Genetic association of lipid-lowering drug target genes with erectile dysfunction and male reproductive health.

Objective: The effect of hypolipidemic drugs on male erectile function is still controversial. This Mendelian randomization (MR) study aimed to explore the potential impact of lipid-lowering drug targets on ED. Methods: We collected seven genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, APOC3 and LPL) from published genome-wide association study (GWAS) statistics, and performed drug target MR analysis. The risk of ED was defined as the primary outcome, sex hormone levels and other diseases as the secondary outcomes. Mediation analyses were performed to explore potential mediating factors. Results: The results showed that LDLR, LPL agonists and APOC3 inhibitors were significantly associated with a reduced risk of ED occurrence. APOB inhibitors were associated with an increased risk of ED occurrence. In terms of sex hormone levels, LDLR and LPL agonists were significantly associated with increased TT levels, and HMGCR was associated with decreased TT and BT levels significantly. In terms of male-related disease, MR results showed that LDLR agonists and PCSK9 inhibitors were significantly associated with an elevated risk of PH; HMGCR, NPC1L1 inhibitors were associated with a reduced risk of PCa; and LDLR agonists were significantly associated with a reduced risk of AS and MI; in addition, HMGCR inhibitors were associated with a reduced risk of PCa. Conclusion: After performing drug-targeted MR analysis, we found that that there was a causal relationship between lipid-lowering drug targets and ED. APOC3, APOB, LDLR and LPL may be new candidate drug targets for the treatment of ED.

Identifying potential biomarkers for non-obstructive azoospermia using WGCNA and machine learning algorithms.

Objective: The cause and mechanism of non-obstructive azoospermia (NOA) is complicated; therefore, an effective therapy strategy is yet to be developed. This study aimed to analyse the pathogenesis of NOA at the molecular biological level and to identify the core regulatory genes, which could be utilised as potential biomarkers. Methods: Three NOA microarray datasets (GSE45885, GSE108886, and GSE145467) were collected from the GEO database and merged into training sets; a further dataset (GSE45887) was then defined as the validation set. Differential gene analysis, consensus cluster analysis, and WGCNA were used to identify preliminary signature genes; then, enrichment analysis was applied to these previously screened signature genes. Next, 4 machine learning algorithms (RF, SVM, GLM, and XGB) were used to detect potential biomarkers that are most closely associated with NOA. Finally, a diagnostic model was constructed from these potential biomarkers and visualised as a nomogram. The differential expression and predictive reliability of the biomarkers were confirmed using the validation set. Furthermore, the competing endogenous RNA network was constructed to identify the regulatory mechanisms of potential biomarkers; further, the CIBERSORT algorithm was used to calculate immune infiltration status among the samples. Results: A total of 215 differentially expressed genes (DEGs) were identified between NOA and control groups (27 upregulated and 188 downregulated genes). The WGCNA results identified 1123 genes in the MEblue module as target genes that are highly correlated with NOA positivity. The NOA samples were divided into 2 clusters using consensus clustering; further, 1027 genes in the MEblue module, which were screened by WGCNA, were considered to be target genes that are highly correlated with NOA classification. The 129 overlapping genes were then established as signature genes. The XGB algorithm that had the maximum AUC value (AUC=0.946) and the minimum residual value was used to further screen the signature genes. IL20RB, C9orf117, HILS1, PAOX, and DZIP1 were identified as potential NOA biomarkers. This 5 biomarker model had the highest AUC value, of up to 0.982, compared to other single biomarker models; additionally, the results of this biomarker model were verified in the validation set. Conclusions: As IL20RB, C9orf117, HILS1, PAOX, and DZIP1 have been determined to possess the strongest association with NOA, these five genes could be used as potential therapeutic targets for NOA patients. Furthermore, the model constructed using these five genes, which possessed the highest diagnostic accuracy, may be an effective biomarker model that warrants further experimental validation.

Comparing Prognosis Associated with Partial Cystectomy and Trimodal Therapy for Muscle-Invasive Bladder Cancer Patients.

OBJECTIVE: This study aimed to compare the survival outcomes between trimodal therapy (TT) and partial cystectomy (PC) in muscle-invasive bladder cancer (MIBC) patients. METHODS: The data of 13,096 patients with MIBC diagnosed between 2004 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database. Among them, 4,041 patients underwent TT and 1,670 patients underwent PC. Propensity score matching was performed to balance the characteristics between the 2 treatment groups. A multivariate Cox regression analysis model and a competing risk model were used to evaluate overall survival (OS) and cancer-specific survival. Cumulative incidence survival curves were obtained using the Kaplan-Meier method. RESULTS: Results of multivariate Cox analysis before propensity score matching showed that the TT group had a 31% reduction in cause-specific survival relative to the PC group (HR: 0.69, 95% CI: 0.61-0.78, p < 0.001) and a 28% reduction in OS (HR: 0.72, 95% CI: 0.66-0.79, p < 0.001). After propensity score matching, the 2 groups yielded 972 patients, with 3-year cause-specific survival rates of 54.1% and 68.5% in the TT group and the PC group, respectively. CONCLUSIONS: Patients who underwent PC had a better prognosis than those who received TT. In addition, for MIBC patients who required bladder-sparing therapy, advanced age (≥80 years), pathological type of squamous cell carcinoma, and tumor stage of T3-4, N2-3, and M1 were independent poor prognostic factors.

Specific gut microbiota may increase the risk of erectile dysfunction: a two-sample Mendelian randomization study.

Objective: Studies have found that gut microbiota may be associated with the development of erectile dysfunction (ED); however, the exact link between the two remains unclear. This study aimed to elucidate the relationship between the gut microbiota and the risk of ED from a genetic perspective. Methods: We investigated the relationship between the gut microflora and ED using two-sample Mendelian randomization. GWAS-pooled data for ED were obtained from 223805 participants in Europe. GWAS summary data for ED were obtained from 223805 subjects in Europe and that for the gut microbiota were obtained from 18340 participants in 24 cohorts. We used the inverse-variance weighted (IVW) estimator as the primary method for the preliminary analysis, and the MR-Egger, weighted median (WM), simple model, and weighted model as secondary methods. We used Cochrane's Q-test, to detect heterogeneity, MREgger to detect pleiotropy, and the leave-one-out method to test the stability of the MR results. Ultimately, we genetically predicted a causal relationship between 211 gut microbiota and ED. Results: A total of 2818 SNPs associated with gut microflora were screened in the ED correlation analysis based on the assumption of instrumental variables. The results of MR analysis showed a causal relationship between the six gut microbes and ED occurrence. The results of the fixed effects IVW method revealed five gut microflora, including Lachnospiraceae (OR, 1.265; P = 0.008), Lachnospiraceae NC2004 group (OR, 1.188; P = 0.019), Oscillibacter (OR, 1.200; P = 0.015), Senegalimassilia (OR, 1.355; P = 0.002), Tyzzerella3 (OR, 1.133; P = 0.022), to be negatively associated with ED. In addition, the IVW method revealed Ruminococcaceae UCG-013 (OR, 0.827; P = 0.049) to be positively associated with ED. Quality control results showed no heterogeneity or horizontal pleiotropy in the MR analysis (P > 0.05). Conclusions: Six gut microbes were genetically associated with ED; of which, Ruminococcaceae UCG-013 was causally associated with a reduced risk of ED development. Our findings provide a new direction for research on the prevention and treatment of ED; however, the mechanisms and details require further investigation.

Impacts of Chemokine (C-X-C Motif) Receptor 2 C1208T Polymorphism on Cancer Susceptibility.

BACKGROUND: The CXC chemokines belong to a unique family of cytokines that participates in the progression and development of many malignant tumors. Evidence for the relationship between chemokine (C-X-C motif) receptor 2 (CXCR2) C1208T polymorphism and susceptibility to cancer remains inconsistent. METHODS: Odds ratios (ORs), 95% confidence intervals (CIs), and combined analysis were used to investigate the effect of CXCR2 variation on cancer risk. Gene Set Enrichment Analysis (GSEA) and enzyme-linked immunosorbent assay (ELISA) were also used to evaluate the expression of CXCR2 in prostate cancer (PCA). RESULTS: Across 11 case-control studies, 4,909 cases and 5,884 controls were involved in the current analysis. Individuals with a TT genotype were associated with increased risk of digestive cancer, compared to those with a TC+CC genotype (OR = 1.16, 95%CI = 1.02-1.31, P = 0.025). Individuals carrying the TT genotype had a 39% higher risk of urinary cancer than those carrying CC genotype (OR = 1.39, 95%CI = 1.04-1.87, P = 0.025). Individuals with a TT genotype showed a 56% augmented breast cancer risk, compared to those with a CC genotype (OR = 1.56, 95%CI = 1.03-2.35, P = 0.034). It was found that CXCR2 expression was downregulated in PCA. Compared with PCA subjects carrying the CC genotype, the expression of CXCR2 was decreased in patients with the TT genotype. CONCLUSIONS: The CXCR2 C1208T variation was associated with elevated risk of urinary, breast, and digestive cancer. However, the C1208T polymorphism was correlated with attenuated risk of lung cancer.

Comparison of the effects of retroperitoneoscopic ureterolithotomy and ureteroscopic lithotripsy in the treatment of upper ureteral calculi.

ABSTRACT: This study compares the efficacy of retroperitoneoscopic ureterolithotomy (RPUL) and ureteroscopic lithotripsy (URL) in the treatment of upper ureteral calculi.The clinical data of 150 patients with upper ureteral calculi who underwent RPUL and 136 patients who underwent URL between January 2014 and October 2019 were retrospectively analyzed. The operation time, postoperative hospital stay, operation success rate, stone clearance rate, and surgical complications were evaluated between the two groups.For the RPUL and URL groups, respectively, the average operation time was 74.5 ±â€Š24.6 minutes and 54.5 ±â€Š13.2 minutes; the postoperative hospital stay was 5.8 ±â€Š1.4 days and 3.2 ±â€Š1.2 days; the operation success rate was 96.0% (144/150) and 85.3% (116/136); the incidence rate of complications was 3.5% (5/144) and 17.5% (18/103); and the stone clearance rate was 100% (144/144) and 88.8% (103/116), which were all statistically significant (P < .05).Both RPUL and URL had the advantages of low trauma and fast recovery rate for patients with upper ureteral calculi. However, patients who underwent RPUL showed higher success and fewer complication rate. RPUL might be a safe and effective laparoscopic method for the treatment of patients with upper ureteral calculi.

Exosome-Derived Long Non-Coding RNAs as Non-Invasive Biomarkers of Bladder Cancer.

OBJECTIVE: As a result of the inconsistency between reports, a meta-analysis was designed to appraise the clinical implications of long non-coding RNAs (lncRNAs) in exosomes for the diagnosis of bladder cancer. METHODS: The PubMed, EMBASE, and Cochrane library databases were searched to identify the relevant literature on lncRNAs in exosomes for bladder cancer diagnosis from database inception to May 2021. The literature was screened according to the inclusion and exclusion criteria, and the Quality Assessment of Diagnostic Accuracy Studies-2 entry tool was applied to evaluate the quality of the literature, and the sources of heterogeneity were explored using meta-regression and subgroup analysis. Stata 14.0 and RevMan 5.3 software were used for statistical analysis. RESULTS: A total of 23 studies described in 10 articles were included, with a total of 1883 patients with bladder cancer and 1721 patients in the non-cancerous control group. The exosome-derived lncRNAs performed better in the diagnosis of bladder cancer with a pooled sensitivity of 0.74 (95% CI, 0.69-0.77), specificity of 0.76 (95% CI, 0.72-0.80), and area under the curve of 0.83. The heterogeneity between studies was partly as a result of differences in specimen type, number of lncRNAs, lncRNA expression form, and reference gene type. Subgroup analysis showed that the detection efficacy based on the combination of multiple lncRNAs (0.86, 95% CI, 0.82-0.88) was higher than that based on a single lncRNA (0.81, 95% CI, 0.78-0.85), and exosomal lncRNAs with blood as the detection sample had a high diagnostic efficacy (0.86, 95% CI, 0.82-0.86). CONCLUSIONS: Exosome-derived lncRNAs hold great promise as non-invasive diagnostic biomarkers of bladder cancer. However, their clinical value needs to be examined in further comprehensive prospective studies.

Exploration of the core genes in ulcerative interstitial cystitis/bladder pain syndrome

ABSTRACT Objective: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic inflammatory disease that can cause bladder pain and accompanying symptoms, such as long-term urinary frequency and urgency. IC/BPS can be ulcerative or non-ulcerative. The aim of this study was to explore the core genes involved in the pathogenesis of ulcerative IC, and thus the potential biomarkers for clinical treatment. Materials and Methods: First, the gene expression dataset GSE11783 was downloaded using the Gene Expression Omnibus (GEO) database and analyzed using the limma package in R to identify differentially expressed genes (DEGs). Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) functional analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed, and key modules and hub genes were determined using the STRING and Cytoscape software. The resulting key modules were then analyzed for tissue-specific gene expression using BioGPS. Results: A total of 216 up-regulated DEGs and 267 down-regulated genes were identified, and three key modules and nine hub genes were obtained. Conclusion: The core genes (CXCL8, CXCL1, IL6) obtained in this study may be potential biomarkers of interstitial cystitis with guiding significance for clinical treatment.

Integrative analysis the characterization of peroxiredoxins in pan-cancer.

BACKGROUND: Peroxiredoxins (PRDXs) are an antioxidant enzymes protein family involved in several biological functions such as differentiation, cell growth. In addition, previous studies report that PRDXs play critical roles in the occurrence and development of carcinomas. However, few studies have conducted systematic analysis of PRDXs in cancers. Therefore, the present study sought to explore the molecular characteristics and potential clinical significance of PRDX family members in pan cancer and further validate the function of PRDX6 in bladder urothelial carcinoma (BLCA). METHODS: A comprehensive analysis of PRDXs in 33 types of cancer was performed based on the TCGA database. This involved an analysis of mRNA expression profiles, genetic alterations, methylation, prognostic values, potential biological pathways and target drugs. Moreover, both the gain and loss of function strategies were used to assess the importance and mechanism of PRDX6 in the cell cycle of BLCA. RESULT: Analysis showed abnormal expression of PRDX1-6 in several types of cancer compared to normal tissues. Univariate Cox proportional hazard regression analysis showed that expression levels of PRDX1, PRDX4 and PRDX6 were mostly associated with poor survival of OS, DSS and PFI, and PRDX2 and PRDX3 with favorable survival. In addition, the expression of PRDX genes were positively correlated with CNV and negatively with methylation. Moreover, analysis based on PharmacoDB dataset showed that the augmented levels of PRDX1, PRDX3 and PRDX6 were significantly correlated with EGFR/VEGFR inhibitor drugs. Furthermore, knocking down of PRDX6 inhibited growth of cancer cells through the JAK2-STAT3 in bladder cell lines. CONCLUSIONS: PRDXs are potential biomarkers and therapeutic targets for several carcinomas, especially for BLCA. In addition, PRDX6 could regulate proliferation of cancer cell via JAK2-STAT3 pathway and involve into the process of cell cycle in BLCA.

Exploration of the core genes in ulcerative interstitial cystitis/bladder pain syndrome.

OBJECTIVE: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic inflammatory disease that can cause bladder pain and accompanying symptoms, such as long-term urinary frequency and urgency. IC/BPS can be ulcerative or non-ulcerative. The aim of this study was to explore the core genes involved in the pathogenesis of ulcerative IC, and thus the potential biomarkers for clinical treatment. MATERIALS AND METHODS: First, the gene expression dataset GSE11783 was downloaded using the Gene Expression Omnibus (GEO) database and analyzed using the limma package in R to identify differentially expressed genes (DEGs). Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) functional analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed, and key modules and hub genes were determined using the STRING and Cytoscape software. The resulting key modules were then analyzed for tissue-specific gene expression using BioGPS. RESULTS: A total of 216 up-regulated DEGs and 267 down-regulated genes were identified, and three key modules and nine hub genes were obtained. CONCLUSION: The core genes (CXCL8, CXCL1, IL6) obtained in this study may be potential biomarkers of interstitial cystitis with guiding significance for clinical treatment.

Clinical effect of Brisson operation modified by Y-shaped incision for treatment of concealed penis in adolescents.

OBJECTIVE: To analyze the clinical effect of the Brisson operation modified by a Y-shaped incision in treating adolescent concealed penis. METHODS: We retrospectively analyzed clinical data of 27 adolescents with a concealed penis treated with the Brisson operation modified by a Y-shaped incision in our hospital from January 2017 to March 2020. RESULTS: The operation went smoothly in all 27 patients. Postoperative foreskin edema occurred in 12 patients and spontaneously resolved within 1 month postoperatively. Two patients developed postoperative retropubic infection. After administering antibiotics and symptomatic treatment, both patients' conditions improved within 1 week. All operations obtained satisfactory results. Postoperatively, when the penis was in a non-erect state, it was clearly exposed without retraction or concealment; thus, demonstrating good surgical results. The prepuce was distributed naturally without obvious accumulation of redundant preputial tissue. The penile scar resembled that after circumcision. The postoperative follow-up period was 6 months, during which no patients developed recurrence. CONCLUSION: The Brisson operation modified by a Y-shaped incision is effective for treating a concealed penis in adolescent patients. This technique may relieve the pathological abnormalities and retain the penile skin's integrity to the greatest extent with minimal scarring and a satisfactory appearance.

Effects of FGFR4 G388R, V10I polymorphisms on the likelihood of cancer.

The correlation between G388R or V10I polymorphisms of fibroblast growth factor receptor (FGFR) 4 gene and the risk of carcinoma has been investigated previously, but the results are contradictory. Odds ratios (ORs) with 95% confidence intervals (95%CIs), in silico tools, and immunohistochemical staining (IHS) were adopted to assess the association. In total, 13,793 cancer patients and 16,179 controls were evaluated in our pooled analysis. Summarization of all the studies showed that G388R polymorphism is associated with elevated susceptibility to cancer under homozygous comparison (OR = 1.21, 95%CI = 1.03-1.43, P = 0.020) and a recessive genetic model (OR = 1.21, 95%CI = 1.04-1.41, P = 0.012). In the stratification analysis by cancer type and ethnicity, similar findings were indicated for prostate cancer, breast cancer, and individuals of Asian descendant. Polyphen2 bioinformatics analysis showed that the G388R mutation is predicted to damage the protein function of FGFR4. IHS analysis indicated that FGFR4 expression is increased in advanced prostate cancer. These findings may guide personalized treatment of certain types of cancers. Up-regulation of FGFR4 may be related to a poor prognosis in prostate cancer.

A Comparative Study on the Clinical Efficacy of Modified Circumcision and Two Other Types of Circumcision.

PURPOSE: To compare the clinical effects of three methods of circumcision: modified circumcision, traditional circumcision, and disposable suturing device circumcision. MATERIALS AND METHODS: Male patients (n = 241) with redundant prepuce and/or phimosis were included in a clinical trial from January 2019 to March 2020. Patients were divided into 3 groups based on the surgical method: group A, traditional circumcision (n = 79); group B, modified circumcision (n = 80); and group C, disposable suturing device circumcision (n = 82). RESULTS: The operation times in groups A, B, and C were 25.2 ± 3.3 min, 10.2 ± 2.7 min, and 6.7 ± 1.4 min, respectively. The volumes of intraoperative blood loss in groups A, B, and C were 12.7 ± 2.3 mL, 8.1 ± 3.4 mL, and 2.2 ± 0.8 mL, respectively (P < 0.05). Groups A and B were superior to group C in terms of the 6-h postoperative visual analog scale score and appearance satisfaction (P < 0.05). There were no obvious differences in the 7-day postoperative pain score and total healing time (P > 0.05). The operating expenses in groups A and B were lower than that in group C (P < 0.05). CONCLUSION: Modified circumcision, with its advantages of shorter operation time, less blood loss and pain, lower cost, and better postoperative penile appearance, is easily accepted by patients and deserves wide clinical application.

XPC exon15 Lys939Gln variant increase susceptibility to prostate adenocarcinoma: Evidence based on 4306 patients and 4779 controls.

BACKGROUND: Previous studies have investigated the correlation between xeroderma pigmentosumcomplementation group C (XPC) variants and prostate adenocarcinoma (PA) risk. Nevertheless, research findings remain inconclusive. METHODS: We conducted a pooled analysis to obtain a more accurate estimation of the relationship on XPC exon15 Lys939Gln polymorphism with susceptibility to PA. Moreover, in silico tools were employed to investigate the effect of XPC expression on PA patients' survival time. RESULTS: A total of 4306 patients and 4779 control subjects were assessed. The overall results indicated that XPC Lys939Gln variant was associated with PA risk (recessive genetic model: odds ratio = 1.15, 95% confidence interval = 1.02-1.30, Pheterogeneity= .044, P = .021, I= 45.2), especially in Asian descendants. Population-based studies revealed similar results (odds ratio = 1.15, 95% confidence interval = 1.01-1.32, Pheterogeneity= .146, P = .040, I = 39.0). In silico tools showed that XPC expression in Caucasian patients was lower than in the normal group. No positive association was observed in African patients. PA subjects with high XPC expression had a longer overall survival time than low expression group. CONCLUSION: Our findings indicated that XPC Lys939Gln variant might contribute to increased PA susceptibility, especially for Asian patients.