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1. The Molecular Basis by Which Polymorphism in the OX40L Gene Predisposes to SLE

Author: Manku, Harinder, Graham, Deborah Cunninghame, Graham, Robert R., Behrens, Timothy W., Althshuler, David, and Vyse, Timothy J.
Published: 2007
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2. Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89

Author: Boswell, C. [Genentech Inc., San Francisco, CA (United States)]
Published: 2017
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3. Structural Analysis and Optimization of Context-Independent Anti-Hypusine Antibodies

Author: Carter, Paul [Genentech Inc., San Francisco, CA (United States)]
Published: 2016
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4. Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

Author: Andrey A. Yurchenko, Oltin T. Pop, Meriem Ighilahriz, Ismael Padioleau, Fatemeh Rajabi, Hayley J. Sharpe, Nicolas Poulalhon, Brigitte Dreno, Amir Khammari, Marc Delord, Antonio Alberti, Nadem Soufir, Maxime Battistella, Samia Mourah, Fanny Bouquet, Ariel Savina, Andrej Besse, Max Mendez-Lopez, Florent Grange, Sandrine Monestier, Laurent Mortier, Nicolas Meyer, Caroline Dutriaux, Caroline Robert, Philippe Saiag, Florian Herms, Jerome Lambert, Frederic J. de Sauvage, Nicolas Dumaz, Lukas Flatz, Nicole Basset-Seguin, Sergey I. Nikolaev, Pecqueret, Valérie, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Brustzentrum Kantonsspital St. Gallen, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The Babraham Institute [Cambridge, UK], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital de la Timone [CHU - APHM] (TIMONE), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Ambroise Paré [AP-HP], Service de Dermatologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Genentech, Inc., and Genentech, Inc. [San Francisco]
Subjects: Cancer Research, Skin Neoplasms, animal structures, integumentary system, Pyridines, [SDV]Life Sciences [q-bio], fungi, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Carcinoma, Basal Cell, Humans, Anilides, Hedgehog Proteins, Cerebellar Neoplasms
Abstract: Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.
Published: 2022

5. Connecting Cohorts to Diminish Alzheimer’s Disease (CONCORD-AD): A Report of an International Research Collaboration Network

Author: Samantha C. Burnham, Valory N. Pavlik, Rachelle Doody, Catherine Helmer, Ronald C. Petersen, Karine Pérès, Preciosa M. Coloma, Oskar Hansson, Sebastian Palmqvist, Lesley M. Butler, Joseph S. Kass, Maria Vassilaki, Mary Sano, Erik Stomrud, Colin L. Masters, Xavier M Teitsma, Jean-François Dartigues, Concord-Ad investigators, Baylor College of Medicine (BCM), Baylor University, CSIRO Health and Biosecurity [Australia], Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lund University [Lund], Skane University Hospital [Lund], Mayo Clinic [Rochester], CHU Bordeaux [Bordeaux], University of Melbourne, F. Hoffmann-La Roche [Basel], Genentech, Inc. [San Francisco], Icahn School of Medicine at Mount Sinai [New York] (MSSM), James J. Peters VA Medical Center [New York], CONCORD-AD investigators, and Admin, Oskar
Subjects: Gerontology, Population ageing, International Cooperation, Population, Disease, Cohort Studies, Computer Communication Networks, Cognition, Alzheimer Disease, Observational study, medicine, Humans, Dementia, education, Aged, education.field_of_study, General Neuroscience, Cohort, General Medicine, medicine.disease, Population characteristics, Observational Studies as Topic, Psychiatry and Mental health, Clinical Psychology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cognitive function, Geriatrics and Gerontology, Psychology, Alzheimer’s disease, Biomarkers, CONCORD-AD network, Cohort study
Abstract: International audience; Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer's disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed.
Published: 2022

6. A tumor volume and performance status model to predict outcome before treatment in diffuse large B-cell lymphoma

Author: Catherine Thieblemont, Loic Chartier, Ulrich Dührsen, Umberto Vitolo, Sally F. Barrington, Jan M. Zaucha, Laetitia Vercellino, Maria Gomes Silva, Ines Patrocinio-Carvalho, Pierre Decazes, Pierre-Julien Viailly, Herve Tilly, Alina Berriolo-Riedinger, Oliver Casasnovas, Andreas Hüttmann, Hajira Ilyas, N. George Mikhaeel, Joel Dunn, Anne-Ségolène Cottereau, Christine Schmitz, Lale Kostakoglu, Joseph N. Paulson, Tina Nielsen, Michael Meignan, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Lymphoma Academic Research Organisation [Lyon] (LYSARC), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), King‘s College London, Guy's and St Thomas' Hospital [London], Medical University of Gdańsk, Service de Médecine Nucléaire [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], University of Virginia, Genentech, Inc. [San Francisco], F. Hoffmann-La Roche [Basel], CHU Henri Mondor, and leboeuf, Christophe
Subjects: Clinical Trials as Topic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medizin, Humans, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Lymphoma, Large B-Cell, Diffuse, Neoplasm Recurrence, Local, Tumor Burden
Abstract: Aggressive large B-cell lymphoma (LBCL) has variable outcomes. Current prognostic tools use factors for risk stratification that inadequately identify patients at high risk of refractory disease or relapse before initial treatment. A model associating 2 risk factors, total metabolic tumor volume (TMTV) >220 cm3 (determined by fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography) and performance status (PS) ≥2, identified as prognostic in 301 older patients in the REMARC trial (#NCT01122472), was validated in 2174 patients of all ages treated in 2 clinical trials, PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas; N = 510) and GOYA (N = 1315), and in real-world clinics (N = 349) across Europe and the United States. Three risk categories, low (no factors), intermediate (1 risk factor), and high (2 risk factors), significantly discriminated outcome in most of the series. Patients with 2 risk factors had worse outcomes than patients with no risk factors in the PETAL, GOYA, and real-world series. Patients with intermediate risk also had significantly worse outcomes than patients with no risk factors. The TMTV/Eastern Cooperative Oncology Group-PS combination outperformed the International Prognostic Index with a positive C-index for progression-free survival and overall survival in most series. The combination of high TMTV > 220 cm3 and ECOG-PS ≥ 2 is a simple clinical model to identify aggressive LBCL risk categories before treatment. This combination addresses the unmet need to better predict before treatment initiation for aggressive LBCL the patients likely to benefit the most or not at all from therapy.
Published: 2022

7. Nonlinear multilevel joint model for individual lesion kinetics and survival to characterize intra-individual heterogeneity in patients with advanced cancer

Author: Kerioui, Marion, Desmée, Solène, Bertrand, Julie, Mercier, François, Jin, Jin, Bruno, René, Guedj, Jérémie, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Université - UFR Pharmacie), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Genentech, Inc., Genentech, Inc. [San Francisco], Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], and Kerioui, Marion
Subjects: Joint model, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Advanced cancer, Bayesian inference, Multilevel modelling, Nonlinear mixed-effects model, [MATH.MATH-ST] Mathematics [math]/Statistics [math.ST]
Abstract: In advanced cancer patients, tumor burden assessment relies on the Sum of the Longest Diameters (SLD) of the target lesions, a marker that lumps all lesions together and ignores intra-patient heterogeneity. Here, we relied on a rich dataset of 342 metastatic bladder cancer patients treated with a novel immunotherapy agent to develop a Bayesian multilevel joint model that can quantify the heterogeneity in lesion dynamics and measure their impact on survival. Using a nonlinear model of tumor growth inhibition, we estimated that dynamics differed greatly among lesions, and inter-lesion variability accounted for about 35% of the total variance of both tumor shrinkage and treatment effect duration. Next, we investigated the impact of individual lesion dynamics on survival. Lesions located in the liver and in the bladder had twice as much impact on the instantaneous risk of death as compared to those located in the lung or the lymph nodes. Finally we evaluated the gain of individual lesion follow-up for dynamic predictions. Consistent with results at the population levels, the individual lesion model outperformed a model relying only on SLD, especially at early landmark times and in patients having liver or bladder target lesions. Our results show that the use of SLD leads to a loss of information and our model can be used to characterize tumor dynamics and survival of advanced cancer patients.
Published: 2022

8. A randomized, placebo‐controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER)

Author: Kathryn Mesh, Kun Peng, John G. Matthews, Prescott G. Woodruff, Wendy S. Putnam, Melissa Gonzalez Edick, Elliot Israel, Peter Bradding, Margaret Solon, Francis Abreu, Arnaud Bourdin, Kit Wong, Monet Howard, Monica Kraft, Cecile T.J. Holweg, Joseph R. Arron, Cary D. Austin, J. Mark FitzGerald, Gail M. Gauvreau, David F. Choy, Fang Cai, Ronald E. Ferrando, Lief Bjermer, Miriam Baca, Julie Olsson, Clavier Investigators, Kaharu Sumino, Clinical Pharmacology [South San Francisco, CA, USA] (Genentech Inc.), Genentech, Inc. [San Francisco], University of Leicester, McMaster University [Hamilton, Ontario], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of British Columbia (UBC), Skane University Hospital [Lund], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Arizona, University of California [San Francisco] (UCSF), University of California, MORNET, Dominique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), and University of California (UC)
Subjects: 0301 basic medicine, Male, Time Factors, Placebo-controlled study, Biochemistry, Lebrikizumab, Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, Immunology and Allergy, Medicine, Anti-Asthmatic Agents, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Lung, Interleukin-13, Antibodies, Monoclonal, respiratory system, Middle Aged, 3. Good health, Treatment Outcome, Eosinophilic inflammation, Airway Remodeling, Original Article, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Biotechnology, medicine.drug, Signal Transduction, Adult, medicine.medical_specialty, Adolescent, Immunology, Placebo, 03 medical and health sciences, Young Adult, Double-Blind Method, Internal medicine, Genetics, Humans, Clinical significance, Molecular Biology, Asthma, Aged, business.industry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Uncontrolled asthma, Eosinophils, 030104 developmental biology, 030228 respiratory system, Asthma and Rhinitis, Exhaled nitric oxide, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, CCL26, ORIGINAL ARTICLES, business, Airway
Abstract: Background The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. Objective To report safety and efficacy results from enrolled participants with available data from CLAVIER. Methods We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling. Results There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. Conclusions & clinical relevance We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling. Clinical trial registration NCT02099656.
Published: 2020

9. Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma

Author: Patrick Schmid, Enos Bernasconi, Ioannis Theodorou, Sophia S. Wang, Pejman Mohammadi, Paul J. McLaren, Huldrych F. Günthard, Matthias Cavassini, Charles S. Rabkin, Matthias Hoffmann, Christian Hammer, Shehnaz K. Hussain, Jacques Fellay, Andri Rauch, Cécile Goujard, Laurence Meyer, Jonathan Niay, Caroline Besson, Nava Ehsan, Tiphaine Oudot-Mellakh, Dominique Costagliola, Manuel Battegay, Christian W. Thorball, Federico Santoni, Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), University of California-University of California, Genentech, Inc. [San Francisco], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Beckman Research Institute of the City of Hope, Cedars-Sinai Medical Center, Lausanne University Hospital, Bern University Hospital [Berne] (Inselspital), University of Bern, University Hospital Basel [Basel], Cantonal Hospital of Olten, Cantonal Hospital St Gallen (KSSG), Lugano Regional Hospital [Lugano], University hospital of Zurich [Zurich], National Microbiology Laboratory [Winnipeg, Canada], Public Health Agency of Canada, University of Manitoba [Winnipeg], Centre Hospitalier de Versailles André Mignot (CHV), University of Zurich, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 10028 Institute of Medical Virology, Follicular lymphoma, HIV Infections, Genome-wide association study, 10234 Clinic for Infectious Diseases, 0302 clinical medicine, MESH: Lymphoma, Non-Hodgkin, hemic and lymphatic diseases, BATF, Immunodeficiency, Lymphoma, AIDS-Related, variants, 0303 health sciences, education.field_of_study, common, Anti-Retroviral Agents/therapeutic use, Case-Control Studies, Chemokine CXCL12, Genome-Wide Association Study, HIV Infections/complications, HIV Infections/drug therapy, HIV Infections/genetics, Humans, Lymphoma, AIDS-Related/drug therapy, Lymphoma, Non-Hodgkin/drug therapy, Lymphoma, Non-Hodgkin/genetics, Polymorphism, Genetic, Lymphoma, Non-Hodgkin, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: HIV Infections, Hematology, MESH: Case-Control Studies, 3. Good health, Anti-Retroviral Agents, 030220 oncology & carcinogenesis, loci, MESH: Chemokine CXCL12, Population, 610 Medicine & health, Biology, MESH: Anti-Retroviral Agents, Article, infected individuals, 03 medical and health sciences, follicular lymphoma, expression, MESH: Polymorphism, Genetic, Genetic variation, cancer-risk, medicine, education, MESH: Lymphoma, AIDS-Related, 030304 developmental biology, Genetic association, MESH: Humans, chemokine, medicine.disease, Lymphoma, MESH: Genome-Wide Association Study, Immunology, genome-wide association, immunodeficiency
Abstract: International audience; Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.
Published: 2020

10. A phase-II study of atezolizumab in combination with obinutuzumab or rituximab for relapsed or refractory mantle cell or marginal zone lymphoma or Waldenström's macroglobulinemia

Author: Panayiotis Panayiotidis, Gayane Tumyan, Catherine Thieblemont, Vadim V. Ptushkin, Ana Marin-Niebla, Ramon García-Sanz, Steven Le Gouill, Anastasios Stathis, Alessia Bottos, Habib Hamidi, Pablo Katz, Thomas Perretti, Jenna C. Willis, Christian Buske, National and Kapodistrian University of Athens (NKUA), N.N. Blokhin Russian Cancer Research Center, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), City Clinical Hospital Named After S.P. Botkin [Moscow, Russian Federation] (2CHNSPB), Vall d'Hebron University Hospital [Barcelona], Universidad de Salamanca, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Università della Svizzera italiana = University of Italian Switzerland (USI), Oncology Institute of Southern Switzerland (IOSI), F. Hoffmann-La Roche [Basel], Genentech, Inc. [San Francisco], Roche Products Ltd, Universitätsklinikum Ulm - University Hospital of Ulm, and Bernardo, Elizabeth
Subjects: obinutuzumab, Adult, Cancer Research, Waldenström’s macroglobulinemia, lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Lymphoma, B-Cell, Marginal Zone, Antibodies, Monoclonal, Humanized, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Humans, Atezolizumab, Waldenstrom Macroglobulinemia, Rituximab
Abstract: International audience; We report efficacy, safety and biomarker data from a phase-II study evaluating atezolizumab (eight 21-day cycle as induction therapy) in combination with obinutuzumab in patients with relapsed/refractory mantle cell lymphoma (MCL, n = 30) or Waldenström's macroglobulinemia (WM, n = 4), and in combination with rituximab in patients with marginal zone lymphoma (MZL, n = 21). All patients received atezolizumab monotherapy as maintenance for ≤10 cycles. Objective response rates at end of induction were 16.7% (MCL) and 42.9% (MZL), with no responses in WM. Median duration of response was 6.8 months (range 5.7-not estimable) for MCL and not reached for MZL. Treatment-emergent adverse events (TEAEs) occurred in 93.3%, 95.2% and 100% of MCL, MZL and WM patients, respectively. One fatal TEAE (pneumonia) occurred in each of the MCL and MZL groups. Biomarker analysis highlighted the importance of characterizing the immune environment to optimize efficacy of immunotherapy regimens.Trial registration details: EudraCT: 2016-003579-22.
Published: 2022

11. BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2

Author: Quang Dinh Tran, Xiaoyan Guo, Jonathan S. Weissman, Jared Carlson-Stevermer, Marco Vignuzzi, Jennifer Oki, Shion A. Lim, Merissa Chen, Sarah J. Rockwood, Kevin Holden, James K. Nuñez, Avi J. Samelson, Travis J. Maures, Veronica V. Rezelj, James A. Wells, Gokul N. Ramadoss, Bruce R. Conklin, Martin Kampmann, Na Liu, Irene Lui, Alice Mac Kain, Ruilin Tian, University of California [San Francisco] (UC San Francisco), University of California (UC), Chan Zuckerberg BioHub [San Francisco, CA], Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity (CNRS-UMR3569), NYU Langone Health [New York], Gladstone Institutes [San Francisco], Genentech, Inc., Genentech, Inc. [San Francisco], Howard Hughes Medical Institute (HHMI), Southern University of Science and Technology (SUSTech), Synthego [Redwood City, CA], Whitehead Institute, Massachusetts Institute of Technology (MIT), A.J.S. is supported by NIH grant F32AG063487. G.N.R. is supported by the NSF Graduate Research Fellowship Program (GRFP) and UCSF Discovery Fellowship. S.A.L. was a Merck Fellow of the Helen Hay Whitney Foundation. I.L. was supported by an NSF GRFP award. M.K. is a Chan Zuckerberg Biohub Investigator., and We thank members of the Kampmann, Vignuzzi and Conklin laboratories, as well as V. Ramani, D. Ruggero, M. Ott and her laboratory and other members of the UCSF QBI Coronavirus Research Group (QCRG) for helpful discussions. We thank K. Leng for feedback on the manuscript. We acknowledge the Gladstone Stem Cell Core for help with cardiomyocyte production.
Subjects: viruses, [SDV]Life Sciences [q-bio], Regulator, Druggability, Endogeny, Biology, Antiviral Agents, Medical and Health Sciences, Article, Cell Line, Vaccine Related, Interferon, Transcription (biology), Biodefense, medicine, Humans, 2.1 Biological and endogenous factors, Aetiology, Receptor, Lung, Gene, Cancer, Membrane Glycoproteins, SARS-CoV-2, Prevention, COVID-19, Epithelial Cells, Pneumonia, Cell Biology, Biological Sciences, In vitro, COVID-19 Drug Treatment, Cell biology, body regions, Emerging Infectious Diseases, Infectious Diseases, Good Health and Well Being, 5.1 Pharmaceuticals, Angiotensin-Converting Enzyme 2, Development of treatments and therapeutic interventions, Infection, Transcription Factors, Developmental Biology, medicine.drug
Abstract: SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. We found that the protein BRD2 is required for ACE2 transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous ACE2 expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia. Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a novel therapeutic target for COVID-19.
Published: 2022

12. Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection

Author: Arnauld Sergé, Mark J. McCarron, Saïdi M. Soudja, Magali Irla, Julien C. Marie, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Genentech, Inc. [San Francisco], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre for Cellular and Molecular Biology of Inflammation, King‘s College London, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), and German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)
Subjects: 0301 basic medicine, Central tolerance, T cell, Cellular differentiation, Science, T cells, General Physics and Astronomy, Autoimmunity, Bone Marrow Cells, Biology, CXCR3, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Transforming Growth Factor beta, medicine, Animals, lcsh:Science, Mice, Knockout, Multidisciplinary, Thymocytes, RANK Ligand, Cell Differentiation, Epithelial Cells, General Chemistry, T lymphocyte, Transforming growth factor beta, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Signal transduction, 030215 immunology, Transforming growth factor, Signal Transduction
Abstract: In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-β) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-β in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms., TGFβ is critical for limiting autoreactive responses of peripheral T cells. Here, the authors show that TGFβ signaling in thymocytes mediates elimination of self-reactive T cells and promotes the expression of self-antigens by medullary thymic epithelial cells.
Published: 2019

13. Powerful gene-based testing by integrating long-range chromatin interactions and knockoff genotypes

Author: Edwin K. Silverman, Justin Lee, Michael H. Cho, Iuliana Ionita-Laza, Chen Wang, Zihuai He, Wendy K. Chung, Joseph D. Buxbaum, Linxi Liu, Hugues Aschard, Richard Gill, James L. Dalgleish, Shiyang Ma, Columbia University [New York], Stanford University, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Genentech, Inc., Genentech, Inc. [San Francisco], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), This research was supported by NIH/National Institute of Mental Health Awards MH106910 and MH095797 (to I.I.-L.), and NIH/National Institute on Aging Award AG066206 (to Z.H.)., and We gratefully acknowledge the studies and participants who provided biological samples and data for the ADSP and TOPMed projects. The full study-specific acknowledgments are detailed in SI Appendix.
Subjects: Linkage disequilibrium, Computer science, gene-based association tests, Genome-wide association study, Linkage Disequilibrium, MESH: Genotype, Japan, MESH: Models, Genetic, Lung, MESH: Japan, [STAT.AP]Statistics [stat]/Applications [stat.AP], Multidisciplinary, MESH: Genetic Testing, Statistics, Replicate, Biological Sciences, Biobank, Chromatin, Phenotype, MESH: Linkage Disequilibrium, fine-mapping, Physical Sciences, MESH: Whole Genome Sequencing, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Genotype, long-range chromatin interactions, Quantitative Trait Loci, Locus (genetics), Computational biology, MESH: Phenotype, MESH: Chromatin, Genetic variation, Genetics, Humans, MESH: Lung, Genetic Testing, Gene, Genetic association, MESH: Humans, Models, Genetic, Whole Genome Sequencing, GWAS and whole-genome sequencing, MESH: Quantitative Trait Loci, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Genome-Wide Association Study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, knockoff statistics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome-Wide Association Study
Abstract: Significance Gene-based tests are important tools for elucidating the genetic basis of complex traits. Despite substantial recent efforts in this direction, the existing tests are still limited, owing to low power and detection of false-positive signals due to the confounding effects of linkage disequilibrium. In this paper, we describe a gene-based test that attempts to address these limitations by incorporating data on long-range chromatin interactions, several recent technical advances for region-based testing, and the knockoff framework for synthetic genotype generation. Through extensive simulations and applications to multiple diseases and traits, we show that the proposed test increases the power over state-of-the-art gene-based tests and provides a narrower focus on the possible causal genes involved at a locus., Gene-based tests are valuable techniques for identifying genetic factors in complex traits. Here, we propose a gene-based testing framework that incorporates data on long-range chromatin interactions, several recent technical advances for region-based tests, and leverages the knockoff framework for synthetic genotype generation for improved gene discovery. Through simulations and applications to genome-wide association studies (GWAS) and whole-genome sequencing data for multiple diseases and traits, we show that the proposed test increases the power over state-of-the-art gene-based tests in the literature, identifies genes that replicate in larger studies, and can provide a more narrow focus on the possible causal genes at a locus by reducing the confounding effect of linkage disequilibrium. Furthermore, our results show that incorporating genetic variation in distal regulatory elements tends to improve power over conventional tests. Results for UK Biobank and BioBank Japan traits are also available in a publicly accessible database that allows researchers to query gene-based results in an easy fashion.
Published: 2021

14. Post hoc Analysis of Clinical Outcomes in Placebo-and Pirfenidone-treated Patients with IPF Stratified by BMI and Weight Loss

Author: Ronan Thibault, Ming Yang, Bruno Crestani, Mathieu Lederlin, Laurent Vernhet, Stéphane Jouneau, Vincent Cottin, Elizabeth Morgenthien, Klaus-Uwe Kirchgaessler, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département de Radiologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], F. Hoffmann-La Roche [Basel], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This analysis was sponsored by Genentech, Inc. and F. Hoffmann-La Roche, Ltd, Jonchère, Laurent, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UR), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and École Pratique des Hautes Études (EPHE)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pyridones, [SDV]Life Sciences [q-bio], Vital Capacity, Interstitial lung disease, Idiopathic pulmonary fibrosis, Placebo, Body composition, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Weight loss, Internal medicine, Post-hoc analysis, Weight Loss, medicine, Humans, 030212 general & internal medicine, Adverse effect, Body mass index, 2. Zero hunger, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Percent Predicted Forced Vital Capacity, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, 030228 respiratory system, Cohort, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, medicine.symptom, business
Abstract: Background: Weight loss is frequently reported in patients with idiopathic pulmonary fibrosis (IPF) and may be associated with worse outcomes in these patients. Objective: The aim of this study was to investigate the relationships between body mass index (BMI) and weight loss, and outcomes over 1 year in patients with IPF. Methods: Data were included from placebo patients enrolled in ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729), and all patients in INSPIRE (NCT00075998) and RIFF Cohort A (NCT01872689). An additional analysis included data from pirfenidone-treated patients. Outcomes (annualized change in percent predicted forced vital capacity [%FVC], percent predicted carbon monoxide diffusing capacity, 6-min walk distance, St. George’s Respiratory Questionnaire total score, hospitalization, mortality, and serious adverse events) were analyzed by baseline BMI (2, 25 kg/m2–2, or ≥30 kg/m2) and annualized percent change in body weight (no loss, >0–Results: Placebo-treated patients with a baseline BMI 2 or annualized weight loss may experience worse outcomes versus those with a baseline BMI ≥25 kg/m2 or no weight loss. The proportion of placebo-treated patients who experienced a relative decline of ≥10% in %FVC or death up to 1 year post-randomization was highest in patients with a baseline BMI 2. Pirfenidone-treated patients with an annualized weight loss ≥5% may also experience worse outcomes versus those with no weight loss. Conclusions: Patients with a baseline BMI 2 or annualized weight loss of >0–2 or no weight loss.
Published: 2021

15. The genomics of heart failure: design and rationale of the HERMES consortium

Author: Svati H. Shah, Olle Melander, Neneh Sallah, Quinn S. Wells, Jerome I. Rotter, Faye Zhao, Charlotte Andersson, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Alex S. F. Doney, Michael E. Dunn, David E. Lanfear, Ian Ford, Eric Boersma, Sonia Shah, Christopher Newton-Cheh, Douglas L. Mann, Niek Verweij, Carolina Roselli, Laura M. Yerges-Armstrong, Jian Yang, Christian Torp-Pedersen, Veikko Salomaa, Mary L. Biggs, Alaa Shalaby, Christoph Nowak, Stefan Gross, Patrick T. Ellinor, Mari Liis Tammesoo, Diane T. Smelser, Peter M. Visscher, Hans L. Hillege, Ruth C. Lovering, Honghuang Lin, Colin N. A. Palmer, Louis Philippe Lemieux Perreault, Jeffrey Brandimarto, Uwe Völker, Perttu Salo, Andrea Koekemoer, Rebecca Gutmann, Åsa K. Hedman, Nilesh J. Samani, Heming Xing, Faiez Zannad, Jaison Jacob, Harry Hemingway, Michael R. Brown, Franco Giulianini, Anubha Mahajan, Xing Chen, Alexander Niessner, Peter Almgren, Daniel I. Swerdlow, Gunnar Engström, Lars Lind, Tõnu Esko, Tomasz Czuba, Anna Helgadottir, Harvey D. White, David J. Stott, Johan Ärnlöv, Lars Køber, Chim C. Lang, Krishna G. Aragam, Kent D. Taylor, Anders Mälarstig, Frederick K. Kamanu, Kenneth B. Margulies, Michelle L. O'Donoghue, Andrew D. Morris, Sahar Ghasemi, J. Wouter Jukema, Jessica van Setten, Abbas Dehghan, Guillaume Paré, Luca A. Lotta, Giorgio E. M. Melloni, Albert Henry, Bruce M. Psaty, Paul M. Ridker, David J. Carey, Marie-Pierre Dubé, John S. Gottdiener, Xiaosong Wang, Per H. Svensson, Xu Chen, Patrik K. E. Magnusson, Claudia Langenberg, Alexander Teumer, Vilmantas Giedraitis, Simon de Denus, Michael W. Nagle, Marcus Dörr, Thomas P. Cappola, André G. Uitterlinden, Michael Morley, Eliana Portilla-Fernandez, J. Gustav Smith, Abirami Veluchamy, Peter Weeke, Ify R. Mordi, Unnur Thorsteinsdottir, Naveed Sattar, Folkert W. Asselbergs, Daniel I. Chasman, Daníel F. Guðbjartsson, Jonathan H. Chung, Marcus E. Kleber, Raul Weiss, Christopher P. Nelson, Spiros Denaxas, Bing Yu, Simon P. R. Romaine, Nicholas A Marston, Anjali T. Owens, Cecilia M. Lindgren, John J.V. McMurray, Joshua D. Backman, Michael V. Holmes, Stella Trompet, Hilma Holm, Kerri L. Wiggins, Jian'an Luan, Stephan B. Felix, Yifan Yang, Jemma B. Wilk, Maryam Kavousi, Markus Perola, Christian T. Ruff, Jean-Claude Tardif, G Sveinbjörnsson, Samuel C. Dudley, Nicholas J. Wareham, Teemu J. Niiranen, Andrew P. Morris, Danny Tuckwell, Maris Teder-Laving, R. Thomas Lumbers, James P. Cook, Géraldine Asselin, William A. Chutkow, Winfried März, Steven A. Lubitz, John G.F. Cleland, Bill Kraus, Ramachandran S. Vasan, Christopher M. Haggerty, Olympe Chazara, Chris Finan, Heather L. Bloom, Hans-Peter Brunner-La Rocca, Francoise Fougerousse, Kenneth Rice, Craig L. Hyde, Graciela E. Delgado, Mark Chaffin, Marc S. Sabatine, Alanna C. Morrison, Kay-Tee Khaw, Kari Stefansson, Felix Vaura, Barry London, Isabella Kardys, Aroon D. Hingorani, Hongsheng Gui, Steen Stender, René Fouodjio, Mohsen Ghanbari, Pim van der Harst, Nicholas L. Smith, Karoline Kuchenbaecker, Adriaan A. Voors, Benoit Tyl, University College of London [London] (UCL), University College London Hospitals (UCLH), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Lund University [Lund], Pfizer, Karolinska Institutet [Stockholm], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Oxford [Oxford], Dalarna University, Massachusetts General Hospital [Boston], Montreal Heart Institute - Institut de Cardiologie de Montréal, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, University of Washington [Seattle], Emory University [Atlanta, GA], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], The University of Texas Health Science Center at Houston (UTHealth), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), AstraZeneca, Novartis Institutes for BioMedical Research (NIBR), University of Glasgow, University of Liverpool, Université de Montréal (UdeM), Imperial College London, University of Heidelberg, Medical Faculty, University of Dundee, Universität Greifswald - University of Greifswald, University of Minnesota Medical School, University of Minnesota System, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Uppsala University, University of Maryland School of Medicine, University of Maryland System, University of Iceland [Reykjavik], deCODE genetics [Reykjavik], Henry Ford Hospital, Carver College of Medicine, University of Iowa, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), ICIN - Netherlands Heart Institute, Leiden University Medical Center (LUMC), Netherlands Heart Institute, Partenaires INRAE, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Leicester, Duke University [Durham], University of Iowa [Iowa City], Genentech, Inc., Genentech, Inc. [San Francisco], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Skane University Hospital [Malmo], University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, University of Turku, National Institute for Health and Welfare [Helsinki], McMaster University [Hamilton, Ontario], Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Harbor UCLA Medical Center [Torrance, Ca.], University Medical Center [Utrecht], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), University of Tartu, Aalborg University [Denmark] (AAU), Leiden University, University of Queensland [Brisbane], Ohio State University [Columbus] (OSU), Auckland City Hospital, GlaxoSmithKline, Glaxo Smith Kline, University of Texas Health Science Center, Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Duke University Medical Center, Regeneron Pharmaceuticals [Tarrytown], Vanderbilt University [Nashville], European Project, Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Cardiology, University of Oxford, University of Pennsylvania, Universiteit Leiden, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology, and Internal Medicine
Subjects: Male, Study Designs, Cardiomyopathy, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, AFRICAN ANCESTRY, Epidemiology, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, Cardiac and Cardiovascular Systems, AGING RESEARCH, RISK, Aged, 80 and over, 0303 health sciences, Kardiologi, Genomics, Middle Aged, Prognosis, 3. Good health, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Heart failure, CLASSIFICATION, Heart Failure/genetics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetic model, medicine, Genetics, Diseases of the circulatory (Cardiovascular) system, Humans, Allele frequency, Genotyping, METAANALYSIS, 030304 developmental biology, Aged, Association studies, Study Design, business.industry, Odds ratio, ADULTS, COHORTS, medicine.disease, RC666-701, REPLICATION, business, Biomarkers, Genome-Wide Association Study
Abstract: Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
Published: 2021

16. Current directions in tau research: Highlights from Tau 2020

Author: Keith A. Johnson, Michael Gold, Yakeel T. Quiroz, Sarah L. DeVos, Howard Feldman, Bradley T. Hyman, Susan Worley, Heather M. Snyder, Adam L. Boxer, Gil D. Rabinovici, Luc Buée, Pat Brannelly, Catherine J. Mummery, Irene Litvan, Leticia M Toledo-Sherman, James Mutamba, Kristin R. Wildsmith, Marc C. Patterson, Celeste M. Karch, Dirk Beher, Jean Pierre Brion, Maria C. Carrillo, Claire Sexton, Gaël Chételat, Martin Citron, Huw R. Morris, Alison Goate, Kristophe Diaz, Stacie Weninger, Amy Rommel, Diana R. Kerwin, Angela Cacace, Melanie B Shulman, Walter J. Koroshetz, Bess Frost, Alzheimer's Association, Asceneuron [Lausanne, Switzerland], University of California [San Francisco] (UC San Francisco), University of California (UC), Alzheimer's Disease Data Initiative [Kirkland, WI, USA] (ADDI), Université libre de Bruxelles (ULB), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neuroscience and Platform Biology [Arvinas, NH, USA] (NPB), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Blood and Brain @ Caen-Normandie [Caen] (BB@C), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UCB Biopharma [Brussels, Belgium] (UCB-B), Denali Therapeutics [San Francisco, CA, USA]. (DT), Cure PSP [New York, NY, USA] (C-PSP), University of California [San Diego] (UC San Diego), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Abbvie Inc. [North Chicago], Harvard Medical School [Boston] (HMS), Department of radiology (Massachusetts General Hospital), Massachusetts General Hospital [Boston], Washington University in Saint Louis (WUSTL), University of Texas Southwestern Medical Center [Dallas], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), UCL Institute of Neurology, Queen Square [London], University College of London [London] (UCL), Longwood Fund [Boston, MA, USA] (LF), Mayo Clinic [Rochester], Rainwater Charitable Foundation [Fort Worth, TX, USA] (RCF), Biogen [Boston, MA, USA], F-Prime Capital [Cambridge, MA, USA] (FBRI), Genentech, Inc. [San Francisco], Independent science writer [Bryn Mawr, PA, USA] (ISW), University of California [San Francisco] (UCSF), University of California, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), University of Texas Health Science Center at San Antonio [San Antonio], Institute of Neurology - UCL/Queen Square [London, UK] (IN-UCL-QS), and BUEE, Luc
Subjects: Aging, Epidemiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Sciences, tau Proteins, Neurodegenerative, Alzheimer's Disease, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Alzheimer Disease, Neurologie, Political science, Drug Discovery, Acquired Cognitive Impairment, therapeutics, Humans, Cognitive Dysfunction, tau, Cognitive decline, 030304 developmental biology, Pace, 0303 health sciences, Government, business.industry, Health Policy, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurosciences, neurodegeneration, Médecine pathologie humaine, biomarkers, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neuropathologie, Sciences bio-médicales et agricoles, Public relations, Alzheimer's, 3. Good health, Brain Disorders, Psychiatry and Mental health, Geriatrics, Dementia, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers
Abstract: Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research., info:eu-repo/semantics/published
Published: 2021

17. Accurate prediction of cell composition, age, smoking consumption and infection serostatus based on blood DNA methylation profiles

Author: Lluis Quintana-Murci, Darragh Duffy, Matthew L. Albert, Etienne Patin, Jacob Bergstedt, Alejandra Urrutia, Lund University [Lund], Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), This work benefited from support of the French government’s Program In vestissement d’Avenir, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). J.B. is a member of the LCCC Linnaeus Center and the ELLIIT Excellence Center at Lund University and is supported by the ELLIIT Excellence Center., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Regulation of gene expression, 0303 health sciences, Cellular differentiation, Genomics, Methylation, Computational biology, Biology, 01 natural sciences, 3. Good health, Predictive medicine, 010104 statistics & probability, 03 medical and health sciences, DNA methylation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Epigenetics, 0101 mathematics, 030304 developmental biology, Epigenomics
Abstract: Posté sur bioRxiv le 30/10/2018; DNA methylation is a stable epigenetic alteration that plays a key role in cellular differentiation and gene regulation, and that has been proposed to mediate environmental effects on disease risk. Epigenome-wide association studies have identified and replicated associations between methylation sites and several disease conditions, which could serve as biomarkers in predictive medicine and forensics. Nevertheless, heterogeneity in cellular proportions between the compared groups could complicate interpretation. Reference-based cell-type deconvolution methods have proven useful in correcting epigenomic studies for cellular heterogeneity, but they rely on reference libraries of sorted cells and only predict a limited number of cell populations. Here we leverage >850,000 methylation sites included in the MethylationEPIC array and use elastic net regularized and stability selected regression models to predict the circulating levels of 70 blood cell subsets, measured by standardized flow cytometry in 962 healthy donors of western European descent. We show that our predictions, based on a hundred of methylation sites or lower, are less error-prone than other existing methods, and extend the number of cell types that can be accurately predicted. Application of the same methods to age, smoking consumption and several serological responses to pathogen antigens also provide accurate estimations. Together, our study substantially improves predictions of blood cell composition based on methylation profiles, which will be critical in the emerging field of medical epigenomics.
Published: 2021

18. Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Author: Ellen Ingalla, Deepak Sampath, Franck Morschhauser, Kylie D. Mason, Guillaume Cartron, Martine E.D. Chamuleau, Arijit Sinha, Divya Samineni, Edith Szafer-Glusman, Constantine S. Tam, Carla Casulo, Andre Goy, Pieternella J. Lugtenburg, Christian Klein, Steven Le Gouill, Adam M. Petrich, Mehrdad Mobasher, Andrew D. Zelenetz, Gilles Salles, Hervé Tilly, Sylvia Herter, Martin Kornacker, Laurie H. Sehn, Hematology, CCA - Cancer Treatment and quality of life, Memorial Sloane Kettering Cancer Center [New York], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), The Royal Melbourne Hospital, University of Rochester Medical Center (URMC), Centre hospitalier universitaire de Nantes (CHU Nantes), BC Cancer Agency (BCCRC), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), VU University Medical Center [Amsterdam], Hackensack University Medical Center [Hackensack], University of Melbourne, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Abbvie Inc. [North Chicago], Roche Products Ltd, Genentech, Inc. [San Francisco], Roche Innovation Center Zurich, Genentech, Inc., F. Hoffmann-La Roche [Basel], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Male, Oncology, Follicular lymphoma, CHOP, MESH: Antineoplastic combined chemotherapy protocols/therapeutic use, Bridged bicyclo compounds, Heterocyclic/therapeutic use, Lymphoma, Non-Hodgkin/drug therapy, Sulfonamides/therapeutic use, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Obinutuzumab, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, B-cell lymphoma, Sulfonamides, 0303 health sciences, Lymphoma, Non-Hodgkin, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Vincristine, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Rituximab, medicine.drug, medicine.medical_specialty, Maximum Tolerated Dose, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, Disease-Free Survival, 03 medical and health sciences, Internal medicine, medicine, Humans, Cyclophosphamide, Aged, 030304 developmental biology, business.industry, Venetoclax, Cell Biology, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, chemistry, Doxorubicin, Prednisone, business, Diffuse large B-cell lymphoma
Abstract: Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.
Published: 2019

19. Targeting BCL ‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma

Author: Jonathan L. Kaufman, Ahmed Salem, Xiaoqing Yang, James M. Pauff, Paulo Maciag, Cyrille Touzeau, Fredrik Schjesvold, Thierry Facon, Lawrence H. Boise, Shaji Kumar, Yanwen Jiang, Stefanie Unger, Wan-Jen Hong, Deeksha Vishwamitra, John Pesko, Fengjiao Dunbar, Yao Yu, Jeremy A. Ross, Cristina Gasparetto, Philippe Moreau, R. N. Tammy Macartney, Emory University [Atlanta, GA], Duke University [Durham], University of Oslo (UiO), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA), Université de Nantes (UN), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), CHU Lille, Hôpital Claude Huriez [Lille], Genentech, Inc. [San Francisco], Abbvie Inc. [North Chicago], AbbVie Deutschland GmbH & Co KG, Abbott GmbH & Co KG, Mayo Clinic [Rochester], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Male, medicine.medical_treatment, Salvage therapy, Kaplan-Meier Estimate, Hematopoietic stem cell transplantation, Gastroenterology, Dexamethasone, Translocation, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Bone Marrow, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Medicine, Research Articles, Multiple myeloma, Sulfonamides, Hematopoietic Stem Cell Transplantation, Antibodies, Monoclonal, Hematology, Middle Aged, Combined Modality Therapy, Neoplasm Proteins, 3. Good health, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, Signal Transduction, Research Article, medicine.drug, medicine.medical_specialty, bcl-X Protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neutropenia, Infections, 03 medical and health sciences, Refractory, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, Aged, Chromosomes, Human, Pair 14, Salvage Therapy, business.industry, Venetoclax, Chromosomes, Human, Pair 11, Daratumumab, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, Hematologic Diseases, Genes, bcl-2, chemistry, business, Follow-Up Studies, 030215 immunology
Abstract: International audience; Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-XL ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM.
Published: 2021

20. Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance)

Author: Jeffrey P. Meyers, Magali Svrcek, Romain Cohen, Pankaj Kumar, Monica M. Bertagnolli, Kristen K. Ciombor, Eileen M. O'Reilly, Johanna C. Bendell, Jeffrey A. Meyerhardt, Charles D. Blanke, DeQuincy Andrew Lewis, Charles S. Fuchs, Anthony F. Shields, Félix Couture, P. Kuebler, Philip A. Philip, A. De Jesus-Acosta, Benjamin R. Tan, Q. Shi, Zhaohui Jin, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Mayo Clinic [Rochester], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Saint-Antoine], Yale University School of Medicine, Genentech, Inc., Genentech, Inc. [San Francisco], L'hôtel-Dieu de Québec [CHU Québec] (HDQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Columbus Community Clinical Oncology Program [Columbus, OH, USA] (CCOP), Vanderbilt University [Nashville], Sarah Cannon Research Institute [Nashville, Tennessee], Johns Hopkins University (JHU), Illinois Cancercare, P.C. [Peoria, IL, USA] (IC), Cone Health Medical Group HeartCare [Asheboro, NC, USA] (CHMGH), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Wayne State University School of Medicine, Oregon Health and Science University [Portland] (OHSU), Weill Medical College of Cornell University [New York], Dana-Farber Cancer Institute [Boston], Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Yale School of Medicine [New Haven, Connecticut] (YSM), and HAL-SU, Gestionnaire
Subjects: Oncology, medicine.medical_specialty, Colorectal cancer, Lymphovascular invasion, stage III, Perineural invasion, tumor deposit, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, adjuvant, Internal medicine, Post-hoc analysis, medicine, Humans, 030212 general & internal medicine, Stage (cooking), Lymph node, Neoplasm Staging, Retrospective Studies, Extranodal Extension, business.industry, Proportional hazards model, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hematology, medicine.disease, Lymphovascular, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Colonic Neoplasms, Lymph Nodes, prognosis, business
Abstract: International audience; Background: In colon cancer, tumor deposits (TD) are considered in assigning prognosis and staging only in the absence of lymph node metastasis (i.e. stage III pN1c tumors). We aimed to evaluate the prognostic value of the presence and the number of TD in patients with stage III, node-positive colon cancer.Patients and methods: All participants from the CALGB/SWOG 80702 phase III trial were included in this post hoc analysis. Pathology reports were reviewed for the presence and the number of TD, lymphovascular and perineural invasion. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated by multivariable Cox models adjusting for sex, treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio.Results: Overall, 2028 patients were included with 524 (26%) TD-positive and 1504 (74%) TD-negative tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e. pN1c), 239 (46.1%) were pN1a/b (
Published: 2021

21. Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440)

Author: Stilgenbauer, Stephan, Morschhauser, Franck, Wendtner, Clemens-Martin, Cartron, Guillaume, Hallek, Michael, Eichhorst, Barbara, Kozloff, Mark, Giever, Thomas, Lozanski, Gerard, Jiang, Yanwen, Huang, Huang, Pignataro, Daniela, Schary, William, Humphrey, Kathryn, Mobasher, Mehrdad, Salles, Gilles, Universität Ulm - Ulm University [Ulm, Allemagne], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), University Hospital of Cologne [Cologne], The University of Chicago Medicine [Chicago], Medical College of Wisconsin [Milwaukee] (MCW), Ohio State University [Columbus] (OSU), Genentech, Inc. [San Francisco], F. Hoffmann-La Roche [Basel], Roche Products Ltd, Abbvie Inc. [North Chicago], Hospices Civils de Lyon (HCL), and Université de Lyon
Subjects: MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Bendamustine Hydrochloride, MESH: Humans, MESH: Antibodies, Monoclonal, Humanized, MESH: Sulfonamides, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Bridged Bicyclo Compounds, Heterocyclic, MESH: Rituximab, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, MESH: Leukemia, Lymphocytic, Chronic, B-Cell
Abstract: International audience; Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100–400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3–4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3–4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.
Published: 2021

22. Mortality and Respiratory-Related Hospitalizations in Idiopathic Pulmonary Fibrosis Not Treated With Antifibrotics

Author: Cottin, Vincent, Spagnolo, Paolo, Bonniaud, Philippe, Nolin, Maëva, Dalon, Faustine, Kirchgässler, Klaus-Uwe, Kamath, Tripthi, van Ganse, Eric, Belhassen, Manon, ROSSI, Sabine, Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de Padoue, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM), PELyon, Pharmacoepidemiologie, Lyon, F. Hoffmann-La Roche [Basel], Genentech, Inc. [San Francisco], Research on Healthcare Performance (RESHAPE - Inserm U1290 - UCBL1), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: données sur les sinistres, mortalité, fibrose pulmonaire idiopatique, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, antifibrotiques, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, hospitalisations aiguës
Abstract: International audience; Background: Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. The claims data from the French National Health System (SNDS) were used to describe outcomes in patients diagnosed with IPF in 2015–2016 but who did not receive antifibrotic therapies. Method: Patients aged
Published: 2021

23. Safety and efficacy of obinutuzumab alone or with chemotherapy in previously untreated or relapsed/refractory chronic lymphocytic leukaemia patients: Final analysis of the Phase IIIb GREEN study

Author: Marcin Wójtowicz, Gianluigi Reda, Robin Foà, Mehmet Turgut, Eugen Tausch, Sebastian Böttcher, Marlies E.H.M. Van Hoef, Thomas Perretti, Jens Kisro, Francesc Bosch, Osman Ilhan, Sue Robinson, Beatrice Mahe, Veronique Leblond, Dzhelil Osmanov, Eva Mikuskova, Stephan Stilgenbauer, Peter Trask, Universität des Saarlandes [Saarbrücken], University of Ulm (UUlm), Vall d'Hebron University Hospital [Barcelona], Ankara University School of Medicine [Turkey], Hôtel-Dieu de Nantes, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Rostock, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Genentech, Inc. [San Francisco], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Institut Català de la Salut, [Stilgenbauer S] Department of Internal Medicine III, Ulm University, Ulm and Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg, Germany. [Bosch F] Servei d’Hematologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Ilhan O] Internal Medical Sciences Departments, Ankara University School of Medicine, Ankara, Turkey. [Kisro J] Onkologische Schwerpunktpraxis Lübeck, Lübeck, Germany. [Mahé B] Clinical Hematology, CHU Nantes Hôtel-Dieu, Nantes, France. [Mikuskova E] Department of Hemato-oncology II, National Cancer Institute, Bratislava, Slovakia Blokhin, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Antibodies, Monoclonal, Humanized, Therapeutic use, IGHV, Neoplasm, Residual, Non-Randomized Controlled Trials as Topic, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Gastroenterology, Biomarkers, Pharmacological, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Obinutuzumab, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Medicine, Bendamustine Hydrochloride, Aged, 80 and over, Hematology, Middle Aged, Progression-Free Survival, 3. Good health, Fludarabine, Treatment Outcome, 030220 oncology & carcinogenesis, Chronisch-lymphatische Leukämie, Female, Safety, Immunoglobulin Heavy Chains, Vidarabine, neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES], medicine.drug, Bendamustine, Adult, medicine.medical_specialty, Neutropenia, Cyclophosphamide, Prognosi, Quimioteràpia combinada, 03 medical and health sciences, Internal medicine, Humans, Leucèmia limfocítica crònica, ddc:610, Chemotherapie, terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Aged, Chemotherapy, Chlorambucil, business.industry, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Molekulartherapie, Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, Minimal residual disease, Leukemia, Lymphocytic, Chronic, B-Cell, Thrombocytopenia, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES], chemistry, minimal residual disease, business, DDC 610 / Medicine & health, chronic lymphocytic leukaemia, 030215 immunology, Leukemia, Lymphoid, Drug therapy
Abstract: Summary The manageable toxicity profile of obinutuzumab (GA101; G) alone or with chemotherapy in first‐line (1L; fit and non‐fit) and relapsed/refractory (R/R) patients with chronic lymphocytic leukaemia (CLL) was established in the primary analysis of the Phase IIIb GREEN trial (Clinicaltrials.gov: NCT01905943). The final analysis (cut‐off, 31 January 2019) is reported here. Patients received G (1000 mg) alone (G‐mono; fit and non‐fit patients) or with chemotherapy [fludarabine and cyclophosphamide (FC; fit patients); chlorambucil (non‐fit patients); bendamustine (any patient)]. Study endpoints were safety (primary) and efficacy (secondary). Subgroup analyses were performed on prognostic biomarkers in 1L CLL. Overall, 630 patients received 1L and 341 received R/R CLL treatment. At the final analysis, no new safety signals were observed [Grade ≥ 3 adverse events (AEs): 1L 82·7%, R/R 84·5%; serious AEs: 1L 58·1%, R/R 62·5%]. Neutropenia (1L 50·5%, R/R 53·4%) and thrombocytopenia (1L 14·6%, R/R 19·1%) were the most common Grade 3–5 AEs. G‐mono‐, G‐bendamustine and G‐FC‐treated patients with unmutated immunoglobulin heavy chain trended towards shorter progression‐free survival. Achievement of minimal residual disease negativity was greatest in 1L patients treated with G‐FC. In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses supported efficacy in the specific subgroups., publishedVersion
Published: 2021
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24. Bayesian inference using Hamiltonian Monte‐Carlo algorithm for nonlinear joint modeling in the context of cancer immunotherapy

Author: Coralie Tardivon, Rene Bruno, Julie Bertrand, Francois Mercier, Jeremie Guedj, Solène Desmée, Marion Kerioui, Université de Paris, IAME, INSERM, Paris, France, MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Clinical Pharmacology [South San Francisco, CA, USA] (Genentech Inc.), Genentech, Inc. [San Francisco], and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques
Subjects: Statistics and Probability, Epidemiology, Computer science, HMC algorithm, Bayesian probability, Bayesian inference, Inference, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, 01 natural sciences, nonlinear mixed effect models, Hybrid Monte Carlo, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Humans, cancer, 030212 general & internal medicine, 0101 mathematics, Markov chain, joint models, Linear model, Bayes Theorem, Markov Chains, [STAT]Statistics [stat], Nonlinear Dynamics, Identifiability, Immunotherapy, Algorithm, Monte Carlo Method, Algorithms
Abstract: International audience; Treatment evaluation in advanced cancer mainly relies on overall survival and tumor size dynamics. Both markers and their association can be simultaneously analyzed by using joint models, and these approaches are supported by many softwares or packages. However, these approaches are essentially limited to linear models for the longitudinal part, which limit their biological interpretation.More biological models of tumor dynamics can be obtained by using nonlinear models, but they are limited by the fact that parameter identifiability require rich dataset. In that context Bayesian approaches are particularly suited to incorporate the biological knowledge and increase the information available, but they are limited by the high computing cost of Monte-Carlo by Markov Chains algorithms. Here, we aimed to assess the performances of the Hamiltonian Monte-Carlo (HMC) algorithm implemented in Stan for inference in a nonlinear joint model. The method was validated on simulated data where HMC provided proper posterior distributions and credibility intervalsin a reasonable computational time. Then the association between tumor size dynamics and survival was assessed in patients with advanced or metastatic bladder cancer treated with atezolizumab, an immunotherapy agent. HMC confirmed limited sensitivity to prior distributions. A cross-validation approach was developed and identified the current slope of tumor size dynamics as the most relevant driver of survival. In summary, HMC is an efficient approach to perform nonlinear joint models in a Bayesian framework, and opens the way for the use of nonlinear models to characterize both the rapid dynamics and the intersubject variability observed during cancer immunotherapy treatment.
Published: 2020

25. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study

Author: Daniil Stroyakovskiy, Yu Guo, Isabelle Rooney, P. Francesco Ferrucci, Keith T. Flaherty, Zeynep Eroglu, Jacopo Pigozzo, S. Troutman, Jacek Mackiewicz, S. Mulla, Athina Voulgari, Piotr Rutkowski, Bethany Pitcher, Brigitte Dréno, Lev V. Demidov, J.M.G. Larkin, A. Arance, M. Castro, Helen Gogas, Yibing Yan, National and Kapodistrian University of Athens (NKUA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Royal Marsden NHS Foundation Trust, N.N. Blokhin Russian Cancer Research Center, Moscow City Oncology Hospital No. 62 [Moscow, Russia] (MCOH), H. Lee Moffitt Cancer Center and Research Institute, European Institute of Oncology [Milan] (ESMO), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Maria Sklodowska-Curie National Research Institute of Oncology [Krakow, Poland], Poznan University of Medical Sciences [Poland] (PUMS), Genentech, Inc. [San Francisco], Roche Products Ltd, F. Hoffmann-La Roche [Basel], Massachusetts General Hospital Cancer Center [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Hospital Clinic [Barcelona, Spain], and Malbec, Odile
Subjects: 0301 basic medicine, atezolizumab, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Pembrolizumab, Gastroenterology, BRAF wild-type, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Atezolizumab, Interquartile range, Internal medicine, medicine, melanoma, education, Adverse effect, cobimetinib, Cobimetinib, education.field_of_study, business.industry, Hazard ratio, Hematology, Rash, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, pembrolizumab, medicine.symptom, business
Abstract: International audience; Background: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAF V600 wild-type advanced melanoma. Patients and methods: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n ¼ 222) or pembrolizumab (n ¼ 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P ¼ 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF V600 wild-type advanced melanoma.
Published: 2020

26. Clinical Outcomes at 1 Year in Patients with Idiopathic Pulmonary Fibrosis (IPF) Stratified by Annualized Weight Loss and Baseline Body Mass Index (BMI): A Post-Hoc Analysis from Ascend, Capacity, Inspire, and Riff

Author: Mathieu Lederlin, Klaus-Uwe Kirchgaessler, Bruno Crestani, Ming Yang, Laurent Vernhet, Ronan Thibault, Stéphane Jouneau, Vincent Cottin, Elizabeth Morgenthien, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], F. Hoffmann-La Roche [Basel], Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Epidémiologie environnementale des cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), F. Hoffmann-La Roche, Ltd.Hoffmann-La Roche, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 2. Zero hunger, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], medicine.disease, 3. Good health, Idiopathic pulmonary fibrosis, Weight loss, Internal medicine, Post-hoc analysis, medicine, In patient, medicine.symptom, Baseline (configuration management), business, Body mass index, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

27. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib ± cobimetinib: a pooled analysis of four clinical trials

Author: Axel Hauschild, Yeung-Chul Mun, Edward McKenna, Paolo A. Ascierto, Karl D. Lewis, Keith T. Flaherty, James Larkin, Brigitte Dréno, Antoni Ribas, Qian Zhu, Grant A. McArthur, Istituto Nazionale Tumori Fondazione Pascale [Naples, Italy], University of California [Los Angeles] (UCLA), University of California (UC), Royal Marsden NHS Foundation Trust, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, University of Colorado Anschutz [Aurora], University Hospital Schleswig-Holstein [Kiel, Germany], Massachusetts General Hospital [Boston], Genentech, Inc. [San Francisco], Nantes Université (Nantes Univ), and Malbec, Odile
Subjects: Oncology, Skin Neoplasms, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lcsh:Medicine, Medical and Health Sciences, Targeted therapy, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Cobimetinib, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, 030212 general & internal medicine, Vemurafenib, Melanoma, Cancer, General Medicine, Prognosis, Dacarbazine, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, 6.1 Pharmaceuticals, medicine.drug, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Clinical Trials and Supportive Activities, Immunology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Clinical Research, Internal medicine, medicine, Humans, Survival analysis, Performance status, business.industry, Research, lcsh:R, Evaluation of treatments and therapeutic interventions, medicine.disease, chemistry, Mutation, Azetidines, business, Progressive disease
Abstract: Background We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS. Methods Recursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAFV600-mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause. Results RPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3–16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8–2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments. Conclusion A combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).
Published: 2020

28. ImmGen at 15

Author: Aguilar, Stephanie Vargas, Aguilar, Oscar, Allan, Rhys, Amir, El Ad David, Angeli, Veronique, Artyomov, Maxim, Asinovski, Natasha, Astarita, Jilian, Austen, K. Frank, Bajpai, Geetika, Barrett, Nora, Baysoy, Alev, Benoist, Christophe, Bellemare-Pelletier, Angelique, Berg, Brad, Best, Adam, Bezman, Natalie, Blair, David, Blander, Julie, Bogunovic, Milena, Brennan, Patrick, Brenner, Michael, Brown, Brian, Buechler, Matthew, Buenrostro, Jason, Casanova, Maria Acebes, Choi, Kyunghee, Chow, Andrew, Chudnovskiy, Aleksey, Cipoletta, Daniela, Cohen, Nadia, Collins, James, Colonna, Marco, Cook, Alison, Costello, James, Cremasco, Viviana, Crowl, Ty, Crozat, Karine, Cruse, Richard, D’angelo, June, Dalod, Marc, Davis, Scott, Demiralp, Cagatay, Deng, Tianda, Desai, Jigar, Desland, Fiona, Dhainaut, Maxime, Ding, Jiarui, Doedens, Andrew, Dominguez, Claudia, Doran, Graeme, Dress, Regine, Dustin, Michael, Dwyer, Daniel, Dzhagalov, Ivan, Elpek, Kutlu, Ergun, Ayla, Ericson, Jeff, Esomonu, Eunice, Fairfax, Keke, Fletcher, Anne, Frascoli, Michela, Fuchs, Anja, Gainullina, Anastasiia, Gal-Oz, Shani, Gallagher, Michael, Gautier, Emmanuel, Gazit, Roi, Gibbings, Sophie, Giraud, Matthieu, Ginhoux, Florent, Goldrath, Ananda, Gotthardt, Dagmar, Gray, Daniel, Greter, Melanie, Grieshaber-Bouyer, Ricardo, Guilliams, Martin, Haidermota, Sara, Hardy, Randy, Hashimoto, Daigo, Helft, Julie, Hendricks, Deborah, Heng, Tracy, Hill, Jonathan, Hyatt, Gordon, Idoyaga, Juliana, Jakubzick, Claudia, Jarjoura, Jessica, Jepson, Daniel, Jia, Baosen, Jianu, Radu, Johanson, Tim, Jordan, Stefan, Jojic, Vladimir, Kamimura, Yosuke, Kana, Veronica, Kang, Joonsoo, Kapoor, Varun, Kenigsberg, Ephriam, Kent, Andrew, Kim, Charles, Kim, Edy, Kim, Francis, Kim, Joel, Kim, Kiwook, Kiner, Evgeny, Knell, Jamie, Koller, Daphne, Kozinn, Larry, Krchma, Karen, Kreslavsky, Taras, Kronenberg, Mitchell, Kwan, Wing-Hong, Laidlaw, David, Lam, Viola, Lanier, Lewis, Laplace, Catherine, Lareau, Caleb, Lavin, Yonit, Lavine, Kory, Leader, Andrew, Leboeuf, Marylene, Lee, Jacob, Lee, Jisu, Li, Bo, Li, Hu, Li, Yuesheng, Lionakis, Michail, Luche, Herve, Lynch, Lydia, Magen, Assaf, Maier, Barbara, Malhotra, Deepali, Malhotra, Nidhi, Malissen, Marie, Maslova, Alexandra, Mathis, Diane, Mcfarland, Adelle, Merad, Miriam, Meunier, Etienne, Miller, Jennifer, Milner, Justin, Mingueneau, Michael, Min-Oo, Gundula, Monach, Paul, Moodley, Devapregasan, Mortha, Arthur, Morvan, Maelig, Mostafavi, Sara, Muller, Soren, Muus, Christoph, Nabekura, Tsukasa, Rao, Tata Nageswara, Narang, Vipin, Narayan, Kavitha, Ner-Gaon, Hadas, Nguyen, Quyhn, Nigrovic, Peter, Novakovsky, German, Nutt, Stephan, Omilusik, Kayla, Ortiz-Lopez, Adriana, Paidassi, Helena, Paik, Henry, Painter, Michio, Paynich, Mallory, Peng, Vincent, Potempa, Marc, Pradhan, Rachana, Price, Jeremy, Qi, Yilin, Qi, Yiqing, Quon, Sara, Ramirez, Ricardo, Ramanan, Deepshika, Randolph, Gwendalyn, Regev, Aviv, Rhoads, Andrew, Robinette, Michelle, Rose, Samuel, Rossi, Derrick, Rothamel, Katie, Sachidanandam, Ravi, Sathe, Priyanka, Scott, Charlotte, Seddu, Kumba, See, Peter, Sergushichev, Alexey, Shaw, Laura, Shay, Tal, Shemesh, Avishai, Shinton, Susan, Shyer, Justin, Sieweke, Michael, Smillie, Chris, Spel, Lotte, Spidale, Nick, Stifano, Giuseppina, Subramanian, Ayshwarya, Sun, Joseph, Sylvia, Katelyn, Tellier, Julie, This, Sébastien, Tomasello, Elena, Todorov, Helena, Turley, Shannon, Vijaykumar, Brinda, Wagers, Amy, Wakamatsu, Ei, Wang, Chendi, Wang, Peter, Wroblewska, Aleksandra, Wu, Jun, Yang, Edward, Yang, Liang, Yim, Aldrin, Yng, Lim Sheau, Yoshida, Hideyuki, Yu, Bingfei, Zhou, Yan, Zhu, Yanan, Ziemkiewicz, Caroline, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Walter and Eliza Hall Institute of Medical Research (WEHI), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National University of Singapore (NUS), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Harvard Medical School [Boston] (HMS), Genentech, Inc. [San Francisco], Brigham & Women’s Hospital [Boston] (BWH), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Brown University, Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Crozat, Karine, and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: 0301 basic medicine, Regulation of gene expression, [SDV.IMM] Life Sciences [q-bio]/Immunology, Test data generation, Computer science, [SDV]Life Sciences [q-bio], Immunology, Gene regulatory network, Genomics, Genome project, Data science, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, microRNA, Immunology and Allergy, DECIPHER, [SDV.IMM]Life Sciences [q-bio]/Immunology, Scientific publishing, ComputingMilieux_MISCELLANEOUS, 030215 immunology
Abstract: International audience; 700 comment | SERIES ImmGen at 15 Nature Immunology's 20 th anniversary is a good opportunity to reminisce about the ImmGen collective endeavor-its goals, successes and horror stories-and the group's exploration of various modes of scientific publishing. The Immunological Genome Project T he Immunological Genome Project (ImmGen) is a collaborative group of immunology and computational biology laboratories that perform a thorough dissection of gene expression and its regulation in the immune system of the mouse. This activity first centered on mRNA expression and then expanded to microRNA (miRNA), chromatin structure, nuclear organization and protein-RNA relationships. Shared protocols, data generation and QC pipelines have yielded data that can be directly compared from >250 stem, lymphoid and myeloid cell types, at baseline or under challenge. The group develops and applies computational tools to decipher regulatory connections and transcriptional control. From its inception, data generated by ImmGen were meant to be a public resource, and they can be accessed through dedicated web and smartphone platforms that use interactive graphic displays that make the results intuitive to users.
Published: 2020

29. Gut microbiome stability and dynamics in healthy donors and patients with non-gastrointestinal cancers

Author: Oliver J. Harrison, Lluis Quintana-Murci, Allyson L. Byrd, Darragh Duffy, Deepti R. Nagarkar, Jacob Bergstedt, Etienne Patin, Menghan Liu, Matthew L. Albert, Bruno Charbit, Kei E. Fujimura, Ira Mellman, Svetlana Lyalina, Genentech, Inc. [San Francisco], New York University School of Medicine, NYU System (NYU), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Benaroya Research Institute [Seattle] (BRI), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Immunologie Translationnelle - Translational Immunology lab, Insitro [San Francisco], This work benefited from support of the French government’s Invest in the Future program. This program is managed by the Agence Nationale de la Recherche, reference ANR-10-LABX-69-01., We thank all the donors for their participation in the study. We thank J. Segre and F. Tamburini for critical reading of the manuscript and helpful comments. We also thank J. Paulson and O. Mayba for expert statistical support., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Darragh Duffy, Matthew L. Albert, and Lluis Quintana-Murci., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génomique humaine et évolution
Subjects: 0301 basic medicine, Adult, Male, Immunology, Host factors, Disease, Technical Advances and Resources, Infectious Disease and Host Defense, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Immunology and Allergy, Humans, Microbiome, Bifidobacterium, Aged, biology, Mucosal Immunology, Middle Aged, biology.organism_classification, Biological sex, Gut microbiome, 3. Good health, Gastrointestinal Microbiome, 030104 developmental biology, Community composition, Cohort, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, 030217 neurology & neurosurgery
Abstract: By characterizing gut microbiome composition across 946 healthy donors, Byrd et al. demonstrate strong influences of age and biological sex. Additionally, they define global shifts in the gut microbiome composition of patients with non-gastrointestinal tumors compared with healthy donors., As microbial therapeutics are increasingly being tested in diverse patient populations, it is essential to understand the host and environmental factors influencing the microbiome. Through analysis of 1,359 gut microbiome samples from 946 healthy donors of the Milieu Intérieur cohort, we detail how microbiome composition is associated with host factors, lifestyle parameters, and disease states. Using a genome-based taxonomy, we found biological sex was the strongest driver of community composition. Additionally, bacterial populations shift across decades of life (age 20–69), with Bacteroidota species consistently increased with age while Actinobacteriota species, including Bifidobacterium, decreased. Longitudinal sampling revealed that short-term stability exceeds interindividual differences. By accounting for these factors, we defined global shifts in the microbiomes of patients with non-gastrointestinal tumors compared with healthy donors. Together, these results demonstrated that the microbiome displays predictable variations as a function of sex, age, and disease state. These variations must be considered when designing microbiome-targeted therapies or interpreting differences thought to be linked to pathophysiology or therapeutic response., Graphical Abstract
Published: 2020

30. Classification and nomenclature of metacaspases and paracaspases: no more confusion with caspases

Author: Christiane Funk, Vanina E. Alvarez, Heinz D. Osiewacz, Juan José Cazzulo, Simon Stael, Boris Zhivotovsky, Chang Jae Choi, Frank Madeo, Jens Staal, Kailash C. Pandey, Lynn A. Megeney, Yigong Shi, Magali Casanova, Andrei Smertenko, Maurício F.M. Machado, Eric Lam, Renier A. L. van der Hoorn, Juergen Ruland, Ilana Berman-Frank, Panagiotis N. Moschou, Peter V. Bozhkov, Jeremy C. Mottram, Kay D. Bidle, Jerry Ståhlberg, Rudi Beyaert, Christopher M. Overall, Frédéric Bornancin, Kris Gevaert, Margot Thome, Assaf Vardi, Núria S. Coll, Patrick Gallois, Frank Van Breusegem, Thomas Nyström, Vishva M. Dixit, Marko Dolinar, Maria F. Suarez, Stephan Hailfinger, Nicolas Fasel, Emilio Gutierrez-Beltran, John A. Berges, Anna Linusson, Hannele Tuominen, Daniel Krappmann, Guy S. Salvesen, Marina Klemenčič, Elena A. Minina, Eugene V. Koonin, Canaan, Stephane, Swedish University of Agricultural Sciences (SLU), Universiteit Gent = Ghent University (UGENT), Universidad Nacional de San Martin (UNSAM), University of Wisconsin - Milwaukee, University of Haifa [Haifa], Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), Novartis Institutes for BioMedical Research (NIBR), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Texas at Austin [Austin], Centre for Research in Agricultural Genomics (CRAG), Genentech, Inc., Genentech, Inc. [San Francisco], University of Ljubljana, Université de Lausanne = University of Lausanne (UNIL), Umeå University, Universidade de Mogi das Cruces = University of Mogi das Cruzes (UMC), Karl-Franzens-Universität Graz, University of Ottawa [Ottawa], Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Foundation for Research and Technology - Hellas (FORTH), University of York [York, UK], University of Gothenburg (GU), Goethe-University Frankfurt am Main, University of British Columbia (UBC), National Institute of Malaria Research [New Dehli, Inde] (NIMR), Indian Council of Medical Research [New Dehli] (ICMR), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Sanford Burnham Prebys Medical Discovery Institute, Westlake University [Zhejiang], Washington State University (WSU), Universidad de Málaga [Málaga] = University of Málaga [Málaga], University of Oxford, Weizmann Institute of Science [Rehovot, Israël], Lomonosov Moscow State University (MSU), Knut and Alice Wallenberg Foundation, Swedish University of Agricultural Sciences and Linnean Center for Plant Biology, Universiteit Gent = Ghent University [Belgium] (UGENT), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), University of Lausanne (UNIL), Karl-Franzens-Universität [Graz, Autriche], University of Oxford [Oxford], University of Graz, and Technical University of Munich (TUM)
Subjects: Consensus, METACASPASES, Protein Conformation, [SDV]Life Sciences [q-bio], Computational biology, Article, purl.org/becyt/ford/1 [https], Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Terminology as Topic, medicine, Animals, Humans, CRYSTAL-STRUCTURE, purl.org/becyt/ford/1.6 [https], SPECIFICITY, Molecular Biology, Nomenclature, Caspase, PARACASPASES, ComputingMilieux_MISCELLANEOUS, Plant Proteins, 030304 developmental biology, Confusion, 0303 health sciences, biology, MALT1, Biology and Life Sciences, Cell Biology, 3. Good health, PROTEASES, [SDV] Life Sciences [q-bio], KEY, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Caspases, biology.protein, CLAN CD, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Metacaspases and paracaspases are proteases that were first identified as containing a caspase-like structural fold (Uren et al., 2000). Like caspases, metacaspases and paracaspases are multifunctional proteins regulating diverse biological phenomena, such as aging, immunity, proteostasis, and programmed cell death. The broad phylogenetic distribution of metacaspases and paracaspases across all kingdoms of life and large variation of their biochemical and structural features complicate classification and annotation of the rapidly growing number of identified homologs. Establishment of an adequate classification and unified nomenclature of metacaspases and paracaspases is especially important to avoid frequent confusion of these proteases with caspases—a tenacious misnomer that unfortunately does not appear to decline with time. This Letter represents a consensus opinion of researchers studying different aspects of caspases, metacaspases, and paracaspases in various organisms, ranging from microbes to plants and animals., This work was supported by the Knut and Alice Wallenberg Foundation.
Published: 2020

31. Quality‐of‐life analysis with intermittent vismodegib regimens in patients with multiple basal cell carcinomas : Patient‐reported outcomes from the MIKIE study

Author: A. Hong, Martina Makrutzki, Brigitte Dréno, Bruno Labeille, Axel Hauschild, Scott W. Fosko, Frank Gilberg, Gary S. Rogers, S. Puig, J.-J. Grob, Rainer Kunstfeld, Dirk Schadendorf, David Zloty, University Hospital [Essen, Germany], University Hospital Schleswig-Holstein [Kiel, Germany], Saint Louis University (SLU), University of British Columbia (UBC), CHU Saint-Etienne, Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), F. Hoffmann-La Roche [Basel], Genentech, Inc. [San Francisco], Nantes Université (Nantes Univ), Tufts University School of Medicine [Boston], Medizinische Universität Wien = Medical University of Vienna, Malbec, Odile, and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Oncology, medicine.medical_specialty, Skin Neoplasms, Pyridines, [SDV]Life Sciences [q-bio], Medizin, Vismodegib, Antineoplastic Agents, Dermatology, Quality of life, Internal medicine, medicine, Humans, In patient, Anilides, Patient Reported Outcome Measures, Multiple Basal Cell Carcinomas, ComputingMilieux_MISCELLANEOUS, business.industry, Hedgehog signaling pathway, [SDV] Life Sciences [q-bio], Infectious Diseases, Carcinoma, Basal Cell, Quality of Life, business, Hamartoma Syndrome, Multiple, medicine.drug
Abstract: International audience
Published: 2020

32. Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4

Author: Armanda Casrouge, Alessandro Aiuti, Silvia Sánchez-Ramón, A V Sauer, Matthew L. Albert, Marta Tejera-Alhambra, R Barreira da Silva, ICAReB, Molly A. Ingersoll, C Cancrini, Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], IRCCS San Raffaele Scientific Institute [Milan, Italie], Genentech, Inc. [San Francisco], Hospital General Universitario 'Gregorio Marañón' [Madrid], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Università degli Studi di Roma Tor Vergata [Roma], Funding was provided by the Institut Pasteur (Pasteur‐Roux post‐doctoral fellowship to R. B. S.), the Ligue Contre le Cancer (M. L. A.), the Fondation ARC pour la recherche sur le cancer (M. L. A.), the Italian Ministero della Salute (GR‐2011‐02346985 to A. V. S.), the European Union Seventh Framework Programme Marie Curie Action (PCIG11‐GA‐2012‐3221170 to M. A. I.) and the French government's Invest in the Future Program, managed by the Agence Nationale de la Recherche (LabEx Immuno‐Onco to A. C., R. B. d. S., M. A. I. and M. L. A.)., The authors thank the numerous patients and healthy volunteers who kindly donated peripheral blood for these experiments. We thank Immacolata Brigida for data management and H. Saklani for providing tetramers. We thank James Di Santo and Darragh Duffy for critical reading of the manuscript. We would like to acknowledge Marie‐Noelle Unheheuer for her role in leadership of the Clinical Investigation and Access to BioResources platform (ICAReB)., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), European Project: 3221170,European Union Seventh Framework Programme Marie Curie Action, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Chemokine, Bodily Secretions, Lymphocyte, T cell, Dipeptidyl Peptidase 4, T-Lymphocytes, Immunology, T cells, chemokines, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Orthomyxoviridae Infections, medicine, Immunology and Allergy, Animals, Humans, Dipeptidyl peptidase-4, Mice, Knockout, Transplantation Chimera, biology, Chemistry, Membrane Proteins, Original Articles, 3. Good health, Hematopoiesis, Mice, Inbred C57BL, immunodeficiency diseases, Haematopoiesis, Disease Models, Animal, Settore MED/02, 030104 developmental biology, medicine.anatomical_structure, Solubility, Influenza A virus, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Severe Combined Immunodeficiency, Bone marrow, CD8, Biomarkers
Abstract: Summary Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease that is expressed constitutively by many haematopoietic and non-haematopoietic tissues. It exists as a membrane-associated protein, as well as in an active, soluble form (herein called sDPP4), present at high concentrations in bodily fluids. Despite the proposed use of sDPP4 as a biomarker for multiple diseases, its cellular sources are not well defined. Here, we report that individuals with congenital lymphocyte immunodeficiency had markedly lower serum concentrations of sDPP4, which were restored upon successful treatment and restoration of lymphocyte haematopoiesis. Using irradiated lymphopenic mice and wild-type to Dpp4–/– reciprocal bone marrow chimeric animals, we found that haematopoietic cells were a major source of circulating sDPP4. Furthermore, activation of human and mouse T lymphocytes resulted in increased sDPP4, providing a mechanistic link between immune system activation and sDPP4 concentration. Finally, we observed that acute viral infection induced a transient increase in sDPP4, which correlated with the expansion of antigen-specific CD8+ T cell responses. Our study demonstrates that sDPP4 concentrations are determined by the frequency and activation state of lymphocyte populations. Insights from these studies will support the use of sDPP4 concentration as a biomarker for inflammatory and infectious diseases.
Published: 2018
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33. A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals

Author: Christian Hammer, Lluis Quintana-Murci, Allyson L. Byrd, Jacques Fellay, Cécile Alanio, Petar Scepanovic, Valentin Partula, Mathilde Touvier, Olivier Lantz, Stanislas Mondot, Jacob Bergstedt, Etienne Patin, Darragh Duffy, Matthew L. Albert, Flavia Hodel, Ecole Polytechnique Fédérale de Lausanne (EPFL), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Genentech, Inc. [San Francisco], Perelman School of Medicine, University of Pennsylvania [Philadelphia], Lund University [Lund], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Swiss Institute of Bioinformatics [Genève] (SIB), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), This work benefited from the support of the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). It was also supported by a grant from the Swiss National Science Foundation (31003A_175603 to JF)., We would like to thank to all the donors for their contribution to the study. The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker, Paris, France), Andres Alcover (Institut Pasteur, Paris, France), Hugues Aschard (Institut Pasteur, Paris, France), Kalla Astrom (Lund University, Lund, Sweden), Philippe Bousso (Institut Pasteur, Paris, France), Pierre Bruhns (Institut Pasteur, Paris, France), Ana Cumano (Institut Pasteur, Paris, France), Caroline Demangel (Institut Pasteur, Paris, France), Ludovic Deriano (Institut Pasteur, Paris, France), James Di Santo (Institut Pasteur, Paris, France), Françoise Dromer (Institut Pasteur, Paris, France), Darragh Duffy (Institut Pasteur, Paris, France), Gérard Eberl (Institut Pasteur, Paris, France), Jost Enninga (Institut Pasteur, Paris, France), Jacques Fellay (EPFL, Lausanne, Switzerland), Odile Gelpi (Institut Pasteur, Paris, France), Ivo Gomperts-Boneca (Institut Pasteur, Paris, France), Milena Hasan (Institut Pasteur, Paris, France), Serge Hercberg (Université Paris 13, Paris, France), Olivier Lantz (Institut Curie, Paris, France), Claude Leclerc (Institut Pasteur, Paris, France), Hugo Mouquet (Institut Pasteur, Paris, France), Sandra Pellegrini (Institut Pasteur, Paris, France), Stanislas Pol (Hôpital Côchin, Paris, France), Antonio Rausell (INSERM UMR 1163 – Institut Imagine, Paris, France), Lars Rogge (Institut Pasteur, Paris, France), Anavaj Sakuntabhai (Institut Pasteur, Paris, France), Olivier Schwartz (Institut Pasteur, Paris, France), Benno Schwikowski (Institut Pasteur, Paris, France), Spencer Shorte (Institut Pasteur, Paris, France), Vassili Soumelis (Institut Curie, Paris, France), Frédéric Tangy (Institut Pasteur, Paris, France), Eric Tartour (Hôpital Européen George Pompidou, Paris, France), Antoine Toubert (Hôpital Saint-Louis, Paris, France), Mathilde Touvier (Université Paris 13, Paris, France), Marie-Noëlle Ungeheuer (Institut Pasteur, Paris, France), Matthew L. Albert (Roche Genentech, South San Francisco, CA, USA), and Lluis Quintana-Murci (Institut Pasteur, Paris, France). Matthew L. Albert and Lluis Quintana-Murci are the co-coordinators of the consortium. Additional information can be found at http://www.milieuinterieur.fr/en., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR: 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Fellay, Jacques [0000-0002-8240-939X], Apollo - University of Cambridge Repository, and Fellay, Jacques
Subjects: Male, population-structure, imputation, Genome-wide association study, dna, Cohort Studies, Feces, 0302 clinical medicine, GWAS, Gut, 16S rRNA gene sequencing, media_common, milieu-interieur, 0303 health sciences, dynamics, Genomics, Middle Aged, Healthy Volunteers, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Medical genetics, lcsh:QR100-130, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Demographics, Sex ratio, Human, Adult, Microbiology (medical), medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, media_common.quotation_subject, Single-nucleotide polymorphism, Biology, Environment, Microbiology, lcsh:Microbial ecology, Young Adult, 03 medical and health sciences, Genetic variation, medicine, Humans, Microbiome, genome, Life Style, Aged, Demography, 030304 developmental biology, inference, Healthy, Bacteria, Host (biology), Research, Gastrointestinal Microbiome, extraction, 030217 neurology & neurosurgery, Imputation (genetics), Diversity (politics)
Abstract: Background The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20–69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. Results Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. Conclusion In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals. Trial registration ClinicalTrials.gov identifier NCT01699893
Published: 2019

34. Introduction of Trifluoroethylamine as Amide Isostere by C–H Functionalization of Heteroarenes

Author: Marie-Gabrielle Braun, Patrick Salvo, Samir Z. Zard, Georgette Castanedo, Ling Qin, Department of Discovery Chemistry, Genentech, Inc. [San Francisco], Laboratoire de synthèse organique (DCSO), and École polytechnique (X)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Isostere, Camphorsulfonic acid, Organic Chemistry, Trifluoroethylamine, 010402 general chemistry, 01 natural sciences, Biochemistry, 0104 chemical sciences, chemistry.chemical_compound, Amide, Surface modification, Organic chemistry, Xanthate, Physical and Theoretical Chemistry
Abstract: International audience; A direct and efficient introduction of a trifluoroethylamine motif into various heteroaromatic structures, using a readily available xanthate S-[1-(N-acetylamino)-2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (5), is reported. Medicinally relevant trifluoroethylaminated heteroarenes containing a wide range of functional groups were successfully synthesized under mild conditions. This amide isostere could be introduced into both electron-rich and -poor heteroarenes to give the desired products in one step. The beneficial effect of camphorsulfonic acid (CSA) was also demonstrated with electron-deficient heteroarenes.
Published: 2017

35. Dying cells actively regulate adaptive immune responses

Author: Nader Yatim, Sean P. Cullen, Matthew L. Albert, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Cancer Immunology, Genentech, Inc. [San Francisco], They also thank the Agence Nationale de la Recherche, France, and the Liliane Bettencourt School of INSERM, Paris, France, for their support of this work., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, History, T cell, Priming (immunology), CD8-Positive T-Lymphocytes, Education, 03 medical and health sciences, Cross-Priming, Immune system, Antigen, Immunity, MHC class I, medicine, Animals, Humans, Antigen Presentation, Cell Death, biology, business.industry, Acquired immune system, Computer Science Applications, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, CD8
Abstract: International audience; Dying cells have an important role in the initiation of CD8(+) T cell-mediated immunity. The cross-presentation of antigens derived from dying cells enables dendritic cells to present exogenous tissue-restricted or tumour-restricted proteins on MHC class I molecules. Importantly, this pathway has been implicated in multiple autoimmune diseases and accounts for the priming of tumour antigen-specific T cells. Recent data have revealed that in addition to antigen, dying cells provide inflammatory and immunogenic signals that determine the efficiency of CD8(+) T cell cross-priming. The complexity of these signals has been evidenced by the multiple molecular pathways that result in cell death and that have now been shown to differentially influence antigen transfer and immunity. In this Review, we provide a detailed summary of both the passive and active signals that are generated by dying cells during their initiation of CD8(+) T cell-mediated immunity. We propose that molecules generated alongside cell death pathways - inducible damage-associated molecular patterns (iDAMPs) - are upstream immunological cues that actively regulate adaptive immunity.
Published: 2017

36. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019

37. Disruption of IRE1α through its kinase domain attenuates multiple myeloma

Author: Heidi J.A. Wallweber, Diego Acosta-Alvear, Yung-Chia Ariel Chen, Maria N. Lorenzo, Jiansheng Wu, Mark Merchant, Anna Shemorry, Michael J VanWyngarden, Klara Totpal, Jonathan M. Harnoss, Alvin Gogineni, Adrien Le Thomas, Daniel W. Sherbenou, Susan Kaufman, Robby M. Weimer, Marie-Gabrielle Braun, David A. Lawrence, Weiru Wang, Kevin R Clark, Mike Reichelt, Tom De Bruyn, Steven T Laing, Min Lu, Avi Ashkenazi, David Kan, Benjamin Haley, Jing Qing, Maureen Beresini, Justin Ly, Amy Heidersbach, Ehud Segal, Wendy Sandoval, Martine Amiot, Peter Walter, Scot A. Marsters, Patricia Gomez-Bougie, Dong Lee, Joachim Rudolph, Department of Cancer Immunology, Genentech, Inc. [San Francisco], Translational Oncology [South San Francisco, CA, USA], Pathology [South San Francisco, CA, USA], Structural Biology [South San Francisco, CA, USA], Biochemical and Cellular Pharmacology [South San Francisco, CA, USA], Microchemistry, Proteomics and Lipidomics [South San Francisco, CA, USA], Protein Chemistry [South San Francisco, CA, USA], Drug Metabolism and Pharmacokinetics [South San Francisco, CA, USA], Molecular Biology [South San Francisco, CA, USA], Biomolecular Imaging [South San Francisco, CA, USA], Safety Assessment [South San Francisco, CA, USA], Department of Discovery Chemistry, Division of Hematology [Aurora, CO, USA] (Department of Medicine), University of Colorado Cancer Center [Aurora, CO, USA], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service d'Hématologie Clinique [CHU Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Biochemistry and Biophysics [San Francisco], University of California, Howard Hughes Medical Institute [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), University of California (UC), University of California [San Francisco] (UC San Francisco), and University of California (UC)-University of California (UC)
Subjects: Male, X-Box Binding Protein 1, Chemokine, Bortezomib, Mice, 0302 clinical medicine, kinase inhibitors, Lenalidomide, Multiple myeloma, media_common, 0303 health sciences, Multidisciplinary, biology, unfolded protein response, Biological Sciences, Middle Aged, Protein-Serine-Threonine Kinases, Endoplasmic Reticulum Stress, 3. Good health, Gene Expression Regulation, Neoplastic, multiple myeloma, PNAS Plus, 030220 oncology & carcinogenesis, Female, Antibody, medicine.drug, Signal Transduction, inositol-requiring enzyme 1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Endoribonucleases, medicine, media_common.cataloged_instance, Animals, Humans, Secretion, European union, Protein Kinase Inhibitors, 030304 developmental biology, Aged, Neoplastic, business.industry, Endoplasmic reticulum, Cell Biology, medicine.disease, Xenograft Model Antitumor Assays, Gene Expression Regulation, Cancer research, biology.protein, business, Homeostasis
Abstract: Significance Multiple myeloma (MM) is a lethal malignancy arising from plasma cells. MM cells experience endoplasmic reticulum (ER) stress due to immunoglobulin hyperproduction. The ER-resident sensor IRE1α mitigates ER stress by expanding protein-folding and secretion capacity, while supporting proteasomal degradation of ER misfolded proteins. IRE1α elaborates these functions by deploying a cytoplasmic kinase–RNase module to activate the transcription factor XBP1s. Although IRE1α has been implicated in MM, its validity as a potential therapeutic target—particularly as a kinase—has been unclear. Using genetic and pharmacologic disruption, we demonstrate that the IRE1α–XBP1s pathway is critical for MM tumor growth. We further show that the kinase domain of IRE1α is an effective and safe potential small-molecule target for MM therapy., Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase–endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α–XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138− cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.
Published: 2019

38. Publisher Correction: Definitions and guidelines for research on antibiotic persistence

Author: Balaban, Nathalie, Helaine, Sophie, Lewis, Kim, Ackermann, Martin, Aldridge, Bree, Andersson, Dan, Brynildsen, Mark, Bumann, Dirk, Camilli, Andrew, Collins, James, Dehio, Christoph, Fortune, Sarah, Ghigo, Jean-Marc, Hardt, Wolf-Dietrich, Harms, Alexander, Heinemann, Matthias, Hung, Deborah, Jenal, Urs, Levin, Bruce, Michiels, Jan, Storz, Gisela, Tan, Man-Wah, Tenson, Tanel, Van Melderen, Laurence, Zinkernagel, Annelies, Racah Institute of Physics, The Hebrew University of Jerusalem (HUJ), Medical Research Council Centre for Molecular Bacteriology and Infection [Londres, Royaume-Uni] (MRC CMBI), Imperial College London, Northeastern University [Boston], Institute of Biogeochemistry and Pollutant Dynamics [ETH Zürich] (IBP), Department of Environmental Systems Science [ETH Zürich] (D-USYS), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Swiss Federal Insitute of Aquatic Science and Technology [Dübendorf] (EAWAG), Tufts University School of Medicine [Boston], Uppsala University, Princeton University, Biozentrum [Basel, Suisse], University of Basel (Unibas), Massachusetts Institute of Technology (MIT), Wyss Institute for Biologically Inspired Engineering [Harvard University], Harvard University, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard T.H. Chan School of Public Health, Génétique des Biofilms, Institut Pasteur [Paris] (IP), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institute of Microbiology [Zurich], Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen [Groningen], Emory University [Atlanta, GA], VIB-KU Leuven Center for Microbiology [Leuven, Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Genentech, Inc. [San Francisco], Institute of technology, University of Tartu, Université libre de Bruxelles (ULB), University hospital of Zurich [Zurich], B.R.L. is funded by the US National Institutes of Health (NIH, R01GM 091875). N.Q.B. is funded by the European Research Council (ERC, 681619)., The authors thank the Congressi Stefano Franscini, the European Molecular Biology Organization (EMBO), the Federation of European Microbiological Societies (FEMS) and the University of Basel for supporting the EMBO Workshop ‘Bacterial Persistence and Antimicrobial Therapy’ and A.-C. Hiebel for taking a major role in its organization. The authors represent the groups attending the workshop but acknowledge the contributions of many other groups in the antibiotic persistence field., Harvard University [Cambridge], Institut Pasteur [Paris], and VIB-KU Leuven Center for Microbiology [Belgium]
Subjects: MESH: Biomedical Research/standards, MESH: Terminology as Topic, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Biomedical Research/methods, Antibiotics, MESH: Anti-Bacterial Agents/pharmacology, Antibacterial drug resistance, MESH: Guidelines as Topic, Antimicrobial resistance, Bacterial physiology, MESH: Bacteria/drug effects, MESH: Drug Tolerance
Abstract: Erratum in : Publisher Correction: Definitions and guidelines for research on antibiotic persistence. [Nat Rev Microbiol. 2019] https://doi.org/10.1038/s41579-019-0207-4; International audience; Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.
Published: 2019

39. APRIL Induces a Novel Subset of IgA+ Regulatory B Cells That Suppress Inflammation via Expression of IL-10 and PD-L1

Author: Cynthia M. Fehres, Nathalie O. van Uden, Nataliya G. Yeremenko, Leticia Fernandez, Gabriela Franco Salinas, Leonie M. van Duivenvoorde, Bertrand Huard, Jacques Morel, Hergen Spits, Michael Hahne, Dominique L. P. Baeten, Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Genentech, Inc., Genentech, Inc. [San Francisco], Salvy-Córdoba, Nathalie, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinical Immunology and Rheumatology, 01 Internal and external specialisms, AII - Inflammatory diseases, Experimental Immunology, and AGEM - Digestive immunity
Subjects: 0301 basic medicine, Regulatory B cells, Dermatitis, Contact, B7-H1 Antigen, Mice, 0302 clinical medicine, Immunology and Allergy, Macrophage, APRIL, Cells, Cultured, Original Research, B-Lymphocytes, Regulatory, education.field_of_study, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Interleukin-10, 3. Good health, Interleukin 10, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, IL-10, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, IgA, lcsh:Immunologic diseases. Allergy, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Tumor Necrosis Factor Ligand Superfamily Member 13, Immunology, Population, B-Lymphocyte Subsets, Mice, Transgenic, Inflammation, Biology, 03 medical and health sciences, Immune system, Immune Tolerance, medicine, Animals, Humans, B-cell activating factor, education, Immunoregulation, Immunoglobulin A, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, lcsh:RC581-607, 030215 immunology
Abstract: International audience; Regulatory B cells (Bregs) are immunosuppressive cells that modulate immune responses through multiple mechanisms. The signals required for the differentiation and activation of these cells remain still poorly understood. We have already shown that overexpression of A PRoliferation-Inducing Ligand (APRIL) reduces the incidence and severity of collagen-induced arthritis (CIA) in mice. Furthermore, we have described that APRIL, but not BAFF, promoted IL-10 production and regulatory functions in human B cells. Therefore, we hypothesized that APRIL, but not BAFF, may be involved in the induction and/or activation of IL-10 producing Bregs that suppress inflammatory responses in vitro and in vivo. Here, we describe that APRIL promotes the differentiation of naïve human B cells to IL-10-producing IgA+ B cells. These APRIL-induced IgA+ B cells display a Breg phenotype and inhibit T cell and macrophage responses through IL-10 and PD-L1. Moreover, APRIL-induced IL-10 producing Bregs suppress inflammation in vivo in experimental autoimmune encephalitis (EAE) and contact hypersensitivity (CHS) models. Finally, we showed a strong correlation between APRIL and IL-10 in the inflamed synovial tissue of inflammatory arthritis patients. Collectively, these observations indicate the potential relevance of this novel APRIL-induced IgA+ Breg population for immune homeostasis and immunopathology.
Published: 2019

40. Associations between usual diet and gut microbiota composition: results from the Milieu Intérieur cross-sectional study

Author: Camille Buscail, Pilar Galan, Lluis Quintana-Murci, Karen E. Assmann, Mélanie Deschasaux, Vincent Rouilly, Darragh Duffy, Emmanuelle Kesse-Guyot, Valentin Partula, Olivier Lantz, Mathilde Touvier, M. Torres, Matthew L. Albert, Chantal Julia, Paule Latino-Martel, Stéphanie Thomas, Stanislas Mondot, Serge Hercberg, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Santé publique France, Hôpital Avicenne, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Evolutive Humaine - Human Evolutionary Genetics, Genentech, Inc. [San Francisco], Immunité et cancer (U932), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé publique France - French National Public Health Agency [Saint-Maurice, France], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Vougny, Marie-Christine, and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Adult, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Colon, Population, Medicine (miscellaneous), Gut flora, Diet Surveys, Food group, 03 medical and health sciences, Feces, Young Adult, Abundance (ecology), RNA, Ribosomal, 16S, Humans, Food science, Microbiome, education, Aged, 2. Zero hunger, education.field_of_study, Analysis of Variance, 030109 nutrition & dietetics, Nutrition and Dietetics, biology, Bacteria, gut microbiota, digestive, oral, and skin physiology, Feeding Behavior, Sequence Analysis, DNA, Middle Aged, biology.organism_classification, Diet, Gastrointestinal Microbiome, 030104 developmental biology, Cross-Sectional Studies, Diet, Western, Milieu Intérieur Consortium, Multivariate Analysis, usual diet, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, epidemiology, Omnivore, Analysis of variance, France, healthy population, Akkermansia muciniphila
Abstract: International audience; BACKGROUND:Diet is widely recognized as one of the main modifiable drivers of gut microbiota variability, and its influence on microbiota composition is an active area of investigation.OBJECTIVE:The present work aimed to explore the associations between usual diet and gut microbiota composition in a large sample of healthy French adults.METHODS:Gut microbiota composition was established through sequencing of the 16S rRNA gene in stool samples from 862 healthy French adults of the Milieu Intérieur study. Usual dietary consumptions were determined through the administration of a food-frequency questionnaire. The associations between dietary variables and α- and β-diversity indexes and relative taxa abundances were tested using Spearman correlations, permutational ANOVAs, and multivariate analyses with linear models, respectively.RESULTS:Foods generally considered as healthy (raw fruits, fish) were positively associated with α-diversity, whereas food items for which a limited consumption is generally recommended (fried products, sodas or sugary drinks, fatty sweet products, processed meats, ready-cooked meals, and desserts) were negatively associated with α-diversity. Fruits, fried products, ready-cooked meals, and cheese contributed to shifts within microbiota composition (β-diversity). Our results also highlighted a number of associations between various food group intakes and abundances of specific phyla, genera, and species. For instance, the consumption of cheese was negatively associated with Akkermansia muciniphila abundance.CONCLUSIONS:This large-scale population-based study supports that the usual consumption of certain food items is associated with several gut microbial features, and extends the mechanistic arguments linking Western diet to an altered microbiota composition. These results provide new insights into the understanding of complex diet-gut microbiota relations, and their implications for host health deserve further investigation because altered microbiota diversity was consistently linked to increased risk of several health outcomes. This trial was registered at clinicaltrials.gov as NCT01699893.
Published: 2019

41. Association between tumor size kinetics and survival in urothelial carcinoma patients treated with atezolizumab: implication for patient's follow‐up

Author: TARDIVON, Coralie, Desmée, Solène, Kerioui, Marion, Bruno, René, Wu, Benjamin, Mentré, France, Mercier, François, Guedj, Jérémie, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Service de Pharmacologie Clinique [Marseille] (Genentech/Roche), Genentech/Roche [Marseille], Clinical Pharmacology [South San Francisco, CA, USA] (Genentech Inc.), Genentech, Inc. [San Francisco], Clinical Pharmacology [Basel, Switzerland] ( Roche Innovation Center), Roche Innovation Center [Basel, Switzerland], Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, TARDIVON, Coralie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)
Subjects: [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, atezolizumab, joint modeling, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.IMM] Life Sciences [q-bio]/Immunology, dynamic individual prediction, personalized healthcare, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, immunotherapy, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Abstract: International audience; We characterized the association between tumor size kinetics and survival in advanced urothelial cancer patients treated with atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) using a joint model. The model, developed on data from 309 patients of a phase 2 clinical trial, identified the time-to-tumor growth and the instantaneous changes in tumor size as the best on-treatment predictors of survival. On the validation dataset containing data from 457 patients from a phase 3 study, the model predicted individual survival probability using 3 or 6-months tumor size follow-up data with an area under the receptor-occupancy curve between 0.75 and 0.84 as compared to values comprised between 0.62 and 0.75 when the model included only information available at treatment initiation. Including tumor size kinetics in a relevant statistical framework improve the prediction of survival probability during immunotherapy treatment, and may be useful to identify most-at-risk patients in "real-time". This article is protected by copyright. All rights reserved.
Published: 2019

42. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth

Author: Clémence Hollande, Wendy Sandoval, Vincent Mallet, Tamaki Nozawa, Darragh Duffy, Vincent Bondet, Stanislas Pol, Jill Schartner, Valerie Paradis, James Ziai, Rosa Barreira da Silva, Gérard Eberl, Binfeng Lu, Matthew L. Albert, Jeremy Boussier, Wilson Phung, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microenvironnement et Immunité - Microenvironment and Immunity, Funding for the work was provided by Fondation ARC pour la recherche sur le cancer, Institut national de la santé et de la recherche médicale (Inserm), Fondation pour la recherche médicale (FRM, FDM 40432) and LabEx Immuno-Onco (ANR)., Thanks to H. Saklani, M. A. Ingersoll and T. Canton for their help with mouse experimental work and ethical statement., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Chemokine CCL11, Chemokine, Lymphocyte, Dipeptidyl Peptidase 4, Immunology, Dipeptidyl peptidase, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, medicine, Immunology and Allergy, CXCL10, Animals, Humans, CCL11, Mice, Knockout, Dipeptidyl-Peptidase IV Inhibitors, Mice, Inbred BALB C, biology, Chemistry, Sitagliptin Phosphate, Degranulation, Neoplasms, Experimental, Eosinophil, Interleukin-33, 3. Good health, Interleukin 33, Eosinophils, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cancer research, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030215 immunology
Abstract: Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited. Eosinophils have been described mainly in allergy settings but are increasingly appreciated as being involved in other aspects of immunity. Albert and colleagues use a clinically approved inhibitor of the dipeptidyl peptidase DPP4 to facilitate the recruitment of eosinophils to mouse tumors, where they are essential in tumor destruction.
Published: 2019

43. The best of both worlds: using semantic web with JSON-LD. An example with NIDM-Results & Datalad

Author: Camille Maumet, Satrajit Ghosh, Yaroslav Halchenko, Dorota Jarecka, Nolan Nichols, Jean-Baptiste Poline, Michael Hanke, Maumet, Camille, Neuroimagerie: méthodes et applications (Empenn), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Massachusetts Institute of Technology (MIT), Darmouth College [Hanover, New Hampshire], Genentech, Inc., Genentech, Inc. [San Francisco], McGill University = Université McGill [Montréal, Canada], Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Institute of Neuroscience and Medicine [Jülich] (INM-1), DataLad development was supported by the NSF (CRCNS 1429999), German federal state of Saxony-Anhalt and the European Regional Development Fund (ERDF), Project: Center for Behavioral Brain Sciences, Imaging Platform. JBP was partially funded by NIH-NIBIB P41 EB019936 (ReproNim) NIH-NIMH R01 MH083320 (CANDIShare) and NIH 5U24 DA039832 (NIF), as well as the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative., Empenn, Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)
Subjects: [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: International audience; NIDM-Results provides a harmonised representation for fMRI results reporting using Semantic Web technologies (Maumet et al. 2016). While those technologies are particularly well suited for aggregation across complex datasets, using them can be costly in terms of initial development time to generate and read the corresponding serialisations. While the technology is machine accessible, it can be difficult to comprehend by humans. This hinders adoption by scientific communities and by software developers used to more-lightweight data-exchange formats, such as JSON. JSON-LD: a JSON representation for semantic graphs (“JSON-LD 1.1” n.d.) was created to address this limitation and recent extensions to the specification allow creating JSON-LD documents that are structured more similar to simple JSON. This representation is simultaneously readable by a large number of JSON-based applications and by Semantic Web tools. Here we review our work on building a JSON-LD representation for NIDM-Results data and exposing it to Datalad (Halchenko et al. 2018), a data-management tool suitable for neuroimaging datasets with built-in support for metadata extraction and search.
Published: 2019

44. Associations entre profils métabolomiques plasmatiques rmn et composition du microbiote intestinal au sein d’une population d’adultes francais en bonne santé

Author: PARTULA, Valentin, Mondot, Stanislas, TORRES, Marion, Kesse-Guyot, Emmanuelle, LECUYER, Lucie, Deschasaux, Mélanie, Assmann, Karen, Latino-Martel, Paule, Buscail, Camille, Julia, Chantal, Galan, Pilar, Hercberg, Serge, Victor-Bala, A, Bouchemal, Nadia, Triba, M, Savarin, Philippe, Rouilly, Vincent, Thomas, S, Quintana-Murci, Lluis, Albert, M, Lantz, Olivier, Duffy, Darragh, Touvier, Mathilde, Consortium Milieu Intérieur, ., Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC), Institut Pasteur [Paris], Department of Cancer Immunology, Genentech, Inc. [San Francisco], Institut Curie [Paris], Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Nutrition and Dietetics, profils metabolomiques, microbiote intestinal, 030309 nutrition & dietetics, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Internal Medicine, 030209 endocrinology & metabolism
Abstract: Discipline Epidemiologie. Introduction et but de l’etude Le co-metabolisme hote-microbiote est a l’origine d’un tres grand nombre de molecules integrees au sein d’axes metaboliques complexes. De nombreuses etudes se sont attachees a la caracterisation fonctionnelle specifique de certaines de ces molecules (AGCC, BCAA, TMAO, etc.), mais les etudes envisageant plus globalement les relations metaboliques entre l’hote et son microbiote intestinal restent rares. A ce titre, l’etude globale des metabolites endogenes et exogenes presents dans le plasma par metabolomique non ciblee semble prometteuse. L’objectif de cette etude etait de caracteriser les associations entre profils metabolomiques plasmatiques et composition du microbiote intestinal dans une population d’adultes en bonne sante. Materiel et methodes La composition du microbiote intestinal a ete determinee dans les selles (sequencage du gene ARNr16S, les matrices de Jaccard et Bray-Curtis ont ete determinees) et les profils metabolomiques ont ete generes en utilisant les sequences RMN CPMG et NOESY sur des echantillons de plasma, chez 846 individus de la population Milieu Interieur. La co-structure globale des donnees 16S et RMN a ete evaluee par co-inertie. Les associations entre variables metabolomiques d’une part et matrices de β-diversite ou abondance des taxons d’autre part ont ete calculees par PERMANOVA ou MaAsLin ajustes sur le sexe, l’âge, l’IMC, le statut tabagique et l’activite physique (PERMANOVA egalement ajustees sur la profondeur de sequencage). Une correction de Benjamini-Hochberg (FDR-10 %) a ete appliquee. Resultats et Analyse statistique La co-inertie globale des donnees microbiote et metabolomique etait limitee (RV ≤ 0,05). En revanche, des associations specifiques ont ete detectees. Les matrices de Jaccard et de Bray-Curtis etaient significativement et respectivement associees a 51 et 3 variables CPMG, dont certaines ont d’ores et deja ete identifiees (pyruvate, tyrosine, choline, glucose, etc.). Des associations entre le pyruvate et 3 genres bacteriens (positives avec Catabacter et Acholeplasma, negative avec Faecalibacterium) ont ete mises en evidence. L’analyse des associations entre variables metabolomiques NOESY et donnees microbiote 16S, et l’identification des metabolites discriminants sont en cours. Conclusion Ces resultats preliminaires permettent de mettre en evidence des associations entre le profil metabolomique RMN determine sur le plasma de l’hote et la composition du microbiote intestinal. Toutefois, cette etude ne permet pas de conclure sur une potentielle relation causale, et d’autres etudes sont necessaires.
Published: 2018

45. Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

Author: Alejandra Urrutia, Darragh Duffy, Vincent Rouilly, Céline Posseme, Raouf Djebali, Gabriel Illanes, Valentina Libri, Benoit Albaud, David Gentien, Barbara Piasecka, Milena Hasan, Magnus Fontes, Lluis Quintana-Murci, Matthew L. Albert, Laurent Abel, Andres Alcover, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Marie-Noëlle Ungeheuer, Illanes Gabriel, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Matemática., Urrutia Alejandra, Rouilly Vincent, Posseme Céline, Djebali Raouf, Libri Valentina, Albaud Benoit, Gentien David, Piasecka Barbara, Hasan Milena, Fontes Magnus, Quintana-Murci Lluis, Albert Matthew L., Genentech, Inc. [San Francisco], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Centro de Matemática [Montevideo] (CMAT), Universidad de la República [Montevideo] (UCUR), International Group for Data Analysis (IGDA), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Centre for Mathematical Sciences, Mathematical Statistics, Lund University [Lund], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work benefited from support of the French government’s Invest in theFuture program managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01), Milieu Intérérieur Consortium (34 collaborateurs) : Abel L, Alcover A, Astrom K, Bousso P, Bruhns P, Cumano A, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Universidad de la República [Montevideo] (UDELAR), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Transcription, Genetic, medicine.medical_treatment, Stimulation, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Complex induced immune responses, Gene expression, medicine, Humans, Lymphocytes, Receptor, Gene, lcsh:QH301-705.5, Innate immune system, Bacteria, Gene Expression Profiling, Toll-Like Receptors, Immunity, 030104 developmental biology, Cytokine, Blood, Gene Expression Regulation, lcsh:Biology (General), Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Female, Whole-blood
Abstract: Figura como autor también el Milieu Intérieur Consortium Systems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes.
Published: 2016
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46. Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus

Author: Lluis Quintana-Murci, Marine Germain, Magnus Fontes, Antoine Toubert, Itauá Leston Araujo, David-Alexandre Trégouët, James P. Di Santo, Emmanuel Clave, Corinne Douay, Silvia Lopez-Lastra, Milena Hasan, Bruno Charbit, Noémie Saut, Breno Luiz Melo-Lima, Darragh Duffy, Cécile Alanio, Jacob Bergstedt, Alejandra Urrutia, Cameron Ross MacPherson, Yan Li, Etienne Patin, Pierre-Emmanuel Morange, Matthew L. Albert, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Alloimmunité-Autoimmunité-Transplantation (A2T), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Lund University [Lund], Genentech, Inc., Genentech, Inc. [San Francisco], Immunité Innée - Innate Immunity, Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), International Group for Data Analysis (IGDA), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, 10-LABX-69-01). I.L.A. was a recipient of the Science without Borders PhD program from Brazil Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). J.B. is a member of the Lund Center for Control of Complex Engineering Systems (LCCC) Linnaeus Center and the Excellence Center at Linköping-Lund in Information Technology (ELLIT) Excellence Center at Lund University and is supported by the ELLIIT Excellence Center. J.P.D.S., Y.L., and S.L.-L. received funding from Institut Pasteur, INSERM, the Laboratoire d’Excellence REVIVE. A.T. and E.C. received funding from ANR grant PriCelAge (ANR-14-CE14-0030-01). Genetic investigations in the MARTHA study were supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), We thank J. Fellay, P. Scepanovic, and C. A. W. Thorball for support with genetic analysis and J.-M. Doisne, G. M. Ranson, and H. Strick-Marchand for support with humanized mouse experiments. We thank V. Asnafi, E. Macintyre, A. Cieslak, and I. André-Schmutz for helpful discussions. We also thank the Centre d’Immunologie Humaine (Institut Pasteur, Paris, France) for support., ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l'âge avancé(2014), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée, Centre recherche en CardioVasculaire et Nutrition (C2VN), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l’âge avancé(2014), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, education.field_of_study, T-cell receptor excision circles, T cell, Population, Genome-wide association study, Locus (genetics), General Medicine, Biology, 3. Good health, Transplantation, 03 medical and health sciences, Haematopoiesis, Thymocyte, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, education
Abstract: International audience; The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.
Published: 2018

47. Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

Author: Lluis Quintana-Murci, Bruno Charbit, Christian W. Thorball, Darragh Duffy, Cécile Alanio, Nimisha Chaturvedi, Flavia Hodel, Jacques Fellay, Jacob Bergstedt, Etienne Patin, Laurent Abel, Petar Scepanovic, Christian Hammer, Matthew L. Albert, Milieu Intérieur Consortium, Abel, L., Alcover, A., Aschard, H., Astrom, K., Bousso, P., Bruhns, P., Cumano, A., Demangel, C., Deriano, L., Di Santo, J., Dromer, F., Duffy, D., Eberl, G., Enninga, J., Fellay, J., Gelpi, O., Gomperts-Boneca, I., Hasan, M., Hercberg, S., Lantz, O., Leclerc, C., Mouquet, H., Pellegrini, S., Pol, S., Rausell, A., Rogge, L., Sakuntabhai, A., Schwartz, O., Schwikowski, B., Shorte, S., Soumelis, V., Tangy, F., Tartour, E., Toubert, A., Touvier, M., Ungeheuer, M.N., Albert, M.L., Quintana-Murci, L., Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], This work benefited from support of the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR,reference 10-LABX-69-01). It was also supported by a grant from the Swiss National Science Foundation (31003A_175603, to JF). C.A. received a Post Doctoral Fellowship from Institut National de la Recherche Médicale., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker, Paris, France), Andres Alcover (Institut Pasteur, Paris, France), Hugues Aschard (Institut Pasteur, Paris, France), Kalla Astrom (Lund University, Lund, Sweden), Philippe Bousso (Institut Pasteur, Paris, France), Pierre Bruhns (Institut Pasteur, Paris, France), Ana Cumano (Institut Pasteur, Paris, France), Caroline Demangel (Institut Pasteur, Paris, France), Ludovic Deriano (Institut Pasteur, Paris, France), James Di Santo (Institut Pasteur, Paris, France), Françoise Dromer (Institut Pasteur, Paris, France), Darragh Duffy (Institut Pasteur, Paris, France), Gérard Eberl (Institut Pasteur, Paris, France), Jost Enninga (Institut Pasteur, Paris, France), Jacques Fellay (EPFL, Lausanne, Switzerland), Odile Gelpi (Institut Pasteur, Paris, France), Ivo Gomperts-Boneca (Institut Pasteur, Paris, France), Milena Hasan (Institut Pasteur, Paris, France), Serge Hercberg (Université Paris 13, Paris, France), Olivier Lantz (Institut Curie, Paris, France), Claude Leclerc (Institut Pasteur, Paris, France), Hugo Mouquet (Institut Pasteur, Paris, France), Sandra Pellegrini (Institut Pasteur, Paris, France), Stanislas Pol (Hôpital Côchin, Paris, France), Antonio Rausell (INSERM UMR 1163–Institut Imagine, Paris, France), Lars Rogge (Institut Pasteur, Paris, France), Anavaj Sakuntabhai (Institut Pasteur, Paris, France), Olivier Schwartz (Institut Pasteur, Paris, France), Benno Schwikowski (Institut Pasteur, Paris, France), Spencer Shorte (Institut Pasteur, Paris, France), Vassili Soumelis (Institut Curie, Paris, France), Frédéric Tangy (Institut Pasteur, Paris, France), Eric Tartour (Hôpital Européen George Pompidou, Paris, France), Antoine Toubert (Hôpital Saint-Louis, Paris, France), Mathilde Touvier (Université Paris 13, Paris, France), Marie-Noëlle Ungeheuer (Institut Pasteur, Paris, France), Matthew L. Albert (Roche Genentech, South San Francisco, CA, USA), Lluis Quintana-Murci (Institut Pasteur, Paris, France)., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Intérieur Consortium, Milieu, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Université de Lausanne (UNIL), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Aging, MESH: Immunity, Humoral/genetics, lcsh:Medicine, Human genomics, Genome-wide association study, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Aging/immunology, MESH: Virus Diseases/immunology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, GWAS, Genetics (clinical), MESH: Aged, HLA-D Antigens, Vaccines, MESH: Middle Aged, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, MESH: HLA-D Antigens/genetics, MESH: Polymorphism, Single Nucleotide, Vaccination, Bacterial Infections, Middle Aged, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, HLA, Serology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Virus Diseases, MESH: Bacterial Infections/immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Molecular Medicine, Female, Sex, Antibody, Infection, Adult, lcsh:QH426-470, Immunoglobulins, Human leukocyte antigen, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, Virus, 03 medical and health sciences, Immune system, Age, Antigen, Genetics, Humans, Seroconversion, MESH: Vaccines/immunology, Humoral immunity, MESH: HLA-D Antigens/immunology, Molecular Biology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Aged, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Research, lcsh:R, MESH: Adult, MESH: Male, Immunity, Humoral, lcsh:Genetics, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, biology.protein, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], MESH: Female
Abstract: Background Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. Methods We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~ 5 million genetic variants and antibody responses using single marker and gene burden tests. Results We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations. Conclusions Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis. Trials registration ClinicalTrials.gov, NCT01699893 Electronic supplementary material The online version of this article (10.1186/s13073-018-0568-8) contains supplementary material, which is available to authorized users.
Published: 2018

48. Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions

Author: Thomas Blauenfeldt, Linda Petrone, Franca del Nonno, Andrea Baiocchini, Laura Falasca, Teresa Chiacchio, Vincent Bondet, Valentina Vanini, Fabrizio Palmieri, Gianni Galluccio, Armanda Casrouge, Jesper Eugen-Olsen, Matthew L. Albert, Delia Goletti, Darragh Duffy, Morten Ruhwald, Statens Serum Institut [Copenhagen], Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Ospedale San Camillo-Forlanini, Hvidovre Hospital, Genentech, Inc., Genentech, Inc. [San Francisco], MR and DG received funding from European Commission H2020 program (grant number TBVAC2020 643381) and Research Council Norway (GLOBVAC 248042/H10). DG received funding from Italian Minister of Health 'Ricerca Finalizzata': RF-2011-02349395., We are grateful for the kind help provided by Anders Johnsen, Department of Clinical Biochemistry at Copenhagen University Hospital, Rigshospitalet Copenhagen Denmark for performing the MALDI-TOF analysis of CXCL10 truncation for initial method optimization (not included in the publication), and to Dr. Carolyn F. Deacon, department of Biological Sciences, Panum Institute for providing valuable input and protocols to setup the DPP4 enzyme activity assay. Finn Schou, Aahus University, and Ove Andersen, Copenhagen University Hospitals for kind support. Drs T. S. Hermansen, C. Drabe, L. de Thurah, and S. T. Hoff for invaluable assistance including controls for this study and to colleagues at the Center for Vaccine Research at SSI for constructive feedback., European Project: 643381,H2020,H2020-PHC-2014-single-stage,TBVAC2020(2015), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Chemokine, Tuberculosis, pulmonary, medicine.medical_treatment, Immunology, CXCR3, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Immune system, DPP4/CD26, Immunology and Allergy, Medicine, CXCL10, Original Research, bronchoalveolar lavage fluid, biology, business.industry, Immunotherapy, biology.organism_classification, medicine.disease, cytokines, 3. Good health, 030104 developmental biology, tuberculosis, Giant cell, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:RC581-607, business
Abstract: Introduction Mycobacterium tuberculosis is one of the world’s most successful pathogens equipped to establish itself within the human host as a subclinical infection without overt disease. Unable to eradicate the bacteria, the immune system contains the infection in a granuloma structure. Th1 cells that are essential for infection control are recruited to the site of infection directed by chemokines, predominantly CXCL10. It has previously been shown that CXCL10 in the plasma of patients chronically infected with hepatitis C virus is present primarily in an antagonist form. This is due to N-terminal truncation by the enzyme DPP4, which results in the antagonist form that is capable of binding its receptor CXCR3, but does not induce signaling. We aimed to explore whether such CXCL10 antagonism may have an impact on the pathogenesis of tuberculosis (TB). Results We measured plasma levels of agonist and antagonist CXCL10 by Simoa digital ELISA, as well as DPP4 enzyme activity in the plasma of 20 patients with active TB infection, 10 patients with pneumonia infection, and a group of 10 healthy controls. We found higher levels of total and antagonist CXCL10 and reduced DPP4 enzyme activity in the plasma of TB patients compared to controls. We traced the source of CXCL10 secretion using immunohistochemical and confocal analysis to multinucleated giant cells in the TB lesions, and variable expression by macrophages. Interestingly, these cells were associated with DPP4-positive T cells. Moreover, the analysis of lymphocytes at the site of TB infection (bronchoalveolar lavage) showed a reduced frequency of CXCR3+ T cells. Interpretation Our data suggests that CXCL10 antagonism may be an important regulatory mechanism occurring at the site of TB pathology. CXCL10 can be inactivated shortly after secretion by membrane bound DPP4 (CD26), therefore, reducing its chemotactic potential. Given the importance of Th1 cell functions and IFN-γ-mediated effects in TB, our data suggest a possible unappreciated regulatory role of DPP4 in TB. Perspectives DPP4 is the target for a class of enzyme inhibitors used in the treatment of diabetes, and the results from this study suggest that these drugs could be repurposed as an adjunct immunotherapy of patients with TB and MDR-TB.
Published: 2018

49. Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses

Author: Brian Webster, Scott W Werneke, Biljana Zafirova, Sébastien This, Séverin Coléon, Elodie Décembre, Helena Paidassi, Isabelle Bouvier, Pierre-Emmanuel Joubert, Darragh Duffy, Thierry Walzer, Matthew L Albert, Marlène Dreux, Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, This work was supported by grants from the ‘Agence Nationale pour la Recherche’ (ANR-JCJC-EXAMIN), the ‘‘Agence Nationale pour la Recherche contre le SIDA et les Hépatites Virales’’ (ANRS-AO 2016–01) and the LabEx Ecofect Grant ANR-11-LABX-0048 to MD, ANR-14-CE14-0015-02 CHIKV-Viro-Immuno to MLA. BW’s postdoctoral fellowship was sponsored by EMBO (ALTF 1466–2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, We thank A Davidson (Bristol University) for providing the DENV-2 strain New Guinea C, P Despres (Pasteur Institut, Paris, France) for the anti-E DENV 3H5 antibody, V Lotteau (CIRI, Lyon, France) for Influenza A virus stocks, FV Chisari (Scripps Research Institute, La Jolla, CA) for the Huh-7.5.1 cells, T Taniguchi (University of Tokyo, Tokyo, Japan) for the Irf3/7 DKO mice, J Tschopp for the cardif-/- mice, and S Akira for the Tlr7-/- mice. We are grateful to Y Jaillais for critical reading of the manuscript, F Fusil for assistance with mice and to our colleagues for encouragement and help. We acknowledge the contribution of SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL) facilities, PBES and cytometry for mice housing and technical assistance., ANR-13-JSV3-0004,EXAMIN,Les Exosomes enrichis en ARN viraux sont Médiateurs de la réponse Interféron(2013), ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vougny, Marie-Christine, Jeunes Chercheuses et Jeunes Chercheurs - Les Exosomes enrichis en ARN viraux sont Médiateurs de la réponse Interféron - - EXAMIN2013 - ANR-13-JSV3-0004 - JC - VALID, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, and Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID
Subjects: Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Science, Interferon Regulatory Factor-7, viruses, Dengue, immunology, Interferon-gamma, Mice, Animals, Humans, dendritic cells, human, Biology (General), mouse, Mice, Knockout, virus diseases, hemic and immune systems, Dengue Virus, Survival Analysis, virology, Killer Cells, Natural, Mice, Inbred C57BL, interferons, Disease Models, Animal, Gene Expression Regulation, inflammation, Host-Pathogen Interactions, Interferon Type I, Medicine, Chikungunya Fever, RNA, Viral, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Interferon Regulatory Factor-3, Chikungunya virus, Spleen, Signal Transduction
Abstract: International audience; Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.
Published: 2018

50. Autophagy diminishes the early interferon-β response to influenza A virus resulting in differential expression of interferon-stimulated genes

Author: Jeremy S. Rossman, Matthew L. Albert, Jeremy Boussier, Molly A. Ingersoll, Brieuc Perot, Nader Yatim, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie, physiopathologie et thérapeutique (ED 394), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7), International Group for Data Analysis (IGDA), Institut Pasteur [Paris] (IP), University of Kent [Canterbury], Genentech, Inc. [San Francisco], This work was supported by Canceropôle Île-de-France and Fondation pour la Recherche médicale (to BP), Ecole normalesuperieure (to JB), Inca and Plan Cancer, INSERM (to NY), Medical Research Council [MR/L00870X/1 and MR/L018578/1] and the European Union Seventh Framework Programme [FP7-PEOPLE-2012-CIG: 333955] (to JDR), European Union Seventh Framework Programme Marie Curie Action (PCIG11-GA-2012-3221170) (to MAI), and ANR, ImmunoOnco LabEx (ANR-10-LABX-15), La Ligue contre le Cancer (to MLA)., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), European Project: 333955,EC:FP7:PEOPLE,FP7-PEOPLE-2012-CIG,INFLUENZA BUDDING(2013), European Project: 3221170,European Union Seventh Framework Programme Marie Curie Action, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Cancer Research, Immunology, ATG5, Biology, medicine.disease_cause, Article, Autophagy-Related Protein 5, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Orthomyxoviridae Infections, Interferon, Gene expression, Influenza A virus, medicine, Animals, lcsh:QH573-671, QR355, Mice, Knockout, lcsh:Cytology, Autophagy, Autophagosomes, Cell Biology, Interferon-beta, Cell biology, 030104 developmental biology, Viral replication, Gene Expression Regulation, Cell culture, 030220 oncology & carcinogenesis, QR180, [SDV.IMM]Life Sciences [q-bio]/Immunology, Protein stabilization, medicine.drug
Abstract: Influenza A virus (IAV) infection perturbs metabolic pathways such as autophagy, a stress-induced catabolic pathway that crosstalks with cellular inflammatory responses. However, the impact of autophagy perturbation on IAV gene expression or host cell responses remains disputed. Discrepant results may be a reflection of in vivo studies using cell-specific autophagy-related (Atg) gene-deficient mouse strains, which do not delineate modification of developmental programmes from more proximal effects on inflammatory response. In vitro experiments can be confounded by gene expression divergence in wild-type cultivated cell lines, as compared to those experiencing long-term absence of autophagy. With the goal to investigate cellular processes within cells that are competent or incompetent for autophagy, we generated a novel experimental cell line in which autophagy can be restored by ATG5 protein stabilization in an otherwise Atg5-deficient background. We confirmed that IAV induced autophagosome formation and p62 accumulation in infected cells and demonstrated that perturbation of autophagy did not impact viral infection or replication in ATG5-stablized cells. Notably, the induction of interferon-stimulated genes (ISGs) by IAV was diminished when cells were autophagy competent. We further demonstrated that, in the absence of ATG5, IAV-induced interferon-β (IFN-β) expression was increased as compared to levels in autophagy-competent lines, a mechanism that was independent of IAV non-structural protein 1. In sum, we report that induction of autophagy by IAV infection reduces ISG expression in infected cells by limiting IFN-β expression, which may benefit viral replication and spread.
Published: 2018

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