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Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention. Design : Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention. Results : In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients. Conclusion : Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases. journal article 2020 Mar 26 2020 03 26 imported This work was supported by ARC, Paris and Institut Hospitalo-Universitaire,Strasbourg (TheraHCC and TheraHCC2.0 IHUARC IHU201301187 and IHUC201901299 TFB), the Foundation of the University of Strasbourg and Roche Institute (HEPKIN), the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (2017/1633), the US Department of Defense (W81XWH-16-1-0363 to TFB and YH), the Cancéropôle du Grand-Est, the National Institutes of Health (DK099558 and T32CA073145-20 to SL, R01CA233794 to YH and TFB, NCI 1R21CA209940-01A1 to TFB), AMED (19fk0210020h0003 to KC), AASLD Foundation (Pinnacle Research Award) and the Massachusetts General Hospital Department of Surgery (KKT) and the Cancer Prevention & Research Institute of Texas RR180016 to YH. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and PLAN CANCER 2014-2019 HCCMICTAR and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the Future Program, INCa (National Institute for Cancer) and INSERM.

Introduction Pris par un profond doute au sujet de la fidélité de son épouse et glissant, angoissé, dans une grave impasse dont il pense ne pouvoir sortir que par la mort, la folie, ou la religion, Ichirô, le personnage principal de L'Homme qui va (Kôjin, 1912-1913) de Natsume Sôseki (1867-1916), aboutit à ce terrible constat : Ce destin auquel toute l'humanité devrait arriver au bout de quelques siècles, je dois le subir moi seul, dans ma seule vie, et cela m'effraie. S'il ne s'agissait enco...

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Dans le dernier paragraphe de Proust, si Samuel Beckett pense l’essence de la musique en se fondant sur un chapitre du Monde comme volonté et comme représentation d’Arthur Schopenhauer, sa démarche ne correspond pas tout à fait à celle du philosophe. Les termes avec lesquels Beckett définit la musique ne viennent pas moins du lexique de Proust que de celui de Schopenhauer. C’est sa lecture des scènes consacrées à l’écoute de la musique dans le texte proustien qui fait l’objet de notre analyse.

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Au cours de la traduction en japonais des Difficultés sur la religion, nous avons rencontré quelques énigmes qui semblent au premier abord incompréhensibles si on ne veut pas y voir d'autres mains que celles de Robert Challe, de Naigeon et de d'Holbach. Cet article essaie de relever ces énigmes pour montrer que les Difficultés et Le Militaire philosophe soulèvent des questions qui n'ont pas encore trouvé de réponses, et qui sont emblématiques des manuscrits philosophiques clandestins., While translating Difficultés sur la religion into Japanese, we came across certain enigmas that seemed at first sight incomprehensible if one does not wish to understand them as emanating from Robert Challe, Naigeon and Holbach. This article attempts to address these enigmas in order to show that the Difficultés and Le Militaire philosophe raise questions that are still unanswered and are emblematic of clandestine philosophical manuscripts.

Tyzzer's organism from mice propagated more remarkably in hepatocytes than in yolk-sac epithelial cells producing confluent necrosis of the liver after intravenous as well as intravitelline inoculation. Some lesions with bacterial growth were also produced in the heart muscles and kidneys. The organisms from mouse, rat, hamster and kitten were shown to be equally pathogenic for chick embryos.

The effects of 14 guanidino compounds on the activity of rabbit brain choline acetyltransferase (CAT) and acetylcholine esterase (ACE) have been studied, comparatively with that of pentylentetrazol. No guanidino compound examined nor pentylentetrazol had an effect on CAT activity. 4 of them showed a moderate inhibitory effect on ACE, of the same order of magnitude as that of pentylentetrazol, but significantly lower than that of the specific inhibitors eserine and mytelase.

Techniques of whole body roentgeno-angiography in the mouse, rat, hamster, guinea pig and rabbit were described. The procedure for forwarding the contrast media to arterioles was ameliorated. In order to visualize the arteries of limbs and tail as distinctly as those of the trunk, extremities were shielded with aluminous plates.

The course of infection with low-virulence mouse hepatitis virus in nude mice was modified by transfer of sensitized or non-sensitized heterozygous spleen cells after the infection had been established. Infected nude mice having received the transfer of heterozygous spleen cells seem to have more severe signs of illness at early stage of infection than those without the heterozygous cell transfer, while they resisted against the infection.

After intraperitoneal inoculation with mouse hepatitis virus (MHv) into mice, the excretory cells of the pancreas showed a marked vacuolar degeneration concomitantly with hepatitis. MHV-specific antigen was evidenced in the cytoplasm of infected cells. Electron microscopy revealed a number of virions within the matrix, spaces of the endoplasmic reticulum and areas of focal cytoplasmic necrosis. The virus titer of the pancreas was equal or superior to that of the liver at least in early stage of infection.

Nude (nu/nu) mice failed to resist to virulent mouse hepatitis virus (MHV) infection after vaccination with inactivated virus. Resistance was induced in nu/nu mice by the transfer of spleen cells from heterozygous haired (nu/ +) mice concomitantly with the vaccination, and the effect was more remarkable with spleen cells from immunized nu/ + mice. Antibody was demonstrable in nu/nu mice having received nu/ + cells and survived challenge infection.

Nude (nu/nu) mice fail to resist to challenge infection of Tyzzer's disease after pretreatment with formalin-killed organisms that was effective for protecting heterozygous haired (nu/ł) mice from challenge. Resistance was induced nu/nu mice after the transfer of spleen cells from immunized nu/ł and concomitant formalin vaccine treatment.

Cette région fait partie de la zone subalpine méridionale, plus précisément de la branche est de l'Arc de Castellane ( environs de St Auban ). On y observe des terrains sédimentaires secondaires et tertiaires. fortement plissés, et qui appartiennent à la couverture sédimentaire de la zone externe alpine, dont le socle n'apparait qu'à plusieurs dizaines de kilomètres au Nord, dans le dôme permien de Barrot. La structure actelle résulte de la superposition de plusieurs phases tectoniques , parmi lesquelles on distingue facilement une phase anté-nummulitique relativement tranquille déformée par une ou plusieurs phases ultérieures, difficiles à dater du fait de l'absence de terrains plus récents que l'Oligocène inférieur. Au cours de ces derniers mouvements se sont produits des chevauchements vers le Sud qui sont le trait le plus caractéristique de la structure de la région. Il en résulte des redoublements de la série, en particulier du niveau repère que constituent les calcaires du Jurassique supérieur, ossature du relief. qui forment une succession de barres regardant au Sud et dominant des dépressions synclinales. Les faciès du Mésozoique et du Nummulitique montrent de nombreuses variations, car cette légion se situe : - au Jurassique et au Crétacé: à la limite des domaines provençaux et vocontiens ; - au Nummulitique: en bordure du bassin marin alpin. le but essentiel de ce mémoire est l'explication d 'une carte détaillée au 1/20 000 destinée à être utilisée pour la publication ultérieure de la feuille Castellane au 1/50 000 de la carte géologique de la France. Nous nous sommes donc surtout attachés à décrire les structures plutôt qu'a en détailler la stratigraphie ., Pas de résumé