Efficacy and safety of tibial nerve stimulation using a wearable device for overactive bladder.

OBJECTIVE: To evaluate the efficacy and safety of a wearable, smartphone-controlled, rechargeable transcutaneous tibial nerve stimulation (TTNS) device in patients with overactive bladder (OAB). PATIENTS AND METHODS: This multicentre, prospective, single-blind, randomised clinical trial included eligible patients with OAB symptoms who were randomly assigned to the stimulation group or sham group. The primary efficacy outcome was change from baseline in voiding frequency/24 h after 4 weeks of treatment. The secondary efficacy outcomes included changes in bladder diary outcomes (urgency score/void, nocturia episodes/day, micturition volume/void, and incontinence episodes/day), questionnaires on Overactive Bladder Symptom Score (OABSS), Patient Perception of Bladder Condition (PPBC), and American Urological Association Symptom Index Quality of Life Score (AUA-SI-QoL) at baseline and after 4 weeks of treatment. Device-related adverse events (AEs) were also evaluated. RESULTS: In the full analysis set (FAS), the mean (sd) change of voiding frequency/24 h in the stimulation group and sham group at 4 weeks were -3.5 (2.9) and -0.6 (2.4), respectively (P < 0.01). Similar results were obtained in the per-protocol set (PPS): -3.5 (2.9) vs -0.4 (2.3) (P < 0.01). In the FAS and PPS, micturition volume/void significantly improved at 4 weeks (P = 0.01 and P = 0.02). PPBC improvement almost reached significance in the FAS (P = 0.05), while it was significant in the PPS (P = 0.02). In the FAS and PPS, AUA-SI-QoL significantly improved at 4 weeks in the two groups (P < 0.01 and P < 0.01), whereas there were no significant differences in urgency score/void, nocturia episodes/day or OABSS between the groups. Also, no device-related serious AEs were reported. CONCLUSIONS: The non-invasive neuromodulation technique using the novel ambulatory TTNS device is effective and safe for treating OAB. Its convenience and easy maintenance make it a new potential home-based treatment modality. Future studies are warranted to confirm its longer-term efficacy.

Comprehensive analysis the diagnosis, malignant progression and immune infiltrate of ANXA6 in prostate cancer.

BACKGROUND: Annexins (ANXAs) play a crucial role in the development and progression of tumors. However, their specific involvement in prostate cancer (PCa) remains unclear. OBJECTIVE: To investigate the function and clinical significance of key ANXAs in PCa. METHODS: Multiple databases were used to analyze the expression levels, genetic variations, potential prognostic value and clinical significance of ANXAs in PCa. Then, the co-expressed genes of ANXA6 were identified, and the correlation between ANXA6 and immune cell infiltration was validated using the Tumor Immune Estimation Resource (TIMER) database. Additionally, in vitro assays such as Cell Counting Kit-8 (CCK-8), Colony Formation, Transwell and T-cell Chemotaxis assays were conducted to validate the functions of ANXA6. Moreover, multiple types of in vivo assays were performed to further validate the identified ANXA6 functions. RESULTS: The results demonstrated that ANXA2, ANXA6 and ANXA8 were significantly downregulated in PCa. ANXA6 upregulation was significantly associated with improved PCa patients' overall survival. Enrichment analysis revealed that ANXA6 and its co-expressed genes were involved in tumor progression, and ANXA6 overexpression could effectively inhibit the proliferation, migration and invasion of PC-3 cells. In vivo studies also demonstrated that ANXA6 overexpression suppressed tumor growth. Importantly, ANXA6 was found to promote the chemotaxis of CD4+ T cells and CD8+ T cells towards PC-3 cells, and the overexpression of ANXA6 in PC-3 cells promoted the polarization of macrophages into M1 macrophages in the supernatant of PCa cells. CONCLUSIONS: ANXA6 demonstrated promising potential for consideration as a prognostic biomarker in PCa as it was found to play key roles in regulating immune cell infiltration and the malignant progression to PCa.

Randomized controlled trial of intravesical electrical stimulation for underactive bladder.

AIM: To evaluate the efficacy and safety of intravesical electrical stimulation (IVES) performed with a novel device in patients with underactive bladder (UAB). PATIENTS AND METHODS: This was a multicentre, prospective, single-blind, randomized controlled clinical trial of patients with UAB in China. Eligible patients were randomly assigned in a 1:1 ratio to receive conventional IVES (n = 38) or IVES with an open circuit (n = 38). The primary efficacy measure was change from baseline in post-void residual urine volume (PVR) after 4 weeks of treatment. Secondary efficacy measures included changes in maximum urinary flow rate (Qmax ), bladder voiding efficiency (BVE), number of 24-h clean intermittent catheterization (CIC) procedures, and Patient Perception of Bladder Condition-Scale (PPBC-S) and American Urological Association Symptom Index Quality of Life (AUA-SI-QoL) scores from baseline after 4 weeks of treatment. Adverse events (AEs) were monitored throughout the trial. RESULTS: In the full analysis set (FAS), the mean (sd) PVR changes in the trial and control groups at 4 weeks were -97.1 (107.5) mL and -10.5 (86.7) mL, respectively (P < 0.01). Similar results were obtained in the per-protocol set (PPS): -102.9 (100.0) mL vs 0.7 (82.5) mL (P < 0.01). In the FAS and PPS, Qmax improved significantly at 4 weeks (P = 0.04 and P = 0.03). In the FAS and PPS, BVE was significantly improved at 4 weeks in the two groups (P < 0.01 and P < 0.01), whereas no significant differences in the number of 24-h CIC procedures, PPBC-S score or AUA-SI-QoL score were observed between the groups. Six possible therapy-related AEs occurred in six patients (four in the trial group and two in the control group; P = 0.67), all of which were urinary tract infections. No severe AEs were reported. CONCLUSIONS: The results of this clinical study strongly demonstrate that UAB patients benefit from this novel IVES device. More research is needed to validate the clinical utility of this device.

Identification and validation of the molecular subtype and prognostic signature for clear cell renal cell carcinoma based on neutrophil extracellular traps.

Background: Renal cell carcinoma (RCC) is one of the most common cancers, with an annual incidence of nearly 400,000 cases worldwide. Increasing evidence has also demonstrated the vital role of neutrophil extracellular traps (NETs) in cancer progression and metastatic dissemination. Methods: Consensus cluster analysis was performed to determine the number of ccRCC subtypes. The Kruskal-Wallis test or Student t-test was performed to evaluate the difference of infiltrating immune cell and gene expression in different groups. The Kaplan-Meier (KM) method was used to draw the survival curve. LASSO cox regression analysis was conducted to construct a NET-related prognostic signature. We also constructed a lncRNA-miRNA-mRNA regulatory axis by several miRNA and lncRNA target databases. Results: A total of 23 differentially expressed NET-related genes were obtained in ccRCC. Three clusters of ccRCC cases with significant difference in prognosis, immune infiltration, and chemotherapy and targeted therapy were identified. LASSO Cox regression analysis identified a NET-related prognostic signature including six genes (G0S2, DYSF, MMP9, SLC22A4, SELP, and KCNJ15), and this signature had a good performance in predicting the overall survival of ccRCC patients. The expression of prognostic signature genes was significantly correlated with the pTMN stage, immune infiltration, tumor mutational burdens, microsatellite instability, and drug sensitivity of ccRCC patients. MMP9 was identified as the hub gene. We also identified the lncRNA UBA6-AS1/miR-149-5p/MMP9 regulatory axis for the progression of ccRCC. Conclusion: Collectively, the current study identified three molecular clusters and a prognostic signature for ccRCC based on neutrophil extracellular traps. Integrative transcriptome analyses plus clinical sample validation may facilitate the biomarker discovery and clinical transformation.

Sacral Neuromodulation Using a Novel Device with a Six-contact-point Electrode for the Treatment of Patients with Refractory Overactive Bladder: A Multicenter, Randomized, Single-blind, Parallel-control Clinical Trial.

BACKGROUND: A novel sacral neuromodulation system (SacralStim) which has an electrode with six contact points was recently designed. OBJECTIVE: To evaluate the effectiveness and safety of the SacralStim system for treating patients with refractory overactive bladder (OAB). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, randomized, single-blind clinical trial. Patients with refractory OAB were enrolled from January 2018 to May 2020. INTERVENTION: Participants were randomly allocated to the treatment group (SNM on) or the control group (SNM off) for a single-blind period of 12 ± 2 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the percentage of patients with a reduction in the average number of voids/24 h of at least 50% at the 12-wk follow-up visit. Other follow-up evaluations, including voiding diary outcomes, questionnaires on Overactive Bladder Symptom Score (OABSS), quality of life (QoL), device satisfaction, and causes of adverse events (AEs), were performed over the first 48 wk after implantation. RESULTS AND LIMITATIONS: The therapeutic success rate at 12 wk was 56.76% in the treatment group and 11.11% in the control group (p < 0.001). There were significant differences in voiding diary variables between the two groups, including changes in the average number of voids/24 h, micturition volume/void, and improvement in the urge incontinence ratio. No severe AEs occurred. A limitation is the sham stimulation used as a control in the study. A head-to-head study is required to make a direct comparison of devices with six and four contact points. CONCLUSIONS: This clinical trial provides strong evidence that patients with refractory OAB benefit from the novel SacralStim system. More research is required for direct comparison of the SacralStim system with traditional four-contact-point devices. PATIENT SUMMARY: This study confirms the effectiveness and safety of a novel SacralStim system that stimulates the sacral nerve for treatment of overactive bladder. The system has an electrode with six contact points and can provide more programming options after implantation.

Silencing circSLC19A1 Inhibits Prostate Cancer Cell Proliferation, Migration and Invasion Through Regulating miR-326/MAPK1 Axis.

BACKGROUND: Emerging evidence indicates that circular RNAs (circRNAs), which form as covalently closed loops, play a regulatory role in various types of cancer, including prostate cancer (PCa). CircSLC19A1, one kind of circRNA, was subjected to the study and its role in PCa was explored. METHODS: Expressions of circSLC19A1, miR-326 and MAPK1 in PCa tissues and cells were assessed by qRT-PCR. CircSLC19A1 was identified by RNase R treatment. The binding relations between circSLC19A1 and miR-326 and between miR-326 and MAPK1 were predicted by RegRNA2.0 or Targetscan7.2 and further confirmed by dual-luciferase reporter assay. Pearson correlation analysis of the correlation among circSLC19A1, miR-326 and MAPK1 was performed. CCK-8, cell colony formation, wound healing and Transwell assays were used to assess PCa cell viability, proliferation, migration and invasion, respectively. RESULTS: CircSLC19A1 expression was up-regulated in PCa tissue and cell cytoplasm. Silencing circSLC19A1 inhibited PCa cell viability, proliferation, migration, invasion and miR-326 expression. MiR-326 inhibitor promoted the luciferase activities of circSLC19A1 and MAPK1, increased MAPK1 expression and facilitated PCa cell progression. MiR-326 expression was down-regulated in PCa tissue and there was a negative correlation between miR-326 and circSLC19A1 expressions. MAPK1 expression was up-regulated in PCa tissue. There was a negative correlation between MAPK1 and miR-326 expressions as well as a positive correlation between MAPK1 and circSLC19A1 expressions. Silencing MAPK1 promoted the viability, proliferation, migration, and invasion of PCa cells co-transfected with siRNA-circSLC19A1a and miR-326 inhibitor. CONCLUSION: CircSLC19A1 silencing inhibited PCa cell proliferation, migration and invasion through regulating miR-326/MAPK1 axis.

NOTCH1 regulates the proliferation and migration of bladder cancer cells by cooperating with long non-coding RNA HCG18 and microRNA-34c-5p.

In recent years, the NOTCH signaling pathway has been gradually studied in human malignancies. Inactivation of the NOTCH signaling pathway was uncovered to be correlated with the carcinogenesis of bladder cancer (BCa). Nevertheless, the specific molecular mechanism of NOTCH1 (one of the core factors of the NOTCH signaling pathway) is not well elucidated in BCa. This study focused on the mechanism by which NOTCH1 affects the biological behaviors of BCa cells. According to the experimental results of quantitative real-time polymerase chain reaction, NOTCH1 was dysregulated in BCa tissues and cell lines. The prognostic value of NOTCH1 for the patients with BCa was determined using the Kaplan-Meier method. Mechanism investigations revealed that NOTCH1 is a target of miR-34c-5p in BCa. Furthermore, microarray analysis was used to find the dysregulated long noncoding RNAs (lncRNA), which can bind with miR-34c-5p. Mechanism experiments further demonstrated the rationality of the HCG18-miR-34c-5p-NOTCH1 pathway. Functional assays were then applied to validate the inhibitory influences of NOTCH1 on the proliferation and migration of BCa cells. Furthermore, the inhibitory effects of NOTCH1 could be affected by miR-34c-5p or lncRNA HCG18. All findings in this study revealed that NOTCH1 suppresses the BCa progression by cooperating with lncRNA HCG18 and miR-34c-5p.