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1. Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation

Author

Olivier Manches, Nicolas Terzi, Dominique Masson, Laurence Chaperot, Claude-Eric Bulabois, Nathalie Sturm, Carole Schwebel, Jean-Yves Cahn, Diane Giovannini, Julie Charles, Marie-Thérèse Leccia, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Service de réanimation médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Département d'anatomie et cythologie pathologique, Laboratoire HLA [EFS - Auvergne-Rhônes-Alpes], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Département Pluridisciplinaire de Médecine, Dermatologie, Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire recherche et développement, EFS, Hematology, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, GVHD, Case Report, lcsh:RC254-282, Polymyositis, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Immune-related adverse events, Internal medicine, Medicine, Myositis, ComputingMilieux_MISCELLANEOUS, lcsh:RC633-647.5, business.industry, lcsh:Diseases of the blood and blood-forming organs, Hematology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Immune checkpoint, 3. Good health, Lymphoma, Allogeneic stem cell transplantation, Transplantation, PD1, 030104 developmental biology, Nivolumab, Oncology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Stem cell, business, Hodgkin lymphoma
Abstract

Background Immune checkpoint inhibitors have radically changed the landscape of anti-tumor therapies in several malignancies. However the adverse events associated with immune checkpoint blockade in combination with other treatments remains to be thoroughly documented. Here we report the case of a 33-year-old male with classical Hodgkin lymphoma who was successfully treated for lymphoma but experienced serious and eventually fatal multisystem organ failure following nivolumab administration and allogeneic stem cell transplantation. Case presentation The patient was diagnosed with stage IIIa nodular sclerosing Hodgkin lymphoma. Originally treated by chemotherapy and autologous stem cell transplantation, he subsequently received two allogeneic stem cell transplants from matched and haplo-identical siblings upon successive disease recurrences. Nivolumab treatment was administered prior to the second allograft, after which complete remission of lymphoma was achieved (year 10), as evidenced by clinical and radiographic examination. However within the next 3 months, the patient went on to develop a constellation of symptoms affecting multiple organs, including acute pneumonia with no evidence of bacterial infection, widespread cutaneous eruptions on trunk and lower limbs, mucosal ulcerations, myositis, diarrhea and colitis. Further complications included hepatic cytolysis, acute renal failure, pancreatitis, as well as complete heart block. Some of these injuries being suggestive of graft-versus-host disease, the patient was administered immunosuppressive therapy (mycophenolate, steroids and polyvalent immunoglobulins), but died shortly afterwards. Tissue biopsies revealed extensive lymphocytic infiltration (mostly CD3 + T cells) in skin, liver, and most peculiarly in muscles, including the myocardium. Massive lymphoid-histiocytic infiltration of muscle fibers was accompanied by acute necrotizing myositis and endomysial inflammation. Conclusions Multi-organ failure represents a rare but potentially fatal outcome of immune checkpoint blockade in patients receiving allogeneic stem cell grafts. Nivolumab may induce atypical immune-mediated tissue inflammation and damage, such as the extensive muscular polymyositis described here in a patient with Hodgkin lymphoma. Nivolumab might also worsen GVHD symptoms in the context of allogeneic stem cell transplantation. Irrespective of the actual pathological mechanisms, clinicians should be alerted to these fatal drug-related toxicities. Electronic supplementary material The online version of this article (10.1186/s40164-019-0132-2) contains supplementary material, which is available to authorized users.

Published
2019
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2. Routinely used immunoassays do not detect circulating anti-GBM antibodies against native NC1 hexamer and EA epitope of the α3 chain of type IV collagen

Author

Clavarino, Giovanna, Gauthier, Arnaud, Hellmark, Thomas, Carron, Pierre-Louis, Giovannini, Diane, Colliard, Sophie, Dragon-Durey, Marie- Agnès, Segelmark, Mårten, Cesbron, Jean-Yves, Dumestre-Pérard, Chantal, Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), LABORATOIRE D'IMMUNOLOGIE, Centre Hospitalier Universitaire [Grenoble] (CHU), kidney reseach laboratory, Lund University [Lund], CHU Grenoble, Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Service d'Immunologie Clinique, Hôpital Européen Georges Pompidou, Paris, Division of Drug Research/Clinical Pharmacology, Department of Medicine and Health, Faculty of Health Sciences, and Linköping University (LIU)

Subjects
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

3. DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer

Author

Anne, Jouinot, Guillaume, Assie, Rossella, Libe, Martin, Fassnacht, Thomas, Papathomas, Olivia, Barreau, Bruno, de la Villeon, Simon, Faillot, Nadim, Hamzaoui, Mario, Neou, Karine, Perlemoine, Fernande, Rene-Corail, Stéphanie, Rodriguez, Mathilde, Sibony, Frédérique, Tissier, Bertrand, Dousset, Silviu, Sbiera, Cristina, Ronchi, Matthias, Kroiss, Esther, Korpershoek, Ronald, de Krijger, Jens, Waldmann, Detlef, K, Bartsch, Marcus, Quinkler, Magalie, Haissaguerre, Antoine, Tabarin, Olivier, Chabre, Nathalie, Sturm, Michaela, Luconi, Franco, Mantero, Massimo, Mannelli, Regis, Cohen, Véronique, Kerlan, Philippe, Touraine, Gaelle, Barrande, Lionel, Groussin, Xavier, Bertagna, Eric, Baudin, Laurence, Amar, Felix, Beuschlein, Eric, Clauser, Joel, Coste, Jérôme, Bertherat, Pathology, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), CHU Cochin [AP-HP], Department of Psychiatry, Chirurgie digestive, hépato-biliaire et endocrinienne [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München (LMU), Comprehensive Cancer Center Mainfranken, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Pathology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Clinical Genetics, Département d'endocrinologie - Bordeaux 2, Université Bordeaux Segalen - Bordeaux 2, Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Department of Endocrinology and Diabetes Mellitus, Hôpital Delafontaine, Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département d'endocrinologie et Médecine Reproductive [AP-HP Hôpital Pitié-Salpétrière], AP-HP Hôpital Universitaire Pitié Salpêtrière - GHU Pitié Salpêtrière, Centre Hospitalier Régional d'Orléans (CHR), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Université de Brest (UBO)-Université de Brest (UBO), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, medical, Biochemistry, 0302 clinical medicine, Endocrinology, Adrenocortical Carcinoma, Methylation, DNA, Neoplasm, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, Prognosis, 3. Good health, Tumor Burden, Diabetes and Metabolism, Survival Rate, CpG site, 030220 oncology & carcinogenesis, Cohort, DNA methylation, Female, Adult, medicine.medical_specialty, Context (language use), Biology, Disease-Free Survival, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, Survival rate, Aged, Neoplasm Staging, Proportional Hazards Models, Retrospective Studies, Biochemistry, medical, Proportional hazards model, Biochemistry (medical), Retrospective cohort study, DNA Methylation, Adrenal Cortex Neoplasms, 030104 developmental biology, Ki-67 Antigen, Multivariate Analysis, CpG Islands, Multiplex Polymerase Chain Reaction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Context:Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival.Objective:The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort.Design:Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).Setting:MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers.Patients:The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors).Main Outcome Measures:DFS and OS.Results:In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors.Conclusions:Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

Published
2017
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4. The Indolylcoumarin Coufin Exhibits Potent Activity Against Renal Carcinoma Cells without Affecting Hematopoietic System

Author

Vincent Peyrot, Etienne Daras, Pascale Barbier, Soazig Douillard, Sébastien Combes, Pierre Champelovier, Bertrand Toussaint, Veronique Curri, Virginie Persoon, Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Indoles, Hematopoietic System, Antineoplastic Agents, Apoptosis, Pharmacology, Biology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Coumarins, In vivo, Tumor Cells, Cultured, Animals, Humans, Colchicine, Carcinoma, Renal Cell, IC50, Cell Proliferation, Microtubule nucleation, Dose-Response Relationship, Drug, Molecular Structure, Cell Cycle, Neoplasms, Experimental, Kidney Neoplasms, In vitro, 3. Good health, Mice, Inbred C57BL, Haematopoiesis, Tubulin, chemistry, Cancer research, biology.protein, Molecular Medicine, Efflux, Drug Screening Assays, Antitumor
Abstract

International audience; : The present work describes the anticancer activity of a new indolylcoumarin named COUFIN and more specifically, its efficiency against clear cell renal carcinoma (CCRC). COUFIN inhibited microtubule formation and bound on tubulin to or near the colchicine site. In vitro, COUFIN showed potent anticancer activity on renal carcinoma cells (RCC) both in monolayer (2D culture) (IC50 of 88±8 nM) and multicellular tumor spheroid (3D culture) (IC50 of 180±20 nM). The compound blocked cell cycle transition at G2/M phase, induced a subsequent apoptotic process but did not modulate clonal growth of CFU-GM. On the other hand, the coumarin derivative decreased the activity of P-gp and BCRP but was not substrate for these ABC pumps. In vivo, the indolylcoumarin increased the survival rate after 3 weeks of treatment. Based on the present study, COUFIN was identified as a bifunctional molecule able to inhibit renal carcinoma cells proliferation without being effluxed by ABC proteins. Thus COUFIN could be a promising chemotherapeutic agent for treating tumor cells over-expressing efflux pumps and tumor cells irrigated by vessels lined with endothelial cells responsible of poor distribution of conventional anticancer agents.

Published
2014

5. Cellular and molecular mechanisms activating the cell death processes by chalcones: Critical structural effects

Author

Pierre Champelovier, Catherine Garrel, Sabrina Vergnaud, François Laporte, Jean Boutonnat, Ahcène Boumendjel, Florence Hazane-Puch, Xavier Chauchet, Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'enzymologie, CHU Grenoble, Département de biologie intégrée, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de pharmacochimie moléculaire (DPM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Programmed cell death, Chalcone, Cyclin B, Antineoplastic Agents, Toxicology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, chemistry.chemical_compound, Chalcones, Glutathione Peroxidase GPX1, 0302 clinical medicine, Bcl-2-associated X protein, Cyclin-dependent kinase, Cell Line, Tumor, Malondialdehyde, Mitotic Index, Humans, Caspase, 030304 developmental biology, Glutathione Peroxidase, 0303 health sciences, Cell Death, biology, Chemistry, Cell Cycle, General Medicine, Catalase, Bcl-2 homologous antagonist killer, Biochemistry, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, Reactive Oxygen Species
Abstract

International audience; Chalcones are naturally occurring compounds with diverse pharmacological activities. Chalcones derive from the common structure: 1,3-diphenylpropenone. The present study aims to better understand the mechanistic pathways triggering chalcones anticancer effects and providing evidences that minor structural difference could lead to important difference in mechanistic effect. We selected two recently investigated chalcones (A and B) and investigated them on glioblastoma cell lines. It was found that chalcone A induced an apoptotic process (type I PCD), via the activation of caspase-3, -8 and -9. Chalcone A also increased CDK1/cyclin B ratios and decreased the mitochondrial transmembrane potential (ΔΨm). Chalcone B induced an autophagic cell death process (type II PCD), ROS-related but independent of both caspases and protein synthesis. Both chalcones increased Bax/Bcl2 ratios and decreased Ki67 and CD71 antigen expressions. The present investigation reveals that despite the close structure of chalcones A and B, significant differences in mechanism of effect were found.

Published
2013
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6. AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations

Author

Jérôme, Guéchot, Renée Claude, Boisson, Jean-Pierre, Zarski, Nathalie, Sturm, Paul, Calès, Elisabeth, Lasnier, E-S, Zafrani, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Biochimie et Toxicologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Pôle Digidune, Pôle DigiDune, Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), and Université d'Angers (UA)

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Organ Dysfunction Scores, Biopsy, [SDV]Life Sciences [q-bio], Biopsy, Fine-Needle, Gastroenterology, digestive system, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Aspartate Aminotransferases, Prospective Studies, Pyridoxal phosphate, Chronic, Prospective cohort study, Pyridoxal, Hepatology, medicine.diagnostic_test, business.industry, AST/ALT ratio, Alanine Transaminase, Hepatitis C, Chronic, Middle Aged, medicine.disease, Hepatitis C, digestive system diseases, 3. Good health, chemistry, Liver, ROC Curve, 030220 oncology & carcinogenesis, Liver biopsy, Pyridoxal Phosphate, Cohort, Fine-Needle, 030211 gastroenterology & hepatology, Female, business, Hepatic fibrosis
Abstract

International audience; OBJECTIVE: The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients.METHODS: ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5'-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard.RESULTS: AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r=0.129, PCONCLUSION: AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations.

Published
2013
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7. Inhibition of c-Jun N-terminal kinase by SP600125: a cDNA microarray analysis

Author

Pierre, Champelovier, Michele, El Atifi-Borel, Jean Paul, Issartel, Jean, Boutonnat, François, Berger, Daniel, Seigneurin, Issartel, Jean-Paul, Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Association Grenobloise d'Etude de la Cellule Cancéreuse (AGECC)

Subjects
MESH: Cell Line, Tumor, Down-Regulation, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Down-Regulation, MESH: Gene Expression Profiling, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Up-Regulation, Cluster Analysis, Humans, Gene Regulatory Networks, MESH: Genes, Neoplasm, Oligonucleotide Array Sequence Analysis, MESH: Gene Regulatory Networks, Anthracenes, MESH: Humans, Gene Expression Profiling, MESH: Anthracenes, JNK Mitogen-Activated Protein Kinases, Reproducibility of Results, MESH: Gene Expression Regulation, Neoplastic, MESH: JNK Mitogen-Activated Protein Kinases, MESH: Cluster Analysis, Up-Regulation, Gene Expression Regulation, Neoplastic, MESH: Reproducibility of Results, MESH: Oligonucleotide Array Sequence Analysis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genes, Neoplasm
Abstract

International audience; BACKGROUND: In a previous investigation, we showed that the janus kinase (JNK) inhibitor SP600125 induced several phenotypic and genomic changes in leukemia cells. However, the molecular mechanisms that sustain these changes remain unknown. The purpose of the present study was to examine gene expression changes in THP-1 leukemia cells treated with SP600125. MATERIALS AND METHODS: Gene expression levels were investigated using Affymetrix hybridization technology and quantitative reverse transcriptase polymerase chain reaction. RESULTS: Affymetrix technology showed that the expression of 1,038 genes with a biological process description well known in gene ontology was modulated. Fifteen genes were related to kinases or phosphatases, 20 genes were involved in the cell cycle regulation, and 23 genes were involved in apoptosis. A network of 15 correlated genes was obtained showing a primordial role for the myelocytomatosis viral oncogene homolog (MYC). CONCLUSION: These findings show that SP600125 exhibits cytostatic and cytolytic activities through MYC gene modulation.

Published
2010

8. Cellular and molecular mechanisms activating the cell death processes by chalcones: Critical structural effects.

Author

Champelovier P, Chauchet X, Hazane-Puch F, Vergnaud S, Garrel C, Laporte F, Boutonnat J, and Boumendjel A

Subjects
Catalase genetics, Cell Cycle drug effects, Cell Death drug effects, Cell Death physiology, Cell Line, Tumor, Glutathione Peroxidase genetics, Humans, Malondialdehyde metabolism, Mitotic Index, Reactive Oxygen Species metabolism, Glutathione Peroxidase GPX1, Antineoplastic Agents pharmacology, Chalcones pharmacology
Abstract

Chalcones are naturally occurring compounds with diverse pharmacological activities. Chalcones derive from the common structure: 1,3-diphenylpropenone. The present study aims to better understand the mechanistic pathways triggering chalcones anticancer effects and providing evidences that minor structural difference could lead to important difference in mechanistic effect. We selected two recently investigated chalcones (A and B) and investigated them on glioblastoma cell lines. It was found that chalcone A induced an apoptotic process (type I PCD), via the activation of caspase-3, -8 and -9. Chalcone A also increased CDK1/cyclin B ratios and decreased the mitochondrial transmembrane potential (ΔΨm). Chalcone B induced an autophagic cell death process (type II PCD), ROS-related but independent of both caspases and protein synthesis. Both chalcones increased Bax/Bcl2 ratios and decreased Ki67 and CD71 antigen expressions. The present investigation reveals that despite the close structure of chalcones A and B, significant differences in mechanism of effect were found., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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9. Inhibition of c-Jun N-terminal kinase by SP600125: a cDNA microarray analysis.

Author

Champelovier P, El Atifi-Borel M, Issartel JP, Boutonnat J, Berger F, and Seigneurin D

Subjects
Cell Line, Tumor, Cluster Analysis, Down-Regulation drug effects, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Gene Regulatory Networks drug effects, Genes, Neoplasm genetics, Humans, Reproducibility of Results, Up-Regulation drug effects, Anthracenes pharmacology, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Oligonucleotide Array Sequence Analysis methods
Abstract

Background: In a previous investigation, we showed that the janus kinase (JNK) inhibitor SP600125 induced several phenotypic and genomic changes in leukemia cells. However, the molecular mechanisms that sustain these changes remain unknown. The purpose of the present study was to examine gene expression changes in THP-1 leukemia cells treated with SP600125., Materials and Methods: Gene expression levels were investigated using Affymetrix hybridization technology and quantitative reverse transcriptase polymerase chain reaction., Results: Affymetrix technology showed that the expression of 1,038 genes with a biological process description well known in gene ontology was modulated. Fifteen genes were related to kinases or phosphatases, 20 genes were involved in the cell cycle regulation, and 23 genes were involved in apoptosis. A network of 15 correlated genes was obtained showing a primordial role for the myelocytomatosis viral oncogene homolog (MYC)., Conclusion: These findings show that SP600125 exhibits cytostatic and cytolytic activities through MYC gene modulation.

Published
2010

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