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31 results on '"McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital"'

1. Immunity of human epithelial ovarian carcinoma: the paradigm of immune suppression in cancer

Author

Vincent Lavoué, Marc-Antoine Belaud-Rotureau, Vincent Jauffret, Jean Levêque, F. Foucher, Véronique Catros, Florian Cabillic, Sébastien Henno, Aurélie Thedrez, Microenvironnement et remodelage, Foie, métabolismes et cancer, 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 )-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 )-Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes]-Lady Davis Institut, McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital-McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, 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 ), Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], 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 )-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 )-Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital-McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital-Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes], 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 ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and BMC, Ed.

Subjects
endocrine system diseases, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Biology, General Biochemistry, Genetics and Molecular Biology, Immune tolerance, 03 medical and health sciences, Ovarian tumor, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, Ovarian carcinoma, Cell Line, Tumor, Immune suppression, medicine, Immune Tolerance, Humans, Neoplasms, Glandular and Epithelial, 030304 developmental biology, Medicine(all), Ovarian Neoplasms, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Biochemistry, Genetics and Molecular Biology(all), Carcinoma, Cancer, General Medicine, Immunotherapy, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Immunoediting, 030220 oncology & carcinogenesis, Immunology, Cancer research, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women, and there has been no substantial decrease in the death rates due to EOC in the last three decades. Thus, basic knowledge regarding ovarian tumor cell biology is urgently needed to allow the development of innovative treatments for EOC. Traditionally, EOC has not been considered an immunogenic tumor, but there is evidence of an immune response to EOC in patients. Clinical data demonstrate that an antitumor immune response and immune evasion mechanisms are correlated with a better and lower survival, respectively, providing evidence for the immunoediting hypothesis in EOC. This review focuses on the immune response and immune suppression in EOC. The immunological roles of chemotherapy and surgery in EOC are also described. Finally, we detail pilot data supporting the efficiency of immunotherapy in the treatment of EOC and the emerging concept that immunomodulation aimed at counteracting the immunosuppressive microenvironment must be associated with immunotherapy strategies.

Published
2013

2. Clinical Prediction Models for Heart Failure Hospitalization in Type 2 Diabetes: A Systematic Review and Meta‐Analysis

Author

Amir Razaghizad, Emily Oulousian, Varinder Kaur Randhawa, João Pedro Ferreira, James M. Brophy, Stephen J. Greene, Julian Guida, G. Michael Felker, Marat Fudim, Michael Tsoukas, Tricia M. Peters, Thomas A. Mavrakanas, Nadia Giannetti, Justin Ezekowitz, Abhinav Sharma, McGill University = Université McGill [Montréal, Canada], Cleveland Clinic, 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), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, McGill University Health Center [Montreal] (MUHC), Duke University [Durham], Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, University of Alberta, and BOZEC, Erwan

Subjects
Heart Failure, Hospitalization, Models, Statistical, Diabetes Mellitus, Type 2, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, Prognosis, Cardiology and Cardiovascular Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

Background Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models’ performance, applicability, and clinical impact is absent. Methods and Results We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts’ clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta‐analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point‐of‐care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta‐analyzed c‐statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta‐analyzed c‐statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact. Conclusions Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps.

Published
2022

3. The Association between Oral Anticoagulants and Cancer Incidence among Individuals with Nonvalvular Atrial Fibrillation

Author

Hui Yin, Jean-Pascal Fournier, Devin Abrahami, Christel Renoux, Laurent Azoulay, Centre for Clinical Epidemiology and Community Studies [Montreal, Canada] (CCECS), Jewish General Hospital, Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Centre for Clinical Epidemiology and Community Studies [Montréal, Canada] (CCECS), Lady Davis Institute for Medical Research [Montréal, Canada] -Jewish General Hospital, Département de médecine générale [Université de Nantes - UFR de Médecine et des Techniques Médicales], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
Male, vitamin K antagonist, medicine.medical_specialty, Vitamin K, Colorectal cancer, [SDV]Life Sciences [q-bio], direct oral anticoagulant, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Internal medicine, Atrial Fibrillation, medicine, Humans, cancer, 030212 general & internal medicine, Aged, Aged, 80 and over, Proportional hazards model, business.industry, Incidence, Incidence (epidemiology), Hazard ratio, Anticoagulants, Cancer, Atrial fibrillation, Hematology, Middle Aged, medicine.disease, Confidence interval, population-based, 3. Good health, 030220 oncology & carcinogenesis, Propensity score matching, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Factor Xa Inhibitors
Abstract

Objective Existing evidence on the association between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) and cancer is limited and contradictory. No observational studies have been conducted to simultaneously address the cancer safety of VKAs and DOACs. The objective of this study was to determine whether use of VKAs and DOACs, separately, when compared with nonuse, is associated with cancer overall and prespecified site-specific incidence. Methods Using the United Kingdom Clinical Practice Research Datalink, we identified patients newly diagnosed with nonvalvular atrial fibrillation (NVAF) between 2011 and 2017. Using a time-varying exposure definition, each person-day of follow-up was classified as use of (1) VKAs, (2) DOACs, (3) VKAs and DOACs (drug switchers), and (4) nonuse of anticoagulants (reference). We also conducted a head-to-head comparison of new users of DOACs versus VKAs using propensity score fine stratification weighting. Hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer overall and prespecified subtypes were estimated using Cox proportional hazards models. Results Compared with nonuse, use of VKAs was not associated with cancer overall (HR: 1.05, 95% CI: 0.91–1.22) or cancer subtypes. Similarly, use of DOACs was not associated with cancer overall (HR: 1.13, 95% CI: 0.93–1.37), but an association was observed for colorectal cancer (HR: 1.73, 95% CI: 1.01–2.99), and pancreatic cancer generated an elevated, though nonsignificant HR (HR: 2.15, 95% CI: 0.72–6.44). Results were consistent in the head-to-head comparison. Conclusion Use of oral anticoagulants is not associated with the incidence of cancer overall among patients with NVAF. Possible associations between DOACs and colorectal and pancreatic cancer warrant further study.

Published
2020

4. Amyloid burden and white matter hyperintensities mediate age-related cognitive differences

Author

Sven Joubert, Guillaume T. Vallet, Maude Joannette, Pénélope Sévigny Dupont, Jim Nikelski, Marie Maxime Lavallée, Howard Chertkow, Christian Bocti, Université de Montréal. Faculté des arts et des sciences. Département de psychologie, Centre de recherche de l'Institut universitaire de gériatrie de Montreal (CRIUGM), Université de Montréal (UdeM), CIUSSS de l'Estrie - CHUS, Université de Sherbrooke (UdeS), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and McGill University = Université McGill [Montréal, Canada]

Subjects
Male, 0301 basic medicine, Aging, Neuroimaging, Cognitive aging, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Positron Emission Tomography Computed Tomography, medicine, Humans, Dementia, Neuropsychological assessment, Episodic memory, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Amyloid beta-Peptides, medicine.diagnostic_test, Working memory, business.industry, General Neuroscience, Cognition, Alzheimer's disease, medicine.disease, Executive functions, Magnetic Resonance Imaging, White Matter, Hyperintensity, 030104 developmental biology, [SCCO.PSYC]Cognitive science/Psychology, Female, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery, Developmental Biology
Abstract

This study examined the additive versus synergistic contribution of beta-amyloid (Aβ) and white matter hyperintensities (WMHs) across 7 cognitive domains in 104 cognitively normal older adults. It also measured the extent to which age-related differences in cognition are driven by measurable brain pathology. All participants underwent neuropsychological assessment along with magnetic resonance imaging and Pittsburg compound B-positron emission tomography imaging for Aβ quantification. WMH severity was quantified using the age-related white matter changes scale. Stepwise regressions, moderation, and mediation modeling were performed. Our findings show that Aβ deposition single-handedly predicts poorer episodic memory performance and that Aβ and WMHs contribute additively to poorer performance in working memory and language while carrying synergistic associations with executive functions and attention. Through mediation modeling, we demonstrated that the influence of age over episodic memory, working memory, executive functions, and language is fully mediated by brain pathology. This study permits to conclude that, in healthy older adults, (1) Aβ burden and WMHs have synergistic associations with some cognitive domains and (2) age-related differences in most cognitive domains are driven by brain pathology associated with dementia.

Published
2020

5. Analgesia and sedation in patients with ARDS

Author

Timothy D. Girard, Yahya Shehabi, Bram Rochwerg, Bhakti K. Patel, Sangeeta Mehta, Samir Jaber, Thomas Langer, Jean François Payen, Hanne T. Olsen, John P. Kress, Claude Guérin, Gilles L. Fraser, E. Wesley Ely, Thomas Strøm, Michael J. Murray, John W. Devlin, Kathleen Puntillo, Jean-Michel Constantin, Matthieu Jabaudon, Gerald Chanques, Céline Gélinas, Pratik P. Pandharipande, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Northeastern University [Boston], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Tufts University School of Medicine [Boston], McGill University = Université McGill [Montréal, Canada], Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Université de Lyon, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Clermont-Ferrand, University of Toronto, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), ASST Grande Ospedale Metropolitano Niguarda, University of Arizona, University of Chicago, CHU Grenoble, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), University of California [San Francisco] (UCSF), University of California, McMaster University [Hamilton, Ontario], Monash University [Clayton], University of New South Wales [Sydney] (UNSW), Odense University Hospital, Odense C, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), University of California [San Francisco] (UC San Francisco), University of California (UC), Chanques, G, Constantin, J, Devlin, J, Ely, E, Fraser, G, Gelinas, C, Girard, T, Guerin, C, Jabaudon, M, Jaber, S, Mehta, S, Langer, T, Murray, M, Pandharipande, P, Patel, B, Payen, J, Puntillo, K, Rochwerg, B, Shehabi, Y, Strom, T, Olsen, H, Kress, J, and MORNET, Dominique

Subjects
medicine.medical_specialty, ARDS, Sedation, medicine.medical_treatment, Pain medicine, [SDV]Life Sciences [q-bio], Remifentanil, Guidelines as Topic, Review, Critical Care and Intensive Care Medicine, law.invention, 03 medical and health sciences, Mechanical ventilation, 0302 clinical medicine, law, Anesthesiology, medicine, Humans, Hypnotics and Sedatives, Pain Management, Intensive care unit, MED/41 - ANESTESIOLOGIA, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, Respiratory Distress Syndrome, Acute respiratory distress syndrome, business.industry, Rehabilitation, COVID-19, 030208 emergency & critical care medicine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030228 respiratory system, Delirium, Analgesia, medicine.symptom, business, medicine.drug
Abstract

Acute Respiratory Distress Syndrome (ARDS) is one of the most demanding conditions in an Intensive Care Unit (ICU). Management of analgesia and sedation in ARDS is particularly challenging. An expert panel was convened to produce a “state-of-the-art” article to support clinicians in the optimal management of analgesia/sedation in mechanically ventilated adults with ARDS, including those with COVID-19. Current ICU analgesia/sedation guidelines promote analgesia first and minimization of sedation, wakefulness, delirium prevention and early rehabilitation to facilitate ventilator and ICU liberation. However, these strategies cannot always be applied to patients with ARDS who sometimes require deep sedation and/or paralysis. Patients with severe ARDS may be under-represented in analgesia/sedation studies and currently recommended strategies may not be feasible. With lightened sedation, distress-related symptoms (e.g., pain and discomfort, anxiety, dyspnea) and patient-ventilator asynchrony should be systematically assessed and managed through interprofessional collaboration, prioritizing analgesia and anxiolysis. Adaptation of ventilator settings (e.g., use of a pressure-set mode, spontaneous breathing, sensitive inspiratory trigger) should be systematically considered before additional medications are administered. Managing the mechanical ventilator is of paramount importance to avoid the unnecessary use of deep sedation and/or paralysis. Therefore, applying an “ABCDEF-R” bundle (R = Respiratory-drive-control) may be beneficial in ARDS patients. Further studies are needed, especially regarding the use and long-term effects of fast-offset drugs (e.g., remifentanil, volatile anesthetics) and the electrophysiological assessment of analgesia/sedation (e.g., electroencephalogram devices, heart-rate variability, and video pupillometry). This review is particularly relevant during the COVID-19 pandemic given drug shortages and limited ICU-bed capacity.

Published
2020

6. Meeting Report

Author

Leitner, Alexander, Bonvin, Alexandre M J J, Borchers, Christoph H, Chalkley, Robert J, Chamot-Rooke, Julia, Combe, Colin W, Cox, Jürgen, Dong, Meng-Qiu, Fischer, Lutz, Götze, Michael, Gozzo, Fabio C, Heck, Albert J R, Hoopmann, Michael R, Huang, Lan, Ishihama, Yasushi, Jones, Andrew R, Kalisman, Nir, Kohlbacher, Oliver, Mechtler, Karl, Moritz, Robert L, Netz, Eugen, Novak, Petr, Petrotchenko, Evgeniy, Sali, Andrej, Scheltema, Richard A, Schmidt, Carla, Schriemer, David, Sinz, Andrea, Sobott, Frank, Stengel, Florian, Thalassinos, Konstantinos, Urlaub, Henning, Viner, Rosa, Vizcaíno, Juan A, Wilkins, Marc R, Rappsilber, Juri, Sub NMR Spectroscopy, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, NMR Spectroscopy, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Utrecht University [Utrecht], University of Victoria [Canada] (UVIC), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Skolkovo Institute of Science and Technology [Moscow] (Skoltech), University of California [San Francisco] (UCSF), University of California, Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Edinburgh, Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, National Institute of Biological Sciences [Beijing, China] (Number 7 Science Park Road), Zhongguancun Life Science Park [Beijing, China], Technische Universität Berlin (TU), University of Campinas [Campinas] (UNICAMP), Institute for Systems Biology [Seattle] (ISB), University of California [Irvine] (UCI), Kyoto University [Kyoto], University of Liverpool, The Hebrew University of Jerusalem (HUJ), University of Tübingen, Max Planck Institute for Developmental Biology, Research Institute of Molecular Pathology (IMP), Charles University [Prague] (CU), Martin-Luther-University Halle-Wittenberg, University of Calgary, University of Leeds, University of Antwerp (UA), University of Konstanz, Birkbeck College [University of London], University College of London [London] (UCL), Max-Planck-Institut für Biophysikalische Chemie - Max Planck Institute for Biophysical Chemistry [Göttingen], Thermo Fisher Scientific (Bremen) GmbH, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of New South Wales [Sydney] (UNSW), This work was supported by the Wellcome Trust through a Senior Research Fellowship to J.R. (103139) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project 329673113). Funded by the DFG under Germany's Excellence Strategy, EXC 2008/1-390540038. The Wellcome Centre for Cell Biology is supported by core funding from the Wellcome Trust (203149)., We thank the participants of the meetings mentioned throughout the text for their many different contributions. Although we made an effort to include all labs that may feel a belonging to the field of Cross-linking MS, we apologize to all those that we missed. Developing standards in Cross-linking MS is to be viewed as an inclusive activity, so please feel warmly invited to join our efforts, University of California [San Francisco] (UC San Francisco), University of California (UC), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technical University of Berlin / Technische Universität Berlin (TU), Universidade Estadual de Campinas = University of Campinas (UNICAMP), University of California [Irvine] (UC Irvine), Kyoto University, Sub NMR Spectroscopy, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, and NMR Spectroscopy

Subjects
0303 health sciences, Computer science, Physics, 030302 biochemistry & molecular biology, Mass spectrometry, Other Quantitative Biology (q-bio.OT), Data science, Quantitative Biology - Other Quantitative Biology, 03 medical and health sciences, Chemistry, White paper, Structural Biology, Transparency (graphic), FOS: Biological sciences, ddc:570, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Human medicine, Molecular Biology, Biology, Reliability (statistics), 030304 developmental biology
Abstract

Crosslinking mass spectrometry (Crosslinking MS) has substantially matured as a method over the last two decades through parallel development in multiple labs, demonstrating its applicability for protein structure determination, conformation analysis and mapping protein interactions in complex mixtures. Crosslinking MS has become a much-appreciated and routinely applied tool especially in structural biology. Therefore, it is timely that the community commits to the development of methodological and reporting standards. This white paper builds on an open process comprising a number of events at community conferences since 2015 and identifies aspects of Crosslinking MS for which guidelines should be developed as part of a Crosslinking MS standards initiative., Comment: 26 pages, 1 figure

Published
2020

7. Education as a Moderator of the Relationship Between Episodic Memory and Amyloid Load in Normal Aging

Author

Maude Joannette, Howard Chertkow, Sven Joubert, Jim Nikelski, Christian Bocti, Guillaume T. Vallet, Pénélope Sévigny Dupont, Marie Maxime Lavallée, Université de Montréal (UdeM), Centre de recherche de l'Institut universitaire de gériatrie de Montreal (CRIUGM), Université de Sherbrooke (UdeS), Research Centre on Aging, Centre integré universitaire de santé et de services sociaux de l'Estrie (CIUSSS de l'Estrie - CHUS), Centre hospitalier universitaire de Sherbrooke, Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Université de Montréal. Faculté des arts et des sciences. Département de psychologie, Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), and CIUSSS de l'Estrie - CHUS

Subjects
Male, Amyloid, THE JOURNAL OF GERONTOLOGY: Biological Sciences, Aging, medicine.medical_specialty, Memory, Episodic, Cognitive reserve, Neuropsychological Tests, Audiology, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Cognition, medicine, Humans, 0501 psychology and cognitive sciences, Neuropsychological assessment, Episodic memory, ComputingMilieux_MISCELLANEOUS, Aged, medicine.diagnostic_test, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, 05 social sciences, Moderation, Magnetic Resonance Imaging, Educational attainment, Brain aging, Positron-Emission Tomography, Cohort, [SCCO.PSYC]Cognitive science/Psychology, Educational Status, Biomarker (medicine), Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

The current study explored whether education, a proxy of cognitive reserve, modifies the association between episodic memory (EM) performance and βeta-amyloid load (Aβ), a biomarker of Alzheimer’s disease, in a cohort of cognitively normal older adults. One hundred and four participants (mean age 73.3 years) evenly spread out in three bands of education were recruited. Participants underwent neuropsychological assessment, structural MRI as well as PET imaging to quantify Aβ load. Moderation analyses and the Johnson–Neyman technique were carried out to examine the interaction of education with Aβ load to predict EM performance. Linear regressions were then performed within each group of education to better illustrate the interaction effect (all analyses were controlled for age and sex). The interaction between education and Aβ load was significant (p < .05) for years of education, reaching a cutoff point of 13.5 years, above which the relationship between Aβ load and EM was no longer significant. Similarly, significant associations were found between Aβ and EM among participants with secondary (p < .01) and pre-university education (p < .01), but not with a university degree (p = .253). EM performance is associated with Aβ load in cognitively normal older individuals, and this relationship is moderated by educational attainment.

Published
2020

8. AntiThrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC):study design and methodology for an international, adaptive Bayesian randomized controlled trial

Author

Brett L. Houston, Robert S. Rosenson, Mansoor Husain, Sophie de Brouwer, John Marshall, Alexis F. Turgeon, Scott M. Berry, Jose C. Nicolau, Emily G. McDonald, Charlotte Bradbury, Bridget-Anne Kirwan, Srinivas Murthy, Ryan Zarychanski, V. Dzavik, Anand Kumar, Michael E. Farkouh, Robert A. Fowler, Jorge Escobedo, Dean Fergusson, Patrick R. Lawler, Jean-Phillippe Galanaud, Peter L. Gross, Marc Carrier, Susan R. Kahn, Arthur S. Slutsky, Ewan C. Goligher, Lindsay Bond, University of Manitoba [Winnipeg], University Health Network, University of Toronto, Toronto General Hospital Research Institute [Canada] (TGHRI), University of Bristol [Bristol], Ottawa Hospital Research Institute [Ottawa] (OHRI), Sunnybrook Health Sciences Centre, McMaster University [Hamilton, Ontario], Hamilton Health Sciences, McGill University Health Center [Montreal] (MUHC), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, St. Michael's Hospital, University of British Columbia (UBC), Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Université Laval [Québec] (ULaval), Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Universidade de São Paulo (USP), SOCAR Research, and London School of Hygiene and Tropical Medicine (LSHTM)

Subjects
Male, MESH: Heparin, Hospitalized patients, MESH: Coronavirus Infections, 030204 cardiovascular system & hematology, heparin, law.invention, MESH: Dose-Response Relationship, Drug, 0302 clinical medicine, Randomized controlled trial, law, MESH: COVID-19, 030212 general & internal medicine, Young adult, MESH: Treatment Outcome, adaptive clinical trial, Covid19, General Medicine, Thrombosis, 3. Good health, Treatment Outcome, MESH: Young Adult, MESH: Betacoronavirus, Female, Coronavirus Infections, Adult, MESH: Antiviral Agents, medicine.medical_specialty, 2019-20 coronavirus outbreak, MESH: Pandemics, Coronavirus disease 2019 (COVID-19), Adolescent, Pneumonia, Viral, MESH: Anticoagulants, Antiviral Agents, 03 medical and health sciences, Betacoronavirus, Young Adult, medicine, Humans, MESH: SARS-CoV-2, MESH: Thrombosis, protocol, Intensive care medicine, Pandemics, thrombosis, Pharmacology, MESH: Adolescent, Adaptive clinical trial, MESH: Humans, Dose-Response Relationship, Drug, business.industry, SARS-CoV-2, Heparin, Anticoagulants, COVID-19, MESH: Adult, medicine.disease, MESH: Male, MESH: Pneumonia, Viral, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. Methods: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. Conclusion: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.

Published
2020

9. Selective reporting of antibiotic susceptibility testing results: a promising antibiotic stewardship tool

Author

Alain Lozniewski, Gianpiero Tebano, Alexandre Charmillon, Veronica Zanichelli, Nathalie Thilly, Sébastien Fougnot, Yosra Mouelhi, Céline Pulcini, Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], 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), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), ATOUTBIO, Service de microbiologie [CHU Nancy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and McGill University-Jewish General Hospital

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Susceptibility testing, medicine.drug_class, 030106 microbiology, Antibiotics, Antibiotic susceptibility testing, Inappropriate Prescribing, Microbial Sensitivity Tests, Microbiology, 03 medical and health sciences, Antimicrobial Stewardship, 0302 clinical medicine, Antibiotic resistance, Selective reporting, Virology, Drug Resistance, Bacterial, medicine, Antimicrobial stewardship, Humans, 030212 general & internal medicine, Cascade reporting, Antibiotic use, Medical prescription, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, business.industry, Bacterial Infections, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, Practice Guidelines as Topic, Antibiotic Stewardship, Community setting, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Guideline Adherence, business
Abstract

Introduction: Selective reporting of antibiotic susceptibility testing (AST) results is a potentially interesting tool for antibiotic stewardship. It consists of performing AST according to usual practices, but the results are reported to the prescriber only for a few antibiotics (i.e. first-line agents) or not reported at all when colonization is likely.Areas covered: We retrieved 20 studies exploring the impact of selective reporting. Overall, selective reporting is able to influence antibiotic use, both discouraging prescription in case of colonization, and promoting the selection of narrow-spectrum agents. Most studies concerned urine samples. Evidence on the impact on antibiotic resistance is insufficient. Unintended consequences were not observed, but evidence on this topic is scarce. Selective reporting is well implemented in a few countries, and a huge heterogeneity of practices exists.Expert opinion: Evidence shows that selective reporting can help reducing inappropriate and unnecessary antibiotic prescriptions. Uncomplicated urinary tract infections are probably the best initial target, both in hospital and community settings, but other non-severe infections can be a suitable option. The implementation of selective reporting should be promoted by the scientific community, with detailed practical guidelines, and its impact should be further assessed in large interventional studies.

Published
2020

10. Long-term risk of postthrombotic syndrome after symptomatic distal deep vein thrombosis: The CACTUS-PTS study

Author

M.-T. Barrellier, Antoine Diard, D. Brisot, David R. Morrison, D. Pontal, Helia Robert-Ebadi, Marc Philip Righini, Susan Solymoss, Jeannine Kassis, Aymeric Douillard, Myriam Martin, Sandrine Accassat, Pascale Faisse, Jean-Philippe Galanaud, Aurélien Delluc, Isabelle Quéré, Lorris Le Collen, Marc Carrier, Susan R. Kahn, Hervé Guenneguez, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Sunnybrook Health Sciences Centre, Geneva University Hospitals and Geneva University, Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Département de Médécine Vasculaire [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Vascular Medicine office, Clinique Mégival, CRP Clinique du Parc, Castelnau-Le-Lez, Vascular Medicine Physician, Centre hospitalier universitaire de Saint-Etienne, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Ottawa Hospital Research Institute [Ottawa] (OHRI), McGill University Health Center [Montreal] (MUHC), and Hôpital Maisonneuve-Rosemont

Subjects
Cactaceae, medicine.medical_specialty, Popliteal Vein, medicine.drug_class, Chronic venous insufficiency, Epidemiology, Deep vein, Low molecular weight heparin, macromolecular substances, 030204 cardiovascular system & hematology, MESH: Anticoagulants, Lower risk, Postthrombotic Syndrome, 03 medical and health sciences, 0302 clinical medicine, Postthrombotic syndrome, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Risk Factors, Risk Factors, Deep vein thrombosis, medicine, otorhinolaryngologic diseases, Humans, cardiovascular diseases, Risk factor, MESH: Cactaceae, Venous Thrombosis, ddc:616, MESH: Humans, business.industry, MESH: Postthrombotic Syndrome, MESH: Popliteal Vein, Anticoagulant, Anticoagulants, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Thrombosis, 3. Good health, Surgery, Pulmonary embolism, Clinical trial, medicine.anatomical_structure, Nadroparin, MESH: Venous Thrombosis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

International audience; After a proximal lower limb deep vein thrombosis (DVT; involving popliteal veins or above), up to 40% of patients develop postthrombotic syndrome (PTS) as assessed by the Villalta scale (VS). Poor initial anticoagulant treatment is a known risk factor for PTS. The risk of developing PTS after isolated distal DVT (infra-popliteal DVT without pulmonary embolism), and the impact of anticoagulant treatment on this risk, are uncertain.Methods: Long-term follow-up of CACTUS double-blind trial comparing 6 weeks of s.c. nadroparin (171 IU/kg/d) versus s.c. placebo for a first symptomatic isolated distal DVT. At least 1 year after randomization, patients had a PTS assessment in clinic or by phone using the VS.Results: After a median follow-up of 6 years, PTS was present in 30% (n = 54) of the 178 patients who had a PTS assessment. PTS was moderate or severe in 24% (n = 13) of cases. There was no statistically significant difference in prevalence of PTS in the nadroparin versus placebo groups (29% versus 32%, P = .6), except in patients without evidence of primary chronic venous insufficiency (9% versus 24%, P = .04). Rates of venous thromboembolism recurrence during follow-up in the nadroparin and placebo groups were, respectively, 8% (n = 7) and 14% (n = 13; P = .2).Conclusion: After a first isolated distal DVT, the risk of PTS is substantial but much lower than that reported after proximal DVT. Anticoagulation with nadroparin doesn't provide any clear benefit to prevent PTS, except in patients without preexisting chronic venous insufficiency. Anticoagulation might be associated with a lower risk of venous thromboembolism recurrence.

Published
2020

11. Stalled developmental programs at the root of pediatric brain tumors

Author

Nicolas De Jay, Gustavo Turecki, Florence M.G. Cavalli, Yixing Hu, Alexis Blanchet-Cohen, Corina Nagy, W. Todd Farmer, Andréa Allaire, Hervé Sartelet, Louis Crevier, Roy W. R. Dudley, Jiannis Ragoussis, Marie Coutelier, Maxime Richer, Maria C. Vladoiu, Livia Garzia, Michael D. Taylor, Claudia L. Kleinman, Valerie Larouche, Jean Monlong, Jeffrey Atkinson, Nada Jabado, Guillaume Bourque, Laura K. Donovan, Keith K. Murai, Benjamin Ellezam, Pierre-Eric Lutz, Jean-Pierre Farmer, Brice Poreau, Leonie G. Mikael, Alexander G. Weil, Mariella G. Filbin, Steven Hébert, Selin Jessa, Santiago Costantino, Steffen Albrecht, Damien Faury, Peter B. Dirks, Brian Krug, Melissa K. McConechy, McGill University = Université McGill [Montréal, Canada], Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, The Hospital for sick children [Toronto] (SickKids), McGill University Health Center [Montreal] (MUHC), Centre Hospitalier Universitaire [Grenoble] (CHU), Santa Cruz Genomics Institute, University of California [Santa Cruz] (UCSC), University of California-University of California, Zebralog GmbH & Co. KG, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry [Montréal], Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal General Hospital, McGill University and Genome Quebec Innovation Centre, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], This work was supported by funding from: a Large-Scale Applied Research Project grant from Genome Quebec, Genome Canada, the Government of Canada and the Ministère de l'Économie, de la Science et de l’Innovation du Québec, with the support of the Ontario Research Fund through funding provided by the Government of Ontario to N.J., M.D.T., C.L.K., P.B.D., G.B., J.R. and L.G., the Canadian Institutes for Health Research (CIHR grant nos. PJT-156086, to C.L.K., and MOP-286756 and FDN-154307, to N.J.), the US National Institutes of Health (NIH grant nos. P01-CA196539, to N.J., R01CA148699 and R01CA159859, to M.D.T.), the Canadian Cancer Society (CCSRI grant no. 705182), NSERC (grant no. RGPIN-2016-04911) and the Fonds de Recherche du Québec en Santé (FRQS) salary award to C.L.K., National Sciences and Engineering Research Council (grant no. NSERC-448167-2013) and FRQS (grant no. 25348) to G.B., CFI Leaders Opportunity Fund (grant nos. 32557, to J.R., and 33902, to C.L.K.), Genome Canada Science Technology Innovation Centre, Compute Canada Resource Allocation Project (grant no. WST-164-AB) and Genome Canada Genome Innovation Node (grant no. 244819) to J.R., and and the Fondation Charles-Bruneau. Data analyses were enabled by computer and storage resources provided by Compute Canada and Calcul Québec. N.J. is a member of the Penny Cole Laboratory and the recipient of a Chercheur Boursier, Chaire de Recherche Award from the FRQS. This work was performed within the context of the International Childhood Astrocytoma Integrated Genomic and Epigenomic (ICHANGE) consortium, and the Stand Up to Cancer (SU2C) Canada Cancer Stem Cell Dream Team Research Funding (grant no. SU2C-AACR-DT-19-15, to M.D.T. and N.J.) and SU2C St. Baldrick’s Pediatric Dream Team Translational Research Grant (no. SU2C-AACR-DT1113, to M.D.T.), with funding from Genome Canada and Genome Quebec. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by The Pediatric Brain Tumour Foundation, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, SWIFTY Foundation, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, Cancer Research UK Brain Tumour Award, Canadian Cancer Society Research Institute Impact grant and the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. S.J. is supported by a fellowship from CIHR. A.B.-C. is supported by a fellowship from FRQS and TD/LDI. N.D.J. is a recipient of a fellowship from FRQS and RMGA. M.K.M. is funded by a CIHR Banting postdoctoral fellowship. We thank K. Mann, S. Spira and J. Di Noia for critical reading of the manuscript, and S. Krumholtz for graphical editing of figures. We are especially grateful for the generous philanthropic donations of the Fondation Charles-Bruneau, and the Kat D-DIPG, Poppies for Irina and We Love You Connie Foundations.

Subjects
[SDV]Life Sciences [q-bio], Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Transcriptome, Mice, 03 medical and health sciences, Nerve Fibers, Prosencephalon, 0302 clinical medicine, Single-cell analysis, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Progenitor cell, Rhabdoid Tumor, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Neuroectoderm, Brain Neoplasms, Wnt signaling pathway, Brain, Gene Expression Regulation, Developmental, Infant, Neoplasms, Germ Cell and Embryonal, 3. Good health, medicine.anatomical_structure, Forebrain, Single-Cell Analysis, Neuroscience, 030217 neurology & neurosurgery, Medulloblastoma
Abstract

International audience; Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Published
2019

12. Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial

Author

Marie-Claude Guertin, Quang T. Nguyen, Jean Guimond, Vincent Finnerty, François Harel, Xavier Levac, Gad Abikhzer, Asmaa Mansour, David Langleben, Myriam Létourneau, Jocelyn Dupuis, Steve Provencher, Alain Fournier, Montreal Heart Institute - Institut de Cardiologie de Montréal, Université de Montréal (UdeM), Lady Davis Institute, McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Jewish General Hospital, Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and Montreal Health Innovation Coordination Center

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Hypertension, Pulmonary, [SDV]Life Sciences [q-bio], Molecular imaging, 030204 cardiovascular system & hematology, Adrenomedullin receptor ligand, Pulmonary hypertension, 030218 nuclear medicine & medical imaging, Adrenomedullin, 03 medical and health sciences, 0302 clinical medicine, Adrenomedullin Receptor, Internal medicine, Spect imaging, Image Processing, Computer-Assisted, medicine, Humans, Radiology, Nuclear Medicine and imaging, Lung, Vascular disease, business.industry, Pulmonary embolism, Reproducibility of Results, General Medicine, Middle Aged, medicine.disease, Vascular endothelium, Radiology Nuclear Medicine and imaging, Case-Control Studies, Nuclear medicine, Peptide, Cardiology, Original Article, Female, Endothelium, Vascular, Safety, business, hormones, hormone substitutes, and hormone antagonists
Abstract

Purpose The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. Methods Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. Results PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. Conclusions In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. Clinical trial ClinicalTrials.gov, NCT02216279 Electronic supplementary material The online version of this article (doi:10.1007/s00259-017-3655-y) contains supplementary material, which is available to authorized users.

Published
2017

13. The relation between episodic memory and amyloid burden in healthy elderly adults is moderated by educational level

Author

Joannette, Maude, Bocti, Christian, Lavallée, Marie, Dupont, Pénélope Sévigny, Vallet, Guillaume T., Nikelski, Jim, Chertkow, Howard, Joubert, Sven, Centre de recherche de l'Institut universitaire de gériatrie de Montreal (CRIUGM), Université de Montréal (UdeM), Faculté de médecine et des sciences de la santé [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS), Centre de Recherche, Institut Universitaire de Gériatrie de Montréal - CIUSSS du Centre-est-de-l’Île-de-Montréal, University of Montreal, Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, McGill University = Université McGill [Montréal, Canada], and LAPSCO, HAL

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SCCO.PSYC] Cognitive science/Psychology, [SCCO.PSYC]Cognitive science/Psychology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2018

14. Poorer cognitive performance in healthy older individuals is associated with the presence of beta-amyloid burden and white matter hyperintensities

Author

Lavallée, Marie, Vallet, Guillaume T., Dupont, Pénélope Sévigny, Joannette, Maude, Chertkow, Howard, Bocti, Christian, Joubert, Sven, Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Université de Montréal (UdeM), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, McGill University = Université McGill [Montréal, Canada], Faculté de médecine et des sciences de la santé [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS), Research Centre on Aging, Centre integré universitaire de santé et de services sociaux de l'Estrie (CIUSSS de l'Estrie - CHUS), Centre hospitalier universitaire de Sherbrooke, and LAPSCO, HAL

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SCCO.PSYC] Cognitive science/Psychology, [SCCO.PSYC]Cognitive science/Psychology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2018

15. Beta-amyloid burden and white matter hyperintensities as mediators of the relationship between age and cognition in normal aging

Author

Dupont, Pénélope Sévigny, Bocti, Christian, Joannette, Maude, Lavallée, Marie, Vallet, Guillaume T., Chertkow, Howard, Joubert, Sven, LAPSCO, HAL, Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Université de Montréal (UdeM), Research Centre on Aging, Centre integré universitaire de santé et de services sociaux de l'Estrie (CIUSSS de l'Estrie - CHUS), Centre hospitalier universitaire de Sherbrooke, Faculté de médecine et des sciences de la santé [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, and McGill University = Université McGill [Montréal, Canada]

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SCCO.PSYC]Cognitive science/Psychology, [SCCO.PSYC] Cognitive science/Psychology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

16. [Immortal time bias in pharmacoepidemiological studies: definition, solutions and examples]

Author

Samy Suissa, Jean-Luc Faillie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Herrada, Anthony

Subjects
Drug, Research design, medicine.medical_specialty, pharmacoepidemiology, databases, media_common.quotation_subject, MEDLINE, bases de données, cohort studies, medicine, Pharmacology (medical), Psychiatry, media_common, Study drug, Mechanism (biology), biais de temps immortel, immortal time bias, Pharmacoepidemiology, humanities, 3. Good health, pharmacoépidémiologie, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, biases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Observational study, étude de cohorte, Psychology, biais, Cohort study
Abstract

Among the observational studies of drug effects in chronic diseases, many of them have found effects that were exaggerated or wrong. Among bias responsible for these errors, the immortal time bias, concerning the definition of exposure and exposure periods, is relevantly important as it usually tends to wrongly attribute a significant benefit to the study drug (or exaggerate a real benefit). In this article, we define the mechanism of immortal time bias, we present possible solutions and illustrate its consequences through examples of pharmacoepidemiological studies of drug effects., Parmi les études observationnelles des effets des traitements médicamenteux des maladies chroniques, nombre d'entre elles ont conclu à des effets qui se sont avérés exagérés ou erronés. Parmi les biais responsables de ces erreurs, le biais de temps immortel, concernant la définition du facteur d'exposition étudié et des périodes d'exposition, occupe une place importante car il a généralement tendance à attribuer à tort un bénéfice important au médicament à l'étude (ou à exagérer un bénéfice réel). Dans cet article, nous définissons le mécanisme du biais de temps immortel, nous présentons les solutions pos-sibles et nous illustrons ses conséquences au travers d'exemples d'études pharmacoépidémiologiques portant sur les effets des traitements médicamenteux.

Published
2015

17. Erythro-myeloid progenitors can differentiate from endothelial cells and modulate embryonic vascular remodeling

Author

Bahar Kasaai, Hanna M. Peacock, Aernout Luttun, Stephanie Lehoux, Elizabeth A. V. Jones, Vincenza Caolo, Elisa Gomez-Perdiguero, Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Lady Davis Institute, Department of Experimental Medicine, McGill University, Macrophages et Cellules endothéliales / Macrophages and Endothelial Cells, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Myeloid, Cell division, Endothelium, [SDV]Life Sciences [q-bio], Lipoproteins, LDL/metabolism, Mice, Transgenic, Vascular Remodeling, Transgenic, Article, 03 medical and health sciences, Mice, Lipoproteins, LDL/metabolism, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics, medicine, Animals, Progenitor cell, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Mouse Embryonic Stem Cells/cytology, Myeloid Progenitor Cells, Yolk Sac, Erythroid Precursor Cells, Microscopy, Multidisciplinary, Microscopy, Confocal, Chemistry, Myeloid Progenitor Cells/cytology, Yolk Sac/blood supply, Endothelial Cells, Venous plexus, Mouse Embryonic Stem Cells, Embryonic stem cell, Cell biology, Hematopoiesis, Lipoproteins, LDL, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics, Erythroid Precursor Cells/cytology, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Confocal, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Myelopoiesis, Endothelial Cells/cytology
Abstract

Erythro-myeloid progenitors (EMPs) were recently described to arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages. Questions remain, however, concerning whether EMPs differentiate directly from the endothelium or merely pass through. We provide the first evidence in vivo that EMPs can emerge directly from endothelial cells (ECs) and demonstrate a role for these cells in vascular development. We find that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein (AcLDL), as ECs do. When the endothelium is labelled with AcLDL before EMPs differentiate, EMPs and EMP-derived cells arise that are AcLDL+. If AcLDL is injected after the onset of EMP differentiation, however, the majority of EMP-derived cells are not double labelled. We find that cell division precedes entry of EMPs into circulation, and that blood flow facilitates the transition of EMPs from the endothelium into circulation in a nitric oxide-dependent manner. In gain-of-function studies, we inject the CSF1-Fc ligand in embryos and found that this increases the number of CSF1R+ cells, which localize to the venous plexus and significantly disrupt venous remodeling. This is the first study to definitively establish that EMPs arise from the endothelium in vivo and show a role for early myeloid cells in vascular development.

Published
2017

18. L’impact des plaques bêta-amyloïdes sur la cognition : au-delà de l’âge et de l’éducation

Author

Lavallée, Marie, Joannette, Maude, Sévigny-Dupont, Pénélope, Vallet, Guillaume T., Bocti, Christian, Chertkow, Howard, Nikelski, Jim, Masse, Benoît, Joubert, Sven, Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Université de Montréal (UdeM), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Neuropsychologie et Neurocognition (CERNEC), Research Centre on Aging, Centre integré universitaire de santé et de services sociaux de l'Estrie (CIUSSS de l'Estrie - CHUS), Centre hospitalier universitaire de Sherbrooke, Faculté de médecine et des sciences de la santé [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, McGill University = Université McGill [Montréal, Canada], Institut universitaire de gériatrie de Sherbrooke, Département de médecine sociale et préventive [ESPUM-Montréal] (ESPUM), CERNEC, and LAPSCO, HAL

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SCCO.PSYC] Cognitive science/Psychology, [SCCO.PSYC]Cognitive science/Psychology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2017

19. La caractérisation de l’hétérogénéité cognitive des personnes âgées en santé : Préservation de l’intelligence cristallisée

Author

Lavallée, Marie, Vallet, Guillaume T., Bocti, Christian, Sévigny-Dupont, Pénélope, Joannette, Maude, Masse, Benoît, Nikelski, Jim, Chertkow, Howard, Joubert, Sven, LAPSCO, HAL, Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Université de Montréal (UdeM), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Faculté de médecine et des sciences de la santé [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS), Research Centre on Aging, Centre integré universitaire de santé et de services sociaux de l'Estrie (CIUSSS de l'Estrie - CHUS), Centre hospitalier universitaire de Sherbrooke, Institut Universitaire de Gériatrie de Sherbrooke (CSSS-IUGS), Département de médecine sociale et préventive [ESPUM-Montréal] (ESPUM), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, McGill University = Université McGill [Montréal, Canada], and CERNEC

Subjects
[SCCO.PSYC]Cognitive science/Psychology, [SCCO.PSYC] Cognitive science/Psychology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2017

20. Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation

Author

Forough Noohi, Christian Poitras, Sharon Yang, Claudia L. Kleinman, Robyn D. Moir, Annie Bouchard, Diane Forget, Timothy E. Kennedy, Geneviève Bernard, Bernard Brais, Roxanne Larivière, Marie Josée Dicaire, Martin Teichmann, Karine Choquet, Nicolas Sgarioto, Joseph Rochford, Ian M. Willis, Benoit Coulombe, Lady Davis Institute for Medical Research [Montréal, QC, Canada], McGill University = Université McGill [Montréal, Canada], Montreal Neurological Institute and Hospital, Department of Human Genetics [Montréal], Department of Biochemistry [Bronx, NY, USA], Albert Einstein College of Medicine [New York], Translational Proteomics Laboratory [Montréal, QC, Canada], Institut De Recherches Cliniques De Montreal - IRCM [Canada], Department of Psychiatry [Montréal, QC, Canada] (Neurophenotyping Centre), Douglas Mental Health University Institute Research Centre [Montréal, QC, Canada], Departments of Neurology & Neurosurgery and Pediatrics [Montréal, QC, Canada], McGill University = Université McGill [Montréal, Canada]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Department of Medical Genetics [Montréal, QC, Canada], Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Child Health and Human Development Program [Montréal, QC, Canada], McGill University Health Center [Montreal] (MUHC), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB), Département de Biochimie et Médecine Moléculaire [UdeM-Montréal], Université de Montréal (UdeM), This project was supported by grants from the Fondation Leuco Dystrophie, the European Leukodystrophy Association and the Canadian Institutes of Health Research (CIHR) (MOP #126141). KC receives a Doctoral Award from the Fonds de recherche du Québec–Santé (FRQS). GB has received a Research Scholar Junior 1 (2012–2016) salary award from the FRQS and the New Investigator salary award (2017–2022) from the CIHR (MOP-G-287547). MT was supported by grants from the INSERM and the Ligue Nationale contre le Cancer (Equipe labellisée). CLK receives salary awards from the FRQS., BMC, BMC, Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, and Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Genetically modified mouse, Transcription, Genetic, [SDV]Life Sciences [q-bio], Short Report, Biology, Motor Activity, Compound heterozygosity, lcsh:RC346-429, Luxol fast blue stain, Mouse model, 03 medical and health sciences, Cellular and Molecular Neuroscience, Myelin, Purkinje Cells, Transfer RNAs, 0302 clinical medicine, Cerebellum, medicine, Animals, Humans, Gene Knock-In Techniques, Molecular Biology, Gene, lcsh:Neurology. Diseases of the nervous system, Myelin Sheath, Mice, Knockout, POLR3A, Leukodystrophy, Homozygote, RNA Polymerase III, medicine.disease, Phenotype, Null allele, Molecular biology, 3. Good health, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Hereditary Central Nervous System Demyelinating Diseases, 030104 developmental biology, medicine.anatomical_structure, Mutation, Hypomyelination, 030217 neurology & neurosurgery
Abstract

Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease. Electronic supplementary material The online version of this article (doi:10.1186/s13041-017-0294-y) contains supplementary material, which is available to authorized users.

Published
2016

21. A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk

Author

Travis, Ruth, Appleby, Paul, Martin, Richard, Holly, Jeff M.P., Albanes, Demetrius, Black, Amanda, Bueno-De-Mesquita, H. Bas, Chan, June, Chen, Chu, Chirlaque, María-Dolores, Cook, Michael, Deschasaux, Mélanie, Donovan, Jenny, Ferrucci, Luigi, Galan, Pilar, Giles, Graham, Giovannucci, Edward, Gunter, Marc, Habel, Laurel, Hamdy, Freddie, Helzlsouer, Kathy, Hercberg, Serge, Hoover, Robert, Janssen, Joseph A.M.J.L., Kaaks, Rudolf, Kubo, Tatsuhiko, Le Marchand, Loïc, Metter, E. Jeffrey, Mikami, Kazuya, Morris, Joan, Neal, David, Neuhouser, Marian, Ozasa, Kotaro, Palli, Domenico, Platz, Elizabeth, Pollak, Michael, Price, Alison, Roobol, Monique, Schaefer, Catherine, Schenk, Jeannette, Severi, Gianluca, Stampfer, Meir, Stattin, Pär, Tamakoshi, Akiko, Tangen, Catherine, Touvier, Mathilde, Wald, Nicholas, Weiss, Noel, Ziegler, Regina, Key, Timothy, Allen, Naomi, Nuffield Department of Population Health [Oxford], University of Oxford [Oxford], School of Social and Community Medicine [Bristol], University of Bristol [Bristol], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), National Institute for Public Health and the Environment [Bilthoven] (RIVM), University of California [San Francisco] (UCSF), University of California, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, 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)), 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), National Institute on Aging [Bethesda, USA] (NIA), University of Melbourne, Harvard School of Public Health, School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Kaiser Permanente, Nuffield (Nuffield), Mercy Medical Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Occupational and Environmental Health [Kitakyushu] (UEOH), University of Hawai‘i [Mānoa] (UHM), Kyoto Prefectural University of Medicine [Kyoto, Japon], Queen Mary University of London (QMUL), University of Cambridge [UK] (CAM), Radiation Effects Research Foundation, Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Cancer Prevention Research Unit, Department of Oncology, McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, University of Washington [Seattle], Cancer Epidemiology Centre, Cancer Council Victoria, Human Genetics Foundation (HuGeF), Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Hokkaido University Hospital [Sapporo], University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), 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)), and Deschasaux-Tanguy, Mélanie

Subjects
Urologic Diseases, Male, Aging, Oncology and Carcinogenesis, Article, growth-factor-i, serum-insulin, Risk Factors, prevention trial, Humans, Oncology & Carcinogenesis, Insulin-Like Growth Factor I, factor axis, igfbp-3, Cancer, Aged, Prostate Cancer, hyperplasia, Prostatic Neoplasms, Middle Aged, susceptibility loci, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, factor-binding protein-2, Centre for Surgical Research, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, factor (igf)-i, diet, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. Aftermutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development.

Published
2016

22. Measuring and Estimating the Effect Sizes of Copy Number Variants on General Intelligence in Community-Based Samples

Author

Thomas Bourgeron, Sonia Nizard, Roberto Toro, Sébastien Jacquemont, Gunter Schumann, Zdenka Pausova, Alexandre Mathieu, Jean-Baptiste Poline, Aurélie Labbe, Celia M. T. Greenwood, Guillaume Huguet, Elise Douard, Tomáš Paus, Emmanuelle Lemyre, Catherine Schramm, Patricia J. Conrod, Eva Loth, Frédérique Tihy, Lai Jiang, Géraldine Mathonnet, Université de Montréal (UdeM), CHU Sainte Justine [Montréal], Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, HEC Montréal (HEC Montréal), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Toronto, McGill University = Université McGill [Montréal, Canada], Rotman Research Institute at the Baycrest Centre (RRI), Child Mind Institute, This research was enabled by support provided by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca). Dr Bourgeron is supported by the Institut Pasteur, the University Paris Diderot, Centre National de la Recherche Scientifique, and the Bettencourt-Schueller Foundation. Dr Jacquemont is a recipient of a Bursary Professor fellowship of the Swiss National Science Foundation, a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. Dr Huguet is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. Dr Schramm is supported by the Institute for Data Valorization fellowship. Dr Loth is supported by European Autism Interventions, which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115300, the resources of which are composed of financial contributions from grant FP7/2007-2013 from the European Union's Seventh Framework Programme, the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and Autism Speaks. This work is supported by a grant from the Brain Canada Multi Investigator initiative (Dr Jacquemont). The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the Saguenay Youth Study. Funding for the project was provided by the Wellcome Trust., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), Université de Montréal [Montréal], McGill University-Jewish General Hospital, Gènes, Synapses et Cognition, McGill University, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Adolescent, DNA Copy Number Variations, Genotype, Intraclass correlation, [SDV]Life Sciences [q-bio], Concordance, Intelligence, Population, Haploinsufficiency, Biology, Sampling Studies, Cohort Studies, 03 medical and health sciences, Loss of Function Mutation, Humans, Copy-number variation, Child, education, Original Investigation, Genetic association, Chromosome Aberrations, Genetics, education.field_of_study, Models, Genetic, Intelligence quotient, Genetic Carrier Screening, Quebec, Exons, Odds ratio, Europe, Psychiatry and Mental health, 030104 developmental biology, Neurodevelopmental Disorders, Female, Gene Deletion
Abstract

Importance; Copy number variants (CNVs) classified as pathogenic are identified in 10% to 15% of patients referred for neurodevelopmental disorders. However, their effect sizes on cognitive traits measured as a continuum remain mostly unknown because most of them are too rare to be studied individually using association studies. Objective To measure and estimate the effect sizes of recurrent and nonrecurrent CNVs on IQ. Design, Setting, and Participants This study identified all CNVs that were 50 kilobases (kb) or larger in 2 general population cohorts (the IMAGEN project and the Saguenay Youth Study) with measures of IQ. Linear regressions, including functional annotations of genes included in CNVs, were used to identify features to explain their association with IQ. Validation was performed using intraclass correlation that compared IQ estimated by the model with empirical data. Main Outcomes and Measures Performance IQ (PIQ), verbal IQ (VIQ), and frequency of de novo CNV events. Results The study included 2090 European adolescents from the IMAGEN study and 1983 children and parents from the Saguenay Youth Study. Of these, genotyping was performed on 1804 individuals from IMAGEN and 977 adolescents, 445 mothers, and 448 fathers (484 families) from the Saguenay Youth Study. We observed 4928 autosomal CNVs larger than 50 kb across both cohorts. For rare deletions, size, number of genes, and exons affect IQ, and each deleted gene is associated with a mean (SE) decrease in PIQ of 0.67 (0.19) points ( P = 6 × 10 −4 ); this is not so for rare duplications and frequent CNVs. Among 10 functional annotations, haploinsufficiency scores best explain the association of any deletions with PIQ with a mean (SE) decrease of 2.74 (0.68) points per unit of the probability of being loss-of-function intolerant ( P = 8 × 10 −5 ). Results are consistent across cohorts and unaffected by sensitivity analyses removing pathogenic CNVs. There is a 0.75 concordance (95% CI, 0.39-0.91) between the effect size on IQ estimated by our model and IQ loss calculated in previous studies of 15 recurrent CNVs. There is a close association between effect size on IQ and the frequency at which deletions occur de novo (odds ratio, 0.86; 95% CI, 0.84-0.87; P = 2.7 × 10 −88 ). There is a 0.76 concordance (95% CI, 0.41-0.91) between de novo frequency estimated by the model and calculated using data from the DECIPHER database. Conclusions and Relevance Models trained on nonpathogenic deletions in the general population reliably estimate the effect size of pathogenic deletions and suggest omnigenic associations of haploinsufficiency with IQ. This represents a new framework to study variants too rare to perform individual association studies and can help estimate the cognitive effect of undocumented deletions in the neurodevelopmental clinic.

Published
2018

23. Le biais de temps immortel dans les études pharmacoépidémiologiques : définition, solutions et exemples

Author

Jean-Luc, Faillie, Samy, Suissa, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], Lady Davis Institute for Medical Research [Montréal], and McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital

Subjects
Time Factors, pharmacoepidemiology, databases, biais de temps immortel, immortal time bias, bases de données, Bias, Pharmaceutical Preparations, cohort studies, pharmacoépidémiologie, Research Design, Chronic Disease, biases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Humans, étude de cohorte, biais
Abstract

International audience; Among the observational studies of drug effects in chronic diseases, many of them have found effects that were exaggerated or wrong. Among bias responsible for these errors, the immortal time bias, concerning the definition of exposure and exposure periods, is relevantly important as it usually tends to wrongly attribute a significant benefit to the study drug (or exaggerate a real benefit). In this article, we define the mechanism of immortal time bias, we present possible solutions and illustrate its consequences through examples of pharmacoepidemiological studies of drug effects.; Parmi les études observationnelles des effets des traitements médicamenteux des maladies chroniques, nombre d'entre elles ont conclu à des effets qui se sont avérés exagérés ou erronés. Parmi les biais responsables de ces erreurs, le biais de temps immortel, concernant la définition du facteur d'exposition étudié et des périodes d'exposition, occupe une place importante car il a généralement tendance à attribuer à tort un bénéfice important au médicament à l'étude (ou à exagérer un bénéfice réel). Dans cet article, nous définissons le mécanisme du biais de temps immortel, nous présentons les solutions pos-sibles et nous illustrons ses conséquences au travers d'exemples d'études pharmacoépidémiologiques portant sur les effets des traitements médicamenteux.

Published
2015

24. IFITM Proteins Incorporated into HIV-1 Virions Impair Viral Fusion and Spread

Author

Chen Liang, Françoise Porrot, Martin Sachse, Olivier Schwartz, Adeline Mallet, Alex A. Compton, Nicoletta Casartelli, Marine Euvrard, Timothée Bruel, Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Imagopole (CITECH), Institut Pasteur [Paris], Département de Biologie, École normale supérieure - Cachan (ENS Cachan), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Work was supported by grants from the ANRS, SIDACTION, AREVA Foundation, the Labex IBEID program, the FP7 program,HIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur, as well as the Vaccine Research Institute, Investissements d’Avenir program (ANR-10-LABX-77), European Project: 305762,HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIT HIDDEN HIV(2012), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Vaccine Research Institute [Créteil, France] (VRI)

Subjects
CD4-Positive T-Lymphocytes, Cancer Research, viruses, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), Gene Products, gag, HIV Infections, Biology, medicine.disease_cause, Microbiology, Article, Virus, Cell Line, Viral envelope, Antigen, Virology, Immunology and Microbiology(all), medicine, Humans, Molecular Biology, Cell Membrane, Virion, Membrane Proteins, RNA-Binding Proteins, Colocalization, Virus Internalization, Antigens, Differentiation, Transmembrane protein, 3. Good health, Cell culture, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, Parasitology
Abstract

Summary The interferon-induced transmembrane (IFITM) proteins protect cells from diverse virus infections by inhibiting virus-cell fusion. IFITM proteins also inhibit HIV-1 replication through mechanisms only partially understood. We show that when expressed in uninfected lymphocytes, IFITM proteins exert protective effects during cell-free virus infection, but this restriction can be overcome upon HIV-1 cell-to-cell spread. However, when present in virus-producing lymphocytes, IFITM proteins colocalize with viral Env and Gag proteins and incorporate into nascent HIV-1 virions to limit entry into new target cells. IFITM in viral membranes is associated with impaired virion fusion, offering additional and more potent defense against virus spread. Thus, IFITM proteins act additively in both productively infected cells and uninfected target cells to inhibit HIV-1 spread, potentially conferring these proteins with greater breadth and potency against enveloped viruses., Graphical Abstract, Highlights • IFITM proteins inhibit HIV spread from infected cells to new target cells • IFITM colocalize with viral Env and Gag proteins and incorporate into virions • When incorporated into virions, IFITM proteins reduce virus particle infectivity • IFITM in viral membranes impair virion fusion more potently than IFITM in cells, Interferon-induced transmembrane (IFITM) proteins are membrane-resident antiviral effectors, protecting cells against infection by diverse viruses. Compton et al. describe a function for IFITM proteins in which incorporation into the membrane of HIV-1 virions and inhibition of fusion between virus and target cell lead to a potent block of HIV-1 spread.

Published
2014

25. Functional and Placental Expression Analysis of the Human NRF3 Transcription Factor

Author

Anna Derjuga, Valerie Bellingard, Susan J. Fisher, Wael Massrieh, Kristy Red-Horse, Volker Blank, Benoît Chénais, Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, University of California [San Francisco] (UCSF), University of California, and McGill University = Université McGill [Montréal, Canada]

Subjects
MafG Transcription Factor, Transcriptional Activation, DNA, Complementary, Placenta, Molecular Sequence Data, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Response Elements, DNA-binding protein, Endocrinology, Maf Transcription Factors, Gene expression, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Cloning, Molecular, Molecular Biology, Transcription factor, Cells, Cultured, ATF3, Base Sequence, Tumor Necrosis Factor-alpha, Gene Expression Profiling, Choriocarcinoma, General Medicine, medicine.disease, Molecular biology, Protein Structure, Tertiary, Trophoblasts, DNA-Binding Proteins, Repressor Proteins, Basic-Leucine Zipper Transcription Factors, medicine.anatomical_structure, Organ Specificity, embryonic structures, Dimerization, Sequence Alignment, Protein Binding, Transcription Factors
Abstract

International audience; Members of the Maf protooncogene and cap'n' collar families of basic-leucine zipper transcription factors play important roles in development, differentiation , oncogenesis, and stress signaling. In this study, we performed an in vivo protein-protein interaction screen to search for novel partners of the small Maf proteins. Using full-length human MAFG protein as bait, we identified the human basic-leucine zipper protein NRF3 [NF-E2 (nuclear factor erythroid 2)-related factor 3] as an interaction partner. Transfection studies confirmed that NRF3 is able to dimerize with MAFG. The resulting NRF3/ MAFG heterodimer recognizes nuclear factor-erythroid 2/Maf recognition element-type DNA-binding motifs. Functional analysis revealed the presence of a strong transcriptional activation domain in the center region of the NRF3 protein. We found that NRF3 transcripts are present in placen-tal chorionic villi from at least week 12 of gestation on through term. In particular, NRF3 is highly expressed in primary placental cytotrophoblasts, but not in placental fibroblasts. The human choriocar-cinoma cell lines BeWo and JAR, derived from tro-phoblastic tumors of the placenta, also strongly express NRF3 transcripts. We generated a NRF3-specific antiserum and identified NRF3 protein in placental choriocarcinoma cells. Furthermore, we showed that NRF3 transcript and protein levels are induced by TNF-in JAR cells. Our functional studies suggest that human NRF3 is a potent transcrip-tional activator. Finally, our expression and induction analyses hint at a possible role of Nrf3 in placental gene expression and development. (Mo-lecular Endocrinology 19: 125-137, 2005)

Published
2005

26. Metformin: From Mechanisms of Action to Therapies

Author

Bruno Guigas, Marc Foretz, Luc Bertrand, Michael Pollak, Benoit Viollet, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dpt of Parasitology [Leiden], Leiden University Medical Center (LUMC), Department of Molecular Cell Biology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Cancer Prevention Research Unit, Department of Oncology, McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, The work of Viollet’s group is performed within the Département Hospitalo-Universitaire (DHU) AUToimmune and HORmonal diseaseS and supported by grants from INSERM, CNRS, Université Paris Descartes, Agence Nationale de la Recherche, Société Francophone du Diabète, Région Ile de France and Association pour la Recherche sur le Diabète. The work of Guigas’ group is supported by Société Francophone du Diabète and European Federation for the Study of Diabetes. The work of Bertrand’s group is supported by the Fonds National de la Recherche Scientifique et Médicale (Belgium), the Actions de Recherche Concertées (Belgium) and Société Francophone du Diabète. LB is Research Associates of the Fonds National de la Recherche Scientifique, Belgium. MP is supported by FRSQ, CIHR and CCSRI., Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pole of Cardiovascular Pathology and Cliniques Universitaires Saint-Luc, INSERM, CNRS, Université Paris Descartes, Agence Nationale de la Recherche, Société Francophone du Diabète, Région Ile de France and Association pour la Recherche sur le Diabète, European Federation for the Study of Diabetes, Fonds National de la Recherche Scientifique et Médicale (Belgium), Actions de Recherche Concertées (Belgium), FRSQ, CIHR and CCSRI., ANR-10-BLAN-1123,AMPLOI,Thérapeutique des désordres métaboliques hépatiques: activation de l'AMPK et contrôle de la ploidie hépatocytaire(2010), Viollet, Benoit, Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL), McGill University - Jewish General Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), McGill University-Jewish General Hospital, and ANR-10-BLAN-1123, AMPLOI, Thérapeutique des désordres métaboliques hépatiques: activation de l'AMPK et contrôle de la ploidie hépatocytaire(2010)

Subjects
Drug, AMPK, Review paper, endocrine system diseases, medicine.drug_class, Physiology, media_common.quotation_subject, Type 2 diabetes, AMP-Activated Protein Kinases, Pharmacology, biguanide, Oxidative Phosphorylation, Diabetes mellitus, mitochondrial respiration, Animals, Humans, Hypoglycemic Agents, Medicine, cancer, metfomrin, Molecular Biology, media_common, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, treatment, diabetes, business.industry, Biguanide, cardiovascular, Gluconeogenesis, nutritional and metabolic diseases, Cell Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Metformin, cardiovascular diseases, Diabetes Mellitus, Type 2, Action (philosophy), Mechanism of action, type 2 diabetes, medicine.symptom, business, metformin, Energy Metabolism, glucose production, medicine.drug
Abstract

International audience; Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin’s mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying metformin action.

Published
2014

27. Diffusion of a collaborative care model in primary care: a longitudinal qualitative study

Author

Liette Lapointe, Joël Ankri, Véronique Ghadi, Christelle Routelous, Isabelle Vedel, Matthieu de Stampa, Howard Bergman, Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), EA Management des Organisations de Santé (EA MOS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut du Management (IDM), Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Matemática y Física - Universidad de Talca, Universidad de Talca, and EHESP, SCD

Subjects
Male, Care process, Time Factors, [SHS.SOCIO] Humanities and Social Sciences/Sociology, Collaborative Care, Nurses, 0302 clinical medicine, Health service research, Medicine, 030212 general & internal medicine, Longitudinal Studies, Cooperative Behavior, Qualitative Research, lcsh:R5-920, [SHS.SOCIO]Humanities and Social Sciences/Sociology, Social phenomenon, 030503 health policy & services, Opinion leadership, Middle Aged, Primary care, Primary care physician, [SHS.GESTION]Humanities and Social Sciences/Business administration, Female, [SHS.GESTION] Humanities and Social Sciences/Business administration, lcsh:Medicine (General), 0305 other medical science, Family Practice, Research Article, Adult, Paris, Physicians, Primary Care, Chronic disease, Critical mass (sociodynamics), Interviews as Topic, 03 medical and health sciences, Decision Theory, Nursing, Humans, Patient Care Team, Primary Health Care, business.industry, Collaboration, Leadership, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Models, Organizational, Diffusion of innovation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Qualitative research
Abstract

Background Although collaborative team models (CTM) improve care processes and health outcomes, their diffusion poses challenges related to difficulties in securing their adoption by primary care clinicians (PCPs). The objectives of this study are to understand: (1) how the perceived characteristics of a CTM influenced clinicians' decision to adopt -or not- the model; and (2) the model's diffusion process. Methods We conducted a longitudinal case study based on the Diffusion of Innovations Theory. First, diffusion curves were developed for all 175 PCPs and 59 nurses practicing in one borough of Paris. Second, semi-structured interviews were conducted with a representative sample of 40 PCPs and 15 nurses to better understand the implementation dynamics. Results Diffusion curves showed that 3.5 years after the start of the implementation, 100% of nurses and over 80% of PCPs had adopted the CTM. The dynamics of the CTM's diffusion were different between the PCPs and the nurses. The slopes of the two curves are also distinctly different. Among the nurses, the critical mass of adopters was attained faster, since they adopted the CTM earlier and more quickly than the PCPs. Results of the semi-structured interviews showed that these differences in diffusion dynamics were mostly founded in differences between the PCPs' and the nurses' perceptions of the CTM's compatibility with norms, values and practices and its relative advantage (impact on patient management and work practices). Opinion leaders played a key role in the diffusion of the CTM among PCPs. Conclusion CTM diffusion is a social phenomenon that requires a major commitment by clinicians and a willingness to take risks; the role of opinion leaders is key. Paying attention to the notion of a critical mass of adopters is essential to developing implementation strategies that will accelerate the adoption process by clinicians.

Published
2013

28. The Peroxisomal 3-keto-acyl-CoA thiolase B Gene Expression Is under the Dual Control of PPARα and HNF4α in the Liver

Author

Grégory Chevillard, Valérie Nicolas-Francès, Stéphane Mandard, F. Hansmannel, Frank J. Gonzalez, J. A. Bonzo, Thierry Pineau, Stephen A. Duncan, Michele A. Battle, Pascal G.P. Martin, J. Chamouton, Norbert Latruffe, Marie Claude Clémencet, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Laboratoire de Pharmacologie et Toxicologie, UR66, INRA, Institut National de la Recherche Agronomique (INRA), The Ministry of Research, National Education and Technology, the Regional Council of Burgundy, the GDR-CNRS no2583 on peroxisome, the French Ministry of Research, National Education and Technology., McGill University-Jewish General Hospital, Mandard, Stéphane, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, National Cancer Institute ( NIH ), Lady Davis Institute for Medical Research, McGill University, and Institut National de la Recherche Agronomique ( INRA )

Subjects
Article Subject, Response element, Peroxisome proliferator-activated receptor, Biology, 03 medical and health sciences, Transactivation, 0302 clinical medicine, Drug Discovery, Gene expression, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, SDV:BBM, Pharmacology (medical), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:QH301-705.5, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Transcription factor, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, chemistry.chemical_classification, Genetics, Endocrinology and metabolism, 0303 health sciences, Thiolase, Intron, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell biology, lcsh:Biology (General), Nuclear receptor, chemistry, 030220 oncology & carcinogenesis, Endocrinologie et métabolisme, Research Article
Abstract

PPARα and HNF4α are nuclear receptors that control gene transcription by direct binding to specific nucleotide sequences. Using transgenic mice deficient for either PPARα or HNF4α, we show that the expression of the peroxisomal3-keto-acyl-CoA thiolase B(Thb) is under the dependence of these two transcription factors. Transactivation and gel shift experiments identified a novel PPAR response element within intron 3 of theThbgene, by which PPARα but not HNF4α transactivates. Intriguingly, we found that HNF4α enhanced PPARα/RXRα transactivation from TB PPRE3 in a DNA-binding independent manner. Coimmunoprecipitation assays supported the hypothesis that HNF4α was physically interacting with RXRα. RT-PCR performed with RNA from liver-specific HNF4α-null mice confirmed the involvement of HNF4α in the PPARα-regulated induction ofThbby Wy14,643. Overall, we conclude that HNF4α enhances the PPARα-mediated activation ofThbgene expression in part through interaction with the obligate PPARα partner, RXRα.

Published
2010
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29. Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the haem binding properties of the protein

Author

Camille Dycke, Jacques Gaillard, Kostas Pantopoulos, Catherine M. Bougault, Jean-Pierre Andrieu, Jean-Marc Moulis, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Lady Davis Institute for Medical Research [Montréal], and McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital

Subjects
Proteolysis, Peptide, Heme, Cleavage (embryo), Biochemistry, Cofactor, 03 medical and health sciences, MESH: Iron Regulatory Protein 2, Ubiquitin, MESH: Spectrophotometry, Ultraviolet, MESH: Nuclear Magnetic Resonance, Biomolecular, medicine, Humans, MESH: Protein Binding, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Iron Regulatory Protein 2, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, MESH: Humans, medicine.diagnostic_test, biology, Hydrolysis, 030302 biochemistry & molecular biology, Electron Spin Resonance Spectroscopy, Life Sciences, Cell Biology, Nuclear magnetic resonance spectroscopy, Cytosol, chemistry, MESH: Heme, biology.protein, MESH: Electron Spin Resonance Spectroscopy, Spectrophotometry, Ultraviolet, MESH: Hydrolysis, Protein Binding, Research Article, Cysteine
Abstract

International audience; Mammalian Iron Regulatory Proteins, IRP1 and IRP2, are cytosolic RNA-binding proteins that post-transcriptionally control the mRNA of proteins involved in storage, transport, and utilization of iron. In iron-replete cells, IRP2 undergoes degradation by the ubiquitin/proteasome pathway. Binding of heme to a 73 amino acids domain (73aa-Domain) that is unique in IRP2 has been previously proposed as the initial iron-sensing mechanism. It is shown here that recombinant IRP2 and the 73aa-Domain are sensitive to proteolysis at the same site. Nuclear Magnetic Resonance data suggest that the isolated 73aa-Domain is not structured. Iron-independent cleavage of IRP2 within the 73aa-Domain also occurs in lung cancer (H1299) cells. Heme interacts with a cysteine residue only in truncated forms of the 73aa-Domain, as shown by a series of complementary physico-chemical approaches, including Nuclear Magnetic Resonance, Electron Paramagnetic Resonance, and ultra-violet visible absorption spectroscopy. In contrast, the cofactor is not ligated by the same residue in the full-length peptide or intact IRP2, although non specific interaction occurs between these molecular forms and heme. Therefore it is unlikely that the iron-dependent degradation of IRP2 is mediated by heme binding to the intact 73aa-Domain, since the sequence resembling a Heme Regulatory Motif in the 73aa-Domain does not provide an axial ligand of the cofactor unless this domain is cleaved.

Published
2007

30. Diabetes mellitus and cancer risk in a population-based case-control study among men from Montreal, Canada

Author

Rousseau, Marie-Claude, Parent, Marie-Elise, Pollak, Michael N, Siemiatycki, Jack, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Cancer Prevention Research Unit, Department of Oncology, McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Département de médecine sociale et préventive, and Université de Montréal (UdeM)

Subjects
Adult, Male, MESH: Quebec, Diabetes Complications, MESH: Liver Neoplasms, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Neoplasms, Odds Ratio, cancer, Humans, MESH: Neoplasms, Aged, MESH: Aged, MESH: Humans, MESH: Middle Aged, Liver Neoplasms, Quebec, MESH: Adult, Middle Aged, MESH: Case-Control Studies, MESH: Male, MESH: Odds Ratio, MESH: Diabetes Complications, Case-Control Studies, diabetes mellitus, populationbased, case-control
Abstract

International audience; Diabetics may have a higher risk of cancer, notably liver and pancreatic cancers. Evidence about other cancer types remains sparse. The authors examined potential associations between diabetes and several types of cancer in a large multicancer case-control project carried out in Montreal, Canada, in the 1980s. This report, based on 3,107 male cancer cases and 509 population controls, uses information on diabetes and several covariates collected by interview. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) were estimated for the associations between diabetes and each of 12 cancer types. Risks of pancreatic and liver cancers were increased among diabetics: adjusted ORs were 2.1 (95% CI: 1.0, 4.3) for pancreatic and 3.1 (95% CI: 1.1, 8.8) for liver cancer. The increased risk of pancreatic cancer was completely restricted to those with recent onset of diabetes; this was likely a manifestation of reverse causality. Conversely, the increased risk of liver cancer was independent of the interval between diabetes and cancer diagnoses. No associations were observed with melanoma, non-Hodgkin's lymphoma, cancers of the esophagus, stomach, colon, rectum, lung, prostate, bladder and kidney. In conclusion, diabetes was associated with an increased risk of liver cancer among men, but with no other cancer type including pancreatic cancer.

Published
2005

31. Systems Analysis of a RIG-I Agonist Inducing Broad Spectrum Inhibition of Virus Infectivity

Author

Zheng-Yun Xu, Suzanne Paz, Mark J. Cameron, Valérie Janelle, S. Mehdi Belgnaoui, Siddharth Balachandran, Stephanie Richards, Salman T. Qureshi, Marilène Paquet, John Hiscott, Suraj Peri, Khader Ghneim, Elias K. Haddad, Rafick Pierre Sekaly, Peter Wilkinson, Rongtuan Lin, Andrew Smith, Meztli Arguello, Alain Lamarre, Ulrich Kalinke, David Olagnier, Erin I. Lafferty, Marie-Line Goulet, Lady Davis Institute, McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, Division of Infectious Diseases, University of South Florida [Tampa] (USF), Division of Experimental Medicine, McGill University = Université McGill [Montréal, Canada]-Faculty of Medicine Montréal, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Comparative Medicine & Animal Resources Centre, McGill University = Université McGill [Montréal, Canada], Institute for Experimental Infection Research, Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Fox Chase Cancer Center, This research was supported by grants from Canadian Institutes of Health Research (www.cihr-irsc.gc.ca/e/795.html, PAP 99022) and the Ministère du Développement économique, de l'Innovation et de l'Exportation (www.mdeie.gouv.qc.ca, PSR-SIIRI-297) to RL and JH., and Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Canada.

Subjects
Pulmonology, Receptors, Retinoic Acid, Interferon Regulatory Factor-7, viruses, Dengue, Mice, Influenza A Virus, H1N1 Subtype, 0302 clinical medicine, RNA interference, Interferon, Immune Response, lcsh:QH301-705.5, Mice, Knockout, 0303 health sciences, biology, RIG-I, Genomics, Innate Immunity, 3. Good health, RNA, Viral/genetics, RNA silencing, STAT1 Transcription Factor, Influenza A Virus, H1N1 Subtype/immunology, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, Infectious diseases, RNA, Viral, Receptors, Retinoic Acid/agonists, RNA Interference, Immunotherapy, STAT1 Transcription Factor/metabolism, Interferon Regulatory Factor-7/metabolism, Research Article, Signal Transduction, medicine.drug, lcsh:Immunologic diseases. Allergy, Interferon Regulatory Factor-3/metabolism, Infectious Disease Control, HIV prevention, Immunology, Viral diseases, Antiviral Agents/pharmacology, Antiviral Agents, Microbiology, Virus, Cell Line, Immune Activation, Immunomodulation, 03 medical and health sciences, Orthomyxoviridae Infections, Virology, Genetics, medicine, Animals, Humans, Biology, Immunity to Infections, Molecular Biology, 030304 developmental biology, Inflammation, Immunity, HIV, Immune Defense, RNA virus, biology.organism_classification, Orthomyxoviridae Infections/drug therapy, Influenza, Immunity, Innate, Enzyme Activation, Mice, Inbred C57BL, lcsh:Biology (General), Respiratory Infections, IRF7, Clinical Immunology, Interferon Regulatory Factor-3, Parasitology, Genome Expression Analysis, lcsh:RC581-607, IRF3
Abstract

The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5′ triphosphate (5′ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5′pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN) signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5′pppRNA, and not by IFNα-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5′pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5′pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5′pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents., Author Summary Development of safe and effective drugs that inhibit virus replication remains a challenge. Activation of natural host defense using interferon (IFN) therapy has proven an effective treatment of certain viral infections. As a distinct variation on this concept, we analyzed the capacity of small RNA molecules that mimic viral components to trigger the host antiviral response and to inhibit the replication of several pathogenic human viruses. Using gene expression profiling, we identified robust antiviral and inflammatory gene signatures after treatment with a 5′-triphosphate containing RNA (5′pppRNA), including an integrated set of genes that is not regulated by IFN treatment. Delivery of 5′pppRNA into lung epithelial cells in vitro stimulated a strong antiviral immune response that inhibited the multiplication of several viruses. In a murine model of influenza infection, inoculation of the agonist protected animals from a lethal challenge of H1N1 influenza and inhibited virus replication in mouse lungs during the first 24–48 h after infection. This report highlights the therapeutic potential of naturally derived RIG-I agonists as potent stimulators of the innate antiviral response, with the capacity to block the replication of diverse human pathogenic viruses.

Published
2013

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