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19 results on '"MESH: Pyrazines"'

1. Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting

Author

Fran Robson, Palma Rocchi, Sinem Demirbag, Thi Khanh Le, Khadija Shahed Khan, Clément Paris, Peter Barfuss, Wai-Lung Ng, University of Bristol [Bristol], The Chinese University of Hong Kong [Hong Kong], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Hanoi University of Science and Technology (HUST), Sabanci University, Nanotechnology Research and Application Center, Sabanci University [Istanbul], Université Paris-Est (UPE), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Rocchi, Palma

Subjects
antisense oligonucleotide, Transcription, Genetic, MESH: Coronavirus Infections, viruses, [SDV]Life Sciences [q-bio], Cell, coronavirus, Cytidine, Viral Nonstructural Proteins, medicine.disease_cause, Virus Replication, Genome, Severity of Illness Index, 0302 clinical medicine, Transcription (biology), MESH: Molecular Targeted Therapy, MESH: COVID-19, Nucleotide, MESH: Adenosine Monophosphate, Molecular Targeted Therapy, Coronavirus, chemistry.chemical_classification, 0303 health sciences, Alanine, non-structural protein 14, virus diseases, ExoN, MESH: Amides, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Pyrazines, MESH: RNA, Viral, Pyrazines, Proofreading, MESH: Betacoronavirus, RNA, Viral, MESH: Genome, Viral, Coronavirus Infections, MESH: Cytidine, medicine.drug, MESH: Antiviral Agents, MESH: Pandemics, MESH: Mutation, exonuclease, MESH: Alanine, CoV, Pneumonia, Viral, antisense oligonucleotide (ASO), Computational biology, Genome, Viral, Biology, Therapeutic targeting, Hydroxylamines, Antiviral Agents, Article, ASO, 03 medical and health sciences, Betacoronavirus, MESH: Severity of Illness Index, Coronavirus (CoV), medicine, Humans, MESH: SARS-CoV-2, anti-coronavirus drugs, Molecular Biology, Pandemics, 030304 developmental biology, Exonuclease (ExoN), MESH: Ribonucleosides, MESH: Humans, Nucleoside analogue, SARS-CoV-2, MESH: Transcription, Genetic, MESH: Virus Replication, nucleoside analog, RNA, COVID-19, Correction, MESH: Hydroxylamines, Cell Biology, Amides, Adenosine Monophosphate, non-structural protein 14 (nsp14), respiratory tract diseases, nucleoside analogue (NA), Viral replication, chemistry, MESH: Pneumonia, Viral, Mutation, nsp14, MESH: Viral Nonstructural Proteins, NA, Ribonucleosides, 030217 neurology & neurosurgery
Abstract

Summary The coronavirus disease 2019 (COVID-19) that is wreaking havoc on global public health and economies has heightened awareness about the lack of effective antiviral treatments for human coronaviruses (CoVs). Many current antivirals, notably nucleoside analogues (NA), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription. Here, we review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. We also consider existing nucleoside analogues and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism., Graphical Abstract, Robson et al. examine the molecular basis of the coronavirus proofreading mechanism and how this contributes to the resistance of this family of viruses to nucleoside analogue (NA) antiviral drugs. They discuss antisense oligonucleotide (ASO) therapy in combination with NAs to potentially improve the potency and delivery of antiviral drugs.

Published
2020

2. Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma

Author

Marie-Claude Jaurand, Robin Tranchant, Jessica Zucman-Rossi, Clément Meiller, Didier Jean, Lisa Quetel, Julien de Wolf, Leanne de Koning, François Montagne, Françoise Le Pimpec-Barthes, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Université Paris 13 (UP13), Service de Chirurgie Thoracique [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, Laboratoire des biomarqueurs tumoraux circulants [Institut Curie, Paris] (SiRIC - Département de recherche translationnelle), Institut Curie [Paris]-Université Paris sciences et lettres (PSL), Service de Chirurgie Thoracique (Hôpital Européen Georges Pompidou [APHP] HEGP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Jean, Didier

Subjects
0301 basic medicine, Mesothelioma, MESH: Signal Transduction, Cancer Research, Lung Neoplasms, MESH: Sulfonamides, Apoptosis, Quinolones, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Target therapy, MESH: Benzamides, 0302 clinical medicine, MESH: Phenols, RNA interference, Tumor Cells, Cultured, Gene knockdown, Sulfonamides, MESH: Gene Expression Regulation, Neoplastic, Verteporfin, 3. Good health, Gene Expression Regulation, Neoplastic, Predictive biomarker, Oncology, MESH: Cell Survival, 030220 oncology & carcinogenesis, Pyrazines, MESH: Pyrazines, Benzamides, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Interference, MESH: Biomarkers, Tumor, Signal transduction, medicine.drug, Signal Transduction, Pulmonary and Respiratory Medicine, Cell Survival, Pleural Neoplasms, MESH: RNA Interference, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Pleural Neoplasms, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Phenols, MESH: Cell Proliferation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Biomarkers, Tumor, Humans, Viability assay, MESH: Tumor Cells, Cultured, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, Thoracic tumor, Cisplatin, MESH: Humans, MESH: Quinolones, MESH: Mesothelioma, Cell growth, business.industry, MESH: Apoptosis, MESH: Verteporfin, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Tumor molecular classification, MESH: Lung Neoplasms, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cancer research, MESH: Antineoplastic Agents, Signal pathway, Carcinogenesis, business
Abstract

International audience; OBJECTIVES:Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited therapeutic options, requiring the development of efficient targeted therapies based on molecular phenotype of the tumor and to identify predictive biomarkers of the response.MATERIALS AND METHODS:The effect of inhibitors was investigated by cell viability assessment on primary MPM cell lines established in our laboratory from patient tumors, well characterized at the molecular level. Effects on apoptosis, cell proliferation and viability on MPM growing in multicellular spheroid were also assessed for verteporfin. Gene and protein expression, and gene knockdown by RNA interference were used to define mechanism of inhibition and specific predictive biomarkers.RESULTS:Anti-tumor effect of eight major signaling pathways inhibitors involved in mesothelial carcinogenesis was investigated. Three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor. Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors.CONCLUSION:Our study shows that drug screening on well-characterized MPM cells allows for the identification of novel potential therapeutic strategies and defining specific biomarkers predictive of the drug response.

Published
2018

3. Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies

Author

Madelain, Vincent, Baize, Sylvain, Jacquot, Frédéric, Reynard, Stéphanie, Fizet, Alexandra, Barron, Stephane, Solas, Caroline, Lacarelle, Bruno, Carbonnelle, Caroline, Mentré, France, Raoul, Hervé, de Lamballerie, Xavier, Guedj, Jérémie, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emergence des Pathologies Virales (EPV), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM), This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 666092, and from the St. Luke’s International University (Tokyo, Japan) in the framework of Research Program on Emerging and Re-emerging Infectious Diseases of the Japan Agency for Medical Research and Development (AMED)., European Project: 666092,H2020,H2020-Adhoc-2014-20,REACTION(2014), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Baize, Sylvain, Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humans - REACTION - - H20202014-11-01 - 2016-10-31 - 666092 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
MESH: Antiviral Agents, Time Factors, [SDV]Life Sciences [q-bio], Science, viruses, Antiviral Agents, Article, Animals, MESH: Animals, MESH: Ebolavirus, lcsh:Science, MESH: Models, Theoretical, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Cytokines, MESH: Host-Pathogen Interactions, MESH: Macaca, MESH: Time Factors, Interferon-alpha, Hemorrhagic Fever, Ebola, Models, Theoretical, Viral Load, Ebolavirus, Amides, Survival Analysis, MESH: Amides, Disease Models, Animal, Pyrazines, MESH: Pyrazines, MESH: Survival Analysis, Host-Pathogen Interactions, MESH: Hemorrhagic Fever, Ebola, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytokines, Macaca, Female, lcsh:Q, MESH: Disease Models, Animal, MESH: Interferon-alpha, MESH: Viral Load, MESH: Female
Abstract

Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks., Optimization of antiviral therapy can be crucial in the management of Ebola virus outbreaks. Here, Madelain et al. use an integrative mathematical model to correlate the dose and the time of treatment initiation with survival rate, enhanced immune response and viral clearance.

Published
2018

4. Understanding the Mechanism of the Broad-Spectrum Antiviral Activity of Favipiravir (T-705): Key Role of the F1 Motif of the Viral Polymerase

Author

Mathy Froeyen, Leen Delang, Stéphanie Beaucourt, Bruno Canard, Ana Theresa Silveira de Morais, Isabelle Imbert, Johan Neyts, Marco Vignuzzi, Hervé Blanc, Pieter Leyssen, Rana Abdelnabi, Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the BELVIR project from BELSPO (IUAP), the EU-FP7/2011-2014 Project SILVER (GA 260644), and the EU-H2020 Innovative Training Network ANTIVIRALS (GA 642434). A.T.S.D.M. was supported by a postdoctoral fellowship from CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico—Brasil). L.D. was supported by a postdoctoral fellowship from the FWO (Fund for Scientific Research of Flanders, Belgium)., European Project: 260644,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,SILVER(2010), European Project: 642434,H2020,H2020-MSCA-ITN-2014,ANTIVIRALS(2015), Pfeiffer, Julie K, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, RdRp, viruses, Amino Acid Motifs, Virus Replication, Mice, chemistry.chemical_compound, MESH: Amino Acid Motifs, Japan, MESH: Chlorocebus aethiops, RNA polymerase, Chlorocebus aethiops, MESH: Animals, Polymerase, MESH: Microbial Viability, MESH: Mutagenesis, MESH: Japan, MESH: Drug Resistance, Viral, biology, MESH: Amides, Enterovirus B, Human, 3. Good health, Pyrazines, MESH: Pyrazines, MESH: RNA Replicase, Chikungunya virus, mutagenesis, MESH: Antiviral Agents, MESH: Mutation, Immunology, RNA-dependent RNA polymerase, MESH: Vero Cells, Favipiravir, favipiravir, Antiviral Agents, Microbiology, Virus, 03 medical and health sciences, Virology, Vaccines and Antiviral Agents, Drug Resistance, Viral, Animals, MESH: Lysine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, CVB3, Vero Cells, MESH: Mice, Microbial Viability, Lysine, MESH: Virus Replication, RNA, MESH: Chikungunya virus, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Processivity, RNA-Dependent RNA Polymerase, Amides, 030104 developmental biology, fidelity, chemistry, Viral replication, MESH: Enterovirus B, Human, Insect Science, Mutation, biology.protein
Abstract

Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for the treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses, including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of positive-sense single-stranded RNA (+ssRNA) viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely, coxsackievirus B3 (CVB3). Introduction of the corresponding K-to-R substitution in the CVB3 RdRp (K159R) resulted in a nonviable virus. Replication competence of the K159R variant was restored by spontaneous acquisition of an A239G substitution in the RdRp. A mutagenesis analysis at position K159 identified the K159M variant as the only other viable variant which had also acquired the A239G substitution. The K159 substitutions markedly decreased the processivity of the purified viral RdRp, which was restored by the introduction of the A239G mutation. The K159R A239G and K159M A239G variants proved, surprisingly, more susceptible than the wild-type virus to T-705 and exhibited lower fidelity in polymerase assays. Furthermore, the K159R A239G variant was found to be highly attenuated in mice. We thus demonstrate that the conserved lysine in the F1 motif of the RdRp of +ssRNA viruses is involved in the broad-spectrum antiviral activity of T-705 and that it is a key amino acid for the proper functioning of the enzyme. IMPORTANCE In this study, we report the key role of a highly conserved lysine residue of the viral polymerase in the broad-spectrum antiviral activity of favipiravir (T-705) against positive-sense single-stranded RNA viruses. Substitutions of this conserved lysine have a major negative impact on the functionality of the RdRp. Furthermore, we show that this lysine is involved in the fidelity of the RdRp and that the RdRp fidelity influences the sensitivity of the virus for the antiviral efficacy of T-705. Consequently, these results provide insights into the mechanism of the antiviral activity of T-705 and may lay the basis for the design of novel chemical scaffolds that may be endowed with a more potent broad-spectrum antiviral activity than that of T-705.

Published
2017

5. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted

Author

Nguyen, Thi Huyen Tram, Guedj, Jérémie, Anglaret, Xavier, Laouénan, Cédric, Madelain, Vincent, Taburet, Anne-Marie, Baize, Sylvain, Sissoko, Daouda, Pastorino, Boris, Rodallec, Anne, Piorkowski, Géraldine, Carazo, Sara, Conde, Mamoudou N, Gala, Jean-Luc, Bore, Joseph Akoi, Carbonnelle, Caroline, Jacquot, Frédéric, Raoul, Hervé, Malvy, Denis, de Lamballerie, Xavier, Mentré, France, JIKI study group, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Programme PAC-CI, ANRS France Recherche Nord & sud Sida-hiv hépatites, Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Emergence des Pathologies Virales (EPV), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Médecins Sans Frontières Belgique, The Alliance for International Medical Action [Dakar, Sénégal] (ONG ALIMA), Université Catholique de Louvain = Catholic University of Louvain (UCL), Laboratoire des Fièvres Hémorragiques en Guinée, Université Gamal Abdel Nasser de Conakry, Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), The JIKI trial was supported by grants from the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France, http://www.anrs.fr/), the French Institute for Health Research (Inserm, Paris, France, http://www.inserm.fr/) and the European Commission (EU Horizon 2020 programme, grant N° 666092 - REACTION, http://ec.europa.eu/programmes/horizon2020/)., European Project: 666092,H2020,H2020-Adhoc-2014-20,REACTION(2014), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], MATEO, MATHIEU, Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humans - REACTION - - H20202014-11-01 - 2016-10-31 - 666092 - VALID, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de génétique médicale UCL, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), and Université Catholique de Louvain (UCL)

Subjects
Male, Physiology, Blood plasma, Biochemistry, MESH: Child, Medicine and Health Sciences, Viral load, Child, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Aged, MESH: Guinea, MESH: Middle Aged, Pharmaceutics, lcsh:Public aspects of medicine, Hematology, Middle Aged, Ebolavirus, MESH: Amides, Body Fluids, Blood, MESH: Young Adult, Child, Preschool, Pyrazines, Creatinine, MESH: Pyrazines, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Drug therapy, Anatomy, Research Article, Adult, MESH: Antiviral Agents, lcsh:Arctic medicine. Tropical medicine, Adolescent, lcsh:RC955-962, Antiviral Agents, Microbiology, Young Adult, Virology, Albumins, Dose prediction methods, Humans, Pharmacokinetics, MESH: Ebolavirus, Aged, Pharmacology, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Biology and Life Sciences, Proteins, lcsh:RA1-1270, MESH: Adult, Hemorrhagic Fever, Ebola, Amides, MESH: Male, MESH: Hemorrhagic Fever, Ebola, Guinea, MESH: Female, Biomarkers, Viral Transmission and Infection
Abstract

Background In 2014–2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations. Methods and findings Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient’s individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient’s characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p, Author summary In 2014–2015, the JIKI trial was conducted in Guinea to test favipiravir tolerance and efficacy in patients with Ebola virus disease (EDV). The main results of the trial were previously published without drug concentrations which were not available at the time of publication. The purpose of this study was to report favipiravir concentrations achieved in participants in the JIKI trial and to compare them with the targeted concentrations. We analyzed drug concentrations obtained at Day-2 and Day-4 and compared them to the targeted concentrations. At Day-2, favipiravir concentrations were significantly below but still close to the targeted concentration. At Day-4, a significant and unanticipated drop of concentrations as compared to Day-2 was observed. The origin of the lower-than-targeted concentrations and the unexpected drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. No significant correlation was found between the drug exposure and the virological response, indicating that it is possible that the favipiravir concentrations in the JIKI trial were not sufficient to strongly inhibit the viral replication. These findings suggest the necessity of performing dose-ranging studies with high doses of favipiravir in healthy volunteers to inform any further development of favipiravir for treatment of EVD.

Published
2017

6. Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice

Author

Pierre Cattan, Julien Castel, Rémy Burcelin, Aurélie Waget, Daniel J. Drucker, Mattieu Armanet, Melis Karaca, Christophe Magnan, Jens J. Holst, Céline Garret, Thierry Sulpice, Gaëlle Payros, Myriam Masseboeuf, Adriano Maida, Cendrine Cabou, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Cell Therapy Unit, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Fonctionnelle et Adaptative ( BFA ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Medicine, University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital ( MSH ), Physiogenex SAS, Prologue Biotech, PHYSIOGENEX S.A.S, Department of Biomedical Sciences, The panum Institute-University of Copenhagen ( KU ), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital [Toronto, Canada] (MSH), Physiogenex, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto-Mount Sinai Hospital [Toronto, Canada] (MSH)-Samuel Lunenfeld Research Institute, and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)

Subjects
MESH : Insulin, medicine.medical_treatment, MESH : Vagus Nerve, MESH : Receptors, Glucagon, 0302 clinical medicine, Endocrinology, MESH: Dipeptides, MESH: Vagus Nerve, Glucose homeostasis, MESH: Animals, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Dipeptidyl-Peptidase IV Inhibitors, 0303 health sciences, Glucose tolerance test, MESH: Middle Aged, MESH: Dipeptidyl-Peptidase IV Inhibitors, medicine.diagnostic_test, MESH : Glucagon, MESH: Glucagon, digestive, oral, and skin physiology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Adult, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glucagon-like peptide-1, 3. Good health, MESH : Pyrazines, MESH: Pyrazines, Sitagliptin, hormones, hormone substitutes, and hormone antagonists, medicine.drug, endocrine system, medicine.medical_specialty, MESH: Glucose Tolerance Test, MESH : Male, MESH : Dipeptides, MESH : Receptors, Gastrointestinal Hormone, Incretin, 030209 endocrinology & metabolism, MESH: Insulin, MESH : Mice, Inbred C57BL, Biology, Sitagliptin Phosphate, MESH : Glucose Tolerance Test, MESH: Receptors, Glucagon, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, MESH : Triazoles, medicine, MESH : Middle Aged, MESH: Mice, Dipeptidyl peptidase-4, 030304 developmental biology, MESH: Humans, MESH: Receptors, Gastrointestinal Hormone, Insulin, MESH : Humans, MESH: Adult, MESH: Dipeptidyl Peptidase 4, MESH : Blood Glucose, MESH: Male, MESH: Triazoles, MESH : Dipeptidyl Peptidase 4, MESH: Blood Glucose, MESH : Animals
Abstract

International audience; Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.

Published
2011

7. Assessment of the early stage of cardiac remodeling of spontaneously hypertensive heart failure rats using the quantitative 3-dimensional analysis provided by acipimox-enhanced FDG-PET

Author

Patrick Lacolley, Mickael Lhuillier, Pierre Y. Marie, Huguette Louis, S. Poussier, Henri Boutley, Gilles Karcher, Simon N. Thornton, Fatiha Maskali, Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Faculté de Médecine [Nancy], Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), and Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)

Subjects
Male, Cardiac Catheterization, Time Factors, Cardiac fibrosis, medicine.medical_treatment, MESH: Rats, Inbred SHR, Rats, Inbred WKY, MESH: Stroke Volume, Ventricular Function, Left, MESH: Ventricular Function, Left, MESH: Hypertension, MESH: Fluorodeoxyglucose F18, Rats, Inbred SHR, MESH: Animals, Cardiac imaging, Cardiac catheterization, MESH: Lipid Metabolism, Ejection fraction, Ventricular Remodeling, MESH: Cardiac Catheterization, Stroke volume, MESH: Positron-Emission Tomography, MESH: Predictive Value of Tests, Pyrazines, MESH: Pyrazines, Hypertension, MESH: Fibrosis, Cardiology, cardiovascular system, Radiographic Image Interpretation, Computer-Assisted, Cardiology and Cardiovascular Medicine, MESH: Radiopharmaceuticals, MESH: Rats, Inbred WKY, medicine.medical_specialty, MESH: Rats, Heart Ventricles, MESH: Arterial Pressure, MESH: Ventricular Remodeling, MESH: Imaging, Three-Dimensional, Imaging, Three-Dimensional, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fluorodeoxyglucose F18, Predictive Value of Tests, Internal medicine, medicine, MESH: Radiographic Image Interpretation, Computer-Assisted, Animals, Arterial Pressure, Radiology, Nuclear Medicine and imaging, Ventricular remodeling, Heart Failure, business.industry, MESH: Time Factors, Stroke Volume, Lipid Metabolism, medicine.disease, Fibrosis, MESH: Male, Rats, Disease Models, Animal, Blood pressure, Endocrinology, Positron-Emission Tomography, Heart failure, MESH: Heart Failure, MESH: Heart Ventricles, Radiopharmaceuticals, MESH: Disease Models, Animal, business
Abstract

International audience; Spontaneously hypertensive heart failure rats (SHHF) appear to constitute an original model for analyzing the evolution of the metabolic syndrome towards heart failure. This study aimed to characterize early cardiac dysfunction and remodeling in SHHF rats: (1) as compared with spontaneously hypertensive rats (SHR) and with a control group of Kyoto rats (WKY), and (2) by using the 3-dimensional quantitative analysis provided by acipimox-enhanced positron emission tomography (PET) with (18)F-fluorodesoxyglucose (FDG). Left ventricular (LV) ejection fraction (EF) and volume were quantified by automatic software on the FDG-PET images recorded in SHR (n = 20), SHHF (n = 18) and WKY-rats (n = 19) at ages 3 or 10 months old. Arterial blood pressure was determined by cardiac catheterization and cardiac fibrosis was quantified after sacrifice. Blood pressure was similarly elevated in SHR and SHHF rats (respective systolic blood pressures at 10-months: 199 ± 39 vs. 205 ± 2 mmHg), but SHHF rats had higher body mass than SHR rats (at 10-months, 630 ± 36 vs. 413 ± 27 g, p < 0.05) and higher blood levels of cholesterol and of triglycerides. At 3 months, cardiac parameters did not show significant differences between groups but at 10-months, SHHF and SHR rats exhibited an enhancement in myocardial mass and fibrosis associated with a clear decline in LV-EF (SHHF: 46 ± 6 %; SHR: 47 ± 5 %) as compared with WKY (56 ± 6 %, p < 0.01 for both comparisons). Cardiac remodeling of SHHF rats was clearly observable by FDG-PET from the age of 10-months, but in a similar way to that observed for SHR rats, suggesting a predominant role of hypertension.

Published
2014

8. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS

Author

A. El Yamani, Roch Houot, J L Harousseau, Kamal Bouabdallah, Stéphane Courby, M. Ojeda Uribe, Nina Arakelyan, M. Alexis Vigier, Hervé Maisonneuve, Philippe Rodon, Caroline Dartigeas, S. Le Gouill, Remy Gressin, O. Tournilhac, Marie-Pierre Moles, Laurent Sutton, Luc Mathieu Fornecker, D. Assouline, Sylvie Caulet-Maugendre, Christiane Mounier, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hematology, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Department of clinical hematology, CHU Grenoble, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Nantes Angers Le Mans (UNAM), Clinical Haematology, CHU Hôtel-Dieu, Service d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre hospitalier du Mans, Centre Hospitalier Le Mans (CH Le Mans), Service greffe de moelle osseuse, 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), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre hospitalier La Roche-Sur-Yon, Université de Rennes (UR)-Hôpital Pontchaillou, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140

Subjects
Male, Oncology, medicine.medical_treatment, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell, Dexamethasone, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, rituximab, MESH: Aged, 80 and over, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, 0303 health sciences, Bortezomib, bortezomib, Hematology, MESH: Chlorambucil, Boronic Acids, Chemotherapy regimen, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Pyrazines, 030220 oncology & carcinogenesis, MESH: Pyrazines, MESH: Dexamethasone, Female, Rituximab, MESH: Boronic Acids, medicine.drug, medicine.medical_specialty, Vincristine, lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, elderly, Disease-Free Survival, 03 medical and health sciences, MESH: Doxorubicin, Internal medicine, medicine, Humans, MESH: Kaplan-Meier Estimate, Aged, 030304 developmental biology, mantle cell, Chemotherapy, MESH: Humans, Chlorambucil, business.industry, medicine.disease, MESH: Male, Surgery, Regimen, Doxorubicin, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Disease-Free Survival, Mantle cell lymphoma, MESH: Lymphoma, Mantle-Cell, business, MESH: Female
Abstract

International audience; BACKGROUND: There is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL. PATIENTS AND METHODS: Patients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C. RESULTS: Thirty-nine patients were enrolled. Median age was 72 years (65-80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity. CONCLUSION: The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.

Published
2012

9. Sitagliptin promotes macrophage-to-faeces reverse cholesterol transport through reduced intestinal cholesterol absorption in obese insulin resistant CETP-apoB100 transgenic mice

Author

François Briand, T. Sulpice, Quentin Thieblemont, Rémy Burcelin, Physiogenex, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise

Subjects
Blood Glucose, Male, Endocrinology, Diabetes and Metabolism, Mice, Obese, Type 2 diabetes, MESH: Metformin, MESH: Lipoproteins, HDL, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, MESH: Cholesterol, MESH: Animals, MESH: Mice, Obese, 0303 health sciences, MESH: Dipeptidyl-Peptidase IV Inhibitors, Reverse cholesterol transport, Metformin, 3. Good health, Cholesterol, MESH: Cholesterol Ester Transfer Proteins, Sitagliptin, MESH: Pyrazines, Pyrazines, Apolipoprotein B-100, Intestinal cholesterol absorption, lipids (amino acids, peptides, and proteins), Lipoproteins, HDL, medicine.drug, MESH: Diabetes Mellitus, Type 2, medicine.medical_specialty, MESH: Mice, Transgenic, MESH: Intestinal Absorption, MESH: Biological Transport, 030209 endocrinology & metabolism, Mice, Transgenic, Sitagliptin Phosphate, 03 medical and health sciences, Internal medicine, MESH: Hypoglycemic Agents, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Animals, Hypoglycemic Agents, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Apolipoprotein B-100, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Macrophages, MESH: Biological Markers, MESH: Macrophages, Biological Transport, Triazoles, medicine.disease, MESH: Male, Cholesterol Ester Transfer Proteins, chemistry, MESH: Triazoles, Diabetes Mellitus, Type 2, Intestinal Absorption, MESH: Blood Glucose, business, Biomarkers, Lipoprotein
Abstract

International audience; Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glycaemic control in type 2 diabetes, but their benefits on reverse cholesterol transport (RCT) remain unknown. We evaluated the effects of DPP-4i sitagliptin 500 mg/kg/day on RCT in obese insulin-resistant CETP-apoB100 transgenic mice. Metformin 300 mg/kg/day orally was used as a reference compound. Both metformin and sitagliptin showed the expected effects on glucose parameters. Although no significant effect was observed on total cholesterol and high-density lipoprotein (HDL) cholesterol levels, sitagliptin, but not metformin, increased faecal cholesterol mass excretion by 132% (p < 0.001 vs. vehicle), suggesting a potent effect on cholesterol metabolism. Mice were then injected i.p. with (3) H-cholesterol labelled macrophages to measure RCT over 48 h. Compared with vehicle, sitagliptin significantly increased macrophage-derived (3) H-cholesterol faecal excretion by 39%. Administration of (14) C-cholesterol labelled olive oil orally showed a significant reduction of (14) C-tracer plasma appearance over time with sitagliptin, indicating that this drug promotes RCT through reduced intestinal cholesterol absorption.

Published
2012

10. Bortezomib combined with low-dose cytarabine in Intermediate-2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM

Author

Natarajan-Amé, Shanti, Park, Sophie, Ades, Lionel, Vey, Norbert, Guerci-Bresler, Agnès, Cahn, Jean-Yves, Etienne, Gabriel, Bordessoule, Dominique, Ravoet, Christophe, Legros, Laurence, Cheze, Stephane, Stamatoullas, Aspasia, Berger, Elisabeth, Schmidt, Aline, Charbonnier, Aude, Chaury, Marie-Pierre, Braun, Thorsten, Fenaux, Pierre, Dreyfus, Francois, Renseigné, Non, Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hematology (IPC-Marseille), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hematology, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Centre Hospitalier de Jolimont-Lobbes, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP]

Subjects
Male, MESH: Anemia, Refractory, with Excess of Blasts, medicine.medical_treatment, Low dose cytarabine, Gastroenterology, Bortezomib, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, MESH: Cytarabine, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Treatment Outcome, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, Cytarabine, Hematology, MESH: Follow-Up Studies, Middle Aged, Boronic Acids, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Leukemia, Myeloid, Acute, Treatment Outcome, 030220 oncology & carcinogenesis, MESH: Pyrazines, MESH: Survival Analysis, Pyrazines, Toxicity, MESH: Boronic Acids, Drug Therapy, Combination, Female, MESH: Leukemia, Myeloid, Acute, MESH: Myelodysplastic Syndromes, medicine.drug, medicine.medical_specialty, MESH: Drug Administration Schedule, Drug Administration Schedule, 03 medical and health sciences, Internal medicine, medicine, Humans, In patient, 030304 developmental biology, Aged, Chemotherapy, MESH: Humans, Anemia, Refractory, with Excess of Blasts, business.industry, Myelodysplastic syndromes, medicine.disease, Survival Analysis, MESH: Male, MESH: Drug Therapy, Combination, Phase i ii, Myelodysplastic Syndromes, Immunology, Proteasome inhibitor, business, MESH: Female, Follow-Up Studies
Abstract

International audience; Marrow cells from patients with higher-risk myelodysplastic syndrome (MDS) exhibit constitutive nuclear factor (NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1*5 mg/m(2) , days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m(2) , then 20 mg/m(2) from days 1-14), every 28 d for four cycles. Median follow-up was 29*7 months. Responses were seen in 12 of the 43 patients (28%), including complete response (CR, n = 1), marrow-CR (n = 3), partial response (PR, n = 5) and haematological improvement (HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2*5% HI), compared to none in the 12 previously treated patients (P < 0*01). Responders had better overall survival (median 18*2 vs. 10 months). One CR and 3 marrow-CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes.

Published
2012

11. Primary Effusion Lymphoma Cell Death Induced by Bortezomib and AG 490 Activates Dendritic Cells through CD91

Author

Luigi Frati, Roberta Gonnella, Livia Di Renzo, Pankaj Trivedi, Valeria Conte, Alberto Faggioni, Lavinia Vittoria Lotti, Roberta Santarelli, Mara Cirone, Department of Experimental Medicine [Roma], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and This work was partially supported by grants from Ministero dell'Istruzione, dell'Universita ' e della Ricerca, Associazione Italiana per la ricerca sul Cancro, progetto strategico ISS 9ACF/1 of Ministero della salute, and Pasteur Cenci-Bolognetti foundation.

Subjects
Anatomy and Physiology, medicine.medical_treatment, lcsh:Medicine, Apoptosis, immunogenicity, Bortezomib, calreticulin, 0302 clinical medicine, Immune Physiology, hemic and lymphatic diseases, Molecular Cell Biology, MESH: Lymphoma, Primary Effusion, Signaling in Cellular Processes, Cytotoxic T cell, lcsh:Science, MESH: Phagocytosis, MESH: HSP70 Heat-Shock Proteins, 0303 health sciences, Multidisciplinary, MESH: Dendritic Cells, MESH: Kinetics, Chemistry, Tyrphostins, Boronic Acids, 3. Good health, Cell biology, Protein Transport, dying tumor cell, Oncology, Pyrazines, MESH: Pyrazines, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Boronic Acids, Primary effusion lymphoma, Cellular Types, Low Density Lipoprotein Receptor-Related Protein-1, Research Article, Signal Transduction, medicine.drug, Programmed cell death, MESH: Protein Transport, MESH: Calreticulin, Immunology, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, 03 medical and health sciences, Immune system, Phagocytosis, Lymphoma, Primary Effusion, medicine, MESH: HSP90 Heat-Shock Proteins, Humans, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, MESH: Tyrphostins, Biology, 030304 developmental biology, MESH: Humans, MESH: Apoptosis, lcsh:R, MESH: Low Density Lipoprotein Receptor-Related Protein-1, Dendritic Cells, Immunotherapy, medicine.disease, MESH: Cell Line, Kinetics, Cancer cell, Cancer research, MESH: Antineoplastic Agents, lcsh:Q, Clinical Immunology, 030215 immunology
Abstract

International audience; To understand how cytotoxic agent-induced cancer cell death affects the immune system is of fundamental importance to stimulate immune response to counteract the high mortality due to cancer. Here we compared the immunogenicity of Primary Effusion Lymphoma (PEL) cell death induced by anticancer drug Bortezomib (Velcade) and Tyrphostin AG 490, a Janus Activated Kinase 2/signal trasducer and activator of transcription-3 (JAK2/STAT3) inhibitor. We show that both treatments were able to induce PEL apoptosis with similar kinetics and promote dendritic cells (DC) maturation. The surface expression of molecules involved in immune activation, namely calreticulin (CRT), heat shock proteins (HSP) 90 and 70 increased in dying cells. This was correlated with DC activation. We found that PEL cell death induced by Bortezomib was more effective in inducing uptake by DC compared to AG 490 or combination of both drugs. However the DC activation induced by all treatments was completely inhibited when these cells were pretreated with a neutralizing antiboby directed against the HSP90/70 and CRT common receptor, CD91. The activation of DC by Bortezomib and AG 490 treated PEL cells, as seen in the present study, might have important implications for a combined chemo and immunotherapy in such patients.

Published
2012

12. [Renal disorders associated with monoclonal gammopathies: diagnostic and therapeutic progress]

Author

Bridoux, Franck, Delbes, Sébastien, Sirac, Christophe, Pourreau, François, Puyade, Matthieu, Desport, Estelle, Jaccard, Arnaud, Fermand, Jean-Paul, Touchard, Guy, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP]

Subjects
MESH: Immunoglobulin Light Chains, Biopsy, Paraproteinemias, Kidney, Dexamethasone, MESH: Kidney Transplantation, Bortezomib, MESH: Biopsy, MESH: Melphalan, MESH: Paraproteinemias, Humans, MESH: Amyloidosis, Melphalan, MESH: Kidney Diseases, MESH: Humans, Plasma Exchange, MESH: Heart Transplantation, MESH: Kidney, Amyloidosis, MESH: Plasma Exchange, Boronic Acids, Kidney Transplantation, MESH: Pyrazines, MESH: Dexamethasone, Pyrazines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Heart Transplantation, MESH: Boronic Acids, Immunoglobulin Light Chains, Kidney Diseases, Immunoglobulin Heavy Chains, MESH: Immunoglobulin Heavy Chains
Abstract

International audience; Various renal disorders are associated with monoclonal gammopathies, secondary to tissue deposition or precipitation of a monoclonal immunoglobulin (Ig) or a fragment thereof (isolated Ig light chain or heavy chain). They are classified according to the localization of renal lesions, either glomerular or tubular and to the pattern of ultrastructural organization of Ig deposits. Renal disease in monoclonal gammopathies may be isolated, or associated with various systemic symptoms particularly in AL amyloidosis, Randall-type monoclonal Ig deposition disease and monoclonal cryoglobulinemias. Except for myeloma cast nephropathy, which occurs in the setting of high-mass myeloma and is recognized after electrophoretic analysis of proteinuria and AL amyloidosis, which diagnosis is usually made after pathological examination of non-invasive tissue specimens (i.e. abdominal fat or minor salivary glands), a kidney biopsy is required to identify the other types of renal disorders associated with monoclonal gammopathies and to estimate renal prognosis. Renal pathological diagnosis is difficult and relies on careful examination of kidney biopsy samples, by light microscopy, immunofluorescence studies using conjugates specific for Ig light and heavy chains, IgG sub-classes and heavy chain constant domains and by electron microscopy. In some cases, additional studies are required to identify the nature of deposits, such as immuno-electron microscopy or mass spectrometric-based proteomic analysis after laser dissection. In patients with renal disorders related to Ig light chain precipitation or deposition (myeloma cast nephropathy, AL amyloidosis, Randall-type light chain deposition disease), measurement of serum free light chains at baseline and throughout follow-up is mandatory to evaluate clonal response to chemotherapy. A more than or equal to 50% decrease in serum free light chain levels is associated with increased renal and patient survival. In AL amyloidosis, serum levels of markers of cardiac disease (NT-proBNP and troponin) are also closely associated with prognosis. Efficient chemotherapy, tailored to the underlying plasma cell or lymphoproliferative disorder and adapted to renal function, should be promptly introduced, even in the absence of overt malignant haematological disease. Renal prognosis and patient survival (particularly in AL amyloidosis and cast nephropathy) are closely associated with the rapid achievement of an haematological response. The combination of melphalan plus dexamethasone (MDex) is currently used as first-line chemotherapy in systemic AL amyloidosis. Bortezomib-based regimens are commonly employed as first-line treatment in myeloma cast nephropathy and Randall-type monoclonal Ig deposition disease and as second line therapy in AL amyloidosis patients with advanced cardiomyopathy or refractory to previous chemotherapy. Solid organ transplantation (heart and kidney) should be considered in patients with AL amyloidosis or Randall-type monoclonal Ig deposition disease and advanced cardiac or renal failure. Prolonged graft and patient survival may be obtained, providing that recipients do not have other severe organ involvement or symptomatic myeloma and that haematological remission has been achieved with chemotherapy before or after organ transplantation.

Published
2011

13. [Current treatment of AL amyloidosis]

Author

Desport, Estelle, Moumas, Eric, Abraham, Julie, Delbès, Sébastien, Lacotte-Thierry, Laurence, Touchard, Guy, Fermand, Jean-Paul, Bridoux, Franck, Jaccard, Arnaud, Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Immunoglobulin Light Chains, Consensus Development Conferences as Topic, Paraproteinemias, Kaplan-Meier Estimate, Dexamethasone, MESH: Kidney Transplantation, Bortezomib, MESH: Paraproteinemias, Natriuretic Peptide, Brain, MESH: Renal Dialysis, MESH: Natriuretic Peptide, Brain, MESH: Peptide Fragments, Lenalidomide, Melphalan, Randomized Controlled Trials as Topic, MESH: Thalidomide, MESH: Heart Transplantation, Amyloidosis, Prognosis, Boronic Acids, Thalidomide, MESH: Kidney Failure, Chronic, Pyrazines, MESH: Paraproteins, MESH: Pyrazines, MESH: Dexamethasone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Therapy, Combination, MESH: Boronic Acids, Cardiomyopathies, Amyloid, MESH: Prognosis, MESH: Melphalan, Renal Dialysis, Humans, MESH: Amyloidosis, MESH: Kaplan-Meier Estimate, MESH: Amyloid, MESH: Humans, MESH: Consensus Development Conferences as Topic, MESH: Biological Markers, Kidney Transplantation, Peptide Fragments, MESH: Drug Therapy, Combination, MESH: Randomized Controlled Trials as Topic, MESH: Cardiomyopathies, Heart Transplantation, Kidney Failure, Chronic, Immunoglobulin Light Chains, Biomarkers, Paraproteins
Abstract

International audience; Systemic AL amyloidosis is a rare complication of monoclonal gammopathies. Renal manifestations are frequent, mostly characterized by heavy proteinuria, with nephrotic syndrome and renal failure in more than half of the patients at diagnosis. Without treatment, median survival does not exceed 12 months. Amyloid heart disease and diffusion of amyloid deposits are associated with reduced survival. Treatment of systemic AL amyloidosis has been profoundly modified with the introduction of international criteria for the definition of organ involvement and hematologic response, and with the use of sensitive tests for the measurement of serum-free light chain levels. Melphalan plus dexamethasone is now established as the gold standard for first line treatment of systemic AL, with similar efficacy and reduced treatment-related mortality compared to high-dose therapy. Modern chemotherapy regimens, based on the use of novel agents such as bortezomib and lenalidomide, might further improve patient survival.

Published
2011

14. Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(Phenyl) pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents

Author

Olivier Lozach, Laurent Meijer, Valérie Bénéteau, Krzysztof Lewiński, Stéphane Bourg, Sylvain Routier, Paméla Kassis, Christiane Guillouzo, Jean-Yves Mérour, Lionel Colliandre, Joanna Brzeszcz, Rémi Le Guével, Institut de Chimie Organique et Analytique (ICOA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Faculty of Chemistry, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), ManRos Therapeutics, Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Indoles, Molecular model, Pyridines, CDK, Molecular Conformation, Chemistry Techniques, Synthetic, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, GSK3, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Drug Discovery, MESH: Protein Kinase Inhibitors, Microwaves, ComputingMilieux_MISCELLANEOUS, MESH: Indoles, 0303 health sciences, biology, General Medicine, Pyrazines, MESH: Pyrazines, pyrazine, cytotoxicity, Selectivity, MESH: Palladium, Palladium, MESH: Models, Molecular, pyridine, MESH: Cell Line, Tumor, Pyrazine, Stereochemistry, Antineoplastic Agents, MESH: Microwaves, Catalysis, 03 medical and health sciences, Structure-Activity Relationship, Cyclin-dependent kinase, Cell Line, Tumor, Pyridine, Humans, Protein Kinase Inhibitors, MESH: Protein Kinases, 030304 developmental biology, Pharmacology, Indole test, MESH: Molecular Conformation, MESH: Humans, molecular modeling, 010405 organic chemistry, Organic Chemistry, MESH: Pyridines, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DYRK1A, MESH: Catalysis, 0104 chemical sciences, Stille reaction, indole, chemistry, Docking (molecular), biology.protein, MESH: Antineoplastic Agents, MESH: Chemistry Techniques, Synthetic, Protein Kinases
Abstract

International audience; We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine, 3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as potential CDK inhibitors. Indoles and phenyls were used to generate several substitutions of the pyridine and pyrazine rings. The synthesis included Stille or Suzuki type reactions, which were carried out on the 3,5-dibromopyridine, 2,4-dichloropyridine and 2,6-dichloro-1-4-pyrazine moieties. Cell effects of the V-shaped family were in the micromolar range. Kinase assays were conducted and showed that compound 11 inhibited CDK5 with an inhibitory concentration of 160 nM with a moderate selectivity over GSK3 compared to the reference C which exhibited a slightly lower activity on CDK5 (1.5 μM). Compound 11 was also found to be the most potent compound in the series and was identified as a new lead for DYRK1A inhibitor discovery (IC(50) = 60 nM). Docking studies were carried out in order to investigate the inhibition of DYRK1A.

Published
2011

15. Renal improvement in myeloma with plasma exchange

Author

Hutchison, Colin, Bridoux, Franck, Fermand, Jean-Paul, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
MESH: Immunoglobulin Light Chains, MESH: Combined Modality Therapy, MESH: Humans, MESH: Acute Kidney Injury, MESH: Pyrazines, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Boronic Acids, MESH: Multiple Myeloma, MESH: Plasma Exchange, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2011

16. Inhibition of GST-pi nuclear transfer increases mantle cell lymphoma sensitivity to cisplatin, cytarabine, gemcitabine, bortezomib and doxorubicin

Author

Rolland, Delphine, Raharijaona, Mahatsangy, Barbarat, Aurélie, Houlgatte, Rémi, Thieblemont, Catherine, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie biologique [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'onco-hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Issartel, Jean-Paul

Subjects
MESH: Cell Line, Tumor, Active Transport, Cell Nucleus, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Growth Processes, Lymphoma, Mantle-Cell, MESH: Active Transport, Cell Nucleus, Deoxycytidine, Bortezomib, MESH: Doxorubicin, MESH: Lectins, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, Cell Line, Tumor, Lectins, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Humans, MESH: Cytarabine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], neoplasms, MESH: Glutathione S-Transferase pi, MESH: Humans, MESH: Drug Screening Assays, Antitumor, MESH: Deoxycytidine, Cytarabine, Boronic Acids, Gemcitabine, MESH: Antineoplastic Combined Chemotherapy Protocols, Glutathione S-Transferase pi, MESH: Cisplatin, Doxorubicin, Pyrazines, MESH: Pyrazines, MESH: Cell Growth Processes, MESH: Antineoplastic Agents, MESH: Boronic Acids, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Lymphoma, Mantle-Cell, Cisplatin, Drug Screening Assays, Antitumor
Abstract

International audience; PURPOSE: Mantle cell lymphoma (MCL) is a chemoresistant lymphoma overexpressing the class pi glutathione-S-transferase (GST-pi). The nuclear localisation of GST-pi is induced by chemotherapy and is correlated to cell resistance. In this study, the effect of the Agaricus bisporus lectin (ABL), a GST-pi nuclear transfer inhibitor, on the chemosensitivity of MCL cells was investigated. METHODS: The proliferation of three MCL cell lines was evaluated in the presence of doxorubicin (DOX), cisplatin (CDDP), cytarabine (Ara-C), gemcitabine (GEM) or bortezomib with or without ABL pre-treatment. RESULTS: The cytotoxic activities of CDDP, Ara-C, GEM and bortezomib were increased in all cell lines. The DOX cytotoxic activity was enhanced in two of three cell lines. The inhibition of GST-pi nuclear transfer led to the potentialisation of all drug combinations. CONCLUSION: The inhibition of the nuclear transfer of GST-pi increases the MCL sensitivity to DOX, CDDP, Ara-C, GEM and bortezomib, alone or in combination.

Published
2010

17. Involvement of pregnane X receptor in the regulation of CYP2B6 gene expression by oltipraz in human hepatocytes

Author

Fabrice Morel, Amélie Piton, André Guillouzo, Claudine Rauch, Sophie Langouët, Détoxication et réparation tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hépatotoxicité et xénobiotiques, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Receptors, Steroid, CYP2B6, Human hepatocytes, MESH: Aryl Hydrocarbon Hydroxylases, Pharmacology, Oltipraz, Toxicology, MESH: Hepatocytes, chemistry.chemical_compound, MESH: Liver Neoplasms, Testosterone, MESH: Carcinoma, Hepatocellular, 0303 health sciences, Pregnane X receptor, 030302 biochemistry & molecular biology, Liver Neoplasms, General Medicine, MESH: Gene Expression Regulation, Cell biology, Pyrazines, MESH: Pyrazines, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Aryl Hydrocarbon Hydroxylases, Carcinoma, Hepatocellular, MESH: Cell Line, Tumor, MESH: Oxidoreductases, N-Demethylating, MESH: Hydroxylation, MESH: Testosterone, Thiophenes, Biology, Retinoid X receptor, Hydroxylation, Nrf2, 03 medical and health sciences, CYP2B6 Gene, MESH: Anticarcinogenic Agents, Cell Line, Tumor, Anticarcinogenic Agents, Humans, RNA, Messenger, Testosterone hydroxylation, Gene, 030304 developmental biology, MESH: RNA, Messenger, Messenger RNA, MESH: Humans, Thiones, Oxidoreductases, N-Demethylating, Cytochrome P-450 CYP2B6, chemistry, Gene Expression Regulation, Microsome, Hepatocytes, MESH: Receptors, Steroid
Abstract

International audience; Oltipraz, a synthetic derivative of the cruciferous vegetable product 1,2-dithiole-3-thione, is considered as a potent chemoprotectant. Previously, we have demonstrated that CYP2B6 expression is induced in cultured human hepatocytes by a 24h treatment with oltipraz. The aim of this study was to further determine mechanisms involved in the regulation of CYP2B6 by this compound. An increase of CYP2B6 mRNA is observed after a 4h exposure and maximum induction is reached after 24h. The rapid induction of CYP2B6 mRNA in oltipraz-treated cells suggests a transcriptional activation of corresponding gene. To test this hypothesis, we performed transient transfections with constructs containing the CYP2B6 gene 5'-flanking region upstream of the luciferase gene in order to measure the transcriptional activity of CYP2B6 gene in human hepatoma HepG2 cells, in absence or presence of oltipraz. The results demonstrate that transcriptional activation of CYP2B6 gene is mediated mainly by the pregnane X receptor (PXR) and the Phenobarbital Responsive Element Module (PBREM). The nuclear factor-erythroid 2-related factor 2 (Nrf2) and an antioxidant responsive element (ARE), located upstream the PBREM, might also have a role in this activation but their involvement remains unclear. Despite increasing CYP2B6 apoprotein levels in human hepatocytes, oltipraz has little effect, if any, on testosterone 16beta-hydroxylation which is catalyzed by CYP2B6. This can be explained by a dose-dependent inhibition of CYP2B6 activity in presence of oltipraz as demonstrated with human hepatocyte microsomes. Altogether, this study provides the first demonstration of PXR involvement in oltipraz transcriptional activation of CYP2B6 gene and of the inhibitory effect of oltipraz on CYP2B6 activity.

Published
2010

18. Synthesis of new 4-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors

Author

Daniel-Henri Caignard, Patrick Dallemagne, Stéphane Larrouture, Christian Jarry, Jean Guillon, Claudine Quentin, Annie Lagardère, Céline Vidaillac, Stéphane Moreau, Corinne Arpin, Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), and Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
Staphylococcus aureus, Pyrazine, Stereochemistry, MESH: Molecular Structure, Microbial Sensitivity Tests, chemistry.chemical_compound, Quinoxaline, Bacterial Proteins, MESH: Quinoxalines, Drug Resistance, Multiple, Bacterial, Quinoxalines, Drug Discovery, MESH: Staphylococcus aureus, MESH: Bacterial Proteins, Pharmacology, MESH: Microbial Sensitivity Tests, Molecular Structure, Chemistry, General Medicine, MESH: Drug Resistance, Multiple, Bacterial, Multiple drug resistance, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Pyrazines, MESH: Pyrazines, Efflux, Bioisostere, Multidrug Resistance-Associated Proteins, MESH: Multidrug Resistance-Associated Proteins
Abstract

The synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives la-1 is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio]pyrrolo[1,2- a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue la, opening the way to further pharmacomodulation.

Published
2007

19. Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes

Author

Emilie Jigorel, Claire Boursier-Neyret, Yannick Parmentier, Marc Le Vee, Olivier Fardel, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
MESH: Neoplasm Proteins, Receptors, Steroid, Polychlorinated Dibenzodioxins, Receptors, Drug, Pharmaceutical Science, Receptors, Cytoplasmic and Nuclear, ATP-binding cassette transporter, Pharmacology, 030226 pharmacology & pharmacy, MESH: Membrane Transport Proteins, MESH: Hepatocytes, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Constitutive androstane receptor, ATP Binding Cassette Transporter, Subfamily G, Member 2, Receptor, 0303 health sciences, Pregnane X receptor, biology, Symporters, Reverse Transcriptase Polymerase Chain Reaction, Multidrug resistance-associated protein 2, MESH: NF-E2-Related Factor 2, Pregnane X Receptor, MESH: Transcription Factors, MESH: Phenobarbital, MESH: Gene Expression Regulation, Multidrug Resistance-Associated Protein 2, 3. Good health, Neoplasm Proteins, Phenobarbital, Pyrazines, MESH: Pyrazines, [SDV.TOX]Life Sciences [q-bio]/Toxicology, MESH: ATP-Binding Cassette Transporters, Multidrug Resistance-Associated Proteins, Rifampin, MESH: Multidrug Resistance-Associated Proteins, Adult, MESH: Symporters, MESH: Xenobiotics, medicine.medical_specialty, MESH: P-Glycoprotein, NF-E2-Related Factor 2, Thiophenes, MESH: Receptors, Cytoplasmic and Nuclear, Xenobiotics, 03 medical and health sciences, MESH: Receptors, Drug, Internal medicine, medicine, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, RNA, Messenger, Constitutive Androstane Receptor, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Activator (genetics), Membrane Transport Proteins, Thiones, Transporter, MESH: Adult, Aryl hydrocarbon receptor, MESH: Rifampin, MESH: Tetrachlorodibenzodioxin, Endocrinology, Gene Expression Regulation, Receptors, Aryl Hydrocarbon, MESH: Receptors, Aryl Hydrocarbon, biology.protein, Hepatocytes, ATP-Binding Cassette Transporters, Transcription Factors, MESH: Receptors, Steroid
Abstract

International audience; Sinusoidal and canalicular hepatic drug transporters constitute key factors involved in drug elimination from liver. Regulation of their expression via activation of xenosensors, such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and nuclear factor E2-related factor 2 (Nrf2), remains incompletely characterized. The present study was therefore designed to carefully analyze expression of major drug transporters in primary human hepatocytes exposed to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) (an AhR activator), rifampicin (RIF) (a PXR activator), phenobarbital (PB) (a CAR activator), and oltipraz (OPZ) (a Nrf2 activator), using mainly reverse transcription-real time polymerase chain reaction assays. With a threshold corresponding to a 1.5-fold factor change in mRNA levels, observed in at least three of seven independent human hepatocyte cultures, efflux transporters such as MDR1, MRP2 and BCRP were up-regulated by PB, RIF, and OPZ, whereas MRP3 was induced by OPZ and RIF. MDR1 and BCRP expression was also increased by TCDD- and RIF-augmented mRNA levels of the influx transporter OATP-C. Bile acid transporters, i.e., bile salt export pump and Na(+)-taurocholate cotransporting polypeptide, and the sinusoidal transporter, OAT2, were down-regulated by all the tested chemicals. Influx transporters such as OCT1, OATP-B, and OATP8 were repressed by PB and TCDD. PB also decreased MRP6 expression, whereas mRNA levels of OCT1 and OATP8 were down-regulated by RIF and OPZ, respectively. Taken together, these data establish a complex pattern of transporter regulation by xenobiotics in human hepatocytes, in addition to interindividual variability in responsiveness. This may deserve further attention with respect to drug-drug interactions and adverse effects of hepatic drugs.

Published
2006

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