Do lower urinary tract symptoms predict cardiovascular diseases in older men?:A systematic review and meta-analysis

To study the incidence of CVD in men at risk, with and without LUTS. We searched all longitudinal studies describing the association between LUTS and CVD (mortality) in October 2013 and December 2014 using MEDLINE, EMBASE, and the Cochrane Library Central Register. PRISMA criteria were met. We included five studies with 6027 men with LUTS and 18,993 men without LUTS in the meta-analyses, with a follow-up period varying from 5 to 17 years. Studies totalled 2780 CVD events. No clear association between CVD and LUTS was demonstrated [pooled effect size: hazard ratio 1.09 (95 % CI 0.90-1.31); p = 0.40]. Two other studies reported the association between nocturia and (CVD) mortality. CVD-specific mortality risk was approximately two times higher for Japanese men with nocturia (357 men aged 70 years and over, 5-year follow-up). A univariable association between nocturia and all-cause mortality was found in Dutch men, but not in age-adjusted analyses (1114 men aged 50-78 years, 13-year follow-up). This meta-analysis conducted on longitudinal studies does not confirm LUTS to be a predictor of CVD in men without a history of CVD, despite the observed association between LUTS and CVD in cross-sectional studies

REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells