Hiromitsu Mimata

Stress urinary incontinence commonly arises with aging or following prostatectomy, yet its underlying mechanisms remain unclear. To address this, we investigated the role of metabolic pathways—particularly the tricarboxylic acid (TCA) cycle—in the differentiation of human external urethral sphincter myoblasts. Immortalized sphincter cells (US2-KD) were induced to differentiate over 192 hours. Metabolomic profiling using gas chromatography–mass spectrometry, along with pathway enrichment analysis, identified key metabolic changes. Inhibition of mitochondrial pyruvate transport with UK5099 markedly suppressed TCA cycle metabolites, including citrate, α-ketoglutarate, fumarate, and malate. This inhibition also significantly reduced MYH7 expression and intracellular adenosine triphosphate levels throughout the differentiation period. These results demonstrate that the TCA cycle plays a critical role in both energy metabolism and the differentiation of urethral sphincter myoblasts. This study is the first to suggest that impaired TCA cycle activity may contribute to the pathogenesis of Stress urinary incontinence and represents a potential therapeutic target. Our findings offer new insight into age-related metabolic decline associated with Stress urinary incontinence and support the development of therapies that combine metabolic modulation with regenerative approaches.

Objective: To evaluate the accuracy of a magnetic resonance imaging (MRI)‐based Likert scoring system in the detection of clinically significant prostate cancer (CSPC), using MRI/ultrasonography (US) image‐fusion targeted biopsy (FTB) as a reference standard. Patients and Methods: We retrospectively reviewed 1218 MRI‐detected lesions in 629 patients who underwent subsequent MRI/US FTB between October 2012 and August 2015. 3‐Tesla MRI was independently reported by one of eight radiologists with varying levels of experience and scored on a five‐point Likert scale. All lesions with Likert scores 1–5 were prospectively defined as targets for MRI/US FTB. CSPC was defined as Gleason score ≥7. Results: The median patient age was 64 years, PSA level 6.97 ng/mL and estimated prostate volume 52.2 mL. Of 1218 lesions, 48% ( n = 581) were rated as Likert 1–2, 35% ( n = 428) were Likert 3 and 17% ( n = 209) were Likert 4–5. For Likert scores 1–5, the overall cancer detection rates were 12%, 13%, 22%, 50% and 59%, respectively, and the CSPC detection rates were 4%, 4%, 12%, 33% and 48%, respectively. Grading using the five‐point scale showed strong positive correlation with overall cancer detection rate ( r = 0.949, P = 0.05) and CSPC detection rate ( r = 0.944, P = 0.05). By comparison, in Likert 4–5 lesions, significant differences were noted in overall cancer detection rate (63% vs 35%; P = 0.001) and CSPC detection rate (47% vs 29%; P = 0.027) for the more experienced vs the less experienced radiologists. Conclusions: The detection rates of overall cancer and CSPC strongly correlated with the five‐point grading of the Likert scale. Among radiologists with different levels of experience, there were significant differences in these cancer detection rates.

Pseudoaneurysms are caused by trauma, tumors, infections, vasculitis, atherosclerosis and iatrogenic complications. In this paper, we report about a patient with rupture of an external iliac artery pseudoaneurysm, which lead to hemorrhagic shock, after undergoing laparoscopic radical cystectomy and extended pelvic lymphadenectomy.

The use of regenerative medicine for the treatment of organic and functional disorders intractable to conventional treatment has increased worldwide. This innovative medical field might particularly hold promise for the treatment of life-threatening diseases or healing of irreplaceable organs, such as the heart, liver and brain. Dysfunction of the urogenital tract and associated organs other than the kidney might not have immediate life-threatening implications; furthermore, the effectiveness of alternative therapy, such as enterocystoplasty for bladder cancer, has been shown. Therefore, most physicians or scientists do not give much importance to these disorders. However, urological disease has increased in developed societies in recent years. Furthermore, medical costs have also escalated. Disorders of the lower urinary tract, such as urinary disturbance or incontinence, can lead to other complications, impairing quality of life and ultimately increasing short- and long-term medical expenses. Regenerative medicine might hold potential solutions to these problems. Recent advances in urogenital regenerative medicine are reviewed in the present article, with particular reference to lower urinary tract reconstruction. The potential of regenerative medicine for the treatment of intractable lower urinary tract dysfunction compared with conventional treatment is also discussed.

The Vav family of Rho/Rac guanosine nucleotide exchange factors comprises three members in mammalian cells. Vav3 enhances androgen receptor (AR) activity during progression to androgen independence in prostate cancer. We examined Vav3 small interfering RNA (siRNA) effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH). We examined individual and combined effects of Vav3 siRNA (si-Vav3) and docetaxel on cell growth and apoptosis under chronic hypoxia by cell proliferation, flow cytometric, DNA fragmentation, and immunoblot analyses. To clarify the molecular basis of si-Vav3- and docetaxel-induced apoptosis, we analyzed alterations in phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulate kinase (ERK), c-jun N-terminal kinase (JNK), and AR pathways using kinase inhibitors in LNCaPH cells. The effects of si-Vav3/atelocollagen complex alone or in combination with docetaxel were assessed on xenografts in nude mice by tumor growth delay. Vav3 overexpression was observed in LNCaPH compared with the expression under normoxia. Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased B-cell lymphoma 2 (Bcl-2) phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis, as characterized by the accumulation of sub-G1 phase cells and DNA fragmentation, through Bcl-xL/Bcl-2-associated death promoter (Bad) dephosphorylation, resulting in increased caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase activation. Xenograft tumor growth was slightly inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3/atelocollagen complex and docetaxel produced a greater effect than docetaxel alone. Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer.

Background: Clinical outcome of patients with high-grade ccRCC (clear cell renal cell carcinoma) remains still poor despite recent advances in treatment strategies. Molecular mechanism of pathogenesis in developing high-grade ccRCC must be clarified. In the present study, we found that SAV1 was significantly downregulated with copy number loss in high-grade ccRCCs. Therefore, we investigated the SAV1 function on cell proliferation and apoptosis in vitro. Furthermore, we attempted to clarify the downstream signaling which is regulated by SAV1. Methods: We performed array CGH and gene expression analysis of 8 RCC cell lines (786-O, 769-P, KMRC-1, KMRC-2, KMRC-3, KMRC-20, TUHR4TKB, and Caki-2), and expression level of mRNA was confirmed by quantitative RT-PCR (qRT-PCR) analysis. We next re-expressed SAV1 in 786-O cells, and analyzed its colony-forming activity. Then, we transfected siRNAs of SAV1 into the kidney epithelial cell line HK2 and renal proximal tubule epithelial cells (RPTECs), and analyzed their proliferation and apoptosis. Furthermore, the activity of YAP1, which is a downstream molecule of SAV1, was evaluated by western blot analysis, reporter assay and immunohistochemical analysis. Results: We found that SAV1, a component of the Hippo pathway, is frequently downregulated in high-grade ccRCC. SAV1 is located on chromosome 14q22.1, where copy number loss had been observed in 7 of 12 high-grade ccRCCs in our previous study, suggesting that gene copy number loss is responsible for the downregulation of SAV1. Colony-forming activity by 786-O cells, which show homozygous loss of SAV1, was significantly reduced when SAV1 was re-introduced exogenously. Knockdown of SAV1 promoted proliferation of HK2 and RPTEC. Although the phosphorylation level of YAP1 was low in 786-O cells, it was elevated in SAV1-transduced 786-O cells. Furthermore, the transcriptional activity of the YAP1 and TEAD3 complex was inhibited in SAV1-transduced 786-O cells. Immunohistochemistry frequently demonstrated nuclear localization of YAP1 in ccRCC cases with SAV1 downregulation, and it was preferentially detected in high-grade ccRCC. Conclusions: Taken together, downregulation of SAV1 and the consequent YAP1 activation are involved in the pathogenesis of high-grade ccRCC. It is an attractive hypothesis that Hippo signaling could be candidates for new therapeutic target.