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Guay S.P.,Universite de Sherbrooke | Brisson D.,ECOGENE 21 and Lipid Clinic | Brisson D.,University of Montreal | Lamarche B.,Laval University | And 6 more authors.

Background: Recent findings suggest that DNA methylation, a well-known epigenetic mechanism, is involved in high-density lipoprotein cholesterol (HDL-C) metabolism and increased cardiovascular disease risk. The aim of this study was thus to assess whether DNA methylation within key genes of lipoprotein metabolism is associated with blood lipid profile variability. Methods and results: Ninety-eight untreated familial hypercholesterolaemia patients (61 men and 37 women) were recruited for leucocyte DNA methylation analyses at the LDLR, CETP, LCAT and LPL gene promoter loci using bisulfite pyrosequencing. LPL DNA methylation was correlated with HDL-C (r=0.22; p=0.031) and HDL particle size (r=0.47, p=0.013). In both sex, CETP DNA methylation was negatively associated with low-density lipoprotein cholesterol levels (r<-0.32; p<0.05). In men, CETP DNA methylation was associated with HDL-C (r=-0.36; p=0.006), HDL-triglyceride levels (r=0.59; p<0.001) and HDL particle size (r=-0.44, p=0.019). In visceral adipose tissue from 30 men with severe obesity, the associations between LPL DNA methylation, HDL-C (r=-0.40; p=0.03) and LPL mRNA levels (r=-0.61, p<0.001) were confirmed. Conclusion: CETP and LPL DNA methylation levels are associated with blood lipid profile, suggesting that further studies of epipolymorphisms should most certainly contribute to a better understanding of the molecular bases of dyslipidemia. © 2013 Elsevier Ireland Ltd. Source

Grzenda A.,Chromatin | Leonard P.,Mayo Medical School | Seo S.,Chromatin | Mathison A.J.,Chromatin | And 8 more authors.
Epigenetics and Chromatin

Background: Previous elegant studies performed in the fission yeast Schizosaccharomyces pombe have identified a requirement for heterochromatin protein 1 (HP1) for spindle pole formation and appropriate cell division. In mammalian cells, HP1γ has been implicated in both somatic and germ cell proliferation. High levels of HP1γ protein associate with enhanced cell proliferation and oncogenesis, while its genetic inactivation results in meiotic and mitotic failure. However, the regulation of HP1γ by kinases, critical for supporting mitotic progression, remains to be fully characterized. Results: We report for the first time that during mitotic cell division, HP1γ colocalizes and is phosphorylated at serine 83 (Ser83) in G 2/M phase by Aurora A. Since Aurora A regulates both cell proliferation and mitotic aberrations, we evaluated the role of HP1γ in the regulation of these phenomena using siRNA-mediated knockdown, as well as phosphomimetic and nonphosphorylatable site-directed mutants. We found that genetic downregulation of HP1γ, which decreases the levels of phosphorylation of HP1γ at Ser83 (P-Ser83- HP1γ), results in mitotic aberrations that can be rescued by reintroducing wild type HP1γ, but not the nonphosphorylatable S83A-HP1γ mutant. In addition, proliferation assays showed that the phosphomimetic S83D-HP1γ increases 5-ethynyl-2́-deoxyuridine (EdU) incorporation, whereas the nonphosphorylatable S83A-HP1γ mutant abrogates this effect. Genome-wide expression profiling revealed that the effects of these mutants on mitotic functions are congruently reflected in G2/M gene expression networks in a manner that mimics the on and off states for P-Ser83-HP1γ. Conclusions: This is the first description of a mitotic Aurora A-HP1γ pathway, whose integrity is necessary for the execution of proper somatic cell division, providing insight into specific types of posttranslational modifications that associate to distinct functional outcomes of this important chromatin protein. © 2013 Grzenda et al.; licensee BioMed Central Ltd. Source

Suh Y.-E.,Kings College London | Raulf N.,Kings College London | Gaken J.,Kings College London | Lawler K.,Kings College London | And 6 more authors.
International Journal of Cancer

Radiotherapy is a major treatment modality for head and neck squamous cell carcinoma (HNSCC). Up to 50% of patients with locally advanced disease relapse after radical treatment and there is therefore a need to develop predictive bomarkers for clinical use that allow the selection of patients who are likely to respond. MicroRNA (miRNA) expression profiling of a panel of HNSCC tumours with and without recurrent disease after surgery and radiotherapy detected miR-196a as one of the highest upregulated miRNAs in the poor prognostic group. To further study the role of miR-196a, its expression was determined in eight head and neck cancer cell lines. Overexpression of miR-196a in HNSCC cells, with low endogenous miR-196a expression, significantly increased cell proliferation, migration and invasion, and induced epithelial to mesenchymal transition. Conversely, miR-196a knockdown in cells with high endogenous expression levels significantly reduced oncogenic behaviour. Importantly, overexpression of miR-196a increased radioresistance of cells as measured by gamma H2AX staining and MTT survival assay. Annexin A1 (ANXA1), a known target of miR-196a, was found to be directly modulated by miR-196a as measured by luciferase assay and confirmed by Western blot analysis. ANXA1 knockdown in HNSCC exhibited similar phenotypic effects to miR-196a overexpression, suggesting the oncogenic effect of miR-196a may at least be partly regulated through suppression of ANXA1. In conclusion, this study identifies miR-196a as a potential important biomarker of prognosis and response of HNSCC to radiotherapy. Furthermore, our data suggest that miR-196a and/or its target gene ANXA1 could represent important therapeutic targets in HNSCC. What's new? There is accumulating evidence that miR-196a plays an important role in the pathogenesis of a number of cancers. Through functional studies, here the authors demonstrate that miR-196a confers an oncogenic phenotype in head and neck cancer cells, through the targeting of ANXA1. The results also show that MiR-196a modulation is associated with response to radiation. MiR-196a may therefore represent both a prognostic and a predictive biomarker in head and neck cancer. Furthermore, the data suggest that miR-196a and/or its target gene ANXA1 could represent important therapeutic targets in head and neck cancer. © 2014 UICC. Source

Chatr-Aryamontri A.,University of Montreal | Breitkreutz B.-J.,Lunenfeld Tanenbaum Research Institute | Oughtred R.,Princeton University | Boucher L.,Lunenfeld Tanenbaum Research Institute | And 20 more authors.
Nucleic Acids Research

The Biological General Repository for Interaction Datasets (BioGRID: http://thebiogrid.org) is an open access database that houses genetic and protein interactions curated from the primary biomedical literature for all major model organism species and humans. As of September 2014, the BioGRID contains 749 912 interactions as drawn from 43 149 publications that represent 30 model organisms. This interaction count represents a 50% increase compared to our previous 2013 BioGRID update. BioGRID data are freely distributed through partner model organism databases and meta-databases and are directly downloadable in a variety of formats. In addition to general curation of the published literature for the major model species, BioGRID undertakes themed curation projects in areas of particular relevance for biomedical sciences, such as the ubiquitinproteasome system and various human diseaseassociated interaction networks. BioGRID curation is coordinated through an Interaction Management System (IMS) that facilitates the compilation interaction records through structured evidence codes, phenotype ontologies, and gene annotation. The BioGRID architecture has been improved in order to support a broader range of interaction and posttranslational modification types, to allow the representation of more complex multi-gene/protein interactions, to account for cellular phenotypes through structured ontologies, to expedite curation through semi-automated text-mining approaches, and to enhance curation quality control. © The Author(s) 2014. Source

Laflamme M.,Center Hospitalier Of Luniversite Laval Chul | Belzile E.L.,CHU de Quebec | Bedard L.,CHU de Quebec | Van Den Bekerom M.P.J.,OLVG | And 2 more authors.
Journal of Orthopaedic Trauma

Objectives: To compare the clinical and radiographic outcome after stabilization of an acute syndesmosis rupture with either a static implant (a 3.5-mm metallic screw through 4 cortices) or a dynamic device (TightRope; Arthrex). Design: Multicenter randomized double-blind controlled trial. Settings: Study realized in 5 trauma centers (2 level 1 and 3 level 2) in 2 countries. Patients/Participants: Seventy subjects admitted for an acute ankle syndesmosis rupture entered the study and were randomized into 2 groups (dynamic fixation 34 and static fixation 36). The 2 groups were similar regarding demographic, social, and surgical data. Sixty-five patients (dynamic 33 and static 32) completed the study and were available for analysis. Intervention: Syndesmosis fixation in the static group was realized with a 4 cortices 3.5-mm cortical screw (Synthes) and in the dynamic group with 1 TightRope (Arthrex). Standardized rehabilitation process for the 2 groups: no weight bearing in a cast for 6 weeks and then rehabilitation without protection. Main Outcome Measurement: Olerud-Molander score. Results: Subjects with dynamic fixation achieved better clinical performances as described with the Olerud-Molander scores at 3 (68.8 vs. 60.2, P 0.067), 6 (84.2 vs. 76.8, P 0.082), and 12 months (93.3 vs. 87.6, P 0.046). We also observed higher American Orthopaedic Foot and Ankle Society scores at 3 months (78.6 vs. 70.6, P 0.016), but these were not significant at 6 (87.1 vs. 83.8, P 0.26) or 12 months (93.1 vs. 89.9, P 0.26). Implant failure was higher in the screw group (36.1% vs. 0%, P < 0.05). Loss of reduction was observed in 4 cases in the static screw group (11.1% vs. 0%, P 0.06). Conclusions: Dynamic fixation of acute ankle syndesmosis rupture with a dynamic device seems to result in better clinical and radiographic outcomes. The implant offers adequate syndesmotic stabilization without failure or loss of reduction, and the reoperation rate is significantly lower than with conventional screw fixation. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. © 2014 Wolters Kluwer Health, Inc. All rights reserved. Source

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