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Table S1: Univariate and multivariate cox regression analyses for overall survival and progression-free survival in non-metastasis ccRCC patients

Transient receptor potential melastatin 7 (TRPM7) is important for the tumorigenesis and progression of several cancers. However, little is known about TRPM7 expression and its clinical significance in clear cell renal cell carcinoma (ccRCC). The expression dynamics of TRPM7 was examined in a clinical cohort of RCC specimens by qPCR, immunoblotting, and IHC staining. A series of in vitro and in vivo assays were performed to elucidate the function of TRPM7 in RCC and the underlying mechanisms. For the first time, results demonstrate that TRPM7 expression is markedly higher in RCC cell lines and clinical samples and had a positive correlation with T status, tumor size, and poor patients' overall survival and progression-free survival. Preclinical studies using multiple RCC cells and a mouse model indicate that TRPM7 promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Mechanistically, TRPM7 promotes AKT phosphorylation, leading to repression of the FOXO1 expression and transcriptional activity. Moreover, luciferase reporter assays demonstrate that miR-129-3p directly targets the 3′-UTR of TRPM7 and acts as a negative regulator of TRPM7. These findings reveal an important role for TRPM7 in the regulation of RCC growth and represent a novel prognostic biomarker for this disease.Implications: TRPM7 is an independent prognostic indicator in RCC, and targeting the TRPM7 signaling pathway may be a novel therapeutic approach for the treatment of RCC. Mol Cancer Res; 16(6); 1013–23. ©2018 AACR.

The effects of blocking antibodies to integrins on PCa cell adherence and migration. A. Adhesion assays showed that the GFP-labeled cancer cells (Green) adhesion to BMECs could be significantly blocked by the antibodies to ITGA4, but not to integrins alpha v, β1, and β3. B. The TEM assay showed the similar results with A. Error bars represent the mean {plus minus} S.D. of three independent experiments. *P < 0.05, **P < 0.01 and ***P < 0.001.

Primer sequences for the knockdown of PSCA and ITGA4 genes and the control

Prostate cancer (PCa) is the second cause of death due to malignancy among men, and metastasis is the leading cause of mortality in patients with PCa. MicroRNAs (miRNAs) play important regulatory roles in tumor development and metastasis. Here, we identified 13 miRNAs related to PCa metastasis by bioinformatics analysis. Moreover, we found that miR-671-5p was increased in metastatic PCa tissues, and its high expression indicated poor prognosis of PCa. MiR-671-5p could facilitate PCa cells proliferation, migration, and invasion in vitro and vivo. We confirmed that miR-671-5p directly bound to the 3’ untranslated regions of NFIA mRNA, and NFIA directly bound to the CRYAB promoter. High expression of NFIA and CRYAB negatively correlated with the advanced clinicopathological characteristics and metastasis status of PCa patients. Our study demonstrated that miR-671-5p promoted PCa development and metastasis by suppressing NFIA/ CRYAB axis.

Aim: To construct a survival prediction signature for prostate cancer (PC) based on the RNA N6-methyladenosine (m6A) methylation regulator. Materials & methods: This paper explores the interaction network of differentially expressed m6A RNA methylation regulators in PC by Pearson correlation analysis. Univariate Cox risk regression and LASSO regression analysis were used to construct a predictive signature of PC. Kaplan–Meier survival analysis compared the overall survival of the high- and low-risk groups. Results & Conclusion: We first constructed a prognostic two gene signature for PC based on the m6A RNA methylation regulators MRTTL14 and YTHDF2. The interaction network of m6A RNA methylation regulators in PC was also established.

Distant metastasis, predominantly to bone, is the leading cause of morbidity and mortality in prostate cancer. However, the mechanisms underlying prostate cancer metastases remain unknown. Prostate cancer cells exhibited discrete adhesion to bone marrow endothelial cells (BMEC), resulting in osteotropic metastasis. Prior data showed an increased metastatic propensity of prostate stem cell antigen (PSCA)–positive prostate cancer cells. The current study sought to characterize the roles of PSCA in the adhesion of prostate cancer cells to BMECs. Cell adhesion was assessed using the adhesion assay and transendothelial migration. The expression and regulation of integrins were evaluated by qRT-PCR, Western blot, promoter-luciferase activity, and chromatin immunoprecipitation (ChIP). Functionally, the potential interacting partners of PSCA in prostate cancer cells were identified by coimmunoprecipitation and mass spectrometry (MS) analysis. The association of PSCA expression with bone metastasis was further analyzed in an in vivo model and prostate cancer patients. We found that overexpression of PSCA enhanced the adhesion capability of prostate cancer cells to BMECs through upregulating integrin-α4 expression, concurrent with transcriptionally activated NF-κB. Growth factor progranulin (PGRN) was identified as a potential interacting partner of PSCA in prostate cancer cells. Functional studies showed that downregulation of PGRN and PSCA with siRNAs in prostate cancer cells significantly suppressed the integrin-α4 expression and the adhesion to BMECs in vitro, respectively, which were restorable by exogenous PGRN. Importantly, PSCA depletion significantly reduced tumors' presence in the bone of a mouse model. Furthermore, PSCA expression is elevated in prostate cancer tissue, and significantly associated with increased Gleason score, advanced stage, bone metastasis, and poor prognosis in prostate cancer patients. We conclude that PSCA/PGRN promoted the adhesion of prostate cancer cells to BMECs through NF-κB/integrin-α4 pathways, to facilitate metastases. Implications: The findings presented here suggest PSCA/PGRN as a potential therapeutic target for prostate cancer metastases, especially for bone metastasis.

Serine palmitoyltransferase long chain-1 (SPTLC1), which is the rate-limiting enzyme for sphingolipid biosynthesis, has been indicated to be essential for carcinoma cell survival and proliferation in recent, but its role in the regulation of renal cell carcinoma (RCC) remains unknown. In the present study, we found that SPTLC1 expression was significantly decreased in RCC tissues compared to non-tumor tissues, and low SPTLC1 expression was associated with poor overall survival of RCC patients. In addition, our results revealed that forced expression of SPTLC1 could significantly inhibit cell growth in vitro and in vivo via, at least in part, modulating Akt/FOXO1 signaling pathway, thus representing a novel role of SPTLC1 in the regulation of tumor growth in RCC for the first time.

Prostate cancer (PCa) has become the most frequently occurring cancer among western men according to the latest report, and patients’ prognosis is often poor in the event of tumor progression, therefore, many researches are devoted to exploring the molecular mechanism of PCa metastasis. MicroRNAs (miRNA) have proved to play an important role in this process. In present study, by combining clinical samples with public databases, we found that miR-629-5p increased to varying degrees in primary localized PCa tissues and metastatic PCa tissues compared with adjacent normal tissues, and bioinformatics analysis suggested that high level of miR-629-5p was related to poor prognosis. Functionally, miR-629-5p drove PCa cell proliferation, migration and invasion in vitro, and promoted growth of PCa cells in vivo. Moreover, A-kinase Anchor Protein 13 (AKAP13) was screened as a direct target of miR-629-5p, that expression was negatively correlated with the malignant phenotype of tumor cells. In the end, through verification in clinical specimens, we found that AKAP13 could be independently used as a clinical prognostic indicator. Overall, the present study indicates that miR-629-5p plays an oncogenic role in PCa by targeting AKAP13, which provides a new idea for clinical diagnosis and treatment of complex refractory PCa.

Erectile dysfunction (ED) is a common ageing male's disease, and vascular ED accounts for the largest proportion of all types of ED. One of the mechanisms of vascular ED in the clinic is arterial insufficiency, which mainly caused by atherosclerosis, trauma and surgical. Moreover, oxidative stress damage after tissue ischemia usually aggravated the progress of ED. As a new way of acellular therapy, mesenchymal stem cell‐derived exosomes (MSC‐Exos) have great potential in ED treatment. In the current study, we have explored the mechanism of MSC‐Exos therapy in a rat model of internal iliac artery injury‐induced ED. Compared with intracavernous (IC) injection of phosphate‐buffered saline after artery injury, of note, we observed that both mesenchymal stem cells (MSCs) and MSC‐Exos through IC injection could improve the erectile function to varying degrees. More specifically, IC injection MSC‐Exos could promote cavernous sinus endothelial formation, reduce the organization oxidative stress damage, and improve the nitric oxide synthase and smooth muscle content in the corpus cavernosum. With similar potency compared with the stem cell therapy and other unique advantages, IC injection of MSC‐ Exos could be an effective treatment to ameliorate erectile function in a rat model of arterial injury.

Background Epidemiological evidence of over 9000 people suggests that daily intake of vinegar whose principal bioactive component is acetic acid is associated with a reduced risk of nephrolithiasis. The underlying mechanism, however, remains largely unknown. Methods We examined the in vitro and in vivo anti-nephrolithiasis effects of vinegar and acetate. A randomized study was performed to confirm the effects of vinegar in humans. Findings We found individuals with daily consumption of vinegar compared to those without have a higher citrate and a lower calcium excretion in urine, two critical molecules for calcium oxalate (CaOx) kidney stone in humans. We observed that oral administration of vinegar or 5% acetate increased citrate and reduced calcium in urinary excretion, and finally suppressed renal CaOx crystal formation in a rat model. Mechanism dissection suggested that acetate enhanced acetylation of Histone H3 in renal tubular cells and promoted expression of microRNAs-130a-3p, −148b-3p and -374b-5p by increasing H3K9, H3K27 acetylation at their promoter regions. These miRNAs can suppress the expression of Nadc1 and Cldn14, thus enhancing urinary citrate excretion and reducing urinary calcium excretion. Significantly these mechanistic findings were confirmed in human kidney tissues, suggesting similar mechanistic relationships exist in humans. Results from a pilot clinical study indicated that daily intake of vinegar reduced stone recurrence, increased citrate and reduced calcium in urinary excretion in CaOx stone formers without adverse side effects. Interpretation Vinegar prevents renal CaOx crystal formation through influencing urinary citrate and calcium excretion via epigenetic regulations. Vinegar consumption is a promising strategy to prevent CaOx nephrolithiasis occurrence and recurrence. Fund National Natural Science Foundations of China and National Natural Science Foundation of Guangdong Province.

Purpose Sexual functioning is an important factor influencing quality of life. Mounting evidence suggests that both male and female patients with epilepsy (PWE) have an increased risk of developing sexual dysfunction (SD). The aim of this meta-analysis was to quantify the association between epilepsy and the risk of SD. Methods PubMed, Embase, and Cochrane Library database were systematically searched to identify the pertinent studies focusing on the association between epilepsy and SD. Relative risk (RR) for SD with 95% confidence interval (CI) was calculated. The overall quality of the evidence was generated by applying the GRADE-profiler. This meta-analysis was registered on the PROSPERO (ID: CRD42018103572, http://www.crd.york.ac.uk/PROSPERO ). Results Nine studies (3 cross-sectional, 5 case-control, and 1 cohort) were included in this meta-analysis, for a total of 1556 subjects and 599 cases of epilepsy. Synthetic results demonstrated that epilepsy was associated with an increased risk of female SD (6 studies, pooled RR = 2.69, 95%CI: 1.48–4.89, P = 0.001; heterogeneity: I2 = 88.9%, P Conclusions Epilepsy is significantly associated with an increased risk of SD in both sexes. These findings suggest that both clinicians and patients should recognize that epilepsy has a potential hazardous effect on sexual functioning.

Objective To assess whether radiotherapy (RT) for prostate cancer (PCa) was a risk factor for secondary bladder cancer (BLCa) through a meta-analysis. Materials and methods The MEDLINE, Embase, and the Cochrane Library were systematically searched for all studies investigating the risk of BLCa in patients with RT. The association between RT and risk of BLCa was summarized using hazard ratio with a 95%CI. The protocol for this meta-analysis is available from PROSPERO (CRD42018090075). Results Overall, 619,479 participants (age: 57-79 years) were included from 15 studies, 206,852 of whom were patients who received RT. Synthesis of results indicated that RT was significantly associated with an increased risk of BLCa compared with the risk in those who received radical prostatectomy or non-RT (overall HR=1.6, 95%CI: 1.33-1.92, P

Purpose: To evaluate whether serum neuroendocrine markers could effectively predict treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: The PubMed, Cochrane Library and Embase databases were sought to identify eligible studies concerning serum neuroendocrine markers and the prognosis of post-treatment mCRPC from inception to April 2018. The association between serum neuroendocrine markers, that is, chromogranin A (CgA) and neurone-specific enolase (NSE), levels and the prognosis of post-treatment mCRPC were summarized using a random-effects model and hazard ratio (HR) with 95% CI Sensitivity analyses were conducted to assess potential bias. Results: A total of 234 participants are included in this meta-analysis (mean age = 71.3 years) from 6 studies. The pooled results show that higher markers’ levels at baseline in patients were associated with unfavorable overall survival (OS; univariate analysis: HR 3.775, 95% CI 1.469–9.698, p = 0.006; multivariate analysis: HR 3.838, 95% CI 1.774–8.304, p = 0.001), and a similar situation was observed in progression-free survival (PFS; univariate analysis: HR 2.785, 95% CI 1.315–5.898, p = 0.007; multivariate analysis: HR 1.266, 95% CI 1.017–1.577, p = 0.035). Estimates of the total effects were generally consistent in the sensitivity analysis. Publication bias was observed when performing the univariate analysis of PFS, and we have the explanation accordingly. Conclusions: The results of this pooled analysis confirm serum neuroendocrine markers could be the effective predictor of treatment outcome in patients with mCRPC. In addition, a combination of CgA and NSE is more valuable to predict worse OS. Further randomized case-control trials are required to validate this relationship.

BACKGROUND An association between inflammatory bowel diseases (IBD) and increased susceptibility to sexual dysfunction (SD) was reported in a number of studies. METHOD MEDLINE (PubMed), EMBASE, and the Cochrane Library were systematically searched for all relevant studies reporting the sexual function in IBD patients. Relative risk (RR) with a 95% confidence interval (CI) was used to summarize the association between IBD and risk of SD. Subgroup and sensitivity analyses were applied to detect potential bias. RESULTS Overall, 351,668 male individuals and 1309 female individuals (the mean age ranged from 33.6 years to 52.4 years) were included from 8 studies (of which 4 studies provided the outcomes of both sexes). Synthesis of results revealed that IBD was significantly associated with an elevated risk of SD in male subjects (7 studies, RR = 1.41, 95% CI, 1.09-1.81, P = 0.008; heterogeneity: I2 = 80.2%, P < 0.001) and female subjects (5 studies, RR = 1.76, 95% CI, 1.28-2.42, P < 0.001; heterogeneity: I2 = 69.6%, P = 0.011). Stratified analysis by the mean age of the individuals indicated that patients with IBD with a relatively young age (male: younger than 50 years; female: younger than 40 years) exhibited a significantly increased odds of SD. Sensitivity analyses showed that no single study dominated the overall combined RR. CONCLUSION Evidence from this meta-analysis revealed that both male and female patients with IBD have a significantly increased risk of SD, which should remind both gastroenterologists and urologists to be aware of the potential hazardous effect of IBD for developing SD.

Introduction It has been reported that multiple sclerosis (MS) would increase the susceptibility to female sexual dysfunction (FSD). Aim To assess whether MS was a risk factor for FSD through a comprehensive literature review and meta-analysis. Methods MEDLINE (PubMed), Embase, Cochrane Library, and PsychINFO databases were systematically searched for all studies reporting sexual function in women with MS. The protocol for this meta-analysis is available from PROSPERO (CRD42018094392). Main Outcome Measures The association between MS and risk of FSD was summarized using relative risk or standard mean differences with 95% CI. Subgroup and sensitivity analyses were conducted to detect potential bias. Results Overall, 1,485 women participants (the mean age ranged from 29.15 to 45.89 years) were included from 9 studies (4 cross-sectional and 5 case-control studies); 826 of them were patients with MS, with a mean disease duration from 2.7 to 16.51 years. Synthesis of results revealed that MS was significantly associated with an increased risk of FSD (relative risk 1.87, 95% CI 1.25–2.78, P = .002; heterogeneity: I 2 = 89.0%, P < .001). Women with MS had significantly lower values in total Female Sexual Function Index scores as compared with healthy controls (standard mean differences –2.41,95% CI −3.87 to −0.96, P = .017; heterogeneity: I 2 = 97.2%, P = .001). The grading of recommendations assessment, development, and evaluation–relevant outcomes revealed that the absolute effect of MS on FSD was 434 more per 1000 (from 125 more to 888 more); and the overall quality of the evidence was judged as low. Clinical Implications The present meta-analysis indicates that women patients with MS have a significant elevated risk of sexual dysfunction, which should raise awareness of the potential association between MS and FSD by both neurologists and urologists. Strengths & Limitations This the first study to summarize all available evidence for combining the odds on the association between MS and the risk of developing FSD. However, all the included studies were observational design, which may downgrade this evidence. Conclusion Results of this meta-analysis revealed a potential hazardous effect of MS for developing FSD. High-quality stringently controlled studies with large sample size are still warranted to validate this relationship.

To evaluate the efficiency of an energy density of 0.05mj/mm2 of low intensity extracorporeal shockwave therapy (Li-ESWT) on erectile dysfunction (ED) patients.A total of 45 ED patients met the inclusion criteria, including 7 PDE5i responders and 38 nonresponders. All the patients have already been delivered 10000 shockwaves of total seven treatment points twice a week for 4 weeks. Simultaneously, questionnaires of International Index of Erectile Function-Erectile Function (IIEF-EF), Erectile Hard Score (EHS) and Minimal Clinical Important Differences (MCID) were evaluated for the efficiency and safety at 8th and 16th weeks.The changes in the IIEF-EF score by MCID suggested that Li-ESWT treatment was effective in 22 PDE5i nonresponders patients (58%) at 8th week. Then at 16th week the number of patients who were effectively treated increased to 27 (71%). Among PDE5i responders, 5 patients (71%) were effective base on MCID at 16th week. Among PDE5i nonresponders 22 patients (58%) achieved erection hard enough for vaginal penetration and increased to 27 (71%) patients at 16th week (EHS ≥3). Moreover, even 3 patients achieved EHS 4 in PDE5i nonresponders at 16th week. Among PDE5i responders, 4 of 7 patients reached EHS of 4 from EHS 3 at 16th week. Apart from this, Li-ESWT treatment was also effective in 9 patients (24%) in PDE5i nonresponders without follow-up PDE5i.Energy flux density (EFD) of 0.05 of Li-ESWT could improve the erectile function of ED patients with PDE5i response. In addition, EFD of 0.05 of Li-ESWT treatment could turn PDE5i nonresponders to responders.

The prostate stem cell antigen (PSCA), as a predominantly prostate-specific marker, is overexpressed in most prostate cancer specimens, is positively correlated with prostate cancer androgen independence, and has the potential to be treated with castration-resistant prostate cancer (CRPC) as a gene therapy target. Using the typical androgen deprivation therapy, most tumors will progress to CRPC, as well as develop into neuroendocrine prostate cancer (NEPC) characterized by the expression of neuroendocrine markers such as enolase 2 (NSE). Our study was aimed at investigating the expressions of PSCA and NSE and the relationship between the two markers, as well as the correlation between the PSCA and NSE expressions and the clinicopathological parameters in prostate cancer specimens from 118 patients by using immunohistochemistry. Our results demonstrated that the PSCA and NSE protein expressions did not correlate with the prostate cancer patients’ age or the hormone therapy but showed a significant correlation with the pathological tumor stage of prostate cancer, the Gleason score, and the presence of metastasis. There is a positive association between PSCA and NSE but a negative one between the prostate-specific antigen (PSA) and PSCA or between PSA and NSE. High PSCA and NSE expressions correlated with a poor prognosis in prostate cancer patients. PSCA may play an important role in the progression of neuroendocrine prostate cancer (NEPC).

Background It has been shown that sexual dysfunction (SD) is highly prevalent among patients with chronic renal failure (CRF), and starting renal replacement therapy may even increase it. However, SD is an infrequently reported problem in these treated patients. Aim To investigate the prevalence of SD among patients with CRF undergoing renal replacement therapy, by a meta-analysis method. Methods PubMed, Embase, and the Cochrane Library were systematically searched for all studies assessing sexual function in patients with CRF receiving renal replacement therapy from January 2000 to April 2020. Relative risk (RR) with 95% CIs was used for analysis to assess the risk of SD in patients with CRF receiving renal replacement therapy. The cross-sectional study quality methodology checklist was used for the cross-sectional study. The methodologic quality of the case-control and cohort studies was assessed with the Newcastle-Ottawa Scale. Data were pooled for the random-effect model. Sensitivity analyses were conducted to assess potential bias. The Begg and Egger tests were used for publication bias analysis. Outcomes The prevalence of SD among patients with CRF receiving renal replacement therapy was summarized using pooled RR and 95% CI. Results This meta-analysis included 3,725 participants from 10 studies. Of these, 737 were patients with CRF receiving renal replacement therapy. The mean age of participants ranged from 32.75 to 56.1 years. Based on the random-effect model, synthesis of results demonstrated that the prevalence of SD was significantly increased among patients with CRF receiving renal replacement therapy in women (RR = 2.07, 95% CI: 1.47–2.91, P = .000; heterogeneity: I2 = 78.7%, P = .000) and in men (RR = 2.95, 95% CI: 2.16–4.02, P = .000; heterogeneity: I2 = 86.1%, P = .000). Estimates of the total effects were generally consistent in the sensitivity analysis. No evidence of publication bias was observed. Clinical Implications Patients with CRF receiving renal replacement therapy had a significantly increased risk of SD, which suggests that clinicians should evaluate sexual function, when managing patients with CRF receiving renal replacement therapy. Strengths and Limitations This is the first study to explore the prevalence of SD among patients with CRF undergoing renal replacement therapy based on all available epidemiologic studies. However, all included studies were an observational design, which may downgrade this evidence. Conclusion The prevalence of SD is significantly increased among patients with CRF receiving renal replacement therapy. More research studies are warranted to clarify the relationship.

Hyperoxaluria is well known to cause renal injury and end-stage kidney disease. Previous studies suggested that the renal function of rats with hyperoxaluria was improved after dietary vinegar intake. However, its underlying mechanisms remain largely unknown. The aim of the present study was to examine changes of gut microbiota and blood and urinary metabolites that associate with changes in kidney function to identify mechanisms involved with vinegar induced amelioration of hyperoxaluria-induced kidney injury. Using an ethylene glycol (EG)-induced hyperoxaluria rat model, we evaluated the effects of the vinegar on renal injury. Oral administration of vinegar (2 ml kg-1 day-1) reduced the elevated serum creatinine, BUN, and protected against hyperoxaluria-induced renal injury, renal fibrosis, and inflammation. Gut microbiota analysis of 16S rRNA gene in the hyperoxaluria-induced renal injury rats showed that vinegar treatment altered their microbial composition, especially the recovery of the levels of the Prevotella, Ruminiclostridium, Alistipes and Paenalcaligenes genus, which were significantly increased in the hyperoxaluria-induced renal injury rats. Additionally, liquid chromatography-mass spectrometry (LC-MS)-based metabolome analysis showed that total of 35 serum and 42 urine metabolites were identified to be associated with protective effects of vinegar on hyperoxaluria-induced renal injury rats. Most of these metabolites were involved in thiamine metabolism, glycerol phosphate shuttle, biotin metabolism, phosphatidylcholine biosynthesis and membrane lipid metabolism. Importantly, the effects of vinegar against renal injury were weakened after depletion of gut microbiota by antibiotic treatment. These results suggest that vinegar treatment ameliorates the hyperoxaluria-induced renal injury by improving the gut microbiota and metabolomic profiles.

5α-reductase inhibitors (5-ARI) are widely employed for the treatment of benign prostatic hyperplasia. It has been noted that 5-ARI exhibit the potential to attenuate the risk of prostate cancer, but consistent agreement has not been achieved. Moreover, the effect of 5-ARI on cancer-specific mortality and progression of prostate cancer remains unclear. Therefore, the goal of the current meta-analysis was to elucidate the impact of 5-ARI on the incidence and progression of prostate cancer. We searched for all studies assessing the effect of 5-ARI on risk of prostate cancer in PubMed, Embase, Medline, and Cochrane Library databases. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were accepted to evaluate the association between 5-ARI and the risk of prostate cancer. Synthetic results implied that subjects who accepted 5-ARI compared with the placebo group experienced a distinctly weakened overall incidence of prostate cancer (RR = 0.74; 95% CI: 0.66–0.82; P < 0.001). Subgroup analyses further revealed that 5-ARI reduction of the incidence of prostate cancer was limited to low-grade (Gleason score 2–6; RR = 0.68; 95% CI: 0.57–0.81; P < 0.001) and intermediate-grade tumors (Gleason score 7; RR = 0.81; 95% CI: 0.67–0.97; P = 0.023), but not high-grade tumors (Gleason score >7; RR = 1.19; 95% CI: 0.98–1.43; P = 0.069). The results also showed that 5-ARI treatment did not significantly alter prostate cancer-specific mortality (RR = 1.0; 95% CI: 0.95–1.05; P = 0.916). In addition, it was worth noting that 5-ARI treatment acted in a protective role that presented a dramatic benefit to delay the progression of low-risk tumors (RR = 0.58; 95% CI: 0.43–0.78; P < 0.001).

With no effective therapy to prevent or treat ureteral stricture (US), a multifactorial fibrotic disease after iatrogenic injury of the ureter, the need for new therapies is urgent. Mesenchymal stem cells (MSCs) have been widely studied for treating tissue defects and excessive fibrosis, and recent studies established that one of the main therapeutic vectors of MSCs is comprised in their secretome and represented by extracellular vesicles (EVs). Thus, we have determined to explore the specific role of MSCs‐derived EVs (MSC‐EVs) treatment in a pre‐clinical model of US. The results firstly showed that either a bolus dose of MSCs or a bolus dose of MSC‐EVs (administration via renal‐arterial) significantly ameliorated ureteral fibrosis and recuperated ureter morphological development in a US rat model. We confirmed our observations through MSCs or MSC‐EVs treatment alleviated hydronephrosis, less renal dysfunction and blunted transforming growth factor‐β1 induced fibration. Due to MSC‐EVs are the equivalent dose of MSCs, and similar curative effects of transplantation of MSCs and MSC‐EVs were observed, we speculated the curative effect of MSCs in treating US might on account of the release of EVs through paracrine mechanisms. Our study demonstrated an innovative strategy to counteract ureteral stricture formation in a rat model of US.

Objective.It has been reported that there is an association between rheumatoid arthritis (RA) and increased susceptibility to sexual dysfunction (SD). This systematic review and metaanalysis aimed to investigate whether RA was a risk factor for SD.Methods.MEDLINE (PubMed), EMBASE, and the Cochrane Library were systematically searched for all studies assessing sexual function in patients with RA. The association between RA and risk of SD was summarized using relative risk (RR) with 95% CI.Results.Overall, 44,745 participants (mean age 43.2 yrs) were included from 7 studies (4 cross-sectional and 3 case-control studies). Of these, 6642 were patients with RA, with the mean disease duration from 5.7 years to 12.17 years. The methodological qualities of the included studies were judged as moderate to high. Synthesis of results demonstrated that RA was significantly associated with an increased risk of SD in females (RR 1.73, 95% CI 1.36–2.22, p < 0.001; heterogeneity: I2 60.3%, p = 0.028) as well as in males (RR 1.99, 95% CI 1.64–2.43, p < 0.001). The outcomes related to the Grading of Recommendations Assessment, Development, and Evaluation approach showed that the absolute effect of RA on SD was 10 more per 1000 (6–15 more); the overall quality of evidence was rated as low.Conclusion.Evidence from included studies indicates that patients with RA have a significantly increased risk of SD, which suggests that both patients and clinicians should be aware of the potential role of RA in the development of SD.

Background The Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored protein. Increasing evidence has indicated PSCA plays an important role in tumorigenesis. However, its function and the underlying molecular mechanisms in prostate cancer (PCa) are still not fully elucidated. In this study, we aimed to explore the effect of PSCA on cell cycle of PCa cells and its mechanism research. Methods Immunohistochemistry, quantitative reverse transcription-PCR (qRT-PCR) and Western blotting were used to quantify PSCA expression pattern in PCa tissues and cell lines. The association of PSCA expression with the biochemical recurrence (BCR)-free survival and overall survival (OS) of PCa patients were analyzed using Kaplan-Meier method. The roles of PSCA in PCa were confirmed based on both in vitro and in vivo systems. Results Immunohistochemistry results showed that PSCA was upregulated in PCa tissue. PSCA overexpression were significantly associated with high Gleason score (GS) (P = 0.028), positive BCR (P = 0.002), and poor OS (P = 0.032) and high c-Myc expression (P = 0.019). PSCA promoted PCa cell cycle progression and tumor growth via increased c-Myc expression. Additional, PI3K/AKT signaling pathways was involved in PSCA-mediated c-Myc expression and cell proliferation. Conclusions PSCA is a novel cell cycle regulator with a key role in mediating c-Myc-induced proliferation. PSCA may be a potential diagnostic marker and therapeutic target for patients with PCa.

Background Opioid analgesics have been widely used to relieve chronic pain conditions; however, a connection between opioid analgesic administration and increased susceptibility to erectile dysfunction (ED) has been hypothesized. Aim To evaluate whether opioid use was a risk factor for ED in a systematic review and meta-analysis. Methods The PubMed, Cochrane Library, and Embase databases were searched to identify eligible studies concerning opioid use and risk of ED from inception to April 2017. The association between opioid use and risk of ED was summarized using the relative risk with 95% CI. Sensitivity analyses were conducted to assess potential bias. The Begg and Egger tests were used for publication bias analysis. The GRADE evidence profile tool was used to assess the quality of the evidence. Outcomes The overall combined risk estimates for the effect of opioid use on ED were calculated using a random-effects model. Results This meta-analysis included 8,829 men (mean age = 41.6 years) from 10 studies, 2,456 of whom received opioid management (duration of intervention = 4 months to 9.5 years). Pooled results demonstrated that the use of opioids was significantly associated with an increased risk of ED (relative risk = 1.96, 95% CI = 1.66–2.32, P < .001). Estimates of the total effects were generally consistent in the sensitivity analysis. No evidence of publication bias was observed. The overall quality of evidence was rated as low. Clinical Implications We found that men with opioid use had a significantly increased prevalence of ED, which suggests that patients and clinicians should be aware of the potential role played by opioid administration in the development of ED. Strengths and Limitations This is the first meta-analysis performed to describe the relation between opioid use and ED risk based on all available epidemiologic studies. However, the direction of causality between opioid use and risk of ED should be interpreted with caution because most included studies used a cross-sectional design. Conclusion Evidence from the included observational studies indicated that men with opioid use had a significantly increased risk of ED. Further randomized controlled trials are still needed to confirm this relation.

Background Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. We previously reported that PSCA involved in proliferation and invasion of PCa cells, however, the underlying mechanisms are unknown. In this study, we aimed to explore the regulating role of PSCA gene expression in interleukin-6 (IL-6) autocrine of PCa cells. Methods The stable knockdown-PSCA and ectopically overexpressed-PSCA vector were constructed and transfected into human PCa DU145 and PC-3M cells. The effects of PSCA overexpression or knockdown were determined in proliferation, invasion, and metastasis assays. The effect of PSCA on the expression and secretion of IL-6 was evaluated by immunoblotting and ELISA. Subcellular localization and expression pattern of PSCA and IL-6 protein were examined by immunohistochemistry. Its clinical significance was statistically analyzed. Results The results showed that stable knockdown of PSCA delayed proliferation, migration, and invasion while overexpressing PSCA enhanced the proliferation, migration, and invasion in vitro and the lung metastasis in vivo of PCa cells. Importantly, the PSCA involved in the IL-6 secretion and positively regulated p38/NF-κB/IL-6 signaling, leading to enhanced PCa cell invasion and metastasis. Both the expression of PSCA and IL-6 were significantly associated with poor biochemical recurrence-free survival of patients with PCa. PSCA protein expression showed a prognostic value in overall survival as indicated by Kaplan-Meier analysis. Conclusions These results indicate that PSCA regulates the expression and secretion of IL-6 in human PCa cells through p38/NF-κB signaling pathways. PSCA may be a potential diagnostic marker and therapeutic target for PSCA-positive PCa.

To investigate the effect of miR-145 on the phenotypic modulation in rat corpus cavernosum smooth muscle cells. Corpus cavernosum smooth muscle cells were treated with either miR-145 mimics or miR-145 negative control. Cell proliferation were analyzed by the MTS assay and colony formation assay. Wound healing assay were performed to detect the effect of miR-145 on cell migration. The mRNA and protein levels of phenotype marker proteins were assessed by quantitative real-time polymerase chain reaction and western blotting. The intracavernosal pressure and mean arterial pressure were measured to assess erectile function at one month after the injection of platelet-derived growth factor-BB and miR-145. Our results showed that miR-145 inhibited the proliferation and migration of cavernosal smooth muscle cells. Smooth muscle cell phenotypic markers were also affected by overexpression of miR-145, as indicated by the increase in α-smooth muscle actin, calponin and smooth muscle myosin heavy chain expression. Moreover, significantly attenuated erectile function was observed in the platelet-derived growth factor-BB group as compared with the platelet-derived growth factor-BB+miR-145 group. These findings indicated that miR-145 regulate phenotypic modulation of corpus cavernosum smooth muscle cells.

Background The prevalence of erectile dysfunction (ED) in men positive for HIV has been reported to exceed the baseline of the general population. However, no meta-analysis or conclusive review has investigated whether individuals with HIV infection have a significantly higher prevalence of ED. Aim To explore the exact association between HIV infection and the prevalence of ED. Methods The PubMed, Embase, Medline, and Cochrane Library databases were searched to identify studies concerning the association between HIV infection and the prevalence of ED that were published up to December 2016. Manual searches also were performed. Relative risks and corresponding 95% confidence intervals were used to estimate the strength of association between HIV infection and the prevalence of ED. The methodologic quality of the included cohort studies was assessed through the Newcastle-Ottawa Scale. The cross-sectional study quality methodology checklist was used to assess the quality of cross-sectional studies. Sensitivity analyses were conducted to assess potential bias. This study was conducted according to the guidelines for Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE). Outcomes The strength of association between HIV infection and the prevalence of ED was evaluated using summarized unadjusted pooled relative risks and 95% confidence intervals. Results Two cohort studies and three cross-sectional studies involving 4,252 participants were included. Mean age of patients ranged from 35.2 to 52 years in the included studies. Based on the random-effects model, analyses of all studies showed that HIV infection was significantly associated with an increased prevalence of ED (relative risk = 2.32, 95% confidence interval = 1.52–3.55, P < .001). There was significant heterogeneity among included studies (I2 = 84%, P < .001). Estimates of total effects were generally consistent with the sensitivity. Clinical Implications Individuals with HIV infection had a significantly increased prevalence of ED, which suggests that ED should be of concern to clinicians when managing men with HIV infection. Strengths and Limitations A strength of this study is that it is the first meta-analysis to explore the relation between HIV infection and the prevalence of ED. A limitation is that all included studies were observational studies, which can induce recall bias or selection bias. Conclusion Evidence from the observational studies suggested that individuals with HIV infection had a significantly increased prevalence of ED despite significant heterogeneity. More research is warranted to clarify the relation between HIV infection and the prevalence of ED.

Previous studies investigating the risk of erectile dysfunction (ED) among patients with gout have produced inconsistent evidence. Therefore, the aim of this meta-analysis was to investigate the relationship between gout and the risk of ED. The Embase, Medline, Scopus, Web of Science and Cochrane Library databases were searched for all studies assessing the risk of ED in patients with gout. Relative risks (RR) and corresponding 95% confidence intervals (CI) were adopted to estimate the association between gout and the risk of ED. Sensitivity analyses were applied to evaluate the robustness of results. Overall, 355,761 participants were included from 8 studies (3 cross-sectional and 5 cohort studies). Of these, 85,067 were patients with gout. Synthesis results showed patients with gout had a 1.2-fold higher risk of ED than individual without gout (RR 1.20, 95% CI 1.10–1.31, P

Objective To evaluate the therapeutic effect of Shengjing capsules on nonobstructive azoospermia (NOA) in the rat model. Methods Twenty-five male Sprague–Dawley rats were randomly divided into five groups as follows (n=5 per group): normal group, NOA group, and three Shengjing capsule treatment groups (low-dose, medium-dose, and high-dose groups, respectively). HE staining and semen smear were performed to assess sperm quality. The expression levels of PI3K/AKT and integrin α6/β1 were measured by qRT-PCR and western blot analyses. Results In the NOA group, almost all of the seminiferous tubules were vacuolated with a thin layer of basal compartment containing some spermatogonial stem cells. The counts of sperms in the NOA group were strongly lower than those of the normal group (P=0.0001). The expression of PI3K/AKT and integrin α6/β1 was scarcely expressed in the NOA group. All indexes mentioned above were significantly different from those of the medium- and high-dose groups (P=0.001, all). The sperm count of rats treated with Shengjing capsules was significantly higher than that of the NOA group (P=0.0001). The rats of Shengjing capsule groups had more layers of spermatogonial stem cells and spermatocytes, and some had intracavitary sperms. Conclusions Shengjing capsules may be a promising therapeutic medicine for NOA. The underlying mechanisms might involve activating SSCs by upregulating the integrin α6/β1 expression via the PI3K/AKT pathway.

Objective. To evaluate the therapeutic effect of Shengjing capsules on nonobstructive azoospermia (NOA) in the rat model. Methods. Twenty-five male Sprague–Dawley rats were randomly divided into five groups as follows (n=5 per group): normal group, NOA group, and three Shengjing capsule treatment groups (low-dose, medium-dose, and high-dose groups, respectively). HE staining and semen smear were performed to assess sperm quality. The expression levels of PI3K/AKT and integrin α6/β1 were measured by qRT-PCR and western blot analyses. Results. In the NOA group, almost all of the seminiferous tubules were vacuolated with a thin layer of basal compartment containing some spermatogonial stem cells. The counts of sperms in the NOA group were strongly lower than those of the normal group (P=0.0001). The expression of PI3K/AKT and integrin α6/β1 was scarcely expressed in the NOA group. All indexes mentioned above were significantly different from those of the medium- and high-dose groups (P=0.001, all). The sperm count of rats treated with Shengjing capsules was significantly higher than that of the NOA group (P=0.0001). The rats of Shengjing capsule groups had more layers of spermatogonial stem cells and spermatocytes, and some had intracavitary sperms. Conclusions. Shengjing capsules may be a promising therapeutic medicine for NOA. The underlying mechanisms might involve activating SSCs by upregulating the integrin α6/β1 expression via the PI3K/AKT pathway.

The aim of this study was to evaluate whether polycystic ovary syndrome (PCOS) is a risk factor for female sexual dysfunction (FSD) by conducting a systematic review and meta-analysis. The databases PubMed, EMBASE and the Cochrane Library were searched for relevant studies. The association between PCOS and risk of FSD was assessed by relative risk or standard mean differences with 95% confidence interval. The protocol for this meta-analysis is available from PROSPERO (CRD42018102247). Overall, 2626 participants (mean age 25–36 years) were included from 10 studies (five cross-sectional and five case-control studies), 1163 of whom were women with PCOS. The pooled results from eight included studies providing the number of cases revealed no significant association between PCOS and increased risk of FSD (RR = 1.09, 95% CI 0.9 to 1.32; heterogeneity: I2 = 11.0%). The combined overall standard mean difference from five studies reporting Female Sexual Function Index (FSFI) scores showed that patients with PCOS had similar values in total FSFI scores compared with healthy controls (standard mean difference = –0.03, 95% CI –0.12 to 0.05; heterogeneity: I2 = 0.0%). Sensitivity analyses yielded similar results. This meta-analysis suggests no direct association between PCOS and risk of FSD. Well-controlled trials with large sample sizes, however, are needed to validate this evidence.

A Correction to this paper has been published: https://doi.org/10.1038/s41416-020-01258-w

Introduction 5α-Reductase inhibitors (5ARIs) are widely used for the treatment of benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA). Aim To review all the available data on the effect of 5ARIs on sexual function and assess whether 5ARIs increase the risk of sexual dysfunction. Methods A systematic search of the literature was conducted using the Medline, Embase, and Cochrane databases. The search was limited to articles published in English and up to October 2015. Article selection proceeded according to the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Data were analyzed using Stata 12.0. A fixed- or a random-effects model was used to calculate the overall combined risk estimates. Publication bias was assessed using Begg and Egger tests. Main Outcome Measures Sexual dysfunction, erectile dysfunction, and decreased libido. Results After screening 493 articles, 17 randomized controlled trials with 17,494 patients were included. Nine studies evaluated the efficacy of 5ARIs in men with BPH. The other eight reported using 5ARIs in the treatment of men with AGA. The mean age of participants was 60.10 years across all studies. We included 10 trials (6,779 patients) on the efficacy and safety of finasteride, 4 trials (6,222 patients) on the safety and tolerability of dutasteride, and 3 trials (4,493 patients) using finasteride and dutasteride for AGA. The pooled relative risks for sexual dysfunction were 2.56 (95% CI = 1.48–4.42) in men with BPH and 1.21 (95% CI = 0.85–1.72) in men with AGA; those for erectile dysfunction were 1.55 (95% CI = 1.14–2.12) in men with BPH and 0.66 (95% CI = 0.20–2.25) in men with AGA; and those for decreased libido were 1.69 (95% CI = 1.03–2.79) in men with BPH and 1.16 (95% CI = 0.50–2.72) in men with AGA. Estimates of the total effects were generally consistent with the sensitivity analysis. No evidence of publication bias was observed. Conclusion Evidence from the randomized controlled trials suggested that 5ARIs were associated with increased adverse effects on sexual function in men with BPH compared with placebo. However, the association was not statistically significant in men with AGA. Well-designed randomized controlled trials are indicated to study further the mechanism and effects of 5ARIs on sexual function.

Background Mounting evidence has emerged suggesting that patients with Parkinson’s disease (PD) are susceptible to sexual dysfunction (SD). Aim To better clarify the relationship between PD and SD. Methods PubMed, Embase, Cochrane Library database, and PsychINFO database were systematically searched for pertinent studies evaluating sexual function in the patients with PD. This systematic review and meta-analysis have been registered on PROSPERO (ID: CRD42018108714; http://www.crd.york.ac.uk/PROSPERO). Outcomes The association between PD and SD was assessed using relative risk (RR) with 95% CI. The quality of evidence was ranked by the GRADE profiler. Results 11 observational studies met the predefined criteria for inclusion, enrolling 30,150 subjects from both the PD group and healthy control group (mean age 54.6–75.1 years). Synthesis results revealed that PD was associated with an elevated risk of SD in males (7 studies; 1.79; 95% CI = 1.26–2.54, P = .001; heterogeneity: I2 = 73.2%, P < .001). However, when restricted to female subjects, the combined RR from 3 eligible studies suggested a lack of significant association between PD and SD (RR = 1.3, 95% CI = 0.64–2.61, P = .469; heterogeneity: I2 = 80.0%, P = .007). The GRADE profiler indicated the overall quality of the evidence was low in studies including males and very low in studies including females. Clinical Implications The current meta-analysis indicated that men with PD were more likely to experience SD than those without PD. In female subjects, however, PD seemed to not be associated with a high prevalence of SD compared with healthy controls. Based on these findings, patients with PD should be routinely assessed for sexual functioning, especially males. Strengths & Limitations This is the first systematic review and meta-analysis of the association between PD and the risks of SD in both males and females. However, substantial heterogeneities were detected across the included studies. Conclusion A hazardous effect of PD for developing SD was detected in men but not in women. As a result, sexual function assessment and appropriate therapy are recommended for men with PD in clinical practice.

Chronic obstructive pulmonary disease (COPD) is a common chronic disease. Mounting evidence shows that male patients with COPD have an increased risk of developing erectile dysfunction (ED). The aim of this meta-analysis was to assess the relationship between COPD and the risk of ED. To identify relevant studies, the PubMed, Cochrane Library and Embase databases, Chinese Biomedical Literature (CBM), China National Knowledge Infrastructure (CNKI) were systematically searched up to September 2018. Relative risks (RR) and corresponding 95% confidence intervals (CI) were used to estimate the strength of association between COPD and the risk of ED by using random-effects models. Finally, four studies (three cross-sectional, one cohort study) involving 58,307 participants were included. Synthesis results demonstrated that patients with COPD was not significantly associated with an increased overall prevalence of ED (RR = 1.31, 95% CI: 0.95–1.81, P = 0.099) compared to the healthy controls. However, the subgroup analyses showed that the prevalence of moderate ED (RR = 2.44, 95% CI: 1.29–4.59, P = 0.006) and severe ED (RR = 2.77, 95% CI: 1.57–4.94, P = 0.001) were significantly higher in patients with COPD. Evidence from this meta-analysis revealed that patients with COPD had a significantly increased susceptibility to moderate and severe ED, which should remind both clinicians and patients to be aware of the potential hazardous effect of COPD for developing ED.