Cuproptosis related gene PDHB is identified as a biomarker inversely associated with the progression of clear cell renal cell carcinoma.

BACKGROUND: Cuproptosis is a newly discovered programmed cell death dependent on mitochondrial respiratory disorder induced by copper overload. Pyruvate dehydrogenase E1 subunit beta (PDHB) is one of the cuproptosis genesand is a nuclear-encoded pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A. However, the mechanism of PDHB in clear cell renal cell carcinoma (ccRCC) remains unclear. METHODS: We used data from TCGA and GEO to assess the expression of PDHB in normal and tumor tissues. We further analyzed the relationship between PDHB and somatic mutations and immune infiltration. Finally, we preliminarily explored the impact of PDHB on ccRCC. RESULTS: The expression level of PDHB was lower in tumor tissue compared with normal tissue. Meanwhile, the expression level of PDHB was also lower in high-grade tumors than low-grade tumors. PDHB is positively correlated with prognosis in ccRCC. Furthermore, PDHB may be associated with decreased risk of VHL, PBRM1 and KDM5C mutations. In 786-O cells, copper chloride could promote the expression of cuproptosis genes (DLAT, PDHB and FDX1) and inhibit cell growth. Last but not least, we found that PDHB could inhibit the proliferation and migration of ccRCC cells. CONCLUSION: Our results demonstrated that PDHB could inhibit the proliferation, migration and invasion in ccRCC cells, which might be a prognostic predictor of ccRCC. Targeting this molecular might provide a new therapeutic strategy for patients with advanced ccRCC.

Estrogen receptor beta increases clear cell renal cell carcinoma stem cell phenotype via altering the circPHACTR4/miR-34b-5p/c-Myc signaling.

Early clinical studies indicated that estrogen receptor beta (ERß) might play key roles to impact the progression of clear cell renal cell carcinoma (ccRCC). The detailed molecular mechanisms, however, remain unclear. Here, we found ERß could increase the cancer stem cell (CSC) population via altering the circPHACTR4/miR-34b-5p/c-Myc signaling. Mechanism dissection revealed that ERß could suppress circular RNA PHACTR4 (circPHACTR4) expression via direct binding to the estrogen response elements (EREs) on the 5' promoter region of its host gene, phosphatase and actin regulator 4 (PHACTR4) to decrease miR-34b-5p expression. The decreased miRNA-34b-5p could then increase c-Myc mRNA translation via targeting its 3' untranslated region (3' UTR). The in vivo mouse model with subcutaneous xenografts of ccRCC cells also validated the in vitro data. Importantly, analysis results from ccRCC TCGA database and our clinical data further confirmed the above in vitro/in vivo data. Together, these results suggest that ERß may increase CSC population in ccRCC via altering ERß/circPHACTR4/miR-34b-5p/c-Myc signaling and that targeting this newly identified signal pathway may help physicians to better suppress ccRCC progression.

Prestenting Versus Nonprestenting on the Outcomes of Flexible Ureteroscopy for Large Upper Urinary Stones: A Systematic Review and Meta-Analysis.

INTRODUCTION: The purpose of this article is to evaluate the efficacy and safety of prestenting (PS) versus non-PS (NPS) of flexible ureteroscopy (fURS) to treat large upper urinary stones. METHODS: We conducted a systematic literature research of PubMed, Ovid, Scopus (up to August 2019), and citation lists to identify eligible studies. All studies comparing PS versus NPS of fURS were included. Data were analyzed using the Cochrane Collaboration's Review Manager (RevMan) 5.3 software. RESULTS: Overall, 7 studies including 3,145 patients (PS 1,408; NPS 1,737) were included in this article. PS group was associated with older age (weighted mean difference [WMD] 0.91 year; p < 0.001) and more male patients (odds ratio [OR] 1.34; p < 0.001). There were no statistical differences between PS and NPS in BMI (WMD 0.34 kg/m2; p = 0.13), stone size (WMD 0.13 mm; p = 0.77), and operative time (WMD 0.44 min; p = 0.86). Compared with NPS, PS showed better initial success rate (OR 4.04; p < 0.001) and higher SFR (OR 1.64; p < 0.001). There were no statistical differences for complications (OR 0.84; p = 0.42) and Clavien-Dindo score ≥3 complications (OR 1.04; p = 0.93). CONCLUSION: PS could improve initial success rate and avoid secondary general anesthesia for first ureteral access sheath failed patients. PS could provide better SFR than NPS in the treatment of large upper urinary stones with fURS.

Development and validation of a six-RNA binding proteins prognostic signature and candidate drugs for prostate cancer.

The dysregulation of RNA binding proteins (RBPs) regulates the progression of several cancers. However, information on the overall functions of RBPs in prostate cancer (PCa) remains largely understudied. Therefore, based on the TCGA dataset, this study identified 144 differentially expressed RBPs in tumors compared to normal tissues. Subsequently, through univariate, LASSO and multivariate Cox regression analysis, 6 RBP genes among them, MSI1, MBNL2, LENG9, REXO2, RNASE1, and PABPC1L were screened as prognostic hub genes and prognostic signature was further identified. Further analysis indicated that the high-risk group was significantly associated with poor RFS, which was validated in the MSKCC cohort. Besides, patients in the high-risk group were closely associated with dysregulation of DNA damage repair pathway, copy number alteration, tumor burden mutation, and low-response to cisplatin (P < 0.001), and bicalutamide (P < 0.001). Using the Connectivity Map, we finally predicted 3 drugs including, ribavirin, carmustine, and carbenoxolone. In summary, we identified six-RBP gene signature and 3 potential drugs against PCa, which might promote the individualized treatment strategies and further improve the quality of life among PCa patients.

Down-regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR-432-5p/ß-catenin feedback loop.

RNA-binding motif protein 5 (RBM5) acts as a tumor suppressor in various human cancers and presents with several important characteristics, such as the potentiation of apoptosis, inhibition of the cell cycle, and alternative splicing of Fas and caspase-2 precursor mRNA. However, its role in bladder urothelial carcinoma (BUC) remains unknown. In this study, we found that RBM5 expression was significantly down-regulated in BUC tissues when compared with the adjacent nontumor tissues. The down-regulation of RBM5 activates ß-catenin, which binds to the T-cell factor/lymphocyte enhancer factor element of the miR-432-5p promoter and elevates the expression of miR-432-5p in bladder cancer cells. The up-regulated miR-432-5p directly targets 3'-UTR and depresses RBM5 expression. Thus, RBM5-miR-432-5p-ß-catenin forms a feedback loop in regulating bladder cancer cell apoptosis. Our findings provide evidence that the regulatory feedback loop among RBM5, miR-432-5p, and Wnt-ß-catenin is responsible for the progress of bladder cancer cells.-Zhang, Y.-P., Liu, K.-L., Wang, Y.-X., Yang, Z., Han, Z.-W., Lu, B.-S., Qi, J.-C., Yin, Y.-W., Teng, Z.-H., Chang, X.-L., Li, J.-D., Xin, H., Li, W. Down-regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR-432-5p/ß-catenin feedback loop.

Photon Counting Imaging with Low Noise and a Wide Dynamic Range for Aurora Observations.

The radiation intensity of observed auroras in the far-ultraviolet (FUV) band varies dramatically with location for aerospace applications, requiring a photon counting imaging apparatus with a wide dynamic range. However, combining high spatial resolution imaging with high event rates is technically challenging. We developed an FUV photon counting imaging system for aurora observation. Our system mainly consists of a microchannel plate (MCP) stack readout using a wedge strip anode (WSA) with charge induction and high-speed electronics, such as a charge sensitive amplifier (CSA) and pulse shaper. Moreover, we constructed an anode readout model and a time response model for readout circuits to investigate the counting error in high counting rate applications. This system supports global rates of 500 kilo counts, 0.610 dark counts s-1 cm-2 at an ambient temperature of 300 K and 111 µm spatial resolution at 400 kilo counts s-1 (kcps). We demonstrate an obvious photon count loss at incident intensities close to the counting capacity of the system. To preserve image quality, the response time should be improved and some noise performance may be sacrificed. Finally, we also describe the correlation between counting rate and imaging resolution, which further guides the design of space observation instruments.

Efficacy and safety of various surgical treatments for proximal ureteral stone ≥10mm: A systematic review and network meta-analysis.

PURPOSE: Various surgical options are available for large proximal ureteral stones, such as extracorporeal shock wave lithotripsy (ESWL), ureteroscopic lithotripsy (URSL), percutaneous nephrolithotomy (PCNL) and laparoscopic ureterolithotomy (LU). However, the best option remains controversial. Therefore, we conducted a network meta-analysis comparing various surgical treatments for proximal ureteral stones ≥10mm to address current research deficiencies. MATERIALS AND METHODS: We searched PubMed, Ovid, Scopus (up to June 2019), as well as citation lists to identify eligible comparative studies. All clinical studies including patients comparing surgical treatments for proximal ureteral stones ≥10mm were included. A standard network meta-analysis was performed with Stata SE 14 (Stata Corp, College Station, TX, USA) software to generate comparative statistics. The quality was assessed with level of evidence according to the Oxford Centre for Evidence-based Medicine and risk of bias with the Cochrane Collaboration's Review Manager (RevMan) 5.3 software. RESULTS: A total of 25 studies including 2.888 patients were included in this network meta-analysis. Network meta-analyses indicated that LU and PCNL had better stone-free rates and auxiliary procedures. PCNL could result in major complications and severe bleeding. In initial stone-free rate, final stone-free rate, and auxiliary procedures results, SUCRA ranking was: LU> PCNL> URSL> ESWL. In Clavien Dindo score ≥3 complications, SUCRA ranking was: LU> ESWL> URSL> PCNL. In fever, SUCRA ranking was: ESWL> LU> URSL> PCNL. In transfusion, SUCRA ranking was: LU> URSL> ESWL> PCNL. In Cluster analysis, LU had the highest advantages and acceptable side effects. Considering the traumatic nature of PCNL, it should not be an option over URSL. ESWL had the lowest advantages. CONCLUSIONS: LU have the potential to be considered as the first treatment choice of proximal ureteral stone ≥10mm.

Subtilisin QK-2: secretory expression in Lactococcus lactis and surface display onto gram-positive enhancer matrix (GEM) particles.

BACKGROUND: Purified from the supernatant of Bacillus subtilis QK02 culture broth, Subtilisin QK-2 is a type of effective thrombolytic reagent that has great exploitable potential. However, the unbearable flavor that occurs with fermentation and the complicated methods that are required to obtain pure products limit the application of this enzyme. Lactic acid bacteria (LAB)-based delivery vehicles are promising as cheap and safe options for medicinal compounds. The secretory expression and surface display using LAB may popularize Subtilisin QK-2 more easily and conveniently with minimal adverse effects. RESULTS: Subtilisin QK-2 was expressed successfully in two forms using lactic acid bacteria. For the secretory expression in Lactococcus lactis, Subtilisin QK-2 was efficiently secreted into the culture using the promoter P nisA and signal peptide SPUsp. The expression levels were not different in L. lactis NZ9000 and NZ3900 without the effect of different selection markers. However, leaky expression was only detected in L. lactis NZ3900. The biological activity of this secreted Subtilisin QK-2 was enhanced by modulating the pH of medium to slightly alkaline during induction and by codon optimization of either the entire gene sequence (qk') or only the propeptide gene sequence (qkpro'). For surface display onto gram-positive enhancer matrix (GEM) particles, n LysM repeats from the C-terminal region of the major autolysin AcmA of L. lactis were fused to either the C-terminus (n = 1, 3, 5) or the N-terminus (n = 1) of the Subtilisin QK-2. These fusion proteins were secreted into the culture medium, and the QK-3LysM was able to bind to the surface of various LAB GEM particles without a loss of fibrinolytic activity. Furthermore, the binding capacity significantly increased with a higher concentration of QK-3LysM. Compared to the free-form Subtilisin QK-2, the QK-3LysM displayed on the surface of GEM particles was more stable in the simulated gastric juice. CONCLUSIONS: Combined with the safety and popularity of LAB, Subtilisin QK-2 may be easily applied worldwide to prevent and control thrombosis diseases.

Expression and immunogenic characterization of recombinant gp350 for developing a subunit vaccine against Epstein-Barr virus.

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is linked to the development of various malignancies. There is an urgent need for effective vaccines against EBV. EBV envelope glycoprotein gp350 is an attractive candidate for a prophylactic vaccine. This study was undertaken to produce the truncated (codons 1-443) gp350 protein (gp350(1-443)) in Pichia pastoris and evaluate its immunogenicity. The gp350(1-443) protein was expressed as a secretory protein with an N-terminal His-tag in P. pastoris and purified through Ni-NTA chromatography. Immunization with the recombinant gp350(1-443) could elicit high levels of gp350(1-443)-specific antibodies in mice. Moreover, gp350(1-443)-immunized mice developed strong lymphoproliferative and Th1/Th2 cytokine responses. Furthermore, the recombinant gp350(1-443) could stimulate CD4(+) and CD8(+) T cell responses in vaccinated mice. Collectively, these findings demonstrated that the yeast-expressed gp350(1-443) retained strong immunogenicity. This study will provide a useful source for developing EBV subunit vaccine candidates.

Genetically predicted asthma and the risk of abnormal spermatozoa.

Background: Several previous animal and human studies have found a strong association between asthma and spermatozoa quality, but whether these associations are causal or due to bias remains to be elucidated. Methods: We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effect of genetically predicted asthma on the risk of abnormal spermatozoa. Asthma, childhood-onset asthma (COA), and adult-onset asthma (AOA) (sample sizes ranging from 327,670 to 408,442) were included as the exposures. Genetic information for abnormal spermatozoa was obtained from a genome-wide association study (GWAS) comprising 209,921 participants. In univariable MR (UVMR) analysis, the inverse variance weighted (IVW) method was conducted as the primary method, with the MR Egger and weighted median used as supplementary methods for causal inference. Sensitivity analyses, including the Cochran Q test, Egger intercept test, MR-PRESSO, and leave-one-out analysis, were performed to verify the robustness of the MR results. Multivariable MR (MVMR) was conducted to evaluate the direct causal effects of asthma on abnormal spermatozoa risk. Results: UVMR detected causal associations between genetically predicted asthma and an increased risk of abnormal spermatozoa (OR: 1.270, 95% CI: 1.045-1.545, p = 0.017). Moreover, we found that AOA (OR: 1.46, 95% CI: 1.051, 2.018, p = 0.024) has positive causal effects on the risk of abnormal spermatozoa rather than COA (p = 0.558). Sensitivity analysis found little evidence of bias in the current study (p > 0.05). MVMR further confirmed that asthma directly affected the risk of abnormal spermatozoa. Conclusion: Our MR study suggested that genetically predicted asthma could be associated with an increased risk of abnormal spermatozoa, and similar results were obtained in AOA. Further studies are warranted to explain the underlying mechanisms of this association and may provide new avenues for prevention and treatment.

Predicting surgical efficacy and diagnosing histological inflammation: the clinical significance of prostate exosome proteins in benign prostatic hyperplasia.

Background: Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) among the aging male population. Recent studies have shown that histological inflammation (HI) plays a significant role in BPH, with prostatic exosomal protein (PSEP) identified as a potential biomarker for prostate diseases. Therefore, this study aimed to explore the effect of HI on LUTS in patients with BPH, and to further explore the clinical value of PSEP as a diagnostic biomarker of BPH complicated with HI and whether PSEP could be used as an index to predict the improvement of LUTS after operation. Methods: This study was an open-label, cohort study. The study enrolled all patients who were clinical diagnosed as BPH with LUTS and prepared to receive operation of the prostate at the Department of Urology of the Second Hospital of Hebei Medical University. International Prostate Symptom Score (IPSS) were used to evaluate the LUTS of the BPH. And the enrolled patients were divided into four groups, including none, mild HI, moderate HI, and severe HI, based on postoperative pathological results. Then the relationships between HI and IPSS, the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), as well as PSEP were analyzed. Simple and multiple linear regression analyses were performed on the preoperative IPSS and the difference of IPSS before and after surgery was examined. SPSS software version 26 was used for statistical analysis and Prism 9.0 was used to make violin plots. Results: A total of 69 patients were enrolled in the study. The violin plot results indicated IPSS and NIH-CPSI scores exhibited significant increases in correlation with the severity levels of HI (P<0.001; P<0.001). Among BPH patients with total prostate-specific antigen (t-PSA) levels higher than 4.0 ng/mL, a significant correlation was observed between PSEP levels and HI (P=0.04). Besides, simple and multiple linear regression analysis showed that HI (P<0.001) or PSEP (P=0.03) was significantly associated with IPSS and improvement of LUTS, assessed by postoperative and preoperative IPSS differences. Conclusions: The study indicated that IPSS and PSEP (when t-PSA >4 ng/mL) were correlated with the severity of HI in patients with BPH. PSEP was linearly correlated with IPSS and the degree of reduction in IPSS after surgery. Consequently, PSEP may serve as a promising predictor for assessing surgical efficacy and diagnosing the severity of HI in patients with BPH.

MMP-9 gene polymorphisms on cancer risk: an updated systematic review and meta-analysis.

To provide a comprehensive account of the association of MMP-9 gene polymorphisms (rs3918242) with susceptibility to cancer. A literature search for eligible candidate gene studies published before May 27, 2022 was conducted in PubMed, Medline, Google Scholar and Web of Science. Potential sources of heterogeneity were sought out across subgroups and sensitivity analysis. Publication bias were also estimated. Overall, a total of 37 articles with 7616 cases and 8165 controls for rs3918242 gene polymorphisms were enrolled. Our meta-analysis suggests that MMP-9 rs3918242 might be associated with breast cancer and gastric cancer susceptibility, and perhaps reduce the risk of lung cancer.

Vaccination with a Human Papillomavirus L2 Multimer Provides Broad Protection against 17 Human Papillomavirus Types in the Mouse Cervicovaginal Challenge Model.

Human papillomavirus (HPV) is a prevalent cause of mucosal and cutaneous infections and underlying conditions ranging from benign warts to anogenital and oropharyngeal cancers affecting both males and females, notably cervical cancer. Cervical cancer is the fourth leading cause of cancer deaths among women globally and is the most impactful in low- and middle-income countries (LMICs), where the costs of screening and licensed L1-based HPV vaccines pose significant barriers to comprehensive administration. Additionally, the licensed L1-based HPV vaccines fail to protect against all oncogenic HPV types. This study generated three independent lots of an L2-based target antigen (LBTA), which was engineered from conserved linear L2-protective epitopes (aa11-88) from five human alphapapillomavirus genotypes in E. coli under cGMP conditions and adjuvanted with aluminum phosphate. Vaccination of rabbits with LBTA generated high neutralizing antibody titers against all 17 HPV types tested, surpassing the nine types covered by Gardasil®9. Passive transfer of naïve mice with LBTA antiserum revealed its capacity to confer protection against vaginal challenge with all 17 αHPV types tested. LBTA shows stability at room temperature over >1 month. Standard in vitro and in vivo toxicology studies suggest a promising safety profile. These findings suggest LBTA's promise as a next-generation vaccine with comprehensive coverage aimed at reducing the economic and healthcare burden of cervical and other HPV+ cancers in LMICs, and it has received regulatory approval for a first-in-human clinical study (NCT05672966).

An amplification-free CRISPR/Cas12a-based fluorescence assay for ultrasensitive detection of nuclease activity.

Nuclease, such as RNase H and DNase I, plays key roles in plenty of cellular processes and could be potential therapeutic target for drug development. It is necessary to establish rapid and simple-to-use methods to detect nuclease activity. Herein, we develop a Cas12a-based fluorescence assay without any nucleic acid amplification steps for ultrasensitive detection of RNase H or DNase I activity. By our design, the pre-assembled crRNA/ssDNA duplex triggered the cleavage of fluorescent probes in the presence of Cas12a enzymes. However, the crRNA/ssDNA duplex was selectively digested with the addition of RNase H or DNase I, which leaded to fluorescence intensity changes. Under optimized conditions, the method exhibited good analytical performance, achieving a limit of detection (LOD) as low as 0.0082 U/mL for RNase H and 0.13 U/mL for DNase I, respectively. The method was feasible for analysis of RNase H in human serum and cell lysates, as well as for screening of enzyme inhibitors. Moreover, it can be adopted to image RNase H activity in living cells. Together, this study provides a facile platform for nuclease detection and could be expanded for other biomedical research and clinical diagnostics.

Laparoscopic ureterolithotomy versus percutaneous nephrolithotomy for large proximal ureteral stones: a systematic review and meta-analysis.

Introduction: Both percutaneous nephrolithotomy (PCNL) and laparoscopic ureterolithotomy (LU) are effective treatment options for large proximal ureteral stones. Aim: To perform a meta-analysis on this topic to assess the efficacy, safety, and potential complications of the two procedures. Material and methods: A systematic literature search was performed using PubMed, Ovid and Scopus to identify eligible suitable studies until May 2022. All studies comparing LU vs PCNL in large proximal ureteral stones were included. The Cochrane Collaboration's Review Manager (RevMan) 5.4 software was used to analyze statistical significance. Results: A total of nine publications involving 933 patients (LU 465; PCNL 468) were included, of which 4 were randomized control trails (RCTs) and 5 were non-RCTs. The meta-analysis of available data showed that compared with PCNL, LU had a higher initial stone-free rate (OR = 3.26; p = 0.004), but longer operative time (WMD = 35.08 min; p = 0.0003). However, the final stone-free rate (OR = 2.08; p = 0.07) and length of hospital stay (WMD = 0.32 d; p = 0.48) were comparable between the two groups. Meanwhile, LU had a lower transfusion rate (OR = 0.13; p = 0.007) than PCNL. There was no significant difference in terms of complications (OR = 0.97; p = 0.84), Clavien-Dindo score ≥ 3 complications (OR = 1.03; p = 0.93), auxiliary procedures (OR = 0.44; p = 0.08), or ureteral stenosis (OR = 0.24; p = 0.13) between LU and PCNL. Conclusions: Our meta-analysis revealed that LU is a safe and feasible option for large proximal ureteral stones with a higher initial stone-free rate and lower transfusion rate compared with PCNL.

Oblique supine position versus prone position for percutaneous nephrolithotomy: a systematic review and meta-analysis.

Introduction: To compare the efficacy and safety of percutaneous nephrolithotomy (PCNL) in the oblique supine position (OSP) and the prone position (PP). Aim: To perform a systematic review and meta-analysis to evaluate the efficacy and safety of OSP versus PP for PCNL. Material and methods: A systematic literature search of PubMed, Ovid, SCOPUS, and citation lists was conducted to identify eligible comparative studies up to November 2022. All studies comparing OSP versus PP for PCNL were included. Statistical analysis was performed with the Collaboration's Review Manager (RevMan) 5.4 software. Results: Overall, eight studies were included involving 1185 patients (OSP = 634; PP = 551). There were no statistically significant differences between OSP and PP in age (WMD = -0.95 years; 95% CI: -2.12 to 0.21; p = 0.83) or proportion of male patients (OR = 0.02; 95% CI: -0.03 to 0.08; p = 0.43). We found that OSP was performed more frequently for smaller stone size and patients with higher BMI (WMD = -0.1 cm, 95% CI: -0.18 to -0.02; p = 0.01) and patients with higher BMI (WMD = 0.66 kg/m2; 95% CI: 0.29 to 1.03; p = 0.0005). The operation time was shorter in OSP than PP (WMD = -14 min; 95% CI: -27.00 to -1.00; p = 0.03). The reduction of hemoglobin was lower in OSP than PP (WMD = -0.39 g/dl; 95% CI: -0.60 to -0.13; p = 0.03). There was no significant difference in stone-free rate and hospitalization between the two groups (OR = 1.32; 95% CI: 0.98 to 1.78; p = 0.07; WMD = -5.99 h; 95% CI: -17.15 to 5.16; p = 0.29). The overall complications were fewer in OSP than in PP (OR = 0.59; 95% CI: 0.43 to 0.81; p = 0.001), but no difference was observed between the positions with regard to the major complications (Clavien-Dindo score ≥ 3) (OR = 0.76; 95% CI: 0.43 to 1.34; p = 0.35). Conclusions: OSP showed non-inferior stone-free rate, blood loss, and hospitalization compared with PP. OSP may be superior in terms of operative time and complications than PP.

eNOS polymorphisms on male infertility: An updated systematic review and meta-analysis.

BACKGROUND: This meta-analysis was performed to examine the association of 3 endothelial nitric oxide synthase (eNOS) gene polymorphisms with male infertility. METHODS: The literature on the relation between the mutant of eNOS and male infertility before July 1, 2022, was conducted in Pubmed, Medline, and Web of Science. The search strategy is as follows: (eNOS OR ECNOS OR nitric oxide synthase 3 OR NOS3) AND (polymorphism OR mutation OR variation OR SNP OR genotype) AND (male infertility). Statistical analysis was performed with the web of MetaGenyo, Stata 12, trial sequential analysis 0.9Beta, and the web of GTEx. RESULTS: Overall, 13 studies (26 case-controls) were included involving 6518 cases and 5461 controls for 3 polymorphisms (rs2070744, rs1799983, rs61722009) of eNOS. We found that eNOS rs2070744 was correlated with an increased risk of male infertility (C vs. T: odds ratio [OR], 1.48; 95% confidence interval [CI], [1.19-1.85]; CC vs. TT: OR, 2.59; 95% CI, [1.40-4.80]; CT vs. TT: OR, 1.17; 95% CI, [1.00-1.38]; CC vs. CT + TT: OR, 2.50; 95% CI, [1.35-4.62]; CC + CT vs. TT: OR, 1.41; 95% CI, [1.21-1.64]). And eNOS rs1799983 was correlated with an increased risk of male infertility (allele contrast T vs. G: OR, 1.41; 95% CI, [1.01-1.96]; P = .043; recessive model TT vs. TG + GG: OR, 2.00; 95% CI, [1.03-3.90]; P = .042). In the stratified analysis of rs61722009, we found Asians might be correlated with an increased risk of male infertility (4a vs. 4b: OR, 1.50; 95% CI, [0.94-2.38]; 4a4a vs. 4b4b: OR, 2.56; 95% CI, [0.70-9.38]; 4a4b vs. 4b4b: OR, 1.36; 95% CI, [0.87-2.13]; 4a4a vs. 4a4b + 4b4b: OR, 2.57; 95% CI, [0.91-7.30]; 4a4a + 4a4b vs. 4b4b: OR, 1.44; 95% CI, [0.87-2.40]). CONCLUSION: The eNOS rs2070744 polymorphism and rs1799983 are associated with the risk of male infertility, and rs61722009 might be a risk factor for Asians.

ESR2 polymorphisms on prostate cancer risk: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis was performed to address the association of 2 ESR2 gene polymorphisms (rs1256049 and rs4986938) with susceptibility to cancer. METHODS: An extensive literature search for eligible candidate gene studies published before May 10, 2022, was conducted in PubMed, Medline, and Web of Science. The search strategy was as follows: (ESR2 OR ERß OR ER beta OR estrogen receptor beta) AND (polymorphism OR mutation OR variation OR SNP OR genotype) AND (PCa OR PC OR prostate cancer). Potential sources of heterogeneity were sought out via trial sequential analysis, subgroup, and sensitivity analysis. RESULTS: Overall, a total of 10 articles involving 18,064 cases and 19,556 controls for 2 polymorphisms of the ESR2 gene were enrolled. In the stratified analysis of rs1256049, we found that Caucasians might be correlated with an increased risk of prostate cancer (PCa), while less susceptibility was found in Asians. We observed that rs4986938 was not associated with PCa risk. CONCLUSION: ESR2 rs1256049 polymorphism is associated with a higher risk of PCa in the Caucasian population and a lower risk of PCa in the Asian population.

MNS16A polymorphism of the TERT gene on cancer risk: a systematic review and meta-analysis.

Some studies have suggested that MNS16A polymorphism in telomerase reverse transcriptase (TERT) gene is associated with cancer risk in various populations and types of cancer. However, the results of previous studies exploring this link have been inconclusive. To be able to accurately assess the association between TERT MNS16A polymorphism and cancer risk, we performed a meta-analysis based on 17 studies described in 12 articles, including 13,764 controls and 7,132 cases. Combined odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated to assess the strength of the association in either a fixed-effects model or, if applicable, a random-effects model. Heterogeneity between articles and their publication bias were also tested. Overall, pooled results showed that no significant association between this polymorphism and cancer was found in the five gene models tested.Considering that there may be too many negative studies in the included studies, diluting the results of the total sample size, we stratified these studies according to ethnicity, source of controls and cancer type. In the stratified analysis, a statistically significant association was observed between Asians and population-based studies. We also analyzed by cancer type and found a significantly increased risk of brain cancer in five genetic models. Our results suggest that TERT MNS16A polymorphism is likely to contribute to increased cancer risk.

DDX58 expression promotes inflammation and growth arrest in Sertoli cells by stabilizing p65 mRNA in patients with Sertoli cell-only syndrome.

Sertoli cell -only syndrome (SCOS) is a type of testicular pathological failure that causes male infertility and no effective treatment strategy, is available for this condition. Moreover, the molecular mechanism underlying its development remains unknown. We identified DExD/H-Box helicase 58 (DDX58) as a key gene in SCOS based on four datasets of testicular tissue samples obtained from the Gene Expression Synthesis database. DDX58 was significantly upregulated in SCOS testicular Sertoli cells. Moreover, high expression of DDX58 was positively correlated with the expression of several testicular inflammatory factors, such as IL -1ß, IL-18, and IL-6. Interestingly, DDX58 could be induced in the D-galactose (D-gal)-stimulated TM4 cell injury model. Whereas silencing of DDX58 inhibited D-gal -mediated p65 expression, inflammatory cytokine release, and growth arrest. Mechanistically, we found that DDX58 acts as an RNA-binding protein, which enhances p65 expression by promoting mRNA stability. Furthermore, p65 gene silencing decreased the expression of inflammatory cytokines and inhibition of cell growth in D-gal-induced cells. In conclusion, our findings demonstrate that DDX58 promotes inflammatory responses and growth arrest in SCOS Sertoli cells by stabilizing p65 mRNA. Accordingly, the DDX58/p65 regulatory axis might be a therapeutic target for SCOS.