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1. TNF-α and IL-10 Control CXCL13 Expression in Human Macrophages

Author

Laurent Vernhet, Francisco Llamas-Gutierrez, Stéphane Jouneau, Valérie Lecureur, Audrey Joannes, Roselyne Viel, Lutz Wollin, Nessrine Bellamri, Bertrand De Latour, Claudie Morzadec, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Boehringer Ingelheim Pharma GmbH & Co. KG, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
Male, Chemokine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, Gene Expression, Neogenesis, stat, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Macrophages, Alveolar, Humans, Immunology and Allergy, Medicine, CXCL13, Lung, Aged, Janus Kinases, 030304 developmental biology, 0303 health sciences, biology, Tumor Necrosis Factor-alpha, business.industry, CD68, Macrophages, NF-kappa B, Interstitial lung disease, respiratory system, biology.organism_classification, medicine.disease, Chemokine CXCL13, Idiopathic Pulmonary Fibrosis, Interleukin-10, respiratory tract diseases, 3. Good health, [SDV] Life Sciences [q-bio], STAT Transcription Factors, Interleukin 10, biology.protein, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lung Diseases, Interstitial, business, Signal Transduction, 030215 immunology
Abstract

The chemokine CXCL13 controls the normal organization of secondary lymphoid tissues and the neogenesis of ectopic lymphoid structures in nonlymphoid organs, particularly the lungs. The progression and severity of idiopathic pulmonary fibrosis (IPF), a fatal and irreversible interstitial lung disease, is predicted by the circulating blood concentrations of CXCL13. Although CXCL13 is produced by pulmonary tissues, it has not been determined which cells are involved. This study examines CXCL13 production by lung tissue macrophages from patients with IPF and the signaling pathways controlling CXCL13 gene expression in human alveolar macrophages (AM) and monocyte-derived macrophages (MoDM). CXCL13 is found in CD68- and CD206-positive AM from patients with IPF, and the CXCL13 gene is induced in these macrophages and MoDM when they are stimulated with LPS. We found that TNF-α and IL-10 control optimal CXCL13 gene expression in MoDM and possibly in AM by activating the NF-κB and JAK/STAT pathways, respectively. We also found that blood TNF-α and CXCL13 concentrations are significantly correlated in patients with IPF, suggesting that TNF-α contributes to CXCL13 production in humans. In conclusion, the results of this study demonstrate that AM from patients with IPF produces CXCL13 and that the NF-κB and JAK/STAT pathways are required to induce the expression of this major chemokine.

Published
2020

2. Exposure of human fetal kidneys to mild analgesics interferes with early nephrogenesis

Author

Christèle Desdoits-Lethimonier, Alain Michel, Antonio Suglia, Cécile Vigneau, Laetitia L Lecante, Roselyne Viel, Vincent Lavoué, Antoine Rolland, Jonathan Maurice Chemouny, Nathalie Dejucq-Rainsford, Emmanuelle Becker, Sabrina Leverrier-Penna, Séverine Mazaud-Guittot, Hugoline Boulay, Nathalie Costet, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (Inserm), Université de Rennes 1 (University of Rennes 1), Ecole des Hautes Etudes en Santé Publique, Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). Grant Number: HAP-2014-073, Agence Nationale de la Recherche (ANR). Grant Number: ANR-15-CE34-0001-01, Société de Néphrologie (French Society of Nephrology), ANR-15-CE34-0001,ACETAMINOV,Antalgiques et différenciation ovarienne fœtale chez l'Homme(2015), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
0301 basic medicine, NSAIDs, Organogenesis, [SDV]Life Sciences [q-bio], Kidney Glomerulus, Physiology, Prostaglandin, nephrogenesis, Biochemistry, Fetal Kidney, Nephrotoxicity, prostaglandins, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fetus, Pregnancy, Genetics, Medicine, Humans, fetal kidney, Molecular Biology, acetaminophen, Kidney, Aspirin, Analgesics, Cell Death, business.industry, Ibuprofen, 3. Good health, Acetaminophen, Pregnancy Trimester, First, 030104 developmental biology, medicine.anatomical_structure, chemistry, Female, business, 030217 neurology & neurosurgery, Ex vivo, Biotechnology, medicine.drug
Abstract

International audience; Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7-12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy.

Published
2021

3. Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

Author

Bertrand Rion, Roselyne Viel, Anne-Sophie Denibaud, Simon Loiodice, Pierre Montagne, Harry Wing Young, Benoît Méot, Christophe Drieu La Rochelle, Biotrial, H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Male, Parkinson's disease, Dopamine, [SDV]Life Sciences [q-bio], Anxiety, Antiparkinson Agents, Levodopa, Rats, Sprague-Dawley, Behavioral Neuroscience, Benserazide, 0302 clinical medicine, Forelimb, L-dopa, 0303 health sciences, Dopaminergic, Substantia Nigra, medicine.symptom, Locomotion, medicine.drug, medicine.medical_specialty, Elevated plus maze, Tyrosine 3-Monooxygenase, Context (language use), Substantia nigra, 6-OHDA, Lesion, 03 medical and health sciences, Internal medicine, medicine, Animals, Interpersonal Relations, Parkinson Disease, Secondary, Maze Learning, Oxidopamine, Gait Disorders, Neurologic, 030304 developmental biology, Memory Disorders, business.industry, Pars compacta, Recognition, Psychology, medicine.disease, Rats, Amphetamine, Disease Models, Animal, Endocrinology, Sympatholytics, Parkinson’s disease, neuropsychiatric symptoms, business, 030217 neurology & neurosurgery
Abstract

This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson’s disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L -dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH). Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with l -dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with l -dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic l -dopa exposure was observed. This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesion-induced anxiety-like behaviour. We did not report any effect of chronic l -dopa exposure in the context of partial nigral cell loss.

Published
2019

4. Dietary Protein Intake Level Modulates Mucosal Healing and Mucosa-Adherent Microbiota in Mouse Model of Colitis

Author

Marta Grauso, Patricia Lepage, Roselyne Viel, Marion Leclerc, François Blachier, Mireille Andriamihaja, Claire Gaudichon, Sandra Vidal-Lletjós, Annaïg Lan, Anne Blais, Anne-Marie Davila, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de Recherche Agronomique - AgroParisTech, Societe Francaise de Nutrition, Association Francois Aupetit, INRA-Universite Paris-Saclay (ALIAS program), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, colitis, [SDV]Life Sciences [q-bio], epithelial repair, Inflammation, lcsh:TX341-641, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Inflammation resolution, dietary protein level, mucosa-adherent microbiota, Internal medicine, Animals, Medicine, Intestinal Mucosa, Colitis, Beneficial effects, 2. Zero hunger, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, medicine.disease, Animal Feed, Diet, Gastrointestinal Microbiome, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Dietary protein, Endocrinology, Mucosal healing, 030211 gastroenterology & hepatology, Dietary Proteins, medicine.symptom, business, lcsh:Nutrition. Foods and food supply, Dietary protein intake, Microbiota composition, Food Science
Abstract

International audience; Mucosal healing after an inflammatory flare is associated with lasting clinical remission. The aim of the present work was to evaluate the impact of the amount of dietary protein on epithelial repair after an acute inflammatory episode. C57BL/6 DSS-treated mice received isocaloric diets with different levels of dietary protein 14% (P14), 30% (P30) and 53% (P53) for 3 (day 10), 6 (day 13) and 21 (day 28) days after the time of colitis maximal intensity. While the P53 diet worsened the DSS- induced inflammation both in intensity and duration, the P30 diet, when compared to the P14 diet, showed a beneficial effect during the epithelial repair process by accelerating inflammation resolution, reducing colonic permeability and increasing epithelial repair together with epithelial hyperproliferation. Dietary protein intake also impacted mucosa-adherent microbiota composition after inflammation since P30 fed mice showed increased colonization of butyrate-producing genera throughout the resolution phase. This study revealed that in our colitis model, the amount of protein in the diet modulated mucosal healing, with beneficial effects of a moderately high-protein diet, while very high-protein diet displayed deleterious effects on this process.

Published
2019

5. Thymoquinone prevents endoplasmic reticulum stress and mitochondria-induced apoptosis in a rat model of partial hepatic warm ischemia reperfusion

Author

Ahlem Bouhlel, Hassen Ben Abdennebi, Anne Corlu, Roselyne Viel, Catherine Ribault, Saber Mannai, Ismail Ben Mosbah, Najet Hadj Abdallah, Bioprédic International, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), UR12ES11, Tunisian Ministry of Higher Education and Scientific Research, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, MAPK/ERK pathway, Male, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mitochondrion, Pharmacology, medicine.disease_cause, Protective Agents, p38 Mitogen-Activated Protein Kinases, Antioxidants, 03 medical and health sciences, chemistry.chemical_compound, Ischemia, Benzoquinones, Medicine, Animals, Warm Ischemia, Phosphorylation, Rats, Wistar, Thymoquinone, business.industry, Tumor Necrosis Factor-alpha, Endoplasmic reticulum, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Endoplasmic Reticulum Stress, Mitochondria, Rats, Oxidative Stress, 030104 developmental biology, chemistry, Liver, Reperfusion Injury, Immunology, Reperfusion, Unfolded protein response, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Oxidative stress, Ischemia reperfusion injury
Abstract

International audience; This study was undertaken to evaluate the protective effect of thymoquinone (TQ), the bioactive compound of Nigella sativa seeds, against warm ischemia-reperfusion (I/R) injury in liver. Rats were given an oral administration of a vehicle solution (sham group) or TQ at the appropriate dose (10, 20, 30 and 40mg/kg) for ten days consecutively. Following, they were subjected to 60min of partial hepatic ischemia followed by 24h of reperfusion. .Transaminase activities, histopathological changes, TNFα and antioxidant parameters were evaluated. Also, endoplasmic reticulum (ER) stress, mitochondrial damage and apoptosis were studied. In addition, ERK and P38 phosphorylation was determined by Western blot technique. We found that TQ at 30mg/kg is the effective dose to protect rat liver against I/R injury. Moreover, 30mg/kg of TQ prevented histological damages, inflammation and oxidative stress. Interestingly, it decreased the expression of ER stress parameters including GRP78, CHOP and caspase-12. In parallel, it improved mitochondrial function and attenuated the expression of apoptotic parameters. Furthermore, TQ significantly enhanced ERK and P38 phosphorylation. In conclusion, we demonstrated the potential of TQ to protect the rat liver against I/R injury through the prevention of ER stress and mitochondrial dysfunction. These effects implicate the prevention of oxidative stress.

Published
2017

6. Implication of nigral dopaminergic lesion and repeated L-DOPA exposure in non-motor symptoms of Parkinson's disease

Author

Pierre Montagne, H. Wing Young, Bertrand Rion, Simon Loiodice, Roselyne Viel, B. Méot, C. Drieu La Rochelle, and Anne-Sophie Denibaud

Subjects
Pharmacology, Parkinson's disease, business.industry, Dopaminergic, medicine.disease, Lesion, Psychiatry and Mental health, Neurology, medicine, Non motor, Pharmacology (medical), Neurology (clinical), medicine.symptom, business, Neuroscience, Biological Psychiatry
Published
2019

7. Wild type VHL clear cell renal cell carcinomas: A distinct morphological and clinical entity with PD-L1 expression

Author

Julien Dagher, Karim Bensalah, Solène-Florence Kammerer-Jacquet, Adélaïde Pladys, Angélique Brunot, Roselyne Viel, Florence Jouan, Pierre Kerbrat, Brigitte Laguerre, Nathalie Rioux-Leclercq, Gregory Verhoest, Julien Edeline, Pascale Bellaud, and Laurence Crouzet

Subjects
Cancer Research, endocrine system diseases, Tumor suppressor gene, business.industry, Cell, Wild type, urologic and male genital diseases, medicine.disease, female genital diseases and pregnancy complications, Clear cell renal cell carcinoma, medicine.anatomical_structure, Oncology, Cancer research, medicine, Pd l1 expression, cardiovascular diseases, business, neoplasms, Clear cell
Abstract

11053 Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor and in most of cases, is characterized by an inactivation of the tumor suppressor gene VHL (Von Hippel-Lindau). This...

Published
2015

8. Synchronous Metastatic Clear-Cell Renal Cell Carcinoma: A Distinct Morphologic, Immunohistochemical, and Molecular Phenotype

Author

Brigitte Laguerre, Romain Mathieu, Frédéric Dugay, Marc-Antoine Belaud-Rotureau, Julien Edeline, Julien Dagher, Gregory Verhoest, Guillaume Bouzillé, Sarah Medane, Jean Mosser, Benoit Peyronnet, Nathalie Rioux-Leclercq, Angélique Brunot, Solène-Florence Kammerer-Jacquet, Adélaïde Pladys, Alexandra Lespagnol, Karim Bensalah, Service de Pathologie [Rennes] = Pathology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis (CRLCC), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'urologie [Rennes] = Urology [Rennes], Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Département d'oncologie médicale [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors would like to acknowledge the Ligue Contre le Cancer, the CORECT, Rennes Hospital, and the French Institute of Cancer (INCa) for their financial aid.The authors would also like to thank the Center of Biological Resources of Rennes Hospital (BB-0033-00056, http://www.crbsante-rennes.com/) for managing patient samples as well as Pascale Bellaud and Roselyne Viel from the Histopathology platform H2P2-BIOSIT, Faculty of Medicine of Rennes for their technical support., Service de Pathologie [CHU Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis ( CRLCC ), École des Hautes Études en Santé Publique [EHESP] ( EHESP ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'urologie, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)

Subjects
Male, Vascular Endothelial Growth Factor A, 0301 basic medicine, Oncology, Clear cell renal cell carcinoma, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Cell, Cell Cycle Proteins, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, B7-H1 Antigen, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Neoplasms, Multiple Primary, chemistry.chemical_compound, 0302 clinical medicine, Neoplasm Metastasis, Aged, 80 and over, Univariate analysis, Clinical outcome, Neoplasms, Second Primary, Middle Aged, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, Primary tumor, VEGF, Kidney Neoplasms, 3. Good health, Gene Expression Regulation, Neoplastic, Vascular endothelial growth factor, medicine.anatomical_structure, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Cohort, Immunohistochemistry, Female, Adult, medicine.medical_specialty, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Diagnosis, Differential, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Carbonic Anhydrase IX, Carcinoma, Renal Cell, VHL gene, Adaptor Proteins, Signal Transducing, Aged, Retrospective Studies, business.industry, Genetic Variation, Membrane Proteins, Synchronous and metachronous metastases, medicine.disease, Survival Analysis, Sarcomatoid component, 030104 developmental biology, chemistry, business, Clear cell
Abstract

International audience; INTRODUCTION: Clear cell renal cell carcinomas (ccRCCs) are highly metastatic tumors with metastases detected at diagnosis (synchronous) or during follow-up (metachronous). To date, there have been no reports comparing primary ccRCC of patients with synchronous and metachronous metastases, who are different in terms of prognosis. Determining whether there is a phenotypic difference between these 2 groups could have important clinical implications. PATIENTS AND METHODS: In a retrospective consecutive cohort of 98 patients with ccRCC, 48 patients had metastases, including 28 synchronous and 20 metachronous presentations, with a follow-up of 10 years. For each primary tumor in these metastatic patients, pathologic criteria, expression of vascular endothelial growth factor, partitioning-defective 3, CAIX, and programmed death ligand 1 as detected by immunohistochemistry, and complete VHL status were analyzed. Univariate analysis was performed, and survival was assessed using Kaplan-Meier curves compared by log-rank test. RESULTS: Compared with primary ccRCC in patients with metachronous metastases, primary ccRCC in patients with synchronous metastases were significantly associated with a poorer Eastern Cooperative Oncology Group performance (P = .045), higher pT status (P = .038), non-inactivated VHL gene (P = .01), sarcomatoid component (P = .007), expression of partitioning-defective 3 (P = .007), and overexpressions of vascular endothelial growth factor (> 50%) (P = .017) and programmed death ligand 1 (P = .019). Patients with synchronous metastases had a worse cancer-specific survival than patients with metachronous metastases even from metastatic diagnosis (median survival, 16 months vs. 46 months, respectively; P = .01). CONCLUSION: This long-term study is the first to support the notion that synchronous m-ccRCC has a distinct phenotype. This is probably linked to the occurrence of oncogenic events that could explain the worse prognosis. These particular patients with metastases could benefit from specific therapy.

Published
2017

9. Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice

Author

Moana Gelu-Simeon, François Tiaho, Valentine Genet, Catherine Lucas-Clerc, Elise Tabet, Claire Piquet-Pellorce, Michel Samson, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], This work was supported by Inserm, Université de Rennes 1 and the ANR (Agence nationale de la recherche, Programme CESA 2011, Acronyme : Hepatochlor). For immunohistochemistry and animal house facilities, we would like to thank the dedicated platforms (i.e. H2P2 (Pascale Bellaud and Roselyne Viel), Arche (Laurence Bernard)) of SFR BIOSIT, University of Rennes 1, France., Jonchère, Laurent, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, CCl4, Male, Insecticides, Cirrhosis, Time Factors, 010501 environmental sciences, Toxicology, Liver Cirrhosis, Experimental, 01 natural sciences, chemistry.chemical_compound, Fibrosis, Carbon Tetrachloride, education.field_of_study, Extracellular Matrix Proteins, [SDV.TOX.ECO] Life Sciences [q-bio]/Toxicology/Ecotoxicology, biology, Alanine Transaminase, General Medicine, 3. Good health, Kepone, Liver, Chlordecone, Chemical and Drug Induced Liver Injury, Chronic, Disease Progression, Collagen, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, Liver cancer, medicine.medical_specialty, Population, digestive system, 03 medical and health sciences, Internal medicine, medicine, Animals, Aspartate Aminotransferases, education, 0105 earth and related environmental sciences, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Alanine transaminase, chemistry, Gene Expression Regulation, biology.protein, Liver function, Hepatic fibrosis, business, Biomarkers
Abstract

International audience; Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury

Published
2015

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