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27 results on '"Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval"'

1. RAD51 protects against nonconservative DNA double-strand break repair through a nonenzymatic function

Author

Ayeong So, Elodie Dardillac, Ali Muhammad, Catherine Chailleux, Laura Sesma-Sanz, Sandrine Ragu, Eric Le Cam, Yvan Canitrot, Jean Yves Masson, Pauline Dupaigne, Bernard S Lopez, Josée Guirouilh-Barbat, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Intégrité du génome et cancers (IGC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Axe Oncologie [CRCHU de Québec], Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Guirouilh-Barbat, Josée

Subjects
DNA End-Joining Repair, DNA Repair, genetic processes, DNA, Single-Stranded, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Chromatin, enzymes and coenzymes (carbohydrates), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, health occupations, Genetics, Humans, DNA Breaks, Double-Stranded, Rad51 Recombinase, biological phenomena, cell phenomena, and immunity
Abstract

Selection of the appropriate DNA double-strand break (DSB) repair pathway is decisive for genetic stability. It is proposed to act according to two steps: 1-canonical nonhomologous end-joining (C-NHEJ) versus resection that generates single-stranded DNA (ssDNA) stretches; 2-on ssDNA, gene conversion (GC) versus nonconservative single-strand annealing (SSA) or alternative end-joining (A-EJ). Here, we addressed the mechanisms by which RAD51 regulates this second step, preventing nonconservative repair in human cells. Silencing RAD51 or BRCA2 stimulated both SSA and A-EJ, but not C-NHEJ, validating the two-step model. Three different RAD51 dominant-negative forms (DN-RAD51s) repressed GC and stimulated SSA/A-EJ. However, a fourth DN-RAD51 repressed SSA/A-EJ, although it efficiently represses GC. In living cells, the three DN-RAD51s that stimulate SSA/A-EJ failed to load efficiently onto damaged chromatin and inhibited the binding of endogenous RAD51, while the fourth DN-RAD51, which inhibits SSA/A-EJ, efficiently loads on damaged chromatin. Therefore, the binding of RAD51 to DNA, rather than its ability to promote GC, is required for SSA/A-EJ inhibition by RAD51. We showed that RAD51 did not limit resection of endonuclease-induced DSBs, but prevented spontaneous and RAD52-induced annealing of complementary ssDNA in vitro. Therefore, RAD51 controls the selection of the DSB repair pathway, protecting genome integrity from nonconservative DSB repair through ssDNA occupancy, independently of the promotion of CG.

Published
2022

2. Human RAD52 stimulates the RAD51-mediated homology search

Author

Ali Akbar Muhammad, Thibault Peterlini, José Guirouilh-Barbat, Xavier Veaute, Didier Busso, Bernard Lopez, Jean-Yves Masson, Gérard Mazon, Eric Le Cam, Pauline Dupaigne, Intégrité du génome et cancers (IGC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Université Laval [Québec] (ULaval), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Axe Oncologie [CRCHU de Québec], Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Guirouilh-Barbat, Josée, and École Pratique des Hautes Études (EPHE)

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Abstract

Homologous recombination (HR) is a DNA repair mechanism of double strand breaks and blocked replication forks that involves a process of homology search and homologous pairing leading to the formation of synaptic intermediates whose architecture and dynamics are tightly regulated to ensure genome integrity. In this mechanism, RAD51 recombinase plays a central role and is supported by many partner including BRCA2 and RAD52. If the mediator function of BRCA2 to load RAD51 on RPA-covered ssDNA is well established, the role of RAD52 in HR, more precisely its interplay with BRCA2 is still far from understood. We have used Transmission Electron Microscopy combined with biochemistry to characterize the sequential participation of RPA, RAD52 and BRCA2 in the assembly of the RAD51 filament, its architecture and its activity. Despite our results confirm that RAD52 lacks a mediator activity, we observed that RAD52 can tightly bind to RPA-coated ssDNA, inhibit the mediator role of BRCA2 and form shorter RAD52- and RAD51-containing mixed filaments that are more efficient in subsequent homology search and formation of synaptic complexes and D-loops, resulting in more frequent multi-invasions as well. Through the characterization of the behavior of RAD52 and BRCA2, these results provide new molecular insights on the formation and regulation of presynaptic and synaptic intermediates during human HR.

Published
2022

3. XAB2 prevents abortive recombinational repair of replication-associated DNA double-strand breaks and its loss is synthetic lethal with RAD52 inhibition

Author

H. Erasimus, Abhishek Sharma, Petr V. Nazarov, Barbara Klink, Sabrina Fritah, Lia Pinto, Jean-Yves Masson, Marie-Christine Caron, Christel Herold-Mende, Van Dyck E, Sébastien Britton, Katrin Neumann, Patrick Calsou, Simone P. Niclou, Luxembourg Institute of Health (LIH), Axe Oncologie [CRCHU de Québec], Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), University clinic Heidelberg, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-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), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Britton, Sébastien

Subjects
RAD52, genetic processes, RAD51, [SDV.CAN]Life Sciences [q-bio]/Cancer, Synthetic lethality, [SDV.GEN] Life Sciences [q-bio]/Genetics, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, DNA Repair Protein, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Temozolomide, biology, Topoisomerase, Molecular biology, enzymes and coenzymes (carbohydrates), chemistry, 030220 oncology & carcinogenesis, biology.protein, Homologous recombination, DNA, medicine.drug
Abstract

Unrepaired O6-methylguanine lesions induced by the alkylating chemotherapy agent temozolomide lead to replication-associated single-ended DNA double-strand breaks (seDSBs) that are repaired predominantly through RAD51-mediated homologous recombination (HR). Here, we show that loss of the pre-mRNA splicing and DNA repair protein XAB2 leads to increased temozolomide sensitivity in glioblastoma cells, which reflects abortive HR due to Ku retention on resected seDSBs. XAB2-dependent Ku eviction also occurred at seDSBs generated by the topoisomerase I poison campthotecin and operated in parallel to an ATM-dependent pathway previously described. Although Ku retention elicited by loss of XAB2 did not prevent RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased engagement of non-homologous-end-joining in S/G2 and genetic instability. Overexpression of RAD51 or the single-stranded DNA annealing factor RAD52 rescued the XAB2 defects. RAD52 depletion led to severe temozolomide sensitivity, whereas a synthetic lethality interaction was observed between RAD52 and XAB2.

Published
2020

4. Evidence for the spread of human-derived mutant huntingtin protein in mice and non-human primates

Author

Steve Lacroix, Benjamin Dehay, Chuan Qin, Giulia Cisbani, Ludivine S. Breger, Abid Oueslati, Zhang Ling, Melanie Alpaugh, Alexander Maxan, Zhu Tao, Jean-Paul Vonsattel, Philippe Gosset, Erwan Bezard, Nadia Fortin, Francesca Cicchetti, Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), China Academy of Medical Sciences [Beijing, China] (Institute of Laboratory Animal Sciences), University of Toronto, Columbia University [New York], Université Laval [Québec] (ULaval), and Dehay, Benjamin

Subjects
0301 basic medicine, Huntingtin, Pathological polyQ, [SDV]Life Sciences [q-bio], Mutant, Endogeny, Disease, Biology, Protein Aggregation, Pathological, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Huntington's disease, medicine, Huntingtin Protein, Animals, Humans, BACHD, Induced pluripotent stem cell, Child, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neurons, Behavior, Animal, Mechanism (biology), Neurodegenerative diseases, Prion-like protein, Brain, Animal behaviour, medicine.disease, Macaca mulatta, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, Neurology, Mutation, Female, 030217 neurology & neurosurgery
Abstract

International audience; In recent years, substantial evidence has emerged to suggest that spreading of pathological proteins contributes to disease pathology in numerous neurodegenerative disorders. Work from our laboratory and others have shown that, despite its strictly genetic nature, Huntington's disease (HD) may be another condition in which this mechanism contributes to pathology. In this study, we set out to determine if the mutant huntingtin protein (mHTT) present in post-mortem brain tissue derived from HD patients can induce pathology in mice and/or non-human primates. For this, we performed three distinct sets of experiments where homogenates were injected into the brains of adult a) Wild-type (WT) and b) BACHD mice or c) non-human primates. Neuropathological assessments revealed that, while changes in the endogenous huntingtin were not apparent, mHTT could spread between cellular elements and brain structures. Furthermore, behavioural differences only occurred in the animal model of HD which already overexpressed mHTT. Taken together, our results indicate that mHTT derived from human brains has only a limited capacity to propagate between cells and does not depict prion-like characteristics. This contrasts with recent work demonstrating that other forms of mHTT - such as fibrils of a pathological polyQ length or fibroblasts and induced pluripotent stem cells derived from HD cases - can indeed disseminate disease throughout the brain in a prion-like fashion.

Published
2020

5. Use of adeno-associated virus-mediated delivery of mutant huntingtin to study the spreading capacity of the protein in mice and non-human primates

Author

Abid Oueslati, Zhang Ling, Ludivine S. Breger, Melanie Alpaugh, Benjamin Dehay, Zhu Tao, Francesca Cicchetti, Giacomo Sciacca, Steve Lacroix, Shireen Salem, Erwan Bezard, Alexander Maxan, Giulia Cisbani, Qin Chuan, Maria Masnata, Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), China Academy of Medical Sciences [Beijing, China] (Institute of Laboratory Animal Sciences), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), University of Shanghai for Science and Technology, University of Toronto, Université Laval [Québec] (ULaval), and Dehay, Benjamin

Subjects
Male, 0301 basic medicine, Two-photon intravital imaging, Huntingtin, Pathological polyQ, [SDV]Life Sciences [q-bio], Genetic Vectors, Green Fluorescent Proteins, Mutant, Central nervous system, Endogeny, Biology, medicine.disease_cause, Protein Aggregation, Pathological, Virus, lcsh:RC321-571, Viral vector, Green fluorescent protein, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Viral vectors, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Adeno-associated virus, Huntingtin Protein, Protein, Neurodegenerative diseases, Dependovirus, Animal behaviour, Macaca mulatta, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Neurology, Prion, Female, Animal behavior, 030217 neurology & neurosurgery
Abstract

International audience; In order to model various aspects of Huntington's disease (HD) pathology, in particular protein spread, we administered adeno-associated virus (AAV) expressing green fluorescent protein (GFP) or GFP coupled to HTT-Exon1 (19Q or 103Q) to the central nervous system of adult wild-type (WT) mice and non-human primates. All animals underwent behavioral testing and post-mortem analyses to determine the long-term consequences of AAV injection. Both mice and non-human primates demonstrated behavioral changes at 2-3 weeks post-surgery. In mice, these changes were absent after 3 months while in non-human primates, they persisted in the majority of tested animals. Post-mortem analysis revealed that spreading of the aggregates was limited, although the virus did spread between synaptically-connected brain regions. Despite the small degree of spreading, the presence of mHTT generated changes in endogenous huntingtin (HTT) levels in both models. Together, these results suggest that viral expression of mHTTExon1 can induce spreading and seeding of HTT in both mice and non-human primates.

Published
2020

6. Isolated isochromosomes i(X)(p10) and idic(X)(q13) are associated with myeloid malignancies and dysplastic features

Author

Isabelle Rafdord-Weiss, Dominique Penther, Carole Barin, Baptiste Gaillard, Benoit Quilichini, Catherine Roche-Lestienne, Pascaline Etancelin, Christine Lefebvre, Daniel Lusina, Gwenaël Nadeau, Francine Mugneret, Catherine Godon, Virginie Eclache, Florence Nguyen-Khac, Yann Ferret, M J Mozziconacci, Antoine Ittel, Nathalie Nadal, Audrey Bidet, Gwendoline Soler, Elise Chapiro, Groupe Francophone de Cytogénétique Hématologique, Agnès Daudignon, Steven Richebourg, Pierre-Julien Viailly, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'hématologie biologique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dpt hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital de la Timone [CHU - APHM] (TIMONE), Thales Communications [Colombes], THALES, CHU Bretonneau, CHU Clermont-Ferrand, Centre Hospitalier de Valenciennes, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Service d'hématologie biologique [Nantes] (Cytologie Hématologique), Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôtel-Dieu de Nantes, Service de Cytogénétique, Centre hospitalier de Valence, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cytogenetics [Québec, Canada], Centre Hospitalier Universitaire du Québec (CHUQ)-Hôpital du Saint-Sacrement [CHU Québec] (HSS), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Picardie Jules Verne (UPJV), and Hôpital Avicenne [AP-HP]

Subjects
Male, Myeloid, [SDV]Life Sciences [q-bio], Isochromosome, Dioxygenases, 03 medical and health sciences, 0302 clinical medicine, Age Distribution, Bone Marrow, Proto-Oncogene Proteins, medicine, Neoplasm, Humans, Sex Distribution, Gene, ComputingMilieux_MISCELLANEOUS, Aged, Chromosomes, Human, X, business.industry, Follow up studies, Neoplasms, Second Primary, Hematology, Middle Aged, medicine.disease, 3. Good health, Neoplasm Proteins, DNA-Binding Proteins, Isochromosomes, Leukemia, medicine.anatomical_structure, Leukemia, Myeloid, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Mutation (genetic algorithm), Mutation, Cancer research, Age distribution, Female, business, 030215 immunology, Follow-Up Studies, Genes, Neoplasm
Abstract

International audience

Published
2019

7. Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms

Author

Luc Bousset, Maria Masnata, Martine Saint-Pierre, Hélèna L Denis, Alexander Maxan, Jeffrey H. Kordower, Giacomo Sciacca, Florian Lauruol, Ronald Melki, Francesca Cicchetti, Melanie Alpaugh, Linda Suzanne David, Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Departement de Psychiatrie & Neurosciences, Université Laval, Québec, QC, Canada, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Neurological Sciences, Rush University Medical Center, Chicago IL, USA, ANR-16-CE16-0020,nicostress,Réseaux neuronaux sous-tendant l'intéraction entre stress et nicotine dans le cadre des troubles psychiatriques(2016), ANR-16-CE16-0019,Neurotunn,Role des nanotubes membranaires dans la propagation d'agrégats protéiques impliqués dans les maladie neurodégénératives(2016), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Male, 0301 basic medicine, Cell type, Huntingtin, Induced Pluripotent Stem Cells, Anxiety, Motor Activity, Cell morphology, Monocytes, Injections, Pathology and Forensic Medicine, Mice, Neuroblastoma, Protein Aggregates, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, In vivo, Cell Line, Tumor, Huntingtin Protein, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, GABAergic Neurons, Maze Learning, Induced pluripotent stem cell, ComputingMilieux_MISCELLANEOUS, Injections, Intraventricular, Original Paper, Chemistry, Brain, Exons, Recombinant Proteins, In vitro, 3. Good health, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, Cell culture, Exploratory Behavior, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Cognition Disorders, 030217 neurology & neurosurgery
Abstract

In recent years, evidence has accumulated to suggest that mutant huntingtin protein (mHTT) can spread into healthy tissue in a prion-like fashion. This theory, however, remains controversial. To fully address this concept and to understand the possible consequences of mHTT spreading to Huntington’s disease pathology, we investigated the effects of exogenous human fibrillar mHTT (Q48) and huntingtin (HTT) (Q25) N-terminal fragments in three cellular models and three distinct animal paradigms. For in vitro experiments, human neuronal cells [induced pluripotent stem cell-derived GABA neurons (iGABA) and (SH-SY5Y)] as well as human THP1-derived macrophages, were incubated with recombinant mHTT fibrils. Recombinant mHTT and HTT fibrils were taken up by all cell types, inducing cell morphology changes and death. Variations in HTT aggregation were further observed following incubation with fibrils in both THP1 and SH-SY5Y cells. For in vivo experiments, adult wild-type (WT) mice received a unilateral intracerebral cortical injection and R6/2 and WT pups were administered fibrils via bilateral intraventricular injections. In both protocols, the injection of Q48 fibrils resulted in cognitive deficits and increased anxiety-like behavior. Post-mortem analysis of adult WT mice indicated that most fibrils had been degraded/cleared from the brain by 14 months post-surgery. Despite the absence of fibrils at these later time points, a change in the staining pattern of endogenous HTT was detected. A similar change was revealed in post-mortem analysis of the R6/2 mice. These effects were specific to central administration of fibrils, as mice receiving intravenous injections were not characterized by behavioral changes. In fact, peripheral administration resulted in an immune response mounting against the fibrils. Together, the in vitro and in vivo data indicate that exogenously administered mHTT is capable of both causing and exacerbating disease pathology. Electronic supplementary material The online version of this article (10.1007/s00401-019-01973-6) contains supplementary material, which is available to authorized users.

Published
2019

8. Intramuscular transplantation in non-human primates of human muscle-derived stem cells (MuStem cells), a promising candidate for cell therapy of muscular dystrophies

Author

CHARRIER, MARINE, Leroux, Isabelle, Couture, V, Larcher, Thibaut, Schleder, Cindy, Pereon, Yann, Lamirault, Guillaume, Tremblay, JP, Skuk, Daniel, Rouger, Karl, Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Axe Neurosciences, Research Center of the CHU de Quebec, Centre Hospitalier Universitaire de Québec, Centre de Référence Maladies Neuromusculaires AOC, Laboratoire d’Explorations Fonctionnelles, Centre Hospitalier Universiatire Hôtel-Dieu de Nantes (CHU Hôtel-Dieu), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), and Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)

Subjects
[SDV]Life Sciences [q-bio], thérapie cellulaire, white muscle disease, cell therapy, dystrophie musculaire, primate
Abstract

Intramuscular transplantation in non-human primates of human muscle-derived stem cells (MuStem cells), a promising candidate for cell therapy of muscular dystrophies. 6eme congrès international de Myologie

Published
2019

9. Tau, Diabetes and Insulin

Author

Maud Gratuze, David Blum, Aurelie Joly-Amado, Didier Vieau, Luc Buée, Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Department of Molecular Pharmacology and Physiology [Tampa, FL, USA] (Byrd Alzheimer’s Institute ), University of South Florida [Tampa] (USF), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Environnement périnatal et croissance - EA 4489 (EPS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille

Subjects
Cell division, Cell morphogenesis, Microtubule-associated protein, Alternative splicing, Tau protein, Biology, 03 medical and health sciences, 0302 clinical medicine, Microtubule, Extracellular, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030212 general & internal medicine, Neuroscience, Intracellular, ComputingMilieux_MISCELLANEOUS
Abstract

Tau protein which was discovered in 1975 [310] became of great interest when it was identified as the main component of neurofibrillary tangles (NFT), a pathological feature in the brain of patients with Alzheimer's disease (AD) [39, 110, 232]. Tau protein is expressed mainly in the brain as six isoforms generated by alternative splicing [46, 97]. Tau is a microtubule associated proteins (MAPs) and plays a role in microtubules assembly and stability, as well as diverse cellular processes such as cell morphogenesis, cell division, and intracellular trafficking [49]. Additionally, Tau is involved in much larger neuronal functions particularly at the level of synapses and nuclei [11, 133, 280]. Tau is also physiologically released by neurons [233] even if the natural function of extracellular Tau remains to be uncovered (see other chapters of the present book).

Published
2019

10. [Brain insulin signaling and Tau: impact for Alzheimer's disease and Tauopathies]

Author

Joly-Amado, Aurélie, Gratuze, Maud, Benderradji, Hamza, Vieau, Didier, Buee, Luc, Blum, David, Department of Molecular Pharmacology and Physiology [Tampa, FL, USA] (Byrd Alzheimer’s Institute ), University of South Florida [Tampa] (USF), Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, and Excellence Laboratory LabEx DISTALZ

Subjects
Tauopathies, Alzheimer Disease, Animals, Brain, Humans, Insulin, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], tau Proteins, Insulin Resistance, Cognition Disorders, Signal Transduction
Abstract

International audience; Alzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive deficits and neuropathological lesions such as Tau aggregates and amyloid plaques, but also associated with metabolic and neuroendocrine abnormalities, such as impairment of cerebral insulin. However, the origin of these symptoms and their relationship to pathology and cognitive disorders remain poorly understood. Insulin is a hormone involved in the control of peripheral and central energy homeostasis, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that brain insulin resistance can exacerbate Tau lesions. Conversely, recent data indicate that Tau protein can modulate insulin signalling in the brain, creating a vicious circle precipitating the pathological AD. This review aims to highlight our current understanding of the role of insulin in the brain and its relationship with Tau protein in the context of AD and Tauopathies.; La maladie d’Alzheimer (MA) est une maladie neurodégénérative caractérisée par des déficits cognitifs et des lésions (agrégats de Tau et plaques amyloïdes), mais également par des troubles métaboliques et neuroendocriniens. Les mécanismes à l’origine de ces processus physiopathologiques demeurent mal compris mais pourraient provenir du développement d’une insulino-résistance centrale. L’altération de l’action de l’insuline dans le cerveau des patients atteints de MA a été décrite comme facteur aggravant les lésions Tau et amyloïdes ainsi que les troubles cognitifs. L’origine de cette résistance centrale est bien moins comprise mais ferait intervenir la protéine Tau, suggérant l’existence d’un cercle vicieux contribuant à l’apparition et à la progression des signes cliniques. La présente revue vise à faire le point sur notre compréhension actuelle du rôle de l’insuline dans le cerveau et de sa relation avec la protéine Tau dans la MA et les Tauopathies.

Published
2018

11. [Brain insulin signaling and Tau: impact for Alzheimer's disease and Tauopathies]

Author

Joly-Amado, Aurélie, Gratuze, Maud, Benderradji, Hamza, Vieau, Didier, Buée, Luc, Blum, David, Department of Molecular Pharmacology and Physiology [Tampa, FL, USA] (Byrd Alzheimer’s Institute ), University of South Florida [Tampa] (USF), Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Environnement périnatal et croissance - EA 4489 (EPS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Excellence Laboratory LabEx DISTALZ, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Blum, David

Subjects
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ComputingMilieux_MISCELLANEOUS
Abstract

Alzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive deficits and neuropathological lesions such as Tau aggregates and amyloid plaques, but also associated with metabolic and neuroendocrine abnormalities, such as impairment of cerebral insulin. However, the origin of these symptoms and their relationship to pathology and cognitive disorders remain poorly understood. Insulin is a hormone involved in the control of peripheral and central energy homeostasis, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that brain insulin resistance can exacerbate Tau lesions. Conversely, recent data indicate that Tau protein can modulate insulin signalling in the brain, creating a vicious circle precipitating the pathological AD. This review aims to highlight our current understanding of the role of insulin in the brain and its relationship with Tau protein in the context of AD and Tauopathies., La maladie d’Alzheimer (MA) est une maladie neurodégénérative caractérisée par des déficits cognitifs et des lésions neuropathologiques (agrégats de Tau et plaques amyloïdes), mais également par des troubles métaboliques et neuroendocriniens. Les mécanismes à l’origine de ces processus physiopathologiques demeurent mal compris mais pourraient provenir du développement d’une insulino-résistance centrale. L’altération de l’action de l’insuline dans le cerveau des patients atteints de MA a été décrite comme facteur aggravant les lésions Tau et amyloïdes ainsi que les troubles cognitifs. L’origine de cette résistance centrale est bien moins comprise mais ferait intervenir la protéine Tau, suggérant l’existence d’un cercle vicieux contribuant à l’apparition et à la progression des signes cliniques. La présente revue vise à faire le point sur notre compréhension actuelle du rôle de l’insuline dans le cerveau et de sa relation avec la protéine Tau dans la MA et les Tauopathies.

Published
2018

12. Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

Author

Uladzislau Rudakou, Edward A. Fon, Petra Oliva, Guy A. Rouleau, Yves Dauvilliers, Elena Antelmi, Birgit Högl, Anna Heidbreder, Jean-François Trempe, Christopher Liong, Bouchra Ouled Amar Bencheikh, Pavlina Wolf, Isabelle Arnulf, Luigi Ferini-Strambi, A. Desautels, Jennifer A. Ruskey, Peter Young, Nicolas Dupré, Valérie Cochen De Cock, Giuseppe Plazzi, Lior Greenbaum, Michele T.M. Hu, Lynne Krohn, Roy N. Alcalay, Guillaume Lamoureux, Ziv Gan-Or, Xiaokui Kate Zhang, Jacques Montplaisir, S. Hassin-Baer, Dan Spiegelman, Ronald B. Postuma, Ambra Stefani, Jean-François Gagnon, Christelle Charley Monaca, Benoît Vanderperre, Sandra B. Laurent, Tugba N. Ozturk, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Montreal Neurological Institute and Hospital, Concordia University [Montreal], Centre for Research in Molecular Modeling and Department of Chemistry & Biochemistry, PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Université de Sherbrooke (UdeS)-Université Laval [Québec] (ULaval)-McGill University = Université McGill [Montréal, Canada]-University of Ottawa [Ottawa]-Université du Québec à Trois-Rivières (UQTR)-Université de Montréal (UdeM)-TransBiotech, Lévis-Concordia University [Montreal]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Innsbruck [Innsbruck], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Alma Mater Studiorum University of Bologna (UNIBO), Institute of Neurological Sciences of Bologna IRCCS, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], Euromov (EuroMov), Université de Montpellier (UM), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Sanofi Genzyme, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Columbia University College of Physicians and Surgeons, Center for advanced research in sleep medicine, Montreal, Université de Montréal (UdeM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Research Center of CIUSSS of the North of Montreal and Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada, Laval University Medical center, Université Laval [Québec] (ULaval), McGill University Health Center [Montreal] (MUHC), Department of Pharmacology and Therapeutics [Montréal], Center for Computational and Integrative Biology [Camden] (CCIB), Rutgers University [Camden], Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Krohn, L., Ozturk, T. N., Vanderperre, B., Ouled Amar Bencheikh, B., Ruskey, J. A., Laurent, S. B., Spiegelman, D., Postuma, R. B., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Stefani, A., Monaca, C. C., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Rudakou, U., Cochen De Cock, V., Young, P., Wolf, P., Oliva, P., Zhang, X. K., Greenbaum, L., Liong, C., Gagnon, J. -F., Desautels, A., Hassin-Baer, S., Montplaisir, J. Y., Dupre, N., Rouleau, G. A., Fon, E. A., Trempe, J. -F., Lamoureux, G., Alcalay, R. N., Gan-Or, Z., Krohn L., Ozturk T.N., Vanderperre B., Ouled Amar Bencheikh B., Ruskey J.A., Laurent S.B., Spiegelman D., Postuma R.B., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Stefani A., Monaca C.C., Plazzi G., Antelmi E., Ferini-Strambi L., Heidbreder A., Rudakou U., Cochen De Cock V., Young P., Wolf P., Oliva P., Zhang X.K., Greenbaum L., Liong C., Gagnon J.-F., Desautels A., Hassin-Baer S., Montplaisir J.Y., Dupre N., Rouleau G.A., Fon E.A., Trempe J.-F., Lamoureux G., Alcalay R.N., and Gan-Or Z.

Subjects
0301 basic medicine, Male, Models, Molecular, Potassium Channels, Synucleinopathies, Genome-wide association study, REM Sleep Behavior Disorder, MESH: Glucosylceramidase, MESH: Genotype, 0302 clinical medicine, TMEM175/GAK/DGKQ, genetics, MESH: Molecular Dynamics Simulation, Parkinson, Genetics, MESH: Aged, MESH: Middle Aged, synucleinopaties, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Parkinson Disease, MESH: Potassium Channels, Middle Aged, MESH: Case-Control Studies, Transmembrane protein, Neurology, MESH: Synucleinopathies, Glucosylceramidase, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, synucleinopathies, MESH: Models, Molecular, Adult, Genotype, Locus (genetics), Single-nucleotide polymorphism, Biology, Molecular Dynamics Simulation, Polymorphism, Single Nucleotide, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Homology modeling, Genetic association, Aged, MESH: Humans, MESH: Adult, MESH: Male, 030104 developmental biology, REM sleep behavior disorder, MESH: REM Sleep Behavior Disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Neurology (clinical), Lysosomes, Glucocerebrosidase, MESH: Female, 030217 neurology & neurosurgery, synucleinopathie, MESH: Parkinson Disease, MESH: Lysosomes
Abstract

Objective The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

Published
2018

13. Emergence and evolution of TP53 mutations are a key feature of disease progression in myelodysplastic patients with lower-risk del(5q) treated with lenalidomide

Author

Anne-Laure Gagez, Jacques Delaunay, Pascal Godmer, Olivier Theisen, Catherine Pellat-Deceunynck, Guillaume Cartron, Laurent Flet, Steven Richebourg, Audrey Ménard, Thérèse Commes-Maerten, Marie C. Béné, Marion Eveillard, Catherine Godon, Marion Loirat, Odile Luycx, Bruno Villemagne, Pierre Peterlin, Laurence Lodé, Thierry Soussi, Yannick Le Bris, Service d'Hématologie Biologique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'hématologie biologique [Nantes] (Cytologie Hématologique), Hôtel-Dieu de Nantes-Centre hospitalier universitaire de Nantes (CHU Nantes), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Bio2M team (Inserm U1183), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Pharmacie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Cytogenetics [Québec, Canada], Centre Hospitalier Universitaire du Québec (CHUQ)-Hôpital du Saint-Sacrement [CHU Québec] (HSS), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Service d'Hématologie [CHRU Montpellier], Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Hématologie Clinique [CH Lorient], CH de Lorient, Hématologie Clinique [CH Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Société d'Hématologie du Confluent [Nantes], Société D'hematologie Du Confluent - Nantes, Biogenouest ® Genomics core facility for technical support., Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bernardo, Elizabeth

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Karyotypic abnormality, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tp53 mutation, Lower risk, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Medicine, Humans, TP53, Online Only Articles, Lenalidomide, ComputingMilieux_MISCELLANEOUS, Laboratory Hematology, business.industry, Myelodysplastic syndromes, Disease progression, Hematology, Middle Aged, Key features, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Mutation, Disease Progression, Chromosomes, Human, Pair 5, Female, Chromosome Deletion, Tumor Suppressor Protein p53, business, Median survival, medicine.drug
Abstract

The cytogenetic anomaly of isolated del(5q) characterizes a subgroup of patients with lower-risk myelodysplastic syndrome (MDS). In the 2016 World Health Organization classification, one additional karyotypic abnormality (except −7 or del7q) can be present in such patients.[1][1] Median survival

Published
2018

14. The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

Author

François Paris, Isabelle Corre, Jacques Huot, Bernardo, Elizabeth, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Axe Oncologie [CRCHU de Québec], Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
0301 basic medicine, Angiogenesis, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Biology, Vascular endothelial growth inhibitor, endothelial dysfunction, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, oxidative stress, cancer, Endothelial dysfunction, medicine.disease, endothelial cells, 3. Good health, Cell biology, Endothelial stem cell, Vascular endothelial growth factor B, Vascular endothelial growth factor A, 030104 developmental biology, Oncology, p38MAPK, medicine.symptom, Signal transduction
Abstract

International audience; By gating the traffic of molecules and cells across the vessel wall, endothelial cells play a central role in regulating cardiovascular functions and systemic homeostasis and in modulating pathophysiological processes such as inflammation and immunity. Accordingly, the loss of endothelial cell integrity is associated with pathological disorders that include atherosclerosis and cancer. The p38 mitogen-activated protein kinase (MAPK) cascades are major signaling pathways that regulate several functions of endothelial cells in response to exogenous and endogenous stimuli including growth factors, stress and cytokines. The p38 MAPK family contains four isoforms p38α, p38β, p38γ and p38δ that are encoded by four different genes. They are all widely expressed although to different levels in almost all human tissues. p38α/MAPK14, that is ubiquitously expressed is the prototype member of the family and is referred here as p38. It regulates the production of inflammatory mediators, and controls cell proliferation, differentiation, migration and survival. Its activation in endothelial cells leads to actin remodeling, angiogenesis, DNA damage response and thereby has major impact on cardiovascular homeostasis, and on cancer progression. In this manuscript, we review the biology of p38 in regulating endothelial functions especially in response to oxidative stress and during the metastatic process.

Published
2017

15. Decisional needs assessment of patients with complex care needs in primary care: a participatory systematic mixed studies review protocol

Author

Bernardo Kremer, Genevieve Gore, Serge Goulet, Edeltraut Kröger, Michel Wensing, Marie-Dominique Beaulieu, Vera Granikov, Mathieu Bujold, Yves Couturier, Pierre Pluye, Rebekah Pratt, Béatrice Débarges, Isabelle Vedel, Marie-Eve Poitras, Catherine Hudon, David Li Tang, Bruno Ventelou, Marie-Claude Beaulieu, Paula L. Bush, Irina Kudrina, Isabelle Samson, Christine Loignon, Nicolas Senn, Bertrand Lebouché, Masashi Tsujimoto, Reem El Sherif, Marie-Thérèse Lussier, Anik Giguère, Justin Gagnon, Roland Grad, Cristiano Martello, Benoît Rihoux, Ellen Rosenberg, Quynh Nguyen, Jeannie Haggerty, Centre de Recherche, CHUQ-Hôpital Saint-François d'Assise [CHU Québec] (HSFA), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Research Centre on Aging, Centre integré universitaire de santé et de services sociaux de l'Estrie (CIUSSS de l'Estrie - CHUS), Centre hospitalier universitaire de Sherbrooke, Montreal Chest Institute, McGill University Health Center [Montreal] (MUHC), Groupement de Recherche en Économie Quantitative d'Aix-Marseille (GREQAM), École Centrale de Marseille (ECM)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Participatory Review Team, and École des hautes études en sciences sociales (EHESS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Decision support system, Canada, patients with complex care needs, Knowledge management, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Decision Making, shared decision making, Psychological intervention, Participatory action research, [SHS]Humanities and Social Sciences, 03 medical and health sciences, primary care, 0302 clinical medicine, Health care, Protocol, Medicine, Humans, 030212 general & internal medicine, Patient participation, Qualitative Research, interprofessional care, Primary Health Care, business.industry, 030503 health policy & services, General Medicine, Focus Groups, Health Services, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Focus group, 3. Good health, Research Design, Needs assessment, Health Services Research, Patient Participation, Health Services/utilization, Needs Assessment, Primary Health Care/organization & administration, 0305 other medical science, business, Qualitative research, Systematic Reviews as Topic
Abstract

IntroductionPatients with complex care needs (PCCNs) often suffer from combinations of multiple chronic conditions, mental health problems, drug interactions and social vulnerability, which can lead to healthcare services overuse, underuse or misuse. Typically, PCCNs face interactional issues and unmet decisional needs regarding possible options in a cascade of interrelated decisions involving different stakeholders (themselves, their families, their caregivers, their healthcare practitioners). Gaps in knowledge, values clarification and social support in situations where options need to be deliberated hamper effective decision support interventions. This review aims to (1) assess decisional needs of PCCNs from the perspective of stakeholders, (2) build a taxonomy of these decisional needs and (3) prioritise decisional needs with knowledge users (clinicians, patients and managers).Methods and analysisThis review will be based on the interprofessional shared decision making (IP-SDM) model and the Ottawa Decision Support Framework. Applying a participatory research approach, we will identify potentially relevant studies through a comprehensive literature search; select relevant ones using eligibility criteria inspired from our previous scoping review on PCCNs; appraise quality using the Mixed Methods Appraisal Tool; conduct a three-step synthesis (sequential exploratory mixed methods design) to build taxonomy of key decisional needs; and integrate these results with those of a parallel PCCNs’ qualitative decisional need assessment (semistructured interviews and focus group with stakeholders).Ethics and disseminationThis systematic review, together with the qualitative study (approved by the Centre Intégré Universitaire de Santé et Service Sociaux du Saguenay-Lac-Saint-Jean ethical committee), will produce a working taxonomy of key decisional needs (ontological contribution), to inform the subsequent user-centred design of a support tool for addressing PCCNs’ decisional needs (practical contribution). We will adapt the IP-SDM model, normally dealing with a single decision, for PCCNs who experience cascade of decisions involving different stakeholders (theoretical contribution). Knowledge users will facilitate dissemination of the results in the Canadian primary care network.PROSPERO registration numberCRD42015020558.

Published
2017

16. A phase I/II clinical trial of autologous myoblast transplantation in facioscapulohumeral muscular dystrophy

Author

Sacconi, Sabrina, Vilquin, Jean-Thomas, Colson, Serge, Bocquet, Jonathan, Darcourt, Jacques, Garcia, Jérémy, Tanant, Véronique, Salort-Campana, Emmanuelle, Carlier, Pierre, Marolleau, Jean-Pierre, Skuk, Daniel, Larghero, Jérome, Desnuelle, Claude, Vilquin, Jean-Thomas, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Sorbonne Université (SU), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] (CAPS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux (TIRO-MATOs - UMR E4320), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), NMR Laboratory, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service clinique des Maladies du Sang, CHU Amiens-Picardie, Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence Maladies Neuromusculaires et SLA, hôpital Archet 1, UMR E4320 (TIRO-MATOs), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Côte d'Azur (UCA)-Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
[SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery
Abstract

International audience; Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most frequent adult myopathies (1/20.000), with selective involvement of specific groups of muscles : facial, scapular fixator, anterior foreleg muscles, abdominal and humeral muscles. Vastus lateralis (VL) is usually spared clinically until late stages of the disease, and myoblasts grown from VL have similar behaviour in vivo and in vitro than myoblasts from control patients-> Proposal:Transplantation of autologous myoblast from spared muscle (VL) into an affected muscle as the Tibialis anterior (TA) muscle could locally improve the muscle’s regenerative capacities. Results and discussion: Cell productions were feasible but the quality of the initial muscle biopsy is important. Cell administrations were feasible and clinically well tolerated by all patients but one. The control of local cell distribution may be improved by echographic monitoring. Results show slight increases in twitch response and slight decrease in fatigue in the 3rd group. The combination of cell type (myoblasts) and of the modality (dense multisite injections) may have positively affected the TA muscle, BUT: No clinically significant gain of function perceived by FSHD patients, and no significant changes were noted at MRI and PET-Scan.The local FSHD1 degenerated muscle environment may be detrimental to the stability of the fibers or of the niches, and muscle regeneration may have been inefficient, too transitory, aborted or too unstable.The slight muscle strength increase may not be clinically significant for FSHD patients, but may improve the quality of life of patients with more advanced muscle loss (e.g. DMD patients) in other indications.

Published
2016

17. Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response

Author

Jacques Huot, Soizic Dutoit, Elise Bénéteau, Isabelle Corre, Maëva Guillonneau, Hala Estephan, François Paris, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Axe Oncologie [CRCHU de Québec], Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), and Bernardo, Elizabeth

Subjects
0301 basic medicine, DNA damage, p38 mitogen-activated protein kinases, Active Transport, Cell Nucleus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, Biochemistry, p38 Mitogen-Activated Protein Kinases, Gene Expression Regulation, Enzymologic, Dephosphorylation, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, medicine, Humans, Protein Phosphatase 2, Phosphorylation, Protein kinase A, Molecular Biology, Nucleophosmin, integumentary system, Endothelial Cells, Nuclear Proteins, Protein phosphatase 2, Cell biology, Oxidative Stress, 030104 developmental biology, Oxidative stress, Biotechnology, DNA Damage, Signal Transduction
Abstract

International audience; Oxidative stress is a leading cause of endothelial dysfunction. The p38 MAPK pathway plays a determinant role in allowing cells to cope with oxidative stress and is tightly regulated by a balanced interaction between p38 protein and its interacting partners. By using a proteomic approach, we identified nucleophosmin (NPM) as a new partner of p38 in HUVECs. Coimmunoprecipitation and microscopic analyses confirmed the existence of a cytosolic NPM/p38 interaction in basal condition. Oxidative stress, which was generated by exposure to 500 mM H 2 O 2 , induces a rapid dephosphorylation of NPM at T199 that depends on phosphatase PP2A, another partner of the NPM/p38 complex. Blocking PP2A activity leads to accumulation of NPM-pT199 and to an increased association of NPM with p38. Concomitantly to its dephosphorylation, oxidative stress promotes translocation of NPM to the nucleus to affect the DNA damage response. Dephosphorylated NPM impairs the signaling of oxidative stress–induced DNA damage via inhibition of the phosphorylation of ataxia-telangiectasia mutated and DNA-dependent protein kinase catalytic subunit. Overall, these results suggest that the p38/NPM/PP2A complex acts as a dynamic sensor, allowing endothelial cells to react rapidly to acute oxidative stress.—Guillonneau, Corre, I. Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response. FASEB J. 30, 000–000 (2016). www.fasebj.org KEY WORDS: reactive oxygen species • p38 MAPK • endothelial dysfunction • phosphatases • double-strand breaks Endothelial cells are heavily exposed to reactive oxygen species (ROS), generated either from endogenous (oxidative enzymes and mitochondria) or exogenous [inflammatory cytokines, xenobiotics, and ionizing radiation (IR)] sources (1). ROS profoundly affects the functions of endothelial cells (2), notably by inducing many morphologic and functional changes, such as major cytoskeleton reorganization (3) and increased permeability (4), up-regulation of adhesion molecules (5, 6), modulation of angiogenesis (7), genomic instability via DNA damage (8), and cell death (9, 10). Alterations of these endothelial functions link oxidative stress not only to such severe cardiovascular pathologies as atherosclerosis (11, 12) and hypertension (13) but also to diabetes (14) and early and late toxicity to normal tissue induced by IR (15). Understanding the molecular mechanisms that underlie endothelial dysfunction in response to oxidative stress remains an important issue. A major oxidative stress–induced signaling pathway involves members of the p38 MAPK cascade (16). p38 MAPKs are serine/threonine kinases of the stress-activated protein kinase family along with c-Jun N-terminal kinase. The p38 family contains 4 isoforms (a, b, g, and d) that are expressed in function of cell types and are activated in response to a large number of chemical, bi-ologic, and physical stresses (17). p38a is the most widely expressed and studied member of the family and is here referred to as p38 (18). p38 activation leads to subsequent phosphorylation and activation of diverse cytoplasmic and nuclear targets that are involved in a broad range of cellular functions, such as proliferation, differentiation, migration, and survival (17). Notably, activation of p38 in response to oxidative stress in endothelial cells induces a quick and

Published
2015

18. The Aurora A-HP1γ pathway regulates gene expression and mitosis in cells from the sperm lineage

Author

Phoebe H. Leonard, Trace A. Christensen, Ezequiel Calvo, Gwen Lomberk, Angela Mathison, Dean E. Morbeck, Charles C. Coddington, Jeffrey L. Salisbury, Juan L. Iovanna, J.R. Fredrickson, Adrienne Grzenda, Thiago M. De Assuncao, Raul Urrutia, BMC, BMC, Division of Reproductive Endocrinology and Infertility, Mayo Clinic [Rochester], Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Department of Medicine, Laboratory of Epigenetics and Chromatin Dynamics - Gastroenterology Research Unit, Mayo Clinic [Rochester]-Mayo Clinic [Rochester], Molecular Endocrinology and Oncology Research Center, Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Translational Epigenomics Program, Mayo Clinic-Center for Individualized Medicine (CIM), and Department of Obstetrics and Gynecology

Subjects
Male, HP1γ, Cell division, Chromosomal Proteins, Non-Histone, Gametes, [SDV]Life Sciences [q-bio], Aurora inhibitor, Mitosis, Preimplantation embryo, Biology, Mice, medicine, Animals, Humans, Cell Lineage, Phosphorylation, Spermatogenesis, Aurora Kinase A, Regulation of gene expression, Embryonic genome activation, Spermatozoa, Molecular biology, Cell biology, [SDV] Life Sciences [q-bio], Gene expression profiling, Meiosis, CBX3, medicine.anatomical_structure, Gene Expression Regulation, Centrosome, Female, Epigenetics, Heterochromatin Protein 1, Germ cell, Research Article, Developmental Biology
Abstract

Background HP1γ, a well-known regulator of gene expression, has been recently identified to be a target of Aurora A, a mitotic kinase which is important for both gametogenesis and embryogenesis. The purpose of this study was to define whether the Aurora A-HP1γ pathway supports cell division of gametes and/or early embryos, using western blot, immunofluorescence, immunohistochemistry, electron microscopy, shRNA-based knockdown, site-directed mutagenesis, and Affymetrix-based genome-wide expression profiles. Results We find that the form of HP1γ phosphorylated by Aurora A, P-Ser83 HP1γ, is a passenger protein, which localizes to the spermatozoa centriole and axoneme. In addition, disruption in this pathway causes centrosomal abnormalities and aberrations in cell division. Expression profiling of male germ cell lines demonstrates that HP1γ phosphorylation is critical for the regulation of mitosis-associated gene expression networks. In female gametes, we observe that P-Ser83-HP1γ is not present in meiotic centrosomes of M2 oocytes, but after syngamy, it becomes detectable during cleavage divisions, coinciding with early embryonic genome activation. Conclusions These results support the idea that phosphorylation of HP1γ by Aurora A plays a role in the regulation of gene expression and mitotic cell division in cells from the sperm lineage and in early embryos. Combined, this data is relevant to better understanding the function of HP1γ in reproductive biology. Electronic supplementary material The online version of this article (doi:10.1186/s12861-015-0073-x) contains supplementary material, which is available to authorized users.

Published
2015

19. Bench-test comparison of 26 emergency and transport ventilators

Author

Annie Roy, Erwan L'Her, Nicolas Marjanovic, Dupuis, Christine, Optimisation Continue des Actions Thérapeutiques par l'Intégration d'Informations Multimodales, Université de Brest (UBO)-Télécom Bretagne-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire de Recherche en Médecine d'Urgence, Université Laval [Québec] (ULaval)-Centre Hospitalier Affilié Universitaire (CHAU) Hôtel-Dieu de Lévis, Département de Médecine Familiale et Médecine d'Urgence, Université Laval [Québec] (ULaval), Centre de Recherche du CHAU Hôtel-Dieu de Lévis, Centre Hospitalier Affilié Universitaire Hôtel-Dieu de Lévis (CHAUHDL)-Hôpital de l'Enfant-Jésus [CHU Québec] (HEJ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec, Pôle Urgences-SAMU, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), and Réanimation Médicale et Urgences Adultes

Subjects
Leak, medicine.medical_specialty, Emergency Medical Services, Ventilators, Mechanical, business.industry, Research, Equipment Design, Critical Care and Intensive Care Medicine, Respiration, Artificial, Bench test, 3. Good health, Reliability engineering, Benchmarking, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Emergency medicine, Emergency medical services, medicine, Respiratory Mechanics, Tidal Volume, Humans, Acute respiratory failure, Noninvasive ventilation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Tidal volume
Abstract

Introduction Numerous emergency and transport ventilators are commercialized and new generations arise constantly. The aim of this study was to evaluate a large panel of ventilators to allow clinicians to choose a device, taking into account their specificities of use. Methods This experimental bench-test took into account general characteristics and technical performances. Performances were assessed under different levels of FIO2 (100%, 50% or Air-Mix), respiratory mechanics (compliance 30,70,120 mL/cmH2O; resistance 5,10,20 cmH2O/mL/s), and levels of leaks (3.5 to 12.5 L/min), using a test lung. Results In total 26 emergency and transport ventilators were analyzed and classified into four categories (ICU-like, n = 5; Sophisticated, n = 10; Simple, n = 9; Mass-casualty and military, n = 2). Oxygen consumption (7.1 to 15.8 L/min at FIO2 100%) and the Air-Mix mode (FIO2 45 to 86%) differed from one device to the other. Triggering performance was heterogeneous, but several sophisticated ventilators depicted triggering capabilities as efficient as ICU-like ventilators. Pressurization was not adequate for all devices. At baseline, all the ventilators were able to synchronize, but with variations among respiratory conditions. Leak compensation in most ICU-like and 4/10 sophisticated devices was able to correct at least partially for system leaks, but with variations among ventilators. Conclusion Major differences were observed between devices and categories, either in terms of general characteristics or technical reliability, across the spectrum of operation. Huge variability of tidal volume delivery with some devices in response to modifications in respiratory mechanics and FIO2 should make clinicians question their use in the clinical setting. Electronic supplementary material The online version of this article (doi:10.1186/s13054-014-0506-0) contains supplementary material, which is available to authorized users.

Published
2014

20. Functional characterization of EZH2β reveals the increased complexity of EZH2 isoforms involved in the regulation of mammalian gene expression

Author

Adrienne Grzenda, Ezequiel Calvo, Gwen Lomberk, Juan L. Iovanna, Yuning Xiong, Angela Mathison, William A. Faubion, Phyllis A. Svingen, Raul Urrutia, BMC, Ed., Laboratory of Epigenetics and Chromatin Dynamics, Mayo Clinic, Molecular Endocrinology and Oncology Research Center, Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Translational Epigenomics Program, Mayo Clinic-Center for Individualized Medicine (CIM), Departments of Medicine, Physiology and Biochemistry, and This work was supported by funding from National Institutes of Health grants DK52913 (RU), Fraternal Order of Eagles Cancer Award (GL), T32CA148073 (AG), the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567), and the Mayo Foundation.

Subjects
[SDV.GEN] Life Sciences [q-bio]/Genetics, macromolecular substances, Biology, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Genetics, Gene silencing, EZH2, Epigenetics, Enhancer, Molecular Biology, 030304 developmental biology, Regulation of gene expression, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Research, Polycomb repressive complex 2, PRC2, Chromatin, Polycomb, Enhancer of zeste homologue 2, Histone methyltransferase, 030220 oncology & carcinogenesis, biology.protein
Abstract

Background Histone methyltransferase enhancer of zeste homologue 2 (EZH2) forms an obligate repressive complex with suppressor of zeste 12 and embryonic ectoderm development, which is thought, along with EZH1, to be primarily responsible for mediating Polycomb-dependent gene silencing. Polycomb-mediated repression influences gene expression across the entire gamut of biological processes, including development, differentiation and cellular proliferation. Deregulation of EZH2 expression is implicated in numerous complex human diseases. To date, most EZH2-mediated function has been primarily ascribed to a single protein product of the EZH2 locus. Results We report that the EZH2 locus undergoes alternative splicing to yield at least two structurally and functionally distinct EZH2 methyltransferases. The longest protein encoded by this locus is the conventional enzyme, which we refer to as EZH2α, whereas EZH2β, characterized here, represents a novel isoform. We find that EZH2β localizes to the cell nucleus, complexes with embryonic ectoderm development and suppressor of zeste 12, trimethylates histone 3 at lysine 27, and mediates silencing of target promoters. At the cell biological level, we find that increased EZH2β induces cell proliferation, demonstrating that this protein is functional in the regulation of processes previously attributed to EZH2α. Biochemically, through the use of genome-wide expression profiling, we demonstrate that EZH2β governs a pattern of gene repression that is often ontologically redundant from that of EZH2α, but also divergent for a wide variety of specific target genes. Conclusions Combined, these results demonstrate that an expanded repertoire of EZH2 writers can modulate histone code instruction during histone 3 lysine 27-mediated gene silencing. These data support the notion that the regulation of EZH2-mediated gene silencing is more complex than previously anticipated and should guide the design and interpretation of future studies aimed at understanding the biochemical and biological roles of this important family of epigenomic regulators.

Published
2013

21. Genetic linkage mapping of the human steroid 5α-reductase type 2 gene (SRD5A2) close to D2S352 on chromosome region 2p23→p22

Author

F. Labrie, J.-F. Leblanc, Francine Durocher, J. Simard, J. Morissette, T. Normand, Molecular Endocrinology and Oncology Research Center, Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, and Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)

Subjects
Cholestenone 5 alpha-Reductase, Genetic Linkage, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Locus (genetics), Biology, Polymerase Chain Reaction, Exon, Gene mapping, Genetic linkage, Chromosome regions, Genetics, Humans, Molecular Biology, Genetics (clinical), Base Sequence, Chromosome Mapping, Molecular biology, Isoenzymes, Genes, Genetic marker, Chromosomes, Human, Pair 2, Microsatellite, Lod Score, Restriction fragment length polymorphism, Oxidoreductases
Abstract

Two steroid 5α-reductase isoenzymes catalyze the conversion of testosterone into dihydrotestosterone, the more bioactive androgen, which is essential for male phenotypic sexual differentiation and for androgen-mediated growth of such tissues and organs as the prostate. Inherited mutations in SRD5A2 cause male pseudohermaphroditism. The SRD5A1 and SRD5A2 genes encoding the steroid 5α-reductase type 1 and type 2 isoenzymes have been previously assigned by in situ hybridization to 5p15 and 2p23, respectively. To map the SRD5A2 gene by linkage analysis, a novel RsaI RFLP detected in exon I and a TA repeat polymorphism found in exon V were genotyped in eight CEPH reference families. A two-point linkage analysis was performed between these polymorphisms and the chromosome 2 microsatellite markers of Généthon and NIH/CEPH. The closest linkage was observed with D2S352 (Zmax = 24.06; Θmax = 0.001) in the region 2p23→p22. To further define the localization of SRD5A2, a framework map, including nine Généthon markers flanking the polymorphic SRD5A2 locus, was built by multipoint linkage analysis. This led to a high-resolution genetic map of the region flanking the polymorphic SRD5A2 gene, including the nine Généthon markers and three NIH/CEPH markers, yielded the following order: tel-D2S48-D2S149-D2S320-D2S171-D2S165-[D2S352/SRD5A2]-D2S367-[D2S19/D2S177]-[D2S391/ CALM]-D2S378-cen.

Published
1996

22. Intermittent PTH(1-84) Is Osteoanabolic but Not Osteoangiogenic and Relocates Bone Marrow Blood Vessels Closer to Bone-Forming Sites

Author

Prisby, Rhonda, Guignandon, Alain, Vanden-Bossche, Arnaud, Mac-Way, Fabrice, Linossier, Marie-Therese, Thomas, Mireille, Laroche, Norbert, Malaval, Luc, Langer, Max, Peter, Zoltz-Andrei, PEYRIN, Françoise, Vico, Laurence, Lafage-Proust, Marie-Helene, Contraintes mécaniques et tissu osseux, Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tissu Osseux et Contraintes Mecaniques (LBTO), Centre de recherche du CHUQ, Université Laval [Québec] (ULaval)-L'hôtel-Dieu de Québec [CHU Québec] (HDQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Centre Hospitalier Universitaire du Québec (CHUQ), Biologie intégrative du tissu osseux, European Synchrotron Radiation Facility (ESRF), Imagerie Tomographique et Radiothérapie, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon

Subjects
[SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2011

23. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal

Author

Michel de Lorgeril, Bruno Pavy, Tomohito Hamazaki, John Abramson, Sylvie Dodin, Willy Kostucki, Harumi Okuyama, Patricia Salen, Mikael Rabaeus, Physiologie cardio-Respiratoire Expérimentale Théorique et Appliquée (TIMC-IMAG-PRETA), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Harvard Medical School [Boston] (HMS), Centre de Recherche, CHUQ-Hôpital Saint-François d'Assise [CHU Québec] (HSFA), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Department of Clinical Sciences, University of Toyama, Cardiology Department, Clinique Antoine Depage, Open Research Center for Lipid Nutrition, Kinjo Gakuin University, Réadaptation Cardiovasculaire, CHU Loire Vendée Océan, and Clinique La Prairie

Subjects
medicine.medical_specialty, MESH: Sulfonamides, 030204 cardiovascular system & hematology, MESH: Anticholesteremic Agents, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MESH: Cholesterol, MESH: Risk Factors, Internal medicine, JUPITER trial, Internal Medicine, medicine, Rosuvastatin, 030212 general & internal medicine, Myocardial infarction, MESH: Incidence, MESH: Hydroxymethylglutaryl-CoA Reductase Inhibitors, Stroke, MESH: Humans, biology, business.industry, Cholesterol, MESH: Cardiovascular Diseases, medicine.disease, 3. Good health, MESH: France, Rosuvastatin Calcium, Hypocholesterolemia, MESH: Drug Therapy, Combination, Endocrinology, MESH: Randomized Controlled Trials as Topic, MESH: Fluorobenzenes, chemistry, MESH: Pyrimidines, HMG-CoA reductase, biology.protein, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, medicine.drug
Abstract

International audience; BACKGROUND: Among the recently reported cholesterol-lowering drug trials, the JUPITER (Justification for the Use of Statins in Primary Prevention) trial is unique: it reports a substantial decrease in the risk of cardiovascular diseases among patients without coronary heart disease and with normal or low cholesterol levels. METHODS: Careful review of both results and methods used in the trial and comparison with expected data. RESULTS: The trial was flawed. It was discontinued (according to prespecified rules) after fewer than 2 years of follow-up, with no differences between the 2 groups on the most objective criteria. Clinical data showed a major discrepancy between significant reduction of nonfatal stroke and myocardial infarction but no effect on mortality from stroke and myocardial infarction. Cardiovascular mortality was surprisingly low compared with total mortality-between 5% and 18%-whereas the expected rate would have been close to 40%. Finally, there was a very low case-fatality rate of myocardial infarction, far from the expected number of close to 50%. The possibility that bias entered the trial is particularly concerning because of the strong commercial interest in the study. CONCLUSION: The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.

Published
2010

24. Variation in the psychosocial determinants of the intention to prescribe hormone therapy prior to the release of the Women's Health Initiative trial: a survey of general practitioners and gynaecologists in France and Quebec

Author

France Legare, Gaston Godin, Virginie Ringa, Sylvie Dodin, Lucile Turcot, Joanna Norton, Centre de Recherche, CHUQ-Hôpital Saint-François d'Assise [CHU Québec] (HSFA), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Canada Research Chair on Behaviour and Health, Université Laval [Québec] (ULaval)-Faculty of Nursing, Recherches épidémiologiques en santé périnatale et santé des femmes, 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), This research was supported by an unrestricted grant from Fournier Pharma and peer-reviewed by a scientific committee from the Fonds de la recherche du Quebec (FRSQ). Dr. Legare is a new clinical scientist who is supported by the FRSQ. Dr. Godin is Tier 1 Canada Research Chair in Health Related Behaviour, Université Laval. Dr Dodin holds the Chaire Andree et Lucie Chagnon pour une approche integrée en santé, Université Laval., and Maylin, Françoise

Subjects
Male, medicine.medical_treatment, MESH: Logistic Models, Intention, Health informatics, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Medicine, 030212 general & internal medicine, MESH: Drug Utilization, Practice Patterns, Physicians', Estrogen replacement therapy, MESH: Middle Aged, 030219 obstetrics & reproductive medicine, Health Policy, Women's Health Initiative, Estrogen Replacement Therapy, Quebec, Theory of planned behavior, MESH: Comparative Study, Middle Aged, humanities, Computer Science Applications, lcsh:R858-859.7, Female, France, Family Practice, Psychosocial, Research Article, Adult, medicine.medical_specialty, Attitude of Health Personnel, MESH: Attitude of Health Personnel, education, MEDLINE, Health Informatics, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, lcsh:Computer applications to medicine. Medical informatics, 03 medical and health sciences, Nursing, Humans, Medical prescription, MESH: Physician's Practice Patterns, Physician's Role, MESH: Family Practice, Paternal Behavior, MESH: Humans, business.industry, MESH: Adult, MESH: Intention, MESH: Estrogen Replacement Therapy, MESH: Male, Drug Utilization, MESH: Paternal Behavior, MESH: France, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Logistic Models, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Gynecology, Family medicine, MESH: P, Women's Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Hormone therapy, MESH: Gynecology, business, MESH: Female
Abstract

Background Theory-based approaches are advocated to improve our understanding of prescription behaviour. This study is an application of the theory of planned behaviour (TPB) with additional variables. It was designed to assess which variables were associated with the intention to prescribe hormone therapy (HT). In addition, variations in the measures across medical specialities (GPs and gynaecologists) and across countries (France and Quebec) were investigated. Methods A survey among 2,000 doctors from France and 1,044 doctors from Quebec was conducted. Data were collected by means of a self-administered questionnaire. A clinical vignette was used to elicit doctors' opinions. The following TPB variables were assessed: attitude, subjective norm, perceived behavioural control, attitudinal beliefs, normative beliefs and power of control beliefs. Additional variables (role belief, moral norm and practice pattern-related factors) were also assessed. A stepwise logistic regression was used to assess which variables were associated with the intention to prescribe HT. GPs and gynaecologists were compared to each other within countries and the two countries were compared within the specialties. Results Overall, 1,085 doctors from France returned their questionnaire and 516 doctors from Quebec (response rate = 54% and 49%, respectively). In the overall regression model, power of control beliefs, moral norm and role belief were significantly associated with intention (all at p < 0.0001). The models by specialty and country were: for GPs in Quebec, power of control beliefs (p < 0.0001), moral norm (p < 0.01) and cytology and hormonal dosage (both at p < 0.05); for GPs in France, power of control beliefs and role belief (both at p < 0.0001) and perception of behavioural control (p < 0.05) and cessation of menses (p < 0.01); for gynaecologists in Quebec, moral norm and power of control beliefs (both at p = 0.01); and for gynaecologists in France, power of control beliefs (p < 0.0001), and moral norm, role belief and lipid profile (all at p < 0.05). Conclusion In both countries, compared with GPs, intention to prescribe HT was higher for gynaecologists. Psychosocial determinants of doctors' intention to prescribe HT varied according to the specialty and the country thus, suggesting an influence of contextual factors on these determinants.

Published
2005

25. Androgenic down-regulation of urotensin II precursor, urotensin II-related peptide precursor and androgen receptor mRNA in the mouse spinal cord

Author

Fernand Labrie, Hubert Vaudry, Isabelle Lihrmann, Christophe Dubessy, Georges Pelletier, Van Luu-The, Molecular Endocrinology and Oncology Research Center, Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Neuroendocrinologie cellulaire et moléculaire

Subjects
Male, medicine.medical_specialty, Time Factors, Peptide Hormones, Urotensins, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Central nervous system, Molecular Sequence Data, Down-Regulation, In situ hybridization, Biology, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Gene expression, medicine, Animals, Castration, RNA, Messenger, Protein Precursors, In Situ Hybridization, 030304 developmental biology, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, General Neuroscience, Dihydrotestosterone, Motor neuron, Androgen receptor, Mice, Inbred C57BL, Endocrinology, medicine.anatomical_structure, chemistry, Spinal Cord, Receptors, Androgen, Autoradiography, Urotensin-II, Precursor mRNA, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; We had previously shown that in rat spinal cord motoneurons urotensin II (UII) precursor mRNA was down-regulated by androgens. Very recently, a gene encoding the precursor of a UII analog, termed UII-related peptide (URP), has been identified. Using in situ hybridization, we studied the localization of UII and URP precursor as well as androgen receptor (AR) mRNA in the male mouse thoracic spinal cord. We also evaluated the androgenic regulation of the two peptide precursor and AR mRNA expression in the ventral horn of the mouse thoracic spinal cord. The results revealed that URP precursor mRNA was localized in motoneurons and that the vast majority of the motoneurons expressed both peptide precursor as well as AR mRNA. Seven-day castration induced an increase in UII and URP precursor and AR mRNA levels. Short term (3-24 h) administration of dihydrotestosterone to castrated animals restored the three protein mRNA levels to the levels observed in intact animals. These results suggest that in the ventral horn of the mouse spinal cord both UII and URP precursor and AR mRNA are expressed by the same neurons and that circulating androgens are exerting a down-regulation of the three protein mRNA expression, possibly by a direct action on motoneurons.

Published
2005

26. Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells

Author

Agnès Noël, Jean Rosenbaum, Jean-Frédéric Blanc, F. Kebers, Silvia Blacher, Jean-Michel Foidart, Myriam Polette, Philippe Birembaut, Bernard Têtu, Christèle Bisson, Joëlle Desreux, Laboratory of Tumor and Development Biology (LTDB), Université de Liège, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Department of Pathology (DP), L'hôtel-Dieu de Québec [CHU Québec] (HDQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), and Birembaut, Philippe

Subjects
Cancer Research, Pathology, Cell, MESH: Collagenases, Matrix metalloproteinase, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Extracellular matrix, 0302 clinical medicine, Neoplasms, Tumor Cells, Cultured, In Situ Hybridization, 0303 health sciences, MESH: In Situ Hy, MESH: Culture Media, Conditioned, MESH: Gene Expression Regulation, Enzymologic, Metalloendopeptidases, Immunohistochemistry, medicine.anatomical_structure, Oncology, MESH: Epithelial Cells, 030220 oncology & carcinogenesis, Disease Progression, Matrix Metalloproteinase 2, MESH: Disease Progression, Matrix Metalloproteinase 1, Breast carcinoma, Myofibroblast, medicine.medical_specialty, MESH: Enzyme Activation, Blotting, Western, Breast Neoplasms, macromolecular substances, Biology, Adenocarcinoma, MESH: Actins, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Breast cancer, Matrix Metalloproteinase 11, Matrix Metalloproteinase 13, medicine, MESH: Blotting, Western, Humans, Collagenases, RNA, Messenger, 030304 developmental biology, MESH: Humans, MESH: Adenocarcinoma, Cancer, MESH: Immunohistochemistry, Epithelial Cells, Muscle, Smooth, Fibroblasts, medicine.disease, Actins, Enzyme Activation, Microscopy, Fluorescence, MESH: Fibroblasts, Culture Media, Conditioned, Cancer cell, Cancer research, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Stromal Cells, MESH: Breast Neoplasms
Abstract

The membrane type-1 matrix metalloproteinase (MT1-MMP), a protease originally identified in breast carcinoma, is characterized by its capacity to activate other MMPs (MMP-2 and MMP-13) and to degrade extracellular matrix. Our study was undertaken to localize and identify the MT1-MMP expressing cells in human breast adenocarcinomas. A textural analysis of images obtained by immunohistochemistry and in situ hybridization showed precisely the co-expression of alpha smooth muscle actin (αSM actin) and MT1-MMP in myofibroblasts. MT1-MMP expression is confined to myofibroblasts in close contact with tumor cells. In sharp contrast, the expression of MMP-2 was more widely distributed in both αSM actin positive and negative cells close to and at distance from cancer cell clusters. Our in vitro observations are consistent with the higher level of MT1-MMP expression and of MMP-2 activation observed in αSM actin positive fibroblasts derived from breast tumors, as compared to normal breast fibroblasts. Collectively, these results implicate myofibroblasts as major producer of MT1-MMP in breast cancer and emphasize the importance of stromal-epithelial cell interactions in their progression. © 2003 Wiley-Liss, Inc.

Published
2003

27. Impact of an obesogenic diet program on bone densitometry, micro architecture and metabolism in male rat

Author

Stéphane Walrand, Lore Metz, Marie-Thérèse Linossier, Daniel Courteix, A. Masgrau, Maude Gerbaix, Cedric Lavet, Christelle Guillet, Laurence Vico, Fabrice Mac-Way, BMC, Ed., Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques (AME2P), UFR Sciences et Techniques des Activités Physiques et Sportives - Clermont-Ferrand (UFR STAPS - UBP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Centre de recherche du CHUQ, Université Laval [Québec] (ULaval)-L'hôtel-Dieu de Québec [CHU Québec] (HDQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Centre Hospitalier Universitaire du Québec (CHUQ), Biologie intégrative du tissu osseux, Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), The authors wish to thank the 'Heart and Arteries Foundation' (Fondation Coeur et Artères) for granting this project and its financial support., Faculté des Sciences du SportFaculté des Sciences du Sport, UFR STAPS-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Université Laval-L'hôtel-Dieu de Québec-Centre Hospitalier Universitaire du Québec (CHUQ), Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Faculté des Sciences du SportFaculté des Sciences du Sport, UFR STAPS, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-UFR Sciences et Techniques des Activités Physiques et Sportives - Clermont-Ferrand (UFR STAPS - UBP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Biologie Intégrative du Tissu Osseux (LBTO), and Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Blood Glucose, Male, HIGH-FAT DIET, Bone density, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Bone tissue, 0302 clinical medicine, Endocrinology, Absorptiometry, Photon, LEPTIN RESISTANCE, Bone Density, Bone cell, Insulin, lcsh:RC620-627, Adiposity, 2. Zero hunger, Bone mineral, 0303 health sciences, Lumbar Vertebrae, biology, INDUCED OBESITY, 3. Good health, lcsh:Nutritional diseases. Deficiency diseases, medicine.anatomical_structure, POSTMENOPAUSAL WOMEN, VISCERAL FAT, Area Under Curve, Osteocalcin, Body Composition, medicine.medical_specialty, VERTEBRAL FRACTURES, Intra-Abdominal Fat, VOLUNTARY WEIGHT-LOSS, MINERAL DENSITY, SUCROSE DIET, OLDER WOMEN, 030209 endocrinology & metabolism, Diet, High-Fat, Bone resorption, Bone and Bones, 03 medical and health sciences, Internal medicine, medicine, Animals, Obesity, Rats, Wistar, 030304 developmental biology, Biochemistry, medical, Tibia, business.industry, Research, Biochemistry (medical), Rats, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, biology.protein, Cortical bone, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

Background The relationships between fat mass and bone tissue are complex and not fully elucidated. A high-fat/high-sucrose diet has been shown to induce harmful effects on bone micro architecture and bone biomechanics of rat. When such diet leads to obesity, it may induce an improvement of biomechanical bone parameters in rodent. Here, we examined the impact of a high-fat/high-sucrose diet on the body composition and its resulting effects on bone density and structure in male rats. Forty three Wistar rats aged 7 months were split into 3 groups: 1 sacrificed before diet (BD, n = 14); 1 subjected to 16 weeks of high-fat/high-sucrose diet (HF/HS, n = 14); 1 subjected to standard diet (Control, n = 15). Abdominal circumference and insulin sensitivity were measured and visceral fat mass was weighed. The bone mineral density (BMD) was analyzed at the whole body and tibia by densitometry. Microcomputed tomography and histomorphometric analysis were performed at L2 vertebrae and tibia to study the trabecular and cortical bone structures and the bone cell activities. Osteocalcin and CTX levels were performed to assess the relative balance of the bone formation and resorption. Differences between groups have been tested with an ANOVA with subsequent Scheffe post-hoc test. An ANCOVA with global mass and global fat as covariates was used to determine the potential implication of the resulting mechanical loading on bone. Results The HF/HS group had higher body mass, fat masses and abdominal circumference and developed an impaired glucose tolerance (p Conclusions The HF/HS diet had induced obesity and impaired glucose tolerance. These changes resulted in an improvement of quantitative, qualitative and metabolic bone parameters. The fat mass increase partly explained these observations.

Published
2012

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