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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.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.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.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.

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

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

Reductions in testosterone concentration play a significant role in the treatment of prostate cancer. We studied the role of testosterone as a prognostic marker for advanced prostate cancer (stage C or higher) treated with primary androgen-deprivation therapy (ADT).A total of 348 patients were treated using ADT as first-line therapy for prostate cancer at Chiba University Hospital between 1999 and 2016. Of these, 222 patients with advanced prostate cancer (stage C or higher) were enrolled onto this study. The prognostic values of serum testosterone level and other clinical factors were evaluated in association with prostate-specific antigen (PSA), progression-free survival during first-line therapy, and overall survival.Median age was 73 years. PSA at baseline was 86 ng/mL. Gleason scores of ≤ 6, 7, 8, and ≥ 9 were seen in 2.3%, 19.4%, 21.2%, and 41.9%, respectively. Mean follow-up was 60.5 months. Median testosterone at baseline was 482 ng/dL and nadir testosterone was 13 ng/dL. No variable associated with testosterone predicted progression-free survival. With regard to overall survival, multivariate analysis identified nadir testosterone ≤ 20 ng/dL (hazard ratio = 0.44, P = .026) and testosterone reduction ≥ 480 ng/dL (hazard ratio = 0.35, P = .030) as independent prognostic factors. With regard to progression-free survival, multivariate analysis identified nadir PSA ≤ 0.1 ng/mL (hazard ratio = 3.07, P .001), presence of lymph node metastasis (hazard ratio = 1.67, P = .017), and time to nadir PSA (hazard ratio = 0.30, P .001) as independent prognostic factors.Our data suggested both nadir testosterone (20 ng/dL; P = .026) and testosterone reduction (≥ 480 ng/dL; P = .030) to be key prognostic factors for primary ADT in advanced prostate cancer in Japanese men.

It is difficult to differentiate multiple system atrophy (MSA) from Parkinson's disease (PD) at least in the early stage. Urodynamic study (UDS) is useful in differentiating MSA from PD. We aimed to clarify which UDS parameter was useful in differentiating MSA from PD.We retrospectively reviewed 273 cases and performed UDS and external anal sphincter electromyography (EAS-EMG) in patients with MSA (n=182) and PD (n=91). We analyzed the utility of UDS parameters, including postvoid residuals (PVR), detrusor overactivity (DO), degree of bladder contraction, and mean duration of motor unit potentials (MUPs) in EAS-EMG, for differentiating MSA from PD.PVR150ml during free-flow study strongly indicated MSA rather than PD (OR 8.723, 95% CI 2.612-29.130, p0.001). 'Weak detrusor' also suggested MSA, but it was not a statistically significant indicator (OR 10.598, 95% CI 0.359-312.473, p=0.172). DO and neurogenic changes in EAS-EMG (mean duration of MUPs10ms) did not significantly contribute to the differentiation of MSA from PD.PVR150ml during free-flow study might be more useful than other UDS parameters in clinically differentiating MSA from PD.

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. 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. 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

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.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.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.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.

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.

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.

Background:Amantadine is a drug used for patients with Parkinson's disease (PD) and vascular parkinsonism (VP). These patients often have lower urinary tract symptoms (LUTS) and nocturnal polyuria (NP). Thus, we investigated the effect of amantadine on these in parkinsonian patients.Methods:Twenty-two patients with LUTS, including 13 with PD and nine with VP, were recruited. We performed a urinary questionnaire, frequency-volume chart, and residual urine (RU) measurement before and after daily administration of 150 mg and 300 mg amantadine.Results:Before amantadine administration, mean daytime urinary frequency was 9.07(standard error [SE], 0.64), nighttime urinary frequency 2.89 (0.24), urinary urgency per week 24.2 (6.69), urge incontinence per month 15.1( 9.94), urine volume per void 145.6( 12.6) mL, and residual urine volume 12.5( 6.30) mL. After daily 150 mg amantadine administration, mean daytime and nighttime urinary frequency, urinary urgency, and urge incontinence decreased to 6.9( 0.42), 1.97( 0.21), 13.0( 3.58), and 14.2( 10.2), respectively, and urine volume per void increased to 174.1( 11.3) mL. NP( N=8) was ameliorated in six patients. No patient had side effects. After daily 300 mg amantadine administration( N=8), mean daytime and nighttimeurinary frequency, urinary urgency, and urge incontinence decreased to 6.90 (0.33), 1.69 (0.10), 5.88 (1.61), and 2.31 (0.61), respectively, and urine volume per void increased to180.2 (15.0) mL. NP (N=4) was ameliorated in two patients. One patient developed hallucination, and two patients developed flashing sensation.Conclusion:Amantadine has beneficial effects on LUTS and NP in patients with VP and PD.

Neuromodulation therapy incorporates electrical stimulation to target specific nerves that control lower urinary tract symptoms (LUTS). The objectives of this article are to review the mechanism of action, the type of neuromodulation, and the efficacy of neuromodulation mainly according to the results of randomized controlled trials. Neuromodulation includes pelvic floor electrical stimulation (ES) using vaginal, anal and surface electrodes, interferential therapy (IF), magnetic stimulation (MS), percutaneous tibial nerve stimulation, and sacral nerve stimulation (SNS). The former four stimulations are used for external periodic (short-term) stimulation, and SNS are used for internal, chronic (long-term) stimulation. All of these therapies have been reported to be effective for overactive bladder or urgency urinary incontinence. Pelvic floor ES, IF, and MS have also been reported to be effective for stress urinary incontinence. The mechanism of neuromodulation for overactive bladder has been reported to be the reflex inhibition of detrusor contraction by the activation of afferent fibers by three actions, i.e., the activation of hypogastric nerve, the direct inhibition of the pelvic nerve within the sacral cord and the supraspinal inhibition of the detrusor reflex. The mechanism of neuromodulation for stress incontinence is contraction of the pelvic floor muscles through an effect on the muscle fibers as well as through the stimulation of pudendal nerves. Overall, cure and improvement rates of these therapies for urinary incontinence are 30-50, and 60-90% respectively. MS has been considered to be a technique for stimulating nervous system noninvasively. SNS is indicated for patients with refractory overactive bladder and urinary retention.

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

OBJECTIVE To determine the ability of sphincter electromyography (EMG) and post-void residual urine volume (PVR) during a free-flow study and a pressure-flow study (PFS) for distinguishing multiple system atrophy (MSA) from Parkinson's disease (PD). METHODS We retrospectively reviewed 241 case records; both urodynamic study and sphincter EMG were performed in patients with MSA (n = 147) and PD (n = 94). RESULTS There was a statistically significant difference (p < 0.01) in the mean PVR during the free-flow study (113.1 ± 7.5 mL in MSA and 40.4 ± 3.8 mL in PD), mean PVR during PFS (230.1 ± 12.6 mL in MSA and 71.7 ± 6.6 mL in PD), and mean duration of MUP for sphincter EMG (9.3 ± 0.1 ms in MSA and 7.7 ± 0.1 ms in PD). The area under the curve used for differentiating MSA from PD was 0.79 and 0.73 for PVR during PFS and the free-flow study, respectively. There was a mean duration of 0.69 ms for the sphincter EMG. CONCLUSIONS The present results suggested that PVR was more appropriate than sphincter EMG for differentiating MSA from PD.

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.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.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.We determined the association of CXCR3 and renal cell carcinoma metastasis. CXCR3 expression may be regulated by hypoxia.

Our recent studies of microRNA (miRNA) expression signatures revealed that microRNA-29s (miR-29s; including miR-29a/b/c) were significantly downregulated in prostate cancer (PCa) and was a putative tumor-suppressive miRNA family in PCa. Herein, we aimed to investigate the functional significance of miR-29 in cancer cells and to identify novel miR-29s-mediated cancer pathways and target genes involved in PCa oncogenesis and metastasis. Restoration of miR-29s in PC3 and DU145 cell lines revealed significant inhibition of cancer cell migration and invasion. To identify miR-29s-mediated molecular pathways and targets, we used gene expression data and in silico database analysis. Our analysis demonstrated that miR-29s modulated the focal adhesion pathway. Moreover, the laminin γ1 (LAMC1) gene was a candidate target of miR-29s regulation. Luciferase reporter assays showed that miR-29s directly regulated LAMC1. Silencing of LAMC1 significantly inhibited cell migration and invasion in cancer cells, and LAMC1 was upregulated in PCa. miR-29s acted as tumor suppressors, contributing to cancer cell migration and invasion and directly targeting laminin signaling. Recognition of tumor-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of PCa oncogenesis and metastasis, and suggests novel therapeutic strategies for treating this disease.

Our recent study of the microRNA expression signature of prostate cancer (PCa) revealed that microRNA-224 (miR-224) is significantly downregulated in PCa tissues. Here, we found that restoration of miR-224 significantly inhibits PCa cell migration and invasion. Additionally, we found that oncogenic TPD52 is a direct target of miR-224 regulation. Silencing of the TPD52 gene significantly inhibits cancer cell migration and invasion. Moreover, TPD52 expression is upregulated in cancer tissues and negatively correlates with miR-224 expression. We conclude that loss of tumour-suppressive miR-224 enhances cancer cell migration and invasion in PCa through direct regulation of oncogenic TPD52.

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

Background Autonomic urinary dysfunction affects patients with progressive supranuclear palsy (PSP); however, the severity and prevalence of urinary dysfunctions in these patients compared with those observed in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA) are unknown. Objective We compared urinary dysfunction characteristics in patients with PSP, PD, and MSA. Patients and Methods Forty-seven patients who satisfied the probable or possible criteria of the National Institute for Neurological Diseases and Stroke and Society for PSP were assessed using the urinary symptoms questionnaire and the urodynamic study at Chiba and Toho Universities (n = 26 and 21, respectively). The results were compared with those of patients with PD and MSA (n = 218 and 193, respectively). Results The mean disease duration of PSP and the mean age were 2.97 ± 0.26 and 71.4 ± 0.88 years, respectively. The mini-mental state examination and frontal assessment battery scores were 22.6 ± 0.70 and 10.7 ± 0.49, respectively. Urinary storage and voiding symptoms were observed in 57% and 56% of patients with PSP, respectively. Detrusor overactivity in the urodynamic study was detected in 81% of patients with PSP, which was slightly more than that found in patients with PD (69%) and MSA (67%); however, this was not statistically significant. Postvoid residual volume in patients with PSP was significantly more than that in patients with PD (P < 0.01), but was equivalent to that in patients with MSA. Conclusions The present study demonstrated that patients with PSP experienced various urinary dysfunctions. Urinary storage dysfunction in patients with PSP was not different from that in patients with PD or MSA, whereas urinary voiding dysfunction in patients with PSP was milder than that in patients with MSA and more severe than that in patients with PD. These features should be taken into account for the differentiation of PSP from PD and MSA.

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.

Hideo Hidaka 1,* , Naohiko Seki 2,* , Hirofumi Yoshino 1 , Takeshi Yamasaki 1 , Yasutoshi Yamada 1 , Nijiro Nohata 2 , Miki Fuse 2 , Masayuki Nakagawa 1 and Hideki Enokida 1 1 Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan 2 Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba, Japan * Denotes equal contribution Received: December 31, 2011; Accepted: January 21, 2012; Published: January 30, 2012; Keywords: microRNA, expression signature, miR-1285, tumor suppressor, renal cell carcinoma, transglutaminase 2 Correspondence: Hideki Enokida, email: // // Abstract MicroRNAs (miRNA) are non-coding RNAs, approximately 22 nucleotides in length, which function as post-transcriptional regulators. A large body of evidence indicates that miRNAs regulate the expression of cancer-related genes involved in proliferation, migration, invasion, and metastasis. The aim of this study was to identify novel cancer networks in renal cell carcinoma (RCC) based on miRNA expression signatures obtained from RCC clinical specimens. Expression signatures revealed that 103 miRNAs were significantly downregulated (< 0.5-fold change) in RCC specimens. Functional screening (cell proliferation assays) was performed to identify tumor suppressive activities of 20 downregulated miRNAs. Restoration of mature miRNAs in cancer cells showed that 14 miRNAs ( miR-1285 , miR-206 , miR-1 , miR-135a , miR-429 , miR-200c, miR-1291, miR-133b, miR-508-3p, miR-360-3p, miR-509-5p, miR-218, miR-335, miR-1255b and miR-1285 ) markedly inhibited cancer cell proliferation, suggesting that these miRNAs were candidate tumor suppressive miRNAs in RCC. We focused on miR-1285 because it significantly inhibited cancer cell proliferation, invasion, and migration following its transfection. We addressed miR-1285 -regulated cancer networks by using genome-wide gene expression analysis and bioinformatics. The data showed that transglutaminase 2 ( TGM2 ) was directly regulated by miR-1285 . Silencing of the target gene demonstrated significant inhibition of cell proliferation and invasion in the RCC cells. Furthermore, immunohistochemistry showed that TGM2 expression levels in RCC specimens were significantly higher than those in normal renal tissues. Downregulation of tumor suppressive miR-1285 , which targets oncogenic genes including TGM2, might contribute to RCC development. Thus, miR-1285 modulates a novel molecular target and provides new insights into potential mechanisms of RCC oncogenesis.

Background: Our recent analyses of miRNA expression signatures showed that miR-1 and miR-133a were significantly reduced in several types of cancer. Interestingly, miR-1 and miR-133a are located on the same chromosomal locus in the human genome. We examined the functional significance of miR-1 and miR-133a in prostate cancer (PCa) cells and identified the novel molecular targets regulated by both miR-1 and miR-133a. Methods and Results: The expression levels of miR-1 and miR-133a were significantly downregulated in PCa compared with non-PCa tissues. Restoration of miR-1 or miR-133a in PC3 and DU145 cells revealed significant inhibition of proliferation, migration, and invasion. Molecular target identification by genome-wide gene expression analysis and luciferase reporter assay showed that purine nucleoside phosphorylase (PNP) was directly regulated by both miRNAs. Silencing of the PNP gene inhibited proliferation, migration, and invasion in both PC3 and DU145 cells. Immunohistochemistry detected positive staining of PNP in PCa specimens. Conclusions: Downregulation of miR-1 and miR-133a was a frequent event in PCa and both function as tumour suppressors. The PNP is a novel target gene of both miRNAs and potentially functions as an oncogene. Therefore, identification of novel molecular networks regulated by miRNAs may provide new insights into the underlying causes of PCa oncogenesis.

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. Prostate 71:1559–1567, 2011. © 2011 Wiley-Liss, Inc.

Based on the microRNA (miRNA) expression signatures of hypopharyngeal and esophageal squamous cell carcinoma, we found that miR-1 was significantly down-regulated in cancer cells. In this study, we investigated the functional significance of miR-1 in head and neck squamous cell carcinoma (HNSCC) cells and identified miR-1-regulated novel cancer pathways. Gain-of-function studies using miR-1 revealed significant decreases in HNSCC cell proliferation, invasion, and migration. In addition, the promotion of cell apoptosis and cell cycle arrest was demonstrated following miR-1e transfection of cancer cells. A search for the targets of miR-1 revealed that transgelin 2 (TAGLN2) was directly regulated by miR-1. Silencing of TAGLN2 significantly inhibited cell proliferation and invasion in HNSCC cells. Down-regulation of miR-1 and up-regulation of TAGLN2 were confirmed in HNSCC clinical specimens. Our data indicate that TAGLN2 may have an oncogenic function and may be regulated by miR-1, a tumor suppressive miRNA in HNSCC. The identification of novel miR-1-regulated cancer pathways could provide new insights into potential molecular mechanisms of HNSCC carcinogenesis.

INTRODUCTION AND OBJECTIVES: High risk prostate cancer potentially cause unfavorable prognosis. Recent PSA screening has been associated with significant decline in tumor volume. However, question arises whether small tumor volume in high risk prostate cancer associated with better prognosis? Here we studied relationship between tumor volume and PSA recurrence after radical prostatectomy, focusing on patients with high-risk prostate cancer. METHODS: The study cohort included 450 patients who underwent radical prostatectomy at Chiba University Hospital. Tumor volume was calculated by scanning the cross-sections of pathological specimens and measuring tumor area using Image J software. Cox hazard analysis, Logistic regression analysis and the Kaplan-Meier method were used for statistical analysis. RESULTS: Of the 450 patients, 85 patients were classified as high risk prostate cancer. The median age was 68 years. The median PSA was 13.4 ng/mL. Distributions of pT2/T3/T4 were 31/42/2, respectively. The mean follow-up period was 25.9 months. On univariate analysis, % Tumor Volume (HR 2.589, p1⁄40.038), Extra-capsular extension (HR 8.68, p1⁄40.008), Surgical margin positivity (HR 13.55, P1⁄40.001) are associated with PSA recurrence. Furthermore, related to Tumor volume (TV), TV

localized (n1⁄42), biochemical recurrence (n1⁄44), metastatic hormone sensitive (n1⁄416), and castration resistant (n1⁄44). In patients with PCa, the median PSA was 3.32 ng/dl (range

Neuromodulation therapy incorporates electrical stimulation to target specific nerves that control lower urinary tract symptoms (LUTS). The objectives of this article are to review the mechanism of action, the type of neuromodulation, and the efficacy of neuromodulation mainly according to the results of randomized controlled trials. Neuromodulation includes pelvic floor electrical stimulation (ES) using vaginal, anal and surface electrodes, interferential therapy (IF), magnetic stimulation (MS), percutaneous tibial nerve stimulation, and sacral nerve stimulation (SNS). The former four stimulations are used for external periodic (short-term) stimulation, and SNS are used for internal, chronic (long-term) stimulation. All of these therapies have been reported to be effective for overactive bladder or urgency urinary incontinence. Pelvic floor ES, IF, and MS have also been reported to be effective for stress urinary incontinence. The mechanism of neuromodulation for overactive bladder has been reported to be the reflex inhibition of detrusor contraction by the activation of afferent fibers by three actions, i.e., the activation of hypogastric nerve, the direct inhibition of the pelvic nerve within the sacral cord and the supraspinal inhibition of the detrusor reflex. The mechanism of neuromodulation for stress incontinence is contraction of the pelvic floor muscles through an effect on the muscle fibers as well as through the stimulation of pudendal nerves. Overall, cure and improvement rates of these therapies for urinary incontinence are 30-50, and 60-90% respectively. MS has been considered to be a technique for stimulating nervous system noninvasively. SNS is indicated for patients with refractory overactive bladder and urinary retention.

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.

INTRODUCTION AND OBJECTIVES: miRNAs are aberrantly expressed in many human cancers and can function as tumor suppressors or oncogenes that target many cancer-related genes. Therefore, genome-wide comprehensive study is necessary for decoding tumor suppressive miRNA-mediated molecular pathways in cancer research field. In this study we identified tumor suppressive miRNAs in prostate cancer (PCa) based on the miRNA expression signature in clinical PCa specimens and seek out of the tumor suppressive miRNA-mediated molecular pathways. METHODS: The miRNA expression signature of PCa was applied to screen 778 miRNAs by the TaqMan LDA Human microRNA® using five PCa tissues and five non-cancerous tissues. Gain-offunction studies were performed to investigate cancer cell proliferation, migration and invasion by restoration of mature miRNAs/siRNA into PCa cell lines. To identify the biological processes or pathways potentially regulated by the miRNAs, we applied gene expression data and in silico analysis using TargetScan database [http://www.targetscan.org/] and GENECODIS software. The GENECODIS software assigned a number of the putative miRNA targets to known pathways in KEGG [http://www.genome.jp/kegg/pathway.html]. RESULTS: The miRNA expression signature in PCa showed that 56 miRNAs were significantly down-regulated in PCa compared to non-PCa tissues. Among them, the functional screening of downregulated miRNAs demonstrated that miR-222, miR-31, miR-133a and miR-1 inhibited cell proliferation, invasion, and migration in PCa cell lines (PC3 and DU145), suggesting that these miRNAs may act as tumor suppressors in PCa. Our in silico analysis showed that these tumor suppressive miRNAs appeared to be an important modulator of tumor cell processes through suppression of many targets, particularly those involved in focal adhesion, MAPK and ErbB signaling pathways. CONCLUSIONS: Aberrant expression of miRNAs has shed light on recent miRNA signatures and identification of tumor suppressive miRNA mediated novel molecular pathways in PCa. Tumor suppressive miRNA-mediated novel molecular pathways provide a new insight of PCa oncogenesis and metastasis. Furthermore, miRNAmediated pathways contribute to discovery of molecular target search of PCa treatments.

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.

A 41-year-old man underwent surgery for treatment of an intervertebral disk hernia and received urethral catheterization at another hospital. After insertion of the catheter, intermittent urethral bleeding occurred. He was brought to our hospital by ambulance because of massive urethral bleeding and urethral pain on the day after the operation. Laboratory tests showed a decrease of hemoglobin, and contrast computed tomography revealed intense enhancement of part of the urethra that resembled an aneurysm. Urethroscopy showed a pseudoaneurysm in the bulbar urethra and the arterial bleeding was stopped by transurethral coagulation.

To evaluate the Japanese version of the Nocturia Quality-of-Life questionnaire for prediction of night-time voiding and risk of falling.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).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 (P0.001). 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.The Nocturia Quality-of-Life questionnaire represents a useful tool to predict nocturia and risk of falling in Japanese patients.