Search

La valeur en sante, consistant a produire de meilleurs resultats tout en maitrisant les couts, necessite d’etablir des mesures normees des resultats, prenant en compte ce qui importe aux patients. Le but etait de construire ce type de questionnaire pour le parcours de soins des patients atteint d’un cancer du pancreas. Methodologie Un groupe de travail multidisciplinaire (GTM), associant des patients a fait une revue systematique des resultats utilises dans les essais cliniques a partir de clinicaltrials.gov., et a selectionne les plus pertinents. Un comite international multidisciplinaire associant des patients a valide par methode Delphi le questionnaire. Resultats 570 etudes cliniques ont ete selectionnees et 3370 parametres ont ete repertories (cliniques = CROM, et de qualite de vie = PROM). De janvier 2018 a juin 2018, parmi ces parametres, le GTM a propose une liste de 102 parametres (92 CROM et 10 PROM) au comite international. Un ensemble de 78 variables a ete retenu apres les 4 etapes du vote Delphi pour constituer le questionnaire final incluant des PROM par l’utilisation de « Fact-Hep ». Conclusions Pour la premiere fois, un questionnaire standardise concernant le cancer du pancreas, axes sur le patient, a ete mis etabli, permettant desormais son deploiement.

BACKGROUND: Global health systems are shifting toward value-based health care to improve patient outcomes in the face of rising health care costs. The challenge is to identify standardized outcome measurements that allow optimal quality-of-care monitoring and comparison to optimize medical practices and patient pathways. A common outcomes definition is required, including medical results (Clinical Reported Outcomes Measurements [CROMs]) and quality-of-life components that matter most to patients (Patient-Reported Outcomes Measurements [PROMs]), which are particularly important for severe pathologies with short life expectancy such as pancreatic cancer. This study aimed to create standardized metrics that could be used for outcomes analysis of pancreatic cancer care. METHODS: A multidisciplinary working group (WG) was assembled. A systematic review was performed to collect the most used outcomes in clinical studies of pancreatic cancers. The study reviewed 570 studies published in the last 10 years. From these studies, 3370 outcomes, including CROMs, and PROMs, were listed and prioritized. The WG reached a consensus on key outcomes, proposed groupings for CROMs and PROMs, identified existing questionnaires that could be used for PROMs collection, and set the timeline for data collection. To refine and validate the final outcomes set, an international external committee completed a Delphi process (two rounds for both CROMS and PROMs). RESULTS: After the systematic literature review, the WG selected 102 outcomes (92 CROMs and 10 PROMs) for submission to the international Delphi vote committee. The committee retrained 89 outcomes (78 CROMs and 11 PROMs). For the PROMs, the WG and the international external committee chose a validated questionnaire, the Functional Assessment of Cancer Therapy-Hepatobiliary, which covers all of the 11 selected PROMs. CONCLUSIONS: A standardized set of outcome measures that need to be validated through international health outcome comparisons and quality-of-care assessments was built. Pilot projects are underway to test and optimize the approach in real-life conditions.

ObjectiveInfection of human hepatocytes by the hepatitis C virus (HCV) is a multistep process involving both viral and host factors. microRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Given that miRNAs were indicated to regulate between 30% and 75% of all human genes, we aimed to investigate the functional and regulatory role of miRNAs for the HCV life cycle.DesignTo systematically reveal human miRNAs affecting the HCV life cycle, we performed a two-step functional high-throughput miRNA mimic screen in Huh7.5.1 cells infected with recombinant cell culture-derived HCV. miRNA targeting was then assessed using a combination of computational and functional approaches.ResultsWe uncovered miR-501-3p and miR-619-3p as novel modulators of HCV assembly/release. We discovered that these miRNAs regulate O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) protein expression and identified OGT and O-GlcNAcylation as regulators of HCV morphogenesis and infectivity. Furthermore, increased OGT expression in patient-derived liver tissue was associated with HCV-induced liver disease and cancer.ConclusionmiR-501-3p and miR-619-3p and their target OGT are previously undiscovered regulatory host factors for HCV assembly and infectivity. In addition to its effect on HCV morphogenesis, OGT may play a role in HCV-induced liver disease and hepatocarcinogenesis.

> Les elements genetiques mobiles representent une fraction considerable de notre genome et les mammiferes ont developpe plusieurs facteurs cellulaires restreignant l’expansion des transposons, retrotransposons et retrovirus. Plusieurs facteurs de restriction inhibant la replication des retrovirus, dont les virus de l’immunodeficience humaine de types 1 et 2 (VIH-1, VIH-2), ont ainsi ete identifies : TRIM5a (tripartite motif-containing protein 5a), la tetherine, SAMHD1 (SAM domain and HD domain 1), et plusieurs membres de la famille des cytidines desaminases APOBEC-3 (apolipoprotein B mRNAediting, enzyme-catalytic, polypeptide-like 3) [1-3]. Parmi ces derniers, A-3G et A-3F, qui sont exprimes dans les cellules cibles naturelles des VIH-1 et VIH-2, sont les plus importants [1, 3]. Les retrovirus ont cependant acquis la capacite de contourner ces facteurs de restriction. Certains ont developpe des proteines dites accessoires dans ce seul but : c’est le cas du facteur d’infectiosite viral (Vif) et de la proteine virale U (Vpu) des VIH-1 et VIH-2, ainsi que de la proteine virale X (Vpx) du VIH-2, qui contrecarrent respectivement A-3C/3DE/3F/3G/3H [1, 3], la tetherine [1] et SAMHD1 [2]. La neutralisation des facteurs de restriction par les retrovirus implique tres souvent le detournement de la voie de degradation des proteines cellulaires par le proteasome en reponse a leur polyubiquitination. Ubiquitinylation des facteurs de restriction par la proteine virale Vif L’ubiquitinylation des proteines eucaryotes fait tout d’abord intervenir une des deux enzymes activatrices, E1, qui transfere l’ubiquitine a l’une des enzymes de conjugaison, E2 ; enfin, une ubiquitine ligase (E3, il en existe plusieurs centaines), transfere l’ubiquitine aux substrats specifiques. Trois proteines accessoires du VIH-1, Vif, Vpu et Vpr sont connues pour detourner trois ubiquitine ligases E3 differentes appartenant a la famille des cullin-RING E3 ligases. La proteine Vif du VIH-1 possede en son centre un motif HCCH liant le zinc et une boite culline qui permettent le recrutement de la culline 5 (Cul-5), Cul-5 etant capable de lier Rbx-2, une proteine possedant un domaine RING. Vif possede en outre dans sa region carboxy-terminale un motif appele SOCS (suppressor of cytokine signaling) box qui recrute l’elongine C (Elo-C) qui forme un heterodimere avec l’elongine B (Elo-B) (Figure 1, voie B). Le complexe Cul-5/Rbx2/Elo-B/Elo-C ainsi recrute par la proteine Vif permet l’ubiquitinylation d’A-3G/A-3F, orientant ainsi ces proteines vers la degradation par le proteasome (Figure 1, voie B).

Hepatitis C virus (HCV)-induced chronic liver disease is a leading cause of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in homeostasis within the liver, and deregulation of miRNAs has been associated with liver disease, including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here we combined a hepatocyte-like cell-based model system, high-throughput small RNA sequencing, computational analysis, and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least 2-fold, including miRNAs that were previously described to target genes associated with inflammation, fibrosis, and cancer development. Further investigation demonstrated that the miR-146a-5p level was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes, as well as in liver tissue from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p overexpression modulates pathways that are related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p has a positive impact on late steps of the viral replication cycle, thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. IMPORTANCE HCV is a leading cause of chronic liver disease and cancer. However, how HCV induces liver cancer remains poorly understood. There is accumulating evidence that a viral cure does not eliminate the risk for HCC development. Thus, there is an unmet medical need to develop novel approaches to predict and prevent virus-induced HCC. miRNA expression is known to be deregulated in liver disease and cancer. Furthermore, miRNAs are essential for HCV replication, and HCV infection alters miRNA expression. However, how miRNAs contribute to HCV-driven pathogenesis remains elusive. Here we show that HCV induces miRNAs that may contribute to liver injury and carcinogenesis. The miR-146a-5p level was consistently increased in different cell-based models of HCV infection and in HCV patient-derived liver tissue. Furthermore, miR-146a-5p increased HCV infection. Collectively, our data are relevant to understanding viral pathogenesis and may open perspectives for novel biomarkers and prevention of virus-induced liver disease and HCC.