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88 results on '"UMS omique (OMIQUE)"'

1. Low-Molecular-Weight Fucoidan Induces Endothelial Cell Migration via the PI3K/AKT Pathway and Modulates the Transcription of Genes Involved in Angiogenesis

Author

Sophie Gandrille, Isabelle Galy-Fauroux, Wassila Carpentier, Sylvia Colliec-Jouault, Anna Lokajczyk, Claire Bouvard, Anne-Marie Fischer, Dominique Helley, Françoise Grelac, Thrombose : Épidémiologie, Physiopathologie et Thérapeutiques Innovantes (UMR_S 765), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase (IThEM - U1140), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), French Ministry of Research and Education, French Society of Hematology, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Français de Recherche pour l'Exploitation de la Mer - Atlantique (IFREMER Atlantique), Thrombose : Épidémiologie, Physiopathologie et Thérapeutiques Innovantes ( UMR_S 765 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ), Université Paris Descartes - Paris 5 ( UPD5 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Innovations thérapeutiques en hémostase ( IThEM - U1140 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut Français de Recherche pour l'Exploitation de la Mer - Nantes ( IFREMER Nantes ), Université de Nantes ( UN ), and HAL-UPMC, Gestionnaire

Subjects
Vascular Endothelial Growth Factor A, Cell signaling, fucoidan, angiogenesis, vasculogenesis, migration, signaling, transcriptomics, Cytoskeleton organization, Angiogenesis, Neovascularization, Physiologic, Pharmaceutical Science, Biology, Article, chemistry.chemical_compound, Vasculogenesis, Cell Movement, Polysaccharides, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Discovery, Human Umbilical Vein Endothelial Cells, Humans, lcsh:QH301-705.5, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Cytoskeleton, PI3K/AKT/mTOR pathway, Cell migration, Cell biology, Molecular Weight, Endothelial stem cell, Vascular endothelial growth factor, Gene Expression Regulation, lcsh:Biology (General), chemistry, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Phosphatidylinositol 3-Kinase, Proto-Oncogene Proteins c-akt
Abstract

International audience; Low-molecular-weight fucoidan (LMWF) is a sulfated polysaccharide extracted from brown seaweed that presents antithrombotic and pro-angiogenic properties. However, its mechanism of action is not well-characterized. Here, we studied the effects of LMWF on cell signaling and whole genome expression in human umbilical vein endothelial cells and endothelial colony forming cells. We observed that LMWF and vascular endothelial growth factor had synergistic effects on cell signaling, and more interestingly that LMWF by itself, in the absence of other growth factors, was able to trigger the activation of the PI3K/AKT pathway, which plays a crucial role in angiogenesis and vasculogenesis. We also observed that the effects of LMWF on cell migration were PI3K/AKT-dependent and that LMWF modulated the expression of genes involved at different levels of the neovessel formation process, such as cell migration and cytoskeleton organization, cell mobilization and homing. This provides a better understanding of LMWF's mechanism of action and confirms that it could be an interesting therapeutic approach for vascular repair.

Published
2015

2. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human

Author

Katia Boutourlinsky, Alexandre Croquelois, Dominique Boucher, Sara Bizzotto, Jamel Chelly, Grazia Maria Mancini, Egbert Welker, Camino de Juan Romero, Anne-Gaëlle Le Moing, Jean-François Deleuze, Wassila Carpentier, Renske Oegema, Richard Belvindrah, Karine Poirier, Michel Kielar, Robert Olaso, Nadia Bahi-Buisson, Fiona Francis, Cécile Lebrand, Françoise Phan Dinh Tuy, Víctor Borrell, Patrick Berquin, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Inserm Avenir program, French Agence National de la Recherche [ANR-08-MNP-013, ANR-13-BSV4-0008-01], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Agence Nationale de la Recherche (France), Fondation Bettencourt Schueller, Fédération pour la Recherche sur le Cerveau (France), Swiss National Science Foundation, European Commission, Fondation pour la Recherche Médicale, and Ministerio de Economía y Competitividad (España)

Subjects
Microtubules, Mice, PAFAH1B1, 0302 clinical medicine, Neural Stem Cells, Cell Movement, Cerebral Cortex, 0303 health sciences, Microscopy, Confocal, Neocortex, General Neuroscience, Cell Cycle, Immunohistochemistry, Phenotype, Experimental models of disease, Electroporation, Heterotopia (medicine), medicine.anatomical_structure, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cortex, Microtubule-Associated Proteins, Intracranial Arteriovenous Malformations, Doublecortin Protein, Retroelements, Molecular Sequence Data, Mitosis, Lissencephaly, Developmental neurogenesis, Classical Lissencephalies and Subcortical Band Heterotopias, Spindle Apparatus, Choristoma, Biology, 03 medical and health sciences, Cortical heterotopias, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Amino Acid Sequence, 030304 developmental biology, Progenitor, Wild type, medicine.disease, Neural progenitors, Embryonic stem cell, Introns, Bromodeoxyuridine, Mutation, Neuroscience, 030217 neurology & neurosurgery
Abstract

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human., We thank the Inserm Avenir program, the French Agence National de la Recherche (ANR-08-MNP-013 (F.F.), ANR-13-BSV4-0008-01 (F.F.), ANR Blanc 1103-01 (J.C.), projet R11039KK, ANR E-Rare Program, convention 2011-RaARE-012-01) (J.C.), the Fondation Bettencourt Schueller and the Federation pour la recherche sur le cerveau (FRC) for grants awarded to F.F., the FRC Rotary for an equipment grant awarded to the Institut du Fer à Moulin, the Swiss National Science Foundation (SNSF 31003A-135574, SPUM-33CM30-124089 and 33CM30-140332) and the Fondation Gianni Biaggi de Blasys for grants awarded to A.C., and the SNSF (31003A-125379) for grants awarded to E.W. The research leading to a part of these results received funding from the European Union Seventh Framework Programme FP7/2007–2013 under the project DESIRE (grant agreement no. 602531), la Fondation pour la Recherche Médicale (FRM, J Chelly–Equipe FRM 2013: DEQ2000326477) la Fondation Jacques Espinasse & Danièle (JED)-Belgique and the Spanish Ministry of Economy and Competitiveness grant (BFU2012-33473) awarded to V.B.

Published
2014

3. A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected patients

Author

Ulveling, Damien, Le Clerc, Sigrid, Cobat, Aurélie, Labib, Taoufik, Noirel, Josselin, Laville, Vincent, Coulonges, Cédric, Carpentier, Wassila, Nalpas, Bertrand, Heim, Markus H., Poynard, Thierry, Cerny, Andreas, Pol, Stanislas, Bochud, Pierre-Yves, Dabis, Francois, Theodorou, Ioannis, Lévy, Yves, Salmon, Dominique, Abel, Laurent, Dominguez, Stéphanie, Zagury, Jean-François, Grp, HEPAVIH ANRS CO13 Cohort Study, Grp, Swiss Hepatitis C Cohort Study, Genoscan, French ANRS HC EP 26, Laboratoire génomique, bioinformatique et applications (GBA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hépatologie [CHU Cochin], Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital Basel [Basel], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epatocentro Ticino, Université de Lausanne (UNIL), Epidemiologie-Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Rockefeller University [New York], French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Merck Sharp and Dohme (France), National Agency for Research on AIDS and Viral Hepatitis (ANRS), Swiss National Science Foundation [33CS30\₁48417, 324730-144054], Leenaards Foundation, Santos-Suarez Foundation, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire génomique, bioinformatique et applications ( GBA ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Human genetics of infectious diseases: Complex predisposition ( Equipe Inserm U1163 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-CHU Cochin [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Pitié-Salpêtrière [APHP], Université de Lausanne ( UNIL ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bordeaux Ségalen [Bordeaux 2], Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -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 ) -Sorbonne Université-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Université, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), CHU Cochin [AP-HP], The Rockefeller University [New-York], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Cochin [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Liver Cirrhosis, medicine.medical_specialty, Linkage disequilibrium, MESH : Hepatitis C, Chronic, Hepatitis C virus, Genome-wide association study, HIV Infections, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, MESH: Genetic Loci, 03 medical and health sciences, Liver disease, Acquired immunodeficiency syndrome (AIDS), MESH : Genetic Loci, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, MESH : HIV Infections, Humans, MESH : Liver Cirrhosis, MESH: Humans, Hepatology, Coinfection, MESH: Polymorphism, Single Nucleotide, MESH : Humans, MESH : Polymorphism, Single Nucleotide, MESH : Disease Progression, MESH: HIV Infections, Hepatitis C, Chronic, medicine.disease, 3. Good health, MESH: Coinfection, MESH: Hepatitis C, Chronic, MESH : Coinfection, 030104 developmental biology, Genetic Loci, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Immunology, MESH: Genome-Wide Association Study, Disease Progression, MESH: Disease Progression, MESH: Liver Cirrhosis, Viral hepatitis, MESH : Genome-Wide Association Study, Genome-Wide Association Study
Abstract

International audience; There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) monoinfection, but this aspect has been little investigated in patients coinfected with HCV and human immunodeficiency virus (HIV). We performed the first genome-wide association study of liver fibrosis progression in patients coinfected with HCV and HIV, using the well-characterized French National Agency for Research on AIDS and Viral Hepatitis CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan), providing a quantitative fibrosis score. After quality control, a genome-wide association study was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed single-nucleotide polymorphisms. Single-nucleotide polymorphisms with P values

Published
2016

4. Early born neurons are abnormally positioned in the doublecortin knockout hippocampus

Author

Virginie Lavilla, Reham Khalaf-Nazzal, Leila Muresan, Melissa A. Stouffer, Audrey Roumegous, Fiona Francis, Robert Olaso, Imane Moutkine, Wassila Carpentier, Hugues Roest Crollius, Benoit Albaud, Sylvie Dumont, Nicolas Cagnard, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Plateforme Affymetrix de biologie moléculaire, Institut Curie [Paris], Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de biologie de l'ENS Paris (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut de biologie de l'ENS Paris (UMR 8197/1024) ( IBENS ), École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité Mixte de Service d'Imagerie et de Cytométrie ( UMS LUMIC ), INSTITUT CURIE, Plate Forme Paris Descartes de Bioinformatique ( BIP-D ), Université Paris Descartes - Paris 5 ( UPD5 ), Cortex development and pathology (U1270), Serotonin, microglia, plasticity and pathology (U1270), Cortical development and pathology (U1270), and HAL-UPMC, Gestionnaire

Subjects
Doublecortin Domain Proteins, Male, 0301 basic medicine, Doublecortin Protein, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Laser Capture Microdissection, Hippocampal formation, Cell morphology, Hippocampus, Mice, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Image Processing, Computer-Assisted, Genetics, medicine, Animals, CA1 Region, Hippocampal, Molecular Biology, Genetics (clinical), Mice, Knockout, Neurons, Microscopy, Confocal, biology, Neuropeptides, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Wild type, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Brain, General Medicine, Anatomy, CA3 Region, Hippocampal, Phenotype, Doublecortin, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, nervous system, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [ SDV.BDD.EO ] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Neuron, Pyramidal cell, Microtubule-Associated Proteins
Abstract

International audience; Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. The Dcx protein plays a key role in neuronal migration, and hippocampal pyramidal neurons in Dcx knockout (KO) mice are disorganized. The single CA3 pyramidal cell layer observed in wild type (WT) is present as two abnormal layers in the KO, and CA3 KO pyramidal neurons are more excitable than WT. Dcx KO mice also exhibit spontaneous epileptic activity originating in the hippocampus. It is unknown, however, how hyperexcitability arises and why two CA3 layers are observed.Transcriptome analyses were performed to search for perturbed postnatal gene expression, comparing Dcx KO CA3 pyramidal cell layers with WT. Gene expression changes common to both KO layers indicated mitochondria and Golgi apparatus anomalies, as well as increased cell stress. Intriguingly, gene expression analyses also suggested that the KO layers differ significantly from each other, particularly in terms of maturity. Layer-specific molecular markers and BrdU birthdating to mark the final positions of neurons born at distinct timepoints revealed inverted layering of the CA3 region in Dcx KO animals. Notably, many early-born ‘outer boundary’ neurons are located in an inner position in the Dcx KO CA3, superficial to other pyramidal neurons. This abnormal positioning likely affects cell morphology and connectivity, influencing network function. Dissecting this Dcx KO phenotype sheds light on coordinated developmental mechanisms of neuronal subpopulations, as well as gene expression patterns contributing to a bi-layered malformation associated with epilepsy.

Published
2016

5. Homogeneous Inflammatory Gene Profiles Induced in Human Dermal Fibroblasts in Response to the Three Main Species of Borrelia burgdorferi sensu lato

Author

Meddeb, Mariam, Carpentier, Wassila, Cagnard, Nicolas, Nadaud, Sophie, Grillon, Antoine, Barthel, Cathy, de Martino, Sylvie, Jaulhac, Benoît, Boulanger, Nathalie, Schramm, Frédéric, Virulence Bactérienne Précoce : fonctions cellulaires et contrôle de l'infection aigüe et subaigüe, Université de Strasbourg (UNISTRA), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), HAL-UPMC, Gestionnaire, Virulence bactérienne précoce, Université de Strasbourg ( EA7290 ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plate Forme Paris Descartes de Bioinformatique ( BIP-D ), Université Paris Descartes - Paris 5 ( UPD5 ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
[ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, bacterial infections and mycoses
Abstract

International audience; In Lyme borreliosis, the skin is the key site for bacterial inoculation by the infected tick and for cutaneous manifestations. We previously showed that different strains of Borrelia burg-dorferi sensu stricto isolated from tick and from different clinical stages of the Lyme borrelio-sis (erythema migrans, and acrodermatitis chronica atrophicans) elicited a very similar transcriptional response in normal human dermal fibroblasts. In this study, using whole transcriptome microarray chips, we aimed to compare the transcriptional response of normal human dermal fibroblasts stimulated by 3 Borrelia burgdorferi sensu lato strains belonging to 3 main pathogenic species (B. afzelii, B. garinii and B. burgdorferi sensu stricto) in order to determine whether " species-related " inflammatory pathways could be identified. The three Borrelia strains tested exhibited similar transcriptional profiles, and no species-specific fingerprint of transcriptional changes in fibroblasts was observed. Conversely , a common core of chemokines/cytokines (CCL2, CXCL1, CXCL2, CXCL6, CXCL10, IL-6, IL-8) and interferon-related genes was stimulated by all the 3 strains. Dermal fibroblasts appear to play a key role in the cutaneous infection with Borrelia, inducing a homogeneous inflammatory response, whichever Borrelia species was involved.

Published
2016

6. An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation

Author

Wassila Carpentier, Isabelle Callebaut, Capucine Picard, Nada Jabado, Patrick Revy, Alain Fischer, Fabien Touzot, Laetitia Kermasson, Nathalie Lambert, Tangui Le Guen, Marina Cavazzana, Patrick Nitschke, Jean Soulier, Chantal Lagresle-Peyrou, Jean-Pierre de Villartay, Annick Lim, Christine Bole-Feysot, Isabelle André-Schmutz, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC-BT 502 INSERM, Departement de Biotherapie, the Study Center of Primary Immunodeficiencies, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Bioinformatique, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (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), Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris] (IP), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), INSERM U944 Laboratoire de Pathologie et Virologie Moléculaire, Laboratoire de Pathologie et Virologie Moléculaire, the Genome Quebec Innovation Centre, McGill University = Université McGill [Montréal, Canada], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Département d'Immunologie, Institut Pasteur [Paris], Institut de minéralogie, de physique des matériaux et de cosmochimie ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de recherche pour le développement [IRD] : UR206, McGill University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Biology, Lymphopenia, MYSM1, medicine, Immunology and Allergy, Gene silencing, Missense mutation, Humans, histone deubiquitinase, MYB, Transcription factor, Gene, Genetics, B-Lymphocytes, Hematopoietic stem cell homeostasis, [ SDV ] Life Sciences [q-bio], Lymphocyte differentiation, Immunologic Deficiency Syndromes, Hematopoietic stem cell, Infant, Cell Differentiation, genetic reversion, 3. Good health, Hematopoiesis, DNA-Binding Proteins, medicine.anatomical_structure, Mutation, Trans-Activators, Ubiquitin-Specific Proteases, immunodeficiency, Transcription Factors
Abstract

Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119- monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. Objectives: We sought to characterize the underlying genetic cause of this syndrome. Methods: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. Conclusions: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.

Published
2015

7. Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability

Author

Tangui Le Guen, Gérard Couillault, Laetitia Gaillard, Jean Soulier, Capucine Picard, Jean-Pierre de Villartay, Fabien Touzot, Patrick Nitschke, Isabelle Callebaut, Arturo Londoño-Vallejo, Michael Schertzer, Nada Jabado, Alain Fischer, Mylène Perderiset, Wassila Carpentier, Patrick Revy, Laurent Jullien, Thomas, Danielle, Centre de recherche en Biologie Cellulaire (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Telomeres and Cancer Laboratory, Institut Curie [Paris], Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de pediatrie, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de minéralogie et de physique des milieux condensés ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IPG PARIS-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), and Department of Human Genetics

Subjects
Genome instability, DNA Replication, Male, DNA damage, DNA repair, Genetic Linkage, Hoyeraal-Hreidarsson syndrome, Biology, medicine.disease_cause, Dyskeratosis Congenita, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Exome, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Telomerase, Genetics (clinical), Cells, Cultured, Telomere Shortening, 030304 developmental biology, 0303 health sciences, Mutation, Fetal Growth Retardation, Sequence Analysis, RNA, DNA replication, DNA Helicases, Infant, Telomere Homeostasis, General Medicine, Telomere, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Child, Preschool, Microcephaly, Female, Sequence Alignment, Dyskeratosis congenita, DNA Damage
Abstract

International audience; Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrowfailure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomeredysfunctionandthese diseases.Bycombining whole-genomelinkage analysisandexomesequencing,we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

Published
2013

8. RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects

Author

Cécile, Jeanpierre, Guillaume, Macé, Mélanie, Parisot, Vincent, Morinière, Audrey, Pawtowsky, Marion, Benabou, Jelena, Martinovic, Jeanne, Amiel, Tania, Attié-Bitach, Anne-Lise, Delezoide, Philippe, Loget, Patricia, Blanchet, Dominique, Gaillard, Marie, Gonzales, Wassila, Carpentier, Patrick, Nitschke, Frédéric, Tores, Laurence, Heidet, Corinne, Antignac, Rémi, Salomon, J, Tantau, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), CHU Necker - Enfants Malades [AP-HP], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], 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), Service de biologie du développement[Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Service de génétique et de foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte ( MARHEA ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Université de Reims Champagne-Ardenne ( URCA ) -IFR53-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Peer, Hal, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université

Subjects
medicine.medical_specialty, endocrine system, congenital, hereditary, and neonatal diseases and abnormalities, DNA Copy Number Variations, endocrine system diseases, 030232 urology & nephrology, Multicystic dysplastic kidney, Kidney development, medicine.disease_cause, Kidney, Polymorphism, Single Nucleotide, Congenital Abnormalities, 03 medical and health sciences, Open Reading Frames, 0302 clinical medicine, Fetus, renal agenesis, evolutionary conserved non-coding regions, Internal medicine, Genetics, medicine, Glial cell line-derived neurotrophic factor, Humans, Glial Cell Line-Derived Neurotrophic Factor, Multiple endocrine neoplasia, Renal agenesis, Genetics (clinical), Alleles, 030304 developmental biology, CNVs, 0303 health sciences, Mutation, variants, biology, Proto-Oncogene Proteins c-ret, Gene Expression Regulation, Developmental, medicine.disease, 3. Good health, Endocrinology, medicine.anatomical_structure, biology.protein, renal hypodysplasia, Kidney Diseases, Kidney disease, Signal Transduction
Abstract

International audience; Background The RET/GDNF signalling pathway plays a crucial role during development of kidneys and enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples. Objective and Methods To better characterize the involvement of RET and GDNF in kidney development defects, we studied a series of 105 fetuses with bilateral defects including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs and RET intron 1 were analysed. Copy number variations (CNVs) at these loci were also investigated. Results We identified: (i) a low frequency (< 7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (ii) no GDNF mutation; (iii) similar allele frequencies in patients and controls for most SNP variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs. 2%, P=0.01); (iv) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (v) absence of CNVs. Conclusion These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.

Published
2011

9. Intrications organo-psychiatriques : le concept de troubles psychiatriques complexes, quels examens complémentaires ?

Author

Antonin Lamaziere, Jérôme Guéchot, Jean Capron, Julien Rossignol, Alaina Borden, Florian Ferreri, Bluenn Quillerou, Arsène Mekinian, Philippe Nuss, Alexis Bourla, Stéphane Mouchabac, Sorbonne Université (SU), Service de psychiatrie adulte [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neurologie [CHU Saint-Antoine], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Médecine Interne [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, Recall, Heart disease, business.industry, MEDLINE, General Medicine, Depressive Syndrome, medicine.disease, 3. Good health, 030227 psychiatry, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Psychiatric diagnosis, Medicine, business, Psychiatry, 030217 neurology & neurosurgery, Anxiety disorder
Abstract

International audience; The purpose of this article is to describe complex psychiatric disorders, to recall “minimal classical” explorations in psychiatry, to describe the concept of “complex psychiatric disorders” and to propose a systematized method of exploration.Some organic diseases are well known for their links with psychiatric disorders (manic syndrome and hyperthyroidism, depressive syndrome and corticotropic insufficiency, anxiety disorder and heart disease, etc.).Many other neurological, autoimmune, metabolic, paraneoplastic or endocrine pathologies can have essentially psycho-behavioral manifestations before being neurological or systemic.A large number of factors (nutritional, toxic, immunological, etc.), often ignored, influence the links between organicity and psychiatric pathologies.It is necessary to optimize the medical management of these patients in whom the psychiatric diagnosis masks a curable organo-psychiatric cause.; Cet article a pour objectifs de décrire des troubles psychiatriques complexes, de rappeler les explorations « classiques minimales » en psychiatrie, de décrire le concept de « troubles psychiatriques complexes » et de proposer une méthode d’exploration systématisée.Certaines pathologies organiques sont bien connues pour leurs liens avec les troubles psychiatriques (syndrome maniaque et hyperthyroïdie, syndrome dépressif et insuffisance corticotrope, trouble anxieux et maladie cardiaque, etc.).De nombreuses autres pathologies neurologiques, auto-immunes, métaboliques, paranéoplasiques ou endocriniennes peuvent avoir des manifestations essentiellement psycho-comportementales avant d’être neurologiques ou systémiques.Un grand nombre de facteurs (nutritionnels, toxiques, immunologiques, etc.), souvent ignorés, exercent une influence sur les liens existants entre organicité et pathologies psychiatriques.Il est nécessaire d’optimiser la prise en charge médicale de ces patients chez qui le diagnostic psychiatrique masque une cause organo-psychiatrique curable.

Published
2019

10. A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family

Author

Audo, Isabelle, Bujakowska, Kinga, Mohand-Said, Saddek, Tronche, Sophie, Lancelot, Marie-Elise, Antonio, Aline, Germain, Aurore, Lonjou, Christine, Carpentier, Wassila, Sahel, Jose-Alain, Bhattacharya, Shomi, Christina Zeitz, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Institute of Ophthalmology [London], University College of London [London] (UCL), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Gestionnaire, Hal Sorbonne Université, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Adult, Male, Genotype, genetic structures, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Genes, Recessive, Polymorphism, Single Nucleotide, Severity of Illness Index, Consanguinity, Humans, Age of Onset, Hearing Loss, Oligonucleotide Array Sequence Analysis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Base Sequence, Portugal, Vision Tests, Homozygote, Chromosome Mapping, Membrane Proteins, Middle Aged, Pedigree, [SDV] Life Sciences [q-bio], Phenotype, Female, sense organs, Usher Syndromes, Retinitis Pigmentosa, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

International audience; PURPOSE:To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition.METHODS:A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing.RESULTS:The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment.CONCLUSIONS:We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.

Published
2020

11. Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia

Author

Charlotte Dubucs, Aurore Siegfried, Emmanuelle Uro-Coste, Gaëlle Pierron, I. Catalaa, Marion Gambart, Julien Masliah-Planchon, Badreddine Mohand-Oumoussa, Franck Tirode, Sarah Péricart, Franck Bourdeaut, Franck-Emmanuel Roux, Delphine Larrieu-Ciron, Yvan Nicaise, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut Curie, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Lyon (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), TIRODE, Franck, Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
medicine.medical_specialty, Pathology, Neurology, CIC-ATXN1-ATXN1L axis, DNA methylation-based classification, Central nervous system, Brain tumor, Oncogenic gene fusions, CIC-ATXN1-ATXN1L axis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC346-429, Pathology and Forensic Medicine, Fusion gene, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ATXN1, medicine, Letter to the Editor, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, NUTM1-rearranged neoplasia, RNA sequencing, NUTM1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Oncogenic gene fusions, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neurology (clinical)
Abstract

International audience

Published
2019

12. Optimization and validation of the methods for the total mercury and methylmercury determination in breast milk

Author

Marion Hulin, Jean-Luc Volatier, Alexandra Rousseau, Jean Dumont, Véronique Sirot, Justine Verdeil, Thierry Guérin, R Serreau, Rachida Chekri, Tabassome Simon, Fabienne Séby, Véronique Vacchina, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
[SDV]Life Sciences [q-bio], chemistry.chemical_element, Food Contamination, 010501 environmental sciences, Isotope dilution, Breast milk, 01 natural sciences, High-performance liquid chromatography, Mass Spectrometry, Analytical Chemistry, chemistry.chemical_compound, Dry weight, Limit of Detection, Humans, Methylmercury, Inductively coupled plasma mass spectrometry, ComputingMilieux_MISCELLANEOUS, Chromatography, High Pressure Liquid, 0105 earth and related environmental sciences, Chromatography, Milk, Human, 010401 analytical chemistry, Mercury, Repeatability, Methylmercury Compounds, 0104 chemical sciences, Mercury (element), chemistry, Environmental chemistry, Linear Models, Food Analysis
Abstract

The objective of the work was to develop and validate methods for the total Hg and methylmercury (MeHg) in breast milk that could be further used to obtain first data on chemical contamination of French breast milk. For total Hg determination, the potential of two techniques, namely Advanced Mercury Analyzer (AMA) and ICP MS, was compared. For MeHg determination, ICP MS detection associated to a quantification by isotopic dilution was used and the potential of a preliminary separation by gas or liquid chromatography was evaluated and discussed. The optimization studies have shown that AMA for total Hg determination and HPLC - ID - ICP MS, after a preconcentration step by freeze-drying, for MeHg quantification were the most relevant methods to use for epidemiologic studies. The figures of merit for both methods were evaluated by means of accuracy profiles in terms of limits of quantification (1.82 and 1.35µg Hg/kg dry weight, corresponding to 0.22 and 0.16µg Hg/kg wet basis for total Hg and MeHg, respectively), repeatability (2-11% and 3-8% for total Hg and MeHg respectively), intermediate precision reproducibility (4-12% and 4-8% for total Hg and MeHg respectively) and trueness bias (-0.1-9% and -4-0% for total Hg and MeHg respectively). The methods were then applied to 180 breast milk samples. Total Hg concentrations ranged from

Published
2017

13. The MPK8-TCP14 pathway promotes seed germination in Arabidopsis

Author

Christophe Bailly, Cédric Pionneau, Marie Boudsocq, Miguel A. Blázquez, Wei Zhang, Juliette Puyaubert, Francesca Resentini, Lucrèce Matheron, Stéphanie Huguet, Françoise Cochet, Sandrine Lebreton, Emmanuel Baudouin, Maharajah Ponnaiah, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut d'écologie et des sciences de l'environnement de Paris (iEES Paris ), Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universitat Politècnica de València (UPV), Chinese Scholarship Council China Scholarship Council [201606690037], Centre National de la Recherche Scientifique (CNRS), Sorbonne Universite, LabEx Saclay Plant Sciences-SPS [ANR-10-LABX-0040-SPS], Laboratoire de Biologie du Développement [IBPS] (LBD), Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Biologie du Développement (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut d'écologie et des sciences de l'environnement de Paris (IEES (UMR_7618 / UMR_D_242 / UMR_A_1392 / UM_113) ), Institut National de la Recherche Agronomique (INRA)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC), Instituto de Biología Molecular y Celular de Plantas, Instituto de Biologia Molecular y Celular de Plantas (UPV-CSIC), and Universidad Politécnica de Valencia

Subjects
0106 biological sciences, 0301 basic medicine, Arabidopsis thaliana, Arabidopsis, MAP kinase 8, Germination, Plant Science, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Cell Wall, Gene Expression Regulation, Plant, Tobacco, Genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Dormancy, Phosphorylation, Transcription factor, Gibberellic acid, ComputingMilieux_MISCELLANEOUS, biology, Seed, Arabidopsis Proteins, Cell Biology, Cell cycle, Plant Dormancy, Plants, Genetically Modified, biology.organism_classification, Gibberellins, Cell biology, 030104 developmental biology, Cycloidea, chemistry, Mutation, Seeds, Gibberellin, Mitogen-Activated Protein Kinases, Teosinte Branched1, Proliferating cell factor 14, Abscisic Acid, Transcription Factors, 010606 plant biology & botany
Abstract

[EN] The accurate control of dormancy release and germination is critical for successful plantlet establishment. Investigations in cereals hypothesized a crucial role for specific MAP kinase (MPK) pathways in promoting dormancy release, although the identity of the MPK involved and the downstream events remain unclear. In this work, we characterized mutants for Arabidopsis thaliana MAP kinase 8 (MPK8). Mpk8 seeds presented a deeper dormancy than wild-type (WT) at harvest that was less efficiently alleviated by after-ripening and gibberellic acid treatment. We identified Teosinte Branched1/Cycloidea/Proliferating cell factor 14 (TCP14), a transcription factor regulating germination, as a partner of MPK8. Mpk8 tcp14 double-mutant seeds presented a deeper dormancy at harvest than WT and mpk8, but similar to that of tcp14 seeds. MPK8 interacted with TCP14 in the nucleus in vivo and phosphorylated TCP14 in vitro. Furthermore, MPK8 enhanced TCP14 transcriptional activity when co-expressed in tobacco leaves. Nevertheless, the stimulation of TCP14 transcriptional activity by MPK8 could occur independently of TCP14 phosphorylation. The comparison of WT, mpk8 and tcp14 transcriptomes evidenced that whereas no effect was observed in dry seeds, mpk8 and tcp14 mutants presented dramatic transcriptomic alterations after imbibition with a sustained expression of genes related to seed maturation. Moreover, both mutants exhibited repression of genes involved in cell wall remodeling and cell cycle G1/S transition. As a whole, this study unraveled a role for MPK8 in promoting seed germination, and suggested that its interaction with TCP14 was critical for regulating key processes required for germination completion., This work was supported by the Chinese Scholarship Council (201606690037 to WZ), CNRS, Sorbonne Universite and the LabEx Saclay Plant Sciences-SPS (ANR-10-LABX-0040-SPS). The authors acknowledge Jean Francois Gilles from the IBPS imaging core facility, which is supported by Conseil Regional Ile-de-France, for help with confocal microscopy. The authors thank Cristina Urbez (CSIC-U Politecnica de Valencia) for technical assistance. The authors thank Pr Brendan Davies (University of Leeds) for providing tcp14.4 seeds, and Dr Jean Colcombet (IPS2 Universite Paris-Saclay) for providing MPK8-pDONOR vector.

Published
2019

14. Long-Term Pantethine Treatment Counteracts Pathologic Gene Dysregulation and Decreases Alzheimer’s Disease Pathogenesis in a Transgenic Mouse Model

Author

Santiago Rivera, Max de Reggi, Wassila Carpentier, Delphine Stephan, Kévin Baranger, Bouchra Gharib, Manuel van Gijsel-Bonnello, Michel Khrestchatisky, Philippe Benech, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), University of Dundee, UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, Genetically modified mouse, Time Factors, Mice, Transgenic, Inflammation, Pharmacology, Hippocampus, Neuroprotection, Drug Administration Schedule, Pathogenesis, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Phagocytosis, Alzheimer Disease, In vivo, medicine, Animals, Humans, Pharmacology (medical), Amyloid beta-Peptides, Pantethine, medicine.disease, 3. Good health, Astrogliosis, Aggression, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, chemistry, Pantetheine, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Astrocyte
Abstract

The low-molecular weight thiol pantethine, known as a hypolipidemic and hypocholesterolemic agent, is the major precursor of co-enzyme A. We have previously shown that pantethine treatment reduces amyloid-β (Aβ)-induced IL-1β release and alleviates pathological metabolic changes in primary astrocyte cultures. These properties of pantethine prompted us to investigate its potential benefits in vivo in the 5XFAD (Tg) mouse model of Alzheimer’s disease (AD).1.5-month-old Tg and wild-type (WT) male mice were submitted to intraperitoneal administration of pantethine or saline control solution for 5.5 months. The effects of such treatments were investigated by performing behavioral tests and evaluating astrogliosis, microgliosis, Αβ deposition, and whole genome expression arrays, using RNAs extracted from the mice hippocampi. We observed that long-term pantethine treatment significantly reduced glial reactivity and Αβ deposition, and abrogated behavioral alteration in Tg mice. Moreover, the transcriptomic profiles revealed that after pantethine treatment, the expression of genes differentially expressed in Tg mice, and in particular those known to be related to AD, were significantly alleviated. Most of the genes overexpressed in Tg compared to WT were involved in inflammation, complement activation, and phagocytosis and were found repressed upon pantethine treatment. In contrast, pantethine restored the expression of a significant number of genes involved in the regulation of Αβ processing and synaptic activities, which were downregulated in Tg mice. Altogether, our data support a beneficial role for long-term pantethine treatment in preserving CNS crucial functions altered by Aβ pathogenesis in Tg mice and highlight the potential efficiency of pantethine to alleviate AD pathology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00754-z) contains supplementary material, which is available to authorized users.

Published
2019

15. SHH medulloblastoma in a young adult with a TCF4 germline pathogenic variation

Author

Lydie Burglen, Olivier Ayrault, Irina Giurgea, Maud Blanluet, Franck Bielle, François Doz, David Gentien, Audrey Rapinat, Julien Masliah-Planchon, Olivier Delattre, Badreddine Mohand Oumoussa, Diane Doummar, Gaëlle Pierron, Christine Bourneix, Stéphane Clemenceau, Elodie Girard, Franck Bourdeaut, Celio Pouponnot, Mamy Andrianteranagna, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), 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), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), École supérieure du professorat et de l'éducation - Académie de Grenoble (ESPE Grenoble), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Grenoble Alpes (UGA), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurogénétique moléculaire, CHU Trousseau [APHP], Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), Signalisation cellulaire et neurobiologie (SNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de recherche translationnelle, Institut Curie, Service de Génétique Oncologique, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropathologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Grenoble Alpes - École supérieure du professorat et de l'éducation - Académie de Grenoble (UGA ESPE Grenoble), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], and Département de Recherche Translationnelle

Subjects
Medulloblastoma, 0303 health sciences, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, TCF4, Biology, medicine.disease, Germline, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Variation (linguistics), medicine, Neurology (clinical), Young adult, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2019

16. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Author

Girard, Elodie, Eon-Marchais, Séverine, Olaso, François, Renault, Anne, Damiola, Francesca, Dondon, Marie-Gabrielle, Barjhoux, Laure, Goidin, Didier, Meyer, François, Le Gal, Dorothée, Beauvallet, Juana, Mebirouk, Noura, Lonjou, Christine, Coignard, Julie, Marcou, Morgane, Cavaciuti, Eve, Baulard, François, Bihoreau, François, Cohen-Haguenauer, Odile, Leroux, Dominique, Penet, Jean, Fert-Ferrer, Sandra, Colas, Chrystelle, Frebourg, Thierry, Eisinger, François, Adenis, Claude, Fajac, Anne, Gladieff, Laurence, Tinat, Julie, Floquet, Anne, Chiesa, Jean, Giraud, Sophie, Mortemousque, Isabelle, Soubrier, Florent, Audebert-Bellanger, Séverine, Limacher, Jean-Marc, Lasset, Christine, Lejeune-Dumoulin, Sophie, Dreyfus, Catherine, Bignon, Yves-Jean, Longy, Michel, Pujol, Pascal, Venat-Bouvet, Laurence, Bonadona, Valérie, Berthet, Pascaline, Luporsi, Elisabeth, Maugard, Christine, Noguès, Catherine, Delnatte, Capucine, Fricker, Paul, Gesta, Paul, Faivre, Laurence, Lortholary, Alain, Buecher, Bruno, Caron, Olivier, Gauthier-Villars, Marion, Coupier, Isabelle, Servant, Nicolas, Boland, Anne, Mazoyer, Sylvie, Deleuze, Jean-François, Stoppa-Lyonnet, Dominique, Andrieu, Nadine, Lesueur, Fabienne, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Life Sciences and Diagnostics Group [Les Ulis, France], Agilent Technologies France, Laboratoire Information, Milieux, Médias, Médiations - EA 3820 (I3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université de Toulon (UTLN), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Traitement Algorithmique et Matériel de la Communication, de l'Information et de la Connaissance (TAMCIC), Ecole Nationale Supérieure des Télécommunications de Bretagne-Centre National de la Recherche Scientifique (CNRS), CRLCC Jean Godinot, Centre Hospitalier de Chambéry (C.H.de Chambéry), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département de Génétique [Institut Curie, Paris] (Unité de Pharmacogénomique), Institut Curie [Paris], Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Claudius Regaud, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département d'oncologie médicale, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital pasteur [Colmar], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Sainte Catherine [Avignon], 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]), Département de pathologie, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Dupuytren [CHU Limoges], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Consultation d'Oncogénétique, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Alexis Vautrin (CAV), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire d'Oncogénétique, CRLCC René Huguenin, CRLCC René Gauducheau, Service d'Oncologie Médicale [Strasbourg] (UNICANCER Centre Paul Strauss), Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Catherine-de-Sienne [Nantes] (CCS), Service de Génétique Oncologique, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, 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), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Grant sponsor: comprehensive cancer center SiRIC, Grant numbers: INCa-DGOS-4654, Grant sponsor: Fondation ARC pour la recherche sur le cancer, Grant numbers: PJA 20151203365, Grant sponsor: France Génomique National infrastructure, Grant numbers: ANR-10-INBS-09, Grant sponsor: Institut National du Cancer (INCa), Grant numbers: b2008-029/LL-LC, Grant sponsor: Ligue Comité de Paris, Grant numbers: RS15/75-78, Grant sponsor: Ligue Nationale Contre le Cancer, Grant numbers: PRE05/DSL PRE07/DSL PRE11/NA., Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des cancers : Radiocarcinogénèse et effets iatrogènes des traitements, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), E06, Centre de Recherche en Cancérologie de Lyon (CRCL), 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)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CRESS, Université de Franche-Comté (UFC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, CHU Saint-Antoine [APHP], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Centre oscar lambert, service d'hématologie chu, CHU Tenon [APHP], CRLCC Institut Claudius Regaud, Centre Beninois pour l'Environnement et le développement économique et Social (CEBEDES), Service de Génétique Clinique [CHRU Nïmes], Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Service de Pédiatrie et de Génétique Médicale, Hôpital Jeanne de Flandre [Lille], Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Université Clermont Auvergne (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin, CRLCC Jean Perrin, Institut Bergonié - CRLCC Bordeaux, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-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 Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de diagnostic génétique, Hôpital Universitaire de Strasbourg, Strasbourg, Centre René Gauducheau, Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Fédération Francophone de la Cancérologie Digestive, FFCD, Institut Gustave Roussy (IGR), Service d'oncogénétique, Institut Curie, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Equipe 6, Université Paris Descartes - Paris 5 (UPD5), Méthodologie statistique et épidémiologie génétique des maladies multifactorielles, Institut National de la Santé et de la Recherche Médicale (INSERM), Section Génétique - Groupe Prédispositions génétiques au cancer, Centre International de Recherche contre le Cancer (CIRC), MINES ParisTech - École nationale supérieure des mines de Paris, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Télécommunications de Bretagne, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Lille Nord de France (COMUE)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), 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), Andrieu, Nadine, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Adult, DNA Repair, case-control study, [SDV]Life Sciences [q-bio], Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Risk Assessment, Cancer Genetics and Epigenetics, breast cancer, multigene panel testing, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Genetic Predisposition to Disease, Genetic Testing, Aged, Aged, 80 and over, [SDV.GEN]Life Sciences [q-bio]/Genetics, Siblings, case–control study, Middle Aged, [SDV] Life Sciences [q-bio], variant, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, exome sequencing
Abstract

Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates., What's new? Pathogenic variants in BRCA1 and BRCA2 only explain the genetic cause of about 10% of hereditary breast and ovarian cancer families, and the clinical usefulness of testing other genes following the recent introduction of cost‐effective multigene panel sequencing in diagnostics laboratories remains questionable. This large case‐control study describes genetic variation in 113 DNA repair genes and specifies breast cancer relative risks associated with rare deleterious‐predicted variants in PALB2, ATM, and CHEK2. Importantly, different types of variants within the same gene can lead to different risk estimates. The results may help improve risk prediction models and define gene‐specific consensus management guidelines.

Published
2019

17. The Tumor Suppressor SASH1 Interacts With the Signal Adaptor CRKL to Inhibit Epithelial–Mesenchymal Transition and Metastasis in Colorectal Cancer

Author

Solenne Chardonnet, Eduardo Domínguez Medina, Fabian Christoph Franke, Johannes Müller, Ulrich Nitsche, Klaus-Peter Janssen, Miguel Abal, Ewa Ninio, Henri Weidmann, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Universidade de Santiago de Compostela [Spain] (USC ), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, DMEM, Dulbecco's modified Eagle medium, Colorectal cancer, Amino Acid Motifs, Metastasis, 0302 clinical medicine, GTPase, guanosine triphosphatase, RNA interference, Neoplasm Metastasis, TGF, transforming growth factor, Original Research, GFP, green fluorescent protein, CRKL, V-Crk avian sarcoma virus CT10 oncogene homolog-like, TNF, tumor necrosis factor, SRC-Kinase, ZEB, zinc-finger δEF1 family, Gastroenterology, EMT, Nuclear Proteins, gRNA, guide RNA, mRNA, messenger RNA, 3. Good health, ddc, CRISPR/Cas9, Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9, Phenotype, 030211 gastroenterology & hepatology, EMT, epithelial-mesenchymal transition, Colorectal Neoplasms, Tumor Suppressor, Chemoresistance, Protein Binding, Signal Transduction, Proto-oncogene tyrosine-protein kinase Src, Epithelial-Mesenchymal Transition, PBS, phosphate-buffered saline, SH3N, N-terminal Src-homology 3 domain, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, SH2, Src-homology 2 domain, src Homology Domains, cDNA, complementary DNA, 03 medical and health sciences, medicine, Humans, Neoplasm Invasiveness, Epithelial–mesenchymal transition, lcsh:RC799-869, Adaptor Proteins, Signal Transducing, Hepatology, Oncogene, Tumor Suppressor Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, HCT116 Cells, medicine.disease, qRT-PCR, quantitative reverse-transcription polymerase chain reaction, CRKL, HEK293 Cells, 030104 developmental biology, MS, mass spectrometry, SH3, Src-homology 3 domain, NLS, nuclear localization signal, Cell culture, Cancer research, lcsh:Diseases of the digestive system. Gastroenterology, BSA, bovine serum albumin, CRISPR-Cas Systems, SASH1, sterile α motif– and Src-homology 3–domain containing 1
Abstract

Background & Aims The tumor-suppressor sterile α motif– and Src-homology 3–domain containing 1 (SASH1) has clinical relevance in colorectal carcinoma and is associated specifically with metachronous metastasis. We sought to identify the molecular mechanisms linking decreased SASH1 expression with distant metastasis formation. Methods SASH1-deficient, SASH1-depleted, or SASH1-overexpressing HCT116 colon cancer cells were generated by the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9-method, RNA interference, and transient plasmid transfection, respectively. Epithelial-mesenchymal transition (EMT) was analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblotting, immunofluorescence microscopy, migration/invasion assays, and 3-dimensional cell culture. Yeast 2-hybrid assays and co-immunoprecipitation/mass-spectrometry showed V-Crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) as a novel interaction partner of SASH1, further confirmed by domain mapping, site-directed mutagenesis, co-immunoprecipitation, and dynamic mass redistribution assays. CRKL-deficient cells were generated in parental or SASH1-deficient cells. Metastatic capacity was analyzed with an orthotopic mouse model. Expression and significance of SASH1 and CRKL for survival and response to chemotherapy was assessed in patient samples from our department and The Cancer Genome Atlas data set. Results SASH1 expression is down-regulated during cytokine-induced EMT in cell lines from colorectal, pancreatic, or hepatocellular cancer, mediated by the putative SASH1 promoter. Deficiency or knock-down of SASH1 induces EMT, leading to an aggressive, invasive phenotype with increased chemoresistance. SASH1 counteracts EMT through interaction with the oncoprotein CRKL, inhibiting CRKL-mediated activation of SRC kinase, which is crucially required for EMT. SASH1-deficient cells form significantly more metastases in vivo, depending entirely on CRKL. Patient tumor samples show significantly decreased SASH1 and increased CRKL expression, associated with significantly decreased overall survival. Patients with increased CRKL expression show significantly worse response to adjuvant chemotherapy. Conclusions We propose SASH1 as an inhibitor of CRKL-mediated SRC signaling, introducing a potentially druggable mechanism counteracting chemoresistance and metastasis formation., Graphical abstract

Published
2019

18. Factors associated with poor adherence to medication among hypertensive patients in twelve low and middle income Sub-Saharan countries

Author

Macquart de Terline, Diane, Kane, Adama, Kramoh, Kouadio Euloge, Ali Toure, Ibrahim, Mipinda, Jean Bruno, Diop, Ibrahima Bara, Nhavoto, Carol, Balde, Dadhi M., Ferreira, Beatriz, Dèdonougbo Houenassi, Martin, Ikama, Méo Stéphane, Kingue, Samuel, Kouam Kouam, Charles, Takombe, Jean Laurent, Limbole, Emmanuel, Mfeukeu Kuate, Liliane, N’guetta, Roland, Damorou, Jean Marc, Sesso, Zouwera, Sidy Ali, Abdallahi, Perier, Marie-Cécile, Azizi, Michel, Empana, Jean Philippe, Jouven, Xavier, Antignac, Marie, Service de Pharmacie [CHU Saint Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Aristide-Le-Dantec, Institute of Cardiology of Abidjan [Abidjan, Côte d’Ivoire], Internal Medicine and Cardiology Department [Niamey, Niger], University Hospital of Lamorde [Niamey, Niger], University hospital of Libreville [Libreville, Gabon], Cardiology Department [Dakar, Senegal], University Hospital of Fann [Dakar, Senegal], Instituto do Coração [Maputo, Mozambique] (ICOR), Department of Cardiology [Conakry, Guinea], University Hospital of Conakry [Conakry, Guinea], National University hospital of Hubert K. MAGA [Cotonou, Bénin] (CNHU-HKM), University Marien Ngouabi of Brazzaville (umng), Université de Yaoundé I, Internal Medicine Department [Bafoussam, Cameroon], Régional Hospital [Bafoussam, Cameroon], General Hospital of Kinshasa [Kinshasa, Democratic Republic of the Congo], Department of Internal Medicine of la Gombe [Kinshasa, Democratic Republic of the Congo] (CMCG), Ngaliema Hospital [Kinshasa, Democratic Republic of the Congo], Hôpital Central de Yaoundé [Yaoundé], Cardiology department [Lomé, Togo], CHU de Lomé [Togo], Cardiology clinics [Nouakchott, Mauritania], Service de médecine vasculaire et hypertension artérielle [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), Université Paris Descartes - Paris 5 (UPD5), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Gestionnaire, Hal Sorbonne Université, CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Questionnaires, Male, Physiology, Blood Pressure, Vascular Medicine, Biochemistry, Ion Channels, Surveys and Questionnaires, Medicine and Health Sciences, Prevalence, Aged, 80 and over, Pharmaceutics, Physics, Drugs, Middle Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Electrophysiology, Antihypertensive Drugs, Research Design, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Hypertension, Physical Sciences, Income, Medicine, Calcium Antagonist Therapy, Female, Research Article, Adult, Science, Biophysics, Cardiology, Neurophysiology, Research and Analysis Methods, Medication Adherence, Complementary and Alternative Medicine, Drug Therapy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, Developing Countries, Poverty, Africa South of the Sahara, Antihypertensive Agents, Aged, Pharmacology, Survey Research, Biology and Life Sciences, Proteins, Traditional Medicine, Cross-Sectional Studies, Socioeconomic Factors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Calcium Channels, Receptor Antagonist Therapy, Neuroscience, Antihypertensives
Abstract

IntroductionOver the past few decades, the prevalence of hypertension has dramatically increased in Sub-Saharan Africa. Poor adherence has been identified as a major cause of failure to control hypertension. Scarce data are available in Africa.AimsWe assessed adherence to medication and identified socioeconomics, clinical and treatment factors associated with low adherence among hypertensive patients in 12 sub-Saharan African countries.MethodWe conducted a cross-sectional survey in urban clinics of both low and middle income countries. Data were collected by physicians on demographics, treatment and clinical data among hypertensive patients attending the clinics. Adherence was assessed by questionnaires completed by the patients. Factors associated with low adherence were investigated using logistic regression with a random effect on countries.ResultsThere were 2198 individuals from 12 countries enrolled in the study. Overall, 678 (30.8%), 738 (33.6%), 782 (35.6%) participants had respectively low, medium and high adherence to antihypertensive medication. Multivariate analysis showed that the use of traditional medicine (OR: 2.28, 95%CI [1.79-2.90]) and individual wealth index (low vs. high wealth: OR: 1.86, 95%CI [1.35-2.56] and middle vs. high wealth: OR: 1.42, 95%CI [1.11-1.81]) were significantly and independently associated with poor adherence to medication. In stratified analysis, these differences in adherence to medication according to individual wealth index were observed in low-income countries (pConclusionThis study revealed the high frequency of poor adherence in African patients and the associated factors. These findings should be useful for tailoring future programs to tackle hypertension in low income countries that are better adapted to patients, with a potential associated enhancement of their effectiveness.

Published
2019

19. Reverse Immunology Approach to Define a New HIV-gp41-Neutralizing Epitope

Author

Pablo Guardado-Calvo, Vincent Vieillard, Patrice Debré, Delphine Sterlin, Guy Gorochov, Nicolas Pietrancosta, Tahar Bouceba, Christophe Piesse, Karim Dorgham, Solenne Chardonnet, Amel Affoune, Cédric Pionneau, Olivier Lucar, Philippe Karoyan, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Ingénierie des protéines, PCR, Interaction Moléculaires [IBPS] (IBPS-IPIM), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Virologie Structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by Sorbonne Université and the Institut National de la Santé et de la Recherche Médicale (INSERM)., Centre d'Immunologie et des Maladies Infectieuses (CIMI), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by Sorbonne Université and the Institut National de la Santé et de la Recherche Médicale (INSERM). The authors acknowledge Delphine Lucas from Minka Therapeutics and Julien Puech and Noemi Asfogo, both students of the CIMI-Paris, for their technical assistance., Service d'Immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dorgham, Karim, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Models, Molecular, lcsh:Immunologic diseases. Allergy, Article Subject, Immunology, Human immunodeficiency virus (HIV), Peptide, HIV Antibodies, Biology, Gp41, medicine.disease_cause, Epitopes, Mice, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, 0302 clinical medicine, Viral envelope, Neutralization Tests, medicine, Animals, Immunology and Allergy, Bacteriophages, 030304 developmental biology, chemistry.chemical_classification, Mice, Inbred BALB C, 0303 health sciences, Mimotope, Antibodies, Monoclonal, General Medicine, Antibodies, Neutralizing, Virology, HIV Envelope Protein gp41, 3. Good health, Neutralizing epitope, Molecular Docking Simulation, Vaccination, chemistry, 030220 oncology & carcinogenesis, HIV-1, biology.protein, Antibody, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Peptides, lcsh:RC581-607, Epitope Mapping, Research Article, Protein Binding
Abstract

International audience; The design of immunogens susceptible to elicit potent and broadly neutralizing antibodies against the human immunodeficiency virus type 1 (HIV-1) remains a veritable challenge in the course of vaccine development. Viral envelope proteins adopt different conformational states during the entry process, allowing the presentation of transient neutralizing epitopes. We focused on the highly conserved 3S motif of gp41, which is exposed to the surface envelope in its trimeric prefusion state. Vaccination with a W614A-modified 3S peptide induces in animals neutralizing anti-HIV-1 antibodies among which we selected clone F8. We used F8 as bait to select for W614A-3S phage-peptide mimics. Binding and molecular docking studies revealed that F8 interacts similarly with W614A-3S and a Mim_F8-1 mimotope, despite their lack of sequence homology, suggesting structural mimicry. Finally, vaccination of mice with the purified Mim_F8-1 phage elicited HIV-1-neutralizing antibodies that bound to the cognate W614A-3S motif. Collectively, our findings provide new insights into the molecular design of immunogens to elicit antibodies with neutralizing properties.

Published
2019

20. Intrications organo-psychiatriques : le concept de troubles psychiatriques complexes, quels examens complémentaires ?

Author

Florian, Ferreri, Alexis, Bourla, Jean, Capron, Bluenn, Quillerou, Julien, Rossignol, Alaina, Borden, Jérome, Guechot, Antonin, Lamaziere, Philippe, Nuss, Arsène, Mekinian, Stéphane, Mouchabac, Sorbonne Université (SU), Service de Psychiatrie adultes [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Service de Médecine Interne [CHU Saint-Antoine]

Subjects
Mental Disorders, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Humans
Abstract

International audience; The purpose of this article is to describe complex psychiatric disorders, to recall “minimal classical” explorations in psychiatry, to describe the concept of “complex psychiatric disorders” and to propose a systematized method of exploration.Some organic diseases are well known for their links with psychiatric disorders (manic syndrome and hyperthyroidism, depressive syndrome and corticotropic insufficiency, anxiety disorder and heart disease, etc.).Many other neurological, autoimmune, metabolic, paraneoplastic or endocrine pathologies can have essentially psycho-behavioral manifestations before being neurological or systemic.A large number of factors (nutritional, toxic, immunological, etc.), often ignored, influence the links between organicity and psychiatric pathologies.It is necessary to optimize the medical management of these patients in whom the psychiatric diagnosis masks a curable organo-psychiatric cause.; Cet article a pour objectifs de décrire des troubles psychiatriques complexes, de rappeler les explorations « classiques minimales » en psychiatrie, de décrire le concept de « troubles psychiatriques complexes » et de proposer une méthode d’exploration systématisée.Certaines pathologies organiques sont bien connues pour leurs liens avec les troubles psychiatriques (syndrome maniaque et hyperthyroïdie, syndrome dépressif et insuffisance corticotrope, trouble anxieux et maladie cardiaque, etc.).De nombreuses autres pathologies neurologiques, auto-immunes, métaboliques, paranéoplasiques ou endocriniennes peuvent avoir des manifestations essentiellement psycho-comportementales avant d’être neurologiques ou systémiques.Un grand nombre de facteurs (nutritionnels, toxiques, immunologiques, etc.), souvent ignorés, exercent une influence sur les liens existants entre organicité et pathologies psychiatriques.Il est nécessaire d’optimiser la prise en charge médicale de ces patients chez qui le diagnostic psychiatrique masque une cause organo-psychiatrique curable.

Published
2019

21. ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors

Author

Marcel Kool, Franck Bourdeaut, Valérie Rigau, Sander Lambo, Isabelle Oliver-Petit, Marie-Bernadette Delisle, Lisa Golmard, Thomas Roujeau, Gilles Palenzuela, Badreddine Mohand-Oumoussa, Emmanuelle Uro-Coste, Frédérique Savagner, Dominique Figarella-Branger, Maud Blanluet, Isabelle Coupier, Julien Masliah-Planchon, Arnault Tauziède-Espariat, Sophie Julia, Aurore Siegfried, Sergio Boetto, Marion Gambart, Anne-Isabelle Bertozzi, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Service de Neurochirurgie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Gui de Chauliac [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), figarella-branger, dominique, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Assistance Publique-Hôpitaux de Marseille (AP-HM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Universitaire de Toulouse, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurochirurgie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM)

Subjects
Ribonuclease III, Pathology, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], Brain, Infant, Neoplasms, Germ Cell and Embryonal, Pathology and Forensic Medicine, DEAD-box RNA Helicases, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Cellular and Molecular Neuroscience, Embryonal tumors, 0302 clinical medicine, 030220 oncology & carcinogenesis, Mutation, medicine, Humans, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

22. Temporal trends in clinical characteristics and management according to sex in patients with cardiogenic shock after acute myocardial infarction: The FAST-MI programme

Author

Marc-Antoine Isorni, Nicolas Danchin, Clément Delmas, Denis Angoulvant, Jean Ferrières, Fast-Mi investigators, Gilles Lemesle, Francois Schiele, Patrick Henry, Laurent Bonello, Nadia Aissaoui, Etienne Puymirat, Tabassome Simon, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, Time Factors, Health Status, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Myocardial Infarction, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Percutaneous coronary intervention, 0302 clinical medicine, Risk Factors, Odds Ratio, Prevalence, Medicine, 030212 general & internal medicine, Myocardial infarction, Aged, 80 and over, Incidence, Cardiogenic shock, Incidence (epidemiology), General Medicine, Middle Aged, 3. Good health, Treatment Outcome, Female, Sex, France, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Shock, Cardiogenic, Infarctus du myocarde, Acute myocardial infarction, MESH: Acute myocardial infarction, Angioplastie coronaire percutanée, Choc cardiogénique, Sexe, 03 medical and health sciences, Sex Factors, Internal medicine, Humans, In patient, Healthcare Disparities, Aged, Proportional Hazards Models, Chi-Square Distribution, business.industry, medicine.disease, Logistic Models, Health Care Surveys, Multivariate Analysis, Linear Models, business
Abstract

Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) occurs more frequently in women, but little is known about its potential specificities according to sex.To analyse the incidence, management and 1-year mortality of CS according to sex using the FAST-MI programme.The FAST-MI programme consists of four nationwide French surveys carried out 5 years apart from 1995 to 2010, including consecutive patients with AMI over a 1-month period, and with a 1-year follow-up.Among the 10,610 patients included in the surveys, the incidence of CS was 4.8% in men and 8.2% in women (P0.001). Absolute incidence of CS decreased from 1995 to 2010 in both sexes. Mean age in patients with CS tended to decrease in men (from 72±12 to 69±13 years) and to increase in women (from 78±10 to 80±9 years). One-year mortality decreased significantly in men (from 70% in 1995 to 48% in 2010) and in women (from 81% to 54%). Using Cox multivariable analysis, female sex was not an independent correlate of 1-year mortality [hazard ratio (HR): 0.98, 95% confidence interval (CI): 0.78-1.22]. Early use of percutaneous coronary intervention was, however, an independent predictor of 1-year survival in women (HR: 0.55, 95% CI: 0.37-0.81), but showed only a non-significant trend in men (HR: 0.85, 95% CI: 0.61-1.19).The incidence of CS-AMI has decreased in both men and women, but remains higher in women. One-year mortality has significantly decreased for both men and women, and the role of early percutaneous coronary intervention as a potential mediator of decreased mortality seems greater in women than in men.

Published
2018

23. Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation

Author

Maria Chatzifrangkeskou, Matteo Dal Ferro, Nathalie Mougenot, Maria-Grazia Biferi, Silvia Crasto, Solenne Chardonnet, Petra Knaus, Wolfgang H. Goldmann, Antoine Muchir, Alain Schmitt, David Yadin, Mathilde Cohen-Tannoudji, Elisa Di Pasquale, Thibaut Marais, Howard J. Worman, Yannick Tanguy, Blanca Morales Rodriguez, Gisèle Bonne, Imen Jebeniani, Coline Macquart, Michel Pucéat, Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Freie Universität Berlin, Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Faculté de Médecine (SU FM), Phénotypage du petit animal (UMS28), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of Trieste, Columbia University [New York], Centre de recherche en Myologie – U974 SU-INSERM, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Trieste = University of Trieste, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)

Subjects
Adult, Cardiomyopathy, Dilated, Cofilin 1, Male, 0301 basic medicine, Adolescent, [SDV]Life Sciences [q-bio], Cardiomyopathy, macromolecular substances, Gene mutation, Biology, environment and public health, LMNA, Mice, Young Adult, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genetics, medicine, Animals, Humans, Phosphorylation, Molecular Biology, Genetics (clinical), Actin, Mitogen-Activated Protein Kinase 1, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mitogen-Activated Protein Kinase 3, Heart, General Medicine, Middle Aged, Lamin Type A, medicine.disease, Actins, Cell biology, 030104 developmental biology, Actin depolymerizing factor, Case-Control Studies, Mutation, Female, Original Article, Lamin, Signal Transduction
Abstract

International audience; Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene (LMNA cardiomyopathy). The mechanism of how this affects cardiac function is unknown. We show that active phosphorylated ERK1/2 directly binds to and catalyzes the phosphorylation of the actin depolymerizing factor cofilin-1 on Thr25. Cofilin-1 becomes active and disassembles actin filaments in a large array of cellular and animal models of LMNA cardiomyopathy. In vivo expression of cofilin-1, phosphorylated on Thr25 by endogenous ERK1/2 signaling, leads to alterations in left ventricular function and cardiac actin. These results demonstrate a novel role for cofilin-1 on actin dynamics in cardiac muscle and provide a rationale on how increased ERK1/2 signaling leads to LMNA cardiomyopathy.

Published
2018

24. Response by Puymirat et al to Letter Regarding Article, 'Acute Myocardial Infarction Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-MI Program (French Registry of Acute ST Elevation or Non-ST-Elevation Myocardial Infarction) 1995 to 2015'

Author

Tabassome Simon, Etienne Puymirat, Nicolas Danchin, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
medicine.medical_specialty, MESH: Registries, [SDV]Life Sciences [q-bio], Myocardial Infarction, Autopsy, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, St elevation myocardial infarction, Physiology (medical), Internal medicine, medicine, Humans, In patient, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Registries, MESH: ST Elevation Myocardial Infarction, Non-ST Elevated Myocardial Infarction, ComputingMilieux_MISCELLANEOUS, MESH: Humans, business.industry, ST elevation, medicine.disease, Infarct size, Acute stage, 3. Good health, MESH: Myocardial Infarction, MESH: Non-ST Elevated Myocardial Infarction, Coagulative necrosis, cardiovascular system, Cardiology, ST Elevation Myocardial Infarction, Cardiology and Cardiovascular Medicine, business
Abstract

We appreciate Dr Rodriguez-Granillo’s comment on the likely impact of a progressive reduction infarct size on the reduction in mortality observed at the acute stage of myocardial infarction. Indeed, their autopsy findings in the prethrombolysis era show that a large infarct extent together with coagulative necrosis was common, leading to lethal complications such as ventricular arrhythmias or ventricular rupture, which have now become quite uncommon. We certainly share their view that the decline in mortality is most certainly linked to a …

Published
2018

25. Increased Fatty Acid Oxidation in Differentiated Proximal Tubular Cells Surviving a Reversible Episode of Acute Kidney Injury

Author

Aurélien Bataille, Iman Sadia, Alexandre Hertig, Badreddine Mohand Oumoussa, Marie-Julia Ziliotis, Stéphane Le Crom, Morgane Commereuc, Sophie Vandermeersch, Eric Rondeau, Pierre Galichon, David Legouis, Nadjim Chelghoum, Raphael Cohen, Yi-Chun Xu-Dubois, Noémie Simon-Tillaux, Sorbonne Université (SU), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Analyse des Données à Haut Débit en Génomique (ADHDG), Evolution Paris Seine, Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service d'Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), Gestionnaire, Hal Sorbonne Université, AP-HP Hôpital Tenon [Paris], Hôpital Lariboisière, Hôpital Lariboisière-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université de Paris, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris-Université Paris-Sud - Paris 11 (UP11)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Sorbonne Paris Nord, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Evolution Paris-Seine, Centre National de la Recherche Scientifique (CNRS)-Université Sorbonne Paris Cité (USPC)-Université des Antilles (UA)-Université Nice Sophia Antipolis (... - 2019) (UNS), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD)

Subjects
0301 basic medicine, medicine.medical_specialty, Physiology, Cell Survival, [SDV]Life Sciences [q-bio], lcsh:Physiology, Epithelium, Kidney Tubules, Proximal, lcsh:Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Mice, Fibrosis, Internal medicine, AC133 Antigen/metabolism, Chronic Kidney Disease, medicine, Renal fibrosis, Animals, Glycolysis, lcsh:QD415-436, AC133 Antigen, Beta oxidation, Kidney, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Fatty acid metabolism, lcsh:QP1-981, business.industry, Fatty Acids, Acute kidney injury, Acute Kidney Injury/metabolism/pathology, Acute Kidney Injury, medicine.disease, [SDV] Life Sciences [q-bio], Fatty Acids/metabolism, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, chemistry, business, Fatty Acid Oxidation, Oxidation-Reduction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease, Kidney Tubules, Proximal/metabolism/pathology
Abstract

International audience; Background/aims: Fatty acid oxidation (FAO), the main source of energy produced by tubular epithelial cells in the kidney, was found to be defective in tubulo-interstitial samples dissected out in kidney biopsies from patients with chronic kidney disease (CKD). Experimental data indicated that this decrease was a strong determinant of renal fibrogenesis, hence a focus for therapeutic interventions. Nevertheless, whether persistently differentiated renal tubules, surviving in a pro-fibrotic environment, also suffer from a decrease in FAO, is currently unknown.Methods: To address this question, we isolated proximal tubules captured ex vivo on the basis of the expression of an intact brush border antigen (Prominin-1) in C57BL6/J mice subjected to a controlled, two-hit model of renal fibrosis (reversible ischemic acute kidney injury (AKI) or sham surgery, followed by angiotensin 2 administration). A transcriptomic high throughput sequencing was performed on total mRNA from these cells, and on whole kidneys.Results: In contrast to mice subjected to sham surgery, mice with a history of AKI displayed histologically more renal fibrosis when exposed to angiotensin 2. High throughput RNA sequencing, principal component analysis and clustering showed marked consistency within experimental groups. As expected, FAO transcripts were decreased in whole fibrotic kidneys. Surprisingly, however, up- rather than down-regulation of metabolic pathways (oxidative phosphorylation, fatty acid metabolism, glycolysis, and PPAR signalling pathway) was a hallmark of the differentiated tubules captured from fibrotic kidneys. Immunofluorescence co-staining analysis confirmed that the expression of FAO enzymes was dependent of tubular trophicity.Conclusions: These data suggest that in differentiated proximal tubules energetic hyperactivity is promoted concurrently with organ fibrogenesis.

Published
2018

26. Identification of Plasmodium falciparum nuclear proteins by mass spectrometry and proposed protein annotation

Author

Briquet, Sylvie, Ourimi, Asma, Pionneau, Cédric, Bernardes, Juliana, Carbone, Alessandra, Chardonnet, Solenne, Vaquero, Catherine, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-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 National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteomics, Ribosomal Proteins, Cytoplasm, Plasmodium, Proteome, Protein Extraction, Plasmodium falciparum, Protozoan Proteins, lcsh:Medicine, Gene Expression, Research and Analysis Methods, Biochemistry, Protein Domains, Tandem Mass Spectrometry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Parasite Groups, DNA-binding proteins, parasitic diseases, Genetics, Gene Regulation, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:Science, Extraction Techniques, Protozoans, lcsh:R, Organisms, Malarial Parasites, Nuclear Proteins, Biology and Life Sciences, Proteins, Eukaryota, Parasitic Protozoans, Regulatory Proteins, lcsh:Q, Parasitology, Apicomplexa, Chromatography, Liquid, Research Article, Transcription Factors
Abstract

International audience; The nuclear proteome of Plasmodium falciparum results from the continual shuttle of proteins between the cell cytoplasm-nucleus and vice versa. Using shotgun proteomics tools, we explored the nuclear proteins of mixed populations of Plasmodium falciparum extracted from infected erythrocytes. We combined GeLC-MS/MS and 2D-LC-MS/MS with a peptide ion exclusion procedure in order to increase the detection of low abundant proteins such as those involved in gene expression. We have identified 446 nuclear proteins covering all expected nuclear protein families involved in gene regulation. All structural ribosomal (40S and 60S) proteins were identified which is consistent with the nuclear localization of ribo-somal biogenesis. Proteins involved in the translation machinery were also found suggesting that translational events might occur in the nucleus in P. falciparum as previously hypothesized in eukaryotes. These data were compared to the protein list established by PlasmoDB and submitted to Plasmobase a recently reported Plasmodium annotation website to propose new functional putative annotation of several unknown proteins found in the nuclear extracts.

Published
2018

27. Plasma levels of hsa-miR-152-3p are associated with diabetic nephropathy in patients with type 2 diabetes

Author

Maguelonne Roux, Pierre-Jean Saulnier, Badreddine Mohand Oumoussa, Claire Perret, Samy Hadjadj, David-Alexandre Trégouët, Eva Feigerlova, Carole Proust, Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Endocrinologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Context (language use), Type 2 diabetes, Diabetic nephropathy, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 03 medical and health sciences, Circulating microRNA, 0302 clinical medicine, microRNA-Sequencing, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, Humans, Diabetic Nephropathies, Gene, Aged, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Transplantation, Type 1 diabetes, MicroRNA sequencing, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Gene Expression Profiling, biomarkers, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, Solute carrier family, MicroRNAs, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation, Nephrology, Case-Control Studies, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, business
Abstract

International audience; Background: MicroRNAs (miRNAs) are small non-coding RNAs participating in post-transcriptional regulation of genes. Their key role in modulating the susceptibility to human diseases is now widely recognized, in particular in the context of cardiometabolic disorders. The aim of the present study was to identify miRNAs associated with diabetic nephropathy (DN) in patients with type 2 diabetes (T2D).Methods: A next-generation sequencing-based miRNA profiling was performed in a case-control study for DN in plasma samples of 23 T2D patients with DN (cases) and 23 T2D without (controls). The main associations were confirmed using quantitative reverse transcription-polymerase chain reaction and tested for replication in an independent case-control collection of 100 T2D patients, 50 with DN and 50 without.Results: From the 381 known mature miRNAs that were found highly expressed in the discovery samples, we observed and replicated an association between increased plasma levels of hsa-miR-152-3p and DN (P = 4.03 × 10-4 in the combined samples). Hsa-miR-152-3p plasma levels were further found to be positively correlated (P = 0.003) to plasma osmolarity, a surrogate marker for solute carrier net activity, whose regulation is controlled by several genes including SLC5A3, one of the predicted targets of hsa-miR-152-3p.Conclusions: We observed strong evidence for the association of hsa-miR-152-3p plasma levels and DN in patients with T2D, confirming an association previously observed in patients with type 1 diabetes.

Published
2018

28. Hyperglycaemia is associated with cancer-related but not non-cancer-related deaths: evidence from the IPC cohort

Author

Tabassome Simon, Sébastien Czernichow, Bruno Pannier, Nicolas Danchin, Jean-Marc Simon, Cédric Lemogne, Frédérique Thomas, Olivier Hanon, BRUNEL, Nadège, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Population, 030209 endocrinology & metabolism, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Neoplasms, Internal Medicine, medicine, Humans, education, Blood Glucose Measurement, ComputingMilieux_MISCELLANEOUS, Aged, Proportional Hazards Models, Aged, 80 and over, Inflammation, Aspirin, education.field_of_study, business.industry, Incidence (epidemiology), Mortality rate, Incidence, Cancer, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Nonlinear Dynamics, 030220 oncology & carcinogenesis, Hyperglycemia, Cohort, Female, business, medicine.drug
Abstract

Hyperglycaemia has been associated with the incidence of all and specific types of cancer, distinct from the risks related to diabetes. The relationships between blood glucose and mortality rates related to all and specific cancers were analysed in comparison with all-cause or non-cancer-related mortality rates in a large, general primary care population in France. Between January 1991 and December 2008, 301,948 participants (193,221 men and 108,727 women), aged 16–95 years (mean ± SD 44.8 ± 12.0 years for men and 45.1 ± 14.2 years for women), had a health check at the IPC Centre. All data collected in standard conditions during the health checks-up were used for statistical analysis All examinations were performed under fasting conditions and included a blood glucose measurement. Participants with known diabetes (

Published
2018

29. Protein profile of mouse ovarian follicles grown in vitro

Author

Anastácio, Amandine, Rodriguez-Wallberg, Kenny A, Chardonnet, Solenne, Pionneau, Cédric, Fédérici, Christian, Almeida Santos, Teresa, Poirot, Catherine, Assistance médicale à la procréation, Biologie de reproduction - Stérilité [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, Proteome, Gene Expression Profiling, Computational Biology, Molecular Sequence Annotation, follicle development, in vitro growth, Mice, Gene Ontology, ovarian follicle, proteomics, Tandem Mass Spectrometry, Databases, Genetic, Protein Interaction Mapping, Mice, Inbred CBA, Animals, Female, Cells, Cultured, Metabolic Networks and Pathways, mouse, Original Research, Chromatography, Liquid
Abstract

International audience; STUDY QUESTION:Could the follicle proteome be mapped by identifying specific proteins that are common or differ between three developmental stages from the secondary follicle (SF) to the antrum-like stage?SUMMARY ANSWER:From a total of 1401 proteins identified in the follicles, 609 were common to the three developmental stages investigated and 444 were found uniquely at one of the stages.WHAT IS KNOWN ALREADY:The importance of the follicle as a functional structure has been recognized; however, up-to-date the proteome of the whole follicle has not been described. A few studies using proteomics have previously reported on either isolated fully-grown oocytes before or after meiosis resumption or cumulus cells.STUDY DESIGN, SIZE, DURATION:The experimental design included a validated mice model for isolation and individual culture of SFs. The system was chosen as it allows continuous evaluation of follicle growth and selection of follicles for analysis at pre-determined developmental stages: SF, complete Slavjanski membrane rupture (SMR) and antrum-like cavity (AF). The experiments were repeated 13 times independently to acquire the material that was analyzed by proteomics.PARTICIPANTS/MATERIALS, SETTING, METHODS:SFs (n = 2166) were isolated from B6CBA/F1 female mice (n = 42), 12 days old, from 15 l. About half of the follicles isolated as SF were analyzed as such (n = 1143) and pooled to obtain 139 μg of extracted protein. Both SMR (n = 359) and AF (n = 124) were obtained after individual culture of 1023 follicles in a microdrop system under oil, selected for analysis and pooled, to obtain 339 μg and 170 μg of protein, respectively. The follicle proteome was analyzed combining isoelectric focusing (IEF) fractionation with 1D and 2D LC-MS/MS analysis to enhance protein identification. The three protein lists were submitted to the 'Compare gene list' tool in the PANTHER website to gain insights on the Gene Ontology Biological processes present and to Ingenuity Pathway Analysis to highlight protein networks. A label-free quantification was performed with 1D LC-MS/MS analyses to emphasize proteins with different expression profiles between the three follicular stages. Supplementary western blot analysis (using new biological replicates) was performed to confirm the expression variations of three proteins during follicle development in vitro.MAIN RESULTS AND THE ROLE OF CHANCE:It was found that 609 out of 1401 identified proteins were common to the three follicle developmental stages investigated. Some proteins were identified uniquely at one stage: 71 of the 775 identified proteins in SF, 181 of 1092 in SMR and 192 of 1100 in AF. Additional qualitative and quantitative analysis highlighted 44 biological processes over-represented in our samples compared to the Mus musculus gene database. In particular, it was possible to identify proteins implicated in the cell cycle, calcium ion binding and glycolysis, with specific expressions and abundance, throughout in vitro follicle development.LARGE SCALE DATA:Data are available via ProteomeXchange with identifier PXD006227.LIMITATIONS, REASONS FOR CAUTION:The proteome analyses described in this study were performed after in vitro development. Despite fractionation of the samples before LC-MS/MS, proteomic approaches are not exhaustive, thus proteins that are not identified in a group are not necessarily absent from that group, although they are likely to be less abundant.WIDER IMPLICATIONS OF THE FINDINGS:This study allowed a general view of proteins implicated in follicle development in vitro and it represents the most complete catalog of the whole follicle proteome available so far. Not only were well known proteins of the oocyte identified but also proteins that are probably expressed only in granulosa cells.STUDY FUNDING/COMPETING INTEREST(S):This study was supported by the Portuguese Foundation for Science and Technology, FCT (PhD fellowship SFRH/BD/65299/2009 to A.A.), the Swedish Childhood Cancer Foundation (PR 2014-0144 to K.A.R-.W.) and Stockholm County Council to K.A.R-.W. The authors of the study have no conflict of interest to report.

Published
2017

30. Gene Expression Analyses Identify Narp Contribution in the Development of l-DOPA-Induced Dyskinesia

Author

Denis Hervé, Desheng Xu, Paul F. Worley, Jean-Antoine Girault, Marion Malerbi, Wassila Carpentier, Cristina Alcacer, Chuansong Wang, Fanny Charbonnier-Beaupel, Khadija Tahiri, Jean-Christophe Corvol, Matthew J. During, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), University Pierre and Marie Curie (UPMC), Inserm (Grant Inserm/DHOS), Fondation pour la Recherche Medicale, Societe francaise de pharmacologie et de therapeutique, Agence Nationale de la Recherche [ANR09-MNPS-014], Michael Stern Parkinson's Research Foundation, European Research Council, program ``Investissements d'avenir' [ANR-10-IAIHU-06], National Institutes of Health [R01 NS039156], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MAPK/ERK pathway, Dyskinesia, Drug-Induced, Parkinson's disease, Nerve Tissue Proteins, Striatum, Biology, Antiparkinson Agents, Levodopa, Transcriptome, Mice, 03 medical and health sciences, 0302 clinical medicine, Dopamine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, medicine, Animals, 030304 developmental biology, Mice, Knockout, NEDD4L, 0303 health sciences, General Neuroscience, Glutamate receptor, Articles, Narp, Cell biology, L-DOPA-induced dyskinesia, Mice, Inbred C57BL, C-Reactive Protein, Gene Expression Regulation, Biochemistry, Female, transcriptome, 030217 neurology & neurosurgery, medicine.drug, FOSB
Abstract

In Parkinson's disease, long-term dopamine replacement therapy is complicated by the appearance ofl-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced byl-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0–6 h after treatment withl-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation byl-DOPA.l-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment withl-DOPA. The intersection list identified five genes:FosB,Th,Nptx2,Nedd4l, andCcrn4l. Nptx2encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increasedNptx2expression afterl-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalatingl-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced byl-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes,Nptx2, in the development of LID.

Published
2015

31. Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome

Author

Qi Zhang, Bart P. Leroy, Mark Consugar, Christina Zeitz, Emily Place, Eric A. Pierce, Marni J. Falk, Marie-Elise Lancelot, Christine Lonjou, L. Ingeborgh van den Born, Xiaowu Gai, José-Alain Sahel, Anneke I. den Hollander, Saddek Mohand-Said, Frans P.M. Cremers, Isabelle Audo, Rob W.J. Collin, Wassila Carpentier, Kinga M. Bujakowska, Qin Liu, Aline Antonio, Anna M. Siemiatkowska, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physics, Shanghai University, Shanghai University, Key Laboratory of Stem Cell Biology, Chinese Academy of Sciences [Changchun Branch] (CAS)-Shanghai Jiao Tong University School of Medicine, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), National Eye Institute [EY012910], Foundation Fighting Blindness (FFB), French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program [ANR-11-IDEX-0004-0], Netherlands Organisation for Scientific Research [91209047], Stichting Wetenschappelijk Onderzoek Oogziekenhuis Prof Dr H.J. Flieringa Foundation, Research to Prevent Blindness, Fleming Family Foundation, FFB [CD-CL-0808-0466-CHNO], FFB center [C-CMM-0907-0428-INSERM04], Foundation Voir et Entendre, Fondation Dalloz prix `pour la recherche en ophtalmologie', Ville de Paris and Region Ile de France, and Labex LIFESENSES [ANR-10-LABX-65]

Subjects
Retinal degeneration, Adult, Male, Adolescent, Biology, Ciliopathies, Joubert syndrome, Retina, Young Adult, Bardet–Biedl syndrome, Intraflagellar transport, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Animals, Humans, Exome, Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12], Molecular Biology, Bardet-Biedl Syndrome, Genetics (clinical), Cells, Cultured, Zebrafish, Adaptor Proteins, Signal Transducing, Cilium, High-Throughput Nucleotide Sequencing, General Medicine, Articles, Sequence Analysis, DNA, medicine.disease, 3. Good health, Pedigree, Rats, Ciliopathy, Cytoskeletal Proteins, Mutation, Female, sense organs, Carrier Proteins, Retinitis Pigmentosa
Abstract

Item does not contain fulltext Primary cilia are sensory organelles present on most mammalian cells. The assembly and maintenance of primary cilia are facilitated by intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium. Mutations in genes coding for IFT components have been associated with a group of diseases called ciliopathies. These genetic disorders can affect a variety of organs including the retina. Using whole exome sequencing in three families, we identified mutations in Intraflagellar Transport 172 Homolog [IFT172 (Chlamydomonas)] that underlie an isolated retinal degeneration and Bardet-Biedl syndrome. Extensive functional analyses of the identified mutations in cell culture, rat retina and in zebrafish demonstrated their hypomorphic or null nature. It has recently been reported that mutations in IFT172 cause a severe ciliopathy syndrome involving skeletal, renal, hepatic and retinal abnormalities (Jeune and Mainzer-Saldino syndromes). Here, we report for the first time that mutations in this gene can also lead to an isolated form of retinal degeneration. The functional data for the mutations can partially explain milder phenotypes; however, the involvement of modifying alleles in the IFT172-associated phenotypes cannot be excluded. These findings expand the spectrum of disease associated with mutations in IFT172 and suggest that mutations in genes originally reported to be associated with syndromic ciliopathies should also be considered in subjects with non-syndromic retinal dystrophy.

Published
2015

32. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Author

Dan M. Roden, Marylyn D. Ritchie, Jae-Gook Shin, Braxton D. Mitchell, Teri E. Klein, Gian Franco Gensini, Jurriën M. ten Berg, Pierre Fontana, Lene Holmvang, Israel Fernandez-Cadenas, Willibald Hochholzer, Stefan Winter, Tabassome Simon, Ruth E. Pakyz, Paul A. Gurbel, Richard B. Horenstein, Ming-Shien Wen, Tobias Geisler, John H. Cleator, Marco Valgimigli, Ho-Sook Kim, Jean-Sébastien Hulot, Jolanta M. Siller-Matula, Dietmar Trenk, Gianluca Campo, Michiaki Kubo, Elke Schaeffeler, Nadia Paarup Dridi, Ming Ta Michael Lee, Li Gong, Joshua P. Lewis, Jean-Pierre Déry, Rossella Marcucci, Kiyuk Chang, Meinrad Gawaz, Kevin P. Bliden, Alan R. Shuldiner, Daniel Aradi, Thomas O. Bergmeijer, Betti Giusti, Russ B. Altman, Dimitrios Alexopoulos, Matthias Schwab, Ryan Whaley, Jean-Luc Reny, Joan Montaner, Eun Young Kim, Reny, Jean-Luc, Fontana, Pierre, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Male, Candidate gene, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Internationality, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular Medicine, MESH: Risk Assessment, MESH: Receptors, Purinergic P2Y12, 0302 clinical medicine, P2Y12, MESH: Molecular Targeted Therapy, Receptors, Medicine, 030212 general & internal medicine, Molecular Targeted Therapy, MESH: Treatment Outcome, MESH: Genetic Association Studies, Cardiology, Cardiovascular Medicine, MESH: Aged, ddc:616, Acute Coronary Syndrome/diagnosis/drug therapy/mortality, MESH: Middle Aged, Purinergic P2Y12/drug effects/genetics, Middle Aged, Clopidogrel, Prognosis, Receptors, Purinergic P2Y12, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Survival Rate, Treatment Outcome, Female, Cardiology and Cardiovascular Medicine, medicine.drug, circulatory and respiratory physiology, Acute coronary syndrome, medicine.medical_specialty, MESH: Survival Rate, Cardiology, MESH: Pharmacogenetics, CYP2C19, Clopidogrel/therapeutic use, Risk Assessment, MESH: Prognosis, Article, NO, 03 medical and health sciences, Internal medicine, Humans, cardiovascular diseases, Acute Coronary Syndrome, Genetic Association Studies, Aged, MESH: Humans, business.industry, MESH: Clopidogrel, medicine.disease, Genome-wide association approach, candidate gene approaches, clopidogrel, efficacy, pharmacodynamic, clinical end points, International Clopidogrel Pharmacogenomics Consortium (ICPC), Cardiovascular Medicine, MESH: Acute Coronary Syndrome, MESH: Male, Pharmacogenetics, Pharmacogenomics, MESH: Genome-Wide Association Study, ddc:618.97, MESH: Internationality, business, MESH: Female, Molecular Targeted Therapy/methods, Genome-Wide Association Study
Abstract

RATIONALE: The P2Y(12) receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention or ischemic stroke. Platelet inhibition by clopidogrel shows wide inter-patient variability and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics and cardiovascular outcomes, to perform candidate gene and genome-wide association studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate (ADP) stimulated platelet function tests included Vasodilator-Stimulated Phosphoprotein (VASP) assay, Light Transmittance Aggregometry (LTA) and the VerifyNow P2Y(12) assay. A proof of principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (p-value = 5.1×10(−40)). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic techniques in a large cohort of clopidogrel-treated patients in order to better understand the genetic basis of on-treatment response variability.

Published
2017

33. Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Author

Hana Flögelová, Marijan Saraga, Maria Szczepańska, John M Darlow, Nicholas Katsanis, Barry Honig, Donald Petrey, Ali Samii, Akira Imamoto, Adele Mitrotti, Vladimir J Lozanovski, Bradley A. Warady, Max Werth, Qingxue Liu, Susan L. Furth, Mirna Saraga-Babić, Silvia E. Racedo, Grażyna Krzemień, Yangfan P. Liu, Rik Westland, Christopher E. Gillies, Iain A. Drummond, Alba Carrea, Matthew G. Sampson, Nicholas J Steers, Rémi Salomon, Rong Deng, Valentina P Capone, V. D’Agati, Virginia E. Papaioannou, Richard P. Lifton, Katarina Vukojević, Claudia Izzi, Małgorzata Mizerska-Wasiak, Francesco Scolari, Marcin Tkaczyk, Joanna A.E. van Wijk, Gabriel Makar, Prem Puri, Esther Lopez-Rivera, Loreto Gesualdo, Bernice E. Morrow, Jonathan Barasch, Velibor Tasic, Marcin Zaniew, Cécile Jeanpierre, Adela Arapović, Asaf Vivante, Donna M. McDonald-McGinn, Terrence B. Crowley, Monica Bodria, Daniele Cusi, Wassila Carpentier, Craig S. Wong, Ali G. Gharavi, Miguel Verbitsky, David Fasel, Zhonghai Yan, Edgar A. Otto, David E. Barton, Zoran Gucev, Monika Miklaszewska, Virginia Vega-Warner, Dorota Drozdz, Jeremiah Martino, Elaine H. Zackai, Agnieszka Szmigielska, Anna Latos-Bielenska, Mariarosa Maiorana, Anna Materna-Kiryluk, Landino Allegri, Dominique Gaillard, Laurence Heidet, Friedhelm Hildebrandt, Hakon Hakonarson, Gian Marco Ghiggeri, Simone Sanna-Cherchi, Nenad Kunac, Przemysław Sikora, Emilio Casolari, Krzysztof Kiryluk, Blair R. Anderson, Pediatric surgery, ACS - Microcirculation, Amsterdam Reproduction & Development (AR&D), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), and Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
0301 basic medicine, Male, Adaptor Proteins, Signal Transducing, Adolescent, Animals, Child, Chromosomes, Human, Pair 22, DiGeorge Syndrome, Exome, Female, Heterozygote, Humans, Infant, Infant, Newborn, Kidney, Mice, Models, Animal, Nuclear Proteins, Sequence Analysis, DNA, Urinary Tract, Young Adult, Zebrafish, Chromosome Deletion, Haploinsufficiency, Medicine (all), Pathology, [SDV]Life Sciences [q-bio], 0302 clinical medicine, Models, DiGeorge syndrome, Medicine, Genetics, education.field_of_study, biology, Adaptor Proteins, General Medicine, 3. Good health, medicine.anatomical_structure, Sequence Analysis, Human, medicine.medical_specialty, Urinary system, Population, Chromosomes, Article, 03 medical and health sciences, education, Animal, business.industry, Signal Transducing, DNA, Odds ratio, Newborn, medicine.disease, biology.organism_classification, 030104 developmental biology, Pair 22, business, 030217 neurology & neurosurgery
Abstract

International audience; Background: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.Methods: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.Results: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.Conclusions: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Published
2017

34. Clinical Impact of Pharmacogenomics of Clopidogrel in Stroke

Author

Nicolas Danchin, Tabassome Simon, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Platelet Aggregation, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Pharmacology, MESH: Genotype, 0302 clinical medicine, P2Y12, 030212 general & internal medicine, Stroke, ComputingMilieux_MISCELLANEOUS, pharmacogenetics, MESH: Platelet Aggregation, MESH: Treatment Outcome, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Clopidogrel, stroke, 3. Good health, Treatment Outcome, MESH: Platelet Aggregation Inhibitors, Platelet aggregation inhibitor, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Ticlopidine, Genotype, MESH: Ticlopidine, MESH: Pharmacogenetics, Boxed warning, CYP2C19, MESH: Stroke, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Humans, cardiovascular diseases, platelet aggregation inhibitors, thrombosis, outcome assessment (health care), MESH: Humans, business.industry, MESH: Clopidogrel, Editorials, medicine.disease, Cytochrome P-450 CYP2C19, MESH: Cytochrome P-450 CYP2C19, Pharmacogenomics, business, Pharmacogenetics
Abstract

Article, see p 21 Despite progress in the diagnosis and treatment of stroke, it is estimated that >900 000 patients each year in the United States have a new stroke or transient ischemic attack (TIA) with an annual risk of 3% to 4% for recurrent events.1 The incidence of stroke or TIA is even higher in some countries such as China.2 Preventing stroke is therefore a major worldwide public health issue. Clopidogrel, in addition to 3 weeks of aspirin therapy, has been effective in reducing the risk of recurrence at 3 months in Chinese patients with TIA or a minor acute ischemic stroke, mainly by reducing the risk of recurrent ischemic stroke.3 To become active, clopidogrel needs to be metabolized via a 2-step oxidation process involving several hepatic cytochrome P450 isoenzymes, notably CYP2C19 , and irreversibly binds to P2Y12 receptors.4 Conversion of clopidogrel to its active metabolite depends on CYP2C19 genetic polymorphisms, with decreased platelet inhibition in carriers of 1 or 2 loss-of-function alleles (ie, intermediate or poor metabolizers). Several studies have shown that in patients with acute coronary syndromes treated by clopidogrel, carriers of at least 1 CYP2C19 loss-of-function allele, notably CYP2C19*2 , were at increased risk of major cardiovascular events and stent thrombosis, with a gene-dose relationship.5–8 Conversely, the CYP2C19*17 variant allele has been related to enhanced levels of active clopidogrel metabolites, greater inhibition of ADP-induced platelet aggregation, and increased risk of bleeding without an impact on ischemic events.9 The US Food and Drug Administration boxed warning in 2010 stated that CYP2C19 genotyping can be used as an aid in assessing the therapeutic safety and for considering alternative strategies to CYP2C19 poor metabolizers. From a clinical standpoint, however, the added value of assessing CYP2C19 polymorphisms depends on 3 factors: the …

Published
2017

35. Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma

Author

Bourcigaux Nathalie, Rubino Carole, Berthaut Isabelle, Bruno Donadille, Toubert Marie Elisabeth, Leenhardt Laurence, Corone Catherine, Petrot-Keller Isabelle, Brailly-Tabard Sylvie, Beaufaron Julie, Simon Tabassome, Siffroi Jean-Pierre, Vathaire Florent De, Sclumberger Martin, Bouchard Philippe, Christin-Maitre Sophie, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and BRUNEL, Nadège

Subjects
[SDV] Life Sciences [q-bio], endocrine system, [SDV]Life Sciences [q-bio]
Abstract

International audience; Thirty six patients were included in the study. At V0, all patients had normal gonadal function. At V3, FSH median levels were significantly increased as compared to V0, respectively 9 UI/l±4.8 (N: 3–7 UI/l) versus 4 UI/l±3 (P

Published
2017

36. Neural mechanisms underlying the disruption of male courtship behavior by adult exposure to Di(2-ethylhexyl) phthalate in mice

Author

Solenne Chardonnet, Valérie Grange-Messent, Carlos Dombret, Isabelle Franceschini, Matthieu Keller, Cédric Pionneau, Daphné Capela, Sakina Mhaouty-Kodja, Kevin Poissenot, Caroline Parmentier, Emma Bergsten, Hélène Hardin-Pouzet, ProdInra, Archive Ouverte, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Early detection of Colon Cancer using Molecular Markers and Microbiota (EA 7375) (EC2M3), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sorbonne Universités, Université Pierre et Marie Curie (Paris 6), Institut National de la Santé et de la Recherche Médicale (INSERM), French Agency for Food, Environmental and Occupational Health & Safety (Anses, Project No 2012-2-077), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]

Subjects
Male, 0301 basic medicine, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], endocrine system, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, media_common.quotation_subject, Zoology, Endocrine Disruptors, Biology, souris, in vitro growth, Courtship, Toxicology, Mice, 03 medical and health sciences, chemistry.chemical_compound, proteomics, Diethylhexyl Phthalate, neurone, comportement sexuel, Animals, Science Selection, préférence olfactive, ComputingMilieux_MISCELLANEOUS, mouse, media_common, phthalates, Behavior, Animal, Courtship display, Research, Public Health, Environmental and Occupational Health, Phthalate, standing reflex, follicle development, phtalate, neuron, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Mice, Inbred C57BL, ovarian follicle, 030104 developmental biology, chemistry, Reproduction, Autre (Sciences du Vivant)
Abstract

Background: Courtship behavior plays a critical role in attracting females and reproduction success. However, the effects of exposure to a ubiquitous contaminant di(2-ethylhexyl) phthalate (DEHP) on these behaviors and, in particular, on courtship vocalizations have not been examined. Objective: The effects of adult exposure to DEHP on courtship and mating behaviors and gonadotropic axis and neural mechanisms involved in DEHP-induced effects were analyzed in male mice. Methods: Adult C57BL/6J males were orally exposed to DEHP (0, 0.5, 5, and 50μg/kg/d) for 4 wk. Olfactory preference, ultrasonic vocalizations (USVs), partner preference and mating, as well as locomotor activity and motor coordination, were measured. The kisspeptin system and testosterone levels were analyzed. Proteomic and molecular studies were conducted on the hypothalamic preoptic nucleus, the key region involved in sexual motivation to vocalize and mate. Results: DEHP at 50μg/kg/d reduced the emission of USVs, whereas lower doses changed the ratio of syllable categories. This was associated with diminished sexual interest of female partners toward males exposed to 5 or 50μg/kg/d and increased latency to mate, despite normal olfactory preference. The kisspeptin system and circulating testosterone levels were unaffected. In DEHP-exposed males, proteomic analysis of the preoptic nucleus identified differentially expressed proteins connected to the androgen receptor (AR). Indeed, exposure to 5 or 50μg/kg/d of DEHP induced selective AR downregulation in this nucleus and upstream chemosensory regions. The involvement of AR changes in the observed alterations was further supported by the reduced emission of courtship vocalizations in males with disrupted neural AR expression. Conclusions: These data demonstrate the critical role of neural AR in courtship vocalizations and raises the possibility that the vulnerability of this signaling pathway to exposure to endocrine disrupters may be detrimental for courtship communication and mating in several species. https://doi.org/10.1289/EHP1443

Published
2017

37. Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors

Author

Poggi, Marjorie, Canault, Matthias, Favier, Marie, Turro, Ernest, Saultier, Paul, Ghalloussi, Dorsaf, Baccini, Veronique, Vidal, Lea, Mezzapesa, Anna, Chelghoum, Nadjim, Mohand-Oumoussa, Badreddine, Falaise, Céline, Favier, Rémi, Ouwehand, Willem H, Fiore, Mathieu, Peiretti, Franck, Morange, Pierre-Emmanuel, Saut, Noémie, Bernot, Denis, Greinacher, Andreas, BioResource, Nihr, Nurden, Alan T, Nurden, Paquita, Freson, Kathleen, Trégouët, David-Alexandre, Raslova, Hana, Alessi, Marie-Christine, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-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), The Wellcome Trust Sanger Institute [Cambridge], NOVABUILD, parent, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CNR Institute of Electronics, Computer and Telecommunication Engineering [Torino] (CNR | IEIIT), CNR Istituto di elettronica e di ingegneria dell'informazione e delle telecomunicazioni (CNR | IEIIT), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR)-National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-10-IAHU-05, FDM20150633607, (NIHR) RG65966 (FWO-Vlaanderen, Belgium) G.0B17.13N (BOF KU Leuven, Belgium) OT/14/098, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Matériaux Géomatériaux et Environnement, Université Badji Mokhtar - Annaba [Annaba] (UBMA), Institute of Electronics, Computer and Telecommunication Engineering (IEIIT-CNR), Politecnico di Torino [Torino] (Polito)-Consiglio Nazionale delle Ricerche [Torino] (CNR), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Canault, Matthias, Institute of Electronics, Computer and Telecommunication Engineering [Torino] (IEIIT-CNR), Politecnico di Torino = Polytechnic of Turin (Polito)-Consiglio Nazionale delle Ricerche [Torino] (CNR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de la Méditerranée - Aix-Marseille 2 - Institut National de la Recherche Agronomique (INRA) - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM), Université Badji Mokhtar [Annaba], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - CHU Pitié-Salpêtrière [APHP], Service de pédiatrie, d'hématologie et d'oncologie [CHU La Timone], Assistance Publique - Hôpitaux de Marseille (APHM) - Hôpital de la Timone [CHU - APHM] (TIMONE), Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Institut National de la Santé et de la Recherche Médicale (INSERM), IEIIT-CNR, Politecnico di Torino [Torino] (Polito), Université Bordeaux Segalen - Bordeaux 2 - CHU Bordeaux [Bordeaux], University of Leuven, Turro Bassols, Ernest [0000-0002-1820-6563], Ouwehand, Willem [0000-0002-7744-1790], and Apollo - University of Cambridge Repository

Subjects
Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Transcription, Genetic, Antigens, CD34, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], progéniteur érythrocytaire, mégacaryocyte, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Familial thrombocytopenia, cellule hematopoietique, ComputingMilieux_MISCELLANEOUS, séquence d'adn, CDC42, Cell Differentiation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Articles, CR-1 GENE, Pedigree, Phenotype, Female, Life Sciences & Biomedicine, Megakaryocytes, EXPRESSION, Platelets, Blood Platelets, Genotype, DNA-BINDING, Immunology, Médecine humaine et pathologie, gène autosomal, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 1102 Cardiovascular Medicine And Haematology, hematopoietic cell, Thrombopoiesis, Megakaryocyte, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], hémopathie, Humans, Family, Germ-Line Mutation, Science & Technology, Hyperplasia, Proto-Oncogene Proteins c-ets, MUTATIONS, Platelet Count, THROMBOCYTOPENIA, AUTOINHIBITION, Hematopoietic Stem Cells, Hematopoiesis, Blood Cell Count, Repressor Proteins, thrombocyte, Gene Expression Regulation, cellule germinale, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, TEL, TEL/AML1 FUSION PROTEIN, Human health and pathology, germ-line cells, LEUKEMIA
Abstract

Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to co-repressors. We also observed large expansion of CFU-MKs derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton Cdc42 and RhoA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels. ispartof: Haematologica vol:102 issue:2 pages:282-294 ispartof: location:Italy status: published

Published
2017

38. Cholesteryl Ester Transfer Protein Polymorphisms, Statin Use, and Their Impact on Cholesterol Levels and Cardiovascular Events

Author

André, Romain, Elbaz, Meyer, Khalife, Khalife, Lim, Pascal, Ennezat, Pierre-Vladimir, Coste, Pierre, Le Breton, Hervé, Bataille, Vincent, Ferrières, Jean, Leusink, M, Onland-Moret, N, Asselbergs, F, Ding, B, Kotti, S, van Zuydam, N, Papp, A, Danchin, Nicolas, Donnelly, L, Morris, A, Chasman, D, Doevendans, P, Klungel, O, Ridker, P, van Gilst, W, Simon, Tabassome, Nyberg, F, Palmer, C, Sadee, W, van Der Harst, P, de Bakker, P, de Boer, A, Verstuyft, C, Maitland-van Der Zee, A, Cardiovascular Centre (CVC), Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Heart disease, [SDV]Life Sciences [q-bio], VARIANT, Myocardial Infarction, chemistry.chemical_compound, HDL-CHOLESTEROL, Odds Ratio, Pharmacology (medical), Myocardial infarction, ComputingMilieux_MISCELLANEOUS, Randomized Controlled Trials as Topic, RISK, biology, Middle Aged, CORONARY ATHEROSCLEROSIS, 3. Good health, Cholesterol, DENSITY-LIPOPROTEIN CHOLESTEROL, Cardiovascular Diseases, Female, lipids (amino acids, peptides, and proteins), medicine.medical_specialty, Statin, medicine.drug_class, Single-nucleotide polymorphism, HEART-DISEASE, Polymorphism, Single Nucleotide, White People, Internal medicine, Cholesterylester transfer protein, CETP, medicine, SNP, Humans, cardiovascular diseases, METAANALYSIS, Aged, Pharmacology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Cholesterol, HDL, Odds ratio, Cholesterol, LDL, medicine.disease, GENE, Cholesterol Ester Transfer Proteins, REDUCTION, Endocrinology, Logistic Models, chemistry, biology.protein, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin x SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 x 10-5) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Published
2014

39. A Genome-Wide Association Study in Caucasian Women Points Out a Putative Role of the STXBP5L Gene in Facial Photoaging

Author

Pilar Galan, Anne Bernard, Toufik Labib, Jean-François Zagury, Cédric Coulonges, Julie Latreille, Wassila Carpentier, R. Jdid, Olivier Delaneau, Lieng Taing, Erwin Tschachler, Serge Hercberg, Frédérique Morizot, Christiane Guinot, Denis Malvy, Sigrid Le Clerc, Safa Melak, Khaled Ezzedine, Laboratoire génomique, bioinformatique et applications (GBA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Laboratoire de Neurobiologie et Diversité Cellulaire, ESPCI ParisTech, Service de Dermatologie et Dermatologie Pédiatrique, CHU Bordeaux [Bordeaux]-Centre National des Maladies Rares de la Peau-Hôpital Saint André, Centre d'enseignement Cnam Paris (CNAM Paris), Résistance et survie des cellules tumorales, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne et maladies tropicales, CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine Ile-de-France, Institut National de la Santé et de la Recherche Médicale (INSERM), Chanel PB, Pantin, CENTRE DE RECHERCHES ET D'INVESTIGATIONS EPIDERMIQUES ET SENSORIELLES (CERIES), CERIES, Université de Tours, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de dermatologie Hôpital Saint-André Bordeaux, CHU Bordeaux [Bordeaux], Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT), and Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Linkage disequilibrium, Photoaging, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Genome-wide association study, Context (language use), HapMap Project, Dermatology, Biology, Bioinformatics, Polymorphism, Single Nucleotide, MINERALS, SU.VI.MAX, Biochemistry, Linkage Disequilibrium, White People, Skin Aging, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, SKIN PATTERN, medicine, LINKAGE, SNP, Humans, ANTIOXIDANT VITAMINS, International HapMap Project, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Aged, Genetics, 0303 health sciences, COMPLEX, MOLECULAR-MECHANISMS, F-Box Proteins, Cell Biology, Middle Aged, MUSCLE, medicine.disease, NONPROGRESSION, PREVENTION, Adaptor Proteins, Vesicular Transport, Face, Female, Carrier Proteins, Genome-Wide Association Study
Abstract

International audience; A genome-wide association study (GWAS) was conducted on 502 French middle-aged Caucasian women to identify genetic factors that may affect skin aging severity. A high-throughput Illumina Human Omni1-Quad beadchip was used. After single-nucleotide polymorphism (SNP) quality controls, 795,063 SNPs remained for analysis purposes. Possible stratification was first examined using the Eigenstrat method, and then the relationships between genotypes and four skin aging indicators (global photoaging, lentigines, wrinkles, and sagging) were investigated separately by linear regressions adjusted on age, smoking habits, lifetime sun exposure, hormonal status, and the two main Eigen vectors. One signal passed the Bonferroni threshold (P=1.53 x 10(-8)) and was significantly associated with global photoaging. It was also correlated with the wrinkling score and the sagging score. According to HapMap, this SNP, rs322458, was in linkage disequilibrium (LD) with intronic SNPs of the STXBP5L gene, which is expressed in the skin. In addition, it was also in LD with another SNP that increases the expression of the FBXO40 gene in the skin. These two genes, which were not previously described in the context of aging, may constitute good candidates for the investigation of molecular mechanisms of skin photoaging. Journal of Investigative Dermatology (2013) 133, 929-935; doi:10.1038/jid.2012.458; published online 6 December 2012

Published
2013
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40. Plasmodium falciparum proteins involved in cytoadherence of infected erythrocytes to chemokine CX3CL1

Author

Christophe Combadière, Philippe Deterre, Patricia Hermand, Cédric Pionneau, Catherine Vaquero, Liliane Cicéron, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and HAL UPMC, Gestionnaire

Subjects
0301 basic medicine, Chemokine, Multidisciplinary, [SDV.IMM] Life Sciences [q-bio]/Immunology, Plasmodium falciparum, Biology, biology.organism_classification, Proteomics, Virology, DNA-binding protein, Article, Epitope, 3. Good health, 03 medical and health sciences, 030104 developmental biology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, biology.protein, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Antibody, CX3CL1, Gene, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

Malaria caused by Plasmodium falciparum is associated with cytoadherence of infected red blood cells (iRBC) to endothelial cells. Numerous host molecules have been involved in cytoadherence, including the adhesive chemokine CX3CL1. Most of the identified parasite ligands are from the multigenic and hypervariable Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family which makes them poor targets for the development of a broadly protective vaccine. Using proteomics, we have identified two 25-kDa parasite proteins with adhesive properties for CX3CL1, called CBP for CX3CL1 Binding Proteins. CBPs are coded by single-copy genes with little polymorphic variation and no homology with other P. falciparum gene products. Specific antibodies raised against epitopes from the predicted extracellular domains of each CBP efficiently stain the surface of RBC infected with trophozoites or schizonts, which is a strong indication of CBP expression at the surface of iRBC. These anti-CBP antibodies partially neutralize iRBC adherence to CX3CL1. This adherence is similarly inhibited in the presence of peptides from the CBP extracellular domains, while irrelevant peptides had no such effect. CBP1 and CBP2 are new P. falciparum ligands for the human chemokine CX3CL1. The identification of this non-polymorphic P. falciparum factors provides a new avenue for innovative vaccination approaches.

Published
2016

41. A genome-wide association study in Caucasian women suggests the involvement of HLA genes in the severity of facial solar lentigines

Author

Sigrid Le Clerc, Pilar Galan, Khaled Ezzedine, Damien Ulveling, Lieng Taing, Wassila Carpentier, Taoufik Labib, Vincent Laville, Erwin Tschachler, Julie Latreille, Denis Malvy, Serge Hercberg, Jean-François Zagury, Cédric Coulonges, R. Jdid, Frédérique Morizot, Laboratoire génomique, bioinformatique et applications (GBA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Universitaire de Bobigny, Unité de Recherche en Epidémiologie Nutritionnelle, UMR U557 Inserm, U1125 INRA, Cnam, CRNH IdF, Université Paris 13 (UP13), and 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)

Subjects
0301 basic medicine, Genetics, Linkage disequilibrium, genome-wide association study, HLA-C, SNP, Genome-wide association study, Single-nucleotide polymorphism, Dermatology, Human leukocyte antigen, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, HLA, 03 medical and health sciences, 030104 developmental biology, Oncology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Expression quantitative trait loci, solar lentigines, Allele, skin ageing
Abstract

International audience; Solar lentigines are a common feature of sun-induced skin ageing. Little is known, however, about the genetic factors contributing to their development. In this genome-wide association study, we aimed to identify genetic loci associated with solar lentigines on the face in 502 middle-aged French women. Nine SNPs, gathered in two independent blocks on chromosome 6, exhibited a false discovery rate below 25% when looking for associations with the facial lentigine score. The first block, in the 6p22 region, corresponded to intergenic SNPs and also exhibited a significant association with forehead lentigines (P = 1.37 x 10(-8)). The second block, within the 6p21 HLA region, was associated with decreased HLA-C expression according to several eQTL databases. Interestingly, these SNPs were also in high linkage disequilibrium with the HLA-C*0701 allele (r(2) = 0.95). We replicated an association recently found by GWAS in the IRF4 gene. Finally, a complementary study on 44 selected candidate SNPs revealed novel associations in the MITF gene. Overall, our results point to several mechanisms involved in the severity of facial lentigines, including HLA/immunity and the melanogenesis pathway.

Published
2016

42. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Bénédicte Dubois, Lucia Corrado, Deborah F. Mason, Allan G. Kermode, Pentti J. Tienari, Annette Bang Oturai, Charles Hillier, Adrian J. Ivinson, Stephen L. Hauser, Ashley Beecham, Jeannette Lechner-Scott, Vincent Thijs, Jonathan L. Haines, Sarah Edkins, Alexander T. Dilthey, Daniele Cusi, Guy Nagels, David A. Hafler, Mark Slee, Petra Nilsson, James S. Wiley, Lou Brundin, Amy Strange, Elizabeth Visser, Mireia Sospedra, Athena Hadjixenofontos, Sergio E. Baranzini, Jenny Link, Robert Andrews, Viola Biberacher, Helle Bach Søndergaard, Vittorio Martinelli, Tomas Olsson, Gillian L Hall, Stephen Sawcer, Stacy J. Caillier, Per Soelberg Sørensen, Céline Bellenguez, Cornelia M. van Duijn, Frauke Zipp, Nikolaos A. Patsopoulos, Cristin McCabe, Colin Freeman, Simon Broadley, Luisa Bernardinelli, Margaret A. Pericak-Vance, Jan Hillert, Wassila Carpentier, Sandip Shaunak, Anne Spurkland, Barnaby Fiddes, Judith Field, Jan Lycke, Christina M. Lill, Federica Esposito, Ioanna Konidari, Elisabeth Gulowsen Celius, Christian Gieger, Helmut Butzkueven, Ling Shen, James F. Wilson, Magdalena Lindén, Tejas S. Shah, Amie Baker, Dionysia K. Xifara, Hong Quach, Laura Bergamaschi, Rogier Q. Hintzen, Jacob L. McCauley, Janna Saarela, J W Thorpe, Christine Lebrun-Frenay, Felix Luessi, Sandra D'Alfonso, B. E. Kendall, Helga Westerlind, Giancarlo Comi, Nathalie Schnetz-Boutaud, Paola Brambilla, Chris Cotsapas, Anders Hamsten, William Camu, Achim Berthele, Kjell-Morten Myhr, Clive Hawkins, Richard Nicholas, James Harley, Carl A. Anderson, Keijo Koivisto, Irene Coman, Neil Robertson, Hakon Hakonarson, Finn Sellebjerg, Fredrik Piehl, Alessia Di Sapio, Loukas Moutsianas, Mehdi Alizadeh, Lars Alfredsson, Catherine Schaefer, David Rog, Virpi Leppa, C. Martin, Bruce A.C. Cree, Christopher Halfpenny, Irina Elovaara, Filippo Martinelli-Boneschi, Cordelia Langford, Hanne F. Harbo, Wim Robberecht, Isabelle Cournu-Rebeix, Steve Vucic, Izaura Lima Bomfim, Irene Y. Frohlich, Michelle Lee, Bertrand Fontaine, Bernhard Hemmer, Eva Zindler, Chris C. A. Spencer, Malin Larsson, Simon Shields, Ilijas Jelcic, Juliane Winkelmann, Jorge R. Oksenberg, Alastair Wilkins, Silvia Delgado, Volker Siffrin, Helena C. Kronsbein, Bruno Brochet, Panos Deloukas, Daniela Galimberti, Nikos Evangelou, Rebecca C. Selter, Maja Jagodic, Martin Duddy, Timothy Harrower, Per Hall, Nadia Barizzone, Siân Price, Matti Pirinen, Pierre-Antoine Gourraud, Thomas M.C. Binder, Giuseppe Liberatore, Mark Lathrop, M.-M. Hoshi, Garrett Hellenthal, Melissa Sorosina, Thomas Korn, Clara Guaschino, Roland Martin, Jeremy Hobart, Marco Salvetti, Peter Donnelly, Ingrid Kockum, An Goris, Alastair Compston, Mariaemma Rodegher, Dorothea Buck, Clara P. Manrique, Christiane Graetz, Benedicte A. Lie, Trevor J. Kilpatrick, Andrew Graham, Anu Kemppinen, Maria Ban, Gil McVean, John Zajicek, Hannah Blackburn, Mary F. Davis, Emilie Sundqvist, Bruce V. Taylor, Maurizio Leone, Lisa F. Barcellos, Fabio Macciardi, Gilles Defer, Vincent Damotte, Satu Männistö, Graeme J. Stewart, Gordon Mazibrada, Inger Lise Mero, Andre Franke, Philip L. De Jager, Verena Grummel, Mauri Reunanen, David R. Booth, Anna Ticca, Angela Jochim, Leentje Cosemans, Julia Y Mescheriakova, Cristina Agliardi, Paola Cavalla, Jeffrey C. Barrett, Sarah E. Hunt, Gavin Band, School of Life Sciences, University of Technology Sydney (UTS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Profium Oy [Helsinki], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Michigan Technological University (MTU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Karolinska Institutet [Stockholm], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [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), Department of Statistics [Oxford], Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Epidemiology and Biostatistics (MEB), University College of London [London] (UCL), Fondation Jean Dausset CEPH, Centre Hospitalier Universitaire de Nice (CHU Nice), Dublin Institute of Technology (DIT), University of California [Irvine] (UCI), University of California, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Kaiser Permanente, Universität Zürich [Zürich] = University of Zurich (UZH), University Hospitals Leuven [Leuven], Department Biostatistics University of North Carolina, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institute of Bioinformatics and Systems Biology [München], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Yale University School of Medicine, Big Data Institute, Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Faculty of Engineering, Neuroprotection & Neuromodulation, Internal Medicine Specializations, Neurology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Oxford, Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of California [Irvine] (UC Irvine), University of California (UC), Cardiology, Epidemiology, Oral and Maxillofacial Surgery, International Multiple Sclerosis Genetics, Consortium, Beecham, Ah, Patsopoulos, Na, Xifara, Dk, Davis, Mf, Kemppinen, A, Cotsapas, C, Shah, T, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli Boneschi, F, Taylor, B, Harbo, Hf, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, Jr, Hintzen, R, Barcellos, Lf, Wellcome Trust Case Control Consortium, 2, International IBD Genetics, Consortium, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, Hb, Baker, A, Band, G, Baranzini, Se, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, Tm, Blackburn, H, Bomfim, Il, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, Sj, Camu, W, Carpentier, W, Cavalla, P, Celius, Eg, Coman, I, Comi, Giancarlo, Corrado, L, Cosemans, L, Cournu Rebeix, I, Cree, Ba, Cusi, D, Damotte, V, Defer, G, Delgado, Sr, Deloukas, P, di Sapio, A, Dilthey, At, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, Iy, Galimberti, D, Gieger, C, Gourraud, Pa, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, Se, Jagodic, M, Jelčić, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun Frenay, C, Lechner Scott, J, Lee, Mh, Leone, Ma, Leppä, V, Liberatore, G, Lie, Ba, Lill, Cm, Lindén, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Männistö, S, Manrique, Cp, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, Mccabe, C, Mero, Il, Mescheriakova, J, Moutsianas, L, Myhr, Km, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, Se, Quach, H, Reunanen, M, Robberecht, W, Robertson, Np, Rodegher, M, Rog, D, Salvetti, M, Schnetz Boutaud, Nc, Sellebjerg, F, Selter, Rc, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, P, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, Em, Vucic, S, Westerlind, H, Wiley, J, Wilkins, A, Wilson, Jf, Winkelmann, J, Zajicek, J, Zindler, E, Haines, Jl, Pericak Vance, Ma, Ivinson, Aj, Stewart, G, Hafler, D, Hauser, Sl, Compston, A, Mcvean, G, De Jager, P, Sawcer, Sj, and Mccauley, J. L.

Subjects
Multiple Sclerosis, Genotype, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Genome-wide association study, CLEC16A, Biology, multiple sclerosis, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, Gene Frequency, Polymorphism (computer science), Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Allele frequency, 030304 developmental biology, 0303 health sciences, Research Support, Non-U.S. Gov't, Multiple sclerosis, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Published
2016

43. Dp71 Delta(78-79) dystrophin mutant stimulates neurite outgrowth in PC12 cells via upregulation and phosphorylation of HspB1

Author

Febe E. Cazáres‐Raga, Candelaria Merino-Jiménez, Solenne Chardonnet, Griselda Rodríguez‐Martínez, Alvaro Rendon, Jorge Aragón, Cédric Pionneau, Víctor Ceja, Cecilia Montañez, Departamento de Genetica Y Molecular Biology, Centro de Investigacion y de estudios Avanzados del I.P.N., Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centro de Investigacion y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Consejo Nacional de Ciencia y Tecnologia (Conacyt) [233893, CB-2013-222054, ECOS-ANUIES-SEP-Conacyt M11-S02], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cell biology, animal structures, Neurite, Cellular differentiation, Neuronal Outgrowth, Biology, Dp71 Delta(78-79), Biochemistry, Antibodies, Dystrophin, 03 medical and health sciences, 0302 clinical medicine, Western blot, Downregulation and upregulation, Heat shock protein, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Nerve Growth Factor, medicine, Animals, Electrophoresis, Gel, Two-Dimensional, Phosphorylation, Molecular Biology, Heat-Shock Proteins, Neurons, Regulation of gene expression, medicine.diagnostic_test, Gene Expression Profiling, Neurite outgrowth, PC12 cells, Cell Differentiation, MS, Molecular biology, Neoplasm Proteins, Rats, HspB1, 030104 developmental biology, Gene Expression Regulation, nervous system, Mutation, Signal transduction, 030217 neurology & neurosurgery, Molecular Chaperones, Signal Transduction
Abstract

International audience; PC12 cells acquire a neuronal phenotype in response to nerve growth factor (NGF). However, this phenotype is more efficiently achieved when the Dp71 Delta(78-79) dystrophin mutant is stably expressed in PC12-C11 cells. To investigate the effect of Dp71 Delta(78-79) overexpression on the protein profile of PC12-C11 cells, we compared the expression profiles of undifferentiated and NGF-differentiated PC12-C11 and PC12 cells by 2DE. In undifferentiated cultures, one protein was downregulated, and five were upregulated. Dp71 Delta(78-79) overexpression had a greater effect on differentiated cultures, with ten proteins downregulated and seven upregulated. The protein with the highest upregulation was HspB1. Changes in HspB1 expression were validated by Western blot and immunofluorescence analyses. Interestingly, the neurite outgrowth in PC12-C11 cells was affected by a polyclonal antibody against HspB1, and the level of HspB1 and HspB1Ser86 decreased, suggesting an important role for this protein in this cellular process. Our results show that Dp71 Delta(78-79) affects the expression level of some proteins and that the stimulated neurite outgrowth produced by this mutant is mainly through upregulation and phosphorylation of HspB1.

Published
2016

44. Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study: The risk of urinary tract cancers, including kidney and bladder cancers, was increased in transplant recipients receiving thiopurines

Author

A, Bourrier, F, Carrat, J-F, Colombel, A-M, Bouvier, V, Abitbol, P, Marteau, J, Cosnes, T, Simon, L, Peyrin-Biroulet, L Beaugerie, CESAME, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

International audience; Ten and six patients developed respectively kidney and bladder cancer. The incidence rates of urinary tract cancer were 0.48/1000 patient-years in patients receiving thiopurines (95% CI: 0.21-0.95), 0.10/1000 patient-years in patients who discontinued thiopurines (95% CI: 0.00-0.56) and 0.30/1000 patient-years in patients never treated with thiopurines (95% CI: 0.12-0.62) at entry. The standardised incidence ratio of urinary tract cancer was 3.40 (95% CI: 1.47-6.71, P = 0.006) in patients receiving thiopurines, 0.64 (95% CI: 0.01-3.56, P = 0.92) in patients previously exposed to thiopurines and 1.17 (95% CI: 0.47-12.42, P = 0.78) in patients never treated with thiopurines. The multivariate-adjusted hazard ratio (HR) of urinary tract cancer between patients receiving thiopurines and those not receiving thiopurines was 2.82 (95% CI: 1.04-7.68, P = 0.04). Other significant risk factors were male gender (HR: 3.98, 95% CI: 1.12-14.10, P = 0.03) and increasing age (HR after 65 years (ref

Published
2016

45. Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

Author

Bourrier, A., Carrat, F., Colombel, F., Bouvier, A., Abitbol, Vered, Marteau, P., Cosnes, J., Simon, T., Peyrin-Biroulet, Laurent, Beaugerie, L., Carbonnel, Franck, Colombel, Jean Frédéric, Filippi, Jérôme, Katsanos, Konstantinos, Allez, Mathieu, Nachury, Maria, Novacek, Gottfried, Danese, Silvio, Bossa, Fabrizio, Moreau, Jacques, Bommelaer, Gilles, Bourreille, Arnaud, Fumery, Mathurin, Roblin, Xavier, Reinisch, Walter, Bouhnik, Yoram, Brixi, Hedia, Seksik, Philippe, Malamut, Georgia, Färkkilä, Martti, Coulibaly, Baya, Dewit, Olivier, Louis, Edouard, Deplanque, Dominique, Michetti, Pierre, Sarter, Hélène, Laharie, David, Demolin, Julie, Détré, Patricia, Brillaut, Gaëlle, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ESIM - Déterminants Sociaux de la Santé et du Recours aux Soins (DS3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), 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 Paris Descartes - Paris 5 (UPD5), Service de Gastro-entérologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hépatogastroentérologie, CHU de Bicêtre, Centre d'Investigation Clinique Lille, PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Nice (CHU Nice), University Hospital of Ioannina, Hôpital Saint-Louis, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Gastroenterology, Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed)-Humanitas University [Milan] (Hunimed), Service de Gastroentérologie et pancréatologie [CHU Toulouse], Pôle Maladies de l'appareil digestif [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Service de Gastro-entérologie et Hépatologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Clinic of Internal Medicine IV, Department of Gastroenterology and Hepathology, Universität Wien, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), 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), Université de Liège, CIC CHU ( Lille)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut National de Veille Sanitaire, Institut national de veille sanitaire, Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Department of Gastroenterology, CHU Toulouse [Toulouse], Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Service de gastroentérologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Hôpital Beaujon, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [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), Laboratoire des technologies de la microélectronique (LTM), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA) - Grenoble-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Epidémiologie, Systèmes dínformation et modélisation (ESIM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département de santé publique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Institut Pierre Louis d'Epidémiologie et de Santé Publique ( iPLESP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Icahn School of Medicine at Mount Sinai [New York], 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 Paris Descartes - Paris 5 ( UPD5 ), Département de gastroentérologie, CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Université de Lorraine ( UL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Tenon [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Laboratoire des technologies de la microélectronique (LTM ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP]

Subjects
Adult, Male, Nonmelanoma Skin Cancers, medicine.medical_specialty, Urologic Neoplasms, Urinary system, Gastroenterology, Cohort Studies, Association, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [ CHIM.ORGA ] Chemical Sciences/Organic chemistry, Risk Factors, Internal medicine, Azathioprine, Medicine, Humans, Pharmacology (medical), Prospective Studies, Prospective cohort study, Proportional Hazards Models, Transplantation, Bladder cancer, Hepatology, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Malignancy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Middle Aged, Metaanalysis, medicine.disease, Inflammatory Bowel Diseases, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, 030220 oncology & carcinogenesis, Cohort, 030211 gastroenterology & hepatology, Female, Therapy, business, Cohort study
Abstract

Background The risk of urinary tract cancers, including kidney and bladder cancers, was increased in transplant recipients receiving thiopurines. Aim To assess the risk of urinary tract cancers in patients with inflammatory bowel disease (IBD) receiving thiopurines in the CESAME observational cohort. Methods Between May 2004 and June 2005, 19 486 patients with IBD, 30.1% of whom were receiving thiopurines, were enrolled. Median follow-up was 35 months (IQR: 29-40). Results Ten and six patients developed respectively kidney and bladder cancer. The incidence rates of urinary tract cancer were 0.48/1000 patient-years in patients receiving thiopurines (95% CI: 0.21-0.95), 0.10/1000 patient-years in patients who discontinued thiopurines (95% CI: 0.00-0.56) and 0.30/1000 patient-years in patients never treated with thiopurines (95% CI: 0.12-0.62) at entry. The standardised incidence ratio of urinary tract cancer was 3.40 (95% CI: 1.47-6.71, P = 0.006) in patients receiving thiopurines, 0.64 (95% CI: 0.01-3.56, P = 0.92) in patients previously exposed to thiopurines and 1.17 (95% CI: 0.47-12.42, P = 0.78) in patients never treated with thiopurines. The multivariate-adjusted hazard ratio (HR) of urinary tract cancer between patients receiving thiopurines and those not receiving thiopurines was 2.82 (95% CI: 1.04-7.68, P = 0.04). Other significant risk factors were male gender (HR: 3.98, 95% CI: 1.12-14.10, P = 0.03) and increasing age (HR after 65 years (ref

Published
2016

46. Transcriptome Analysis of Peripheral Blood in Chronic Inflammatory Demyelinating Polyradiculoneuropathy Patients Identifies TNFR1 and TLR Pathways in the IVIg Response

Author

Céline Labeyrie, Karine Viala, Fleur Cohen Aubart, Jean-Christophe Corvol, Pauline Reach, Khadija Tahiri, Justine Gueguen, Vincent Guillemot, Wassila Carpentier, David H. Adams, Alexandra Richard, Rabab Debs, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurosciences translationnelles de Paris (NeurATRIS - IHU-A-ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [APHP], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre de référence des neuropathies amyloïdes et autres neuropathies rares, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, d'Eggis, Gilles, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, 0301 basic medicine, UNC93B1, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Observational Study, medicine.disease_cause, Autoimmunity, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Humans, Medicine, Receptor, Aged, Innate immune system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tumor Necrosis Factor-alpha, business.industry, Gene Expression Profiling, Toll-Like Receptors, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Immunoglobulins, Intravenous, Polyradiculoneuropathy, General Medicine, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Pharmacogenetics, Receptors, Tumor Necrosis Factor, Type I, Antibody Formation, Immunology, Female, Tumor necrosis factor alpha, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, Research Article
Abstract

International audience; We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83–6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC] > 1.2, P

Published
2016

47. Fifteen-year trends in the management of cardiogenic shock and associated 1-year mortality in elderly patients with acute myocardial infarction: the FAST-MI programme

Author

Aissaoui, N, Puymirat, E, Juilliere, Y, Jourdain, P, Blanchard, D, Schiele, F, Guéret, P, POPOVIC, B, Ferrieres, J, Simon, Tabassome, Danchin, N., Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

48. PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes

Author

Jean-Sébastien Hulot, Dirk Sibbing, Jean-Philippe Collet, Guillaume Paré, Stephen D. Wiviott, Tabassome Simon, Sandra L Close, Matthew J. Price, Jessica T. Delaney, Elliott M. Antman, Scott S. Sundseth, Michael Man, Jessica L. Mega, Marc S. Sabatine, Suman Duvvuru, Dietmar Trenk, Joseph R. Walker, Sabina A. Murphy, BRUNEL, Nadège, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, Acute coronary syndrome, Ticlopidine, Prasugrel, [SDV]Life Sciences [q-bio], Mutation, Missense, 030204 cardiovascular system & hematology, Pharmacology, Gastroenterology, 03 medical and health sciences, Percutaneous Coronary Intervention, 0302 clinical medicine, Internal medicine, medicine, Humans, cardiovascular diseases, 030212 general & internal medicine, Acute Coronary Syndrome, Stroke, ComputingMilieux_MISCELLANEOUS, Aged, Randomized Controlled Trials as Topic, Prasugrel Hydrochloride, Aryldialkylphosphatase, business.industry, Hematology, Middle Aged, medicine.disease, Clopidogrel, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid Substitution, Pharmacodynamics, Female, Cardiology and Cardiovascular Medicine, business, Mace, medicine.drug
Abstract

Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84-1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77-2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77-1.27) and 1.23 (0.74-2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.

Published
2016

49. CESAME study group.: Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease : a prospective observational cohort study

Author

Pouche, M, Ruidavets, JB, Ferrières, J, Iliou, MC, Douard, H, Lorgis, L, Carrié, D, Brunel, P, Simon, Tabassome, Bataille, V, Danchin, N., Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

50. RAD51 Haploinsufficiency Causes Congenital Mirror Movements in Humans

Author

Delphine Bouteiller, Vanessa Brochard, Emmanuel Roze, Christel Depienne, Jean-Paul Saraiva, Sabine Meunier, Kailash P. Bhatia, Aurélie Méneret, Ségolène Billot, Constance Flamand-Roze, Rosine Wehrlé, Stephan Klebe, Jean-Christophe Corvol, Isabelle Dusart, Massimo Cincotta, Sergiu Groppa, Y. Marie, Norbert Brueggemann, Giovanni Stevanin, Wassila Carpentier, Marion Gaussen, Marie Vidailhet, Alexis Brice, Christine Klein, Fanny Charbonnier-Beaupel, Développement et plasticité des réseaux neuronaux = Development and Plasticity of Neural Networks (NPS-14), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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 National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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 National de la Recherche Scientifique (CNRS)

Subjects
Heterozygote, DNA Repair, DNA repair, RAD51, Down-Regulation, Receptors, Cell Surface, Haploinsufficiency, Biology, medicine.disease_cause, Congenital Abnormalities, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Report, Netrin, medicine, Genetics, Humans, DNA Breaks, Double-Stranded, Exome, Genetics(clinical), Nerve Growth Factors, RNA, Messenger, Homologous Recombination, Genetics (clinical), Exome sequencing, 030304 developmental biology, Family Health, 0303 health sciences, Mutation, Dyskinesias, Movement Disorders, Tumor Suppressor Proteins, Motor Cortex, Netrin-1, DCC Receptor, Axons, Pedigree, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rad51 Recombinase, 030217 neurology & neurosurgery, Genome-Wide Association Study, Motor cortex
Abstract

International audience; Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans.

Published
2012
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