Kindlin-2 mediates Peyronie's disease through activation of TGF-ß/Smad signaling pathway under the presence of TGF-ß1.

BACKGROUND: Peyronie's disease (PD) causes benign plaques or induration in tunica albuginea (TA). Kindlin-2 regulates the TGF-ß1/Smad3 pathway, which accelerates kidney fibrosis. The study is aimed mainly to investigate the impact of Kindlin-2 on PD formation and its signaling pathways, notably the TGF-ß/Smad pathway in the presence of TGF-ß1. METHODS: In this mouse investigation, adenovirus TGF-ß1 was injected into TA to produce PD. The model was successfully induced 45 days later. Western Blot (WB) and immunohistochemistry (IHC) were utilized to measure Kindlin-2 in PD model tissue. WB and immunofluorescence assays were utilized to confirm the impact of TGF-ß1 on Kindlin-2 levels in vitro. The interaction among Kindlin-2, TßRI, and Smad3 was detected using immunoprecipitation (IP) experiments. We examined how TGF-ß1 affects Smad3 phosphorylation and downstream gene activation process. Finally, Kindlin-2 and the level of tissue fibrosis were examined in PD model. RESULTS: Kindlin-2 levels were elevated in the TGF-ß1-induced PD model, confirming that TGF-ß1 can increase Kindlin-2 levels in primary PD cells. Moreover, Kindlin-2 mediates Smad3-TßRI interaction, activates p-Smad3, and enhances TGF-ß1 target gene expression. In vivo investigations reveal that Kindlin-2 promotes PD development and tissue fibrosis. The regulatory effects of Kindlin-2 need the presence of TGF-ß1. Tissue fibrosis can be reduced by downregulating Kindlin-2. CONCLUSION: Kindlin-2 does not directly activate Smad3 to induce tissue fibrosis. Instead, it exerts its effect through the combined influence of TGF-ß1. Inhibiting Kindlin-2 could potentially be a treatment for PD.

Comparative analysis of holmium: YAG laser internal urethrotomy versus Cold-Knife optical internal urethrotomy in the management of urethral stricture - a systematic review and meta-analysis.

OBJECTIVE: Urethral stricture management has posed enduring challenges in urology, demanding innovative and effective treatment modalities. This study addresses the persistent issues associated with urethral strictures, focusing on the comparative evaluation of two contemporary treatment modalities: Ho: YAG Laser Internal Urethrotomy (HIU) and Cold Knife Optical Internal Urethrotomy (CIU). METHODS: A comprehensive search of PubMed, Embase, Web of Science, Cochrane Library, and ResearchGate was conducted to identify relevant studies up to November 2023. Inclusion criteria encompassed comparative studies evaluating HIU and CIU in patients with urethral stricture. Data extraction, quality assessment, and subgroup analyses were performed using standardized methods. Outcome measures included preoperative and postoperative mean the maximum urine flow rate (Qmax), mean surgical time, recurrence rates, and perioperative complications. RESULTS: Nine articles met the inclusion criteria, and their data were analyzed using RevMan 5.4.1. Forest plots were generated for preoperative and postoperative mean Qmax, mean surgical time, recurrence rates, and perioperative complications. While postoperative mean Qmax (MD -0.06; 95% CI: -0.28-0.16; P =0.60, I2 =75%) and mean surgical time (MD 2.16; 95% CI: -1.66-5.99; P =0.27, I2 =98%) showed no significant differences between HIU and CIU, a trend towards lower recurrence rates (RR 0.71; 95% CI: 0.48-1.06; P =0.09, I2 =46%) was observed with HIU but without statistical significance. Perioperative complications, particularly bleeding (RR 0.21; 95% CI: 0.08-0.53; P =0.001, I2 =0%), favored HIU over CIU. The subanalysis indicates that for the treatment of complex urethral strictures, the two surgical methods differ in terms of mean Qmax at 6 months postoperatively (MD -2.51; 95% CI: -4.10--0.91; P =0.002, I2 =59%) and 12 months postoperatively (MD 2.62; 95% CI: 0.93-4.30; P =0.002, I2 =0%). The HIU group shows a significant decrease in recurrence rate at 12 months postoperatively (RR 0.44; 95% CI: 0.21-0.92; P =0.03, I2 =0%). For short-segment urethral strictures with a length ≤1.5 cm, CIU had a shorter operative time compared to the HIU (MD 4.49; 95% CI: 3.87-5.10; P <0.00001, I2 =44%). CONCLUSION: Overall, both interventions demonstrated similar efficacy in improving postoperative mean Qmax, mean surgical time, and recurrence rates. However, subanalysis indicates that in the short-term, CIU is more effective than HIU in improving Qmax after complex urethral stricture surgery. In long-term Qmax follow-up after surgery, HIU is significantly higher than CIU, and HIU has a low recurrence rate. In addition, for short-segment urethral stricture (≤1.5 cm), CIU requires less time. In terms of complications, HIU has a lower risk of bleeding.

Research progress on the microbiota in bladder cancer tumors.

The microbiota, also referred to as the microbial community, is a crucial component of the human microenvironment. It is located predominantly in various organs, including the intestines, skin, oral cavity, respiratory tract, and reproductive tract. The microbiota maintains a symbiotic relationship with the human body, influencing physiological and pathological functions to a significant degree. There is increasing evidence linking the microbial flora to human cancers. In contrast to the traditional belief that the urethra and urine of normal individuals are sterile, recent advancements in high-throughput sequencing technology and bacterial cultivation methods have led to the discovery of specific microbial communities in the urethras of healthy individuals. Given the prevalence of bladder cancer (BCa) as a common malignancy of the urinary system, researchers have shifted their focus to exploring the connection between disease development and the unique microbial community within tumors. This shift has led to a deeper investigation into the role of microbiota in the onset, progression, metastasis, prognosis, and potential for early detection of BCa. This article reviews the existing research on the microbiota within BCa tumors and summarizes the findings regarding the roles of different microbes in various aspects of this disease.

Efficacy of collagenase Clostridium histolyticum combination therapies for Peyronie's disease: a systematic review and meta-analysis.

INTRODUCTION: Peyronie's disease (PD) is a common penile disorder characterized by the formation of fibrous noncompliant hard nodules in the tunica albuginea of the penis. Collagenase Clostridium histolyticum (CCH) is an injectable drug that treats PD by enzymatically degrading plaque interstitial collagen. CCH has been used in patients with varying curvature, as well as in the acute and stable phases of the disease, through a variety of treatment regimens and combinations. We carried out a systematic review and meta-analysis to assess the efficacy of CCH combination therapies for PD. METHODS: We selected 4 observational comparative studies and 3 randomized controlled trials including 532 participants from the PubMed, Embase, and Cochrane databases (until December 2023) to evaluate the efficacy of CCH combination therapies for PD. The primary outcome was clinical efficacy as evaluated by improvement in penile curvature and penile length, as well as by scores on the Peyronie's Disease Questionnaire (PDQ) for symptom bother, penile pain, and psychological symptoms. Continuous data were represented by mean difference (MD) and 95% CI. All data were analyzed by Review Manager version 5.3. RESULTS: For penile length (MD, 0.81 cm; 95% CI, 0.17-1.45; P = .01), PDQ symptom bother (MD, -1.02; 95% CI, -1.83 to -0.21; P = .01), and PDQ penile pain (MD, -0.93; 95% CI, -1.50 to -0.36; P = .001), CCH combination therapy showed significantly greater improvements vs CCH monotherapy. However, in the other indicators, penile curvature and PDQ psychological symptoms, there was no significant difference between the therapies. CONCLUSION: This meta-analysis supports that CCH combination therapies can partially increase penile length and ameliorate symptom bother and penile pain to some extent. However, CCH combination therapies still need to be evaluated through more high-quality research.

Research advances in Peyronie's disease: a comprehensive review on genomics, pathways, phenotypic manifestation, and therapeutic targets.

INTRODUCTION: Penile induration disease, commonly known as Peyronie's disease (PD), is a connective tissue disorder that affects the penis, leading to the development of fibrous plaques, penile curvature, and erectile dysfunction. PD is a common male reproductive system disease with a complex etiology involving multiple genes, signaling pathways, and different phenotypes. OBJECTIVES: The etiology and pathogenesis of PD remain poorly understood, hindering the development of effective treatment strategies. By understanding the underlying mechanisms of PD, we can pave the way for targeted therapies and improved patient outcomes. METHODS: We reviewed the epidemiology and pathophysiology of PD. We performed database searches on Google Scholar, PubMed, Medline, and Web of Science from inception to September 2023. The literature reviewed included priapism guidelines, review articles, current trial studies, and various literature related to PD. RESULTS: This article provides a comprehensive overview of the current research progress on the disease, focusing on its genetic factors, signaling pathways, cellular mechanisms, phenotypic manifestations, and therapeutic targets. It can help identify individuals at higher risk, aid in early detection and intervention, and provide insights into fibrosis and tissue remodeling. It can also reveal potential therapeutic targets, guide accurate diagnoses and treatment strategies, and address the impact of the disease on patients' quality of life. CONCLUSION: By integrating insights from genomics, molecular pathways, clinical phenotypes, and therapeutic potentials, our research aims to achieve a deeper and more comprehensive understanding of PD, propelling the field toward innovative strategies that enhance the lives of those affected by PD. The complex manifestations and pathogenesis of PD necessitate the use of multiple treatment methods for personalized care.

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.

A comparative analysis of perioperative complications and biochemical recurrence between standard and extended pelvic lymph node dissection in prostate cancer patients undergoing radical prostatectomy: a systematic review and meta-analysis.

INTRODUCTION: Pelvic lymph node dissection (PLND) is commonly performed during radical prostatectomy (RP) for prostate cancer staging. This study aimed to comprehensively analyze existing evidence compare perioperative complications associated with standard (sPLND) versus extended PLND templates (ePLND) in RP patients. METHODS: A meta-analysis of prospective studies on PLND complications was conducted. Systematic searches were performed on Web of Science, Pubmed, Embase, and the Cochrane Library until May 2023. Risk ratios (RRs) were estimated using random-effects models in the meta-analysis. The statistical analysis of the data was carried out using Review Manager software. RESULTS: Nine studies, including three randomized clinical trial and six prospective studies, with a total of 4962 patients were analyzed. The meta-analysis revealed that patients undergoing ePLND had a higher risk of partial perioperative complications, such as lymphedema ( I2 =28%; RR 0.05; 95% CI: 0.01-0.27; P <0.001) and urinary retention ( I2 =0%; RR 0.30; 95% CI: 0.09-0.94; P =0.04) compared to those undergoing sPLND. However, there were no significant difference was observed in pelvic hematoma ( I2 =0%; RR 1.65; 95% CI: 0.44-6.17; P =0.46), thromboembolic ( I2 =57%; RR 0.91; 95% CI: 0.35-2.38; P =0.85), ureteral injury ( I2 =33%; RR 0.28; 95% CI: 0.05-1.52; P =0.14), intraoperative bowel injury ( I2 =0%; RR 0.87; 95% CI: 0.14-5.27; P =0.88), and lymphocele ( I2 =0%; RR 1.58; 95% CI: 0.54-4.60; P =0.40) between sPLND and ePLND. Additionally, no significant difference was observed in overall perioperative complications ( I2 =85%; RR 0.68; 95% CI: 0.40-1.16; P =0.16). Furthermore, ePLND did not significantly reduce biochemical recurrence ( I2 =68%; RR 0.59; 95% CI: 0.28-1.24; P =0.16) of prostate cancer. CONCLUSION: This analysis found no significant differences in overall perioperative complications or biochemical recurrence between sPLND and ePLND, but ePLND may offer enhanced diagnostic advantages by increasing the detection rate of lymph node metastasis.

Expression of EPB41L2 in Cancer-Associated Fibroblasts: Prognostic Implications for Bladder Cancer and Response to Immunotherapy.

BACKGROUND: Immunotherapy response in patients with bladder cancer (BLCA) treated with immune checkpoint inhibitors (ICIs) is variable. The accurate evaluation of immunotherapy efficacy may be facilitated by the tumor microenvironment (TME). Erythrocyte membrane protein band 4.1 like 2 (EPB41L2), a cytoskeletal protein with a regulatory role in the TME was intensively investigated to determine its biological characterization, clinical relevance, and predictive value for immunotherapy in BLCA. METHODS: Comprehensive bioinformatics and statistical analyses were conducted to examine gene expression profile, TME components, immune contexture, molecular features, and prediction of immunotherapy response. Immunohistochemistry (IHC) validated the results of the bioinformatics analysis. Association between immune checkpoint genes (ICGs) and EPB41L2-based risk stratification was validated in the IMvigor210 cohort, and their association with ICI response was assessed. RESULTS: EPB41L2 mRNA levels were decreased in BLCA compared to normal tissue. IHC showed reduced EPB41L2 staining intensity in early BLCA tissue. Nevertheless, elevated EPB41L2 expression was observed in cancer-associated fibroblasts (CAFs) with higher histological grade and pathological stage. High EPB41L2 expression served as a poor prognostic factor for BLCA. Single-cell RNA-seq and further analyses revealed that EPB41L2 was mainly expressed in CAFs and promoted TME remodeling. EPB41L2low/ICGshigh patients showed greater benefit from immunotherapy. Gene mutation analysis revealed a close relationship between EPB41L2 and the frequency of oncogenic mutations, including TP53 and FGFR3. CONCLUSION: Comprehensive analysis and IHC confirmed the upregulation of EPB41L2 in BLCA CAFs and its association with TME remodeling. EPB41L2 and ICG expression were identified as combinatorial biomarkers to predict the response to immunotherapy.

The systematic review and meta-analysis evaluated the efficacy and safety of nefopam for catheter-related bladder discomfort based on randomized controlled trials.

Background: Catheter-related bladder discomfort (CRBD) is a frequent occurrence following urinary catheterization during surgical procedures, as well as a commonly experienced bladder pain syndrome after surgery. There have been various studies on drugs and interventions to manage CRBD, but their comparative efficacy and safety are still a topic of debate. We conducted a meta-analysis to assess the efficacy and safety of nefopam for managing postoperative CRBD. Methods: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted to find randomized controlled trials (RCTs) on using nefopam in postoperative CRBD. The study employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Data analysis was performed using RevMan version 5.4.1. Results: Five RCTs with 405 patients were analyzed to evaluate the efficacy of nefopam on postoperative CRBD. Short-term and long-term periods were defined as within 6 h and longer than 12 h after surgery, respectively. The incidence and severity of CRBD were compared between the two groups during these time periods. The analysis proved that nefopam reduced the short-term incidence of postoperative CRBD (RR 0.36; 95% CI, 0.18-0.70; p = 0.003, I2 = 78%) and the long-term incidence (RR 0.49; 95% CI, 0.32-0.74; p = 0.0007, I2 = 0%) significantly. We compared the incidence of moderate-to-severe CRBD between groups based on the scaling system (none, mild, moderate, and severe). This was used to assess the severity of postoperative CRBD. The results showed that patients in the nefopam group had a significantly lower incidence of moderate-to-severe CRBD compared to those in the placebo group in the short-term (RR 0.19; 95% CI, 0.10-0.34; p < 0.00001; I2 = 0%). However, there were no significant differences between the two groups in the incidence of moderate-to-severe CRBD in the long-term (RR 0.61; 95% CI, 0.21-1.76; p = 0.36; I2 = 0%). There were no significant variations in the occurrence of adverse events between the nefopam and control groups, mainly including postoperative nausea and vomiting (PONV) (RR 1.14; 95% CI, 0.40-3.21; p = 0.81), and tachycardia (RR 0.25; 95% CI, 0.03-2.11, p = 0.20). Conclusion: The findings of this meta-analysis indicate that nefopam significantly reduced the incidence of short or long-term postoperative CRBD. Nefopam decreased the severity of postoperative CRBD, particularly significantly reducing the occurrence of moderate to severe CRBD in the short-term. Overall, patients have good tolerance and no apparent side effects. Systematic Review Registration: identifier PROSPERO (CRD42023475012).

Updated recommendations on the therapeutic role of extracorporeal shock wave therapy for peyronie's disease: systematic review and meta-analysis.

BACKGROUND: The therapeutic role of extracorporeal shockwave therapy (ESWT) for Peyronie's disease (PD) has been controversial in a long term. We aimed to further evaluate the therapeutic effect of ESWT for PD on the basis of available high-quality studies. METHODS: The PubMed, CENTRAL and Embase databases were searched for articles published from January 1st, 2000 to December 31, 2022. Only randomized controlled trials (RCTs) using ESWT to treat PD were included. Meta-analysis and forest plots were carried out using Review Manager 5.4.1 software, and outcomes were reviewed by 2 authors independently. Using the Risk of Bias assessment form (ROB-2) by Cochrane Collaboration for quality assessment. PRISMA 2020 guidelines were used in this article to achieve the quantitative and qualitative synthesis of data. RESULTS: A total of four RCTs were included. 151 patients in the ESWT group and 150 patients in the control group. The meta-analysis results showed that ESWT could significantly reduce plaque size (OR 2.59, 95%CI 1.15 to 5.85, P = 0.02) and relieve pain (MD -1.55, 95%CI -2.46 to -0.64, P = 0.0008); but it has no significant effect on reducing the penile curvature (OR 1.93, 95%CI 0.87-4.26, P = 0.11) and improving sexual function (MD 2.6, 95%CI -1.63 to 6.83, P = 0.23), there is also no significant difference in complication rates between groups (OR 2.94, 95%CI 0.66 to 13.03, P = 0.16). The risk of bias of results is low. The limitations of this study are that the number of included studies is too small, some experimental outcomes are missing, and the expression of outcomes is not unified. CONCLUSIONS: For PD, ESWT can be considered as a safe short-term treatment, which can reduce plaque size and relieve pain, but cannot improve penile curvature and sexual function. Its long-term efficacy remains to be discussed. REGISTRATION NUMBER: PROSPERO (ID: CRD42023436744).

Robot-assisted radical cystectomy vs open radical cystectomy in patients with bladder cancer: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Even though there isn't enough clinical evidence to demonstrate that robot-assisted radical cystectomy (RARC) is preferable to open radical cystectomy (ORC), RARC has become a widely used alternative. We performed the present study of RARC vs ORC with a focus on oncologic, pathological, perioperative, and complication-related outcomes and health-related quality of life (QOL). METHODS: We conducted a literature review up to August 2022. The search included PubMed, EMBASE and Cochrane controlled trials register databases. We classified the studies according to version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). The data was assessed by Review Manager 5.4.0. RESULTS: 8 RCTs comparing 1024 patients were analyzed in our study. RARC was related to lower estimated blood loss (weighted mean difference (WMD): -328.2; 95% CI -463.49--192.92; p < 0.00001), lower blood transfusion rates (OR: 0.45; 95% CI 0.32 - 0.65; p < 0.0001) but longer operation time (WMD: 84.21; 95% CI 46.20 -121.72; p < 0.0001). And we found no significant difference in terms of positive surgical margins (P = 0.97), lymph node yield (P = 0.30) and length of stay (P = 0.99). Moreover, no significant difference was found between the two groups in terms of survival outcomes, pathological outcomes, postoperative complication outcomes and health-related QOL. CONCLUSION: Based on the present evidence, we demonstrated that RARC and ORC have similar cancer control results. RARC is related to less blood loss and lower transfusion rate. We found no difference in postoperative complications and health-related QOL between robotic and open approaches. RARC procedures could be used as an alternate treatment for bladder cancer patients. Additional RCTs with long-term follow-up are needed to validate this observation.

The efficacy of CO2 laser in the treatment of genitourinary syndrome of menopause: a systematic review and meta-analysis of randomized controlled trials.

CO2 laser has been proposed as a treatment strategy for genitourinary syndrome of menopause (GSM). In order to assess its efficacy for treating GSM, we conducted a systematic review and meta-analysis. To identify the current state of randomized controlled trials on CO2 laser therapy for GSM, a literature review was conducted. We systematically searched the following databases: PUBMED, EMBASE and the Cochrane Controlled Trials Register. In addition, a review of the references in the retrieved studies was carried out. Of 562 identified studies, 9 were eligible and were included in our analysis, involving 523 patients in total. Based on our analysis, CO2 laser has no statistical difference compared with estrogen in VHI (p = 0.87), FSFI total score (p = 0.19), FSFI-Arousal (p = 0.11), FSFI-Desire (p = 0.72), FSFI-Orgasm (p = 0.45) and FSFI-Satisfaction (p = 0.08). The meta-analysis also showed that CO2 laser significantly improved FSFI-Lubrication scores compared with estrogen therapy (p = 0.0004). Furthermore, compared with the sham group, CO2 laser group had statistically improved VHI scores (p = 0.003) and FSFI scores (p < 0.00001). CO2 laser therapy may be an effective alternative to estrogen therapy for GSM both in cases where estrogen is not applicable because of comorbidities and in cases in which women do not desire to take estrogen.

The Efficacy of Cyclooxygenase-2 Inhibitors for the Male Treatment of Lower Urinary Tract Symptoms: A Systematic Review and Meta-Analysis.

To investigate the potential use of cyclooxygenase-2 (COX-2) inhibitors in the treatment of lower urinary tract symptoms (LUTS) in male patients, we conducted a comprehensive meta-analysis. Our study involved the identification and collection of randomized controlled trials (RCTs) from leading databases including PubMed, MEDLINE, EMBASE, and Cochrane Library. The primary objective of this analysis was to evaluate the effectiveness of COX-2 inhibitors for the treatment of LUTS. Our analysis involved six short-term (within 3 months) RCTs involving 707 patients. We found that COX-2 inhibitor treatment significantly improved the International Prostate Symptom Score (IPSS) of patients (mean difference [MD] = -2.99, 95% confidence interval (CI): -3.65 to -2.33, p < .00001), nocturia frequency (MD = -1.90; 95% CI: -3.18 to -0.61, p = .004), and maximum flow rate (Qmax) (MD = 1.02; 95% CI: 0.06 to 1.98, p = .04). However, no significant differences were found between patients in terms of changes in prostate-specific antigen (PSA) (MD = 0.02; 95% CI: -0.39 to 0.43, p = .92) and total prostate volume (TPV) (MD = -2.93; 95% CI: -6.45 to 0.59, p = .10). Therefore COX-2 inhibitors are an effective treatment for LUTS.