Nouveau mécanisme de régulation de l'apoptose par les récepteurs couplés aux protéines G

L’apoptose est un processus dont l’importance physiologique et pathophysiologique est de mieux en mieux appréciée. Si plusieurs mécanismes expliquant son initiation et son exécution ont été décrits, les détails de sa régulation fine restent à être précisés. Par ces travaux, nous démontrons une interaction directe entre la protéine pro-apoptotique Siva1 et la queue C-terminale de plusieurs récepteurs couplés aux protéines G, incluant TP, IP, PAF, AT?R et CHRM3. Pour TP, nous prouvons que la stimulation du récepteur par le U46619 entraîne une translocation et une accumulation cytoplasmique de Sival, ainsi qu’une modulation de ses interactions avec Mdm2, XIAP et TRAF2, résultant en une induction de l’apoptose. Nous rapportons également que l’expression de Siva1 potentialise l’ubiquitinylation de TP en réponse à une stimulation et que cette ubiquitinylation n’affecte ni la dégradation, ni l’internalisation du récepteur. Nous démontrons par ailleurs que la stimulation de TP diminue l’expression totale d’i?B?, l’inhibiteur principal de la voie NF?B et que cet effet corrèle avec le niveau d’expression de Siva1. En démontrant l’existence d’un complexe entre TP et TRAF2 suite à une stimulation réceptorielle, nous proposons que la modulation NF?B par TP pourrait résulter d’une signalisation dépendant de l’ubiquitine et analogue à celle des TNFR. D’autre part, nous présentons une interaction entre Siva1 et l’arrestine et apportons des données suggérant que l’expression de Siva1 pourrait moduler l’activation des MAPK. Nous proposons finalement un modèle réconciliant les fonctions anti- et pro-apoptotiques de TP et dans lequel le phénotype final d’une stimulation dépendrait de l’expression relative de Siva1. Les corolaires de ce modèle pourraient possiblement bonifier la prise en charge d’incidents ischémiques comme l’infarctus du myocarde ou l’accident vasculaire cérébral, et améliorer le traitement du cancer par une diminution de la toxicité d’agents chimiothérapeutiques et l’amélioration de la sensibilité tumorale.[symboles non conformes

Study Protocol on Defining Core Outcomes and Data Elements in Chronic Subdural Haematoma

Abstract BACKGROUND Core Outcome Sets (COSs) are necessary to standardize reporting in research studies. This is urgently required in the field of chronic subdural hematoma (CSDH), one of the most common disease entities managed in neurosurgery and the topic of several recent trials. To complement the development of a COS, a standardized definition and baseline Data Elements (DEs) to be collected in CSDH patients, would further improve study quality and comparability in this heterogeneous population. OBJECTIVE To, first, define a standardized COS for reporting in all future CSDH studies; and, second, to identify a unified CSDH Definition and set of DEs for reporting in future CSDH studies. METHODS The overall study design includes a Delphi survey process among 150 respondents from 2 main stakeholder groups: healthcare professionals or researchers (HCPRs) and Patients or carers. HCPR, patients and carers will all be invited to complete the survey on the COS, only the HCPR survey will include questions on definition and DE. EXPECTED OUTCOMES It is expected that the COS, definition, and DE will be developed through this Delphi survey and that these can be applied in future CSDH studies. This is necessary to help align future research studies on CSDH and to understand the effects of different treatments on patient function and recovery. DISCUSSION This Delphi survey should result in consensus on a COS and a standardized CSDH Definition and DEs to be used in future CSDH studies. </jats:sec

SIVA1 directs the E3 ubiquitin ligase RAD18 for PCNA monoubiquitination

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Identification and analysis of miRNAs in human breast cancer and teratoma samples using deep sequencing

<p>Abstract</p> <p>Background</p> <p>MiRNAs play important roles in cellular control and in various disease states such as cancers, where they may serve as markers or possibly even therapeutics. Identifying the whole repertoire of miRNAs and understanding their expression patterns is therefore an important goal.</p> <p>Methods</p> <p>Here we describe the analysis of 454 pyrosequencing of small RNA from four different tissues: Breast cancer, normal adjacent breast, and two teratoma cell lines. We developed a pipeline for identifying new miRNAs, emphasizing extracting and retaining as much data as possible from even noisy sequencing data. We investigated differential expression of miRNAs in the breast cancer and normal adjacent breast samples, and systematically examined the mature sequence end variability of miRNA compared to non-miRNA loci.</p> <p>Results</p> <p>We identified five novel miRNAs, as well as two putative alternative precursors for known miRNAs. Several miRNAs were differentially expressed between the breast cancer and normal breast samples. The end variability was shown to be significantly different between miRNA and non-miRNA loci.</p> <p>Conclusion</p> <p>Pyrosequencing of small RNAs, together with a computational pipeline, can be used to identify miRNAs in tumor and other tissues. Measures of miRNA end variability may in the future be incorporated into the discovery pipeline as a discriminatory feature. Breast cancer samples show a distinct miRNA expression profile compared to normal adjacent breast.</p

Insects as Stem Engineers: Interactions Mediated by the Twig-Girdler Oncideres albomarginata chamela Enhance Arthropod Diversity

Background: Ecosystem engineering may influence community structure and biodiversity by controlling the availability of resources and/or habitats used by other organisms. Insect herbivores may act as ecosystem engineers but there is still poor understanding of the role of these insects structuring arthropod communities. Methodology/Principal Findings: We evaluated the effect of ecosystem engineering by the stem-borer Oncideres albomarginata chamela on the arthropod community of a tropical dry forest for three consecutive years. The results showed that ecosystem engineering by O. albomarginata chamela had strong positive effects on the colonization, abundance, species richness and composition of the associated arthropod community, and it occurred mainly through the creation of a habitat with high availability of oviposition sites for secondary colonizers. These effects cascade upward to higher trophic levels. Overall, ecosystem engineering by O. albomarginata chamela was responsible for nearly 95 % of the abundance of secondary colonizers and 82 % of the species richness. Conclusions/Significance: Our results suggest that ecosystem engineering by O. albomarginata chamela is a keystone process structuring an arthropod community composed by xylovores, predators and parasitoids. This study is the first to empirically demonstrate the effect of the ecosystem engineering by stem-boring insects on important attributes o

Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19–9 (CA 19–9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC

Pathophysiology and Nonsurgical Treatment of Chronic Subdural Hematoma: From Past to Present to Future

Background: Chronic subdural hematoma (CSDH) is one of the more frequent pathologic entities in daily neurosurgical practice. Historically, CSDH was considered progressive recurrent bleeding with a traumatic cause. However, recent evidence has suggested a complex intertwined pathway of inflammation, angiogenesis, local coagulopathy, recurrent microbleeds, and exudates. The aim of the present review is to collect existing data on pathophysiology of CSDH to direct further research questions aiming to optimize treatment for the individual patient. Methods: We performed a thorough literature search in PubMed, Ovid, EMBASE, CINAHL, and Google scholar, focusing on any aspect of the pathophysiology and nonsurgical treatment of CSDH. Results: After a (minor) traumatic event, the dural border cell layer tears, which leads to the extravasation of cerebrospinal fluid and blood in the subdural space. A cascade of inflammation, impaired coagulation, fibrinolysis, and angiogenesis is set in motion. The most commonly used treatment is surgical drainage. However, because of the pathophysiologic mechanisms, the mortality and high morbidity associated with surgical drainage, drug therapy (dexamethasone, atorvastatin, tranexamic acid, or angiotensin-converting enzyme inhibitors) might be