Characterization of extrachromosomal circular DNAs in plasma of patients with clear cell renal cell carcinoma.

BACKGROUND AND PURPOSE: Extrachromosomal circular DNAs (eccDNAs) have been recognized for their significant involvement in numerous biological processes. Nonetheless, the existence and molecular characteristics of eccDNA in the peripheral blood of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have not yet been reported. Our aim was to identify potentially marked plasma eccDNAs in ccRCC patients. METHODS AND MATERIALS: The detection of plasma eccDNA in ccRCC patients and healthy controls was performed using the Tn5-tagmentation and next-generation sequencing (NGS) method. Comparisons were made between ccRCC patients and healthy controls regarding the distribution of length, gene annotation, pattern of junctional nucleotide motif, and expression pattern of plasma eccDNA. RESULTS: We found 8,568 and 8,150 plasma eccDNAs in ccRCC patients and healthy controls, respectively. There were no statistical differences in the length distribution, gene annotation, and motif signature of plasma eccDNAs between the two groups. A total of 701 differentially expressed plasma eccDNAs were identified, and 25 plasma eccDNAs with potential diagnostic value for ccRCC have been successfully screened. These up-regulated plasma eccDNAs also be indicated to originate from the genomic region of the tumor-associated genes. CONCLUSION: This work demonstrates the characterization of plasma eccDNAs in ccRCC and suggests that the up-regulated plasma eccDNAs could be considered as a promising non-invasive biomarker in ccRCC.

Upregulated PPP1R14B is connected to cancer progression and immune infiltration in kidney renal clear cell carcinoma

Background Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) is an oncogenic gene found in a variety of tumors, but its role in the prognosis and development of kidney renal clear cell carcinoma (KIRC) remains unknown. Our study aimed to determine whether PPP1R14B could be a prognostic biomarker for KIRC and its role in the development of KIRC. Methods In this work, we used The Cancer Genome Atlas (TCGA) database to explore the expression of PPP1R14B in tumor tissues, its relationship with the prognosis of tumor patients, and its role in tumor occurrence and development. We validated our findings using the International Cancer Genome Consortium (ICGC) cohort, our clinical samples, and in vitro experiments. Results PPP1R14B was upregulated in KIRC compared to adjacent normal tissue. Moreover, multivariate analysis revealed that upregulated PPP1R14B expression was an independent risk factor for KIRC progression. High-PPP1R14B groups had shorter overall survival (OS) and disease-free survival (DFS) in TCGA and ICGC cohorts. We used Cell Counting Kit-8 (CCK8) and scratch wound healing assay to explore the proliferation and migration of KIRC cells following PPP1R14B knockdown. Our results indicated that PPP1R14B knockdown significantly reduced the proliferation and migration of KIRC cells in vitro. We also explored the possible cellular mechanisms of PPP1R14B through the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) analysis, and TISIDB analysis. The function enrich analysis revealed that PPP1R14B-related genes were mainly enriched in purine metabolism and the macromolecule catabolic process. PPP1R14B expression was associated with tumor-infiltrating immune cells (TIICs) in the TCGA cohort, and the results of single-cell RNA-seq (scRNA) further demonstrated that PPP1R14B expression was associated with the enhanced infiltration of CD8 + T lymphocytes (AU)

Upregulated PPP1R14B is connected to cancer progression and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) is an oncogenic gene found in a variety of tumors, but its role in the prognosis and development of kidney renal clear cell carcinoma (KIRC) remains unknown. Our study aimed to determine whether PPP1R14B could be a prognostic biomarker for KIRC and its role in the development of KIRC. METHODS: In this work, we used The Cancer Genome Atlas (TCGA) database to explore the expression of PPP1R14B in tumor tissues, its relationship with the prognosis of tumor patients, and its role in tumor occurrence and development. We validated our findings using the International Cancer Genome Consortium (ICGC) cohort, our clinical samples, and in vitro experiments. RESULTS: PPP1R14B was upregulated in KIRC compared to adjacent normal tissue. Moreover, multivariate analysis revealed that upregulated PPP1R14B expression was an independent risk factor for KIRC progression. High-PPP1R14B groups had shorter overall survival (OS) and disease-free survival (DFS) in TCGA and ICGC cohorts. We used Cell Counting Kit-8 (CCK8) and scratch wound healing assay to explore the proliferation and migration of KIRC cells following PPP1R14B knockdown. Our results indicated that PPP1R14B knockdown significantly reduced the proliferation and migration of KIRC cells in vitro. We also explored the possible cellular mechanisms of PPP1R14B through the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) analysis, and TISIDB analysis. The function enrich analysis revealed that PPP1R14B-related genes were mainly enriched in purine metabolism and the macromolecule catabolic process. PPP1R14B expression was associated with tumor-infiltrating immune cells (TIICs) in the TCGA cohort, and the results of single-cell RNA-seq (scRNA) further demonstrated that PPP1R14B expression was associated with the enhanced infiltration of CD8 + T lymphocytes. CONCLUSION: PPP1R14B may serve as a prognostic biomarker in KIRC, affect purine metabolism, activate immune infiltration, and promote KIRC cell migration.

Dominant negative TGFß receptor II and truncated TIM3 enhance the antitumor efficacy of CAR-T-cell therapy in prostate cancer.

BACKGROUND: The immune checkpoint molecules, Transforming growth factor beta receptor II (TGFßRII) and T cell immunoglobulin and mucin domain 3 (TIM3), have been identified as contributors to T cell immune suppression in prostate cancer. The objective of this investigation was to improve the tumor killing capability of prostate-specific membrane antigen (PSMA)-chimeric antigen receptor T (CAR-T) cells by targeting TIM3 and TGFßRII simultaneously. METHODS: To generate dnTGFßRII-trTIM3-PSMA-CAR-T (DT-PSMA-CAR-T) cells, the surface of PSMA-CAR-T cells was overexpressed with dominant negative TGFßRII (dnTGFßRII) and truncated extracellular TIM3 (trTIM3). The efficacy of DT-PSMA-CAR-T cells was assessed through in vitro killing experiments and animal experiments. RESULTS: The DT-PSMA-CAR-T cells demonstrated the ability to eradicate PSMA-positive prostate cancer cells, even in the presence of exogenous TGF-ß and/or TIM3 activating antibodies. In addition, the cells demonstrated the ability to eliminate tumor tissue in an immunodeficient mouse model transplanted with GAL9-PSMA-PC3 cells in vitro, prolonging survival without significant toxic side effects. CONCLUSIONS: This study emphasizes that upregulating dnTGFßRII and trTIM3 on the surface of T cells can potentially diminish the inhibitory effects of TGFßRII and TIM3.

CircHIPK3 negatively regulates autophagy by blocking VCP binding to the Beclin 1 complex in bladder cancer.

Circular RNA HIPK3 (circHIPK3) mediates the progression of multiple cancers, including bladder cancer, by regulating cell migration, autophagy and epithelial mesenchymal transition. However, the mechanism by which circHIPK3 regulates autophagy in bladder cancer cells remains unclear. Autophagy is a common self-protection mechanism in eukaryotic cells and is essential for cell survival and death regulation. However, it is unclear whether circHIPK3 affects the level of autophagy in bladder cancer through binding proteins, and the potential regulatory mechanism is unknown. Here, we found that circHIPK3 levels were significantly lower and autophagy-related proteins were significantly upregulated in bladder cancer cells and tissues compared to normal controls. CircHIPK3 downregulation promoted bladder cancer cell proliferation, while circHIPK3 overexpression inhibited proliferation. CircHIPK3 overexpression significantly suppressed autophagy in bladder cancer cells. Overexpression of circHIPK3 did not affect VCP protein expression but inhibited the VCP/Beclin 1 interaction. VCP also stabilized Beclin 1 and promoted autophagy in bladder cancer cells by downregulating ataxin-3. Thus, circHIPK3 may play an important role in bladder cancer by inhibiting VCP-mediated autophagy.

Vital function of DRD4 in dapoxetine medicated premature ejaculation treatment.

BACKGROUND: Recently, dapoxetine has been widely accepted to treat premature ejaculation by fast-inhibiting 5-hydroxytryptamine reuptake. However, dapoxetine is not suitable for all premature ejaculation patients in clinical treatment. We need to investigate and reveal the mechanism deeply to solve this problem. OBJECTIVES: To investigate and reveal the function of dopamine D4 receptor in dapoxetine medicated premature ejaculation treatment. MATERIALS AND METHODS: A rat model was used to screen rapid ejaculators. The molecular mechanisms of histone serotonylation-mediated regulation of dopamine D4 receptor were demonstrated by chromatin immunoprecipitation, DNA pull-down, mass spectrometry analysis, and coimmunoprecipitation experiments. The biological function of dopamine D4 receptor was investigated through in vivo experiments by intrathecal injection of shDRD4 to knockdown dopamine D4 receptor. RESULTS: In this study, we found that dapoxetine increased expression of 5-hydroxytryptamine and dopamine D4 receptor. We demonstrated that dapoxetine increased levels of 5-hydroxytryptamine, which promoted histone serotonylation (H3K4me3Q5ser) and transcription factor myeloid zinc-finger 1 complex binding on the dopamine D4 receptor promoter, upregulated the expression of dopamine D4 receptor and thus delayed ejaculation. DISCUSSION: In this study, we demonstrated that dapoxetine increased the levels of 5-hydroxytryptamine, which promoted histone serotonylation and myeloid zinc-finger 1 complex binding to the dopamine D4 receptor promoter and upregulated the expression of dopamine D4 receptor, thus delaying ejaculation. CONCLUSION: It is a novel mechanism that dapoxetine take effect of premature ejaculation treatment through upregulating the dopamine D4 receptor, which indicated that upregulated dopamine D4 receptor would enhance the dapoxetine effect in premature ejaculation treatment. This may lead to the development of novel therapeutic interventions for premature ejaculation.

Attenuation Effect of Recovery Sleep for Impaired Reproductive Function in Male Rats by Sleep Deprivation.

PURPOSE: The aim of the present study was to test the hypothesis that recovery sleep could counteract the detrimental effects of sleep deprivation (SD) on male rats' fertility. MATERIALS AND METHODS: Twenty-two rats were housed in groups of six per cage with unrestricted access to food and water in a room. The modified multiple platform method was used to induce SD in rats over a 96-hour period. We examined the effect of SD on semen quality, reproductive hormones, and testicular histology in adult male rats. Then, we investigated the effect of 7 days recovery sleep on impaired reproductive function induced by SD. RESULTS: After the acclimation period, 22 rats were randomly separated into three experimental groups (SD, recovery sleep, and the control groups). Ninety-six hours of SD resulted in a significant decrease in sperm motility (24.33±10.93 vs. 48.20±8.55, p<0.001) and the number of morphologically normal sperm (9.68±2.77 vs. 26.21±14.60, p<0.01) in rats, accompanied by a decrease in testosterone levels (1.53±0.55 vs. 4.44±0.56, p<0.001) and destruction of testicular tissue structure compared with control group. After 7 days of recovery sleep, semen quality, especially sperm motility, was improved and testosterone levels were significantly higher compared to post-SD (3.70±0.53 vs. 1.53±0.55, p<0.05), but remained low compared to the control group. CONCLUSIONS: In conclusion, 96 hours of SD deteriorated the parameters of sperm motility and the number of morphologically normal sperm in rats, probably due to the decrease in serum testosterone levels and the disruption of testicular tissue structure when compared to the control group. After 7 days of recovery sleep, semen parameter, especially sperm motility and testosterone levels did not return to baseline levels compared to the control group.

LncRNA GAS5 regulates the Wnt/ß-catenin pathway through the miR-18a-5p/AXIN2/GSK3ß axis to inhibit the proliferation and migration of bladder cancer cells.

LncRNA growth arrest specific 5 (GAS5) has been confirmed to play an essential role in a number of biological processes, such as tumor regulation and gene transcription. GAS5 has been shown to be a tumor suppressor gene in many types of cancer, but its specific mechanism of action in bladder cancer (BC) remains to be elucidated. In this study, we explored the biological properties of GAS5 in BC and its mechanism of action in BC. We analyzed the expression of GAS5 in 50 pairs of BC tissues and found that GAS5 was low expressed in BC tissues compared with normal mucosal tissues. In vitro and in vivo experiments showed that GAS5 could affect the proliferation and migration of BC cells. Nucleoplasmic isolation assays and fluorescence in situ hybridization (FISH) assays demonstrated the localization of GAS5 in cell cytoplasm. Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP) and luciferase assay demonstrated the target binding relationship of GAS5 with miR-18a-5p. Rescue experiments demonstrated that GAS5 promoted the proliferation and migration of BC cells through target binding of miR-18a-5p. Moreover, miR-18a-5p bound to its targets AXIN2 and GSK3ß, which in turn affected the expression of Wnt/ß-catenin pathway-related proteins. Our findings demonstrate that GAS5 regulates Wnt/ß-catenin pathway activity by regulating the miR-18a-5p/AXIN2/GSK3ß axis to modulate BC progression, providing a new potential therapeutic strategy for the treatment of BC.

The relationship between serum 25-hydroxy vitamin D and arteriogenic erectile dysfunction.

This study aimed to assess the relationship between 25(OH) levels and erectile dysfunction (ED), particularly arteriogenic ED (A-ED). From September 2020 to January 2022, 150 patients diagnosed with ED by the International Index of Erectile Function-5 (IIEF-5) questionnaire were included. All patients were classified as organic ED and psychological ED by nocturnal penile tumescence and rigidity (NPTR) examination. Organic ED patients were divided into A-ED and NA-ED by penile doppler ultrasound (PDU) examination. Finally, 150 patients complaining of ED were enrolled in our study. 25(OH)D levels were significantly lower in patients with organic ED (18.24 ± 6.04 ng/ml) than in patients with psychogenic ED (20.90 ± 8.79 ng/ml) (p = 0.032). In A-ED and NA-ED, the mean of peak systolic flow velocity (PSV) values was 18.94 ± 5.28 cm/s and 51.57 ± 15.42 cm/s (p < 0.001), and the mean of 25(OH)D was 15.66 ± 5.86 ng/ml and 20.48 ± 5.90 ng/ml, respectively (p < 0.001). The results showed that 25(OH)D levels were positively correlated with IIEF-5 scores and the PSV values in A-ED patients. The 25(OH)D cut-off value differentiating between A-ED and NA-ED was 15.05 ng/ml. Low 25(OH)D levels may be an independent risk factor for ED, especially A-ED. ED patients should routinely undergo serum 25(OH)D level measurement, and 25(OH)D replacement therapy is necessary for patients with low vitamin D levels.

Significance of detailed hematological parameters as markers of arteriogenic erectile dysfunction.

BACKGROUND: Several hematologic parameters have been shown to be strongly associated with cardiovascular disease, yet few studies were conducted to assess their relationship with atherogenic erectile dysfunction. OBJECTIVES: To find out the differences in hematological parameters between patients with atherogenic erectile dysfunction and healthy controls through as comprehensive a hematological examination as possible and try to assess and predict atherogenic erectile dysfunction using possible indicators. MATERIALS AND METHODS: We collected hematological parameters in detail from 105 healthy controls and 183 patients with erectile dysfunction (119 patients with atherogenic erectile dysfunction patients and 64 patients with venous erectile dysfunction) who were selected by nocturnal penile tumescence and rigidity and color duplex doppler ultrasound. RESULTS: Statistically significant differences were found between the atherogenic erectile dysfunction and venous erectile dysfunction groups in platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, and mean platelet volume (all p < 0.01). When comparing atherogenic erectile dysfunction with the healthy population, we found statistically significant differences between the two groups in white blood cell, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, mean platelet volume, triglycerides, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol (neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, mean platelet volume, triglycerides, and high-density lipoprotein cholesterol, p < 0.01; white blood cell, p = 0.024; non-high-density lipoprotein cholesterol, p = 0.036). Receiver operator characteristic curve analysis showed that neutrophil to lymphocyte ratio and platelet to lymphocyte ratio had the highest diagnostic value (neutrophil to lymphocyte ratio: area under the curve = 0.810, p < 0.001, cut-off = 1.995; platelet to lymphocyte ratio: area under the curve = 0.782, p < 0.001, cut-off = 126.3). CONCLUSION: Several hematological parameters (white blood cell, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, mean platelet volume, triglycerides, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol) can be considered markers of atherogenic erectile dysfunction, while these parameters were not significantly different in venous erectile dysfunction compared to healthy subjects. This suggests that hematological examinations may be a convenient and effective method to help evaluate and diagnose atherogenic erectile dysfunction.

Comprehensive analysis of MFN2 as a prognostic biomarker associated with immune cell infiltration in renal clear cell carcinoma.

BACKGROUND: Treatment of advanced kidney renal clear cell carcinoma (KIRC) remains challenging in clinic. The functional role and prognostic significance of MFN2 in KIRC are still unclear. METHODS: In this study, we first performed a bioinformatic analysis to determine the expression level and prognostic value of MFN2 in KIRC using The Cancer Genome Atlas (TCGA) dataset, and then validated the MFN2 mRNA expression in our cohort of clinical tissue samples and cell lines of KIRC via RT-qPCR. Cox regression model was used to identify the independent prognostic factors. A nomogram was constructed to predict the prognosis of KIRC patients. Gene set enrichment analysis (GSEA) was performed to predict the involved functional pathways of MFN2 co-expressed genes. The association between MFN2 expression level and immune cell infiltration was assessed using the TIMER and the TIDISB databases. In addition, cell proliferation and migration abilities of two KIRC cell lines with MFN2 overexpression were evaluated by MTS and wound healing assays, respectively. RESULTS: Downregulation of MFN2 was observed in KIRC tissues and cell lines compared to the normal controls. Kaplan-Meier curve analysis indicated an inferior survival outcomes in KIRC patients with lower MFN2 expression, uncovering the tumor-suppressive role of MFN2 in KIRC. Cox regression results showed that higher MFN2 expression was one of the independent protective factors in KIRC. Besides, function predictive analysis revealed that MFN2 co-expressed genes were enriched in the biological processes of energy metabolism and autophagy. Moreover, MFN2 expression was observed to be significantly associated with immune cell infiltration and a variety of markers of tumor infiltrating immune cells (TIICs) including multiple immune checkpoints in KIRC tissues. Finally, MFN2 overexpression significantly inhibited cell proliferation and migration abilities of two KIRC cell lines examined. CONCLUSION: Generally, our data suggested that MFN2 may serve as a potential prognostic biomarker and therapeutic target in KIRC.

The Association Between Erectile Dysfunction and Sleep Parameters: Data from a Prospective, Controlled Cohort.

BACKGROUND: Many studies have reported a possible strong relationship between poor sleep quality, sleep disruption, sleep disorders, and erectile dysfunction (ED). AIM: This study aimed to investigate the relationship between sleep quality and ED. METHODS: Patients diagnosed with ED by the International Index of Erectile Function-5 (IIEF-5) questionnaire and 72 healthy adult men were included. Participants completed the questionnaire, underwent a detailed physical examination, and provided blood samples. All enrolled subjects then wore the Fitbit Charge 2 that monitored sleep throughout the night. OUTCOMES: Primary outcome measures included scores on the IIEF-5, General Anxiety Disorder-7 (GAD-7) scale, Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), and sleep monitoring parameters obtained from Fitbit Charge 2. RESULTS: Finally, a total of 107 ED patients and 72 healthy adult men were enrolled in this study. Univariate analysis indicated that the GAD-7 (P < .001), PHQ-9 (P < .001), and PSQI scores (P < .001) significantly differed according to the presence/absence of ED. Further multiple logistic regression analysis showed that the PHQ-9 (odds ratio [OR]: 1.227, 95% confidence interval [CI]: 1.070-1.407; P = .003) and PSQI scores (OR: 1.220, 95%CI: 1.116-1.334; P < .001) were independent risk factors for ED. Analysis of objective sleep monitoring parameters showed that total sleep time (TST) (P = .001), sleep onset latency (SOL) (P = .026), deep sleep (N3) duration (P = .011) and rapid eye movement (REM) sleep duration (P < .001) were significantly differed between the 2 groups, with durations in the ED group significantly lower than those in the non-ED group. In addition, receiver operating characteristic (ROC) curve analysis indicated that the REM sleep duration had the highest area under the curve (AUC: 0.728) of all sleep parameters, with a P value < .001, a sensitivity of 72.2% and a specificity of 73.8%. CLINICAL IMPLICATIONS: Urologists and andrologists should be aware of impacted sleep quality and depression in ED patients. STRENGTHS & LIMITATIONS: The strength of this study is that the relationship between sleep quality and ED was assessed with both a subjective scale and an objective sleep monitoring tool. However, our study only described an association between sleep quality and ED and did not establish a causal relationship. CONCLUSION: Sleep parameters are strongly associated with ED, indicating that poor sleep quality may increase the likelihood of ED. Wu X, Zhang Y, Zhang W, et al. The Association Between Erectile Dysfunction and Sleep Parameters: Data from a Prospective, Controlled Cohort. J Sex Med 2022;19:1387-1396.

An objective correlation of specific haematological parameters with ED severity.

This study aims to investigate the role of nocturnal penile tumescence and rigidity (NPTR) and laboratory features in patients with mild, moderate and severe ED and then explored the correlation between ED severity with certain blood count parameters such as WBC and NLR. A total of 86 ED patients (age 29.8 ± 7.09 years) were enrolled. Classification of ED severity according to IIEF-5 scores was as follows: mild ED, 43.02% (37/86); moderate ED, 27.91% (24/86) and severe ED, 29.07% (25/86). Patients with moderate and severe ED had declined IIEF-5 scores and increased GAD-7 and PHQ-9 scores compared with mild ED. The mean NLR value of the mild, moderate and severe ED groups was 1.43 ± 0.39, 1.74 ± 0.45 and 2.0 ± 0.58, respectively. Stratification analysis according to NPTR results indicated that there was a significant difference in WBC and NLR between the two groups. Patients with abnormal NPTR had increased WBC and NLR levels compared with the normal groups. Multivariate logistic regression analysis suggested that severe ED (OR [95% CI]: 5.736 [1.248-26.354]), WBC (OR [95% CI]: 1.676 [1.094-2.567]) and NLR (OR [95% CI]: 5.595 [1.478-21.178]) were identified as independent risk factors for severe ED (abnormal NPTR results). In conclusion, this study indicates a significant difference in NLR, PLR, PDW, MPV and HDL between the mild, moderate and severe ED groups. The WBC and NLR are significantly increased in patients with severe ED (abnormal NPTR results) and it can be available as a quick, easy and cheap investigation compared with the RigiScan to evaluate the severity of ED with good sensitivity and specificity, which is important for the diagnosis and evaluation of ED.

Novel predictive risk factor for erectile dysfunction: Serum high-sensitivity C-reactive protein.

BACKGROUND: C-reactive protein (CRP), as a marker of inflammation, may be closely related to erectile dysfunction (ED), however, there is no meta-analysis exists for it. OBJECTIVES: We aimed to verify the relationship between CRP and erectile dysfunction and to explore the changes of CRP levels in ED patients after first-line treatment. MATERIALS AND METHODS: We searched databases including the Cochrane Library, PubMed, and MEDLINE to identify studies up to January 1, 2022. We performed a comprehensive analysis of the included studies by STATA software and calculated standardized mean differences (SMDs) and their corresponding 95% confidence intervals. RESULTS: A total of 12 studies were included and the analysis showed that CRP levels were higher significantly in patients with erectile dysfunction than the healthy controls (p < 0.001) and decreased by a mean of 0.38 mg/L after first-line PDE5i drug treatment (p = 0.001). DISCUSSION AND CONCLUSION: This novel meta-analysis suggests that CRP is statistically significantly associated with erectile dysfunction and may be a predictor or risk factor for the assessment of ED. However, further original studies with large sample sizes are needed to validate this.

Erectile Dysfunction in Multiple Sclerosis: A Prevalence Meta-Analysis and Systematic Review.

BACKGROUND: A connection between multiple sclerosis (MS) and erectile dysfunction (ED) has been debatable. AIM: To assess the pooled prevalence of ED among men with MS and whether MS was a risk factor for ED. METHODS: A systematic review of the literature was conducted in PubMed, Scopus, Web of Science, and the Cochrane Library to find relevant English-language studies published up to February 2022 that assessed the prevalence of ED in MS patients. Two authors independently evaluated the full text of the enrolled studies to determine eligibility, and if there was disagreement, the decision was made by a third author after discussion. Assessment tools adapted for prevalence studies were used to evaluate the quality of cross-sectional studies, and the quality of case-control studies was assessed by Newcastle-Ottawa scale. The relative risk (RR) and its 95% confidence interval (CI) were used to assess the strength of association between MS and the risk of ED. The sources of heterogeneity were investigated by subgroup analysis. Sensitivity analysis was conducted to evaluate the stability of the results. OUTCOMES: The pooled prevalence of ED in MS patients as well as 95% CIs were estimated, and the RR and its 95% CI were used to assess the strength of association between MS and the risk of ED. RESULTS: Sixteen studies included collectively gave information about ED in 2,760 MS men, resulting in a pooled prevalence of 49% (95% CI = 42-56%) for ED with a large heterogeneity. Synthesis of results revealed that MS was significantly associated with an increased risk of ED (RR = 3.17, 95% CI = 2.31-4.36, P < .001; heterogeneity: I2 = 0.0%, P = .716). The pooled prevalence estimates of ED were 55, 63, and 57% in the age >40, IIEF diagnostic tool, and mean disease duration >10 years subgroups, respectively. CLINICAL IMPLICATIONS: The present meta-analysis indicates that MS patients had a significantly increased risk of ED, which should raise awareness of the potential association between MS and ED by clinicians. STRENGTHS & LIMITATIONS: This is the first meta-analysis to provide the global prevalence of ED in MS patients and to demonstrate that MS is a risk factor for ED. However, all enrolled studies were observational in design, which may reduce the robustness of this evidence. CONCLUSION: Results of this meta-analysis showed that ED was highly prevalent in adult men with MS and MS was a potential risk factor for ED development. Wu X, Zhang Y, Zhang W, et al. Erectile Dysfunction in Multiple Sclerosis: A Prevalence Meta-Analysis and Systematic Review. J Sex Med 2022;19:1255-1268.

The Prevalence and Associated Risk Factors of Erectile Dysfunction in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Erectile dysfunction (ED) may be common in patients with inflammatory bowel disease (IBD), but its prevalence and risk factors still remain debatable. AIM: To evaluate the prevalence of ED in the IBD population and the potential role of risk factors in the development of ED. METHODS: An extensive search in the PubMed, Cochrane Library, and Web of Science was performed to identify relevant English-language articles published up to December 2021 that evaluated the prevalence of ED on IBD patients. The included studies were evaluated by 2 independent reviewers for eligibility. We used an adapted Assessment Tool for Prevalence Studies to evaluate the quality of enrolled studies. Data were analyzed and graphed using the STATA software (version 16.0; Stata Corporation, College Station, TX, USA). The ORs with 95% CIs were pooled using a fixed or random-effects model according to heterogeneity. Subgroup analysis was performed to explore the source of heterogeneity. Sensitivity analysis was conducted to evaluate the stability of the results. OUTCOMES: The pooled prevalence of ED in IBD patients was calculated, and the OR value and 95% CIs were used to assess the strength of the association between IBD-related risk factors and ED. RESULTS: Fourteen studies included 32,858 individuals totally were enrolled for this meta-analysis. The overall pooled prevalence estimate of ED in IBD patients was 27% (95% CI: 20-34%). Operation (OR 1.28; 95% CI: 1.17-1.39; P < .00001; I2 = 0.0%), disease activity (OR 2.06; 95% CI: 1.07-3.05; P < .00001), and depression (crude OR 3.31; 95% CI: 1.08-5.54; P = .004; I2 = 0.0%) significantly increase the risk of ED in people with IBD. The association of depression and ED was further confirmed by calculating the pooled estimates of adjusted OR (1.58; 95% CI: 0.05-3.12; P < .05; I2 = 0.0%). The pooled prevalence estimates of ED were 30, 33, and 17% in the age <40, IIEF diagnostic tool, and IPAA surgery subgroups, respectively. CLINICAL IMPLICATIONS: IBD patients had a significantly increased prevalence of ED, indicating that erectile function in men with IBD should be concerned by clinicians. STRENGTHS & LIMITATIONS: The strength of this study is that this is the first meta-analysis to assess the global prevalence and risk factors of ED in IBD patients. A limitation is that the results after pooling the included articles showed significant heterogeneity. CONCLUSION: The results of our meta-analysis and systematic review provide evidence of the high prevalence and risk factors of ED in IBD patients. Wu X, Zhang Y, Zhang W, et al. The Prevalence and Associated Risk Factors of Erectile Dysfunction in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Sex Med 2022;19:950-960.

Correlation between Drug Resistance of Klebsiella Pneumonia and Antimicrobial Drug Usage.

Objective. To assess the correlation between the drug resistance of Klebsiella pneumoniae and antimicrobial drug usage. Methods. The drug resistance rate of Klebsiella pneumoniae and the antimicrobial drug dosage of inpatients admitted to The Second Affiliated Hospital of Wannan Medical College from January 2016 to December 2020 were retrospectively recorded, and their correlation was analyzed using the Pearson method. Results. There are 6493 strains of Gram-negative bacteria, including 1272 strains of Klebsiella pneumoniae, ranking first in respiratory medicine. Klebsiella pneumoniae showed an overall increasing trend in resistance to piperacillin/tazobactam and ampicillin/sulbactam and a high resistance to aztreonam, ceftazidime, and ciprofloxacin (all P < 0.05). The top 3 antimicrobial drugs used in 2016-2020 were ß-lactams, quinolones, and macrolides. The rates of resistance to piperacillin/tazobactam, cefoperazone/sulbactam, and ampicillin/sulbactam were highly positively correlated with the use of ß-lactams. The use of carbapenems and glycopeptides was negatively correlated with the resistance to ciprofloxacin, and the resistance to ceftazidime had a high positive correlation with the use of glycopeptides and carbapenems. Conclusion. The use of antimicrobial drugs is correlated with the resistance rate of Klebsiella pneumoniae. To reduce bacterial drug resistance, the rational use of antimicrobial drugs requires joint control through multiple departments to improve the clinical use of antimicrobial drugs and improve in-hospital control.

High estradiol level is associated with erectile dysfunction: A systematic review and meta-analysis.

Numerous studies conducted to study the role of testosterone in erectile dysfunction (ED) extensively, but less is known of the association between estradiol level and ED. To assess the strong association between estradiol and ED by quantitatively synthesizing all studies evaluating the relationship between estradiol and ED. An extensive literature search was conducted by two authors independently in three electronic databases, including PubMed, Web of Science and Cochrane Library, up to January 10, 2021. The Patient Population or Problem, Intervention, Comparison, Outcomes and Setting (PICOS) were used for inclusion criteria to identify studies. The Newcastle-Ottawa Scale was applied to assess the quality of studies. The standardized mean difference (SMD) and their corresponding 95% confidence intervals (95% CIs) were used to compare the estradiol level between ED patients and healthy subjects, and the pooled OR and 95%CI were used to evaluate the strong association between estradiol level and ED. Finally, six studies were included in this meta-analysis, satisfying predefined inclusion criteria. Five studies were considered to be high quality, and only one was judged of moderate quality. The estradiol level of ED patients was statistically higher than that in healthy subjects (SMD 0.45, 95%CI 0.28-0.63, p <0.0001). The pooled OR demonstrated that the estradiol was correlated to the ED significantly (OR 1.08, 95%CI 1.05-1.12, p <0.0001). Subgroup analyses were conducted based on age, diagnosis way, country, sample size, detection method and estradiol level. There was no substantial change in the result of SMD ranging from 0.41 (95% CI 0.31-0.51) to 0.53 (95% CI 0.44-0.62) when performing sensitivity analysis. No publication bias was detected by the Begg test or Egger test. This meta-analysis demonstrated that the estradiol level is correlated to ED significantly.

Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer.

Abnormal RNA methylation and dysregulation of miRNA are frequently occurred in bladder cancer. Melittin is a potential drug candidate for intravesical chemotherapy against bladder cancer. However, the underlying epigenetic mechanism by which melittin-induced anti-tumor effect remains unclear. Here, we showed that melittin selectively induced apoptosis of bladder cancer cells in a METTL3-dependent manner. Ectopic expression of METTL3 significantly blocked melittin-induced apoptosis in vitro and in vivo. MicroRNA-sequence analysis identified miR-146a-5p suppression contributed to the melittin-induced selective antitumor effect. Further investigation revealed that METTL3-guided m6A modification methylated pri-miR-146 at the flanking sequence, which was responsible for the pri-miR-146 maturation. Moreover, NUMB/NOTCH2 axis was identified as a downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of patients with bladder cancer. Our study indicates that METTL3 acts as a fate determinant that controls the sensitivity of bladder cancer cells to melittin treatment. Moreover, METTL3/miR-146a-5p/NUMB/NOTCH2 axis plays an oncogenic role in bladder cancer pathogenesis and could be a potential therapeutic target for recurrent bladder cancer treatment.