Urinary Exosomal miR-17-5p Accelerates Bladder Cancer Invasion by Repressing its Target Gene ARID4B and Regulating the Immune Microenvironment.

BACKGROUND: Urothelial bladder cancer (BCa) is a common malignant tumor of the urinary system. It has been identified that exosomal miRNAs contribute to the development of BCa. However, its significance and mechanism in the malignant biological behavior of BCa remain unclear. In this study, the influence of exosomal miRNAs on BCa progression was investigated. METHODS: High-throughput sequencing was conducted to analyze the microRNA-expression profile in urinary exosomes to screen out the key miRNA of muscle-invasive bladder cancer (MIBC). Then, candidate miRNA expression was verified and validated in urinary exosomes and tissue samples. To address the potential role of the candidate miRNA, we overexpressed and knocked down the candidate miRNA and explored its activity in BCa cell lines. Furthermore, the target gene of the selected miRNA was predicted and validated. RESULTS: The expression profile of miRNAs revealed increased expression of miR-17-5p in MIBC urinary exosomes, and this was later confirmed in urinary exosomes and tissue samples. Cell function studies revealed that exosomal miR-17-5p significantly promoted the growth and invasion of BCa cells. Bioinformatics and luciferase experiments demonstrated that the ARID4B mRNA 3' UTR might be the binding site for miR-17-5p. Low ARID4B levels were linked to high-grade BCa patients and were associated with a better prognosis. CONCLUSION: Elevated miR-17-5p contributes to BCa progression by targeting ARID4B and influencing the immune system. Based on these findings, miR-17-5p has the potential to be a new therapeutic target for the treatment of BCa.

Assessment of Three-Dimensional Reconstruction in Percutaneous Nephrolithotomy for Complex Renal Calculi Treatment.

Introduction: Three-dimensional (3D) reconstruction is a novel imaging technique widely used to improve surgical operations. Some studies have identified its role in Urology for percutaneous nephrolithotomy (PCNL). Objective: To explore the potential benefits of 3D reconstruction technology in PCNL for complex renal calculi treatment. Methods: A retrospective study involving 139 patients with complex kidney stones who underwent PCNL was conducted between September 30, 2018, to September 30, 2019. Group A patients (72) underwent the 3D reconstruction technique before PCNL, while group B (67) did not. The operation time, the duration of the hospital stay, the puncture accuracy, the decrease in hemoglobin concentration, the stone clearance rate, and the postoperative complications were noted and compared between the two groups. Results: The initial stone clearance rates 2 weeks after PCNL were 81.9 and 64.2% in groups A and B, respectively (P < 0.05). The first-time puncture success rates were 87.5 and 47.8 % in groups A and B, respectively (P < 0.05). Group A had a shorter operation time than group B (62 vs. 79 min, P < 0.05). Besides, the 3D reconstructive technique-assisted patients (91.7%) had no or mild complications, compared with (74.6%) group B patients. There was no significant difference in hemoglobin decline and hospital stay between the two groups. Conclusions: The 3D reconstruction technology is an effective adjunct to PCNL in the complex renal calculi treatment.

Complete retroperitoneal laparoscopic nephroureterectomy with bladder cuff excision for upper tract urothelial carcinoma without patient repositioning: a single-center experience.

OBJECTIVE: This study was performed to evaluate the outcome of complete retroperitoneal laparoscopic nephroureterectomy with bladder cuff excision (RLNU-BCE), which is performed to treat urothelial carcinomas in the renal pelvis or in the ureter higher than the crossing of the common iliac artery without patient repositioning. METHODS: We retrospectively analyzed the clinical data of 48 patients with upper tract urothelial carcinoma who underwent complete RLNU-BCE in our institution from May 2017 to September 2019. RESULTS: RLNU-BCE was successfully performed in all 48 patients. The median operation time was 110 minutes [interquartile range (IQR), 100-130 minutes], and the median postoperative anesthesia recovery time was 10 minutes (IQR, 7-15 minutes). The median postoperative hospitalization period was 5 days (IQR, 4-6 days). Pathologic examination revealed that the margin of all resected specimens was negative. After a median follow-up of 13 months (IQR, 7-20 months), no local recurrence or distant metastasis was found. No complications occurred during follow-up. CONCLUSION: Based on our experience with this technique, RLNU-BCE deserves application and promotion in clinical practice. Long-term comparative studies are required to confirm its superiority over other techniques.

Importance of PNO1 for growth and survival of urinary bladder carcinoma: Role in core-regulatory circuitry.

PNO1 (partner of Nob1) was known as a RNA-binding protein in humans, and its ortholog PNO1 was reported to participate ribosome and proteasome biogenesis in yeasts. Yet there have been few studies about its functions in mammalian cells, and so far its role in human cells has never been reported, especially in urinary bladder cancer (UBC).We interrogated the cellular functions and clinical significance of PNO1 in, and its molecular mechanism through microarrays and bioinformatics analysis. Our findings support that PNO1 participates in promoting proliferation and colonogenesis, while reducing apoptosis of UBC cells, and is also predicted to be associated with the migration and metastasis of UBC PNO1 knockdown (KD) attenuated the tumorigenesis ability of UBC in mouse. PNO1 KD led to the altered expression of 1543 genes that are involved in a number of signalling pathways, biological functions and regulation networks. CD44, PTGS2, cyclin D1, CDK1, IL-8, FRA1, as well as mTOR, p70 S6 kinase, p38 and Caspase-3 proteins were all down-regulated in PNO1 KD cells, suggesting the involvement of PNO1 in inflammatory responses, cell cycle regulation, chemotaxis, cell growth and proliferation, apoptosis, cell migration and invasiveness. This study will enhance our understanding of the molecular mechanism of UBC and may eventually provide novel targets for individualized cancer therapy.

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

AIM: 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. METHODS: Randomized controlled trials (RCTs) of mirabegron and solifenacin for OAB were searched systematically by using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of retrieved studies were also perused. RESULTS: Five RCTs which compared solifenacin with mirabegron were studied. Mirabegron achieved the same effect as solifenacin in treating OAB. The mean number of incontinence episodes per 24 h (P = 0.20), mean number of micturitions per 24 h (P = 0.11), mean number of urgency episodes per 24 h (P = 0.23), and mean volume voided per micturition (P = 0.05) suggested that mirabegron and solifenacin had no significant differences in terms of OAB treatment. With regard to drug-related treatment-emergent adverse events (DR-TEAEs) and dry mouth, mirabegron showed better tolerance than solifenacin. Post-voiding residual volume showed a distinct difference in the two groups. Hypertension and tachycardia did not show a significant difference between the two groups, but the pulse rate did. CONCLUSION: The therapeutic effect of mirabegron is similar to that of solifenacin, and mirabegron does not increase the risk of adverse events (AEs).

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-ß-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.

Knockdown of mediator subunit Med19 suppresses bladder cancer cell proliferation and migration by downregulating Wnt/ß-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/ß-catenin pathway, and the target genes of Wnt/ß-catenin pathway were down-regulated, including Wnt2, ß-catenin, Cyclin-D1 and MMP-9. However, protein levels of Gsk3ß 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/ß-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.

Knockdown of Mediator Complex Subunit 19 Suppresses the Growth and Invasion of Prostate Cancer Cells.

Prostate cancer (PCa) is one of the most common cancers in elderly men. Mediator Complex Subunit 19 (Med19) is overexpressed and plays promotional roles in many cancers. However, the roles of Med19 in PCa are still obscure. In this study, by using immunohistochemical staining, we found higher expression level of Med19 in PCa tissues than in adjacent benign prostate tissues. We then knocked down the Med19 expression in PCa cell lines LNCaP and PC3 by using lentivirus siRNA. Cell proliferation, anchor-independent growth, migration, and invasion were suppressed in Med19 knockdown PCa cells. In nude mice xenograft model, we found that Med19 knockdown PCa cells formed smaller tumors with lower proliferation index than did control cells. In the mechanism study, we found that Med19 could regulate genes involved in cell proliferation, cell cycle, and epithelial-mesenchymal transition, including P27, pAKT, pPI3K, IGF1R, E-Cadherin, N-Cadherin, Vimentin, ZEB2, Snail-1 and Snail-2. Targeting Med19 in PCa cells could inhibit the PCa growth and metastasis, and might be a therapeutic option for PCa in the future.

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

BACKGROUND: To evaluate the efficacy and safety of silodosin as a medical expulsive therapy for ureteral stones by means of a systematic review and meta-analysis. METHODS: We 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. RESULTS: Six 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. CONCLUSION: This meta-analysis indicates silodosin is an effective and safe treatment option for ureteral stones with a low occurrence of side effects.

Initial Experience of Sorafenib Neoadjuvant Therapy Combined with Retroperitoneoscopy in Treating T2 Large Renal Carcinoma.

OBJECTIVES: To investigate the safety and feasibility of sorafenib neoadjuvant therapy combined with retroperitoneoscopic radical nephrectomy (RRN) in treating T2 large renal cell carcinoma (RCC). METHODS: Retrospectively analyzed 5 cases (2 males and 3 females, aged 52-73 years) of T2 stage large RCC who receive preoperative sorafenib targeted treatment (400 mg bid for 1-3 months) and RRN between March, 2013, and July, 2014. Patient information, therapeutic regimen, drug adverse effect, tumor changes before and after surgery, and perioperative parameters were recorded. RESULTS: During the sorafenib therapy adverse effects included 2 cases of hypertension (Grade I toxicity), 1 case of hand-foot syndrome (Grade I), and 1 case of diarrhea (Grade II), which were all tolerable for patients. CT scan and histopathological tests confirmed significant reduction in the longest dimension (LD) and medium density (MD) of the tumor after therapy as well as tumor hemorrhage, necrosis, and cystic degeneration. All 5 patients received RRN surgery successfully around 2 weeks after drug discontinuation with only 1 case of perioperative complication. CONCLUSIONS: Sorafenib neoadjuvant therapy could significantly reduce the size and aggressiveness of T2 large renal tumors, thus reducing the operative challenge and enabling patients who were previously disqualified for operation to receive surgical treatment.

Minimally invasive treatment of renal transplant nephrolithiasis.

PURPOSE: Urolithiasis is a rare complication of renal transplantation, and there is limited evidence to guide treatment. Management of stones in the transplanted kidney can be challenging. We present our experience in treating upper urinary tract (UUT) allograft lithiasis using minimally invasive procedures, with the aim of demonstrating their efficacy and safety in renal transplant recipients. METHODS: The records of 1615 patients undergoing kidney transplantation and follow-up in our center between August 2000 and July 2014 were reviewed. The mode of presentation, donor type, onset time, immunosuppression protocol, stone character, therapeutic intervention and outcomes of those with UUT allograft lithiasis were recorded. Extracorporeal shock wave lithotripsy (SWL), flexible ureteroscopy (F-URS) and percutaneous nephrolithotomy (PCNL) were used in the management of these calculi. Stone composition was analyzed after the procedure. RESULTS: Nineteen renal transplant recipients (1.2 %, nine males and ten females) were found to have UUT allograft calculi. Of these, five underwent SWL (26.3 %), four had F-URS combined with lithotomy forceps extraction or holmium laser disruption (21.1 %), six had PNCL (31.6 %), one submitted to F-URS after two failed sessions of SWL (5.3 %), one combined PCNL and F-URS (5.3 %), and two spontaneously of stones (10.5 %). All patients were rendered stone-free with a combination of treatments, and none required a blood transfusion. CONCLUSIONS: The incidence of calculi in the transplanted kidney is low. Minimally invasive procedures are safe and effective means of removing allograft calculi.