacino, C.A., Gerkes, E., Brouwer, A.P.M. de, Pfundt, R., Sikkema-Raddatz, B., Scherer, S.W., Marshall, C.R., Potocki, L., Bokhoven, J.H.L.M. van & Kleefstra, T. (2010). Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome. European Journal of Human Genetics, 18(4), DCN 2 - Hum Gen, IGMD 3 - Hum Gen, NCEBP 7 - Hum Gen, NCEBP 7 - Primary Health, NCEBP 9 - Hum Gen, NCMLS 3A - Hum Gen - Wetensch. publ. refereed (artikel - letter to the editor) Wilmer, M.J.G., Emma, F. & Levtchenko, E.N. (2010). The pathogenesis of cystinosis: mechanisms beyond cystine accumulation. American Journal of Physiology-Renal Physiology, 299(5), F IGMD 9 - Paediatrics, IGMD 9 - Pharm Tox, NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Wilmer, M.J.G., Saleem, M.A., Masereeuw, R., Ni, L., Velden, T.J.A.M. van der, Russel, F.G.M., Mathieson, P.W., Monnens, L.A.H., Heuvel, L.P.W.J. van den & Levtchenko, E.N. (2010). Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters. Cell and Tissue Research, 339(2), IGMD 9 - Lab LGEM, IGMD 9 - Paediatrics, IGMD 9 - Pharm Tox, IGMD 9 - Physiology, NCMLS 2A - Lab LGEM, NCMLS 2A - Paediatrics, NCMLS 2B - Pharm Tox, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Wiria, A.E., Prasetyani, M.A., Hamid, F., Wammes, L.J., Lell, B., Ariawan, I., Uh, H.W., Wibowo, H., Djuardi, Y., Wahyuni, S., Sutanto, I., May, L., Luty, A.J.F., Verweij, J.J., Sartono, E., Yazdanbakhsh, M. & Supali, T. (2010). Does treatment of intestinal helminth infections influence malaria? Background and methodology of a longitudinal study of clinical, parasitological and immunological parameters in Nangapanda, Flores, Indonesia (ImmunoSPIN Study). BMC Infectious Diseases, 10, N4i 3 - Med Microbiol, NCMLS 1A - Med Microbiol - Wetensch. publ. refereed (artikel - letter to the editor) Witte, T.J.M. de, Hagemeijer, A., Suciu, S., Belhabri, A., Delforge, M., Kobbe, G., Selleslag, D., Schouten, H.C., Ferrant, A., Biersack, H., Amadori, S., Muus, P., Jansen, J.H., Hellstrom-Lindberg, E., Kovacsovics, T., Wijermans, P., Ossenkoppele, G., Gratwohl, A., Marie, J.P. & Willemze, R. (2010). Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial. Haematologica, 95(10), NCMLS 1B - Lab LH, NCMLS 1B - Tumorimmunology, ONCOL 3 - Haematology, ONCOL 3 - Lab LH, ONCOL 3 - Tumorimmunology - Woudenberg, J., Rembacz, K.P., Heuvel, F.A. van den, Woudenberg-Vrenken, T.E., Buist-Homan, M., Geuken, M., Hoekstra, M., Deelman, L.E., Enrich, C., Henning, R.H., Moshage, H. & Faber, K.N. (2010). Caveolin-1 is enriched in the peroxisomal membrane of rat hepatocytes. Hepatology, 51(5), IGMD 2 - Gastroenterology, IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Woudenberg-Vrenken, T.E., Buist-Homan, M., de la Rosa, L. Conde, Faber, K.N. & Moshage, H. (2010). Anti-oxidants do not prevent bile acid-induced cell death in rat hepatocytes. Liver International, 30(10), IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor) Woudenberg-Vrenken, T.E., Sukinta, A., Kemp, A. van der, Bindels, R.J.M. & Hoenderop, J.G.J. (2010). Transient Receptor Potential Melastatin 6 Knockout Mice Are Lethal whereas Heterozygous Deletion Results in Mild Hypomagnesemia. Nephron Physiology, 117(2), p11-p19. - IGMD 9 - Physiology, NCMLS 2B - Physiology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Xi, Q., Umstot, E., Zhao, G., Narayanan, D., Leffler, C.W. & Jaggar, J.H. (2010). Glutamate regulates Ca2+ signals in smooth muscle cells of newborn piglet brain slice arterioles through astrocyte- and heme oxygenase-dependent mechanisms. American Journal of Physiology-Heart and Circulatory Physiology, 298(2), H IGMD 9 - Physiology, NCMLS 2B - Physiology - 96 Scientific publications 2010 NCMLS

97 Yang, X., Yang, F., Walboomers, X.F., Bian, Z., Fan, M. & Jansen, J.A. (2010). The performance of dental pulp stem cells on nanofibrous PCL/ gelatin/nha scaffolds. Journal of Biomedical Materials Research Part A, 93(1), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Yigit, R., Massuger, L.F.A.G., Figdor, C.G. & Torensma, R. (2010). Ovarian cancer creates a suppressive microenvironment to escape immune elimination. Gynecologic Oncology, 117(2), NCMLS 1C - Tumorimmunology, ONCOL 3 - Obs Gyn - Wetensch. publ. refereed (artikel - letter to the editor) Yim, C.B., Dijkgraaf, I., Merkx, R., Versluis, C., Eek, A., Mulder, G.E., Rijkers, D.T., Boerman, O.C. & Liskamp, R.M. (2010). Synthesis of DOTA-conjugated multimeric [Tyr3]octreotide peptides via a combination of Cu(I)-catalyzed click cycloaddition and thio acid/sulfonyl azide sulfo-click amidation and their in vivo evaluation. Journal of Medicinal Chemistry, 53(10), NCMLS 1B - Nuclear Med, ONCOL 3 - Nuclear Med - Zande, M. van der, Walboomers, X.F., Brannvall, M., Olalde, B., Jurado, M.J., Alava, J.I. & Jansen, J.A. (2010). Genetic profiling of osteoblast-like cells cultured on a novel bone reconstructive material, consisting of poly-l-lactide, carbon nanotubes and microhydroxyapatite, in the presence of bone morphogenetic protein-2. Acta Biomaterialia, 6(11), NCMLS 1C - Dentistry - Wetensch. publ. refereed (artikel - letter to the editor) Zanten, T.S. van, Cambi, A. & Garcia-Parajo, M.F. (2010). A nanometer scale optical view on the compartmentalization of cell membranes. Biochimica et Biophysica Acta, 1798(4), NCMLS 1B - Tumorimmunology - Zanten, T.S. van, Gomez, J., Manzo, C., Cambi, A., Buceta, J., Reigada, R. & Garcia-Parajo, M.F. (2010). Direct mapping of nanoscale compositional connectivity on intact cell membranes. Proc Natl Acad Sci U S A, 107(35), NCMLS 1B - Tumorimmunology - Wetensch. publ. refereed (artikel - letter to the editor) Zarif Yeganeh, M., Mirabzadeh, A., orram Khorshid, H.R. Kh, Kamali, K., Heshmati, Y., Gozalpour, E., Veissy, K., Olad Nabi, M., Najmabadi, H. & Ohadi, M. (2010). Novel extreme homozygote haplotypes at the human caveolin 1 gene upstream purine complex in sporadic Alzheimer s disease. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 153B(1), NCMLS 2B - Pharm Tox - Wetensch. publ. refereed (artikel - letter to the editor) Zeeuwen, P.L.J.M., Vlijmen-Willems, I.M.J.J. van, Cheng, T., Rodijk-Olthuis, D., Hitomi, K., Hara-Nishimura, I., John, S., Smyth, N., Reinheckel, T., Hendriks, W.J.A.J. & Schalkwijk, J. (2010). The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. FASEB Journal, 24(10), DCN 3 - Cell Biology, NCMLS 1A - Dermatology, NCMLS 3B - Cell Biology - Wetensch. publ. refereed (artikel - letter to the editor / SCI en SSCI-tijdschriften) Zhernakova, A., Elbers, C.C., Ferwerda, B., Romanos, J., Trynka, G., Dubois, P.C., Kovel, C.G.F. de, Franke, L., Oosting, M., Barisani, D., Bardella, M.T., Joosten, L.A.B., Saavalainen, P., Heel, D.A. van, Catassi, C., Netea, M.G. & Wijmenga, C. (2010). Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. American Journal of Human Genetics, 86(6), N4i 1 - Gen Int Med, NCMLS 1A - Gen Int Med - Zhou, H. & Bokhoven, J.H.L.M. van (2010). Regulation of vitamin metabolism by p53 and p63 in development and cancer. Cell Cycle, 9(14), DCN 2 - Hum Gen, NCMLS 3A - Hum Gen - Zuo, Y., Yang, F., Wolke, J.G.C., Li, Y. & Jansen, J.A. (2010). Incorporation of biodegradable electrospun fibers into calcium phosphate cement for bone regeneration. Acta Biomaterialia, 6(4), NCMLS 1C - Dentistry - Annual Report 2010 Scientific publications