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18 results on '"Laboratoire d'anatomie pathologique"'

1. Thoracic manifestations of <scp>IgG4</scp> ‐related disease

Author

Romain Muller, Mikael Ebbo, Paul Habert, Laurent Daniel, Antoine Briantais, Pascal Chanez, Jean Yves Gaubert, Nicolas Schleinitz, Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire d'Imagerie Interventionnelle Expérimentale (LIIE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Nord [CHU - APHM], Laboratoire d'anatomie pathologique - [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Service de Pneumologie-Allergologie [Hôpital de la Timone - APHM], and Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )

Subjects
IgG4, interstitial lung disease, Pulmonary and Respiratory Medicine, thoracic, [SDV]Life Sciences [q-bio], immunoglobulin G4-related disease, rare systemic fibroinflammatory disease
Abstract

International audience; Immunoglobulin G4-related disease (IgG4-RD) is a recently described rare systemic fibroinflammatory disease with an estimated incidence of less than 1 in 100,000 persons per year. The disease can affect virtually any organ and is characterized by unifying histopathological findings. Recently, four subgroups of patients have been characterized: hepatobiliary, head and neck, Mikulicz syndrome and retroperitoneal fibrosis, who illustrate the mainly abdominal and ENT tropism of the disease. Yet, thoracic involvement is not uncommon. It can be detected in up to 30% of patients with systemic IgG4-RD and is the exclusive manifestation of the disease in about 10% of cases. Clinical symptoms are nonspecific and may include dyspnoea, cough or chest pain. Chest CT findings are heterogeneous and primarily include peribronchovascular thickening, nodules, ground-glass opacities and lymphadenopathy. There is no specific diagnostic test for IgG4-RD thoracic involvement, which may mimic malignancy or vasculitis. Therefore, a cautious approach is needed to make an accurate diagnosis: a search for extra-thoracic manifestations, elevated serum IgG4 levels, circulating levels of plasmablasts and pathologic evidence of disease is warranted. Although very suggestive, neither the presence of a polyclonal IgG4 lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis are sufficient to confirm the histological diagnosis. Steroids are recommended as first-line therapy. Rituximab or disease-modifying antirheumatic drugs may be used in relapsed or rare cases of steroid-refractory disease. In this review, we summarize current knowledge regarding the pathophysiology, epidemiology, diagnostic modalities (clinical-biological-imaging-histopathology) and treatment of IgG4-RD thoracic involvement.

Published
2022
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2. Adult H3K27M mutated thalamic glioma patients display a better prognosis than unmutated patients

Author

Stéphan Grimaldi, Vincent Harlay, Romain Appay, Céline Bequet, Grégorio Petrirena, Chantal Campello, Maryline Barrié, Didier Autran, Sébastien Boissonneau, Thomas Graillon, Dominique Figarella-Branger, Isabelle Nanni, Olivier Chinot, Emeline Tabouret, Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neuro-Oncologie [Hôpital de la Timone - APHM], and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Adult, Cancer Research, Brain Neoplasms, [SDV]Life Sciences [q-bio], Glioma, Prognosis, Histones, Thalamus, Neurology, Oncology, Mutation, Humans, Neurology (clinical), Retrospective Studies
Abstract

Adult thalamic gliomas are a rare entity whose management is challenging for physicians. The aim of this study is to describe the characteristics and prognostic factors of thalamic gliomas in adult patients.We retrospectively analyzed the clinical, neuro-radiological, histological, and molecular characteristics of all cases of adult thalamic glioma in our regional center.We included 38 adult patients. Median age at diagnosis was 56.5 years old (range, 24-80). Median KPS at diagnosis was 70%. Two-thirds of patients presented with tumor necrosis on MRI. Bithalamic lesions were present in four patients. The median volume of enhancement associated with lesions was relatively small (14 mmThalamic adult glioma differs from bithalamic glioma in children with regards to its clinical, radiological and molecular profiles. Long-term survival is observed in young patients with limited symptoms and H3K27M mutation. A larger prospective cohort is needed to validate these findings.

Published
2022
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3. Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Author

Marianne Begorre, Daniel Cailliez, Claire Beneteau, Pierre Chenal, Thierry Frebourg, Guillaume Benoist, François Lecoquierre, Raphaele Mangione, Florence Petit, Nicolas Gruchy, Louise Devisme, Sophie Patrier, Juliette Coursimault, Fanny Pelluard, Hubert Journel, Bénédicte Gérard, Marion Gérard, Pascale Saugier-Veber, Valérie Layet, Alain Liquier, Corinne Jeanne, Mirjam M. de Jong, Nadia Tillouche, Anne Bazin, Gaël Nicolas, Conny M. A. van Ravenswaaij-Arts, Anne-Claire Brehin, Wilfrid Finck, Sophie Coutant, Sophie Degre, Christine Francannet, Madeleine Joubert, Hélène Laurichesse Delmas, 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), Laboratoire CERBA [Saint Ouen l'Aumône], Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Lausanne = University of Lausanne (UNIL), Service de Gynécologie-Obstétrique et Médecine de la Reproduction [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe Hospitalier du Havre, University of Groningen [Groningen], Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique prénatale [CHU Caen], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de Génétique [CHU Caen], Clinical Cognitive Neuropsychiatry Research Program (CCNP), Université de Lausanne (UNIL), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Genotype, audal dysgenesis, Ectromelia, [SDV]Life Sciences [q-bio], REQUIREMENT, Malformation sequence, Biology, Sirenomelia, CAUDAL REGRESSION, Frameshift mutation, 03 medical and health sciences, Genetics, medicine, Humans, CDX2 Transcription Factor, Genetic Predisposition to Disease, CDX2, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Calcium-Binding Proteins, 030305 genetics & heredity, Wnt signaling pathway, Heterozygote advantage, DEFECTS, medicine.disease, caudal dysgenesis, de novo mutation, Pedigree, Phenotype, Amino Acid Substitution, GROWTH, Female, CDX2 de novo mutation, exome sequencing
Abstract

Full access; International audience; Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio‐based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2 . We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Published
2020
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4. The Use of Pro-Angiogenic and/or Pro-Hypoxic miRNAs as Tools to Monitor Patients with Diffuse Gliomas

Author

Guénaëlle Levallet, Fatéméh Dubois, Arthur Leclerc, Edwige Petit, Lien Bekaert, Maxime Faisant, Christian Creveuil, Evelyne Emery, Gérard Zalcman, Emmanuèle Lechapt-Zalcman, Département de Pathologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurochirurgie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Anatomie Pathologique [CHU Caen], Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and APRI 2012

Subjects
Brain Neoplasms, hypoxia, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Organic Chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Isocitrate Dehydrogenase, Catalysis, Computer Science Applications, Inorganic Chemistry, MicroRNAs, angiogenesis, glioma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Mutation, Humans, miRNA, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

CERVOXY; International audience; IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O2, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma.

Published
2022
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5. Prognostic value of circulating lymphocyte subsets in primary central nervous system lymphoma

Author

Axel Berthelot, Celine Bequet, Vincent Harlay, Gregorio Petrirena, Chantal Campello, Maryline Barrié, Romain Appay, Olivier Chinot, Emeline Tabouret, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Neuro-Oncologie [Hôpital de la Timone - APHM], and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Central Nervous System, Cancer Research, [SDV]Life Sciences [q-bio], Prognosis, Lymphocyte Subsets, Neurology, Oncology, Lymphopenia, Antineoplastic Combined Chemotherapy Protocols, Humans, Neurology (clinical), Lymphocyte Count, Lymphoma, Large B-Cell, Diffuse, Rituximab, Retrospective Studies
Abstract

Immunity plays an important role in CNS-DLBCL development. CNS-DLBCL predictive factors need to be improved.To evaluate the predictive value of circulating lymphocyte subsets in PCNSL patients.We prospectively analyzed blood lymphocyte immunophenotyping (LIP) in newly CNS-DLBCL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected.Fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). Thirty-three patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4+/CD8+ ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results. Complete, partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4+/CD8+ ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077, ROC AUC: 0.684). Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI 6.5-22.9) and 43.2 (95%CI 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4+/CD8+ ratio 1.97 was associated with poor PFS [p = 0.043, HR = 3.32 (1.02-4.88)] and tended to be associated with worse OS (p = 0.064).LIP at baseline may predict refractory disease and exhibits a prognostic value in CNS-DLBCL patients.

Published
2022
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6. Complex Management of Nephrotic Syndrome and Kidney Failure during Pregnancy in a Type 1 Diabetes Patient: A Challenging Case

Author

Leo Drapeau, Mathilde Beaumier, Julie Esbelin, François Comoz, Lucile Figueres, Giorgina Piccoli, Delphine Kervella, Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Service de Néphrologie [CHPC - Site Louis Pasteur], Site Louis Pasteur [CHPC], CH Centre Hospitalier Public du Cotentin (CHPC)-CH Centre Hospitalier Public du Cotentin (CHPC), Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Le Mans (CH Le Mans), Team 3 : Integrative transplantation, HLA, Immunology and genomics of kidney injury (U1064 Inserm - CR2TI), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), and KERANDEL-DION, Céline

Subjects
[SDV] Life Sciences [q-bio], acute kidney injury, type 1 diabetes, nephrotic syndrome, [SDV]Life Sciences [q-bio], pregnancy, General Medicine
Abstract

International audience; Pregnancy with chronic kidney disease is challenging, and patients with diabetic nephropathy are at particular risk of a rapid kidney function decline during pregnancy. While indications for the management of pregnant patients with initial diabetic nephropathy are widely available in the literature, data on patients with severe nephrotic syndrome and kidney function impairment are lacking, and the decision on whether and when dialysis should be initiated is not univocal. We report a type 1 diabetes patient who started pregnancy with a severe nephrotic syndrome and shifted from CKD stage 3b to stage 5 during pregnancy. The management was complicated by a fetal heart malformation and by poorly controlled diabetes. The evidence for and against starting dialysis was carefully evaluated, and the choice of strict nephrological and obstetrical monitoring, nutritional management, and diuretic treatment made it possible to avoid dialysis in pregnancy, after ruling out pre-eclampsia. This experience enables examination of some open issues and contributes to the discussion of when to start dialysis in pregnancy.

Published
2022
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7. TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma

Author

Qi Song, Harish C. Pant, Zhengping Zhuang, Emeline Tabouret, Jinkyu Jung, Antonio Cardone, Jing Cui, Mark R. Gilbert, Herui Wang, Deric M. Park, Romain Appay, Niranjana D. Amin, Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), University of Maryland Institute for Advanced Computer Studies, University of Maryland [College Park], University of Maryland System-University of Maryland System, and University of Chicago

Subjects
0301 basic medicine, Cancer Research, DNA damage, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], CDK5, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemotherapy, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, In vivo, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Viability assay, radiotherapy, Chemotherapy, Temozolomide, Kinase, Chemistry, glioblastoma, Cell cycle, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, targeted therapy, 3. Good health, 030104 developmental biology, Oncology, nervous system, Apoptosis, 030220 oncology & carcinogenesis, ATM, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, medicine.drug
Abstract

We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of &gamma, H2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma.

Published
2020
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8. Machine Learning for Better Prognostic Stratification and Driver Gene Identification Using Somatic Copy Number Variations in Anaplastic Oligodendroglioma

Author

Luc Bauchet, Denys Fontaine, D. Larrieu‐Ciron, M. Andraud, H. Aubriot‐Lorton, Fabien Forest, G. Runavot, Shai Rosenberg, I. Carpiuc, François Labrousse, Christine Desenclos, Annie Laquerrière, Georges Noël, Olivier Chinot, Catherine Godfraind, Patrick Beauchesne, Jean-Yves Delattre, Caroline Dehais, T. Cruel, Danchristian Chiforeanu, F. Dhermain, Dominique Cazals-Hatem, Claude Gaultier, W. Lahiani, Marie-Laure Tanguy, C. Dehais, S. Elouadhani‐Hamdi, Pomone Richard, François Ghiringhelli, Olivier Langlois, Ca. Maurage, Dominique Figarella-Branger, Ahmed Idbaih, Carole Ramirez, Philippe Menei, François Ducray, Benoit Lhermitte, Nabila Elarouci, M. Campone, F. Vandenbos‐Burel, Mj. Motso‐Fotso, C. Blechet, Nicolas Desse, Sandrine Eimer, Valérie Rigau, Agusti Alentorn, Anne Jouvet, Damien Ricard, Mc. Tortel, T. Khallil, Clovis Adam, Hugues Loiseau, L. Bekaert, Henri Sevestre, Chiara Villa, M. Fesneau, Isabelle Quintin-Roue, Antoine Petit, Philippe Colin, Elodie Vauleon, S. Lopez, S. Gaillard, Guillaume Gauchotte, Antoine F. Carpentier, Phong Dam-Hieu, Md. Diebold, Yannick Marie, Thierry Faillot, Serge Milin, Aurélien de Reyniès, Emmanuelle Lechapt-Zalcman, Fabrice Parker, E. Cohen‐Moyal, Delphine Loussouarn, Emmanuelle Uro-Coste, Em. Gueye, Audrey Rousseau, F. Ducray, M‐I Mihai, Aurelie Kamoun, Karima Mokhtari, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, Cancer Research, DNA Copy Number Variations, Survival, Somatic cell, [SDV]Life Sciences [q-bio], Oligodendroglioma, Machine learning, computer.software_genre, medicine.disease_cause, Cohort Studies, Loss of heterozygosity, 03 medical and health sciences, microRNA, medicine, Humans, Neuro‐Oncology, Copy-number variation, Gene, Pathological, business.industry, Genomics, Glioma, Middle Aged, Prognosis, Precision medicine, 3. Good health, 030104 developmental biology, Oncology, Female, Artificial intelligence, Carcinogenesis, business, computer
Abstract

Background 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type. Materials and Methods A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables. Results Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment. Conclusion Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy. Implications for Practice Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction.

Published
2018
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9. Fatty acid composition and mechanisms of the protective effects of myrtle berry seed aqueous extract in alcohol-induced peptic ulcer in rat

Author

Mohsen Sakly, Mohamed-Amine Jabri, Lamjed Marzouki, Kais Rtibi, Karim Hosni, Hichem Sebai, Haifa Tounsi, Laboratoire d’Anatomie Pathologique Humaine et Expérimentale, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire des Substances Naturelles (LR02INRAP10), Institut National de Recherche et d'Analyse Physico-chimique [Ariana, Tunisie] (INRAP), Laboratoire de Physiologie Intégrée, Faculté des Sciences de Bizerte [Université de Carthage], and Université de Carthage - University of Carthage-Université de Carthage - University of Carthage

Subjects
myrtle berries, Male, 0301 basic medicine, Peptic Ulcer, antioxidant, Antioxidant, Duodenum, Physiology, Iron, medicine.medical_treatment, Alcohol, Berry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, free acidity, Physiology (medical), medicine, Animals, Food science, Rats, Wistar, Flavonoids, Pharmacology, Aqueous extract, Ethanol, Plant Extracts, Chemistry, Fatty Acids, Stomach, Polyphenols, Water, Hydrogen Peroxide, General Medicine, medicine.disease, Myrtus, Rats, 3. Good health, 030104 developmental biology, Biochemistry, Cytoprotection, 030220 oncology & carcinogenesis, Peptic ulcer, Seeds, Calcium, Lipid Peroxidation, Fatty acid composition, unsaturated fatty acids, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

This study aimed to investigate the antiulcer and antioxidant activities of myrtle berry seed aqueous extract (MBSAE) in a peptic ulcer model induced by ethanol in male Wistar rats. MBSAE is rich in total polyphenols, total flavonoids, and unsaturated fatty acids, particularly linoleic (18:2) and oleic (18:1) acids. MBSAE also exhibited in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50= 172.1 μg/mL) and superoxide anion (IC50= 200.24 μg/mL) scavenging activities. In vivo, MBSAE provided dose-dependent protection against ethanol-induced gastric and duodenal macroscopic and histological alterations. Also, it inhibited secretory profile disturbances and lipid peroxidation, and preserved normal antioxidant enzyme activities and nonenzymatic antioxidant levels. More importantly, we showed that acute alcohol intoxication increased gastric and duodenal calcium, hydrogen peroxide, and free iron levels, whereas MBSAE treatment protected against intracellular mediator deregulation. In conclusion, we suggest that MBSAE has potent protective effects against alcohol-induced peptic ulcer in rat. This protection might be related in part to its antioxidant properties as well as its opposite effects on some studied intracellular mediators.

Published
2017
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10. MYD88 Somatic Mutation Is a Diagnostic Criterion in Primary Cutaneous Large B-Cell Lymphoma

Author

Vanessa Szablewski, François Le Gall, Anne de Muret, Jean-Philippe Merlio, Nicolas Ortonne, Agnès Carlotti, Maxime Battistella, David Cappellen, Marie Beylot-Barry, Béatrice Vergier, Audrey Gros, F. Franck, François Comoz, Anne Pham-Ledard, Sarah Menguy, Anne Croue, Brigitte Balme, Marie-Hélène Lorton, Laurence Lamant, Physiopathologie du cancer du foie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2, Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U955, équipe 9, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'anatomie et cytologie pathologiques [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Pathologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pontchaillou [Rennes], CHU Clermont-Ferrand, Département de Pathologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de biologie de la tumeur, CHU Bordeaux [Bordeaux], Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], and Jonchère, Laurent

Subjects
PCFCL, [SDV.CAN]Life Sciences [q-bio]/Cancer, Primary cutaneous B-cell lymphoma, Dermatology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, primary cutaneous follicle center lymphoma, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, primary cutaneous B-cell lymphoma, PCBCL, B-cell lymphoma, Molecular Biology, ComputingMilieux_MISCELLANEOUS, primary cutaneous marginal zone lymphoma, GC, business.industry, Germinal center, Cell Biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, PCLBCL-LT, medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, germinal center, primary cutaneous large B-cell lymphoma-leg type, 030220 oncology & carcinogenesis, PCMZL, Immunology, Mutation (genetic algorithm), Cancer research, Myeloid Differentiation Factor 88, Primary cutaneous marginal zone lymphoma, Differential diagnosis, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; no abstract

Published
2016
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11. Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations

Author

Sonia Chelouah, Martine Raphael, Guillaume Meurice, Philippe Gaulard, Catherine Pioche-Durieu, Aude Robert, Patrice Codogno, Joëlle Wiels, Lyubomir T. Vassilev, Catherine Guettier, Anaïs Pujals, Nadine Martin-Garcia, Marc Lipinski, Marion Le Gentil, Loëtitia Favre, Eric Le Cam, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut des Matériaux, de Microélectronique et des Nanosciences de Provence (IM2NP), Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Gustave Roussy (IGR), Signalisation, noyaux et innovations en cancérologie (UMR8126), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Génomique [Gustave Roussy], Laboratoire d'Anatomie Pathologique [AP-HP - Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), and Le Cam, Eric

Subjects
0301 basic medicine, Herpesvirus 4, Human, Lymphoma, [SDV]Life Sciences [q-bio], Gene Expression, Apoptosis, Biology, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, hemic and lymphatic diseases, Autophagy, medicine, Humans, NFKB Signaling Pathway, Molecular Biology, ComputingMilieux_MISCELLANEOUS, PI3K/AKT/mTOR pathway, B cell, Cell Proliferation, B-Lymphocytes, Cell growth, Imidazoles, Cell Biology, BECN1, Basic Research Paper, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Tumor Suppressor Protein p53
Abstract

The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders and lymphomas. We have previously demonstrated that treating wild-type TP53-expressing B cell lines with the TP53 pathway activator nutlin-3 induced apoptosis in EBV-negative and EBV-positive latency I cells whereas EBV-positive latency III cells remained much more apoptosis-resistant. Here, we report a constitutively high level of autophagy in these resistant cells which express high levels of the proautophagic protein BECN1/Beclin 1 based, at least in part, on the activation of the NFKB signaling pathway by the viral protein LMP1. Following treatment with nutlin-3, several autophagy-stimulating genes were upregulated both in EBV-negative and EBV-positive latency III cells. However the process of autophagy was only triggered in the latter and was associated with an upregulation of SESN1/sestrin 1 and inhibition of MTOR more rapid than in EBV-negative cells. A treatment with chloroquine, an inhibitor of autophagy, potentiated the apoptotic effect of nutlin-3, particularly in those EBV-positive cells which were resistant to apoptosis induced by nutlin-3 alone, thereby showing that autophagy participates in this resistant phenotype. Finally, using immunohistochemical staining, clinical samples from various B cell lymphoproliferations with the EBV-positive latency II or III phenotype were found to harbor a constitutively active autophagy.

Published
2015
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12. Protective Effect of Argan and Olive Oils against LPS-Induced Oxidative Stress and Inflammation in Mice Livers

Author

Kamouni, Soufiane, Kebbaj, Riad, Andreoletti, Pierre, El Ktaibi, Abderrahim, Rharrassi, Issam, Essamadi, Abdelkhalid, El Kebbaj, M’hammed Saïd, Mandard, Stéphane, Latruffe, Norbert, Vamecq, Joseph, Nasser, Boubker, Cherkaoui-Malki, Mustapha, Laboratoire de Biochimie et Neurosciences [Settat, Maroc], Faculté des Sciences et Techniques de Settat-Université Hassan I [Maroc], Laboratoire des Sciences et Technologies de la Santé [Settat, Maroc], Institut Supérieur des Sciences de la Santé [Settat, Maroc] ( ISSS ) -Université Hassan I [Settat, Maroc], Laboratoire Bio-PeroxIL. Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique ( Bio-PeroxIL ), Université de Bourgogne ( UB ), Laboratoire d’Anatomie Pathologique [Marrakech, Maroc], Hôpital Militaire Avicenne [Marrakech, Maroc], Laboratoire de Biochimie [Casablanca, Maroc], Université Hassan II Ain Chock, Casablanca.-Faculté des Sciences Ain Chock Casablanca, Equipe LIPNESS (LNC - U1231) ( LIPNESS ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction ( RADEME ), Hôpital Jeanne de Flandre [Lille]-Université de Lille-Centre Hospitalier Régional Universitaire de Lille ( CHRU de Lille ) -Clinique de Génétique médicale Guy Fontaine [CHRU LIlle]-Centre de référence maladies rares Anomalies du développement [CHRU Lille], Laboratoire d'Hormonologie, Métabolisme-Nutrition & Oncologie ( HMNO ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Département de Biochimie et Biologie Moléculaire-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-INSERM Structures Partenaires, This work was supported by the Ministère de l’enseignement et de la Recherche, Morocco. The Projet PPR from the Centre National Pour la Recherche Scientifique et Technique (CNRST)-Morocco. The followship 'bourse Jeunes chercheurs' from Lafarge, Andzoa and Agrotech. The Action Intégrée of the Comité Mixte Inter-universitaire Franco-Marocain (CMIFM, AIMA/14/310, Campus France N° 30293PA) from the PHC Volubulis program, Ministère des Affaires Etrangères, the Conseil Régional de Bourgogne and the Ministère de l’enseignement et de la Recherche. The authors would like to acknowledge networking support by the COST Action CA 16112 NutRedOx (Personalized Nutrition in aging society: redox control of major age-related diseases), supported by COST (European Cooperation in Science and Technology)., Faculté des Sciences et Techniques [Settat] (FSTS), Université Hassan 1er [Settat]-Université Hassan 1er [Settat], Université Hassan 1er [Settat]-Institut Supérieur des Sciences de la Santé [Settat, Maroc] (ISSS), Laboratoire Bio-PeroxIL. Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique (Bio-PeroxIL), Université de Bourgogne (UB), Faculté des Sciences Aïn Chock [Casablanca] (FSAC), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Equipe LIPNESS (LNC - U1231) (LIPNESS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Hormonologie, Métabolisme-Nutrition & Oncologie (HMNO), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Département de Biochimie et Biologie Moléculaire-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-INSERM Structures Partenaires, INSERM Structures Partenaires-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-Département de Biochimie et Biologie Moléculaire, and Mandard, Stéphane

Subjects
argan oil, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Liver Diseases, Anti-Inflammatory Agents, lipopolysaccharides, Antioxidants, Article, cytokines, sepsis, lcsh:Chemistry, Mice, Liver, lcsh:Biology (General), lcsh:QD1-999, antioxidant enzymes, inflammation, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Dietary Supplements, Animals, Plant Oils, oxidative stress, Olive Oil, lcsh:QH301-705.5, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Sepsis causes severe dysregulation of organ functions, via the development of oxidative stress and inflammation. These pathophysiological mechanisms are mimicked in mice injected with bacterial lipopolysaccharide (LPS). Here, protective properties of argan oil against LPS-induced oxidative stress and inflammation are explored in the murine model. Mice received standard chow, supplemented with argan oil (AO) or olive oil (OO) for 25 days, before septic shock was provoked with a single intraperitoneal injection of LPS, 16 hours prior to animal sacrifice. In addition to a rise in oxidative stress and inflammatory markers, injected LPS also caused hepatotoxicity, accompanied by hyperglycemia, hypercholesterolemia and hyperuremia. These LPS-associated toxic effects were blunted by AO pretreatment, as corroborated by normal plasma parameters and cell stress markers (glutathione: GSH) and antioxidant enzymology (catalase, CAT; superoxide dismutase, SOD and glutathione peroxidase, GPx). Hematoxylin–eosin staining revealed that AO can protect against acute liver injury, maintaining a normal status, which is pointed out by absent or reduced LPS-induced hepatic damage markers (i.e., alanine aminotransferase (ALT) and aspartate transaminase (AST)). Our work also indicated that AO displayed anti-inflammatory activity, due to down-regulations of genes encoding pro-inflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) and in up-regulations of the expression of anti-inflammatory genes encoding Interleukin-4 (IL-4) and Interleukin-10 (IL-10). OO provided animals with similar, though less extensive, protective changes. Collectively our work adds compelling evidence to the protective mechanisms of AO against LPS-induced liver injury and hence therapeutic potentialities, in regard to the management of human sepsis. Activations of IL-4/Peroxisome Proliferator-Activated Receptors (IL-4/PPARs) signaling and, under LPS, an anti-inflammatory IL-10/Liver X Receptor (IL-10/LXR) route, obviously indicated the high potency and plasticity of the anti-inflammatory properties of argan oil.

Published
2017
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13. Quantification of portal–bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C

Author

Jean-Pierre Zarski, Jérôme Boursier, Victor de Lédinghen, Brigitte Le Bail, Jeremy Sandrini, Paul Calès, Marie-Christine Rousselet, Julien Chaigneau, Nathalie Sturm, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département d'hépatologie et de gastroentérologie [CHU Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], BaRITOn - Bordeaux Research in Translational Oncology, and Université de Bordeaux Ségalen [Bordeaux 2]

Subjects
Adult, Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Cirrhosis, [SDV]Life Sciences [q-bio], Gastroenterology, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, image analysis, Fibrosis, Internal medicine, medicine, Humans, automated segmentation, Stage (cooking), liver biopsy, medicine.diagnostic_test, business.industry, Hepatitis C, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Fatty Liver, Fibroscan, Liver, 030220 oncology & carcinogenesis, Portal fibrosis, Liver biopsy, Disease Progression, Elasticity Imaging Techniques, Female, 030211 gastroenterology & hepatology, Elastography, Steatosis, business, Algorithms, morphometry
Abstract

International audience; Morphometry provides an objective evaluation of fibrosis in liver diseases. We developed an image analysis algorithm using automated thresholding and segmentation to separately quantify the areas and the fractal dimensions of portal–bridging fibrosis and perisinusoidal fibrosis in chronic hepatitis C liver biopsies. We studied 427 digitized liver biopsies and compared the automated measures of the different fibrosis compartments with (1) the Metavir F (fibrosis) and A (activity) histological scores, (2) the digitally assessed area of steatosis, and (3) the liver stiffness measured by elastography (Fibroscan). The perisinusoidal fibrosis area was higher than that of portal fibrosis in stages ≤F2; it reached its highest value in F2 stage and stabilized thereafter. The F3 stage was characterized by equal proportions of portal–bridging and perisinusoidal fibrosis, whereas portal–bridging area was predominant in cirrhosis. Measurement of portal–bridging fibrosis showed highly significantly different values between contiguous F stages; the ratio of portal–bridging fibrosis/perisinusoidal fibrosis displayed less overlap between Metavir stages than did the whole fibrosis area values. Fractal dimension showed that portal–bridging fibrosis tended to display a homogeneous surface-like spatial organization, whereas perisinusoidal fibrosis appeared more heterogeneous according to stage and curvilinear. The portal–bridging fibrosis area was low in cases with low Metavir activity and little steatosis, and became predominant with increasing activity and steatosis. Using stepwise multiple linear regression analysis, the liver stiffness was independently correlated to the portal–bridging fibrosis area (first step, P

Published
2014
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14. Signature patterns of human papillomavirus type 16 in invasive anal carcinoma

Author

Bernadette Kantelip, Jean-Luc Prétet, Francine Arbez-Gindre, Marie Joly, Christiane Mougin, Benoit Girardo, Jean-François Bosset, Elise Jacquin, Franck Monnien, Séverine Valmary-Degano, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), and Service d'Oncologie Médicale [CHRU Besançon]

Subjects
Adult, Male, Proliferative index, Anal Carcinoma, viruses, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Genotype, Prevalence, Humans, DNA Integration, Gene, Polymerase chain reaction, Aged, Neoplasm Staging, 030304 developmental biology, Aged, 80 and over, Human papillomavirus 16, 0303 health sciences, Carcinoma, Papillomavirus Infections, virus diseases, Middle Aged, Viral Load, Anus Neoplasms, Immunohistochemistry, Virology, 3. Good health, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, DNA, Viral, Cancer research, Female, Viral load
Abstract

International audience; Many studies have reported that most invasive anal carcinomas contain high-risk human papillomaviruses (HPVs), HPV16 being the most prevalent type. This study aimed to investigate HPV status and cellular biomarkers in invasive anal cancers. HPV genotype distribution was determined in 76 anal cancers by the INNO-LiPA assay (Innogenetics, Gent, Belgium). HPV16-positive samples were then tested for viral load and physical state with type-specific real-time polymerase chain reaction targeting E6, E2, and albumin genes. Samples were also subjected to immunohistochemical analysis of p16, Ki-67, p53, and p21. Of the analyzable tumors, 98.6% were positive for α-HPV DNA. HPV16 was the most prevalent genotype (89.0%), followed by HPV39 (4.1%) and HPV33 (2.7%). HPV16 viral load was high, ranging from 2.1 × 10(3) to 1.5 × 10(7) copies/10(3) cells. Integration of HPV16 estimated by the E2/E6 ratio was detected in 77.8% of cases, among which 70.4% were mixed integrated and episomal DNA cases and 7.4% were fully integrated DNA cases. The latter cases were associated with a low HPV16 load compared with cases containing either episomes or mixed integrated and episomal DNA. As expected, most HPV16-positive tumors expressed p16 (92.6%) with a high proliferative index, whereas a minority of them overexpressed p53 (10.3%). p21 expression did not appear to correlate with p53 expression. Although HPV16 was almost exclusively detected, high viral load and differences in DNA integration have been identified in the present series of anal cancers. HPV features assessed in conjunction with expression of cell-cycle regulators could be helpful, as joint biomarkers, in predicting clinical outcome.

Published
2013
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15. Diagnostic value of labial minor salivary gland biopsy for Sjögren's syndrome: A systematic review

Author

Dewi Guellec, Thierry Marhadour, Sandrine Jousse-Joulin, Pascale Marcorelles, Divi Cornec, Alain Saraux, Jacques-Olivier Pers, Valérie Devauchelle-Pensec, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'Anatomie Pathologique, Hôpital Morvan Brest-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Centre d'Investigation Clinique (CIC - Brest), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Pathology, medicine.medical_specialty, Biopsy, Immunology, Salivary gland biopsy, Salivary Glands, Minor, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, Sicca syndrome, Humans, Immunology and Allergy, Medicine, In patient, Focus score, 030304 developmental biology, 030203 arthritis & rheumatology, 0303 health sciences, medicine.diagnostic_test, business.industry, Predictive value, Dermatology, 3. Good health, stomatognathic diseases, Sjogren's Syndrome, Meta-analysis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Sjogren s, business
Abstract

International audience; OBJECTIVES: To assess the diagnostic value of minor salivary gland biopsy (MSGB) for primary Sjögren's syndrome (pSS). METHODS: Systematic review of studies retrieved from PUBMED and EMBASE using the terms 'salivary glands' AND 'Sjögren's syndrome' AND 'biopsy', conducted in patients with suspected pSS, and defining positive biopsies as a focus score (FS)≥1. Sensitivity and specificity of MSGB were abstracted from the articles or calculated when possible. RESULTS: Of 238 publications identified initially, 9 were included in the study. MSGB sensitivity ranged from 63.5% to 93.7% and specificity from 61.2% to 100%. Specificity was >89% in six studies. An attempt to separate patients with and without pSS without using MSGB findings or via clinical re-evaluation was made in only two studies, in 73 and 120 patients, respectively, with sicca syndrome in the first study and suspected pSS in the other. The reference standard for diagnosing pSS was a set of criteria that did not include MSGB in the first and patient re-evaluation by three experienced rheumatologists who were aware of MSGB findings in the other. In these studies, sensitivity was 63.9% and 85.7% and specificity was 91.9% and 89.7%, respectively. CONCLUSIONS: Few published studies have evaluated the diagnostic usefulness of MSGB in pSS. Only two studies used a methodology that precluded circular reasoning. Our study indicates a lack of information about the diagnostic value of MSGB. Specificity and positive predictive values (PPV) are high and sensitivity is variable.

Published
2013
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16. Galectin-1 is a powerful marker to distinguish chondroblastic osteosarcoma and conventional chondrosarcoma

Author

Sophie Le Guelec, Claudine Schiff, Pierre-Antoine Gourraud, A. Gomez-Brouchet, Frédéric Mourcin, Gonzague de Pinieux, Marie-Bernadette Delisle, Corinne Bouvier, Pierre Brousset, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Immunologie de Marseille Luminy (CIML - INSERM U631 - CNRS UMR 6102), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire d'Anatomie Pathologique [Purpan], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Male, musculoskeletal diseases, Pathology, medicine.medical_specialty, Adolescent, Galectin 1, Blotting, Western, Chondrosarcoma, Bone Neoplasms, Cell Count, Bone Sarcoma, Biology, Pathology and Forensic Medicine, Diagnosis, Differential, Immunoenzyme Techniques, Periostitis, 03 medical and health sciences, Chondrocytes, 0302 clinical medicine, Chondroblastic Osteosarcoma, Biomarkers, Tumor, medicine, Humans, Osteoblastoma, 030304 developmental biology, Osteosarcoma, 0303 health sciences, Tissue microarray, Middle Aged, medicine.disease, 3. Good health, Staining, Tissue Array Analysis, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunohistochemistry, Female, Sarcoma
Abstract

International audience; The clinical management of osteosarcoma differs significantly from that of chondrosarcoma; therefore, it is extremely important to diagnose these 2 types of bone tumor accurately. In the absence of a specific marker, differential diagnosis by histochemistry is sometimes impossible, especially between chondroblastic osteosarcoma and conventional chondrosarcoma. We analyzed 165 bone sarcomas by immunohistochemical staining of tissue microarrays for expression of the galectin-1 (GAL1) lectin and by Western blot experiments. We found that GAL1 was abundant in normal human osteoblasts from benign proliferations and in osteosarcomas, including chondroblastic osteosarcomas, but not in chondrosarcomas. There was a highly significant statistical difference in the percentage of stained cells (P < 10(-4)) and in the staining intensity (P < 10(-3)) of chondroblastic osteosarcomas compared to conventional chondrosarcomas. This discriminatory potential of GAL1 staining for osteosarcoma-derived tumors was confirmed by Western blotting. We propose a diagnostic test for bone tumors that takes into account the optimal discriminative values for the percentage of cells stained and the intensity of staining. The positive and negative predictive values were 85.7% (trust interval of 63.7%-97%) and 90% (trust interval of 80%-95.9%), respectively, demonstrating the pertinence of the test. Altogether, our data indicate that GAL1 is a powerful diagnostic marker that distinguishes chondroblastic osteosarcomas from conventional chondrosarcomas.

Published
2010
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17. Detection of alpha- and beta-human papillomavirus (HPV) in cutaneous melanoma: a matched and controlled study using specific multiplex PCR combined with DNA microarray primer extension

Author

Jean Luc Prétet, Bernadette Kantelip, Christiane Mougin, Tarik Gheit, Jean Baptiste Ruer, Line Pépin, François Aubin, Chrystelle Vidal, Massimo Tommasino, Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Université libre de Bruxelles (ULB)

Subjects
Male, Oncology, Skin Neoplasms, Microarray, Gammapapillomavirus, MESH : Aged, MESH : Gammapapillomavirus, Alphapapillomavirus, Polymerase Chain Reaction, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Aged, 80 and over, 0302 clinical medicine, MESH : Alphapapillomavirus, MESH : Neoplasm Staging, MESH : Female, MESH : DNA, Viral, Melanoma, MESH : Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Skin, MESH: Human papillomavirus 16, Aged, 80 and over, MESH: Aged, Human papillomavirus 16, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH : Prognosis, HPV infection, virus diseases, MESH: Neoplasm Staging, Middle Aged, MESH : Adult, Prognosis, female genital diseases and pregnancy complications, 3. Good health, MESH : Oligonucleotide Array Sequence Analysis, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, MESH: Melanoma, MESH : Male, Population, MESH : Melanoma, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Biology, MESH: Betapapillomavirus, MESH: Prognosis, Young Adult, 03 medical and health sciences, MESH: Skin, Internal medicine, Multiplex polymerase chain reaction, MESH : Skin, medicine, Betapapillomavirus, Humans, MESH : Middle Aged, MESH : Aged, 80 and over, education, MESH: Alphapapillomavirus, Molecular Biology, Aged, Neoplasm Staging, 030304 developmental biology, MESH: Humans, MESH : Betapapillomavirus, MESH: Skin Neoplasms, MESH : Skin Neoplasms, MESH : Humans, MESH : Human papillomavirus 16, Cancer, MESH: Adult, MESH: Polymerase Chain Reaction, medicine.disease, DNA extraction, MESH: Male, MESH: DNA, Viral, DNA, Viral, MESH: Oligonucleotide Array Sequence Analysis, Cutaneous melanoma, Immunology, MESH: Female, MESH: Gammapapillomavirus
Abstract

International audience; There are few contradictory studies investigating the involvement of HPV in melanoma. We designed a controlled study to evaluate the HPV DNA prevalence in melanoma. One hundred patients with cutaneous malignant melanoma diagnosed between 2002 and 2006 were included. Complementary wide excision (healthy skin) was performed in 85 patients and was used as internal control. After DNA extraction, 68 different HPV types were studied using a multiplex PCR combined with microarray primer extension. We did not observe any statistical significant difference in terms of HPV DNA prevalence in melanoma (38.8%) and in healthy skin from wide excision (42.4%). Twenty-one different HPV types were detected but only one type was present in the majority of our samples (80/85 melanoma vs 59/66 HS). The distribution of HPV genera and types was similar in melanoma and HS, and beta-HPV was predominant (30.6% and 31.8%). Among alpha-HPV (10.6%), high-risk mucosal HPV16 was predominant. Among beta-HPV, melanoma harboured significantly more type 22 than control normal skin from the same patients and significantly less type 21 than paired control normal skin. No correlation between clinical and pathological melanoma characteristics and HPV DNA prevalence was found. Our data do not support a role of HPV infection in melanocarcinogenesis, but confirm the previous data suggesting that HPV DNA is widely distributed among the population and that occult HPV infections are frequent. Furthermore, specific HPV types, such as a-HPV16 and beta-HPV species 2 may be involved in a sub-group of melanoma.

Published
2009
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18. Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

Author

Anne Rullier, Nathalie Dugot-Senant, Jean Rosenbaum, Jennifer Gillibert-Duplantier, Gérard Déléris, Cyril Petibois, Pierre Costet, Gaelle Cubel, Valérie Haurie, Paulette Bioulac-Sage, Danièle Taras, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Animalerie spécialisée, Université Bordeaux Segalen - Bordeaux 2, Chimie Nucléaire Analytique et Bio-environnementale (CNAB), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), and Rosenbaum, Jean

Subjects
Liver Cirrhosis, Male, Physiology, T-Lymphocytes, MESH: Cell Hypoxia, MESH: Chemotaxis, Leukocyte, MESH: Collagen Type I, MESH: Mice, Knockout, MESH: Lipid Peroxidation, MESH: Thrombin, MESH: Genotype, Mice, MESH: Animals, Receptor, Carbon Tetrachloride, Chemokine CCL2, Mice, Knockout, Thrombin, Gastroenterology, Cell Hypoxia, Cell biology, MESH: Receptor, PAR-1, Chemotaxis, Leukocyte, Liver, Coagulation, Intercellular Signaling Peptides and Proteins, Matrix Metalloproteinase 2, MESH: Liver Cirrhosis, medicine.drug, medicine.medical_specialty, Genotype, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Collagen Type I, Immediate early protein, Immediate-Early Proteins, Receptor, Platelet-Derived Growth Factor beta, Necrosis, MESH: Mice, Inbred C57BL, MESH: Transaminases, Physiology (medical), Internal medicine, medicine, Animals, Receptor, PAR-1, RNA, Messenger, MESH: Intercellular Signaling Peptides and Proteins, MESH: Mice, MESH: Chemokine CCL2, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Transaminases, MESH: RNA, Messenger, MESH: Necrosis, Hepatology, MESH: Carbon Tetrachloride, Connective Tissue Growth Factor, MESH: Immediate-Early Proteins, Chemotaxis, MESH: Male, Mice, Inbred C57BL, MESH: Matrix Metalloproteinase 2, Disease Models, Animal, MESH: T-Lymphocytes, Endocrinology, Protease-Activated Receptor 1, Hemostasis, Lipid Peroxidation, MESH: Disease Models, Animal, MESH: Receptor, Platelet-Derived Growth Factor beta, Hepatic fibrosis, MESH: Liver
Abstract

Thrombin inhibition protects against liver fibrosis. However, it is not known whether the thrombin profibrogenic effect is due to effects on blood coagulation or to signaling via protease-activated receptors (PARs). We took advantage of the lack of blood coagulation defects in PAR-1-knockout mice. Acute carbon tetrachloride (CCl4) toxicity was similar in wild-type (WT), PAR-1−/−, and PAR-1+/−mice as judged by aminotransferase levels, area of liver necrosis, and liver peroxidation measured by Fourier-transformed infrared spectroscopy. Fifteen mice/group received CCl4or its solvent for 6 wk (300 μl/kg, 3 times a week). Fibrosis area was increased 10-fold by CCl4treatment in WT mice. PAR-1 deficiency protected against fibrosis, with 36% and 56% decrease in PAR-1+/−and PAR-1−/−mice, respectively ( P < 0.001). Similar results were obtained for area of activated fibrogenic cells (64% and 79% decrease in PAR-1+/−and PAR-1−/−mice, respectively, P < 0.001). These findings were corroborated by measurements of type I collagen, matrix metalloproteinase-2, and PDGF-β receptor mRNA levels. There was also a significant decrease in T lymphocyte infiltration in PAR-1-deficient mice. Altogether, these results suggest that thrombin profibrogenic effects are independent of effects on blood coagulation and are instead due to direct effects on fibrogenic cells and possibly on T lymphocytes.

Published
2008
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