Details of a Researcher - Oya, Mototsugu

Papers - Oya, Mototsugu

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VISCERAL ADIPOSITY IS STRONG PARAMETER OF PERIOPERATIVE OUTCOME FOR LAPAROSCOPIC NEPHRECTOMY.

Hagiwara Masayuki, Miyajima Akira, Jinzaki Masahiro, Hasegawa Masanori, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

JOURNAL OF ENDOUROLOGY 25 A208 - A208 2011.11

Research paper (scientific journal), Joint Work, ISSN 0892-7790

WHAT PREVENTS LYMPHOCELE DEVELOPMENT AFTER LAPAROSCOPIC RADICAL PROSTATECTOMY?

Yasumizu Yota, Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Shinoda Kazunobu, Kono Hidaka, Mizuno Ryuichi, Kikuchi Eiji, Nagata Hirohiko, Asanuma Hiroshi, Nakagawa Ken, Oya Mototsugu

JOURNAL OF ENDOUROLOGY 25 A227 - A227 2011.11

Research paper (scientific journal), Joint Work, ISSN 0892-7790

Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer

Tanaka N., Miyajima A., Kosaka T., Miyazaki Y., Shirotake S., Shirakawa H., Kikuchi E., Oya M.

British Journal of Cancer 105 ( 9 ) 1331 - 1337 2011.10

ISSN 0007-0920

Background: We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer. Methods: Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months. Results: Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model. Conclusion: Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.

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Incidence of seed migration to the chest, abdomen, and pelvis after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko, Mizuno Ryuichi, Seki Satoshi, Shiraishi Yutaka, Kouta Ryuichi, Oya Mototsugu, Shigematsu Naoyuki

Radiation Oncology 6 ( 1 ) 2011.10

Background: The aim was to determine the incidence of seed migration not only to the chest, but also to the abdomen and pelvis after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds.Methods: We reviewed the records of 267 patients who underwent prostate brachytherapy with loose ¹²⁵I seeds. After seed implantation, orthogonal chest radiographs, an abdominal radiograph, and a pelvic radiograph were undertaken routinely to document the occurrence and sites of seed migration. The incidence of seed migration to the chest, abdomen, and pelvis was calculated. All patients who had seed migration to the abdomen and pelvis subsequently underwent a computed tomography scan to identify the exact location of the migrated seeds. Postimplant dosimetric analysis was undertaken, and dosimetric results were compared between patients with and without seed migration.Results: A total of 19,236 seeds were implanted in 267 patients. Overall, 91 of 19,236 (0.47%) seeds migrated in 66 of 267 (24.7%) patients. Sixty-nine (0.36%) seeds migrated to the chest in 54 (20.2%) patients. Seven (0.036%) seeds migrated to the abdomen in six (2.2%) patients. Fifteen (0.078%) seeds migrated to the pelvis in 15 (5.6%) patients. Seed migration occurred predominantly within two weeks after seed implantation. None of the 66 patients had symptoms related to the migrated seeds. Postimplant prostate D90 was not significantly different between patients with and without seed migration.Conclusion: We showed the incidence of seed migration to the chest, abdomen and pelvis. Seed migration did not have a significant effect on postimplant prostate D90.

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Phosphorylated Akt up-regulates angiotensin II type-1 receptor expression in castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Kikuchi Eiji, Oya Mototsugu

Prostate 71 ( 14 ) 1510 - 1517 2011.10

ISSN 0270-4137

BACKGROUND Accumulating evidences has suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that castration-resistant prostate cancer (CRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that AT1R blockade (ARB) exerted protective effects by inhibiting angiogenesis. However, the detailed molecular mechanisms for the increase of AT1R expression in CRPC has not been fully elucidated yet. METHODS In this study we used C4-2 and C4-2AT6 cells, which were PTEN-null, androgen receptor (AR) positive, PSA-producing CRPC cell lines. We investigated the association between phosphorylated Akt (pAkt) and AT1R expression, and used LY294002 as a PI3K/Akt inhibitor. RESULTS Western blot analysis revealed C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells, although there were no significant differences in total Akt (tAkt) expression. Immunohistochemical (IHC) analysis also revealed significant higher pAkt expression in C4-2AT6 tumors obtained from castrated male nude mice. These results indicated that C4-2AT6 cells acquired elevated pAkt status under androgen-ablated treatment in vitro. Treatment with LY294002 at the same dose reduced the viability of C4-2AT6 more effectively than that of C4-2, reflecting the dependency of cancer cells on PI3K/Akt pathway. The up-regulated AT1R expression in C4-2AT6 cells was reduced by LY294002 in a dose-dependent manner. On the other hand, in C4-2 cells, serum starvation induced pAkt up-regulation, which led to an increase of AT1R expression. CONCLUSIONS These findings indicated that up-regulation of pAkt contributed to elevated AT1R expression in CRPC.

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Expression of snail and slug in renal cell carcinoma

Mikami Shuji, Katsube Ken Ichi, Oya Mototsugu, Ishida Masaru, Kosaka Takeo, Mizuno Ryuichi, Mukai Makio, Okada Yasunori

Laboratory Investigation 91 ( 10 ) 1443 - 1458 2011.10

ISSN 0023-6837

The Snail family transcription factors have been proposed as important mediators of epithelial-mesenchymal transition because of their role in down-regulation of E-cadherin and up-regulation of matrix metalloproteinases (MMPs). The present study was undertaken to investigate the expression of Snail, Slug and their associations with cancer invasion and prognosis in renal cell carcinomas (RCCs). Ninety-seven primary RCCs were analyzed for the protein expression of Snail, Slug, MMP2 and MMP9 by immunohistochemistry. Snail protein expression level was positively correlated with pathological tumor stage, histological grade and the presence of sarcomatoid carcinoma. On the contrary, Slug protein expression level was negatively correlated with pathological tumor stage, suggesting that Slug was down-regulated in advanced RCCs. Because Snail was positively associated with malignant potential of RCCs, involvement of Snail in the invasiveness of an RCC cell line 786-O was examined in the Matrigel invasion assay by down-regulating the gene expression with small interfering RNA (siRNA). Targeting the Snail, not Slug, expression in 786-O cells with siRNA caused down-regulation of the gene expression of Snail, vimentin, MMP2 and MMP9, but up-regulated the E-cadherin. Invasion of the cells through Matrigel in vitro was inhibited under this condition. Furthermore, expression levels of MMP2 and MMP9 were positively correlated with pathological tumor stage and the presence of sarcomatoid carcinoma. Statistical analysis indicated that elevated Snail, MMP2 and MMP9 protein expression are significantly worse predictors of disease-free and disease-specific survival of the patients with RCC. In conclusion, these data suggest that Snail has an important role in invasion and metastasis, and that silencing the gene may be a potential therapeutic target in RCCs.

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Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis

Mikami Shuji, Katsube Ken-Ichi, Oya Mototsugu, Ishida Masaru, Kosaka Takeo, Mizuno Ryuichi, Mukai Makio, Okada Yasunori

LABORATORY INVESTIGATION 91 ( 10 ) 1443 - 1458 2011.10

Research paper (scientific journal), Joint Work, ISSN 0023-6837

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Biomarkers of response to molecular targeted therapy in renal cell carcinoma

Mizuno Ryuichi, Oya Mototsugu

Japanese Journal of Cancer and Chemotherapy 38 ( 7 ) 1088 - 1091 2011.07

ISSN 0385-0684

Therapeutic options for metastatic renal cell carcinoma (mRCC) have been evolving rapidly, with the approval of a variety of effective molecular targeted agents. With increasing choices of treatment modalities that may potentially improve survival, it is of great clinical benefit to be able to predict the clinical outcome of mRCC patients treated with molecular targeted agents. In addition, predictors of severe adverse events are warranted since those molecular targeted agents present a toxicity profile that is very different from that of conventional chemotherapeutic agents. Their use requires knowledge of a large number of possible adverse events. Although validation of previous criteria, such as the Motzer criteria, is important, a further implementation of RCC molecular biology knowledge would be ideal for finding a new predictive marker in this new age of molecular targeted therapies. The most prominent biomarker is vascular endothelial-derived growth factor (VEGF). Those patients who presented low serum VEGF showed prolonged progression-free survival when treated with sunitinib. Genetic markers such as single nucleotide polymorphisms (SNPs) are continuously being validated as markers, predicting molecular targeted therapy response as well as severe adverse events. The identification of biomarkers that predict response or severe adverse events from molecular targeted agents will aid in patient selection and guide therapy development.

Neoadjuvant gemcitabine plus cisplatin for muscle-invasive bladder cancer

Kaneko Gou, Kikuchi Eiji, Matsumoto Kazuhiro, Obata Jun, Nakamura So, Miyajima Akira, Oya Mototsugu

Japanese Journal of Clinical Oncology 41 ( 7 ) 908 - 914 2011.07

ISSN 0368-2811

Objective: Downstaging by neoadjuvant chemotherapy improves the survival of patients with muscle-invasive bladder cancer. In salvage setting, gemcitabine plus cisplatin has demonstrated an efficacy similar to that of methotrexate, vinblastine, doxorubicin and cisplatin with less toxicity. Therefore, the application of neoadjuvant gemcitabine plus cisplatin is also being anticipated. Methods: Twenty-two patients who received neoadjuvant gemcitabine plus cisplatin were evaluated. The rate of downstaging, chemotherapy delivery profile and toxicity data were assessed. As comparator group, nine patients who were administered with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were evaluated. Results: A mean of 1.9 cycles of neoadjuvant gemcitabine plus cisplatin were performed. Achieved drug intensity for gemcitabine and cisplatin was 83.8 and 95.4%. Downstaging to pT0 and <pT2 was achieved in 50.0 and 63.6%. Grade 3 or 4 neutropenia, anemia, thrombocytopenia and febrile neutropenia appeared in 14.3, 2.4, 21.4 and 2.4%, respectively. Grade 3 or 4 non-hematologic toxicity was not observed. Thrombocytosis developed in 26.2%. A mean of 2.3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were performed. The achieved drug intensities for methotrexate, vinblastine, doxorubicin and cisplatin were 59.6, 69.8, 100 and 88.6%. In patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin, downstaging to pT0 and <pT2 was achieved in 22.2 and 44.4%. Grade 3 or 4 neutropenia, anemia and thrombocytopenia was present in 19.1, 9.5 and 4.8%. Grade 3 nausea developed in 28.6%. Conclusions: The rate of downstaging by neoadjuvant gemcitabine plus cisplatin was comparable with that by methotrexate, vinblastine, doxorubicin and cisplatin. Gemcitabine plus cisplatin was associated with less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin.

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Coactivation of SF-1-mediated transcription of steroidogenic enzymes by Ubc9 and PIAS1

Suda Noriko, Shibata Hirotaka, Kurihara Isao, Ikeda Yayoi, Kobayashi Sakiko, Yokota Kenichi, Murai-Takeda Ayano, Nakagawa Ken, Oya Mototsugu, Murai Masaru, Rainey William E., Saruta Takao, Itoh Hiroshi

Endocrinology 152 ( 6 ) 2266 - 2277 2011.06

ISSN 0013-7227

Steroidogenic factor-1 (SF-1) is a nuclear orphan receptor, which is essential for adrenal development and regulation of steroidogenic enzyme expression. SF-1 is posttranslationally modified by small ubiquitin-related modifier-1 (SUMO-1), thus mostly resulting in attenuation of transcription. We investigated the role of sumoylation enzymes, Ubc9 and protein inhibitors of activated STAT1 (PIAS1), in SF-1-mediated transcription of steroidogenic enzyme genes in the adrenal cortex. Coimmunoprecipitation assays showed that both Ubc9 and PIAS1 interacted with SF-1. Transient transfection assays in adrenocortical H295R cells showed Ubc9 and PIAS1 potentiated SF-1-mediated transactivation of reporter constructs containing human CYP17, CYP11A1, and CYP11B1 but not CYP11B2 promoters. Reduction of endogenous Ubc9 and PIAS1 by introducing corresponding small interfering RNA significantly reduced endogenous CYP17, CYP11A1, and CYP11B1 mRNA levels, indicating that they normally function as coactivators of SF-1. Wild type and sumoylation-inactive mutants of Ubc9 and PIAS1 can similarly enhance the SF-1-mediated transactivation of the CYP17gene, indicating that the coactivation potency of Ubc9 and PIAS1 isindependentof sumoylation activity. Chromatin immunoprecipitation assays demonstrated that SF-1, Ubc9, and PIAS1 were recruited to an endogenous CYP17 gene promoter in the context of chromatin in vivo. Immunohistochemistry and Western blotting showed that SF-1, Ubc9, and PIAS1 were expressed in the nuclei of the human adrenal cortex. In cortisol-producing adenomas, the expression pattern of SF-1 and Ubc9 were markedly increased, whereas that of PIAS1 was decreased compared with adjacent normal adrenals. These results showed the physiological roles of Ubc9 and PIAS1 as SF-1 coactivators beyond sumoylation enzymes in adrenocortical steroidogenesis and suggested their possible pathophysiological roles in human cortisol-producing adenomas.

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Coactivation of SF-1-Mediated Transcription of Steroidogenic Enzymes by Ubc9 and PIAS1

ENDOCRINOLOGY 152 ( 6 ) 2266 - 2277 2011.06

Research paper (scientific journal), Joint Work, ISSN 0013-7227

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[History and current review of basic research for prostate cancer].

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 5 7 - 12 2011.06

ISSN 0047-1852

Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Suzuki Eriko, Kikuchi Eiji, Oya Mototsugu

Journal of Urology 185 ( 6 ) 2376 - 2381 2011.06

ISSN 0022-5347

Purpose: There are still few effective therapeutic options for advanced prostate cancer. One of the most troublesome aspects of prostate cancer is that androgen dependent prostate cancer inevitably progresses to highly aggressive, life threatening castration resistant prostate cancer after androgen ablation therapy. To our knowledge it remains unknown how sensitivity to docetaxel changes during progression to more aggressive castration resistant prostate cancer under androgen ablation. Materials and Methods: We investigated sensitivity to docetaxel and phosphorylated Akt status in C4-2 and C4-2AT6 cells established at our institution. Results: C4-2AT6 cells established under androgen ablation conditions for 6 months showed significantly higher resistance to docetaxel than C4-2 cells in vivo and in vitro. Resistance was accompanied by increased phosphorylated Akt. In C4-2AT6 cells phosphorylated Akt activity was significantly up-regulated by docetaxel in a dose dependent manner. After treatment with docetaxel and a phosphatidylinositol 3-kinase/Akt inhibitor the sensitivity of C4-2AT6 cells to docetaxel markedly increased through enhanced apoptotic death. Conclusions: Findings indicated that up-regulation of phosphorylated Akt during androgen ablation and its further activation by docetaxel explains at least in part the resistance to docetaxel and progression to castration resistant prostate cancer under androgen ablation conditions.

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Selection and efficacy of PDE5 inhibitors

Kikuchi Eiji, Ando Toshiyuki, Oya Mototsugu

Japanese Journal of Clinical Urology 65 ( 6 ) 377 - 383 2011.05

ISSN 0385-2393

Prospective survey of erectile dysfunction after external beam radiotherapy for prostate cancer

Kikuchi Eiji, Nakashima Jun, Ando Toshiyuki, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Marumo Ken, Oya Mototsugu

Japanese Journal of Urology 102 ( 3 ) 575 - 580 2011.05

ISSN 0021-5287

(Objective) We prospectively evaluated the effect of external beam radiotherapy on erectile function in patients with localized or locally advanced prostate cancer using the Japanese version of the International Index of Erectile Function (IIEF) survey. (Patients and methods) From 2000 to 2007, we identified 55 patients who underwent external beam radiotherapy at our institution for localized or locally advanced prostate cancer and could respond to the IIEF survey. The patients did not receive neo- and/or adjuvant hormone therapy and they were followed-up for at least 12 months after radiotherapy. Mean patient age was 69 years and the mean PSA level before radiotherapy was 24.9 ng/ml. (Results) First we evaluated the change of the erectile function domain score over time before and after radiotherapy. The population of severe erectile dysfunction (ED) increased while those with no or mild ED decreased after radiotherapy. The erectile function and intercourse satisfaction domain score of the IIEF declined significantly after radiotherapy, however, the orgasmic function, sexual desire, and overall satisfaction domain scores did not change after external beam radiation. Of the 34 patients who had erectile function at baseline, 10 patients could maintain erectile function 12 months after radiotherapy. Though there were no significant differences in clinical features between patients who could maintain erectile function and those who had worsening erectile function 12 months after radiotherapy, the sexual desire domain score before radiotherapy was significantly higher in patients who could maintain erectile function than their counterparts. (Conclusion) Using the IIEF survey, external beam radiation was found to affect erectile function in patients with localized or locally advanced prostate cancer.

Preoperative hydronephrosis grade independently predicts worse pathological outcomes in patients undergoing nephroureterectomy for upper tract urothelial carcinoma

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Miyajima Akira, Mikami Shuji, Jinzaki Masahiro, Oya Mototsugu

Journal of Urology 185 ( 5 ) 1621 - 1626 2011.05

ISSN 0022-5347

Purpose: We analyzed the prognostic impact of hydronephrosis grade on disease specific survival and evaluated whether hydronephrosis grade could preoperatively predict worse pathological outcomes in cases of upper tract urothelial carcinoma treated surgically. Materials and Methods: We identified and retrospectively reviewed the records of 91 patients who were evaluated by multidetector computerized tomography and/or magnetic resonance imaging preoperatively, and treated with nephroureterectomy at our institution from 2000 to 2009. Ipsilateral hydronephrosis was graded 0 to 4 by 2 urological radiologists blinded to clinical outcomes. We analyzed the associations between hydronephrosis grade, and pathological findings and patient outcomes. Results: Preoperatively 67 patients (73.6%) had ipsilateral hydronephrosis. Grade was 1 to 4 in 3 (3.3%), 17 (18.7%), 23 (25.3%) and 24 cases (26.4%), respectively. Higher hydronephrosis grade was significantly associated with a ureteral tumor (p = 0.0307), higher pT stage (p = 0.0002) and lymphovascular invasion (p = 0.0014). Higher hydronephrosis grade was not associated with disease specific or metastasis-free survival. On preoperative multivariate analysis high hydronephrosis grade predicted pathological T stage (T3 or greater) (HR 4.98, p = 0.0228), positive lymphovascular invasion (HR 6.37, p = 0.0022) and grade 3 (HR 2.98, p = 0.0311). Conclusions: On image analysis preoperative hydronephrosis grade was associated with features of aggressive disease and predicted an advanced pathological outcome in patients with upper tract urothelial carcinoma. This information could prove useful to select candidates for neoadjuvant chemotherapy and make decisions concerning surgical options.

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Could patient age influence tumor recurrence rate in non-muscle-invasive bladder cancer patients treated with BCG immunotherapy?

Yuge Kazuyuki, Kikuchi Eiji, Matsumoto Kazuhiro, Takeda Toshikazu, Miyajima Akira, Oya Mototsugu

Japanese Journal of Clinical Oncology 41 ( 4 ) 565 - 570 2011.04

ISSN 0368-2811

Objective: The effect of local immunotherapy with bacille Calmette-Guérin in elderly patients with non-muscle-invasive bladder cancer has not yet been fully evaluated. The aim of the present study was to evaluate whether patients' age influences the response to bacille Calmette-Guérin treatment for the prevention of tumor recurrence and whether the side effects were tolerable. Methods: We reviewed 1252 cases with non-muscle-invasive bladder cancer treated with transurethral bladder tumor resection, and 447 cases who underwent bacille Calmette- Guérin immunotherapy were included. The associations between patient age or pathological findings and tumor recurrence were determined. Side effects were classified as minor or major and were analyzed on the basis of their incidences in each age group. Results: The patients were divided into four age categories: younger than 55 (n = 86), 55-64 (n = 143), 65-74 (n = 132) and equal or older than 75 years (n = 86). The Kaplan-Meier curves of recurrence-free survival rates demonstrated that patients aged 55-64 had been continuously tumor-free than the equal or older than 75 group. The presence of previous bladder cancer and Grade 3 were independent predictors for tumor recurrence; however, patients' age was not selected. The incidence of fever was slightly higher and that of cystitis was lower in the younger group. Conclusions: Age does not certainly affect recurrence in patients with bladder cancer treated with bacille Calmette-Guérin therapy. The related side effects in the elderly patients were almost equal to those in the younger. With careful monitoring, bacille Calmette-Guérin therapy is safe even in elderly patients.

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Could Patient Age Influence Tumor Recurrence Rate in Non-muscle-invasive Bladder Cancer Patients Treated with BCG Immunotherapy?

Yuge Kazuyuki, Kikuchi Eiji, Matsumoto Kazuhiro, Takeda Toshikazu, Miyajima Akira, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 ( 4 ) 565 - 570 2011.04

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer

Shirotake Suguru, Miyajima Akira, Kosaka Takeo, Tanaka Nobuyuki, Maeda Takahiro, Kikuchi Eiji, Oya Mototsugu

Urology 77 ( 4 ) 2011.04

ISSN 0090-4295

Objectives: To determine whether angiotensin II type 1 receptor (AT1R) expression and tumor angiogenesis in human bladder cancer (BCa) specimens acquired by transurethral resection (TUR). It has recently been reported that AT1R is expressed in several tumors and is involved in tumor angiogenesis. However, no study has investigated AT1R expression in association with angiogenesis in clinical specimens of bladder cancer. Methods: Surgical specimens were obtained from 108 patients who had undergone TUR for bladder cancer. All specimens were pathologically diagnosed as urothelial carcinoma. AT1R expression and microvessel density (MVD) were determined by immunostaining. The clinical and pathologic characteristics were retrospectively reviewed. Results: The MVD was greater in muscle-invasive BCa (MIBC; 29 cases, 34.4 ± 4.1/0.25 mm²) than in non-MIBC (NMIBC; 79 cases, 17.4 ± 1.1/0.25 mm², P < .0001). AT1R expression was greater in the MIBC (P = .0004) and high-grade (P = .0063) specimens than in the NMIBC and low-grade specimens. In addition, the greater expression of AT1R was significantly associated with MVD (P < .05). In NMIBC, the factors significantly affecting recurrence-free survival on univariate analysis were AT1R (P = .02), MVD (P < .0001), tumor multiplicity (P = .0007), and bacille Calmette-Guérin intravesical instillation after TUR (P = .0026). Multivariate analysis revealed that tumor multiplicity and no BCG intravesical instillation after TUR were independent predictors of 5-year recurrence-free survival, and AT1R and MVD were independent predictors of 1-year recurrence-free survival (P < .01). Conclusions: AT1R expression and MVD were related to early intravesical recurrence in NMIBC. The results suggest that AT1R could become a new molecular target and a prognostic factor for NMIBC.

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A germ cell-specific gene, Prmt5, works in somatic cell reprogramming

Nagamatsu Go, Kosaka Takeo, Kawasumi Miyuri, Kinoshita Taisuke, Takubo Keiyo, Akiyama Hideo, Sudo Tetsuo, Kobayashi Takashi, Oya Mototsugu, Suda Toshio

Journal of Biological Chemistry 286 ( 12 ) 10641 - 10648 2011.03

ISSN 0021-9258

Germ cells possess the unique ability to acquire totipotency during development in vivo as well as give rise to pluripotent stem cells under the appropriate conditions in vitro. Recent studies in which somatic cells were experimentally converted into pluripotent stem cells revealed that genes expressed in primordial germ cells (PGCs), such as Oct3/4, Sox2, and Lin28, are involved in this reprogramming. These findings suggest that PGCs may be useful for identifying factors that successfully and efficiently reprogram somatic cells into toti- and/or pluripotent stem cells. Here, we show that Blimp-1, Prdm14, and Prmt5, each of which is crucial forPGCdevelopment, have the potential to reprogram somatic cells into pluripotent stem cells. Among them, Prmt5 exhibited remarkable reprogramming of mouse embryonic fibroblasts into which Prmt5, Klf4, and Oct3/4 were introduced. The resulting cells exhibited pluripotent gene expression, teratoma formation, and germline transmission in chimeric mice, all of which were indistinguishable from those induced with embryonic stem cells. These data indicate that some of the factors that play essential roles in germ cell development are also active in somatic cell reprogramming.

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