A randomized controlled study of the efficacy of tadalafil monotherapy versus combination of tadalafil and mirabegron for the treatment of persistent overactive bladder symptoms in men presenting with lower urinary tract symptoms (CONTACT Study).

AIM: To evaluate efficacy and safety of combination of tadalafil + mirabegron for overactive bladder/benign prostatic hyperplasia (OAB/BPH). METHODS: Male patients with lower urinary tract symptoms (50 to 89 years), with remaining OAB symptoms even after administering tadalafil for more than 8 weeks were randomly assigned to either tadalafil monotherapy group (5 mg/day) or tadalafil/mirabegron combination therapy group (5 mg/50 mg/day). The primary endpoint was change from baseline in total OAB symptom score (OABSS) at week 12. The secondary endpoints were changes in International Prostate Symptom Score (IPSS), NIH-chronic prostatitis symptom index (NIH-CPSI), and micturition chart parameters at weeks 4 and 12. RESULTS: A total of 176 patients were randomized to either monotherapy (87 patients) or combination therapy (89 patients). The baseline characteristics of patients in the two groups were similar. The total OABSS (95% confidence interval) of combination therapy was significantly decreased by 1.78 (1.05-2.50) points compared with that of monotherapy (P < .001). Changes from baseline in OABSS nighttime voiding score, urgency score, urgency incontinence score, IPSS storage subscores, NIH-CPSI total score, and numbers of voids, nighttime-voids, and urgency episodes/day in micturition chart were significantly reduced in combination therapy (all P < .001). Patient-reported outcome was significantly more satisfactory in combination therapy than in monotherapy (P < .001). One moderate adverse event (pain in hip joint) with hardly presumed causal relationship with therapy and seven mild adverse events were noted in monotherapy and combination therapy group, respectively. CONCLUSIONS: The effect of tadalafil/mirabegron combination therapy on relieving OAB symptoms appeared to be greater than that of tadalafil monotherapy and can be safely used.

Urodynamic efficacy of fesoterodine for the treatment of neurogenic detrusor overactivity and/or low compliance bladder.

OBJECTIVE: To examine the urodynamic effects of fesoterodine on neurogenic detrusor overactivity and/or low compliance bladder. METHODS: A total of 77 patients (52 men, 25 women; aged 61.6 ± 20.3 years) were given fesoterodine 4-8 mg/day and prospectively followed for 12 weeks. The primary end-point variable was change in the maximum cystometric capacity on urodynamic study. The secondary end-point was to assess the number of patients whose neurogenic detrusor overactivity disappeared, and the changes in the urodynamic parameters, lower urinary tract symptoms questionnaires and the 3-day frequency volume chart parameters after the treatment. RESULTS: A total of 13 patients (16.9%) withdrew because of adverse events (dry mouth or blurred vision), and four patients dropped out for unknown reasons. Finally, 60 patients completed the study. Bladder capacity at first desire to void, maximum cystometric capacity and bladder compliance increased by 29.2 mL, 79.9 mL and 22.2 mL/cm H2 O, respectively, showed statistical significance (P = 0.026, P < 0.001 and P < 0.001). Neurogenic detrusor overactivity disappeared in 12 of 51 patients (23.5%), and a significant increase was observed in bladder capacity at first involuntary contraction (P < 0.001), and a significant decrease was observed in maximum detrusor contraction (P < 0.001). In patients with low compliance bladder (with detrusor underactivity without neurogenic detrusor overactivity; n = 9), maximum cystometric capacity and bladder compliance increased significantly (P = 0.003 and P = 0.006, respectively). Overactive bladder symptom score, International Consultation on Incontinence Questionnaire-Short Form, most items of King's Health Questionnaire, and the number of urgency episodes and leaks in a day decreased significantly after treatment. CONCLUSIONS: Fesoterodine seems to be a valid treatment option for neurogenic detrusor overactivity and/or low compliance bladder in neurogenic bladder patients.

Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets.

Interstitial cystitis (IC), also known as bladder pain syndrome, is a chronic inflammatory disease that affects the bladder. The symptoms of IC vary, including feeling an urgent need for immediate urination and of needing to urinate often, as well as bladder or pelvic pain. Despite its high incidence, no molecular diagnostic methods are available for IC, and the molecular pathogenesis is unknown. microRNAs (miRNA) can regulate expression of RNA transcripts in cells and aberrant expression of miRNAs is associated with several human diseases. Here, we investigated the molecular pathogenesis of IC based on miRNA expression signatures. RNA sequencing of miRNA levels in IC tissues and comparison with levels in normal bladder tissue and bladder cancer revealed dysregulated expression of 366 miRNAs (203 and 163 down- and upregulated miRNAs, respectively). In particular, miR-320 family miRNAs(miR-320a, miR-320b, miR-320c, miR-320d and miR-320e) had downregulated expression in IC tissues. Genome-wide gene expression analyses and in silico database analyses showed that three transcription factors, E2F-1, E2F-2 and TUB, are regulated by miR-320 family miRNAs. Immunostaining of IC tissues confirmed that these transcription factors are overexpressed in IC tissues. Novel approaches that identify aberrantly expressed miRNA regulatory networks in IC could provide new prognostic markers and therapeutic targets for this disease.

Testicular function among testicular cancer survivors treated with cisplatin-based chemotherapy.

Purpose: The aim of our study was to identify the clinical predictors of spermatogenesis recovery in testicular cancer (TC) patients after chemotherapy and to determine the recuperation period for spermatogenesis. Methods: Patients treated for TC from January 1982 to November 2001 at Chiba University Hospital were retrospectively assessed. Thirty-five patients who met the following criteria were examined-(i) underwent both high orchiectomy and cisplatin-based chemotherapy; (ii) had semen analyses and hormonal measurements; and (iii) were alive with no evidence of disease. Clinical variables associated with normalization of spermatogenesis after chemotherapy were examined. Time to recover normospermia was also evaluated using Kaplan-Meier analysis. Results: The observation period was 13.3 ± 5.6 years. Reappearance of sperm was confirmed in 85.7 % of patients, and 54.3 % of patients recovered normospermia. Age at diagnosis <25 years (p = 0.0057), number of chemotherapy cycles <4 cycles (p = 0.0042), and follicle-stimulating hormone at the end of chemotherapy <18 mIU/ml (p = 0.0220) were independent factors related to post-chemotherapy normalization of semen findings. The median (95 % CI) time to recover normospermia was 40 (range 22-96) months. Conclusions: These findings help to predict whether spermatogenesis will recover and its timing. They may also help clinicians identify and manage TC patients at a higher risk of prolonged azoospermia after chemotherapy.

Nadir Testosterone after Long-Term Followup Predicts Prognosis in Patients with Prostate Cancer Treated with Combined Androgen Blockade.

PURPOSE: We examined the clinical significance of long-term serum testosterone monitoring to predict the prognosis of patients with prostate cancer treated with combined androgen blockade. MATERIALS AND METHODS: We retrospectively analyzed the records of 225 patients who underwent combined androgen blockade as first line therapy for prostate cancer. The prognostic values of testosterone and other clinical factors were evaluated with respect to prostate specific antigen progression-free and overall survival. RESULTS: Median patient age was 73.0 years, median prostate specific antigen was 42.6 ng/ml and median followup was 45.8 months. No variable associated with testosterone was predictive of progression-free survival. With regard to overall survival on univariate analysis nadir testosterone less than 16 ng/dl (p = 0.0190), less than 20 ng/dl (p = 0.0020) and less than 32 ng/dl (p = 0.0146) were significant together with other clinical factors. In contrast, nadir testosterone less than 8 and less than 12 ng/dl were not significant. Multivariate analysis showed that nadir testosterone less than 20 ng/dl was the significant prognostic factor (p = 0.0048). In addition, time to nadir testosterone was about 1 year (11.3 months). Patients were divided into rapid and slow types based on time to testosterone less than 20 ng/dl before and after 6 months, respectively. No significant difference in overall survival was observed between the 2 types. The current results suggest that the critical factor for prognosis was not a rapid decrease but whether nadir testosterone achieved a level of less than 20 ng/dl. CONCLUSIONS: Nadir testosterone 20 ng/dl was the most significant cutoff level for overall survival in Japanese patients with prostate cancer treated with combined androgen blockade.

The role of muscarinic receptor subtypes on carbachol-induced contraction of normal human detrusor and overactive detrusor associated with benign prostatic hyperplasia.

The aim of this study was to compare the effect of antimuscarinic antagonists on carbachol-induced contraction of normal human bladder and detrusor overactivity associated with benign prostatic hyperplasia (DO/BPH). Samples of human bladder muscle were obtained from patients undergoing total cystectomy for bladder cancer (normal bladder), and those undergoing retropubic prostatectomy for BPH. All of the patients with DO/BPH had detrusor overactivity according to urodynamic studies. Detrusor muscle strips were mounted in 10-ml organ baths containing Krebs solution, and concentration-response curves for carbachol were obtained in the presence of antimuscarinic antagonists (4-DAMP, methoctramine, pirenzepine, tolterodine, solifenacin, trospium, propiverine, oxybutynin, and imidafenacin) or vehicle. All antagonists competitively antagonized concentration-response curves to carbachol with high affinities in normal bladder. The rank order of mean pA2 values was as follows: trospium (10.1) > 4-DAMP (9.87), imidafenacin (9.3) > solifenacin (8.8) > tolterodine (8.6) > oxybutynin (8.3) > propiverine (7.7) > pirenzepine (7.4) > methoctramine (6.6). The effects of these antimuscarinic antagonists did not change when tested with DO/BPH bladder, suggesting that each antimuscarinic antagonist has a similar effect in this condition. Schild plots showed a slope corresponding to unity, except for propiverine with DO/BPH detrusor. In conclusion, M3-receptors mainly mediate contractions in human bladder strips with normal state and DO/BPH.

Six-year follow up of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: What are the factors for continuation or withdrawal?

OBJECTIVES: To investigate the factors for continuation or withdrawal as an extension of a prospective study of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia for more than 6 years. METHODS: A total of 104 patients (age 71.5 ± 8.2 years) were enrolled in the present study. The mean prostate volume was 44.1 ± 23.9 mL. International Prostate Symptom Score, quality of life index, maximum flow rate, and postvoid residual urine volume were determined at baseline, and at 1, 3, 6 and 12-72 months after treatment. RESULTS: Adverse events were noted in 14 patients (13.5%), and the most frequent adverse event was ejaculatory dysfunction (5.8%). Withdrawal was noted in 78 patients, and 26 patients (25.0%) were still taking silodosin at 72 months (continuing group). The reasons for withdrawals were: unknown in 27 patients (26.0%), adverse events in nine patients (8.7%), unsatisfactory effects in 30 patients (28.8%) and satisfied with the current condition for six patients (5.8%). In 30 patients who withdrew because of unsatisfactory effects, surgery was carried out in 21 patients (surgery group). The baseline total International Prostate Symptom Score did not differ between the continuing group and the surgery group. However, patients with the continuing group had significantly smaller baseline prostate volume, and lower baseline quality of life index and prostate-specific antigen, than in the surgery group. The mean total International Prostate Symptom Score, quality of life index and maximum flow rate improved significantly at 1 month, and remained stable up to 72 months. CONCLUSIONS: The withdrawal rate was higher in patients with a larger prostate. The effects of silodosin for lower urinary tract symptoms was immediate and stable up to 72 months.

The association of CXCR3 and renal cell carcinoma metastasis.

PURPOSE: Renal cell carcinoma expresses CXCR3 but the function of CXCR3 in renal cell carcinoma has not been clarified. We explored the function of CXCR3 in renal cell carcinoma and investigated CXCR3 regulating factors. MATERIALS AND METHODS: We obtained 56 clinical samples of clear cell renal cell carcinoma and corresponding normal renal tissue samples from the surgical specimens of Japanese patients who underwent radical nephrectomy at Chiba University Hospital between 2000 and 2011. As renal cell carcinoma cell lines, we used 786-O, ACHN and Caki-1. The expression profiles of CXCR3 and its splice variants were examined. For functional analyses 786-O and interferon-γ inducible 10 kDa protein or IP-10 (CXCL10) were selected as representatives. RESULTS: CXCR3 and its ligands were abundant in renal cell carcinoma samples compared to corresponding normal kidney samples. The CXCR3-A-to-CXCR3-B ratio was 1.5 times higher in renal cell carcinoma samples than in normal kidney samples. CXCL10 treatment induced 786-O cell migration and invasion, and these effects were inhibited by neutralizing antibody. Phosphorylated RhoA and pro/active matrix metalloproteinase-9 expression was up-regulated by CXCL10 treatment. In clinical samples CXCR3 and CXCR3-A expression was significantly higher in metastatic than in nonmetastatic carcinoma samples. Finally, the expression of CXCR3-A and HIF-1α correlated significantly in clinical samples. In 786-O treatment with CoCl2 up-regulated CXCR3 and HIF-1α expression 4.5 and 2.2-fold, respectively. CONCLUSIONS: We determined the association of CXCR3 and renal cell carcinoma metastasis. CXCR3 expression may be regulated by hypoxia.

The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer.

Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 (miR-143/145) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or miR-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 (GOLM1) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1. Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.

Nocturia Quality-of-Life questionnaire is a useful tool to predict nocturia and a risk of falling in Japanese outpatients: a cross-sectional survey.

OBJECTIVES: To evaluate the Japanese version of the Nocturia Quality-of-Life questionnaire for prediction of night-time voiding and risk of falling. METHODS: A survey was carried out from October 2008 to June 2009 in outpatients at 15 general hospitals and 80 general clinics in Tochigi, Japan, using the Nocturia Quality-of-Life questionnaire, overactive bladder symptom score and self-administered questionnaires on night-time symptoms (awakening, number of voids, incontinence and falling). RESULTS: The survey was completed by 2494 participants (1154 men, 1208 women; mean age 63.2 ± 15.1 years). Overactive bladder was diagnosed in 625 participants (25.1%) according to the Japanese overactive bladder guideline using overactive bladder symptom score. Awakening during sleep was reported by 80.1% of the participants, and 70.4% awakened to go to the toilet. The mean Nocturia Quality-of-Life score was 86.8 ± 16.9. The Nocturia Quality-of-Life score was lower in patients with overactive bladder, benign prostatic hyperplasia, diabetes, hypertension and cardiovascular diseases. The Nocturia Quality-of-Life score was significantly decreased in patients with night-time symptoms (P < 0.001). Nocturia Quality-of-Life scores and those for subdomains were correlated with overactive bladder symptom score. Nocturia Quality-of-Life ≤90 had 63.1% sensitivity and 78.6% specificity in indicating night-time voiding more than twice, and Nocturia Quality-of-Life questionnaire ≤80 had 70.2% sensitivity and 79.5% specificity in indicating the probability of falling at least once. Logistic analysis showed that 10-year increase in age and overactive bladder in all participants were significant risk factors for Nocturia Quality-of-Life ≤90. CONCLUSIONS: The Nocturia Quality-of-Life questionnaire represents a useful tool to predict nocturia and risk of falling in Japanese patients.

Transrectal ultrasound vector projectile imaging for time-resolved visualization of flow dynamics in the male urethra: A clinical pilot study.

BACKGROUND: Quantitative and comprehensive visualization of urinary flow dynamics in the urethra is crucial for investigating patient-specific mechanisms of lower urinary tract symptoms (LUTS). Although some methods can evaluate the global properties of the urethra, it is critical to assess the local information, such as the location of the responsible lesion and its interactions with urinary flow in relation to LUTS. This approach is vital for enhancing personalized and focal treatments. However, there is a lack of such diagnostic tools that can directly observe how the urethral shape and motion impact urinary flow in the urethra. PURPOSE: This study aimed to develop a novel transrectal ultrasound imaging modality based on the contrast-enhanced urodynamic vector projectile imaging (CE-UroVPI) framework and validate its clinical applicability for visualizing time-resolved flow dynamics in the urethra. METHODS: A new CE-UroVPI system was developed using a research-purpose ultrasound platform and a custom transrectal linear probe, and an imaging protocol for acquiring urodynamic echo data in male patients was designed. Thirty-four male patients with LUTS participated in this study. CE-UroVPI was performed to acquire ultrasound echo signals from the participant's urethra and urinary flow at various voiding phases (initiation, maintenance, and terminal). The ultrasound datasets were processed with custom software to visualize urinary flow dynamics and urethra tissue deformation. RESULTS: The transrectal CE-UroVPI system successfully visualized the time-resolved multidirectional urinary flow dynamics in the prostatic urethra during the initiation, maintenance, and terminal phases of voiding in 17 patients at a frame rate of 1250 fps. The maximum flow speed measured in this study was 2.5 m/s. In addition, when the urethra had an obstruction or an irregular partial deformation, the devised imaging modality visualized complex flow patterns, such as vortices and flow jets around the lesion. CONCLUSIONS: Our study findings demonstrate that the transrectal CE-UroVPI system developed in this study can effectively image fluid-structural interactions in the urethra. This new diagnostic technology has the potential to facilitate quantitative and precise assessments of urethral voiding functions and aid in the improvement of focal and effective treatments for patients with LUTS.

Novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation and long-term outcomes for a single surgeon.

Although novel techniques for avoiding incontinence during robot-assisted radical prostatectomy have been developed, long-term oncological outcomes are unknown. The objective of this study was to determine the long-term oncological outcomes and functional outcomes of novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation for a single surgeon. Data from 100 patients who underwent structure-preserving prostatectomies performed by a single surgeon were retrospectively analyzed. The median console time was 123 min. Bilateral nerve-sparing was performed in 43% of patients underwent, and 57% underwent unilateral nerve-sparing surgery. Most patients (96%) reached complete pad-zero urinary continence by one year after surgery. Satisfactory erectile function was achieved in 97% of patients who underwent bilateral nerve-sparing surgery, and 80% of patients who underwent unilateral nerve-sparing surgery. The surgical margin was positive for 25% of patients, and the biochemical recurrence-free rate at 5 years was 77%. The cancer-specific survival rate was 100% during the median follow-up period of 4.5 years. Clavien-Dindo grade III complications occurred in 1% of cases. The outcomes for novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation were similar to previously reported oncological outcomes, with satisfactory functional outcomes. This operative method may be useful for patients who are eligible for nerve-sparing surgery.

Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma.

Our recent studies of microRNA (miRNA) expression signatures demonstrated that the epithelial-mesenchymal transition (EMT)-related microRNA-200 family (miR-200s: miR-200a/b/c, miR-141 and miR-429) were significantly downregulated in renal cell carcinoma (RCC) and putative tumor-suppressive miRNAs in RCC. In this study, our aim was to investigate the functional significance of the miR-200s in cancer cells and to identify novel miR-200s-regulated molecular targets and pathways in RCC. Expression levels of all the miR-200s members were significantly downregulated in human RCC tissues compared with normal renal tissues. Restoration of mature miR-200s in RCC cell line resulted in significant inhibition of cell proliferation and migration, suggesting that miR-200s function as tumor suppressors in RCC. Furthermore, we utilized gene expression analysis and in silico database analysis to identify miR-200s-regulated molecular targets and pathways in RCC. The miR-200s was categorized into two groups, according to their seed sequences, miR-200b/c/429 and miR-200a/141. Our data demonstrated that the 'Focal adhesion' and 'ErbB signaling' pathways were significantly regulated by miR-200b/c/429 and miR-200a/141, respectively. The identification of novel tumor-suppressive miR-200s-regulated molecular targets and pathways has provided new insights into RCC oncogenesis and metastasis.

Efficacy of Transcutaneous Tibial Nerve Stimulation With Silver Spike Point® Electrodes for Refractory Overactive Bladder: A Single-Arm Study.

Background Tibial nerve stimulation therapy is a treatment option for an overactive bladder. A surface electrode called a Silver Spike Point® electrode, which does not directly puncture the skin as in transcutaneous tibial nerve stimulation, but is expected to exert the same therapeutic effect as percutaneous tibial nerve stimulation, was developed. This study investigated the efficacy and safety of tibial nerve stimulation with Silver Spike Point® electrodes for refractory overactive bladder. Methodology This was a six-week, single-arm, prospective study on the efficacy and safety of transcutaneous tibial nerve stimulation for patients with refractory overactive bladder. Each treatment lasted 30 minutes and was performed twice a week. The stimulation sites of the tibial nerve were the Sanyinjiao point (SP6) and Zhaohai point (KI6) in both legs. The primary endpoint was the change in the total overactive bladder symptom score. Results In total, 29 patients (20 males and nine females: 64.86 ± 17.98 years old) were included in this study. Two women dropped out; one because of an adverse event and the other as requested. Therefore, 27 patients completed the study. The total overactive bladder symptom and International Consultation on Incontinence Questionnaire-Short Form scores significantly decreased by 2.22 and 2.39 points, respectively (p < 0.01 each). In the frequency volume chart, the numbers of urgency episodes and leaks in 24 hours significantly decreased by 1.53 and 0.44, respectively (p = 0.02 each). Conclusions Transcutaneous tibial nerve stimulation therapy using Silver Spike Point® electrodes was useful for patients with refractory overactive bladder and, thus, has potential as a new treatment option for refractory overactive bladder.

Tumor suppressive microRNA-133a regulates novel targets: moesin contributes to cancer cell proliferation and invasion in head and neck squamous cell carcinoma.

Recently, many studies suggest that microRNAs (miRNAs) contribute to the development, invasion and metastasis of various types of human cancers. Our recent study revealed that expression of microRNA-133a (miR-133a) was significantly reduced in head and neck squamous cell carcinoma (HNSCC) and that restoration of miR-133a inhibited cell proliferation, migration and invasion in HNSCC cell lines, suggesting that miR-133a function as a tumor suppressor. Genome-wide gene expression analysis of miR-133a transfectants and TargetScan database showed that moesin (MSN) was a promising candidate of miR-133a target gene. MSN is a member of the ERM (ezrin, radixin and moesin) protein family and ERM function as cross-linkers between plasma membrane and actin-based cytoskeleton. The functions of MSN in cancers are controversial in previous reports. In this study, we focused on MSN and investigated whether MSN was regulated by tumor suppressive miR-133a and contributed to HNSCC oncogenesis. Restoration of miR-133a in HNSCC cell lines (FaDu, HSC3, IMC-3 and SAS) suppressed the MSN expression both in mRNA and protein level. Silencing study of MSN in HNSCC cell lines demonstrated significant inhibitions of cell proliferation, migration and invasion activities in si-MSN transfectants. In clinical specimen with HNSCC, the expression level of MSN was significantly up-regulated in cancer tissues compared to adjacent non-cancerous tissues. These data suggest that MSN may function as oncogene and is regulated by tumor suppressive miR-133a. Our analysis data of novel tumor-suppressive miR-133a-mediated cancer pathways could provide new insights into the potential mechanisms of HNSCC oncogenesis.

Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer.

microRNAs (miRNAs) have key roles in human tumorigenesis, tumor progression and metastasis. miRNAs are aberrantly expressed in many human cancers and can function as tumor suppressors or oncogenes that target many cancer-related genes. This study seeks to identify novel miRNA-regulated molecular pathways in prostate cancer (PCa). The miRNA expression signature in clinical specimens of PCa showed that 56 miRNAs were significantly downregulated in PCa compared with non-PCa tissues. We focused on the top four downregulated miRNAs (miR-187, miR-205, miR-222 and miR-31) to investigate their functional significance in PCa cells. Expression levels of these four miRNAs were validated in PCa specimens (15 PCa tissues and 17 non-PCa tissues) to confirm that they were significantly reduced in these PCa tissues. Gain-of-function analysis demonstrated that miR-222 and miR-31 inhibited cell proliferation, invasion and migration in PCa cell lines (PC3 and DU145), suggesting that miR-222 and miR-31 may act as tumor suppressors in PCa. Genome-wide gene expression analysis using miR-222 or miR-31 transfectants to identify the pathways they affect showed that many cancer-related genes are regulated by these miRNAs in PC3 cells. Identification and categorization of the molecular pathways regulated by tumor suppressive miRNAs could provide new information about the molecular mechanisms of PCa tumorigenesis.

The Efficacy of Compression Stockings on Patients With Nocturia: A Single-Arm Pilot Study.

OBJECTIVES:  Behavioral treatment for nocturia includes wearing compression stockings. However, a reading of the cited literature for evidence shows that there is not enough research data to support this recommendation, and it is controversial. The present study aimed to investigate and supplement evidence on the effects of wearing compression stockings during the daytime in patients with nocturia. METHODS: This was a single-arm prospective study to investigate the effects of compression stockings on nocturia for four weeks. Patients were asked to record a frequency-volume chart and complete various questionnaires at baseline and after four weeks, and also provide feedback on treatment satisfaction. The primary endpoint was a change in night-time frequency in the frequency-volume chart from the baseline to the end of treatment. RESULTS: Thirty-four patients (19 men and 15 women; age: 72.3 ± 12.6 years) were included. Two patients dropped out because of pain associated with wearing compression stockings and one due to a refusal to wear compression stockings every day. Therefore 31 patients were analyzed. In the frequency-volume chart, night-time and 24-hour frequencies significantly decreased by 0.5 and 1.1 episodes, respectively (P = 0.004 and P = 0.035, respectively). The hours of undisturbed sleep significantly increased by 0.8 h (P = 0.013). No significant differences were observed in nocturnal or 24-h urine volumes, the number of urgency or urinary incontinence episodes, the mean or maximum voided volume, the nocturnal polyuria index, or the first night-time voided volume. The total overactive bladder symptom score significantly decreased (P = 0.006). Significant reductions were also observed in all overactive bladder symptom score subscores, except for the daytime frequency score. CONCLUSION: The present results suggest the effectiveness of wearing compression stockings during the day was satisfactory in most patients with nocturia, and the treatment was safely continued in patients who experienced no pain when wearing the stockings. Based on the results of this study, we believe that it is worth considering as a treatment for nocturia.

SWAP70, actin-binding protein, function as an oncogene targeting tumor-suppressive miR-145 in prostate cancer.

BACKGROUND: MiR-145 is down-regulated in various human cancers. We previously demonstrated that some actin-binding proteins were targeted by several microRNAs (miRNAs), including miR-145, in bladder and prostate cancer (CaP). The aim of this study is to determine a novel oncogenic gene targeted by miR-145 by focusing on actin-binding proteins in CaP. METHODS: We focused on the SWAP switching B-cell complex 70 kDa subunit (SWAP70), which is an F-actin binding protein involved in activating B-cell transformation. A luciferase reporter assay was used to identify the actual binding sites between miR-145 and SWAP70 mRNA. Cell viability was evaluated by cell proliferation, wound healing, and matrigel invasion assays in si-SWAP70 transfectants. A total of 75 clinical prostate specimens were subjected to immunohistochemistry of SWAP70. RESULTS: Molecular target searches of this miRNA and the luciferase reporter assay showed that SWAP70 was directly regulated by miR-145. Silencing of SWAP70 studies demonstrated significant inhibitions of cell migration and invasion in CaP cell lines. The SWAP70 positive-staining was significantly higher in percentage in the CaP than in benign prostate hyperplasia tissue. CONCLUSIONS: Down-regulation of miR-145 was a frequent event in CaP, and it may have a tumor suppressive function. SWAP70 may be a target of miR-145, and it might have a potential oncogenic function. The novel molecular networks though which miR-145 acts, may provide new insights into the underlying molecular mechanisms of CaP.

Effects of magnetic stimulation on urodynamic stress incontinence refractory to pelvic floor muscle training in a randomized sham-controlled study.

OBJECTIVE: The aim of the present study was to evaluate the effect of magnetic stimulation on urodynamic stress incontinence refractory to pelvic floor muscle training in a randomized sham-controlled study. METHODS: Female patients with urodynamic stress incontinence who had not been cured by pelvic floor muscle training were randomly assigned at a ratio of 2 : 1 to either active treatment or sham treatment for 10 weeks. The randomization was made using magnetic cards for individuals indicating active or sham stimulation. The primary endpoint was changes in the number of incontinence episodes/week, with secondary endpoints of the degree of incontinence (in g/day; determined using the pad test), the total score on the International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF), the ICIQ quality of life (QOL) score, and the abdominal leak point pressure (ALPP) on urodynamic study. RESULTS: Although 39 patients were enrolled in the study, 9 dropped out, leaving a total patients for analysis (18 in the active treatment group, 12 in the sham treatment group). The number of incontinence episodes/week, the degree of incontinence, total ICIQ-SF score, ICIQ-QOL score, and ALPP were significantly improved after active treatment compared with baseline (all P < .05), but did not change significantly after sham treatment. There was a significant intergroup difference with regard to changes from baseline in the ICIQ-SF and ALPP in favor of the active treatment group (P < .05). There were no significant differences in any other parameters between the 2 groups. Treatment-related adverse events were not found in both groups. CONCLUSION: Magnetic stimulation was effective in treating urodynamic stress incontinence.

Autologous and heterotopic transplantation of adipose stromal vascular fraction ameliorates stress urinary incontinence in rats with simulated childbirth trauma.

INTRODUCTION: Autologous transplantation of adipose stromal vascular fraction (SVF) is a cost-effective and technically accessible option for cell therapy. Clinical study of SVF transplantation for male stress urinary incontinence (SUI) is underway, but the effectiveness remains unknown for female SUI, majority of which is caused by childbirth trauma. METHODS: Vaginal Distension (VD) rats were generated as in vivo model for female SUI. To quantitate the severity of SUI, leak point pressure (LPP) was measured by placing a bladder catheter. There was a characteristic waveform of LPP with two-peaks, and we counted the second peak as an LPP value. Adipose SVF was separated from inguinal fat and delivered into external urethral sphincter (EUS) through transperineal injection. LPP was measured 7 or 14 days after SVF transplantation. Tissue damage and collagen synthesis around the EUS were visualized by Masson's trichrome and eosin staining. Antibody against α-smooth muscle actin (α-SMA) was used to stain smooth muscle or activated stromal cells. Donor SVF cells were distinguished from recipient EUS tissue by tracking with GFP transgene. RESULTS: VD procedure decreased the frequency at which the normal LPP waveform appeared and lowered the LPP value. SVF injection normalized the waveform as well as the level of LPP. VD disrupted histological structure of EUS and SVF failed to differentiate into striatal muscles. Instead, SVF increased α-SMA positive cells and collagen synthesis but the phenomena depended on VD stimulus. GFP tracking indicated that the transplanted SVF cells persisted for four weeks and synthesized α-SMA protein simultaneously. CONCLUSIONS: Autologous transplantation of adipose SVF displayed bulking effects through collagen synthesis. However, such heterotopic activation was dependent on tissue damage.