TGF-ß inhibitor treatment of H2O2-induced cystitis models provides biochemical mechanism for elucidating interstitial cystitis/painful bladder syndrome patients.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic disease for which no effective treatment is available. Transforming growth factor-ß (TGF-ß) is thought to be involved in the pathogenesis of IC/PBS, and previous studies have suggested that administrations of a TGF-ß inhibitor significantly ameliorated IC/PBS in a mouse model. However, the molecular mechanisms underlying the therapeutic effect of a TGF-b inhibitor on IC/PBS has not been comprehensively analyzed. TGF-ß has a variety of actions, such as regulation of immune cells and fibrosis. In our study, we induced IC/PBS-like disease in mice by an intravesical administration of hydrogen peroxide (H2O2) and examined the effects of three TGF-ß inhibitors, Repsox, SB431542, and SB505124, on the urinary functions as well as histological and gene expression profiles in the bladder. TGF-ß inhibitor treatment improved urinary function and histological changes in the IC/PBS mouse model, and SB431542 was most effective among the TGF-ß inhibitors. In our present study, TGF-ß inhibitor treatment improved abnormal enhancement of nociceptive mechanisms, immunity and inflammation, fibrosis, and dysfunction of bladder urothelium. These results show that multiple mechanisms are involved in the improvement of urinary function by TGF-ß inhibitor.

Novel device for dividing core needle biopsy specimens to provide paired mirror image-like tissues for genetic and pathological tests.

In a world that seeks precision medicine, genetic testing is gaining importance in clinical decision making. We previously reported the utility of a novel tool for longitudinally dividing core needle biopsy (CNB) tissues into two filamentous tissues that can provide paired mirror image-like tissues (mirror-tissues) that spatially match each other. In this study, we investigated its application in gene panel testing in patients who underwent prostate CNB. Four hundred and forty-three biopsy cores were obtained from 40 patients. Of them, 361 biopsy cores (81.5%) were judged by a physician to be appropriate for dividing into two pieces using the new device, of which a histopathological diagnosis was successfully reached in 358 biopsy cores (99.2%). Among them, the quality and quantity of nucleic acid in 16 appropriately divided cores were assessed and found to be sufficient for gene panel testing, and histopathological diagnosis was successfully obtained from the remaining divided cores. The novel device for longitudinally-dividing CNB tissue provided mirror image-like paired-tissues for gene panel and pathology testing. The device might be a promising tool for obtaining genetic and molecular biological information, in addition to histopathological diagnosis, helping to advance personalized medicine.

Usefulness of a novel device to divide core needle biopsy specimens in a spatially matched fashion.

We developed a novel dividing device that can split needle biopsy tissues along longitude axis aiming to achieve definitive molecular-biological and genetical analysis with reference of pathological diagnosis of the side-by-side divided tissue as spatially matched information. The aim of this study was to evaluate the feasibility and potential usefulness of the novel dividing device to provide the appropriate materials for molecular diagnosis. The new device was examined using mouse xenograft tumors. Real-time quantitative PCR and genetic test were performed to evaluate the feasibility and usefulness of the device. All the samples from needle biopsy were successfully divided into two pieces. Quality and quantity from divided samples harbor high enough to perform gene expression analysis (real-time PCR) and genetic test. Using two divided samples obtained from xenograft tumor model by needle biopsy, the % length of xenograft tumor (human origin) was significantly correlated with the % human genomic DNA (p = 0.00000608, r = 0.987), indicating that these divided samples were spatially matched. The novel longitudinally dividing device of a needle biopsy tissue was useful to provide the appropriate materials for molecular-biological and genetical analysis with reference of pathological diagnosis as spatially matched information.

Direct conversion of fibroblasts into urothelial cells that may be recruited to regenerating mucosa of injured urinary bladder.

Urothelial cells play essential roles in protection of urine exudation and bacterial invasion at the urothelial mucosa, so that defect or damage of urothelial cells associated with urinary tract diseases may cause serious problems. If a sufficient number of functional urothelial cells are prepared in culture and transplanted into the damaged urothelial lesions, such technology may provide beneficial effects to patients with diseases of the urinary tract. Here we found that human adult dermal fibroblasts were converted into urothelial cells by transducing genes for four transcription factors, FOXA1, TP63, MYCL and KLF4 (FTLK). The directly converted urothelial cells (dUCs) formed cobblestone-like colonies and expressed urothelium-specific markers. dUCs were successfully expanded and enriched after serial passages using a specific medium that we optimized for the cells. The passaged dUCs showed similar genome-wide gene expression profiles to normal urothelial cells and had a barrier function. The FTLK-transduced fibroblasts were also converted into urothelial cells in vivo and recruited to the regenerating urothelial tissue after they were transplanted into the bladder of mice with interstitial cystitis. Our technology may provide a promising solution for a number of patients with urinary tract disorders.

[A Case of Primary Testicular Mucinous Carcinoma].

A 68-year-old man presented withleft testicular painless swelling. His carbohydrate antigen 19-9 and carcinoembryonic antigen levels were elevated but his germ cell tumor markers were not high. Magnetic resonance imaging showed multiloculated cystic lesions with solid components in his left testis. Abdominal and chest computed tomography revealed multiple lung metastases, peritoneal dissemination and multiple lymph node metastases. Left high orchiectomy was performed. Histopathological examination demonstrated testicular mucinous carcinoma withsimilarity to gastric cancer. Since no tumor was found by the endoscopy of the upper gastrointestinal and the lower digestive tract, we diagnosed the patient with primary testicular mucinous carcinoma. Standard chemotherapy for gastric cancer, which consisted of tegafur, gimeracil and oteracil (TS-1) and cisplatin was administered for 16 months, and there was no progression of the disease. He died from testicular mucinous cancer 30 months after the diagnosis. In the literature, only 4 cases of testicular mucinous carcinoma have been reported. TS-1 and cisplatin are useful chemotherapeutic options for testicular mucinous carcinoma withmetastasis.