Ken Aikawa

The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat†‡

To develop a rat model of atherosclerosis‐induced chronic bladder ischemia and investigate the effect of chronic bladder ischemia on voiding behavior and bladder function.

Increased bladder activity is associated with elevated oxidative stress markers and proinflammatory cytokines in a rat model of atherosclerosis-induced chronic bladder ischemia.

To further characterize, in a rat model, the effects of atherosclerosis‐induced chronic bladder ischemia on bladder function and associated changes in oxidative stress markers and proinflammatory cytokines.

Urinary incontinence after robot-assisted radical prostatectomy: pathophysiology and intraoperative techniques to improve surgical outcome.

Robot‐assisted radical prostatectomy has been shown to have comparable and possibly improved postoperative continent rates compared with retropubic and laparoscopic radical prostatectomy. However, postoperative urinary incontinence has remained one of the most bothersome postoperative complications. The basic concept of the intraoperative technique to improve postoperative urinary continence is to maintain as normal anatomical and functional structure in the pelvis as possible. Therefore, improved knowledge of the normal structure in the pelvis should lead to a greater understanding of the pathophysiology of urinary incontinence, and further development of intraoperative techniques to improve the outcomes of urinary continence. It might be necessary to carry out three steps to realize improvement of the early return of urinary continence after robot‐assisted radical prostatectomy: (i) preservation (bladder neck, neurovascular bundle, puboprostatic ligament, pubovesical complex, and/or urethral length, etc.); (ii) reconstruction (posterior and/or anterior reconstruction, and/or reattachment of the arcus tendineus to the bladder neck, etc.); and (iii) reinforcement (bladder neck plication and/or sling suspension, etc.). On the basis of these steps, further modifications during robot‐assisted radical prostatectomy should be developed to improve urinary continence and quality of life after robot‐assisted radical prostatectomy.

Alpha1-Adrenoceptor Antagonists Improve Bladder Storage Function Through Reduction of Afferent Activity in Rats With Bladder Outlet Obstruction†‡

Using a rat BOO model, we determined whether α1‐adrenoceptor (AR) antagonists (silodosin, prazosin) improve the bladder storage function by reducing afferent input from the lower urinary tract.

Obstruction alters muscarinic receptor-coupled RhoA/Rho-kinase pathway in the urinary bladder of the rat†

The present study investigated the effects of the bladder outlet obstruction (BOO) on the muscarinic receptor (MR)‐coupled RhoA/Rho‐kinase (ROK) pathway in the detrusor smooth muscle of the rat.

Suppression of SOCS3 increases susceptibility of renal cell carcinoma to interferon-α.

Interferon (IFN)‐α is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN‐α, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN‐induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN‐α on SOCS3 expression and cell proliferation was examined using IFN‐resistant 786‐O and IFN‐sensitive ACHN cell lines. The effects of SOCS3‐targeted siRNA on 786‐O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The SOCS3 mRNA expression level was significantly increased by IFN‐α stimulation in 786‐O, but not in ACHN cells. The overexpression of SOCS3 by gene transfection in ACHN cells significantly inhibited the growth‐inhibitory effect of IFN‐α. Suppression of SOCS3 expression in 786‐O cells by siRNA activated the IFN signaling pathway through signal transducer and activator of transcription 1 phosphorylation and recovered sensitivity to IFN‐α. An in vivo study indicated that co‐administration of SOCS3‐targeted siRNA promoted IFN‐α‐induced cell death and growth suppression in 786‐O cell xenograft in nude mice. Morphological observation of the tumors revealed the inhibition of SOCS3‐induced apoptosis, invasion of inflammatory cells and fibrosis. SOCS3 could be a key component in the resistance to IFN treatment of renal cell carcinoma. Silencing SOCS3 gene expression could be an effective strategy to enhance the antitumor effect of IFN in human renal cell carcinoma cells. (Cancer Sci 2011; 102: 57–63)

Place of overactive bladder in male lower urinary tract symptoms

Lower urinary tract symptoms (LUTS) are highly prevalent in older men and women. Overactive bladder symptom syndrome (OAB) comprises the storage subset of LUTS and, in both sexes, is the most bothersome. The management of male LUTS has however, been disproportionately dominated in the past by an emphasis on prostatic pathology (bladder outlet obstruction (BOO) and prostatic enlargement). Pharmacotherapy that targets the prostate (e.g., α1-adrenoceptor antagonists) often fails to alleviate OAB symptoms, while many studies suggest that antimuscarinic therapy alone, or in combination with α1-adrenoceptor antagonists, can improve OAB symptoms in men with and without BOO. Recent studies suggest that arterial obstructive disease, such as atherosclerosis, may cause OAB in both men and women via ischemia, hypoxia and oxidative stress in the bladder. In this context, the use of phosphodiesterase inhibitors has been suggested to be a potential pharmacotherapy for men with LUTS. This article provides a review of the place of OAB in male LUTS and its treatment and provides an opportunity to draw data from a number of sources into one manuscript for critical review.

Overexpression of fatty acid synthase in human urinary bladder cancer and combined expression of the synthase and Ki-67 as a predictor of prognosis of cancer patients

To investigate the status of fatty acid synthase (FAS) in bladder tumors and evaluate its prognostic significance, we immunohistochemically examined the expression of FAS in normal urothelium, carcinoma in situ (CIS), and urothelial carcinoma (UC) in cystectomized bladder. In normal urothelium, only the surface layer expressed FAS, whereas the protein was detected in the basal layer or whole layer of CIS and UC in every specimen. Of the clinicopathological factors in UC, pathological tumor (pT) stage and histological grade were significantly correlated to FAS expression (P = 0.002, P < 0.0001, respectively). Univariate analysis for disease-specific survival indicated that the combination scores of FAS and Ki-67 expression, which were not associated with each other, was a more predictive variable than the individual score of each protein expression. Kaplan-Meier analysis showed that high combination scores of both proteins were significantly associated with poor prognosis (P = 0.04). In conclusion, FAS expression can be a biomarker for tumor aggressiveness and loss of differentiation of bladder cancer, and the evaluation of its expression level in combination with Ki-67 labeling index may be a precise predictor for poor prognosis of cancer patients.

Effect of Long-Term Oxybutynin Administration on c-Fos Expression in Spinal Neurons: Inhibition of Antimuscarinics on Bladder Afferents in Conscious Rats

OBJECTIVES To investigate the effect of long-term administration of oxybutynin on afferent input from the bladder by evaluating c-Fos expression in the spinal cord. METHODS Using an osmotic pump, long-term administration of oxybutynin (4 weeks) was performed in the rat. The effects of oxybutynin (2 doses) on the urodynamic parameters were determined by continuous cystometry in conscious rats. After cystometry, c-Fos expression in the spinal cord was measured by immunohistochemistry. RESULTS The long-term administration of low-dose oxybutynin (0.36 mg/kg/d) significantly increased the micturition interval and bladder capacity, but it did not affect micturition pressure. However, administration of high-dose oxybutynin (3.6 mg/kg/d) significantly decreased the micturition pressure and increased the residual volume. In the rats that received low-dose oxybutynin, the number of c-Fos-positive neurons in the spinal cord was significantly lower than that in controls. CONCLUSIONS Administration of low-dose oxybutynin decreased the c-Fos expression induced by continuous infusion of saline into the bladder. This result suggests that the antimuscarinic drug oxybutynin at clinically recommended doses can exert an inhibitory effect on afferent input from the bladder during the storage phase without affecting detrusor contractions.

Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression

Interleukin-6 (IL-6), one of the proinflammatory cytokines, is considered to be one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). Suppressor of cytokine signalling-3 (SOCS3) is rapidly up-regulated by IL-6 and a negative regulator of cytokine signalling. SOCS3 not only suppresses cytokine-mediated JAK/STAT signalling, but also sustains MAPK pathways. In our study, among the RCC cell lines, IL-6 mRNA expression was the highest in the 786-O cells, which also showed the highest level of SOCS3 mRNA expression under the condition of interferon stimulation. In contrast, ACHN cells had the lowest expression of both IL-6 and SOCS3 mRNA under the same condition. Our study is undertaken to evaluate the effect of humanised antihuman IL-6 receptor (IL-6R) antibody, which completely neutralises IL-6 activity, in RCC cell proliferation and its effect on signalling pathways. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells with interferon stimulation. Western blot analysis revealed that the tocilizumab enhanced the interferon-induced phosphorylation of STAT1 and inhibited SOCS3 expression and the phosphorylation of both STAT3 and ERK. In contrast, the IL-6 inhibited STAT1 phosphorylation, enhanced STAT3 phosphorylation and accelerated cell proliferation in ACHN cells. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumour growth in a xenograft model. Morphological observation of the tumours revealed the apoptosis, invasion of inflammatory cells and fibrosis. These findings suggest that combination therapy using an antihuman IL-6R antibody with interferon may represent a novel therapeutic approach for the treatment of RCC.