Genetically proxied inhibition of tumor necrosis factor and the risk of colorectal cancer: A drug-target mendelian randomization study.

Background: Previous studies suggested that anti-TNF drugs might be repurposed as a preventive treatment for colorectal cancer. We aimed to examine whether genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) reduces the absolute risk of colorectal cancer through mendelian randomization (MR) analysis. Methods: We obtained 28 single nucleotide polymorphisms (SNPs) that were located within a ±15 kilobase window of the TNFRSF1A-the gene that encodes the TNFR1 protein, and we used genetic data from three GWAS studies of circulating levels of TNFR1, C-reactive protein (CRP), and white blood counts (WBC) to screen SNPs that proxied the inhibition of TNFR1. Positive control analyses were then performed by using another three GWAS data from the ulcerative colitis cohort (n = 45,975), Crohn's disease cohort (n = 40,266), and multiple sclerosis cohort (n = 115,803) to confirm the effect of the included SNPs. A two-sample mendelian randomization analysis was performed to examine the association between TNFR1 inhibition and the absolute risk reduction (ARR) of colorectal cancer. Results: We finally included seven SNPs to proxy the anti-TNF effect, and these SNPs caused lower levels of TNFR1, CRP, and white blood counts. In positive control analyses, the included SNPs caused lower odds ratio of ulcerative colitis and Crohn's disease but a higher odds ratio of multiple sclerosis, consistent with drug mechanistic actions and previous trial evidence. By using the inverse-variance weighted analyses to combine the effects of the seven SNPs, we found that the anti-TNF effect was associated with a 0.988 (95%CI 0.985-0.991) mg/L decrease in CRP levels and a reduction in the risk of colorectal cancer (absolute risk reduction -2.1%, 95%CI -3.8% to -0.4%, p = 0.01). Conclusion: Our study confirmed that anti-TNF drugs were associated with a risk reduction in colorectal cancer. Physicians could consider using anti-TNF drugs for the prevention of colorectal cancer, especially in patients with high risks of developing cancer.

Management of haemorrhoids: protocol of an umbrella review of systematic reviews and meta-analyses.

INTRODUCTION: The prevalence of haemorrhoidal diseases was high in general population, and many treatments are proposed for the management of haemorrhoids. The treatments include conservative and surgical interventions; the credibility and strength of current evidence of their effectiveness are not comprehensively evaluated. We aim to evaluate the credibility of systematic reviews and meta-analyses that assess the effectiveness of the treatments for haemorrhoidal diseases through an umbrella review. METHODS AND ANALYSIS: We will search Ovid Medline, Embase, Cochrane library and Web of Science from inception to March 2020 without any language restriction. We will include meta-analyses that examine the effectiveness of treatments in the management of haemorrhoids. Two reviewers will independently screen the titles and abstracts of retrieved articles, and they will extract data from the included meta-analyses. For each meta-analysis, we will estimate the effect size of a treatment through the random-effect model and the fixed-effect model, and we will evaluate between-study heterogeneity (Cochrane's Q and I2 statistics) and small-study effect (Egger's test); we will also estimate the evidence of excess significance bias. Evidence of each treatment will be graded according to prespecified criteria. Methodological quality of each meta-analysis will be evaluated by using Assessment of Multiple Systematic Reviews 2. The corrected cover area method will be used to assess the impact of overlap in reviews on the findings of the umbrella review. ETHICS AND DISSEMINATION: We will present the results of the umbrella review at conferences and publish the final report in a peer-reviewed journal. The umbrella review does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42019140702.

Somatosensory stimulation treatments for postoperative analgesia of mixed hemorrhoids: Protocol for a systematic review and network meta-analysis.

BACKGROUND: Pain after hemorrhoidal surgery bothers both clinicians and patients. Somatosensory stimulation treatments have shown promising effect on the pain after hemorrhoidal surgery, but the comparative effectiveness between them has not been studied. We aim to determine the relative effectiveness among these treatments on pain relief after hemorrhoidal surgery by using network meta-analysis. METHOD: We will search the following electronic databases: MEDLINE, EMBASE, the Cochrane library, Chinese Biomedicine database (CBM), China National Knowledge Infrastructure (CNKI). We will include randomized controlled trials (RCTs) that examine the effect of somatosensory stimulation treatments on pain after hemorrhoidal surgery. The primary outcome will be the responder rate after treatment. The secondary outcomes will include the assessments with pain intensity scales (visual analog scale, numeric rating scale, or other scales) on day 1 to 7 after surgery. Two independent reviewers will extract needed information from eligible trials using standardized electronic forms. Network meta-analysis will be performed using a frequentist framework based on electrical network theory. The relative effectiveness of the treatments will be ranked by using P score, which is the mean probability of a treatment ranking the best in all treatments. Meta-regression will be performed to assess the impact of surgery type, anesthesia methods, and funding source on the treatment ranking. The quality of the eligible RCTs will be evaluated by the Cochrane risk of bias tool. ETHICS AND DISSEMINATION: The result of this network meta-analysis will clarify which is the relatively best somatosensory-stimulation treatment in relieving postoperative pain caused by hemorrhoidal surgery, and the review will, therefore, guide the management of postoperative pain after hemorrhoidal surgery for clinicians and patients. This review does not require ethical approval and will be reported in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018115558.

Clip domain prophenoloxidase activating protease is required for Ostrinia furnacalis Guenée to defend against bacterial infection.

The prophenoloxidase (PPO) activating system in insects plays an important role in defense against microbial invasion. In this paper, we identified a PPO activating protease (designated OfPAP) containing a 1203 bp open reading frame encoding a 400-residue protein composed of two clip domains and a C-terminal serine protease domain from Ostrinia furnacalis. SignalP analysis revealed a putative signal peptide of 18 residues. The mature OfPAP was predicted to be 382 residues long with a calculated Mr of 44.8 kDa and pI of 6.66. Multiple sequence alignment and phylogenetic analysis indicated that OfPAP was orthologous to the PAPs in the other lepidopterans. A large increase of the transcript levels was observed in hemocytes at 4 h post injection (hpi) of killed Bacillus subtilis, whereas its level in integument increased continuously from 4 to 12 hpi in the challenged larvae and began to decline at 24 hpi. After OfPAP expression had been silenced, the median lethal time (LT50) of Escherichia coli-infected larvae (1.0 day) became significantly lower than that of E. coli-infected wild-type (3.0 days, p < 0.01). A 3.5-fold increase in E. coli colony forming units occurred in larval hemolymph of the OfPAP knockdown larvae, as compared with that of the control larvae not injected with dsRNA. There were notable decreases in PO and IEARase activities in hemolymph of the OfPAP knockdown larvae. In summary, we have demonstrated that OfPAP is a component of the PPO activation system, likely by functioning as a PPO activating protease in O. furnacalis larvae.