DNA damage provokes cohesin sumoylation in Saccharomyces cerevisiae

Cohesin tethers sister chromatids together from their creation during S-phase until their separation at the metaphase to anaphase transition. Cohesion is essential for correct segregation and therefore genomic stability. Cohesin is also involved the regulation of transcription and in DNA repair. Cohesin affects these processes by its ability to hold two pieces of DNA together. Cohesin is subject to a variety of post-translational modifications. In this study, the modification of cohesin, more specifically the Scc1 subunit, by Small ubiquitin-like modifier (SUMO) was analysed. It was found that cohesin is sumoylated during an unperturbed cell cycle, but is hyper-modified after DNA damage. To determine the function Scc1 modification by SUMO, attempts were made to identify the modified residues. Mass spectrometry techniques for SUMO site identification were developed in parallel to site-directed mutagenesis studies. Potential sumoylation sites were identified on Scc1, but when these were mutated there was little effect on either viability or the sumoylation pattern obtained. Mutants were then constructed in which only one lysine was present. Surprisingly, several of these were viable, not sensitive to methyl methanesulfonate and were not sumoylated, suggesting that either sumoylation of Scc1 is not essential and not required after DNA damage, or that sumoylation of the rest of the cohesin complex can compensate. To investigate this, Scc1 fusions with the SUMO E2 ligase, Ubc9, and a SUMO isopeptidase, Ulp1, to mimic constitutively sumoylated and unsumoylatable cohesin respectively, were constructed. Unexpectedly, it was found that both fusions relocalized to a double strand break, and that the Ulp1 fusion was recruited to a greater extent. Data from our laboratory suggests that the Ubc9 fusion is not competent for cohesion after damage, although it is sufficient for viability. Sumoylation may therefore be involved in cohesin unloading or turnover, which might be required after DNA damage

Prognostic models for predicting recurrence and survival in women with endometrial cancer

This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To review all prognostic models that combine two or more clinical, histological or molecular variables, or a combination of these variables, to provide an individualised assessment of risk of recurrence or death from disease and evaluate their performance to predict these outcomes in people undergoing curative treatment for endometrial cancer

Use of Mendelian Randomization for Identifying Risk Factors for Brain Tumors

Gliomas are a group of primary brain tumors, the most common and aggressive subtype of which is glioblastoma. Glioblastoma has a median survival of just 15 months after diagnosis. Only previous exposure to ionizing radiation and particular inherited genetic syndromes are accepted risk factors for glioma; the vast majority of cases are thought to occur spontaneously. Previous observational studies have described associations between several risk factors and glioma, but studies are often conflicting and whether these associations reflect true casual relationships is unclear because observational studies may be susceptible to confounding, measurement error and reverse causation. Mendelian randomization (MR) is a form of instrumental variable analysis that can be used to provide supporting evidence for causal relationships between exposures (e.g., risk factors) and outcomes (e.g., disease onset). MR utilizes genetic variants, such as single nucleotide polymorphisms (SNPs), that are robustly associated with an exposure to determine whether there is a causal effect of the exposure on the outcome. MR is less susceptible to confounding, reverse causation and measurement errors as it is based on the random inheritance during conception of genetic variants that can be relatively accurately measured. In previous studies, MR has implicated a genetically predicted increase in telomere length with an increased risk of glioma, and found little evidence that obesity related factors, vitamin D or atopy are causal in glioma risk. In this review, we describe MR and its potential use to discover and validate novel risk factors, mechanistic factors, and therapeutic targets in glioma

Does testosterone mediate the relationship between vitamin D and prostate cancer progression? A systematic review and meta-analysis

PURPOSE: Observational studies and randomized controlled trials (RCTs) have shown an association between vitamin D levels and prostate cancer progression. However, evidence of direct causality is sparse and studies have not examined biological mechanisms, which can provide information on plausibility and strengthen the evidence for causality. METHODS: We used the World Cancer Research Fund International/University of Bristol two-stage framework for mechanistic systematic reviews. In stage one, both text mining of published literature and expert opinion identified testosterone as a plausible biological mechanism. In stage two, we performed a systematic review and meta-analysis to assess the evidence from both human and animal studies examining the effect of vitamin D on testosterone, and testosterone on advanced prostate cancer (diagnostic Gleason score of ≥ 8, development of metastasis) or prostate cancer-specific mortality. RESULTS: A meta-analysis of ten human RCTs showed evidence of an effect of vitamin D on total testosterone (standardised mean difference (SMD) = 0.133, 95% CI =  − 0.003–0.269, I(2) = 0.0%, p = 0.056). Five human RCTs showed evidence of an effect of vitamin D on free testosterone (SMD = 0.173, 95% CI =  − 0.104–0.450, I(2) = 52.4%, p = 0.220). Three human cohort studies of testosterone on advanced prostate cancer or prostate cancer-specific mortality provided inconsistent results. In one study, higher levels of calculated free testosterone were positively associated with advanced prostate cancer or prostate cancer-specific mortality. In contrast, higher levels of dihydrotestosterone were associated with lowering prostate cancer-specific mortality in another study. No animal studies met the study eligibility criteria. CONCLUSION: There is some evidence that vitamin D increases levels of total and free testosterone, although the effect of testosterone levels within the normal range on prostate cancer progression is unclear. The role of testosterone as a mechanism between vitamin D and prostate cancer progression remains inconclusive. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10552-022-01591-w

Lack of Evidence for Ribavirin Treatment of Lassa Fever in Systematic Review of Published and Unpublished Studies

Ribavirin has been used widely to treat Lassa fever in West Africa since the 1980s. However, few studies have systematically appraised the evidence for its use. We conducted a systematic review of published and unpublished literature retrieved from electronic databases and gray literature from inception to March 8, 2022. We identified 13 studies of the comparative effectiveness of ribavirin versus no ribavirin treatment on mortality outcomes, including unpublished data from a study in Sierra Leone provided through a US Freedom of Information Act request. Although ribavirin was associated with decreased mortality rates, results of these studies were at critical or serious risk for bias when appraised using the ROBINS-I tool. Important risks for bias related to lack of control for confounders, immortal time bias, and missing outcome data. Robust evidence supporting the use of ribavirin in Lassa fever is lacking. Well-conducted clinical trials to elucidate the effectiveness of ribavirin for Lassa fever are needed

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide:a comprehensive meta-analysis based on a Cochrane Review

BACKGROUND: The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use. METHODS: We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients. RESULTS: Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP. CONCLUSIONS: We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only