Yuanshan Cui

Efficacy and Safety of Flibanserin in Women with Hypoactive Sexual Desire Disorder: A Systematic Review and Meta-Analysis

INTRODUCTION Flibanserin, is a postsynaptic agonist of serotonin receptor 1A and an antagonist of serotonin receptor 2A, has been shown to increase sexual desire and reduce distress in women with hypoactive sexual desire disorder (HSDD). AIM We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug in women with HSDD. METHODS A literature review was performed to identify all published randomized double-blind, placebo-controlled trials of flibanserin for the treatment of HSDD. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. MAIN OUTCOME MEASURES Four publications involving a total of 3,414 patients were used in the analysis, including four randomized controlled trials that compared flibanserin with placebo. RESULTS For the comparison of flibanserin with placebo, primary efficacy endpoints: satisfying sexual events (the standardized mean difference [SMD] = 0.59, 95% confidence interval [CI] = 0.37-0.80, P < 0.00001); sexual desire score (the SMD = 1.91, 95% CI = 0.21 to 3.60, P = 0.03) and Female Sexual Function Index (FSFI) desire domain score (the SMD = 0.32, 95% CI = 0.19-0.46, P < 0.00001) and key secondary efficacy endpoints: FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, FSDS-R Item 13 score, Patients Global Impression of Improvement score and Patient Benefit Evaluation indicated that flibanserin was more effective than the placebo. Safety assessments included the proportion of women who experienced an adverse event (odds ratio = 1.54, 95% CI =  .34 to 1.76, P < 0.00001), nervous system disorders and fatigue indicated that flibanserin was well tolerated. CONCLUSIONS This meta-analysis indicates that flibanserin to be an effective and safe treatment for HSDD in women.

Efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors in treating erectile dysfunction after bilateral nerve-sparing radical prostatectomy

We carried out a systematic review and meta‐analysis to assess the efficacy and safety of phosphodiesterase type 5 (PDE5) inhibitors for treating erectile dysfunction (ED) after bilateral nerve‐sparing radical prostatectomy (BNSRP). A literature review was performed to identify all published randomised double‐blind, placebo‐controlled trials of PDE5 inhibitors for the treatment of ED after BNSRP. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Six publications involving a total of 1678 patients were used in the analysis, including six RCTs that compared PDE5 inhibitors (tadalafil, sildenafil, avanafil and vardenafil) with placebo. Co‐primary efficacy end points: International Index of Erectile Function‐Erectile Function (IIEF‐EF) domain score [the standardised mean difference (SMD) = 4.04, 95% confidence interval (CI) = 2.87–5.22, P < 0.00001]; successful vaginal penetration (SEP2) [the odds ratio (OR) = 14.87, 95%CI = 4.57–48.37, P < 0.00001]; and successful intercourse (SEP3) (OR = 47, 95%CI = 3–13.98, P < 0.00001) indicated that PDE5 inhibitors was more effective than the placebo. Specific adverse events with PDE5 inhibitors included headache (12.08%), dyspepsia (6.76%) and flushing (6.52%), which were significantly less likely to occur with placebo. This meta‐analysis indicates that PDE5 inhibitors to be an effective and well‐tolerated treatment for ED after BNSRP.

Screening the key microRNAs and transcription factors in prostate cancer based on microRNA functional synergistic relationships.

Abstract Prostate cancer (PC) is a common neoplasm, and metastatic PC remains incurable. The study aims to screen key microRNAs (miRNAs) and transcription factors (TFs) involved in PC. The miRNA expression profile dataset (GSE45604) was downloaded from Gene Expression Omnibus database, including 50 PC and 10 normal specimens. Differentially expressed miRNAs (DEmiRNAs) were identified through limma package in R, and DEmiRNA–DEmiRNA co-regulation network was constructed based on the number of co-regulated target genes. Functional enrichment analysis of co-regulated target genes was performed using clusterProfiler package in R, and miRNA interactions sharing at least 1 functional term were used to construct a DEmiRNA–DEmiRNA functional synergistic network (MFSN). Based on Transcriptional Regulatory Element Database, cancer-related TFs which were co-regulated by DEmiRNAs were utilized to construct a DEmiRNA–TF regulation network. A total of 66 DEmiRNAs were identified, including 7 up-regulated miRNAs with 18,642 target genes and 59 down-regulated miRNAs with 130,694 target genes. Then, the DEmiRNA–DEmiRNA co-regulation network was constructed, including 66 DEmiRNAs and 2024 co-regulation relationships. In MFSN, hsa-miR-1184, hsa-miR-1207-5p, and hsa-miR-24 had significant functional synergistic relationships. The DEmiRNA–TF network contained 6 up-regulated DEmiRNAs and 4 of them were highlighted, as hsa-miR-1184, hsa-miR-1207-5p, hsa-miR-182, and hsa-miR-183. In subnetwork of the 4 miRNAs, peroxisome proliferative activated receptor, alpha (PPARA) and cyclic AMP-responsive element modulator (CREM) were the critical regulated TFs. Four up-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-1184, hsa-miR-182, and hsa-miR-183) and 2 TFs (PPARA and CREM) were identified as key regulators in PC progression. The above 4 miRNAs might participate in PC progression by targeting PPARA and CREM.

The efficacy and safety of silodosin for the treatment of ureteral stones: a systematic review and meta-analysis

BackgroundTo evaluate the efficacy and safety of silodosin as a medical expulsive therapy for ureteral stones by means of a systematic review and meta-analysis.MethodsWe searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register to identify randomized controlled trials (RCTs) of silodosin in the treatment of ureteral stones. The reference lists of retrieved studies were also investigated.ResultsSix RCTs, including 916 participants and comparing silodosin with controls, were used in the meta-analysis. Silodosin was superior to controls in terms of stone expulsion rate, the primary efficacy end point in all six RCTs (odds ratio [OR] for expulsion 2.16, 95 % confidence interval [CI] 1.62 to 2.86, p <0.00001). Silodosin was also more effective for secondary efficacy end points; the stone expulsion time (standardized mean difference [SMD] −3.66, 95 % CI −6.61 to −0.71; p =0.01) and analgesic requirements (SMD −0.89, 95 % CI −1.19 to −0.60; p < 0.00001) were significantly reduced compared with those of controls. Other than the incidence of abnormal ejaculation, which was higher in the silodosin groups (OR 2.84, 95 % CI 1.56 to 5.16, p =0.0006), few adverse effects were observed.ConclusionThis meta-analysis indicates silodosin is an effective and safe treatment option for ureteral stones with a low occurrence of side effects.

Meta-Analysis of the Efficacy and Safety of Mirabegron Add-On Therapy to Solifenacin for Overactive Bladder

Purpose We performed a meta-analysis to evaluate the efficacy and safety of mirabegron add-on therapy to solifenacin for patients with overactive bladder (OAB). Methods We conducted a systematic literature review to identify all randomized, double-blind, controlled trials (RCTs) of this combination (mirabegron and solifenacin) for OAB. Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched. A manual search was also performed to investigate relevant references from the retrieved studies. Results Four publications describing 5 RCTs that compared combination therapy with solifenacin, including a total of 3,309 patients, were analyzed. The mean number of micturitions per 24 hours (mean difference [MD], -0.45; 95% confidence interval [CI], -0.65 to -0.26; P<0.00001), number of episodes of incontinence per 24 hours (MD, -0.71; 95% CI, -0.14 to -0.02; P=0.04), volume voided per micturition, and number of urgency episodes per 24 hours demonstrated that combination therapy was more effective than solifenacin therapy alone. Safety assessments, including common treatment-emergent adverse events (odds ratio, 1.09; 95% CI, 0.95–1.27; P=0.23) and discontinuations due to adverse events (P=0.30), demonstrated that the combination therapy was well tolerated. Conclusions This meta-analysis suggests that mirabegron therapy as an add-on to solifenacin provides a satisfactory therapeutic effect for OAB symptoms with a low occurrence of side effects.

Effects of increased Kindlin-2 expression in bladder cancer stromal fibroblasts

Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin-embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression (p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of α-smooth muscle actin (α-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-β-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin-embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression (p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of α-smooth muscle actin (α-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-β-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.

Meta-analysis of the efficacy and safety of mirabegron and solifenacin monotherapy for overactive bladder.

We conducted a meta‐analysis to evaluate the safety and efficacy of mirabegron (50 mg) and solifenacin (5 mg) monotherapy for overactive bladder (OAB) during a 12‐week cycle.

Knockdown of mediator subunit Med19 suppresses bladder cancer cell proliferation and migration by downregulating Wnt/β-catenin signalling pathway

Mediator complex subunit 19 (Med19), a RNA polymerase II‐embedded coactivator, is reported to be involved in bladder cancer (BCa) progression, but its functional contribution to this process is poorly understood. Here, we investigate the effects of Med19 on malignant behaviours of BCa, as well as to elucidate the possible mechanisms. Med19 expression in 15 BCa tissues was significantly higher than adjacent paired normal tissues using real‐time PCR and Western blot analysis. Immunohistochemical staining of 167 paraffin‐embedded BCa tissues was performed, and the results showed that high Med19 protein level was positively correlated with clinical stages and histopathological grade. Med19 was knocked down in BCa cells using short‐hairpin RNA. Functional assays showed that knocking‐down of Med19 can suppress cell proliferation and migration in T24, UM‐UC3 cells and 5637 in vitro, and inhibited BCa tumour growth in vivo. TOP/FOPflash reporter assay revealed that Med19 knockdown decreased the activity of Wnt/β‐catenin pathway, and the target genes of Wnt/β‐catenin pathway were down‐regulated, including Wnt2, β‐catenin, Cyclin‐D1 and MMP‐9. However, protein levels of Gsk3β and E‐cadherin were elevated. Our data suggest that Med19 expression correlates with aggressive characteristics of BCa and Med19 knockdown suppresses the proliferation and migration of BCa cells through down‐regulating the Wnt/β‐catenin pathway, thereby highlighting Med19 as a potential therapeutic target for BCa treatment.

Efficacy and Adverse Events Associated With Use of OnabotulinumtoxinA for Treatment of Neurogenic Detrusor Overactivity: A Meta-Analysis

Purpose OnabotulinumtoxinA is used widely for the treatment of neurogenic detrusor overactivity. We conducted a systematic review and meta-analysis to assess its efficacy and safety for neurogenic detrusor overactivity treatment. Methods A systematic literature review was performed to identify all published randomized double-blind, placebo-controlled trials of onabotulinumtoxinA for neurogenic detrusor overactivity treatment. MEDLINE, Embase, and the CENTRAL were employed. Reference lists of retrieved studies were reviewed carefully. Results Six publications involving 871 patients, which compared onabotulinumtoxinA with a placebo were analyzed. Efficacy of onabotulinumtoxinA treatment was shown as a reduction of the mean number of urinary incontinence episodes per day (mean difference, -1.41; 95% confidence interval [CI], -1.70 to -1.12; P<0.00001), maximum cystometric capacity (135.48; 95% CI, 118.22–152.75; P<0.00001), and maximum detrusor pressure (-32.98; 95% CI, -37.33 to -28.62; P<0.00001). Assessment of adverse events revealed that complications due to onabotulinumtoxinA injection were localized primarily to the urinary tract. Conclusions This meta-analysis suggests that onabotulinumtoxinA is an effective treatment for neurogenic detrusor overactivity with localized advent events.

Cathelicidin LL37 promotes epithelial and smooth-muscle-like differentiation of adipose-derived stem cells through the Wnt/β-catenin and NF-κB pathways

Ureter reconstruction is a difficult procedure in urology. Adipose-derived stem cells (ADSCs), along with multipotency and self-renewal capacity, are a preferred choice for tissue engineering-based ureteral reconstruction. We explored the synergic role of cathelicidin LL37 (LL37) in epithelial and smooth-muscle-like differentiation. ADSCs were separated from adipose tissues of mouse and characterized by flow cytometry. The ADSCs were then stably transfected with pGC-FU-GFP (pGC) or pGC containing full-length LL37 (pGC-LL37), respectively. Cell viability and apoptosis were respectively estimated in the stably transfected cells and non-transfected cells. Then, qRT-PCR and Western blot analysis were used for determinations of epithelial marker expressions after induction by all-trans retinoic acid as well as smooth-muscle-like marker expressions after induction by transforming growth factor-β1. Then, possibly involved signaling pathways and extracellular expression of LL37 were detected. Cell viability and apoptosis were not changed after LL37 overexpression. Expression levels of epithelial and smooth-muscle-like markers were significantly upregulated by LL37 overexpression. Moreover, expressions of key kinases involved in the Wnt/β-catenin pathway as well as epithelial marker were upregulated by the LL37 overexpression, while it was reversed by Wnt/β-catenin inhibitor. Likewise, expressions of key kinases involved in the nuclear factor κB (NF-κB) pathway as well as smooth-muscle-like markers were upregulated by LL37 overexpression, which was reversed by NF-κB inhibitor. LL37 was found in the culture medium. LL37, which could be released into the medium, had no impact on cell proliferation and apoptosis of ADSCs. However, LL37 promoted epithelial and smooth-muscle-like differentiation through activating the Wnt/β-catenin and NF-κB pathways, respectively.