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  • 1
    Publication Date: 2018-10-23
    Description: Genome-wide association studies have recently illuminated that WDFY4 is genetically associated with systemic lupus erythematosus (SLE) susceptibility in various ethnic groups. Despite strong genetic evidence suggesting a role of WDFY4 in SLE pathogenesis, its functional relevance is largely unknown. In this study, we generated Wdfy4 B lymphocyte conditional knockout ( Wdfy4 -CKO) mice and found that loss of Wdfy4 led to a decrease in number of total B cells and several subpopulations of B cells in the periphery and a defect in the transition from the pro– to pre–B cell stage in bone marrow. Also, Wdfy4 -CKO mice showed impaired Ab responses as compared with controls when challenged with Ag. SLE phenotypes were effectively alleviated in Wdfy4 -CKO mice, with significantly diminished pristane-elicited production of autoantibodies and glomerulonephritis. Genetic silencing of WDFY4 in B cells increased lipidation of LC3 independent of p62 and Beclin1, which are essential proteins of canonical autophagy. Our in vivo and in vitro data suggest that WDFY4 facilitates noncanonical autophagic activity. Our findings provide a novel functional link underlying the mechanism of SLE in which WDFY4 influences B cell fate via noncanonical autophagy.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 2
    Publication Date: 2018-08-16
    Description: Purpose: The current tumor–node–metastasis (TNM) staging system is inadequate at identifying patients with high-risk colorectal cancer. Using a systematic and comprehensive biomarker discovery and validation approach, we aimed to identify an miRNA recurrence classifier (MRC) that can improve upon the current TNM staging as well as is superior to currently offered molecular assays. Experimental Design: Three independent genome-wide miRNA expression profiling datasets were used for biomarker discovery ( N = 158) and in silico validation ( N = 109 and N = 40) to identify an miRNA signature for predicting tumor recurrence in patients with colorectal cancer. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh-frozen ( N = 127, cohort 1) and formalin-fixed paraffin-embedded (FFPE; N = 165, cohort 2 and N = 139, cohort 3) specimens. Results: We identified an 8-miRNA signature that significantly predicted recurrence-free interval (RFI) in the discovery ( P = 0.002) and two independent publicly available datasets ( P = 0.00006 and P = 0.002). The RT-PCR–based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in patients with stage II and III colorectal cancer [cohort 1: hazard ratio (HR), 3.44 (1.56–7.45), P = 0.001; cohort 2: HR, 6.15 (3.33–11.35), P = 0.001; and cohort 3: HR, 4.23 (2.26–7.92), P = 0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence and achieved superior predictive accuracy over the currently available molecular assays. The RT-PCR–based MRC risk score = (–0.1218 x miR-744) + (–3.7142 x miR-429) + (–2.2051 x miR-362) + (3.0564 x miR-200b) + (2.4997 x miR-191) + (–0.0065 x miR-30c2) + (2.2224 x miR-30b) + (–1.1162 x miR-33a). Conclusions: This novel MRC is superior to currently used clinicopathologic features, as well as National Comprehensive Cancer Network (NCCN) criteria, and works regardless of adjuvant chemotherapy status in identifying patients with high-risk stage II and III colorectal cancer. This can be readily deployed in clinical practice with FFPE specimens for decision-making pending further model testing and validation. Clin Cancer Res; 24(16); 3867–77. ©2018 AACR . See related commentary by Rodriguez et al., p. 3787
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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