Author: "Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM )" - Searchworks@Jio Institute Digital Library Search Results

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524 results on '"Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM )"'

1. High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

Author: Arthur Sorlin, Antonio Vitobello, Benoit Daubail, Christel Thauvin-Robinet, Marie Hervieu-Bègue, Laurence Faivre, Agnès Fromont, Ange-Line Bruel, Frédéric Tran Mau-Them, Thibault Moreau, Julian Delanne, Guy-Victor Osseby, Quentin Thomas, Patrick Callier, Christophe Philippe, Sébastien Moutton, Maurice Giroud, Anne-Sophie Denommé-Pichon, Agnès Jacquin-Piques, Sophie Nambot, Yannis Duffourd, Philippine Garret, Y Béjot, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (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, Service de Neurophysiologie Clinique (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Proband, Pediatrics, medicine.medical_specialty, Movement disorders, Neurology, Neurodegeneration with brain iron accumulation, [SDV]Life Sciences [q-bio], Encephalopathy, Neurogenetics, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Genetics, Humans, Medicine, Exome, Clinical significance, 030212 general & internal medicine, Genetic Testing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Nervous System Diseases, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.
Published: 2021

2. Cystoid maculopathy is a frequent feature of Cohen syndrome-associated retinopathy

Author: Eléonore Lizé, Grazia M.S. Mancini, Christel Thauvin-Robinet, Vincent Lhussiez, Hélène Dollfus, Saddek Mohand-Said, Niyazi Acar, Xavier Zanlonghi, José-Alain Sahel, Pierre-Henry Gabrielle, Isabelle Audo, Emeline F. Nandrot, Laurence Duplomb, Catherine Creuzot-Garcher, Alberta A H J Thiadens, Yaumara Perdomo, Muhammad Ansar, Romain Da Costa, Christina Zeitz, Laurence Faivre, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), DHU Sight Restore [Paris], CHU Pontchaillou [Rennes], Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Institute of Molecular and Clinical Ophthalmology Basel [Basel, Switzerland] (IMCOB), Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne], Centre de Référence Déficiences Intellectuelles de Causes Rares [CHU Dijon] (CRDICR), Service d'Ophtalmologie (CHU de Dijon), 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, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institute of Molecular and Clinical Ophthalmology Basel, CH-4031 Basel, Switzerland, Jules Gonin Eye Hospital, Université de Lausanne = University of Lausanne (UNIL), Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon) (CRMR des déficiences intellectuelles de causes rares), the Conseil Régional de Bourgogne and the European Union through the Plan d'Actions Régional pour l'Innovation (PARI) and the PO FEDER-FSE Bourgogne 2014/2020 programs. This work is also supported by a research grant from the University of Pennsylvania Orphan Disease Center in partnership with COH1 Research Alliance (L.F., R.D.C., C.T., L.D.), and with funds from the JED Fondation (L.F.) as well as from Ville de Paris and Region Ile de France, LABEX LIFESENSES [reference ANR-10-LABX-65] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program [ANR-11-IDEX-0004–0], IHU FOReSIGHT [ANR-18-IAHU-0001] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program and Foundation Fighting Blindness center grant [C-CMM-0907–0428-INSERM04]., ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), Julien, Sabine, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, Ophthalmology, Clinical Genetics, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Lausanne (UNIL)
Subjects: Male, genetic structures, Developmental Disabilities, Macular Degeneration, 0302 clinical medicine, Myopia, Medicine, Young adult, Child, 0303 health sciences, Multidisciplinary, Retinal Degeneration, Medical genetics, Retinal diseases, 3. Good health, VPS13B, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Preschool, Cohort, Microcephaly, Muscle Hypotonia, Female, Tomography, Optical Coherence, Retinopathy, Adult, medicine.medical_specialty, Adolescent, Science, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Macular Edema, Article, Retina, Fingers, Young Adult, 03 medical and health sciences, Intellectual Disability, Ophthalmology, Humans, Obesity, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retrospective Studies, 030304 developmental biology, Cohen syndrome, business.industry, Dystrophy, Hereditary eye disease, medicine.disease, eye diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, Maculopathy, sense organs, business
Abstract: Cohen syndrome (CS) is a rare syndromic form of rod-cone dystrophy. Recent case reports have suggested that cystoid maculopathy (CM) could affect CS patients with an early onset and high prevalence. Our study aims at improving our understanding and management of CM in CS patients through a retrospective case series of ten CS patients with identified pathogenic variants in VPS13B. Longitudinal optical coherence tomography (OCT) imaging was performed and treatment with carbonic anhydrase inhibitors (CAI) was provided to reduce the volume of cystoid spaces. CM affected eight out of ten patients in our cohort. The youngest patient showed a strong progression of macular cysts from the age of 4.5 to 5 years despite oral CAI medication. Other teenage and young adult patients showed stable macular cysts with and without treatment. One patient showed a moderate decrease of cystoid spaces in the absence of treatment at 22 years of age. Through a correlative analysis we found that the volume of cystoid spaces was positively correlated to the thickness of peripheral and macular photoreceptor-related layers. This study suggests that CAI treatments may not suffice to improve CM in CS patients, and that CM may resolve spontaneously during adulthood as photoreceptor dystrophy progresses.
Published: 2021

3. Un nouvel acteur dans la perception gustative des lipides alimentaires : le canal calcique TRPC3

Author: Naim Akhtar Khan, Amira Sayed Khan, Aziz Hichami, Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), 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-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-Université de Bourgogne (UB), and Sciences, EDP
Subjects: [SDV] Life Sciences [q-bio], 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], General Medicine, Biology, Humanities, 030217 neurology & neurosurgery, General Biochemistry, Genetics and Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2021

4. Development of a new methodology to determine size differences of nanoparticles with nanoparticle tracking analysis

Author: Jean-Michel Rebibou, Gernot Zissel, Isabelle Severin, Gilbert Zanetta, Yann Pellequer, Marie-Christine Chagnon, Renaud Seigneuric, Fabrice Neiers, Pathologies et épithéliums : prévention, innovation, traitements, évaluation (EA 4267) (PEPITE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de néphrologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Derttech Packtox, 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)-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)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Freiburg University Medical Center, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), State University of New York (SUNY), and The Région Bourgogne Franche-Comté PARI (grant number 9201AAO050S01716), Ligue contre le Cancer (grant number R18032MM) and Nano2Bio and FEDER (Grant Number BG0005900).
Subjects: Materials Science (miscellaneous), In silico, Drug delivery system, Nanoparticle tracking analysis, Nanoparticle, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Extracellular vesicles, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Electrical and Electronic Engineering, Physical and Theoretical Chemistry, Cell Biology, Extracellular vesicle, 021001 nanoscience & nanotechnology, Atomic and Molecular Physics, and Optics, 0104 chemical sciences, 3. Good health, Liposome, Nanoscience, Proof of concept, Drug delivery, 0210 nano-technology, Biological system, Biotechnology
Abstract: International audience; The current frontiers in Biology thus in Medicine and Pharmacy are at the nanoscale. Indeed, this is the relevant scale for extracting or synthetizing, visualizing, counting, characterizing and/or modifying nanoparticles. Nanoparticles are highly diverse including: extracellular vesicles (e.g.: exosomes), proteins, viruses and nanovectors or drug delivery systems for instance. To quantify the concentration of nano-sized objects, a growing number of size-tracking instruments is being developed. However, to date, the generated data is only used to provide a concentration measurement. The objective of this study was to determine which sizes of nanoparticles are statistically significant between 2 groups of samples. Using different samples (in silico data; calibrated beads; various biological samples), an approach that statistically compares 2 groups of samples was developed and validated. The proof of concept of the proposed approach was illustrated with applications in the field of Biology, Medicine and Pharmacy using liposomes and extracellular vesicles. For the first time to our knowledge, our results suggest that the presented approach enables comparing different groups of biological samples. It may be extended to situations such as batch 1 versus batch 2; healthy versus disease or non-treated versus treated.
Published: 2021

5. Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Author: Erwan Garo, Charles Thomas, Kristina Schoonjans, Dany Gaillard, Maamar Souidi, Jacques Grober, Philippe Besnard, Jean-Paul Pais de Barros, David Masson, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University of Colorado Anschutz [Aurora], Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Radiobiologie des expositions accidentelles (IRSN/PSE-SANTE/SERAMED/LRAcc), Service de recherche en radiobiologie et en médecine régénérative (IRSN/PSE-SANTE/SERAMED), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratoire de Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Dijon, Institut Agro, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, Plateforme Lipidomique [Dijon] (LAP), 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)-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)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe NuTox (LNC - U1231) (NUTOX), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Muricholic acid, Drug Evaluation, Preclinical, Receptors, Cytoplasmic and Nuclear, Cholesterol, Dietary, chemistry.chemical_compound, 0302 clinical medicine, Biology (General), Spectroscopy, 2. Zero hunger, Kidney, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Bile acid, Chemistry, General Medicine, 3. Good health, Computer Science Applications, Blot, medicine.anatomical_structure, Cholesterol, FXR, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), LXR, medicine.medical_specialty, Oxysterol, QH301-705.5, medicine.drug_class, Hypercholesterolemia, Article, Catalysis, Bile Acids and Salts, Inorganic Chemistry, 03 medical and health sciences, In vivo, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Physical and Theoretical Chemistry, Liver X receptor, QD1-999, Molecular Biology, Organic Chemistry, Cholic Acids, Bile acids, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. Methods: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. Results: Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. Conclusions: These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia.
Published: 2021

6. The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancer

Author: Le Corre, Delphine, Ghazi, Alexandre, Balogoun, Ralyath, Pilati, Camilla, Aparicio, Thomas, Martin-Lannerée, Séverine, Marisa, Laetitia, Djouadi, Fatima, Poindessous, Virginie, Crozet, Carole, Emile, Jean-François, Mulot, Claire, Le Malicot, Karine, Boige, Valérie, Blons, Hélène, De Reyniès, Aurélien, Taïeb, Julien, Ghiringhelli, François, Bennouna, Jaafar, Launay, Jean-Marie, Laurent-Puig, Pierre, Mouillet-Richard, Sophie, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Paris-Saclay, Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), F. Hoffmann-La Roche [Basel], École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint Louis [APHP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, 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-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, 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, Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut de Cancérologie de l'Ouest, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Adult, Male, Research paper, Epithelial-Mesenchymal Transition, animal diseases, Hippo pathway, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Kaplan-Meier Estimate, Protein Serine-Threonine Kinases, Prion Proteins, Transforming Growth Factor beta, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cell Line, Tumor, mental disorders, Animals, Humans, Hippo Signaling Pathway, RNA, Messenger, Aged, Aged, 80 and over, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, TGFß pathway, Middle Aged, Prognosis, Colorectal cancer, nervous system diseases, Prion protein, Molecular classification, Female, Colorectal Neoplasms, Biomarkers, Signal Transduction
Abstract: International audience; BACKGROUND: Comprehensive transcriptomic analyses have shown that colorectal cancer (CRC) is heterogeneous and have led to the definition of molecular subtypes among which the stem-cell, mesenchymal-like group is associated with poor prognosis. The molecular pathways orchestrating the emergence of this subtype are incompletely understood. In line with the contribution of the cellular prion protein PrPC to stemness, we hypothesize that deregulation of this protein could lead to a stem-cell, mesenchymal-like phenotype in CRC.METHODS:We assessed the distribution of the PrPC-encoding PRNP mRNA in two large CRC cohorts according to molecular classification and its association with patient survival. We developed cell-based assays to explore the impact of gain and loss of PrPC function on markers of the mesenchymal subtype and to delineate the signalling pathways recruited by PrPC. We measured soluble PrPC in the plasmas of 325 patients with metastatic CRC and probed associations with disease outcome.FINDINGS: We found that PRNP gene expression is enriched in tumours of the mesenchymal subtype and is associated with poor survival. Our in vitro analyses revealed that PrPC controls the expression of genes that specify the mesenchymal subtype through the recruitment of the Hippo pathway effectors YAP and TAZ and the TGFß pathway. We showed that plasma levels of PrPC are elevated in metastatic CRC and are associated with poor disease control.INTERPRETATION: Our findings define PrPC as a candidate driver of the poor-prognosis mesenchymal subtype of CRC. They suggest that PrPC may serve as a potential biomarker for patient stratification in CRC.FUNDING: Grant support was provided by the following: Cancéropôle Ile de France (grant number 2016-1-EMERG-36-UP 5-1), Association pour la Recherche sur le Cancer (grant number PJA 20171206220), SATT Ile de France Innov (grant number 415) as well as INSERM.
Published: 2019

7. How to make a tongue: Cellular and molecular regulation of muscle and connective tissue formation during mammalian tongue development

Author: Hadeel Adel Al-Lami, Karen J. Liu, Sachiko Iseki, Martyn T. Cobourne, Guilherme M. Xavier, Christel Thauvin-Robinet, Anahid A. Birjandi, Department of Craniofacial Development & Orthodontics, London Dental Institute (LDI), King‘s College London-King‘s College London, Section of Molecular Craniofacial Embryology (Graduate School of Tokyo Medical and Dental University), Department of Orthodontics (University of Baghdad College of Dentistry), University of Baghdad, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Organogenesis, Hedgehog signaling, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Bifid tongue, Mesoderm, Wnt, 03 medical and health sciences, 0302 clinical medicine, Cranial neural crest, Tongue, Macroglossia, medicine, Animals, Humans, TGF-beta, Hedgehog, Mammals, Aglossia, Muscles, Myogenesis, Gene Expression Regulation, Developmental, Cell Biology, Anatomy, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Connective Tissue, Neural Crest, Embryology, Gross anatomy, medicine.symptom, 030217 neurology & neurosurgery, Signal Transduction, Developmental Biology
Abstract: IF 6.614 (2016); International audience; The vertebrate tongue is a complex muscular organ situated in the oral cavity and involved in multiple functions including mastication, taste sensation, articulation and the maintenance of oral health. Although the gross embryological contributions to tongue formation have been known for many years, it is only relatively recently that the molecular pathways regulating these processes have begun to be discovered. In particular, there is now evidence that the Hedgehog, TGF-Beta, Wnt and Notch signaling pathways all play an important role in mediating appropriate signaling interactions between the epithelial, cranial neural crest and mesodermal cell populations that are required to form the tongue. In humans, a number of congenital abnormalities that affect gross morphology of the tongue have also been described, occurring in isolation or as part of a developmental syndrome, which can greatly impact on the health and well-being of affected individuals. These anomalies can range from an absence of tongue formation (aglossia) through to diminutive (microglossia), enlarged (macroglossia) or bifid tongue. Here, we present an overview of the gross anatomy and embryology of mammalian tongue development, focusing on the molecular processes underlying formation of the musculature and connective tissues within this organ. We also survey the clinical presentation of tongue anomalies seen in human populations, whilst considering their developmental and genetic etiology.
Published: 2019

8. Innovative Magnetic Nanoparticles for PET/MRI Bimodal Imaging

Author: Thomas, Guillaume, Boudon, Julien, Maurizi, Lionel, Moreau, Mathieu, Walker, Paul, Séverin, Isabelle, Oudot, Alexandra, Goze, Christine, Poty, Sophie, Vrigneaud, Jean-Marc, Demoisson, Frédéric, Denat, Franck, Brunotte, François, Millot, Nadine, Laboratoire Interdisciplinaire Carnot de Bourgogne [Dijon] (LICB), Université de Bourgogne (UB)-Université de Technologie de Belfort-Montbeliard (UTBM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme d'imagerie préclinique [Centre Georges-François Leclerc] (CGFL), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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-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, and Dijon, Institut Agro
Subjects: lcsh:Chemistry, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, lcsh:QD1-999, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, technology, industry, and agriculture, Nanoparticles, Imaging agents, Tomography, Article, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Nanostructures
Abstract: International audience; Superparamagnetic iron oxide nanoparticles were developed as positron emission tomography (PET) and magnetic resonance imaging (MRI) bimodal imaging agents. These nanoparticles (NPs), with a specific nanoflower morphology, were first synthesized and simultaneously functionalized with 3,4-dihydroxy-l-phenylalanine (LDOPA) under continuous hydrothermal conditions. The resulting NPs exhibited a low hydrodynamic size of 90 ± 2 nm. The functional groups of LDOPA (-NH2 and -COOH) were successfully used for the grafting of molecules of interest in a second step. The nanostructures were modified by poly(ethylene glycol) (PEG) and a new macrocyclic chelator MANOTA for further ⁶⁴Cu radiolabeling for PET imaging. The functionalized NPs showed promising bimodal (PET and MRI) imaging capability with high r2 and r2∗ (T2 and T2∗ relaxivities) values and good stability. They were mainly uptaken from liver and kidneys. No cytotoxicity effect was observed. These NPs appear as a good candidate for bimodal tracers in PET/MRI.
Published: 2019

9. Impact of time-varying cumulative bevacizumab exposures on survival: re-analysis of data from randomized clinical trial in patients with metastatic colo-rectal cancer

Author: Michal Abrahamowicz, Adrien Guilloteau, Karine Le Malicot, Olayidé Boussari, Thomas Aparicio, Christine Binquet, Valérie Jooste, Catherine Quantin, Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), McGill University = Université McGill [Montréal, Canada], Fédération Francophone de la Cancérologie Digestive, FFCD, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Université de Bourgogne (UB)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Malbec, Odile, 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-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, Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses (B2PHI), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, medicine.medical_specialty, Randomization, Bevacizumab, Survival, Epidemiology, [SDV]Life Sciences [q-bio], Cumulative Exposure, Health Informatics, 01 natural sciences, law.invention, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Time varying cumulative exposure to maintenance treatment, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, 0101 mathematics, lcsh:R5-920, Cumulative dose, Proportional hazards model, business.industry, Rectal Neoplasms, Hazard ratio, Confounding, Colorectal cancer, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Colonic Neoplasms, business, lcsh:Medicine (General), Colorectal Neoplasms, medicine.drug, Research Article
Abstract: Background As cancer treatment, biotherapies can be as effective as chemotherapy while reducing the risk of secondary effects, so that they can be taken over longer periods than conventional chemotherapy. Thus, some trials aimed at assessing the benefit of maintaining biotherapies during chemotherapy-free intervals (CFI). For example, the recent PRODIGE9 trial assessed the effect of maintaining bevacizumab during CFI in metastatic colorectal cancer (mCRC) patients. However, its analysis was hindered by a small difference of exposure to the treatment between the randomized groups and by a large proportion of early drop outs, leading to a potentially unbalanced distribution of confounding factors among the trial completers. To address these limitations, we re-analyzed the PRODIGE9 data to assess the effects of different exposure metrics on all-cause mortality of patients with mCRC using methods originally developed for observational studies. Methods To account for the actual patterns of drug use by individual patients and for possible cumulative effects, we used five alternative time-varying exposure metrics: (i) cumulative dose, (ii) quantiles of the cumulative dose, (iii) standardized cumulative dose, (iv) Theoretical Blood Concentration (TBC), and (v) Weighted Cumulative Exposure (WCE). The last two metrics account for the timing of drug use. Treatment effects were estimated using adjusted Hazard Ratio from multivariable Cox proportional hazards models. Results After excluding 112 patients who died during the induction period, we analyzed data on 382 patients, among whom 320 (83.8%) died. All time-varying exposures improved substantially the model’s fit to data, relative to using only the time-invariant randomization group. All exposures indicated a protective effect for higher cumulative bevacizumab doses. The best-fitting WCE and TBC models accounted for both the cumulative effects and the different impact of doses taken at different times. Conclusions All time-varying analyses, regardless of the exposure metric used, consistently suggested protective effects of higher cumulative bevacizumab doses. However, the results may partly reflect the presence of a confusion bias. Complementing the main ITT analysis of maintenance trials with an analysis of potential cumulative effects of treatment actually taken can provide new insights, but the results must be interpreted with caution because they do not benefit from the randomization. Trial registration clinicaltrials.gov, NCT00952029. Registered 8 August 2009.
Published: 2021

10. Impact of the polycarbonate strippers used in assisted reproduction techniques on embryonic development

Author: C Naylies, Y Lippi, M Guilleman, Patricia Fauque, N. Gatimel, Véronique Gayrard, G Tavenier, A A Huesca, Jean Parinaud, Roger Leandri, Jessika Moreau, CHU Toulouse [Toulouse], Groupe de recherche en fertilité humaine ( GRFH), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), UMS006 Service d'Experimentation Animale, Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, 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, Université Bourgogne Franche-Comté [COMUE] (UBFC), Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Chronic exposure, bisphenol A, [SDV]Life Sciences [q-bio], Preimplantation Embryos, Biology, Andrology, Embryo Culture Techniques, 03 medical and health sciences, 0302 clinical medicine, In vivo, Pregnancy, medicine, Humans, Blastocyst, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, Zygote, Polycarboxylate Cement, Rehabilitation, Embryogenesis, Obstetrics and Gynecology, Embryo, ARTs, Embryonic stem cell, Europe, medicine.anatomical_structure, Reproductive Medicine, polycarbonate, embryonic development, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Female, transcriptome
Abstract: STUDY QUESTION Do daily manipulations of preimplantation embryos with polycarbonate (PC)—made bisphenol A (BPA)—releasing strippers influence embryo development? SUMMARY ANSWER Compared to glass strippers, PC strippers enhance the blastocyst development rate but this does not seem to be BPA-related. WHAT IS KNOWN ALREADY PC strippers have been shown to release tiny amounts (around 0.5 ng/ml BPA) of BPA in routine human IVF procedures. A chronic exposure to BPA either in vivo or in vitro during the preimplantation period can impact post-implantation and post-natal development. BPA can act rapidly by binding to membrane receptors and inducing rapid non-genomic effects. STUDY DESIGN, SIZE, DURATION This experimental study using mouse embryos had a balanced design and blinded evaluations of the endpoints. PARTICIPANTS/MATERIALS, SETTING, METHODS In vivo fertilized zygotes were obtained from outbred Swiss CD1 mice crossings after an ovarian stimulation. The zygotes were allocated to three daily handling conditions (HCs) and cultured until Day 4 in a single human commercial medium. Each day, the embryos were handled for 20 s either in a PC stripper (HC1) or in a glass stripper (HC2). In HC3, the embryos were pre-exposed to 0.5 ng/ml BPA before being handled for 20 s in a glass stripper. Handling operations were repeated on Days 1, 2 and 3. Embryo development was assessed blindly on Day 4. Expanded blastocysts were selected for a transcriptomic analysis using Agilent Sureprint G3 Mouse GE v2 microarrays and the retrotransposon LINE1-Orf2 expression was analysed using qRT-PCR, as a proxy for a global evaluation of the epigenetic status. MAIN RESULTS AND THE ROLE OF CHANCE Compared to the embryos manipulated in HC2 (n = 243), those in HC1 (n = 228) developed significantly more often to the blastocyst stage (55 vs 46%; P LARGE SCALE DATA https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE148868. LIMITATIONS, REASONS FOR CAUTION Our results using a mouse model designed to mimic human conditions (outbred strain, human commercial IVF dishes and a unique commercial human embryonic culture media) are reassuring since no gene was found to be differentially expressed, including LINE-1 genes, as a proxy for a global evaluation of the epigenetic status. However, no global epigenetic analysis of the genome has been performed. Furthermore, we did not evaluate post-implantation events, although BPA exposure during peri-conception could affect foeto-placental and post-natal development. WIDER IMPLICATIONS OF THE FINDINGS Based on the precautionary principle, several European countries banned the use of BPA in baby bottles and food packaging several years before European Agencies took an official position. The question of applying this principle to plastics in closed contact with human embryos is raised. Further studies are needed for a decision to be made. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a grant from the Agence de Biomédecine (AOR 2016). The authors declare no competing interest.
Published: 2021

11. Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Author: Matalonga, Leslie, Hernández-Ferrer, Carles, DITF-ITHACA, Solve-RD, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cohen, Enzo, DITF-euroNMD, Solve-RD, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G, Horvath, Rita, Houlden, Henry, Johari, Mridul, Lau, Jarred, Lochmüller, Hanns, DITF-RND, Solve-RD, Macken, William L, Musacchia, Francesco, Nascimento, Andres, Natera-de Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D S, Polavarapu, Kiran, Cruz, Pedro M Rodriguez, Tonda, Raul, Sarkozy, Anna, Savarese, Marco, Selvatici, Rita, Thompson, Rachel, Udd, Bjarne, Van de Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Balicza, Peter, Laurie, Steven, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Fernandez-Callejo, Marcos, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Schüle-Freyer, Rebecca, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, Picó, Daniel, van de Warrenburg, Bart, van Os, Nienke, Wayand, Melanie, Wilke, Carlo, Haack, Tobias B, Graessner, Holm, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Garcia-Linares, Carles, Sturm, Marc, Schulze-Hentrich, Julia M, Kessler, Christoph, Heutink, Peter, Brunner, Han, Scheffer, Hans, Papakonstantinou, Anastasios, Hoogerbrugge, Nicoline, 't Hoen, Peter A C, Steyaert, Wouter, Sablauskas, Karolis, Te Paske, Iris, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Corvó, Alberto, Brookes, Anthony J, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Piscia, Davide, Joshi, Ricky, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Duffourd, Yannis, Tisserant, Emilie, Diez, Hector, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Bullich, Gemma, Gut, Ivo, Corvo, Alberto, Garcia, Carles, Hernández, Carles, Paramonov, Ida, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hoischen, Alexander, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Consortia, Solve-RD, Spalding, Dylan, Senf, Alexander, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, de Jonghe, Peter, Banfi, Sandro, Torella, Annalaura, Cuesta, Isabel, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A, Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B, group, Solve-RD SNV-indel working, Denommé-Pichon, Anne-Sophie, Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F Javier Alonso García, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Gilissen, Christian, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Beeson, David, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Li, Shuang, Prasanth, Sivakumar, Robinson, Peter, van der Velde, Joeri K, de Voer, Richarda M, Evans, Gareth, Sommer, Anna Katharina, Töpf, Ana, Paske, Iris Te, Tischkowitz, Marc, Casari, Giorgio, Ciolfi, Andrea, Dallapiccola, Bruno, de Boer, Elke, Vissers, Lisenka E L M, Hammarsjö, Anna, Havlovicova, Marketa, Hugon, Anne, de Voer, Richarda, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, DITF-GENTURIS, Solve-RD, Posada, Manuel, Ryba, Lukas, Schwarz, Martin, Trimouille, Aurélien, Solve RD SNV Indel Working Grp, Solve RD DITF GENTURIS, Solve RD DITF ITHACA, Solve RD DITF-euroNMD, Solve RD DITF RND, Solve RD Consortia, Matalonga, L., Hernandez-Ferrer, C., Piscia, D., Cohen, E., Cuesta, I., Danis, D., Denomme-Pichon, A. -S., Duffourd, Y., Gilissen, C., Johari, M., Laurie, S., Li, S., Nelson, I., Peters, S., Paramonov, I., Prasanth, S., Robinson, P., Sablauskas, K., Savarese, M., Steyaert, W., van der Velde, J. K., Vitobello, A., Schule, R., Synofzik, M., Topf, A., Vissers, L. E. L. M., de Voer, R., Aretz, S., Capella, G., de Voer, R. M., Evans, G., Pelaez, J. G., Holinski-Feder, E., Hoogerbrugge, N., Laner, A., Oliveira, C., Rump, A., Schrock, E., Sommer, A. K., Steinke-Lange, V., Paske, I., Tischkowitz, M., Valle, L., Banka, S., Benetti, E., Casari, G., Ciolfi, A., Clayton-Smith, J., Dallapiccola, B., de Boer, E., Ellwanger, K., Faivre, L., Graessner, H., Haack, T. B., Hammarsjo, A., Havlovicova, M., Hoischen, A., Hugon, A., Jackson, A., Kleefstra, T., Lindstrand, A., Lopez-Martin, E., Macek, M., Morleo, M., Nigro, V., Nordgren, A., Pettersson, M., Pinelli, M., Pizzi, S., Posada, M., Radio, F. C., Renieri, A., Rooryck, C., Ryba, L., Schwarz, M., Tartaglia, M., Thauvin, C., Torella, A., Trimouille, A., Verloes, A., Vissers, L., Votypka, P., Vyshka, K., Zurek, B., Baets, J., Beijer, D., Bonne, G., Cossins, J., Evangelista, T., Ferlini, A., Hackman, P., Hanna, M. G., Horvath, R., Houlden, H., Lau, J., Lochmuller, H., Macken, W. L., Musacchia, F., Nascimento, A., Natera-de Benito, D., Piluso, G., Pini, V., Pitceathly, R. D. S., Polavarapu, K., Cruz, P. M. R., Sarkozy, A., Selvatici, R., Thompson, R., Udd, B., Van de Vondel, L., Vandrovcova, J., Zaharieva, I., Balicza, P., Chinnery, P., Durr, A., Haack, T., Hengel, H., Kamsteeg, E. -J., Kamsteeg, C., Lohmann, K., Macaya, A., Marce-Grau, A., Maver, A., Molnar, J., Munchau, A., Peterlin, B., Riess, O., Schols, L., Schule-Freyer, R., Stevanin, G., Timmerman, V., van de Warrenburg, B., van Os, N., Wayand, M., Wilke, C., Tonda, R., Fernandez-Callejo, M., Pico, D., Garcia-Linares, C., Papakonstantinou, A., Corvo, A., Joshi, R., Diez, H., Gut, I., Beltran, S., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Kessler, C., Heutink, P., Brunner, H., Scheffer, H., 't Hoen, P. A. C., te Paske, I., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Alexander, E., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Bullich, G., Garcia, C., Hernandez, C., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Allamand, V., Yaou, R. B., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Kremlik, V., Parkinson, H., Keane, T., Spalding, D., Senf, A., Robert, G., Costa, A., Patch, C., Hanna, M., Reilly, M., Muntoni, F., de Jonghe, P., Banfi, S., Rossi, R., Neri, M., Spier, I., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Castello, R., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Molnar, M. J., Herzog, R., Pauly, M., Osorio, A. N., de Benito, D. N., Beeson, D., Unión Europea. Comisión Europea. H2020, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), Government of Catalonia (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto Nacional de Bioinformatica (España), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Instituto de Salud Carlos III [Madrid] (ISC), Radboud University Medical Center [Nijmegen], Lipides - Nutrition - Cancer [Dijon - U1231] (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, Equipe GAD (LNC - U1231), 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-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, Barcelona Institute of Science and Technology (BIST), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Folkhälsan Research Center, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Myologie, University of Helsinki, Department of Medical and Clinical Genetics, Medicum, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Genetic testing, Computer science, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], EXOME, MEDICAL GENETICS, Diseases, Disease, VARIANTS, Genome informatics, Genomic analysis, Diseases, Genetic testing, Genome informatics, Genomic analysis, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Genetics (clinical), Exome sequencing, 0303 health sciences, Application programming interface, methods [Genomics], 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Pedigree, diagnosis [Rare Diseases], Chemistry, Medical genetics, medicine.medical_specialty, methods [Genetic Testing], MEDLINE, Socio-culturale, Phenome, AMERICAN-COLLEGE, INHERITANCE, Sensitivity and Specificity, Article, standards [Genetic Testing], 03 medical and health sciences, Rare Diseases, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetics, medicine, Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Data science, Workflow, 3111 Biomedicine, standards [Genomics], Human medicine, Software
Abstract: Correction to: Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. Eur J Hum Genet. 2021 Sep;29(9):1466-1469. doi: 10.1038/s41431-021-00934-6. PMID: 34393220 Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. We also acknowledge the support of the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement and the Co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. Sí
Published: 2021

12. Comparative Effects of Di-(2-ethylhexyl)phthalate and Di-(2-ethylhexyl)terephthalate Metabolites on Thyroid Receptors: In Vitro and In Silico Studies

Author: Valérie Sautou, Marie-Christine Chagnon, Laurence Dahbi, Nicolas Kambia, Isabelle Severin, Emmanuel Moreau, Amaury Farce, Thierry Dine, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), CHU Clermont-Ferrand, SIGMA Clermont (SIGMA Clermont), Institut de Chimie de Clermont-Ferrand (ICCF), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and COLO, Mouniati
Subjects: 0301 basic medicine, Agonist, endocrine system, medicine.drug_class, Endocrinology, Diabetes and Metabolism, lcsh:QR1-502, hormonal activities, 010501 environmental sciences, 01 natural sciences, Biochemistry, Partial agonist, Article, lcsh:Microbiology, 03 medical and health sciences, chemistry.chemical_compound, medicine, T-screen assay, Receptor, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Molecular Biology, 0105 earth and related environmental sciences, Chemistry, Phthalate, DEHT, thyroid receptors, In vitro, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, 030104 developmental biology, Endocrine disruptor, Hormone receptor, in silico, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Hormone
Abstract: International audience; Plasticizers added to polyvinylchloride (PVC) used in medical devices can be released into patients’ biological fluids. Di-(2-ethylhexyl)phthalate (DEHP), a well-known reprotoxic and endocrine disruptor, must be replaced by alternative compounds. Di-(2-ethylhexyl) terephthalate (DEHT) is an interesting candidate due to its lower migration from PVC and its lack of reprotoxicity. However, there is still a lack of data to support the safety of its human metabolites with regard to their hormonal properties in the thyroid system. The effects of DEHT metabolites on thyroid/hormone receptors (TRs) were compared in vitro and in silico to those of DEHP. The oxidized metabolites of DEHT had no effect on T3 receptors whereas 5-hydroxy-mono-(ethylhexyl)phthalate (5-OH-MEHP) appeared to be primarily an agonist for TRs above 0.2 µg/mL with a synergistic effect on T3. Monoesters (MEHP and mono-(2-ethylhexyl)terephthalate, MEHT) were also active on T3 receptors. In vitro, MEHP was a partial agonist between 10 and 20 µg/mL. MEHT was an antagonist at non-cytotoxic concentrations (2–5 µg/mL) in a concentration-dependent manner. The results obtained with docking were consistent with those of the T-screen and provide additional information on the preferential affinity of monoesters and 5-OH-MEHP for TRs. This study highlights a lack of interactions between oxidized metabolites and TRs, confirming the interest of DEHT.
Published: 2021

13. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author: Anne Miret, Lola Lemasson, Benjamin Cogné, Laurence Perrin, Frédéric Tran Mau-Them, Rémi Mathevet, Marion Boucon, Elise Schaefer, Christel Thauvin-Robinet, Christine Juif, Juliette Piard, Solène Bourgouin, Jenny Cornaton, Bertrand Isidor, Catherine Sarret, Fabienne Prieur, Coralie Gonin-Olympiade, Alexandra Afenjar, Christine Coubes, Boris Keren, Bénédicte Gérard, Catherine Vincent-Delorme, Kim Giraudat, Laurence Faivre, Amélie Piton, Antonio Vitobello, Thomas Smol, Annick Toutain, Arthur Sorlin, Sylvie Odent, Yann Trousselet, Fanny Tessier, Martin Chevarin, David Geneviève, Sébastien Moutton, Anne-Claire Gelineau, Ange-Line Bruel, Claire Nicolas, Aurore Garde, Philippe Khau-Van-Kien, Christophe Philippe, Solveig Heide, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Etienne, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, [SDV]Life Sciences [q-bio], Neurocognitive Disorders, Transposases, Neuropsychological Tests, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, [SCCO]Cognitive science, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Global developmental delay, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Dysexecutive syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Neuropsychology, Genetic Variation, medicine.disease, 3. Good health, Developmental disorder, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Mutation, Autism, Female, France, business, Neurocognitive
Abstract: White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.
Published: 2020

14. Hepatic transcriptome and DNA methylation patterns following perinatal and chronic BPS exposure in male mice

Author: Axelle, Brulport, Daniel, Vaiman, Elias, Bou-Maroun, Marie-Christine, Chagnon, Ludovic Le, Corre, Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Physico-Chimie de l'Aliment et du Vin (PCAV), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: Male, DNA methylation, lcsh:QH426-470, Bisphenol S, lcsh:Biotechnology, Perinatal and chronic exposure, Phosphatidate Phosphatase, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mice, lcsh:Genetics, Phenols, Liver, Pregnancy, lcsh:TP248.13-248.65, Animals, Female, Sulfones, Benzhydryl Compounds, Transcriptome, hormones, hormone substitutes, and hormone antagonists, Research Article
Abstract: Background Bisphenol S (BPS) is a common bisphenol A (BPA) substitute, since BPA is virtually banned worldwide. However, BPS and BPA have both endocrine disrupting properties. Their effects appear mostly in adulthood following perinatal exposures. The objective of the present study was to investigate the impact of perinatal and chronic exposure to BPS at the low dose of 1.5 μg/kg body weight/day on the transcriptome and methylome of the liver in 23 weeks-old C57BL6/J male mice. Results This multi-omic study highlights a major impact of BPS on gene expression (374 significant deregulated genes) and Gene Set Enrichment Analysis show an enrichment focused on several biological pathways related to metabolic liver regulation. BPS exposure also induces a hypomethylation in 58.5% of the differentially methylated regions (DMR). Systematic connections were not found between gene expression and methylation profile excepted for 18 genes, including 4 genes involved in lipid metabolism pathways (Fasn, Hmgcr, Elovl6, Lpin1), which were downregulated and featured differentially methylated CpGs in their exons or introns. Conclusions This descriptive study shows an impact of BPS on biological pathways mainly related to an integrative disruption of metabolism (energy metabolism, detoxification, protein and steroid metabolism) and, like most high-throughput studies, contributes to the identification of potential exposure biomarkers. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12864-020-07294-3.
Published: 2020

15. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Author: Katharina Steindl, Alain Verloes, Cornelia Kraus, Rachel Fisher, Katrin Õunap, Amber Begtrup, Steffen Syrbe, Theresa Brunet, Antonio Vitobello, Laurence Faivre, Reza Asadollahi, Jessica Becker, Maja Hempel, Dave A Dyment, Christiane Zweier, John H McDermott, Bernt Popp, Elaine Suk-Ying Goh, Lynette G. Sadleir, Anaïs Begemann, Siddharth Banka, Gwenaël Le Guyader, Elisabeth Schuler, Anne-Sophie Denommé-Pichon, Kathleen Brown, Gaetan Lesca, Frédéric Tran Mau-Them, Lucia Ribeiro Machado Haertel, Maryline Carneiro, Amelie Theresa Van der Ven, Markus Zweier, Hartmut Engels, Heinrich Sticht, Theresia Herget, Jessika Johannsen, Bader Alhaddad, Nadine N. Hauer, Robert C. Day, Tiia Reimand, M. J. Hajianpour, Manuel Schiff, Kirsty McWalter, Margarita Saenz, Tatjana Bierhals, Pierre Meyer, Ange-Line Bruel, Martina Russo, Korbinian M. Riedhammer, Kirsten Cremer, Anita Rauch, Marjolaine Willems, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Robert Debré
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, WAVEregulatory complex (WRC), 030105 genetics & heredity, Biology, Article, Intellectual disability, Epilepsy, CYFIP2, WAVE-regulatory complex (WRC), WASF, 03 medical and health sciences, Neurodevelopmental disorder, Seizures, medicine, Missense mutation, Humans, Genetics(clinical), Gene, Genetics (clinical), Actin, Adaptor Proteins, Signal Transducing, Genetics, medicine.disease, Actin cytoskeleton, Phenotype, Hypotonia, Actins, 3. Good health, ddc, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neurodevelopmental Disorders, intellectual disability, epilepsy, medicine.symptom
Abstract: International audience; Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype–phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
Published: 2020

16. Multigenerational study of the obesogen effects of bisphenol S after a perinatal exposure in C57BL6/J mice fed a high fat diet

Author: Guillaume Maquart, Aurélie Dastugue, Virginie Barbet, Ludovic Le Corre, Marie-Christine Chagnon, Daniel Vaiman, Isabelle Severin, Axelle Brulport, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe NuTox (LNC - U1231) (NUTOX), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-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, Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: medicine.medical_specialty, 010504 meteorology & atmospheric sciences, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, Adipose tissue, 010501 environmental sciences, Toxicology, Diet, High-Fat, 01 natural sciences, chemistry.chemical_compound, Mice, NEFA, Phenols, Pregnancy, Low dose exposure, Internal medicine, medicine, Lipolysis, Animals, Obesogen, Sulfones, Peri-natal exposure, 0105 earth and related environmental sciences, 2. Zero hunger, Triglyceride, business.industry, General Medicine, medicine.disease, Pollution, Endocrinology, Transgenerational effects, chemistry, Endocrine disruptor, Prenatal Exposure Delayed Effects, Lipogenesis, Female, business, Dyslipidemia
Abstract: International audience; Background : Bisphenol S is an endocrine disruptor exhibiting metabolic disturbances, especially following perinatal exposures. To date, no data are available on the obesogen effects of BPS in a mutligenerational issue.Objectives : We investigated obesogen effects of BPS in a multigenerational study by focusing on body weight, adipose tissue and plasma parameters in male and female mice.Methods : Pregnant C57BL6/J mice were exposed to BPS (1.5 μg/kg bw/day ie a human equivalent dose of 0.12 μg/kg bw/day) by drinking water from gestational day 0 to post natal day 21. All offsprings were fed with a high fat diet during 15 weeks. Body weight was monitored weekly and fat mass was measured before euthanasia. At euthanasia, blood glucose, insuline, triglyceride, cholesterol and no esterified fatty acid plasma levels were determined and gene expressions in visceral adipose tissue were assessed. F1 males and females were mated to obtain the F2 generation. Likewise, the F2 mice were cross-bred to obtain F3. The same analyses were performed.Results : In F1 BPS induced an overweight in male mice associated to lipolysis gene expressions upregulation. In F1 females, dyslipidemia was observed. In F2, BPS exposure was associated to an increase in body weight, fat and VAT masses in males and females. Several plasma parameters were increased but with a sex related pattern (blood glucose, triglycerides and cholesterol in males and NEFA in females). We observed a down-regulation in mRNA expression of gene involved in lipogenesis and in lipolysis for females but only in the lipogenesis for males. In F3, a decrease in VAT mass and an upregulation of lipogenesis gene expression occurred only in females.Conclusions : BPS perinatal exposure induced sex-dependent obesogen multigenerational effects, the F2 generation being the most impacted. Transgenerational disturbances persisted only in females.
Published: 2020

17. Modeling excess hazard with time‐to‐cure as a parameter

Author: Laurent Remontet, Valérie Jooste, Olayidé Boussari, Marc Colonna, Nadine Bossard, Laurent Bordes, Gaëlle Romain, Registre Bourguignon des Cancers Digestifs, 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)-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)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Registre du Cancer de l’Isère, Grenoble University Hospital, Grenoble, France, Réseau Français des Registres de Cancers, FRANCIM, Toulouse, France, Fédération Francophone de Cancérologie Digestive, Département de Méthodologie, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Statistics and Probability, Hazard (logic), Computer science, Maximum likelihood, Probability density function, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, 010104 statistics & probability, 03 medical and health sciences, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Neoplasms, Econometrics, Humans, Fraction (mathematics), 0101 mathematics, ComputingMilieux_MISCELLANEOUS, Proportional Hazards Models, 030304 developmental biology, Event (probability theory), Simple (philosophy), Estimation, Likelihood Functions, 0303 health sciences, Models, Statistical, General Immunology and Microbiology, Applied Mathematics, Regression analysis, General Medicine, Survival Analysis, 3. Good health, General Agricultural and Biological Sciences
Abstract: Cure models have been widely developed to estimate the cure fraction when some subjects never experience the event of interest. However, these models were rarely focused on the estimation of the time-to-cure, that is, the delay elapsed between the diagnosis and "the time from which cure is reached," an important indicator, for instance, to address the question of access to insurance or loans for subjects with personal history of cancer. We propose a new excess hazard regression model that includes the time-to-cure as a covariate-dependent parameter to be estimated. The model is written similarly to a Beta probability distribution function and is shown to be a particular case of the non-mixture cure models. Parameters are estimated through a maximum likelihood approach and simulation studies demonstrate good performance of the model. Illustrative applications to three cancer data sets are provided and some limitations as well as possible extensions of the model are discussed. The proposed model offers a simple and comprehensive way to estimate more accurately the time-to-cure.
Published: 2020

18. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Author: Tania Attié-Bitach, Philippe Jonveaux, Alice Goldenberg, Antonio Vitobello, Nicole Laurent, Marjolaine Willems, Valérie Kremer, Dominique Gaillard, Chloé Quélin, Sebastien Moutton, Marion Aubert-Lenoir, Yannis Duffourd, Anne-Sophie Lebre, Anne-Claire Brehin, James Lespinasse, Yline Capri, Nolwenn Jean-Marçais, Maria Cristina Antal, Frédéric Tran Mau-Them, Nathalie Marle, Daphné Lehalle, Nicolas Bourgon, Sophie Blesson, Bernard Foliguet, Laetita Lambert, Nicole Bigi, Mélanie Fradin, Emilie Tisserant, Christel Thauvin-Robinet, Ange-Line Bruel, Elisabeth Alanio, Marie-Hélène Saint-Frison, Christine Francannet, Anne-Marie Guerrot, Paul Kuentz, Elise Schaefer, Anne-Marie Beaufrere, Sylvie Odent, Francine Arbez-Gindre, Laurence Faivre, Christophe Philippe, Julien Thevenon, Sophie Patrier-Sallebert, Nada Houcinat, Celine Poirisier, Sophie Nambot, Mathilde Lefebvre, Mirna Assoum, Françoise Girard-Lemaitre, Sophie Collardeau-Frachon, Marie-José Perez, Jean-Louis Mandel, Jean-Pierre Mazutti, Renaud Touraine, Philippe Loget, Salima El Chehadeh, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), European Organization for Nuclear Research (CERN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Métropole Savoie [Chambéry], CHU Saint-Etienne, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire [Grenoble] (CHU), CarMeN, laboratoire, 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, 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-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, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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 Hospitalier Régional Universitaire de Tours (CHRU Tours), 14-013 FOETEX, Interregional French PHRC, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Candidate gene, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Biology, Congenital Abnormalities, Cohort Studies, complex traits, 03 medical and health sciences, Fetus, Molecular genetics, medicine, Humans, Abnormalities, Multiple, Exome, Clinical significance, genetics, Gene, Genetic Association Studies, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, 030305 genetics & heredity, Sequence Analysis, DNA, Phenotype, [SDV] Life Sciences [q-bio], molecular genetics, reproductive medicine
Abstract: PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.
Published: 2020

19. NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients

Author: Laurence Perrin, Silvia Cappello, Francesco Neri, Arthur Sorlin, Philippe Khau Van Kien, Ludovico D'Incerti, Françoise Devillard, Rossella Di Giaimo, Paul Kuentz, Agnès Loubat, Marjolaine Willems, Laurence Faivre, Frédéric Tran Mau-Them, Salvatore Oliviero, Michèle Studer, Anna Lisa Romano, Christophe Philippe, Michele Bertacchi, Carolina Frassoni, Aurore Garde, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Robert Debré Paris, Hôpital Robert Debré, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique biologique histologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Université de Naples, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Bertacchi, Michele, Romano, Anna Lisa, Loubat, Agnè, Tran Mau-Them, Frederic, Willems, Marjolaine, Faivre, Laurence, Khau van Kien, Philippe, Perrin, Laurence, Devillard, Françoise, Sorlin, Arthur, Kuentz, Paul, Philippe, Christophe, Garde, Aurore, Neri, Francesco, Di Giaimo, Rossella, Oliviero, Salvatore, Cappello, Silvia, D'Incerti, Ludovico, Frassoni, Carolina, and Studer, Michèle
Subjects: cell cycle dynamics, PAX6 Transcription Factor, [SDV]Life Sciences [q-bio], cell cycle dynamic, Neocortex, Biology, Regenerative Medicine, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Neural Stem Cells, Optic Atrophies, Hereditary, Parietal Lobe, Cortex (anatomy), BBSOAS, medicine, Animals, Humans, Molecular Biology, Gyrification, 030304 developmental biology, 0303 health sciences, COUP Transcription Factor I, General Immunology and Microbiology, General Neuroscience, Neurogenesis, Articles, Human brain, NR2F1/COUP-TFI, cortical folding, medicine.disease, Disease Models, Animal, neurodevelopmental disease, medicine.anatomical_structure, NR2F1/COUP‐TFI, Occipital Lobe, PAX6, Haploinsufficiency, Development & Differentiation, Neuroscience, 030217 neurology & neurosurgery
Abstract: The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra‐Bosch‐Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss‐of‐function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria‐like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long‐term self‐renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area‐specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification., Reduced levels of the neuronal differentiation factor NR2F1/COUP‐TFI impairs brain cortex folding in humans, and disrupts regional neural progenitor dynamics in the neocortex of a BBSOAS disease mouse model.
Published: 2020

20. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome

Author: Gerarda Cappuccio, Camille Sayou, Pauline Le Tanno, Emilie Tisserant, Ange-Line Bruel, Sara El Kennani, Joaquim Sá, Karen J. Low, Cristina Dias, Markéta Havlovicová, Miroslava Hančárová, Evan E. Eichler, Françoise Devillard, Sébastien Moutton, Julien Van-Gils, Christèle Dubourg, Sylvie Odent, Bénédicte Gerard, Amélie Piton, Toshiyuki Yamamoto, Nobuhiko Okamoto, Helen Firth, Kay Metcalfe, Anna Moh, Kimberly A. Chapman, Erfan Aref-Eshghi, Jennifer Kerkhof, Annalaura Torella, Vincenzo Nigro, Laurence Perrin, Juliette Piard, Gwenaël Le Guyader, Thibaud Jouan, Christel Thauvin-Robinet, Yannis Duffourd, Jaya K. George-Abraham, Catherine A. Buchanan, Denise Williams, Usha Kini, Kate Wilson, Nicola Brunetti-Pierri, Giorgio Casari, Michele Pinelli, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Valeria Capra, Giancarlo Parenti, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Sandro Banfi, Marcella Zollino, Mario Montomoli, Donatelli Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, Claudia Santoro, Angela Peron, Chiara Pantaleoni, Raffaele Castello, Stefano D’Arrigo, Sérgio B. Sousa, Raoul C.M. Hennekam, Bekim Sadikovic, Julien Thevenon, Jérôme Govin, Antonio Vitobello, Università degli studi di Napoli Federico II, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Motol [Prague], University of Washington [Seattle], Centre Hospitalier Universitaire [Grenoble] (CHU), Université de Bordeaux (UB), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), London Health Sciences Center (LHSC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), GSP15001, Fondazione Telethon, 209568/Z/17/Z, Wellcome Trust, Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, M., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., University of Naples Federico II = Università degli studi di Napoli Federico II, 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, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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-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, General Paediatrics, APH - Quality of Care, and Brunetti-Pierri, Nicola
Subjects: Foot Deformities, Foot Deformities, Congenital, [SDV]Life Sciences [q-bio], Biology, Blepharophimosis, Settore MED/03 - GENETICA MEDICA, Hypotrichosis, Chromatin remodeling, 03 medical and health sciences, Congenital, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, SMARCA2, medicine, Humans, Gene, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, BIS, Facies, medicine.disease, Phenotype, neurodevelopmental disorder, Nicolaides–Baraitser syndrome, intellectual disability, DNA methylation, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.
Published: 2020

21. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author: Julien Van-Gils, Kyoko Takano, Victor P. Pedro, Lauren Brick, Pascale Saugier-Veber, Tugce B. Balci, Antonio Vitobello, Marielle Alders, Justine Rousseau, Frédéric Laumonnier, Christel Thauvin-Robinet, Raoul C.M. Hennekam, Tjitske Kleefstra, Matt Tedder, Jennifer Kerkhof, Damien Sanlaville, Gaël Nicolas, François Lecoquierre, Delphine Héron, Hanxin Lin, Sophie Rondeau, Mariya Kozenko, Simone Pizzi, Alexandra Afenjar, Victoria Mok Siu, Christèle Dubourg, David Geneviève, Erfan Aref-Eshghi, Solveig Heide, Barbara R. DuPont, Peter Ainsworth, David I. Rodenhiser, Boris Keren, Nicole de Leeuw, Sandra Whalen, Martine Raynaud, Damien Ulveling, Nathalie Ruiz-Pallares, Valérie Cormier-Daire, Mouna Barat-Houari, Michael A. Levy, Roger E. Stevenson, Jennifer A. Lee, Steven A. Skinner, Alan Graham Stuart, Laurence Faivre, Marie Shaw, Gaetan Lesca, Peter Henneman, Thierry Bienvenu, Marco Tartaglia, Charles E. Schwartz, Andrea Ciolfi, Michael J. Friez, Michael Field, Mike Kadour, Guillaume Velasco, Jozef Gecz, Claire Francastel, Didier Lacombe, Philippe M. Campeau, Jean-Christophe Andrau, Bekim Sadikovic, Marcel M.A.M. Mannens, Jennifer Masters, Cyril Mignot, Patricia Fergelot, Nicolas Chatron, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, General Paediatrics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Quality of Care, London Health Sciences Center (LHSC), Schulich School of Medicine and Dentistry, University of Western Ontario (UWO), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Bordeaux (UB), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Medical Center [Amsterdam], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases [IRCSS San Raffaele Scientific Institute, Milan], IRCCS San Raffaele Scientific Institute [Milan, Italie], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Cytogénétique et Embryologie [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), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Sainte Justine [Montréal], McMaster University [Hamilton, Ontario], University of Tasmania [Hobart, Australia] (UTAS), Shinshu University Hospital, Radboud University Medical Center [Nijmegen], Hunter Genetics, University of Notre Dame [Indiana] (UND), University of South Australia [Adelaide], The Greenwood Genetic Center, Greenwood Genetic Center [Greenwood, South Carolina, USA], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Amsterdam Reproduction and Development Institute, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre épigénétique et destin cellulaire (EDC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Computational biology, 030105 genetics & heredity, Biology, Pediatrics, Article, Cohort Studies, molecular diagnostics, 03 medical and health sciences, symbols.namesake, Genetic Heterogeneity, Gene duplication, Genetics, Humans, Hunter-McAlpine syndrome, Genetics (clinical), Mass screening, 030304 developmental biology, EpiSign, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DNA methylation, Genetic heterogeneity, 030305 genetics & heredity, Correction, Syndrome, DNA Methylation, Molecular diagnostics, Phenotype, Penetrance, Human genetics, 3. Good health, episignature, genomic DNA, 030104 developmental biology, Neurodevelopmental Disorders, uncertain clinical cases, Mendelian inheritance, symbols, Identification (biology), VUS classification
Abstract: Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access) Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.
Published: 2020

22. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20

Author: Anne-Sophie Denommé-Pichon, Laetitia Gouas, Martin Chevarin, Marlène Rio, Elodie Gautier, Sonia Bouquillon, Nolwenn Jean-Marçais, Jennifer Fabre-Teste, Dominique Martin, Elise Schaefer, Fabienne Giuliano, Didier Lacombe, Sophie Nambot, Gaëlle Vieville, Sophie Blesson, Paul Kuentz, Christine Francannet, Yannis Duffourd, Aurélien Juven, Alice Masurel, Patrick Callier, Arnold Munnich, Salima El Chehadeh, Sophie Rondeau, Christophe Philippe, Amélie Piton, Fanny Laffargue, Catherine Vincent Delorme, Marie Vincent, Olivier Pichon, Bénédicte Gérard, Anne-Laure Mosca-Boidron, Bertrand Isidor, Christel Thauvin-Robinet, Laurence Perrin-Sabourin, Nathalie Marle, Cédric Le Caignec, Laurence Faivre, Hubert Journel, Klaus Dieterich, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de cytogénétique (CHU de Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique-Hôpitaux de Paris, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Génétique Médicale, Hôpital Civil, Strasbourg, DGA Maîtrise de l'information (DGA.MI), Direction générale de l'Armement (DGA), Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Hôpital l'Archet, Service de Génétique Médicale, Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), FHU TRANSLAD (CHU de Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), 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, 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-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, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut cellule souche et cerveau (SBRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Adolescent, Hearing loss, [SDV]Life Sciences [q-bio], Mutation, Missense, Nerve Tissue Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioinformatics, Article, Corpus Callosum, 03 medical and health sciences, Ectopic calcification, Ptosis, Intellectual Disability, Genetics, Medicine, Missense mutation, Humans, Abnormalities, Multiple, Child, Ear Diseases, Wasting, Genetics (clinical), Muscle contracture, 0303 health sciences, business.industry, 030305 genetics & heredity, Macrocephaly, Calcinosis, medicine.disease, Primrose syndrome, Muscular Atrophy, Phenotype, Child, Preschool, Chromosomes, Human, Pair 3, medicine.symptom, Chromosome Deletion, business, Transcription Factors
Abstract: International audience; Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.
Published: 2020

23. Genome sequencing in cytogenetics: Comparison of short‐read and linked‐read approaches for germline structural variant detection and characterization

Author: Uguen, Kévin, Jubin, Claire, Duffourd, Yannis, Bardel, Claire, Malan, Valérie, Dupont, Jean‐Michel, El Khattabi, Laila, Chatron, Nicolas, Vitobello, Antonio, Rollat‐Farnier, Pierre‐Antoine, Baulard, Céline, Lelorch, Marc, Leduc, Aurelie, Tisserant, Emilie, Tran Mau‐Them, Frédéric, Danjean, Vincent, Délépine, Marc, Till, Marianne, Meyer, Vincent, LYONNET, Stanislas, Mosca‐Boidron, Anne‐laure, Thevenon, Julien, Faivre, Laurence, Thauvin‐Robinet, Christel, Schluth‐Bolard, Caroline, Boland, Anne, Olaso, Robert, Callier, Patrick, Romana, Serge, Deleuze, Jean‐François, Sanlaville, Damien, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Centre Albert Trillat [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Performance analysis and optimization of LARge Infrastructures and Systems (POLARIS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Pôle Couple-Enfant, Département de Génétique et Procréation, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Eco-Anthropologie et Ethnobiologie (EAE), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Interactions Arbres-Microorganismes (IAM), Université de Lorraine (UL)-Institut National de la Recherche Agronomique (INRA), Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Laboratoire Information, Milieux, Médias, Médiations - EA 3820 (I3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Université de Toulon (UTLN), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service d'Histologie-Embryologie et Cytogénétique Assistance Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: Whole Genome Sequencing, lcsh:QH426-470, Method, structural variants, Chromosome Disorders, bioinformatics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], genome sequencing, Cytogenetics, lcsh:Genetics, 10X Genomics: Illumina, Intellectual Disability, Genomic Structural Variation, Humans, Abnormalities, Multiple, Genetic Testing, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS
Abstract: Background Structural variants (SVs) include copy number variants (CNVs) and apparently balanced chromosomal rearrangements (ABCRs). Genome sequencing (GS) enables SV detection at base‐pair resolution, but the use of short‐read sequencing is limited by repetitive sequences, and long‐read approaches are not yet validated for diagnosis. Recently, 10X Genomics proposed Chromium, a technology providing linked‐reads to reconstruct long DNA fragments and which could represent a good alternative. No study has compared short‐read to linked‐read technologies to detect SVs in a constitutional diagnostic setting yet. The aim of this work was to determine whether the 10X Genomics technology enables better detection and comprehension of SVs than short‐read WGS. Methods We included 13 patients carrying various SVs. Whole genome analyses were performed using paired‐end HiSeq X sequencing with (linked‐read strategy) or without (short‐read strategy) Chromium library preparation. Two different bioinformatic pipelines were used: Variants are called using BreakDancer for short‐read strategy and LongRanger for long‐read strategy. Variant interpretations were first blinded. Results The short‐read strategy allowed diagnosis of known SV in 10/13 patients. After unblinding, the linked‐read strategy identified 10/13 SVs, including one (patient 7) missed by the short‐read strategy. Conclusion In conclusion, regarding the results of this study, 10X Genomics solution did not improve the detection and characterization of SV., We compared linked‐read and short‐read sequencing in patients with structural variants. We conclude that linked‐read strategy did not improve the detection and characterization of structural variants.
Published: 2020

24. Age-Related Changes in the Gut Microbiota Modify Brain Lipid Composition

Author: Mayssa Albouery, Bénédicte Buteau, Stéphane Grégoire, Claire Cherbuy, Jean-Paul Pais de Barros, Lucy Martine, Florian Chain, Stéphanie Cabaret, Olivier Berdeaux, Alain M. Bron, Niyazi Acar, Philippe Langella, Marie-Agnès Bringer, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AgroParisTech, Equipe LIPNESS (LNC - U1231) (LIPNESS), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Agence Nationale de la Recherche [ANR-11-LABX-0021-01], INRA, Conseil Régional Bourgogne, Franche-Comté [PARI grant], and FEDER (European Funding for Regional Economical Development), Fondation de France/Fondation de l'oeil., ProdInra, Migration, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Fatty Acid Desaturases, Male, 0301 basic medicine, lcsh:QR1-502, Gene Expression, Gut flora, lcsh:Microbiology, Fatty Acids, Monounsaturated, Mice, Cellular and Infection Microbiology, Aging brain, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Original Research, chemistry.chemical_classification, Fatty Acids, Age Factors, Brain, Lipids, cortex, Infectious Diseases, Fatty Acids, Unsaturated, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Sphingomyelin, Stearoyl-CoA Desaturase, Polyunsaturated fatty acid, Microbiology (medical), medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Fatty Acid Elongases, FADS1, FADS2, 030106 microbiology, Immunology, Biology, liver, digestive system, Microbiology, 03 medical and health sciences, lipid, Internal medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, microbiota, Animals, Germ-Free Life, phospholipid, aging, Fatty acid, cholesterol, Lipid Metabolism, biology.organism_classification, Gastrointestinal Microbiome, Transplantation, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, Endocrinology, chemistry, fatty acid, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: PMCID: PMC6970973; International audience; Understanding the molecular mechanisms underlying the changes observed during aging is a prerequisite to design strategies to prevent age-related diseases. Aging is associated with metabolic changes, including alteration in the brain lipid metabolism. These alterations may contribute to the development of pathophysiological conditions. Modifications in the gut microbiota composition are also observed during aging. As communication axes exist between the gut microbiota and the brain and knowing that microbiota influences the host metabolism, we speculated on whether age-associated modifications in the gut microbiota could be involved in the lipid changes observed in aging brain. For that purpose, germ-free mice were colonized by the fecal microbiota of young or old donor mice. Lipid classes and fatty acid profiles were determined in the brain (cortex), plasma and liver by thin-layer chromatography on silica gel-coated quartz rods and gas chromatography. Gut colonization by microbiota of old mice resulted in a significant increase in total monounsaturated fatty acids (MUFA) and a significant decrease in the relative amounts of cholesterol and total polyunsaturated fatty acids (PUFA) in the cortex. Among the eight most represented fatty acids in the cortex, the relative abundances of five (C18:1n-9, C22:6n-3, C20:4n-6, C18:1n-7, and C20:1n-9) were significantly altered in mice inoculated with an aged microbiota. Liquid chromatography analyses revealed that the relative abundance of major species among phosphatidyl and plasmenylcholine (PC 16:0/18:1), phosphatidyl and plasmenylethanolamine (PE 18:0/22:6), lysophosphatidylethanolamine (LPE 22:6) and sphingomyelins (SM d18:1/18:0) were significantly altered in the cortex of mice colonized by the microbiota obtained from aged donors. Transplantation of microbiota from old mice also modified the lipid class and fatty acid content in the liver. Finally, we found that the expression of several genes involved in MUFA and PUFA synthesis (Scd1, Fads1, Fads2, Elovl2, and Elovl5) was dysregulated in mice inoculated with an aged microbiota. In conclusion, our data suggest that changes in gut microbiota that are associated with aging can impact brain and liver lipid metabolisms. Lipid changes induced by an aged microbiota recapitulate some features of aging, thus pointing out the potential role of microbiota alterations in the age-related degradation of the health status.
Published: 2020
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25. A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis

Author: Dominique Bonneau, Bruno Delobel, Catherine Boileau, Guillaume Jondeau, Christine Coubes, Jean-Luc Alessandri, Laurence Faivre, V. Carmignac, Sylvie Odent, Pauline Arnaud, Christel Thauvin-Robinet, Nadine Hanna, Caroline Racine, Carine Le Goff, Julien Thevenon, Laurent Gouya, Jill Clayton-Smith, Sophie Dupuis-Girod, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Université de Paris, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Grenoble, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Manchester [Manchester], Hôpital Lapeyronie [Montpellier] (CHU), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Hospices Civils de Lyon (HCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), 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, Burgundy Regional Council through the Plan d'Actions Regional pour l'Innovation (PARI 2015), European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs, Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, Proband, Marfan syndrome, Connective Tissue Disorder, Adolescent, [SDV]Life Sciences [q-bio], Context (language use), Biology, Marfan Syndrome, Craniosynostoses, 03 medical and health sciences, Proto-Oncogene Proteins, Intellectual disability, Genetics, medicine, Humans, Pathology, Molecular, Craniofacial, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, Marfanoid, Middle Aged, medicine.disease, Human genetics, 3. Good health, DNA-Binding Proteins, Arachnodactyly, Child, Preschool, Mutation, Female
Abstract: International audience; SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
Published: 2020

26. Épidémiologie des tumeurs neuroendocrines intestinales

Author: C. Lepage, Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon )
Subjects: Gynecology, medicine.medical_specialty, business.industry, Incidence, Gastroenterology, 030209 endocrinology & metabolism, Tumeur neuroendocrine intestinale, Prévalence, Épidémiologie, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Internal Medicine, Medicine, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, business, Tumeur carcinoïde
Abstract: International audience; Few data are available about the epidemiology of digestive neuroendocrine tumours (NETs). Malignant digestive (MD) NETs remain as a rare cancer representing 1 % of digestive cancers. In France, the incidence rates of MD-NETs are estimated to around 1.1/100,000 inhabitants in males and 0.9/100,000 in females which then increased over time, with probably more than 1,000 new cases per year. Due to the relative good prognosis, NETs are the second more prevalent digestive cancer next to colorectal cancer. Most gastroenteropancreatic NETs are well-differentiated (WD-NETs); poorly differentiated neuroendocrine carcinomas (PDNEC) account for less than 20% of the cases in most of the series. Among WD-NETs, the most frequent anatomical localisations are small bowel and pancreas. Functional NETs are rare (< 20%); most of them are carcinoids, insulinomas and gastrinomas. More than half NETs are metastatic at diagnosis, mainly in the liver. Tumour differentiation, histologic grade, anatomic site and stage are the main prognostic factors. WD-NETs are slow-growing tumours (relative survival rate of 55% in 5 years), whereas PDNEC are highly aggressive (relative survival rate of 4.5% in 5 years).; Peu de données sont disponibles concernant l'incidence et les facteurs pronostiques des tumeurs neuroendocrines (TNE) digestives malignes. Les TNE sont rares et représentent environ 1 % des cancers digestifs. En France, l'incidence des TNE digestives malignes est estimée dans le registre Bourguignon à 1,1/100 000 chez l'homme et à 0,9/100 000 chez la femme. L'incidence augmente au cours du temps. Du fait de leur longue survie, les TNE constituent, après le cancer colorectal, le cancer digestif dont la prévalence est la plus élevée. La plupart des TNE sont bien différenciées, les carcinomes neuroendocrines peu différenciés représentent moins de 20 % des TNE digestives. Parmi les TNE bien différenciées, les localisations les plus fréquentes sont l'intestin grêle et le pancréas. Plus de la moitié des TNE sont diagnostiquées au stade métastatique, principalement au niveau hépatique. Le degré de différenciation, le grade histologique, la localisation du primitif et le stade sont les principaux facteurs pronostiques. Les taux de survie relative à cinq ans étaient de 4,5 % pour les tumeurs peu différenciées versus plus de 55 % pour les TNE bien différenciées.
Published: 2020

27. The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author: Amy McTague, Siddharth Srivastava, Tamison Jewett, Ali Al-Beshri, Constance Smith-Hicks, Shelagh Joss, Jennifer A. Sullivan, Sarju G. Mehta, Koenraad Devriendt, Pascal Joset, Laurence Faivre, Emma Kivuva, William G. Wilson, Gunnar Houge, Naama Orenstein, Yana Hoorne, Vickie L. Hannig, Malou Heijligers, Bart Loeys, Vandana Shashi, Katrina Prescott, Iris Verbinnen, Annick Toutain, Lauren M. Baldwin, Stephen P. Fulton, Katharina Steindl, Anne Marie Childs, Anna Chassevent, Shelley Towner, Cornelia Daumer-Haas, Oded Wechsberg, Alison Male, Hannah F. Johnson, Wendy K. Chung, Anita Rauch, Anna Ruiz, Isabelle Maystadt, Sara Reynhout, Sébastien Moutton, Yvette van Ierland, Veerle Janssens, Frédéric Laumonnier, Martina Baethmann, Lisa Lenaerts, Vani Jain, Vinod Varghese, Suzanne M. Koudijs, Elisabeth Gabau, Frédérique Bonnet-Brilhault, Rizwan Hamid, Susan E. Holder, Barbara Plecko, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Queen Elizabeth University Hospital (Glasgow), Kennedy Krieger Institute [Baltimore], University of Antwerp (UA), Universität Zürich [Zürich] = University of Zurich (UZH), Addenbrooke’s Hospital [Cambridge, UK], Columbia University Medical Center (CUMC), Columbia University [New York], North West Thames Regional Genetics Service [London, UK] (Harrow), North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow-Northwick Park Hospital [Harrow, UK] (NPH), Wake Forest University, University of Virginia [Charlottesville], Boston Children's Hospital, Prenatal Medicine Munich [Munich, Germany] (PMM), Klinikum Dritter Orden [Munich], Universitat Autònoma de Barcelona (UAB), University Hospital of Wales [Cardiff, UK], University of Alabama at Birmingham [ Birmingham] (UAB), Le Bonheur Children's Hospital [Memphis, TN, USA] (LBCH), Schneider Children’s Medical Center of Israel [Petah Tikva], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Leeds Teaching Hospitals NHS Trust, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Duke University Medical Center, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Royal Devon and Exeter NHS Foundation Trust [UK], Great Ormond Street Institute of Child Health [London, UK] (UCL), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University Graz, Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Haukeland University Hospital, University of Bergen (UiB), Leuven Brain Institute [Leuven, Belgium] (LBI), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), 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-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, Clinical Genetics, University of Virginia, University Hospital of Wales (UHW), Tel Aviv University (TAU), Great Ormond Street Institute of Child Health (UCL), and Laumonnier, Frédéric
Subjects: 0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Intellectual disability, 030105 genetics & heredity, Bioinformatics, Epilepsy, Neurodevelopmental disorder, CORE, Protein Phosphatase 2, SPECIFICITY, Genetics (clinical), PROTEIN PHOSPHATASE 2A, Phenotype, Hypotonia, FAMILY, 3. Good health, PP2A, [SDV] Life Sciences [q-bio], PPP2R1A, PPP2R5D, INSIGHTS, intellectual disability, Muscle Hypotonia, medicine.symptom, Language delay, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, business.industry, Macrocephaly, DEPHOSPHORYLATION, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, SUBUNIT, epilepsy, Human medicine, TAU, business, Transcription Factors
Abstract: PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported. ispartof: Genetics In Medicine vol:23 issue:2 ispartof: location:United States status: Published online
Published: 2020

28. Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Author: Florence Petit, Clémence Vanlerberghe, Thomas Smol, Fabienne Giuliano, M.F. Odou, Sylvie Manouvrier-Hanu, Perrine Brunelle, William Dufour, Malika Balduyck, Fabienne Escande, Jamal Ghoumid, Marion Gérard, Philippe Khau Van Kien, Gilles Morin, Cindy Colson, Alice Goldenberg, Elise Brischoux-Boucher, Anne Dieux, Daphné Lehalle, Anne-Sophie Jourdain, Sébastien Moutton, Simon Boussion, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de dynamique des systèmes neuroendocriniens, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Laboratoire Pierre Süe (LPS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pôle de Biologie Pathologie Génétique [CHU Lille], Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Génétique [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), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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-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, Inserm, Université de Lille, Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Maladies RAres du DÉveloppement embryonnaire et du Métabolisme : du phénotype au génotype et à la Fonction (RADEME) - ULR 7364, CIC CHU ( Lille)/inserm, Centre Hospitalier Régional Universitaire de Besançon [CHRU Besançon], Service de Génétique Clinique [CHU Caen], Université de Lausanne = University of Lausanne [UNIL], Hôpital Universitaire Carémeau [Nîmes] [CHU Nîmes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon], Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME], and Richard, Nicolas
Subjects: Male, Candidate gene, limb malformation, molecular diagnosis, targeted high-throughput sequencing, genetics, DNA Copy Number Variations, DNA Mutational Analysis, Limb Deformities, Congenital, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Real-Time Polymerase Chain Reaction, Bioinformatics, DNA sequencing, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Multiplex, Genetic Testing, Uncertain significance, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Likely pathogenic, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, Phenotype, 3. Good health, Radiography, Clinical Practice, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female
Abstract: International audience; Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high-throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3-year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy-number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high-throughput sequencing works as an efficient and cost-effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.
Published: 2020

29. Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia

Author: J. Küsel, Julien Thevenon, Emmanuelle Bourrat, Steffen Hörer, Rudolf Happle, Lisa Heinz, Pierre Vabres, Svenja Alter, Alrun Hotz, Andreas Zimmer, Judith Fischer, Fakultät für Biologie = Faculty of Biology [Freiburg], Albert-Ludwigs-Universität Freiburg, Center for Human Genetics Freiburg, Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD (CHU de Dijon), University of Freiburg [Freiburg], Department of Dermatology, University Medical Center Freiburg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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-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, and FHU TRANSLAD
Subjects: Adult, Zygote, DNA Mutational Analysis, Dermatology, Biology, Postzygotic mutation, medicine.disease_cause, PORCN, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Missense mutation, Goltz syndrome, Skin, Genetics, Mutation, Mosaicism, Mouth Mucosa, Genetic disorder, High-Throughput Nucleotide Sequencing, Membrane Proteins, cutaneous mosaicism, Karyotype, medicine.disease, Focal dermal hypoplasia, 3. Good health, focal dermal hypoplasia, Female, Klinefelter syndrome, Acyltransferases, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Focal dermal hypoplasia (FDH, Goltz syndrome, MIM: #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In males, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are males presenting either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is thereby of practical importance to analyse DNA from the affected skin in order to identify low level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads. This article is protected by copyright. All rights reserved.
Published: 2018

30. Pathology of Rotavirus-driven Multiple Organ Failure in a 16-month-old Boy

Author: Patrick Callier, Georges Tarris, Alexis de Rougemont, Frédéric Huet, Laurent Martin, Gaël Belliot, Laboratoire de sérologie-virologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre National de Référence des virus entériques [CHU de Dijon] (CNR virus entériques), Service de Pathologie [CHU de Dijon], Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])
Subjects: Microbiology (medical), Male, Rotavirus, Fatal outcome, Multiple Organ Failure, Autopsy, medicine.disease_cause, Rotavirus Infections, 03 medical and health sciences, 0302 clinical medicine, Fatal Outcome, Antigen, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030225 pediatrics, medicine, Humans, 030212 general & internal medicine, Human histo-blood group antigens, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Fetal Growth Retardation, Growth retardation, business.industry, Rotavirus severe acute gastroenteritis, Infant, virus diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Nephrons, Acute gastroenteritis, Acute Kidney Injury, Shock, Septic, 3. Good health, Gastroenteritis, Rotavirus infection, Infectious Diseases, Pediatrics, Perinatology and Child Health, Immunology, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Autopsy investigation of a fatal case of rotavirus severe acute gastroenteritis and multiple organ failure in a 16-month boy with previous intrauterine growth retardation showed colocalization of nonstructural and structural rotavirus proteins within viroplasms in nephrons. This case brings new insights into extraintestinal rotavirus infection and new clues to its abilities to bind to human histo-blood group antigens.
Published: 2019

31. Cost-effectiveness of diagnostic tests for threatened preterm labor in singleton pregnancy in France

Author: Catherine Lejeune, Paul Sagot, Jonathan Cottenet, Thomas Desplanches, Catherine Quantin, Service de Gynécologie Obstétrique, Médecine Foetale et Stérilité Conjugale - Chirurgie Gynécologie et Oncologique [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe EPICAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Biostatistiques et Informatique Médicale (CHU de Dijon) (DIM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses (B2PHI), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), No funding., 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, 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-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, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and université de Bourgogne, LNC
Subjects: medicine.medical_specialty, Cost effectiveness, medicine.medical_treatment, Population, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Bed rest, 03 medical and health sciences, 0302 clinical medicine, Threatened preterm labor, Medicine, 030212 general & internal medicine, education, education.field_of_study, lcsh:R5-920, 030219 obstetrics & reproductive medicine, Health economics, Fetal fibronectin, business.industry, Obstetrics, Research, Health Policy, Gestational age, Preterm birth, Diagnostic test, Economic evaluation, 3. Good health, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Gestation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cost-effectiveness, business, lcsh:Medicine (General), Decision analysis
Abstract: Background Previous studies have showed that the early diagnosis of threatened preterm labor decreases neonatal morbidity and mortality, avoids maternal morbidity induced by antepartum bed rest and unnecessary treatment, and reduces costs. Although there are many diagnostic tests, none is clearly recommended by international guidelines. The aim of our study was to compare seven diagnostic methods in terms of effectiveness and cost using a decision analysis model in singleton pregnancy presenting threatened preterm labor, between 24 and 34 weeks of gestation. Methods Seven diagnostic strategies based on individual or combined use of the following tests: cervical length, cervical fibronectin test, cervical interleukin test and protein in maternal serum, were compared using a decision analysis model. Effectiveness was expressed in terms of serious adverse neonatal events avoided (neonatal morbidity and mortality) at the hospital discharge. The economic analysis was performed from the health care system perspective. Deterministic and probabilistic analyses were performed to test the robustness of the model. Results At 24–34 weeks of gestation, the association of cervical length and qualitative fibronectin was the most efficient strategy dominating all alternatives, reducing the perinatal death or severe neonatal morbidity rate up to 15% and the costs up to 31% according to the gestational age. This result was confirmed by the deterministic sensitivity analyses. The probabilistic analysis showed that the association of cervical length and qualitative fibronectin dominated cervical length
Published: 2018

32. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2)

Author: Jean Reignier, Julie Boisramé-Helms, Laurent Brisard, Jean-Baptiste Lascarrou, Ali Ait Hssain, Nadia Anguel, Laurent Argaud, Karim Asehnoune, Pierre Asfar, Frédéric Bellec, Vlad Botoc, Anne Bretagnol, Hoang-Nam Bui, Emmanuel Canet, Daniel Da Silva, Michael Darmon, Vincent Das, Jérôme Devaquet, Michel Djibre, Frédérique Ganster, Maité Garrouste-Orgeas, Stéphane Gaudry, Olivier Gontier, Claude Guérin, Bertrand Guidet, Christophe Guitton, Jean-Etienne Herbrecht, Jean-Claude Lacherade, Philippe Letocart, Frédéric Martino, Virginie Maxime, Emmanuelle Mercier, Jean-Paul Mira, Saad Nseir, Gael Piton, Jean-Pierre Quenot, Jack Richecoeur, Jean-Philippe Rigaud, René Robert, Nathalie Rolin, Carole Schwebel, Michel Sirodot, François Tinturier, Didier Thévenin, Bruno Giraudeau, Amélie Le Gouge, Hervé Dupont, Marc Pierrot, François Beloncle, Danièle Combaux, Romain Mercier, Hadrien Winiszewski, Gilles Capellier, Gilles Hilbert, Didier Gruson, Pierre Kalfon, Bertrand Souweine, Elizabeth Coupez, Jean-Damien Ricard, Jonathan Messika, François Bougerol, Pierre-Louis Declercq, Auguste Dargent, Audrey Large, Djillali Annane, Bernard Clair, Agnès Bonadona, Rebecca Hamidfar, Christian Richard, Mathieu Henry-Lagarrigue, Ahiem Yehia Yehia, Johanna Temime, Stephanie Barrailler, Raphaël Favory, Erika Parmentier-Decrucq, Mercé Jourdain, Loredana Baboi, Marie Simon, Thomas Baudry, Mehran Monchi, Jérôme Roustan, Patrick Bardou, Alice Cottereau, Philippe Guiot, Noelle Brule, Mickael Landais, Antoine Roquilly, Thierry Boulain, Dalila Benzekri, Benoit Champigneulle, Jalel Tahiri, Gabriel Preda, Benoit Misset, Virginie Lemiale, Lara Zafrani, Muriel Fartoukh, Guillaume Thiéry, Delphine Chatellier, Rémi Coudroy, Renaud Chouquer, Samuel Gay, Christine Brasse, Arnaud Delahaye, Luis Ferreira, Régine Vermesch, Stéphanie Chevalier, Charlotte Quentin, Quentin Maestraggi, Francis Schneider, Ferhat Meziani, Charles Cerf, Grégoire Trebbia, Charlotte Salmon-Gandonnière, Laetitia Bodet-Contentin, Service d'anesthésie et réanimation chirurgicale [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Réanimation Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Stress vasculaire et tissulaire en transplantation : microparticules et environnement, Université de Strasbourg (UNISTRA), Service de réanimation médicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anésthésie Réanimation [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Groupement Hospitalier - Hôpital Edouard Herriot, Service de Réanimation Médicale, Hospices Civils de Lyon (HCL), Service de médecine intensive - réanimation et médecine hyperbare [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de réanimation et de surveillance continue [CH Mautauban], Centre hospitalier de Montauban, Service de réanimation (CH Saint-Malo), Centre hospitalier de Saint-Malo, Service de Réanimation Polyvalente - CHR d’Orleans, Service de Réanimation Médicale [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Service d’anesthésie-réanimation [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), réanimation et soins continus [CH Saint-Denis], Centre Hospitalier de Saint-Denis [Ile-de-France], Service des Urgences et de Réanimation Médicale (Urg - SAINT ETIENNE), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de réanimation polyvalente [Hôpital Foch, Suresnes], Hôpital Foch [Suresnes], Service de Réanimation et USC Médico-Chirurgicale = Médecine intensive réanimation [CHU Tenon], CHU Tenon [AP-HP], Service de réanimation chirurgicale [Centre Hospitalier Emile Muller, Mulhouse], Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Soins Intensifs [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Le Mans (CH Le Mans), Biomatériaux et Bioingénierie (BB), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Matériaux et nanosciences d'Alsace (FMNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de réanimation (CH La Roche-sur-Yon), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Service de Réanimation Médicale (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (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, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Réanimation, Hôpital Jean Bernard, CHU de Poitiers, Poitiers, France, Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Tours, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation Médicale, CHU Gabriel Montpied, CHU de Clermont-Ferrand, France, AP-HP Hôpital Saint-Louis, Service de réanimation et USC médico-chirurgicale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Radiopharmaceutiques biocliniques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), CIC Tours, Hôpital Bretonneau-Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation et USC Médico-Chirurgicale [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Strasbourg ( UNISTRA ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hospices Civils de Lyon ( HCL ), CHU Angers, CH Saint-Denis, Service des Urgences et de Réanimation Médicale ( Urg - SAINT ETIENNE ), Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Centre Hospitalier Emile Muller [Mulhouse] ( CH E.Muller Mulhouse ), Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ) -Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ), Infection, Antimicrobiens, Modélisation, Evolution ( IAME ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Le Mans, Biomatériaux et Bioingénierie, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Bretonneau-Université de Tours-CHRU Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and CHRU Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Adult, Male, Parenteral Nutrition, Pediatrics, medicine.medical_specialty, Time Factors, Critical Care, Secondary infection, Enteral feeding, Clinical nutrition, Enteral administration, law.invention, 03 medical and health sciences, Enteral Nutrition, 0302 clinical medicine, Randomized controlled trial, law, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Humans, Vasoconstrictor Agents, Medicine, Cumulative incidence, Hospital Mortality, 030212 general & internal medicine, Nutritional support, Aged, Acute critical illness, business.industry, Malnutrition, Hazard ratio, Shock, 030208 emergency & critical care medicine, General Medicine, Length of Stay, Middle Aged, Interim analysis, Respiration, Artificial, The enteral route, 3. Good health, Treatment Outcome, Parenteral nutrition, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BackgroundWhether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition.MethodsIn this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20–25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate
Published: 2018

33. Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance

Author: Etienne Humblin, Virginie Aires, Valentin Derangère, Marion Thibaudin, Patrick Hillon, Maxime Fredon, Alessandra Scagliarini, Dominique Delmas, Jean-Paul Pais de Barros, Emeric Limagne, Alexia Karen Cotte, François Ghiringhelli, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe CADIR (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Plateforme Lipidomique [Dijon] (LAP), 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)-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)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Bourgogne Franche-Comté ( UBFC ), Plateforme Lipidomique [Dijon] ( LAP ), 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 ) -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 ) -IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), université de Bourgogne, LNC, 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-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-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-Université de Bourgogne (UB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)
Subjects: 0301 basic medicine, Organoplatinum Compounds, Colorectal cancer, General Physics and Astronomy, CD8-Positive T-Lymphocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, Lipid droplet, Homeostasis, Neoplasm Metastasis, lcsh:Science, Caspase, Mice, Inbred BALB C, Multidisciplinary, Cell Death, biology, Chemistry, Liver Neoplasms, 1-Acylglycerophosphocholine O-Acyltransferase, Lipids, 3. Good health, Oxaliplatin, Phenotype, Caspases, Phosphatidylcholines, Immunogenic cell death, Female, Fluorouracil, Colorectal Neoplasms, Programmed cell death, Science, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, General Biochemistry, Genetics and Molecular Biology, Colorectal cancer chemoresistance, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Animals, Humans, Triglycerides, Cancer, General Chemistry, medicine.disease, digestive system diseases, 030104 developmental biology, Drug Resistance, Neoplasm, Cell culture, Cancer research, biology.protein, lcsh:Q, Neoplasm Transplantation, CD8
Abstract: Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8+ T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity., Lipid droplets (LD) accumulation correlates with colorectal cancer (CRC) relapse. Here the authors show that chemotherapy induces LD synthesis via acyltransferase LPCAT2 which, in turn, promotes chemoresistance via LD accumulation both in vitro and in vivo by blocking chemotherapy-induced ER stress.
Published: 2018

34. Connexins, important players in the dissemination of prostate cancer cells

Author: Arnaud Monvoisin, Justine Vix, Jonathan Boucher, Laurent Cronier, Dominique Thuringer, Marc Mesnil, Françoise Debiais, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, 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, Signalisation et Transports Ioniques Membranaires ( STIM ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de physiologie et biologie cellulaires ( IPBC ), Department of Rhumatology, Université de Poitiers, Institut de physiologie et biologie cellulaires (IPBC), and Université de Poitiers-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Stromal cell, Biophysics, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Breast cancer, Invasion, Prostate, Tumor Microenvironment, medicine, Animals, Humans, Connexin43, Neoplasm Metastasis, Migration, Tropism, Melanoma, Gap Junctions, Prostatic Neoplasms, Cancer, Bone metastasis, Cell Biology, medicine.disease, Neoplasm Proteins, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Connexin 43, GJIC, 030220 oncology & carcinogenesis, Immunology, Cancer research
Abstract: International audience; Over the past 50years, increasing experimental evidences have established that connexins (Cxs) and gap junctional intercellular communication (GJIC) ensure an important role in both the onset and development of cancerous processes. In the present review, we focus on the impact of Cxs and GJIC during the development of prostate cancer (PCa), from the primary growth mainly localized in acinar glands and ducts to the distant metastasis mainly concentrated in bone. As observed in several other types of solid tumours, Cxs and especially Cx43 exhibit an ambivalent role with a tumour suppressor effect in the early stages and, conversely, a rather pro-tumoural profile for most of invasion and dissemination steps to secondary sites. We report here the current knowledge on the function of Cxs during PCa cells migration, cytoskeletal dynamics, proteinases activities and the cross talk with the surrounding stromal cells in the microenvironment of the tumour and the bones. In addition, we discuss the role of Cxs in the bone tropism even if the prostate model is rarely used to study the complete sequence of cancer dissemination compared to breast cancer or melanoma. Even if not yet fully understood, these recent findings on Cxs provide new insights into their molecular mechanisms associated with progression and bone targeted behaviour of PCa. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
Published: 2018

35. FGF9 prevents pleural fibrosis induced by intrapleural adenovirus injection in mice

Author: Audrey Joannes, Bruno Crestani, Jean-Michel Sallenave, Joëlle Marchal-Somme, Brigitte Solhonne, Raphael Borie, Pierre Mordant, Hervé Mal, Aurélie Cazes, Phillippe Bonniaud, Yves Castier, Arnaud Mailleux, Madeleine Jaillet, Valérie Besnard, Aurélien Justet, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Hospitalo-Universitaire Fibrosis, Inflammation, Remodeling in cardiovascular, respiratory and renal diseases (Paris), LabEx Inflamex, Université Sorbonne Paris Cité (USPC), Service de Pneumologie [Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Centre de Compétence pour les Maladies Pulmonaires Rares, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Thoracique et Vasculaire [Hôpital Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie B et Transplantation [Hôpital Bichat], Département d'Anatomo-Pathologie [Hôpital Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre de Compétence pour les Maladies Pulmonaires Rares, 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, Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Sorbonne Paris Cité ( USPC ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre de Compétence pour les Maladies Pulmonaires Rares, Université Paris Diderot - Paris 7 ( UPD7 ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), and Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Physiology, Cellular differentiation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Inflammation, Biology, Fibroblast growth factor, Epithelium, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Adenoviridae, 03 medical and health sciences, Cell Movement, In vivo, Physiology (medical), medicine, Animals, Humans, Lung, mesothelial cells, fibroblast growth factor 9, Cell Differentiation, Epithelial Cells, differentiation, Cell Biology, Idiopathic Pulmonary Fibrosis, Rats, 3. Good health, Mice, Inbred C57BL, Mesothelium, Fibronectin, stomatognathic diseases, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Pleura, medicine.symptom, Mesothelial Cell
Abstract: International audience; Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14 Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14 The altered pleura cells strongly expressed α-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14 FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-β1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.
Published: 2017

36. Decreasing CB1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice

Author: Jie Liu, George Kunos, Nathan J. Coffey, Yuefei Shen, Michael P. Czech, Bin Gao, Sarah M. Nicoloro, Resat Cinar, Grzegorz Godlewski, Zhou Zhou, Tony Jourdan, Myriam Aouadi, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Equipe PADYS (LNC - U1231), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratory of Liver Diseases, National Institutes of Health ( NIH ) -National Institute on Alcohol Abuse and Alcoholism, University of Massachusetts Medical School [Worcester] ( UMASS ), Karolinska Institutet [Stockholm], Lipides - Nutrition - Cancer [Dijon - U1231] (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, 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-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, National Institutes of Health [Bethesda] (NIH)-National Institute on Alcohol Abuse and Alcoholism, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), and université de Bourgogne, LNC
Subjects: 0301 basic medicine, lcsh:Internal medicine, medicine.medical_specialty, Cell type, Cannabinoid receptor, CB(1) receptors, Inflammation, Biology, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Internal medicine, Gene expression, medicine, Kupffer cells, lcsh:RC31-1245, Molecular Biology, Gene, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell Biology, [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, medicine.disease, Obesity, Insulin receptor, 030104 developmental biology, Endocrinology, siRNA, 030220 oncology & carcinogenesis, biology.protein, medicine.symptom, CB1 receptors
Abstract: International audience; Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance.Methods: We used intravenously administered beta-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs.Results: We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation.Conclusion: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro inflammatory mechanism. Published by Elsevier GmbH.
Published: 2017

37. Terminal weaning or immediate extubation for withdrawing mechanical ventilation in critically ill patients (the ARREVE observational study)

Author: Anne Claire Hyacinthe, Olivier Lesieur, Antoine Roquilly, Jérôme Devaquet, Anne Renault, Philippe Mateu, Sebastien Jochmans, François Brenas, Isabelle Vinatier, Olivier Guisset, Alexandre Boyer, Alice Cottereau, Jean Philippe Rigaud, Ségolène Robin, Juliette Audibert, Djillali Annane, Frédérique Ganster, Jean Reignier, Mercé Jourdain, Nancy Kentish-Barnes, Maité Garrouste-Orgeas, Patrice Tirot, Jonathan Messika, Bruno Giraudeau, Paul Morin-Longuet, Xavier Repessé, Bruno Mégarbane, Bénédicte Philippon-Jouve, Simon Bourcier, Didier Thevenin, Jeremy Bourenne, Vincent Das, François Barbier, Mélanie Adda, Elie Azoulay, Emmanuelle Mercier, Guillaume Grillet, Patrick Bardou, Amélie Le Gouge, Alexandre Lautrette, Jean Pierre Quenot, Fabien Lion, René Robert, Nicolas Lerolle, Arnaud Desachy, Amélie Seguin, M. Feissel, Sybille Merceron, Rebecca Hamidfar-Roy, Institut Français de Recherche pour l'Exploitation de la Mer - Brest ( IFREMER ), Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ), Epidémiologie, santé publique et développement, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR99-ISPED, Service de réanimation médicale, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Tours, COIITSS Study Investigators, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP Hôpital Raymond Poincaré [Garches], Institut de Recherche en Horticulture et Semences ( IRHS ), Université d'Angers ( UA ) -Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Service de Réanimation Médico-Chirurgicale [CH Montauban], CH Montauban, Institut Pierre Louis d'Epidémiologie et de Santé Publique ( iPLESP ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de Réanimation Médicale [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Service d'anesthésie-réanimation SAMU94-SMUR94 [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Réanimation, Maladies Infectieuses, Centre Hospitalier de Belfort-Montbéliard, Service de réanimation Médicale, CHU Strasbourg, Epidémiologie pronostique des cancers et affections graves, Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital St-André, Réanimation, CHU Bordeaux [Bordeaux], Clinique de réanimation médicale, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Hôpital Albert Michallon, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Unité de soins intensifs [Clermont Ferrand], CHU Clermont-Ferrand-Hôpital Gabriel Montpied, Réanimation Médicale, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire Ethique Politique et Santé ( EA 4569 ), Université Paris Descartes - Paris 5 ( UPD5 ), Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique ( NAVVEC (UM 81) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de soins intensifs, Centre Hospitalier de Versailles (CHV), Réanimation médicale, CHU Bretonneau, Hopital Louis Mourier - AP-HP [Colombes], Service de Réanimation Médicale (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Equipe LIPNESS (LNC - U1231) ( LIPNESS ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie ( CIC-P803 ), Université de Bourgogne ( UB ) -Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Ambroise Paré, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP), Thérapeutiques Cliniques et Expérimentales des Infections, Université de Nantes ( UN ), Service de réanimation médicale [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Service de biostatistiques et information médicale [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Université de Nantes - Faculté de médecine et des techniques médicales ( UN Médecine ), Service de réanimation médicale [CHU Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, Time Factors, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Anxiety, Critical Care and Intensive Care Medicine, Stress Disorders, Post-Traumatic, Mechanical ventilation, 0302 clinical medicine, Personnel, 80 and over, Medicine, Prospective Studies, 030212 general & internal medicine, Stress Disorders, Aged, 80 and over, Depression, Pain scale, Middle Aged, 3. Good health, Intensive Care Units, Anesthesia, Female, medicine.symptom, Ventilator Weaning, Adult, Critical Illness, Airway Extubation, Hospital, 03 medical and health sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Humans, Weaning, Family, Aged, Ethics, Chi-Square Distribution, Job strain, business.industry, Treatment limitation, 030208 emergency & critical care medicine, Immediate extubation, Length of Stay, Airway obstruction, medicine.disease, Complicated grief, Personnel, Hospital, Critical care, Post-Traumatic, Terminal weaning, Grief, business
Abstract: International audience; PURPOSE: The relative merits of immediate extubation versus terminal weaning for mechanical ventilation withdrawal are controversial, particularly regarding the experience of patients and relatives. METHODS: This prospective observational multicentre study (ARREVE) was done in 43 French ICUs to compare terminal weaning and immediate extubation, as chosen by the ICU team. Terminal weaning was a gradual decrease in the amount of ventilatory assistance and immediate extubation was extubation without any previous decrease in ventilatory assistance. The primary outcome was posttraumatic stress symptoms (Impact of Event Scale Revised, IES-R) in relatives 3~months after the death. Secondary outcomes were complicated grief, anxiety, and depression symptoms in relatives; comfort of patients during the dying process; and job strain in staff. RESULTS: We enrolled 212 (85.5%) relatives of 248 patients with terminal weaning and 190 relatives (90.5%) of 210 patients with immediate extubation. Immediate extubation was associated with airway obstruction and a higher mean Behavioural Pain Scale score compared to terminal weaning. In relatives, IES-R scores after 3~months were not significantly different between groups (31.9~±~18.1 versus 30.5~±~16.2, respectively; adjusted difference, -1.9; 95% confidence interval, -5.9 to 2.1; p~=~0.36); neither were there any differences in complicated grief, anxiety, or depression scores. Assistant nurses had lower job strain scores in the immediate extubation group. CONCLUSIONS: Compared to terminal weaning, immediate extubation was not associated with differences in psychological welfare of relatives when each method constituted standard practice in the ICU where it was applied. Patients had more airway obstruction and gasps with immediate extubation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01818895.
Published: 2017

38. A constitutive BCL2 down-regulation aggravates the phenotype of PKD1-mutant-induced polycystic kidney disease

Author: Virginie Carmignac, David Vandroux, Nathalie Droin, Patrick Callier, Guillaume Meurice, Laurence Faivre, Noémie Pata-Merci, Romaric Loffroy, Christel Thauvin-Robinet, Ange-Line Bruel, Romain Da Costa, Julien Thevenon, Olivier Bouchot, Laurence Duplomb, Eric Solary, Lipides - Nutrition - Cancer [Dijon - U1231] (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, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cardio-vasculaire et thoracique (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD (CHU de Dijon), Laboratoire de cytogénétique (CHU de Dijon), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Plateforme de Génomique [Gustave Roussy], Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), NVH Medicinal Biotechnology (Dijon), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), FHU TRANSLAD, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Plateforme de Génomique, Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine )
Subjects: Adult, Male, 0301 basic medicine, TRPP Cation Channels, phenotype, bcl2 gene, Biology, micro rna, Mice, 03 medical and health sciences, down-regulation, symptom aggravating factors, hemic and lymphatic diseases, t-lymphocyte, Gene expression, Genetics, medicine, Polycystic kidney disease, Animals, Humans, Genetic Predisposition to Disease, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, genes, Molecular Biology, Gene, Genetics (clinical), Exome sequencing, Mice, Knockout, PKD1, apoptosis, Exons, General Medicine, Polycystic Kidney, Autosomal Dominant, medicine.disease, Phenotype, Pedigree, Up-Regulation, 3. Good health, MicroRNAs, 030104 developmental biology, MRNA Sequencing, Proto-Oncogene Proteins c-bcl-2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Cancer research, Lymphocytopenia, polycystic kidney diseases, bcl-2 protein
Abstract: IF 5.340; International audience; The main identified function of BCL2 protein is to prevent cell death by apoptosis. Mice knock-out for Bcl2 demonstrate growth retardation, severe polycystic kidney disease (PKD), gray hair and lymphopenia, and die prematurely after birth. Here, we report a 40-year-old male referred to for abdominal and thoracic aortic dissection with associated aortic root aneurysm, PKD, lymphocytopenia with a history of T cell lymphoblastic lymphoma, white hair since the age of 20, and learning difficulties. PKD, which was also detected in the father and sister, was related to an inherited PKD1 mutation. The combination of PKD with gray hair and lymphocytopenia was also reminiscent of Bcl2-/- mouse phenotype. BCL2 gene transcript and protein level were observed to be dramatically decreased in patient peripheral blood T-cells and in his aorta vascular wall cells, which was not detected in parents and sister T-cells, suggesting an autosomal recessive inheritance. Accordingly, spontaneous apoptosis of patient T-cells was increased and could be rescued through stimulation with an anti-CD3 antibody. Direct sequencing of BCL2 gene exons, promoter and 3'UTR region as well as BCL2 mRNA sequencing failed in identifying any pathogenic variant. Array-CGH was also normal and whole exome sequencing of the patient, parents and sister DNA did not detect any significant variant in genes encoding Bcl2-interacting proteins. miRNA array identified an up-regulation of miR-181a, which is a known regulator of BCL2 expression. Altogether, miR-181a-mediated decrease in BCL2 gene expression could be a modifying factor that aggravates the phenotype of a PKD1 constitutive variant.
Published: 2017

39. Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study

Author: J. Guigay, Catherine Cardot-Bauters, Patricia Niccoli, H. Du Boullay, B. Delemer, M. Le Bras, Catherine Lombard-Bohas, Olivier Chabre, Pierre B. A. Lecomte, Jean-Yves Scoazec, Christine Binquet, Ph. Caron, P. Chanson, Marc Klein, Carmen Vulpoi, Pierre Goudet, F. Borson-Chazot, T. Aparicio, Vincent Rohmer, E. Cosson, Albert Beckers, I. Guilhem, Eric Baudin, Bruno Vergès, A. Tabarin, Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (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-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, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Gastro-entérologie [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), HESAM Université (HESAM)-HESAM Université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'endocrinologie, diabétologie et nutrition, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Cité (USPC)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF), Institut des Sciences de la Terre (ISTerre), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de recherche pour le développement [IRD] : UR219-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Pontchaillou [Rennes], Service d'Endocrinologie (ANGERS - Endocrino), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Service de Chirurgie Digestive, Cancérologique, Générale, Endocrinienne et Urgences (CHU de Dijon), Eq 4, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est-Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers (INSU - CNRS)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université Joseph Fourier - Grenoble 1 (UJF), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Groupement Hospitalier Lyon-Est ( GHE ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Centre de médecine nucléaire, Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Université de Reims Champagne-Ardenne ( URCA ) -Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims ( CHU Reims ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle ( CRESS - U1153 ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Sorbonne Paris Cité ( USPC ) -Hôpital Jean Verdier-Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF), Institut des Sciences de la Terre ( ISTerre ), Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers ( INSU - CNRS ) -Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université Joseph Fourier - Grenoble 1 ( UJF ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'Endocrinologie ( ANGERS - Endocrino ), and CHU Angers
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Pathology, Neuroendocrine tumors, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Gastroenterology, Metastasis, Cohort Studies, br-NETs, 03 medical and health sciences, 0302 clinical medicine, Cause of Death, Internal medicine, Biopsy, Multiple Endocrine Neoplasia Type 1, Humans, Medicine, Survival analysis, Aged, Cause of death, medicine.diagnostic_test, business.industry, Large cell, Bronchial Neoplasms, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Neuroendocrine Tumors, 030104 developmental biology, survival in MEN1 patients, 030220 oncology & carcinogenesis, Cohort, Female, Surgery, business, [ SDV.MHEP.PSR ] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Follow-Up Studies, Cohort study
Abstract: IF 2.673; International audience; ObjectiveTo evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death.Summary background databr-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis.MethodsThe 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5–59.6] years by the Groupe d’étude des Tumeurs Endocrines was analyzed using time-to-event techniques.Resultsbr-NETs were found in 51 patients (4.8%, [95% CI 3.6–6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28–66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02–5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10−4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths.ConclusionsAround 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.
Published: 2017

40. ERK1 and ERK2 activation modulates diet-induced obesity in mice

Author: Naim Akhtar Khan, Douadi Khelifi, Amira Sayed Khan, Gado Dramane, Selvakumar Subramaniam, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) ( NUTox ), 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 ) -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 ), Département de Biochimie, Biologie Cellulaire et Moléculaire (Université des Frères Mentouri)), Faculté des Sciences de la Nature et de la Vie, Université Frères Mentouri-Université Mentouri Constantine, Biochemistry Department (Bharathiar University), Bharathiar University, 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 ), Département des Sciences de la Vie (Ecole Normale Supérieure de Natitingou, Université de Parakou), Université de Parakou, Université de Parakou-Université de Parakou, Laboratoire de Génétique (Université des Frères Mentouri), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Equipe NuTox (LNC - U1231) ( NUTOX ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), 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)-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), Faculté des Sciences de la Nature et de la Vie, Université Frères Mentouri-Université Mentouri Constantine [Algérie] (UMC), 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), Université de Parakou (UP), Université Mentouri Constantine [Algérie] (UMC)-Faculté des Sciences de la Nature et de la Vie, Université Frères Mentouri, Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), and 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-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
Subjects: Blood Glucose, Male, 0301 basic medicine, medicine.medical_treatment, Mice, Obese, Biochemistry, Mice, chemistry.chemical_compound, Phosphorylation, Beta oxidation, Cells, Cultured, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Reverse Transcriptase Polymerase Chain Reaction, General Medicine, Lipids, Fatty acid synthase, Liver, Lipogenesis, Homeostatic model assessment, medicine.medical_specialty, Blotting, Western, Biology, Diet, High-Fat, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Obesity, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Inflammation, Triglyceride, Insulin, Body Weight, Lipid Metabolism, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, biology.protein, MAP kinase, Insulin Resistance
Abstract: IF 3.112; International audience; Obesity is a worldwide problem, and dietary lipids play an important role in its pathogenesis. Recently, Erk1 knock-out (ERK1(-/-)) mice have been shown to exhibit low preference for dietary fatty acids. Hence, we maintained Erk1(-/-) mice on a high-fat diet (HFD) to assess the implication of this mitogen-activated protein (MAP) kinase in obesity. The Erk1(-/-) mice, fed the HFD, were more obese than wild-type (WT) animals, fed the same diet. Erk1(-/-) obese mice gained more fat and liver mass than WT obese animals. No difference was observed in daily food and energy intake in HFD-fed both group of animals. However, feed efficiency was higher in Erk1(-/-) than WT animals. Blood cholesterol, triglyceride and insulin concentrations were higher in Erk1(-/-) obese mice compared to WT obese animals. Accordingly, homeostatic model assessment of insulin resistance (HOMA-IR) value was higher in Erk1(-/-) obese mice compared to WT obese animals. Interestingly, only Erk1(-/-) obese mice, but not WT-obese animals, exhibited high degree of phosphorylation of liver MEK, the upstream regulator of ERK1/2. This phenomenon was associated with high liver ERK2 phosphorylation in Erk1(-/-) obese mice which also had high liver acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) mRNA expression, suggesting high lipogenesis in these animals. The Erk1(-/-) obese mice also had low PPAR-α and CPT1β mRNA, indicating low fatty acid oxidation. Our observations suggest that ERK1 and ERK2 might play key roles in the regulation of obesity.
Published: 2017

41. Effect of cadmium exposure on essential omega-3 fatty acids in the edible bivalve Donax trunculus

Author: Sandrine Bellenger, Naim Akhtar Khan, Isma Merad, Noureddine Soltani, Aziz Hichami, Laboratoire de Biologie Animale Appliquée [Annaba] ( LBAA ), Université Badji Mokhtar - Annaba [Annaba] ( UBMA ), Equipe LIPNESS (LNC - U1231) ( LIPNESS ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Equipe NuTox (LNC - U1231) ( NUTOX )
Subjects: Male, 0301 basic medicine, Donax trunculus, Health, Toxicology and Mutagenesis, media_common.quotation_subject, chemistry.chemical_element, 010501 environmental sciences, 01 natural sciences, [ SDE ] Environmental Sciences, 03 medical and health sciences, Fatty Acids, Omega-3, Botany, Omega-3 fatty acids, Animals, Humans, Environmental Chemistry, Ecotoxicology, Food science, Shellfish, 0105 earth and related environmental sciences, media_common, Cadmium, biology, EPA, General Medicine, biology.organism_classification, Pollution, Eicosapentaenoic acid, Bivalvia, DHA, Salinity, CADMIUM EXPOSURE, 030104 developmental biology, chemistry, Docosahexaenoic acid, Algeria, Female, lipids (amino acids, peptides, and proteins), Reproduction, Water Pollutants, Chemical, Environmental Monitoring
Abstract: IF 2.741; International audience; Donax trunculus is the most consumed bivalve by the local population of the Northeast Algeria for its nutritional value. Therefore, the aim of the current study was to determine the effects of cadmium (Cd), a known toxic metal, on the alterations in main essential omega-3 fatty acids, i.e., eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), in male and female gonads of D. trunculus during the reproduction period at spring (before spawning). Additionally, this work seeks to describe the relation between EPA and DHA with non-methylene-interrupted dienoic (NMID) fatty acids, and explores their possible contribution of to protect against Cd stress. The samples were collected at El Battah, a relatively clean sea shore, and reared in the laboratory. Physico-chemical parameters such as temperature, pH, salinity, and dissolved oxygen were measured. Cd was added to the rearing water at two sublethal concentrations (LC10 and LC25-96h, as determined previously). A two-way ANOVA analysis indicated significant effects of concentrations and genders for both fatty acids. Our results showed a significant reduction in EPA and DHA concentrations in the both genders, with a strong effect in females. There was also a negative correlation between NMID fatty acids and the two essential omega-3 fatty acids for each gender.
Published: 2017

42. A retrospective analysis of the impact of treatments and blood counts on survival and the risk of vascular events during the course of polycythaemia vera

Author: François Girodon, Valérie Jooste, Hans Carl Hasselbalch, Bjorn Andreasson, Peter Johansson, Marie Bak, Anneli Enblom-Larsson, Ditte Hersby, Sunderby Hospital, Service d'hématologie biologique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Roskilde Hospital, Registre Bourguignon des Cancers Digestifs, 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 ) -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 ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Sahlgrenska University Hospital, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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)-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)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sahlgrenska University Hospital [Gothenburg]
Subjects: Male, medicine.medical_specialty, Polycythaemia, Blood count, polycythaemia vera, Hydroxycarbamide, Hemoglobins, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Vascular Diseases, myeloproliferative disease, Polycythemia Vera, venesection, Aged, Retrospective Studies, Platelet Count, business.industry, hydroxycarbamide, Hazard ratio, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Retrospective cohort study, Hematology, Phlebotomy, medicine.disease, Confidence interval, 3. Good health, Surgery, Hematocrit, 030220 oncology & carcinogenesis, Female, business, Complication, 030215 immunology, medicine.drug
Abstract: International audience; Vascular and non-vascular complications are common in patients with polycythaemia vera. This retrospective study of 217 patients with polycythaemia vera aimed to determine whether blood counts with respect to different treatments influenced the complication rate and survival. We found that 78 (36%) patients suffered from at least one complication during follow-up. Older age and elevated lactate dehydrogenase at diagnosis were found to be risk factors for vascular complications. When the vascular complication occurred, 41% of the patients with a complication had elevated white blood cells (WBC) compared with 20% of patients without a complication (P = 0·042). Patients treated with hydroxycarbamide (HC; also termed hydroxyurea) experienced significantly fewer vascular complications (11%) than patients treated with phlebotomy only (27%) (P = 0·013). We also found a survival advantage for patients treated with HC, when adjusted for age, gender and time period of diagnosis (Hazard ratio for phlebotomy-treated patients compared to HC-treated patients at 5 years was 2·42, 95% confidence interval 1·03-5·72, P = 0·043). Concerning survival and vascular complications, HC-treated patients who needed at least one phlebotomy per year were not significantly different from HC-treated patients with a low phlebotomy requirement. We conclude that complementary phlebotomy in HC-treated patients in order to maintain the haematocrit, is safe.
Published: 2017

43. Early screening for type 2 diabetes following gestational diabetes mellitus in France: hardly any impact of the 2010 guidelines

Author: Anne-Sophie Mariet, Jonathan Cottenet, Karine Goueslard, Paul Sagot, Catherine Quantin, Jean-Michel Petit, Service Biostatistiques et Informatique Médicale (CHU de Dijon) (DIM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB), Service de Gynécologie Obstétrique, Médecine Foetale et Stérilité Conjugale - Chirurgie Gynécologie et Oncologique [CHU de Dijon], Lipides - Nutrition - Cancer [Dijon - U1231] (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, Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses (B2PHI), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Biostatistiques et Informatique Médicale (CHU de Dijon) ( DIM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Bourgogne ( UB ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses ( B2PHI ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Institut Pasteur [Paris], Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: endocrine system diseases, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Gestational diabetes mellitus, Glucose test, 0302 clinical medicine, Endocrinology, Pregnancy, Mass Screening, 030212 general & internal medicine, education.field_of_study, medicine.diagnostic_test, Obstetrics, Postpartum Period, General Medicine, [ 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, 3. Good health, Gestational diabetes, Practice Guidelines as Topic, Screening, Female, France, Adult, medicine.medical_specialty, Population, 030209 endocrinology & metabolism, Guidelines, 03 medical and health sciences, Internal medicine, Type 2 diabetes mellitus, Internal Medicine, medicine, Humans, education, Mass screening, Retrospective Studies, business.industry, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Glucose Tolerance Test, medicine.disease, Diabetes, Gestational, Early Diagnosis, Diabetes Mellitus, Type 2, business, Postpartum period, Follow-Up Studies
Abstract: IF 3.340; International audience; AIMS:Women who had gestational diabetes mellitus (GDM) have a high risk of type 2 diabetes mellitus (T2DM) in the years following pregnancy. Most follow-up screening studies have been conducted in limited geographical areas leading to large variability in the results. The aim of our investigation was to measure how the publication of guidelines affected early screening for T2DM after a pregnancy with GDM during the period 2007-2013, in France.METHODS:We conducted a retrospective cohort study in a representative sample of 1/97th of the French population using data from the "National Health Insurance Inter-Regime Information System," which collects individual hospital and non-hospital data for healthcare consumption.RESULTS:The sample included 49,080 women who gave birth in 2007-2013. In the following 3 months, only 18.49% of women with GDM had an oral glucose tolerance test or a blood glucose test in 2007. This rate had not significantly increased in 2013 (p = 0.18). The proportion of women with GDM who had the recommended glycemic follow-up at 3 months (20.30 vs. 21.58%, p = 0.19) and 6 months (32.48 vs. 37.16%, p = 0.08) was not significantly different before the guidelines (2008-2009) and after the guidelines (2012-2013). At 12 months, the difference was significant (46.77 vs. 54.05%, p = 0.009).CONCLUSION:Postpartum screening has improved only slightly since the guidelines and remains largely insufficient, with less than 25% of women with GDM screened in the first 3 months. In the first year after delivery, less than 60% of women were screened for T2DM.
Published: 2017

44. Sirtuin-1 Activation Controls Tumor Growth by Impeding Th17 Differentiation via STAT3 Deacetylation

Author: Romain Euvrard, Cédric Rébé, François Ghiringhelli, Hélène Berger, Emeric Limagne, Dominique Delmas, Frédérique Végan, Valentin Derangère, Marion Thibaudin, Lionel Apetoh, Sylvain Ladoire, Pauline Chalons, Etienne Humblin, Romain Boidot, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Plateforme de transfert en biologie cancérologique [Dijon], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Centre d'épidémiologie des populations ( CEP ), and Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL )
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, endocrine system diseases, Cellular differentiation, Melanoma, Experimental, Regulator, environment and public health, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, STAT3, Mice, Sirtuin 1, RAR-related orphan receptor gamma, lcsh:QH301-705.5, Mice, Inbred BALB C, biology, Acetylation, Cell Differentiation, Nuclear Receptor Subfamily 1, Group F, Member 3, Metformin, Cell biology, Th17, RORγt, medicine.symptom, biological phenomena, cell phenomena, and immunity, hormones, hormone substitutes, and hormone antagonists, STAT3 Transcription Factor, Agonist, medicine.drug_class, Transplantation, Heterologous, Carbazoles, Mice, Nude, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Heterocyclic Compounds, 4 or More Rings, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SIRT1, Cell Line, Tumor, medicine, Animals, Humans, cancer, Molecular biology, Mice, Inbred C57BL, enzymes and coenzymes (carbohydrates), 030104 developmental biology, lcsh:Biology (General), biology.protein, Th17 Cells
Abstract: International audience; Sirtuin-1 deacetylates proteins and has emerged as a critical regulator of different cellular processes, particularly inflammation. Basal SIRT1 activity was previously found to limit Th9 and enhance Th17 differentiation in mice, but the effect of pharmacological SIRT1 activation on T cell differentiation and antitumor responses remains unclear. Here, we find that SIRT1 pharmacological agonists selectively impede mouse and human Th17 cell differentiation. SIRT1 activation induces STAT3 deacetylation, thus reducing its ability to translocate into the nucleus, bind to Rorc promoter, and induce its transcription. SIRT1 agonists reduce tumor growth in mice by blocking Th17 cell differentiation. In cancer patients, the SIRT1 agonist metformin reduced the frequency of Th17 cells and STAT3 acetylation levels. Altogether, these data underscore that SIRT1 activation impedes Th17 cell differentiation and thereby limits tumor growth and suggest that SIRT1 activators may directly target IL-17A functions.
Published: 2017

45. The Hsp70 inhibiting peptide aptamer A17 potentiates radiosensitization of tumor cells by Hsp90 inhibition

Author: Daniela Schilling, Stephanie E. Combs, Gabriele Multhoff, Carmen Garrido, Klinikum rechts der Isar der TU München, ZAUM, Equipe HSPpathies (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER
Subjects: 0301 basic medicine, Radiation-Sensitizing Agents, Cancer Research, Aptamer, Blotting, Western, Heat shock protein 70 (Hsp70), [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Myeloma, Expression, Shock Proteins 90, Bladder-Cancer, Radiation Tolerance, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Hsp90 inhibitor, 03 medical and health sciences, Heat shock protein 90 (Hsp90), 0302 clinical medicine, NVP-AUY922, Cell Line, Tumor, Heat-Shock-Protein-70, Heat shock protein, Humans, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Small-Molecule Inhibitor, Radiosensitivity, HSF1, Radiosensitization, biology, Induced Apoptosis, Drug Synergism, Isoxazoles, Resorcinols, Agents, Carcinoma-Cells, Hsp90, 3. Good health, Hsp70, 030104 developmental biology, Oncology, Apoptosis, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Lines, Aptamers, Peptide
Abstract: IF 5.992; International audience; The inhibition of heat shock protein 90 (Hsp90) is a promising strategy to increase the radiosensitivity of tumor cells. However, Hsp90 inhibition induces the expression of Hsp70 which is a prominent cytoprotective protein. Therefore, dual targeting of Hsp70 and Hsp90 might be beneficial to increase the radiosensitivity of tumor cells. Hsp70 inhibiting peptide aptamers have been shown to increase the sensitivity of tumor cells to apoptosis induced by different anticancer drugs. Herein, we studied the radiosensitizing activity of the Hsp70 inhibiting peptide aptamer A17 in combination with the Hsp90 inhibitor NVP-AUY922. Whereas A17 significantly increased apoptosis induction by NVP-AUY922 it did not significantly affect the radiosensitivity of human lung and breast cancer cells. However, Hsp70 inhibition by the aptamer A17 potentiated the radiosensitizing effects of the Hsp90 inhibitor NVP-AUY922. Mechanistically we speculate that an increased number of DNA double strand breaks and an enhanced G(2)/M arrest might be responsible for the increased radiosensitization in A17 expressing tumor cells. Therefore, the simultaneous inhibition of Hsp90 and Hsp70 combined with radiotherapy might provide a promising anti-cancer strategy. (C) 2017 Elsevier B.V. All rights reserved.
Published: 2017

46. In vitro cytotoxic effects of DEHP-alternative plasticizers and their primary metabolites on a L929 cell line

Author: Teuta Eljezi, Pierre Pinta, Marie-Christine Chagnon, Damien Richard, Jean-Michel Chezal, Jérémy Pinguet, Valérie Sautou, Gaël Grimandi, Emmanuel Moreau, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), CHU Clermont-Ferrand, Laboratoire d'ingénierie osteo-articulaire et dentaire ( LIOAD ), Université de Nantes ( UN ) -IFR26-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Pharmacologie Médicale [Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], Equipe NuTox (LNC - U1231) ( NUTOX ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Caractérisation et sécurité biologique des surfaces nanostructurées ( C-BIOSENSS ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Matériaux d'intérêt biologique, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service Pharmacie [CHU Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Louise Michel [Clermont-Ferrand], Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Gestion et en Economie (IREGE), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Service de Pharmacologie Médicale [CHU Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Caractérisation et sécurité biologique des surfaces nanostructurées (C-BIOSENSS), Université d'Auvergne - Clermont-Ferrand I (UdA), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), CHU Louise Michel [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Jehan, Frederic
Subjects: 0301 basic medicine, Environmental Engineering, Metabolite synthesis, Biocompatibility, Cell Survival, Cytotoxicity, Health, Toxicology and Mutagenesis, Metabolite, Phthalic Acids, In Vitro Techniques, DEHP-alternative plasticizers, 010501 environmental sciences, 01 natural sciences, [ SDE ] Environmental Sciences, Mice, 03 medical and health sciences, chemistry.chemical_compound, Phthalates, Plasticizers, In vivo, Diethylhexyl Phthalate, Animals, Environmental Chemistry, Organic chemistry, Polyvinyl Chloride, Cells, Cultured, 0105 earth and related environmental sciences, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Chromatography, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Public Health, Environmental and Occupational Health, Plasticizer, Primary metabolite, Esters, General Medicine, General Chemistry, Fibroblasts, Pollution, In vitro, 3. Good health, Phthalic acid, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, chemistry
Abstract: IF 4.208; International audience; Phthalic acid esters have been widely used to improve the plasticity of PVC medical devices. They carry a high exposure risk for both humans and the environment in clinical situations. Our study focuses on the cytotoxicity of alternative plasticizers. Postulated primary metabolites were synthesized, not being commercially available. Cytotoxicity assays were performed on L929 murine cells according to the ISO-EN 10993-5 standard design for the biocompatibility of medical devices. The tested concentrations of plasticizers (0.01, 0.05 and 0.1 mg/ml) covered the range likely to be found in biological fluids coming into direct contact with the medical devices. DEHP, DINP and DINCH were cytotoxic at the highest concentration (0.1 mg/ml) for 7 days of exposure. Their corresponding metabolites were found to be more cytotoxic, for the same concentration. By contrast, TOTM and its corresponding metabolite MOTM were not found to be cytotoxic. DEHA showed no cytotoxicity, but its corresponding monoester (MEHA) produced a cytotoxic effect at 0.05 mg/ml. In clinical situations, medical devices can release plasticizers, which can come into contact with patients. In vivo, the plasticizers are quickly transformed into primary metabolites. It is therefore important to measure the effects of both the plasticizers and their corresponding metabolites. Standard first-line cytotoxicity assays should be performed to ensure biocompatibility.
Published: 2017

47. Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data

Author: C. Thauvin-Robinet, Nada Houcinat, Daphné Lehalle, A Vital, Laurence Faivre, Agnès Rötig, Jaak Jaeken, Fan Xia, Matthew N. Bainbridge, Marlène Rio, Sophie Nambot, Jean-Baptiste Rivière, Paul Kuentz, Julien Thevenon, D Gavrilov, Cyril Goizet, Ange-Line Bruel, Fanny Mochel, N Niu, Arthur L. Beaudet, Yannis Duffourd, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), FHU TRANSLAD, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and FHU TRANSLAD (CHU de Dijon)
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Candidate gene, Adolescent, data sharing, Mitochondrial disease, Compound heterozygosity, Bioinformatics, Young Adult, 03 medical and health sciences, Mitochondrial myopathy, Mitochondrial Encephalomyopathies, Exome Sequencing, Genetics, Humans, Medicine, Genetic Predisposition to Disease, Oxidoreductases Acting on Sulfur Group Donors, whole-exome sequencing, Child, Exome, Cytochrome Reductases, Genetics (clinical), Exome sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, GFER, Disease gene identification, medicine.disease, Pedigree, 3. Good health, 030104 developmental biology, mitochondrial condition, Mutation, Congenital cataracts, Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business
Abstract: Background Alterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19-year-old girl with a strikingly similar phenotype, but this ultra-rare entity remains however unknown from most of the scientific community. Materials and methods Whole exome sequencing was performed as part of a "diagnostic odyssey" for suspected mitochondrial condition in 2 patients, presenting congenital cataracts, progressive encephalomyopathy and hypotrophy and detected unreported compound heterozygous variants in GFER. Results Thanks to an international data sharing, we found 2 additional patients carrying compound heterozygous variants in GFER. Reverse phenotyping confirmed the phenotypical similarities between the 4 patients. Together with the first literature reports, the review of these 8 cases from 4 unrelated families enables us to better describe this apparently homogeneous disorder, with the clinical and biological stigmata of mitochondrial disease. Conclusion This report highlights the clinical utility of whole exome sequencing and reverse phenotyping for the diagnosis of ultra-rare diseases and underlines the importance of a broad data sharing for accurate clinical delineation of previously unrecognized entities.
Published: 2017

48. Diagnostic genetic screening for assisted reproductive technologies patients with macrozoospermia

Author: J.-M. Dupont, R. C. Fierro, Jacques Auger, Patricia Fauque, Virginie Carmignac, N. Lieury, Céline Bruno, Julie Barberet, Emmanuel Dulioust, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nancy University, Service Commun de Microscopie, Nancy-University, Universidad Autónoma Metropolitana [Mexico] ( UAM ), Universidad Autonoma Metropolitana - Cuajimalpa (UAM), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Service d'Histologie-Embryologie, Biologie de la Reproduction ( CECOS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Burgundy Regional Research Council, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad Autónoma Metropolitana [Mexico] (UAM), Universidad Autonoma Metropolitana, Unidad Cuajimalpa, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Histologie-Embryologie, Biologie de la Reproduction (CECOS Paris Cochin), Hôpital Cochin [AP-HP], 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, and CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Adult, Male, 0301 basic medicine, Reproductive Techniques, Assisted, pregnancy outcomes, Urology, Endocrinology, Diabetes and Metabolism, Twins, men, Semen, Reproductive technology, Biology, medicine.disease_cause, Andrology, Teratozoospermia, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Polyploid, c c.144delc mutation, medicine, Humans, Aurora Kinase C, Genetic Testing, Aurora Kinase C Gene, [SDV.GEN]Life Sciences [q-bio]/Genetics, aurora kinase C gene, Mutation, assisted reproductive technologies, 030219 obstetrics & reproductive medicine, urogenital system, tailed spermatozoa, Genetic Status, head, Sperm, 3. Good health, macrozoospermia, human sperm, 030104 developmental biology, Reproductive Medicine, male-infertility, Sperm Head, aneuploidy rate, flow-cytometry, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, polyploid spermatozoa
Abstract: International audience; Macrozoospermia is characterized by a high proportion of abnormal spermatozoa with enlarged heads. So far, it has been associated with mutations only in the Aurora Kinase C gene (AURKC) in some cases. Although many publications have reported failure to conceive in couples with macrozoospermia, a few others have described successful pregnancies, thus raising questions as to whether ICSI and AURKC genetic screening should be recommended in all patients with macrozoospermia. First, we report on two monozygotic twins presenting macrozoospermia for whom the genetic status was explored (Aurora Kinase C sequencing) and whole semen and gradient-selected spermatozoa were analyzed, using Fluorescent In Situ Hybridization (FISH), Electron Microscopy and flow cytometry. Additionally, FISH analysis was performed on individually selected uniflagellate spermatozoa with normal sized heads. Second, we also provide an updated review of patients with macrozoospermia gathering the percentage of enlarged head spermatozoa, the genetic status and pregnancy outcomes. Both twins carried a homozygous mutation of AURKC. Spermocytograms showed means of 86% and 83.5% of enlarged head forms. FISH analyses showed that normal head size, uniflagellate spermatozoa had an aneuploid or polyploid nucleus despite a high level of selection. SEM analysis also showed special intranuclear inclusions in enlarged head spermatozoa. Our data together with cases reported in the literature allowed us to recommend that the AURKC gene should be sequenced when the sperm contains 30% or more of enlarged head spermatozoa, and when a mutation is found, ART should not be performed. Our analyses provide information that could greatly help practitioners in their decision-making with regard to optimal care of patients with macrozoospermia.
Published: 2017

49. Trends in incidence of small bowel cancer according to histology: a population-based study

Author: Anne-Marie, Bouvier, Michel, Robaszkiewicz, Valérie, Jooste, Mélanie, Cariou, Antoine, Drouillard, Véronique, Bouvier, Jean-Baptiste, Nousbaum, Anne-Sophie, Woronoff, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe EPICAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), FRANCIM, Réseau des registres français du cancer, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Soins Primaires, Santé Publique, Registre des cancers de Bretagne Occidentale (SPURBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Université de Bourgogne (UB), Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), French Network of Cancer Registries (FRANCIM) : Amadeo B, Arveux P, Baldi I, Bara S, Bouvier AM, Bouvier V, Clavel J, Colonna M, Coureau G, Cowppli-Bony A, Dabakuyo S, Dalmeida T, Daubisse-Marliac L, Defossez G, Delafosse P, Deloumeaux J, Grosclaude P, Guizard AV, Joachim C, Jooste V, Lacour B, Lapôtre-Ledoux B, Launoy G, Marrer E, Maynadié M, Molinié F, Monnereau A, Nousbaum JB, Plenet J, Plouvier S, Pouchieu C, Robaszkiewicz M, Schvartz C, Trétarre B, Troussard X, Velten M, Woronoff AS., LUCAS, Marie-Jo, 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, 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-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, Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), 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)-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)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Small bowel cancer, medicine.medical_specialty, Histology, Lymphoma, Colorectal cancer, Population, Adenocarcinoma, Neuroendocrine tumors, Gastroenterology, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Duodenal Neoplasms, Internal medicine, medicine, Humans, Registries, education, Aged, Aged, 80 and over, education.field_of_study, Jejunal Neoplasms, business.industry, Incidence (epidemiology), Incidence, Cancer, Sarcoma, Middle Aged, Cancer registry, medicine.disease, 3. Good health, Ileal Neoplasms, Neuroendocrine Tumors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Trends, business
Abstract: International audience; BACKGROUND:Small bowel cancer is not a single entity. Population-based studies taking into account histological diversity are scarce. The aim of this study was to report on their trends in incidence by histology in France over the past 20 years.METHODS:All patients with a small bowel cancer diagnosed in 15 French administrative areas covered by a registry from the network of French cancer registries (FRANCIM) were included. Age-standardized incidence rates were estimated using the world standard population. Incidence rates were calculated by gender, age group, histology, and 5-year period.RESULTS:The overall age-standardized incidence rates were 1.46/100,000 inhabitants in men and 0.9/100,000 inhabitants in women. Adenocarcinoma was the most common histological type (38%), followed by neuroendocrine tumors (35%), lymphoma (15%) and sarcoma (12%). Age at diagnosis and tumor location differed between adenocarcinoma and neuroendocrine tumors. The incidence of all four tumor types increased significantly over the 20-year period, with the exception of lymphoma in men. The annual percentage change for neuroendocrine tumors was 3.89% in men and 3.61% in women; for sarcoma, it was 3.38% and 4.08%, respectively. The incidence of adenocarcinoma and lymphoma also increased in women with an annual percentage change of 3.05% and 3.32%, respectively.CONCLUSION:Small bowel cancer incidence has increased over time. This increase occurred with different amplitudes and patterns in the four major histological types. The improvement in imaging techniques could partly explain this increase. It is necessary to determine whether predisposing conditions may contribute to this change.
Published: 2019

50. Linearity and Efficiency Characterization of AlGaN/GaN and InAlGaN/GaN HEMTs devices using Multi-tone Large Signal Measurements

Author: Stéphane Piotrowicz, Mohamed Bouslama, C. Potier, Christophe Chang, Vincent Gillet, O. Patard, J-C. Nallatamby, Raymond Quéré, Michel Prigent, Laboratoire matériaux ENSET d'Oran, ENSET [Oran], ENSET [Oran]-ENSET [Oran], Alcatel-Thalès, Marcoussis (91), Courant Institute of Mathematical Sciences [New York] (CIMS), New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Equipe SAPHIHR (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Materials science, business.industry, 020208 electrical & electronic engineering, Transistor, Linearity, 020206 networking & telecommunications, 02 engineering and technology, High-electron-mobility transistor, Signal, law.invention, [SPI]Engineering Sciences [physics], Third order, law, Modulation, 0202 electrical engineering, electronic engineering, information engineering, Demodulation, Optoelectronics, business, ComputingMilieux_MISCELLANEOUS, Intermodulation
Abstract: In this paper, the linearity and efficiency of 2 different technologies of HEMT transistors (AlGaN/GaN and InAlGaN/GaN) has been performed using multi-tone large signal measurement in C-band. The transistors size is 8x50µm with 0.15µm gate length. This nonlinear characterization has been carried out using a multi-tone signal with a particularly property: it doesn't exist overlapping between the signal tones and all the third order intermodulation products (IM3) allowing to measure the C/I characteristic in few milliseconds. Moreover, the statistical properties of this signal (probability density function -PDF, Peak to Average Power Ratio -PAPR, …) can mimic those of complex modulation signals used in telecommunications (QAM, OFDM, …). To do that an Unequally Spaced Multi-Tone (USMT) test signal is generated by means of IQ modulated synthesiser. Note that the great interest of this signal is the lack of demodulator at reception which simplifies the C/I measurement. After measuring the DC characteristic of each device (IV, PIV, current leakage), the C/I, PAE, Gain and low frequency drain current of these HEMT transistor will be performed with a load-pull setup to reach the optimum load in terms of PAE.
Published: 2019

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