Updated on 2024/11/14

写真a

 
WATANABE Masami
 
Organization
Okayama University Hospital Professor
Position
Professor
External link

Degree

  • 医学博士 ( 岡山大学 )

Research Interests

  • 悪性腫瘍

  • 細胞治療

  • 遺伝子治療

  • 再生医療

  • 泌尿器科

Research Areas

  • Life Science / Urology

Research History

  • Okayama University   岡山大学病院   Professor

    2016.2

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  • Okayama University   岡山大学病院   Associate Professor

    2010.4 - 2016.1

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  • Okayama University   岡山大学病院   Assistant Professor

    2009 - 2010.3

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  • Okayama University   医歯薬学総合研究科

    2006 - 2009

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Papers

  • Circadian Rhythms Fluctuate the Treatment Effects of Intravesical Treatments on Rat Urinary Frequency Models Reviewed

    Tomofumi Watanabe, Takuya Sadahira, Yusuke Tominaga, Yuki Maruyama, Naoya Nagasaki, Takanori Sekito, Kohei Edamura, Toyohiko Watanabe, Motoo Araki, Masami Watanabe

    Veterinary Medicine International   2024   1 - 9   2024.5

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    Publishing type:Research paper (scientific journal)   Publisher:Hindawi Limited  

    Objectives. It is still not clear how the intravesical instillation of drugs affects rat urinary frequency. This study aimed to examine the dynamics of intravesical treatments’ treatment effect on rat urinary frequency models by real-time and extended monitoring using a novel continuous urination monitoring system. Methods. Nine eleven-week-old female Wistar rats were divided into three groups to receive intravesical instillation of 0.1% acetic acid (AA), 1.0% AA, or phosphate-buffered saline (PBS). Thirty minutes later, these drugs were voided, and rats were moved to a continuous urination monitoring system, UM-100. UM-100 monitored rat urination quantitatively and continuously for 24 hours. Rats were then euthanized, and histopathologic examinations using a damage score validated the severity of bladder inflammation. We used nine additional rats to determine the treatment effect of various drugs against the urinary frequency. These rats were also treated with 1.0% AA in the same way and divided into three groups (n = 3 each) to receive intravesical instillation of lidocaine, silver nitrate (AgNO3), or dimethyl sulfoxide (DMSO), respectively. Thirty minutes later, rats were catheterized again and moved to the UM-100, and their voiding was monitored for 24 hours. Results. Intravesical instillation of AA increased the urinary frequency and decreased the mean voided volume (VV) in a concentration-dependent manner, with statistical significance at a concentration of 1.0% (urinary frequency; , mean VV; , respectively) compared with PBS. Histopathological analysis of these models demonstrated a significantly higher damage score of bladder mucosa in both 0.1% AA and 1.0% AA compared with PBS, with the severity in concordance with the clinical severity of urinary frequency (0.1% AA: , 1.0% AA: ). Moreover, intravesical instillation of lidocaine, AgNO3, and DMSO decreased the urinary frequency. Continuous monitoring with UM-100 also demonstrated that the treatment effect of these intravesically instilled drugs occurred only at night. Conclusions. The extended monitoring of rat urination by UM-100 revealed a significant fluctuation in the treatment effect of intravesically instilled drugs between day and night. These findings may help establish novel therapies for urinary frequency.

    DOI: 10.1155/2024/6505595

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    Other Link: http://downloads.hindawi.com/journals/vmi/2024/6505595.xml

  • Trans men can achieve adequate muscular development through low-dose testosterone therapy: A long-term study on body composition changes. Reviewed International journal

    Yusuke Tominaga, Tomoko Kobayashi, Yuko Matsumoto, Takatoshi Moriwake, Yoshitaka Oshima, Misa Okumura, Satoshi Horii, Takuya Sadahira, Satoshi Katayama, Takehiro Iwata, Shingo Nishimura, Kensuke Bekku, Kohei Edamura, Morito Sugimoto, Yasuyuki Kobayashi, Masami Watanabe, Yuzaburo Namba, Yosuke Matsumoto, Mikiya Nakatsuka, Motoo Araki

    Andrology   2024.4

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    Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: Transgender individuals undergo the gender-affirming hormone therapy (GAHT) to achieve physical changes consistent with their gender identity. Few studies are available on the long-term safety and efficacy of GAHT. OBJECTIVES: To investigate the long-term physical effects and the safety of the testosterone therapy for trans men and to assess the impact of differential hormone dose. MATERIALS AND METHODS: Trans men who initiated GAHT between May 2000 and December 2021 were included in this retrospective analysis. Physical findings (body mass index, body fat percentage (BFP), lean body mass (LBM), and grip strength), blood testing results (hemoglobin, hematocrit, uric acid, creatinine, total cholesterol, triglycerides, and total testosterone), and menstrual cessation were recorded. We assessed the effects of testosterone on body composition changes and laboratory parameters, comparing a low-dose group (≤ 62.5 mg/wk) to a high-dose group (> 62.5 mg/wk). RESULTS: Of 291 participants, 188 patients (64.6%) were in the low-dose group and 103 (35.4%) in the high-dose group. Cumulative menstrual cessation rates up to 12 months were not significantly different between groups. Both groups showed a decrease in BFP and an increase in LBM during the first year of therapy, followed by a slight increase in both over the long term. The high-dose group exhibited greater LBM gains during the first year. Higher hormone doses and lower initial LBM values were associated with LBM increases at 3 and 6 months (3 mo, P = 0.006, P < 0.001; 6 mo, P = 0.015, P < 0.001). There were no long-term, dose-dependent side effects such as polycythemia or dyslipidemia. CONCLUSION: Long-term GAHT for trans men is safe and effective. Low-dose testosterone administration is sufficient to increase LBM in trans men. Higher testosterone doses can lead to an earlier increase in muscle mass.

    DOI: 10.1111/andr.13640

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  • Establishment of Induced Pancreatic Stem Cells by Yes-Associated Protein 1 Reviewed

    Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Yuka Onishi, Issei Saitoh, Masami Watanabe

    Cell Transplantation   2024.1

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    DOI: 10.1177/09636897241248942

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  • Exploration of the protein-dependent mechanism of Lactobacillus crispatus GAI98322 to prevent recurrent cystitis. Reviewed International journal

    Tomofumi Watanabe, Takuya Sadahira, Hidetada Hirakawa, Peng Huang, Tianyun Zhou, Takehiro Iwata, Takanori Sekito, Ayano Ishii, Masami Watanabe, Motoo Araki

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   29 ( 10 )   1001 - 1004   2023.6

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    OBJECTIVES: To elucidate the mechanism of Lactobacillus crispatus (L. crispatus) suppositories to prevent patients from recurrent cystitis (RC), independent from viable-Lactobacilli-bacteria- and acid-dependent ones such as hydrogen peroxide and lactate. METHODS: We used the GAI98322 strain of L. crispatus in all experiments and pH-matched. cell-free culture supernatant of L. crispatus (CFCS) was collected. The growth inhibitory activity and the biofilm formation inhibitory activity of the CFCS against uropathogenic Escherichia coli (UPEC), Extended Spectrum beta (β) Lactamase producing (ESBL+) UPEC, and Pseudomonas aeruginosa (P. aeruginosa) was assessed by agar-disk diffusion tests and crystal violet assay. Also, CFCS was subjected to mass spectrometry to specify ingredients. RESULTS: The CFCS suppressed the proliferation of E. coli, ESBL + E. coli, and P. aeruginosa. Also, the CFCS at a concentration of 40% significantly impeded the biofilm formation of these three bacteria. The aggregation-promoting factor and Lysin was detected from CFCS. CONCLUSIONS: The cell-free supernatant from the GAI98322 strain of L. crispatus inhibits the growth/biofilm formation of broad pathogens by aggregation promoting factor and lysin, which may prevent hosts from RC regardless of the antimicrobial resistance of the pathogens and even under pH modulation.

    DOI: 10.1016/j.jiac.2023.06.013

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  • Pacsin 2-dependent N-cadherin internalization regulates the migration behaviour of malignant cancer cells Reviewed

    Haymar Wint, Jianzhen Li, Tadashi Abe, Hiroshi Yamada, Yasutomo Nasu, Masami Watanabe, Kohji Takei, Tetsuya Takeda

    J Cell Sci   136 ( 10 )   2023.5

  • The Genotypic and Phenotypic Characteristics Contributing to Flomoxef Sensitivity in Clinical Isolates of ESBL-Producing E. coli Strains from Urinary Tract Infections Reviewed

    Kazuma Sakaeda, Takuya Sadahira, Yuki Maruyama, Takehiro Iwata, Masami Watanabe, Koichiro Wada, Motoo Araki

    Antibiotics   12 ( 3 )   522 - 522   2023.3

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    Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    We carried out a molecular biological analysis of extended-spectrum β-lactamase (ESBL)-producing E. coli strains and their sensitivity to flomoxef (FMOX). Sequence type (ST) analysis by multilocus sequence typing (MLST) and classification of ESBL genotypes by multiplex PCR were performed on ESBL-producing E. coli strains isolated from urine samples collected from patients treated at our institution between 2008 and 2018. These sequences were compared with results for antimicrobial drug susceptibility determined using a micro-liquid dilution method. We also analyzed cases treated with FMOX at our institution to examine its clinical efficacy. Of the 911 E. coli strains identified, 158 (17.3%) were ESBL-producing. Of these, 67.7% (107/158) were strain ST-131 in ST analysis. Nearly all (154/158; 97.5%) were CTX-M genotypes, with M-14 and M-27 predominating. The isolated strains were sensitive to FMOX in drug susceptibility tests. Among the patient samples, 33 cases received FMOX, and of these, 5 had ESBL-producing E. coli. Among these five cases, three received FMOX for surgical prophylaxis as urinary carriers of ESBL-producing E. coli, and postoperative infections were prevented in all three patients. The other two patients received FMOX treatment for urinary tract infections. FMOX treatment was successful for one, and the other was switched to carbapenem. Our results suggest that FMOX has efficacy for perioperative prophylactic administration in urologic surgery involving carriers of ESBL-producing bacteria and for therapeutic administration for urinary tract infections. Use of FMOX avoids over-reliance on carbapenems or β-lactamase inhibitors and thus is an effective antimicrobial countermeasure.

    DOI: 10.3390/antibiotics12030522

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  • Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. Reviewed International journal

    Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Junichiro Futami, Léna Audebert, Youyi Chen, Ni Luh Gede Yoni Komalasari, Fan Jiang, Chikako Yoshizawa, Hitoshi Murata, Ken-Ichi Yamamoto, Masami Watanabe, Hiromi Kumon, Masakiyo Sakaguchi

    Journal of molecular medicine (Berlin, Germany)   101 ( 4 )   431 - 447   2023.3

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    The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3-namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects. KEY MESSAGES: • REIC/Dkk-3 protein effectively suppresses breast cancer progression through an acceleration of PD-L1 degradation. • PD-L1 stability on the cancer cell membrane is kept high by binding with mainly CMTM6. • Competitive binding of REIC/Dkk-3 protein with CMTM6 liberates PD-L1, leading to PD-L1 degradation.

    DOI: 10.1007/s00109-023-02292-w

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  • Etiology of recurrent cystitis in postmenopausal women based on vaginal microbiota and the role of Lactobacillus vaginal suppository. Reviewed International journal

    Takanori Sekito, Koichiro Wada, Ayano Ishii, Takehiro Iwata, Takehiro Matsubara, Shuta Tomida, Masami Watanabe, Motoo Araki, Takuya Sadahira

    Frontiers in microbiology   14   1187479 - 1187479   2023

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    BACKGROUND: The vaginal microbiota can be altered by uropathogenic bacteria associated with recurrent cystitis (RC), and the vaginal administration of Lactobacillus have suggested certain effects to prevent RC. The relationship between vaginal microbiota and the development of RC has not been elucidated. We aimed to clarify the etiology of RC from vaginal microbiota and importance of vaginal Lactobacillus. METHODS: Vaginal samples obtained from 39 postmenopausal women were classified into four groups: healthy controls; uncomplicated cystitis; RC; and prevention (prevented RC by Lactobacillus crispatus-containing vaginal suppositories). Principal coordinate analysis and beta-diversity analysis was used to assess 16S rRNA gene sequencing data from the vaginal microbiome. RESULTS: Cluster analysis divided the vaginal bacterial communities among 129 vaginal samples into three clusters (A, B, and C). Fourteen of 14 (100%) samples from the RC group and 51 of 53 (96%) samples from the prevention group were in clusters B and C, while 29 of 38 (76%) samples from the healthy group and 14 of 24 (58%) samples from the uncomplicated cystitis group were in cluster A. The principal coordinate analysis showed that plots in the uncomplicated cystitis group were similar to the healthy group, indicating a large separation between the RC group and the uncomplicated cystitis group. On beta-diversity analysis, there were significant differences between the healthy group and the uncomplicated cystitis group (p = 0.045), and between the RC group and the uncomplicated cystitis group or the healthy group (p = 0.001, p = 0.001, respectively). There were no significant differences between the RC group and the prevention group (p = 0.446). The top six taxa were as follows: Prevotella, Lactobacillus, Streptococcus, Enterobacteriaceae, Anaerococcus, and Bifidobacterium. Among patients with RC, Lactobacillus was undetectable before administration of suppositories, while the median relative abundance of Lactobacillus was 19% during administration of suppositories (p = 0.0211), reducing the average cystitis episodes per year (6.3 vs. 2.4, p = 0.0015). CONCLUSION: The vaginal microbiota of postmenopausal women with RC is differed from healthy controls and uncomplicated cystitis in terms of lack of Lactobacillus and relatively dominant of Enterobacteriaceae. Vaginal administration of Lactobacillus-containing suppositories can prevent RC by stabilizing vaginal dysbiosis and causing a loss of pathogenic bacteria virulence.

    DOI: 10.3389/fmicb.2023.1187479

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  • Canine Mammary Tumor Cell Lines Derived from Metastatic Foci Show Increased RAD51 Expression but Diminished Radioresistance via p21 Inhibition. Reviewed International journal

    Kei Shimakawa, Kazuhiko Ochiai, Sachi Hirose, Eri Tanabe, Masaki Michishita, Motoharu Sakaue, Yasunaga Yoshikawa, Masami Morimatsu, Tsuyoshi Tajima, Masami Watanabe, Yoshikazu Tanaka

    Veterinary sciences   9 ( 12 )   2022.12

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    Due to the high incidence of mammary tumors in dogs, it is important to elucidate the pathogenesis of these tumors in veterinary medicine. Radiation therapy is often used to treat mammary tumors that target DNA lesions. RAD51 is a key molecule that repairs DNA damage via homologous recombination. We examined the relationship between RAD51 expression and radiosensitivity in mammary tumor cell lines. CHMp and CHMm from the same individual were selected based on the differences in RAD51 expression. The radiosensitivity of both cell lines was examined using MTT and scratch assays; CHMm, which has high RAD51 expression, showed higher sensitivity to radiation than CHMp. However, the nuclear focus of RAD51 during DNA repair was formed normally in CHMp, but not in most of CHMm. Since irradiation resulted in the suppression of cell cycle progression in CHMp, the expression of p21, a cell cycle regulatory factor, was detected in CHMp after 15 Gy irradiation but not in CHMm. These results indicate that functional expression is more important than the quantitative expression of RAD51 in canine mammary tumor cells in response to DNA damage.

    DOI: 10.3390/vetsci9120703

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  • Protocol for the generation of human induced hepatic stem cells using Sendai virus vectors. Reviewed International journal

    Hirofumi Noguchi, Yoshiki Nakashima, Masami Watanabe, Masayuki Matsushita, Masayoshi Tsukahara, Issei Saitoh, Chika Miyagi-Shiohira

    STAR protocols   3 ( 4 )   101884 - 101884   2022.12

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    Our recent study demonstrated the generation of induced tissue-specific stem/progenitor (iTS/iTP) cells by the transient overexpression of reprogramming factors combined with tissue-specific selection. Here, we present a protocol to reprogram human hepatocytes to generate human induced tissue-specific liver stem (iTS-L) cells. Human hepatocytes are transfected with Sendai virus vectors (SeV) expressing OCT3/4, SOX2, KLF4, and c-MYC. iTS-L cells continuously express mRNA of hepatocyte-specific markers (HNF1β and HNF4α) and do not form teratomas. For complete details on the use and execution of this protocol, please refer to Nakashima et al. (2022).1.

    DOI: 10.1016/j.xpro.2022.101884

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  • Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation Reviewed

    Acosta Gonzalez Herik Rodrigo, Nahoko Tomonobu, Haruka Yoneda, Rie Kinoshita, Yosuke Mitsui, Takuya Sadahira, Shin-ichi Terawaki, Yuma Gohara, Ni Luh Gede Yoni Komalasari, Fan Jiang, Hitoshi Murata, Ken-ichi Yamamoto, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Yusuke Inoue, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masami Watanabe, Yasutomo Nasu, Masakiyo Sakaguchi

    Biochemical and Biophysical Research Communications   634   83 - 91   2022.12

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.bbrc.2022.09.116

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  • Induced hepatic stem cells are suitable for human hepatocyte production. Reviewed International journal

    Yoshiki Nakashima, Chika Miyagi-Shiohira, Issei Saitoh, Masami Watanabe, Masayuki Matsushita, Masayoshi Tsukahara, Hirofumi Noguchi

    iScience   25 ( 10 )   105052 - 105052   2022.10

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    Human hepatocytes were transfected with Sendai virus vectors (SeV) expressing OCT3/4, SOX2, KLF4, and C-MYC to produce hepatocyte-derived induced pluripotent stem cells (iPSCs). The messenger RNA (mRNA) expression of undifferentiated markers (passage 19-21) and hepatocyte-specific markers (HSMs) (passage 0-20) in 48 established hepatocyte-derived iPSC-like colonies was examined. Among the 48 clones, 10 clones continuously expressed HSM mRNA (HNF1β and HNF4α) in passage 0-20. The colonies which expressed HSMs (iTS-L cells: induced tissue-specific stem cells from liver) showed a different tendency in microarray and methylation analyses to fibroblast-derived iPSCs (strain: 201B7). iTS-L cells were less likely to form teratomas in mice than iPSCs (He). The iTS-L cells were differentiated into hepatocyte-like cells more efficiently than iPSCs (He) or iPSCs (201B7). These data suggest that SeV expressing OCT3/4, SOX2, KLF4, and C-MYC induce the generation of iPSCs and iTS-L cells.

    DOI: 10.1016/j.isci.2022.105052

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  • AP39, a Mitochondrial-Targeted H2S Donor, Improves Porcine Islet Survival in Culture. Reviewed International journal

    Misaki Shinzato, Chika Miyagi-Shiohira, Kazuho Kuwae, Kai Nishime, Yoshihito Tamaki, Tasuku Yonaha, Mayuko Sakai-Yonaha, Ikuo Yamasaki, Ryusei Otsuka, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Journal of clinical medicine   11 ( 18 )   2022.9

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    The rapid deterioration of transplanted islets in culture is a well-established phenomenon. We recently reported that pancreas preservation with AP39 reduces reactive oxygen species (ROS) production and improves islet graft function. In this study, we investigated whether the addition of AP39 to the culture medium could reduce isolated islet deterioration and improve islet function. Isolated islets from porcine pancreata were cultured with 400 nM AP39 or without AP39 at 37 °C. After culturing for 6-72 h, the islet equivalents of porcine islets in the AP39(+) group were significantly higher than those in the AP39(-) group. The islets in the AP39(+) group exhibited significantly decreased levels of ROS production compared to the islets in the AP39(-) group. The islets in the AP39(+) group exhibited significantly increased mitochondrial membrane potential compared to the islets in the AP39(-) group. A marginal number (1500 IEs) of cultured islets from each group was then transplanted into streptozotocin-induced diabetic mice. Culturing isolated islets with AP39 improved islet transplantation outcomes in streptozotocin-induced diabetic mice. The addition of AP39 in culture medium reduces islet deterioration and furthers the advancements in β-cell replacement therapy.

    DOI: 10.3390/jcm11185385

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  • Pancreas Preservation in Modified Histidine-lactobionate Solution Is Superior to That in University of Wisconsin Solution for Porcine Islet Isolation. Reviewed International journal

    Mayuko Sakai-Yonaha, Chika Miyagi-Shiohira, Kazuho Kuwae, Yoshihito Tamaki, Kai Nishime, Tasuku Yonaha, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Transplantation   106 ( 9 )   1770 - 1776   2022.9

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    BACKGROUND: We previously reported that modified extracellular-type trehalose-containing Kyoto (MK) solution, which contains a trypsin inhibitor (ulinastatin), significantly improved the islet yield compared with University of Wisconsin (UW) preservation, which is the gold standard for organ preservation for islet isolation. In this study, we evaluated the efficiency of a modified histidine-lactobionate (MHL) solution in addition to UW or MK solution. The MHL solution has a high sodium-low potassium composition with low viscosity compared with the UW solution. Moreover, similar to MK solution, MHL solution also contains ulinastatin. METHODS: Porcine pancreata were preserved in UW, MK, or MHL solution, followed by islet isolation. An optimized number (1500 IE) of isolated islets from each group were then transplanted into streptozotocin-induced diabetic mice. RESULTS: The islet yield before and after purification was significantly higher in the MHL group than in the UW group. On the contrary, the islet yield before and after purification was not significantly different between the MHL and MK groups. Preserving the porcine pancreata in MHL solution improved the outcome of islet transplantation in streptozotocin-induced diabetic mice compared with that in UW solution. CONCLUSIONS: Pancreas preservation with MHL solution preserves islet function better than UW solution. The effect of MHL solution is similar to that of MK solution, suggesting that MHL solution can be used as an alternative to MK solution for pancreatic islet transplantation.

    DOI: 10.1097/TP.0000000000003636

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  • Pancreas Preservation with a Neutrophil Elastase Inhibitor, Alvelestat, Contributes to Improvement of Porcine Islet Isolation and Transplantation. Reviewed International journal

    Ryusei Otsuka, Chika Miyagi-Shiohira, Kazuho Kuwae, Kai Nishime, Yoshihito Tamaki, Tasuku Yonaha, Mayuko Sakai-Yonaha, Ikuo Yamasaki, Misaki Shinzato, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Journal of clinical medicine   11 ( 15 )   2022.7

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    For pancreatic islet transplantation, pancreas procurement, preservation, and islet isolation destroy cellular and non-cellular components and activate components such as resident neutrophils, which play an important role in the impairment of islet survival. It has been reported that inhibitors of neutrophil elastase (NE), such as sivelestat and α1-antitrypsin, could contribute to improvement of islet isolation and transplantation. In this study, we investigated whether pancreatic preservation with alvelestat, a novel NE inhibitor, improves porcine islet yield and function. Porcine pancreata were preserved with or without 5 μM alvelestat for 18 h, and islet isolation was performed. The islet yields before and after purification were significantly higher in the alvelestat (+) group than in the alvelestat (-) group. After islet transplantation into streptozotocin-induced diabetic mice, blood glucose levels reached the normoglycemic range in 55% and 5% of diabetic mice in the alvelestat (+) and alvelestat (-) groups, respectively. These results suggest that pancreas preservation with alvelestat improves islet yield and graft function and could thus serve as a novel clinical strategy for improving the outcome of islet transplantation.

    DOI: 10.3390/jcm11154290

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  • Intravesical indwelling lidocaine‑releasing devices for IC/BPS (Review) Reviewed

    Tomofumi Watanabe, Takuya Sadahira, Masami Watanabe, Yuki Maruyama, Koichiro Wada, Takanori Sekito, Kohei Edamura, Yasuyuki Kobayashi, Motoo Araki, Toyohiko Watanabe

    World Academy of Sciences Journal   4 ( 4 )   2022.6

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    Publishing type:Research paper (scientific journal)   Publisher:Spandidos Publications  

    DOI: 10.3892/wasj.2022.163

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  • In vitro anticancer effects of alpelisib against PIK3CA‑mutated canine hemangiosarcoma cell lines. Reviewed International journal

    Marika Maeda, Kazuhiko Ochiai, Masaki Michishita, Masami Morimatsu, Hiroki Sakai, Nayuta Kinoshita, Motoharu Sakaue, Eri Onozawa, Daigo Azakami, Masami Yamamoto, Katsumi Ishioka, Takuya Sadahira, Masami Watanabe, Yoshikazu Tanaka

    Oncology reports   47 ( 4 )   2022.4

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    Hemangiosarcoma (HSA) is a malignant neoplasm that occurs in humans and canines with a poor prognosis owing to metastatic spread, despite effective treatment. The frequency of spontaneous HSA development is higher in canines than in humans. Therefore, canine HSA is a useful model of intractable human disease, which requires early detection and an effective therapeutic strategy. A high frequency of the p110α phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA) mutations is detected in a comprehensive genome‑wide analysis of canine cases of HSA. The present cloned the full‑length cDNA of canine PIK3CA and identified a mutation in codon 1047 from canine cases of HSA and cell lines that were established from these. The enforced expression of the 1047th histidine residue (H1047)R or L mutants of canine PIK3CA in HeLa cells enhanced epidermal growth factor receptor (EGFR) signaling via Akt phosphorylation. PIK3CA mutant canine HSA cell lines exhibited the hyperphosphorylation of Akt upon EGF stimulation as well. Alpelisib, a molecular targeted drug against PIK3CA activating mutations, exerted a significant antitumor effect in canine PIK3CA‑mutated HSA cell lines. By contrast, it had no significant effect on canine mammary gland tumor cell lines harboring PIK3CA mutations. On the whole, the findings of the present study suggest that alpelisib may be highly effective against PIK3CA mutations that occur frequently in canine HSA.

    DOI: 10.3892/or.2022.8295

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  • Dkk3/REIC Deficiency Impairs Spermiation, Sperm Fibrous Sheath Integrity and the Sperm Motility of Mice. Reviewed International journal

    Ruizhi Xue, Wenfeng Lin, Hirofumi Fujita, Jingkai Sun, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, Masami Watanabe, Hideyo Ohuchi, Masakiyo Sakaguchi, Zhengyan Tang, Peng Huang, Yasutomo Nasu, Hiromi Kumon

    Genes   13 ( 2 )   2022.1

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    The role of Dickkopf-3 (Dkk3)/REIC (The Reduced Expression in Immortalized Cells), a Wnt-signaling inhibitor, in male reproductive physiology remains unknown thus far. To explore the functional details of Dkk3/REIC in the male reproductive process, we studied the Dkk3/REIC knock-out (KO) mouse model. By examining testicular sections and investigating the sperm characteristics (count, vitality and motility) and ultrastructure, we compared the reproductive features between Dkk3/REIC-KO and wild-type (WT) male mice. To further explore the underlying molecular mechanism, we performed RNA sequencing (RNA-seq) analysis of testicular tissues. Our results showed that spermiation failure existed in seminiferous tubules of Dkk3/REIC-KO mice, and sperm from Dkk3/REIC-KO mice exhibited inferior motility (44.09 ± 8.12% vs. 23.26 ± 10.02%, p < 0.01). The Ultrastructure examination revealed defects in the sperm fibrous sheath of KO mice. Although the average count of Dkk3/REIC-KO epididymal sperm was less than that of the wild-types (9.30 ± 0.69 vs. 8.27 ± 0.87, ×106), neither the gap (p > 0.05) nor the difference in the sperm vitality rate (72.83 ± 1.55% vs. 72.50 ± 0.71%, p > 0.05) were statistically significant. The RNA-seq and GO (Gene Oncology) enrichment results indicated that the differential genes were significantly enriched in the GO terms of cytoskeleton function, cAMP signaling and calcium ion binding. Collectively, our research demonstrates that Dkk3/REIC is involved in the process of spermiation, fibrous sheath integrity maintenance and sperm motility of mice.

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  • Medical uses for silver nitrate in the urinary tract (Review) Reviewed

    Takanori Sekito, Takuya Sadahira, Toyohiko Watanabe, Yuki Maruyama, Tomofumi Watanabe, Takehiro Iwata, Koichiro Wada, Kohei Edamura, Motoo Araki, Masami Watanabe

    World Academy of Sciences Journal   4 ( 1 )   2022.1

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    DOI: 10.3892/wasj.2022.141

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  • p Identification of MICALL2 as a Novel Prognostic Biomarker Correlating with Inflammation and T Cell Exhaustion of Kidney Renal Clear Cell Carcinoma Reviewed

    Wenfeng Lin, Wenwei Chen, Jisheng Zhong, Hideo Ueki, Abai Xu, Masami Watanabe, Motoo Araki, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    JOURNAL OF CANCER   13 ( 3 )   1214 - 1228   2022

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    Purpose: The interplay of inflammation and immunity affects all stages from tumorigenesis to progression, and even tumor response to therapy. A growing interest has been attracted from the biological function of MICALL2 to its effects on tumor progression. This study was designed to verify whether MICALL2 could be a prognostic biomarker to predict kidney renal clear cell carcinoma (KIRC) progression, inflammation, and immune infiltration within tumor microenvironment (TME). Methods: We firstly analyzed MICALL2 expressions across 33 cancer types from the UCSC Xena database and verified its expression in KIRC through GEPIA platform and GEO datasets. The clinicopathological characteristics were further analyzed based on the median expression. Kaplan-Meier method, univariate and multivariate analyses were applied to compare survival outcomes. ESTIMATE and CIBERSORT algorithms were performed to assess immune infiltration, and a co-expression analysis was conducted to evaluate the correlation between MICALL2 and immunoregulatory genes. Enrichment analysis was finally performed to explore the biological significance of MICALL2. Results: MICALL2 was highly expressed in 16 types of cancers compared with normal tissues. MICALL2 expression increased with advanced clinicopathological parameters and was an independent predictor for poor prognosis in KIRC. Moreover, MICALL2 closely correlated with inflammation-promoting signatures and immune infiltration including T cell exhaustion markers. Consistently, MICALL2 involved in the regulation of signaling pathways associated with tumor immunity, tumor progression, and impaired metabolic activities. Conclusion: MICALL2 can function as a prognostic biomarker mediating inflammation, immune infiltration, and T cell exhaustion within the microenvironment of KIRC.

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  • Testosterone Recovery after Neoadjuvant Gonadotropin-Releasing Hormone Antagonist versus Agonist on Permanent Iodine-125 Seed Brachytherapy in Prostate Cancer Patients: A Propensity Score Analysis.

    Takehiro Iwata, Yuki Maruyama, Tatsushi Kawada, Takuya Sadahira, Satoshi Katayama, Atsushi Takamoto, Tomoko Sako, Koichiro Wada, Kohei Edamura, Yasuyuki Kobayashi, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Acta medica Okayama   75 ( 6 )   705 - 711   2021.12

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    Optimal neoadjuvant hormone therapy (NHT) for reducing prostate cancer (PC) patients' prostate volume pre-brachytherapy is controversial. We evaluated the differential impact of neoadjuvant gonadotropin-releasing hormone (GnRH) antagonist versus agonist on post-brachytherapy testosterone recovery in 112 patients treated pre-brachytherapy with NHT (GnRH antagonist, n=32; GnRH agonists, n=80) (Jan. 2007-June 2019). We assessed the effects of patient characteristics and a GnRH analogue on testosterone recovery with logistic regression and a propensity score analysis (PSA). There was no significant difference in the rate of testosterone recovery to normal levels (> 300 ng/dL) between the GnRH antagonist and agonists (p=0.07). The GnRH agonists induced a significantly more rapid testosterone recovery rate at 3 months post-brachytherapy versus the GnRH antagonist (p<0.0001); there was no difference in testosterone recovery at 12 months between the GnRH antagonist/agonists (p=0.8). In the multivariate analysis, no actor was associated with testosterone recovery. In the PSA, older age and higher body mass index (BMI) were significantly associated with longer testosterone recovery. Post-brachytherapy testosterone recovery was quicker with the neoadjuvant GnRH agonists than the antagonist, and the testosterone recovery rate was significantly associated with older age and higher BMI. Long-term follow-ups are needed to determine any differential effects of GnRH analogues on the quality of life of brachytherapy-treated PC patients.

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  • Clinical Efficacy and Safety of Sitafloxacin 200 mg Once Daily for Refractory Genitourinary Tract Infections. Reviewed

    Takehiro Iwata, Takuya Sadahira, Yuki Maruyama, Takanori Sekito, Kasumi Yoshinaga, Shogo Watari, Kentaro Nagao, Tatsushi Kawada, Yusuke Tominaga, Shingo Nishimura, Atsushi Takamoto, Tomoko Sako, Kohei Edamura, Yasuyuki Kobayashi, Motoo Araki, Ayano Ishii, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu, Koichiro Wada

    Acta medica Okayama   75 ( 6 )   763 - 766   2021.12

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    The aim of this ongoing trial is to evaluate the clinical efficacy and safety of sitafloxacin (STFX) 200 mg once daily (QD) for 7 days in patients with refractory genitourinary tract infections, which include recurrent or complicated cystitis, complicated pyelonephritis, bacterial prostatitis, and epididymitis. The primary endpoint is the microbiological efficacy at 5-9 days after the last administration of STFX. Recruitment began in February 2021, and the target total sample size is 92 participants.

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  • In vivo evaluation of GG2-GG1/A2 element activity in the insulin promoter region using the CRISPR-Cas9 system. International journal

    Hirofumi Noguchi, Chika Miyagi-Shiohira, Takao Kinjo, Issei Saitoh, Masami Watanabe

    Scientific reports   11 ( 1 )   20290 - 20290   2021.10

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    The insulin promoter is regulated by ubiquitous as well as pancreatic β-cell-specific transcription factors. In the insulin promoter, GG2-GG1/A2-C1 (bases - 149 to - 116 in the human insulin promoter) play important roles in regulating β-cell-specific expression of the insulin gene. However, these events were identified through in vitro studies, and we are unaware of comparable in vivo studies. In this study, we evaluated the activity of GG2-GG1/A2 elements in the insulin promoter region in vivo. We generated homozygous mice with mutations in the GG2-GG1/A2 elements in each of the Ins1 and Ins2 promoters by CRISPR-Cas9 technology. The mice with homozygous mutations in the GG2-GG1/A2 elements in both Ins1 and Ins2 were diabetic. These data suggest that the GG2-GG1/A2 element in mice is important for Ins transcription in vivo.

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  • Efficacy of Lactobacillus vaginal suppositories for the prevention of recurrent cystitis: A phase II clinical trial. International journal

    Takuya Sadahira, Koichiro Wada, Motoo Araki, Ritsuko Mitsuhata, Masumi Yamamoto, Yuki Maruyama, Takehiro Iwata, Masami Watanabe, Toyohiko Watanabe, Reiko Kariyama, Yasutomo Nasu, Ayano Ishii

    International journal of urology : official journal of the Japanese Urological Association   28 ( 10 )   1026 - 1031   2021.10

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    OBJECTIVES: To prospectively assess the efficacy and safety of Lactobacillus vaginal suppositories for the prevention of recurrent cystitis. METHODS: In this single-arm, open-label, phase II clinical trial, participants used vaginal suppositories containing the GAI 98322 strain of Lactobacillus crispatus for 1 year either every 2 days or three times per week. The primary end-point was the response rate, as assessed by the number of episodes of recurrent cystitis during the year of administration. The secondary end-points were the response rate, as assessed by episodes of recurrent cystitis during the 1 year after completion of the administration period; the total number of episodes of recurrent cystitis before, during and after administration; adverse events; and changes in urine bacteria and the vaginal microbiome. RESULTS: A total of 28 women were enrolled, and 21 completed the study. A total of 18 patients achieved an effective response (86%) during administration. The suppressive effects of Lactobacillus vaginal suppositories on episodes of cystitis continued up to 1 year after the last suppository was administered. There was a significant reduction in the mean number of episodes of cystitis, both during and after administration of Lactobacillus vaginal suppositories. No treatment-related adverse events were observed. Amplicon sequencing analysis of the vaginal microbiome showed that Lactobacillus species colonized the vagina during the periods when episodes of cystitis were absent. CONCLUSIONS: Vaginal suppositories containing the GAI 98322 strain of Lactobacillus crispatus effectively prevent episodes of recurrent cystitis, both during administration and for at least 1 year after administration.

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  • Impact of Sarcopenia on Erectile Function after Nerve-Sparing Robot-Assisted Radical Prostatectomy. International journal

    Yosuke Mitsui, Takuya Sadahira, Yuki Maruyama, Ryota Sato, Acosta Gonzalez Herik Rodrigo, Koichiro Wada, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    The world journal of men's health   39 ( 4 )   673 - 682   2021.10

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    PURPOSE: To determine the impact of sarcopenia on erectile functional outcomes after a nerve-sparing (NS) robot-assisted radical prostatectomy (RARP) using patient-reported validated questionnaires. MATERIALS AND METHODS: In this retrospective study, RARP was performed on 841 patients at Okayama University Hospital, of which 132 underwent NS RARP. Erectile functional outcomes were assessed using the 5-item version of the International Index of Erectile Function (IIEF-5) and the Expanded Prostate Cancer Index Composite before and 1, 3, 6, and 12 months after surgery. Automated measurement of skeletal muscle at L3 was achieved using volume analyzer software and normalizing for height (cm²/m²) to calculate skeletal muscle index (SMI). Patients who had an IIEF-5≤4 comprised the group with erectile dysfunction (ED), and those with an IIEF-5≤5 made up the non-ED group. RESULTS: This study enrolled 95 patients of median age 65 years with a preoperative IIEF-5 of 16. There were no significant differences between patients with and without sarcopenia among those with preoperative IIEF-5. Postoperatively, in the ED group, SMI and preoperative IIEF-5 were significantly lower than in the non-ED group. Multiple linear regression analysis revealed that (1) both SMI and preoperative IIEF-5 were independent predictors of ED, and (2) sarcopenia and preoperative IIEF-5 were predictors of ED at 12 months after NS RARP. CONCLUSIONS: Patients with sarcopenia can have worse erectile functional outcomes after NS RARP. Sarcopenia and a lower preoperative IIEF-5 score may be predictive of postoperative ED.

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  • Blood concentrations of tacrolimus upon conversion from rabeprazole to vonoprazan in renal transplant recipients: Correlation with cytochrome P450 gene polymorphisms. International journal

    Shogo Watari, Motoo Araki, Jun Matsumoto, Kasumi Yoshinaga, Takanori Sekito, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Koichiro Wada, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Shinji Kitamura, Hitoshi Sugiyama, Noritaka Ariyoshi, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Drug metabolism and pharmacokinetics   40   100407 - 100407   2021.10

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    We evaluated the impact of vonoprazan on blood concentrations of tacrolimus via a retrospective analysis of 52 renal transplant recipients who took tacrolimus and converted from rabeprazole to vonoprazan between August 2018 and September 2019. We compared tacrolimus trough levels upon conversion among groups that were classified based on cytochrome P450 (CYP) gene polymorphisms. CYP3A5 groups were heterozygous or homozygous for CYP3A5∗1 and CYP3A5∗3 alleles. CYP2C19 genotypes were classified as extensive (∗1/∗1), intermediate (∗1/∗2 and ∗1/∗3) or poor metabolizers (∗2/∗2, ∗2/∗3 and ∗3/∗3). Tacrolimus trough levels increased only 0.3 ng/mL upon conversion in the CYP3A5∗3/∗3 group: 5.8 [3.4-7.2] vs 6.1 [3.8-7.9]; p = 0.06. No statistically significance changes in tacrolimus levels also occurred in the CYP3A5∗1/∗1 or CYP3A5∗1/∗3 groups. Subgroup analyses of CYP3A5∗3/∗3 demonstrated low changes for all three CYP2C19 subgroups: 5.2 [4.3-6.5] vs 6.2 [4.3-7.9]; p = 0.07, 6.1 [3.4-7.2] vs 6.7 [4.6-7.9]; p = 0.12 and 5.4 [3.6-6.5] vs 4.7 [3.8-6.3]; p = 1.00, respectively. Conversion to vonoprazan thus resulted in little increase of tacrolimus trough levels, even in the group predicted to be most susceptible (CYP3A5∗3/∗3 and 2C19∗1/∗1), thus supporting the safety of concomitant use of vonoprazan with tacrolimus.

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  • Presence of decoy cells for 6 months on urine cytology efficiently predicts BK virus nephropathy in renal transplant recipients. International journal

    Takanori Sekito, Motoo Araki, Kasumi Yoshinaga, Yuki Maruyama, Takuya Sadahira, Shingo Nishimura, Koichiro Wada, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Tanabe, Hidemi Takeuchi, Hiroshi Morinaga, Masashi Kitagawa, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Hiroyuki Yanai, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   28 ( 12 )   1240 - 1246   2021.9

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    OBJECTIVES: To investigate the association between duration of consecutive presence of decoy cells on urine cytology and BK virus nephropathy after kidney transplantation. METHODS: In total, 121 kidney transplant recipients were retrospectively evaluated. The best duration of consecutive presence of decoy cells that could be used to predict BK virus nephropathy was analyzed using the area under the curve for each duration, and recipients were divided into two groups based on the best predictive performance. The effectiveness of SV40 immunostaining on urinary cytology was also analyzed. RESULTS: In total, 2534 urine specimens as well as SV40 immunostaining in 2241 urine specimens were analyzed. Six consecutive months of decoy cell positivity had the best predictive performance for BK virus nephropathy (area under the curve = 0.832). The incidence of BK virus nephropathy in recipients with positive decoy cells for 6 months or more consecutive months (5/44) was significantly higher than in those who had positive decoy cells for less than 6 months (0/77; P = 0.005). Decoy cell positivity had a sensitivity, specificity, positive predictive value, and negative predictive value for BK virus nephropathy of 100%, 66%, 11%, and 100% respectively. SV40 immunostaining provided slightly better specificity (68%) and positive predictive value (12%). CONCLUSIONS: The detection of decoy cells at 6 months or more on urine cytology had high predictive value for BK virus nephropathy in kidney transplant recipients. SV40 immunostaining on urine cytology added minimal diagnostic accuracy.

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  • The Cell Cycle Checkpoint Gene, RAD17 rs1045051, Is Associated with Prostate Cancer Risk. Reviewed International coauthorship

    Jingkai Sun, Wenfeng Lin, Qixu Wang, Akiko Sakai, Ruizhi Xue, Masami Watanabe, Chunxiao Liu, Takuya Sadahira, Yasutomo Nasu, Abai Xu, Peng Huang

    Acta medica Okayama   75 ( 4 )   415 - 421   2021.8

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    Human RAD17, as an agonist of checkpoint signaling, plays an essential role in mediating DNA damage. This hospital-based case-control study aimed to explore the association between RAD17 rs1045051, a missense sin-gle nucleotide polymorphism (SNP), and prostate cancer risk. Subjects were 358 prostate cancer patients and 314 cancer-free urology patients undergoing treatment at the Zhujiang Hospital of Southern Medical University in China. RAD17 gene polymorphism rs1045051 was evaluated by the SNaPshot method. Compared with the RAD17 gene polymorphism rs1045051 AA genotype, there was a higher risk of prostate cancer for the CC gen-otype (adjusted odds ratio [AOR] = 1.731, 95% confidence interval [95%CI] = 1.031-2.908, p = 0.038). Compared with the A allele, the C allele was significantly associated with the disease status (AOR = 1.302, 95%CI = 1.037-1.634, p = 0.023). All these findings indicate that in the SNP rs1045051, both the CC genotype and C allele may have a substantial influence on the prostate cancer risk.

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  • Successful deceased donor kidney transplantation to a recipient with a history of COVID-19 treatment. International journal

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Kou Hasegawa, Takanori Sekito, Shuji Miyake, Shogo Watari, Yuki Maruyama, Takuya Sadahira, Shingo Nishimura, Katsuyuki Tanabe, Hidemi Takeuchi, Yuri Nakashima, Masaru Kinomura, Herik Acosta, Yosuke Mitsui, Risa Kubota, Hirochika Nakajima, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Fumio Otsuka, Jun Wada, Yasutomo Nasu

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 7 )   1097 - 1101   2021.7

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    CASE PRESENTATION: A 49-year-old Asian male, who had undergone hemodialysis for >16 years, complained of a fever, dysgeusia and dysosmia, and was diagnosed with COVID-19 pneumonia based on severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (SARS-CoV-2 PCR) and computed tomography (CT). Treatment was started with oral favipiravir and ciclesonide inhalation. On the 10th day of treatment, the patient had a persistent high fever and a chest CT showed exacerbation of pneumonia, so dexamethasone was intravenously started. He was discharged after confirming two consecutive negative SARS-CoV-2 PCR tests. Three months after COVID-19 treatment, a SARS-CoV-2 PCR test was negative and he underwent a deceased donor kidney transplantation. Basiliximab induction with triple drug immunosuppression consisting of extended-release tacrolimus, mycophenolate mofetil and prednisolone, which is our regular immunosuppression protocol, was used. He was discharged on postoperative day 18 without the need for postoperative hemodialysis or any complications. The serum creatinine level was 1.72 mg/dL 95 days postoperatively and he had a favorable clinical course that was similar to deceased donor kidney recipients without a history of SARS-CoV-2 infection. CONCLUSION: We report the first case of a kidney transplantation after COVID-19 treatment in Japan and the fourth case globally. We would like to provide information about our successful case due to the anticipated increase in similar candidates in the near future.

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  • Cytopathic effects and local immune responses in repeated neoadjuvant HSV-tk + ganciclovir gene therapy for prostate cancer. International journal

    Nobuyuki Yanagisawa, Takefumi Satoh, Ken-Ichi Tabata, Hideyasu Tsumura, Yasutomo Nasu, Masami Watanabe, Timothy C Thompson, Isao Okayasu, Yoshiki Murakumo, Shiro Baba, Masatsugu Iwamura

    Asian journal of urology   8 ( 3 )   280 - 288   2021.7

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    Objective: Cytopathic effects and local immune response were analyzed histologically in prostatic cancer (PCa) with in situ herpes simplex virus-thymidine kinase (HSV-tk)/ganciclovir (GCV) gene therapy (GT). Methods: Four high-risk PCa patients who received HSV-tk/GCV GT were investigated. After two cycles of intraprostatic injection of HSV-tk and administration of GCV, radical prostatectomy was performed. Formalin-fixed, paraffin-embedded sections were evaluated using immunohistochemistry. PCa with hormone therapy (HT, n=3) or without neoadjuvant therapy (NT, n=4) that were equivalent in terms of risk were also examined as reference. Immunoreactively-positive cells were counted in at least three areas in cancer tissue. Labeling indices (LI) were calculated as percentage values. Results: ssDNA LI in GT increased, indicating apoptosis, as well as tumor-infiltrating lymphocytes and CD68-positive macrophages, compared with their biopsies. GT cases showed significantly higher numbers of single-stranded DNA (ssDNA) LI, CD4/CD8-positive T cells and CD68-positive macrophages including M1/M2 macrophages than HT or NT cases. However, there was no significant difference in CD20-positive B cells among the types of case. There were strong correlations between CD8+ T cells and CD68+ macrophages (ρ=0.656, p<0.0001) as well as CD4+ T cells and CD20+ B cells (ρ=0.644, p<0.0001) in PCa with GT. Conclusions: Enhanced cytopathic effect and local immune response might be indicated in PCa patients with HSV-tk/GCV gene therapy.

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  • Feasible kidney donation with living marginal donors, including diabetes mellitus. International journal

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Takanori Sekito, Shogo Watari, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Kohei Edamura, Yasuyuki Kobayashi, Katsuyuki Tanabe, Hidemi Takeuchi, Masashi Kitagawa, Shinji Kitamura, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Immunity, inflammation and disease   9 ( 3 )   1061 - 1068   2021.6

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    OBJECTIVES: To compare the donor outcomes of living donor kidney transplantation between standard donors (SDs) and marginal donors (MDs) including diabetic patients (MD + DM). METHODS: MDs were defined according to Japanese guideline criteria: (a) age >70-years, (b) blood pressure ≤130/80 mmHg on hypertension medicine, (c) body mass index >25 to ≤32 kg/m2 , (d) 24-h creatinine clearance ≥70 to <80 ml/min/1.73 m2 , and (e) hemoglobin A1c > 6.2 or ≤6.5 with oral diabetic medicine. Fifty-three of 114 donors were MDs. We compared donor kidney functions until 60 months postoperatively. RESULTS: No kidney function parameters were different between SDs and MDs. When comparing SD and MD + DM, MD + DM had a lower postoperative eGFR (48 vs. 41 (1 (month), p = .02), 49 vs. 40 (12, p < .01), 48 vs. 42 (24, p = .04), 47 vs. 38 (36, p = .01)) and the percentage of residual eGFR (SD vs. MD + DM: 63 vs. 57 (1 (month), p < .01), 63 vs. 57 (2, p < .01), 64 vs. 56 (12, p < .01), 63 vs. 57 (24, p < .01), 63 vs. 52 (36, p = .02)). However, when MD with a single risk factor of DM was compared to SD, the difference disappeared. Nine out of 12 (75%) MD + DM had ≥2 risk factors. CONCLUSIONS: Although long-term observation of donor kidney function is necessary, careful MD + DM selection had the potential to expand the donor pool.

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  • Comparison of intracorporeal versus extracorporeal urinary diversion after robot-assisted radical cystectomy at a medium-sized facility.

    Takehiro Iwata, Yasuyuki Kobayashi, Yuki Maruyama, Tatsushi Kawada, Takuya Sadahira, Yuko Oiwa, Satoshi Katayama, Shingo Nishimura, Atsushi Takamoto, Tomoko Sako, Koichiro Wada, Kohei Edamura, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    International journal of clinical oncology   26 ( 9 )   1714 - 1721   2021.6

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    BACKGROUND: The aim of this study is to compare the perioperative outcomes and learning curves between intracorporeal and extracorporeal urinary diversion at our medium-sized institution. METHODS: Between January 2018 and September 2020, a single surgeon at our institution performed 46 consecutive robot-assisted radical cystectomies with ileal conduit. We compared the perioperative outcomes between patients who underwent intracorporeal versus extracorporeal urinary diversion. We also investigated learning curves for the first and last 10 patients in each group. RESULTS: The extracorporeal group had shorter overall operative time (P = 0.003) and urinary diversion time (P < 0.0001) than the intracorporeal group. The intracorporeal group had shorter length of hospital stay (P = 0.02). There was no difference in complication and readmission rates. The extracorporeal group demonstrated no difference between the first and last 10 patients for overall operative time or time for cystectomy, lymph node dissection, or urinary diversion. However, the intracorporeal group had shorter urinary diversion time for the last 10 patients compared with the first 10 patients. The first 10 patients in the extracorporeal group had shorter overall operative time than the first 10 in the intracorporeal group, but there was no difference for the last 10 patients. CONCLUSIONS: Intracorporeal urinary diversion requires longer overall operative time than extracorporeal diversion for the first 10 patients, due to longer urinary diversion time. However, there is no difference in overall operative time for the last 10 patients. The benefit of intracorporeal over extracorporeal urinary diversion was not confirmed at our medium-sized institution.

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  • The number of glutamines in the N-terminal of the canine androgen receptor affects signalling intensities. International journal

    Kazuhiko Ochiai, Samak Sutijarit, Mitsuki Uemura, Masami Morimatsu, Masaki Michishita, Eri Onozawa, Marika Maeda, Takanori Sasaki, Masami Watanabe, Yoshikazu Tanaka, Toshinori Omi

    Veterinary and comparative oncology   19 ( 2 )   399 - 403   2021.6

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    Most male dogs are castrated at young ages, making them easy to rear following androgen deprivation. Although the incidence of canine prostate cancer is low, several patients have resistance to androgen therapy and poor clinical prognosis. These outcomes are similar to those of end-stage human androgen-independent prostate cancer. The androgen receptor (AR) of canines has two polyglutamine (polyQ) sequences (Q × 10 and Q × 23) at its N-terminal. The length of polyQ may be a risk factor for the development of prostate cancer in dogs; however, there is no evidence to support this. Hence, we artificially created polyQ deletion mutants of canine AR and evaluated their effects on AR signalling. The deletions of Q × 10 and Q × 23 were associated with significant reductions in AR signalling intensities. The Q × 10 mutants, which increase or decrease Q sequentially, also altered AR signalling. Furthermore, the Q × 10 deletion mutant, compared with the Q × 10 control, altered the intensities of the binding of polyQ to the C-terminal of AR, which contains a ligand-binding domain; this was not observed with the Q × 9, 11, and 12 variants. The number of glutamines in the N-terminals of canine ARs may influence AR signalling intensities and contribute to the risk of prostate cancer in dogs.

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  • A Case of Metastatic Fumarate Hydratase-Deficient-like Renal Cell Carcinoma Successfully Managed by Ipilimumab plus Nivolumab.

    Takanori Sekito, Atsushi Takamoto, Yasuyuki Kobayashi, Masao Mitsui, Shogo Watari, Risa Kubota, Takuya Sadahira, Takehiro Iwata, Shingo Nishimura, Kohei Edamura, Tomoko Sako, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Rei Shibata, Daisuke Ennishi, Yasutomo Nasu

    Acta medica Okayama   75 ( 3 )   397 - 402   2021.6

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    We report a 62-year-old male with metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) without fumarate hydratase (FH) mutation (FH-deficient-like RCC). The International Metastatic RCC Database Consortium risk score was intermediate, and immunotherapy with nivolumab and ipilimumab (Ipi/ Nivo) was initiated. Four cycles of Ipi/Nivo and 5 cycles of nivolumab resulted in a complete response of the metastases. Hypophysitis occurred as an immune-related adverse event after four cycles of Ipi/Nivo. The prognosis of patients with FH-deficient RCC is generally poor. Few reports of FH-deficient RCC successfully treated with Ipi/Nivo have been published. Ipi/Nivo can be effective for treating FH-deficient RCC.

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  • ABO Blood Incompatibility Positively Affects Early Graft Function: Single-Center Retrospective Cohort Study. International journal

    Shogo Watari, Motoo Araki, Koichiro Wada, Kasumi Yoshinaga, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Transplantation proceedings   53 ( 5 )   1494 - 1500   2021.6

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    BACKGROUND: We investigated the association between ABO-incompatible (ABO-I) kidney transplantation and early graft function. METHODS: We retrospectively analyzed 95 patients who underwent living donor kidney transplantation between May 2009 and July 2019. It included 61 ABO-compatible (ABO-C) and 34 ABO-I transplantations. We extracted data on immunologic profile, sex, age, cold ischemic time, type of immunosuppression, and graft function. Two definitions were used for slow graft function (SGF) as follows: postoperative day (POD) 3 serum creatinine level >3 mg/dL and estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2. Logistic regression analysis was performed to analyze the effect of ABO-I on the incidence of SGF. RESULTS: The characteristics between the ABO-C and ABO-I were not different. ABO-I received rituximab and plasma exchange. Patients also received tacrolimus and mycophenolate mofetil for 2 weeks and prednisolone for 1 week before transplantation as preconditioning. Of the 95 study patients, 19 (20%) and 21 (22%) were identified with SGF according to POD 3 serum creatinine level or eGFR, respectively. Multivariable analysis revealed that ABO-I significantly reduced the incidence of SGF (odds ratio, 0.15; 95% confidence interval, 0.03-0.7; P = .02), and cold ischemic time >150 min increased the incidence of SGF (odds ratio, 6.5; 95% confidence interval, 1.7-25; P = .006). Similar results were identified in POD 3 eGFR. Inferior graft function in patients with SGF was identified up to 6 months after transplantation. CONCLUSION: ABO-I reduces the incidence of SGF, which is associated with an inferior graft function up to 6 months.

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  • Evaluation of Neutrophil Dynamics Change by Protective Effect of Tadalafil After Renal Ischemia/Reperfusion Using In Vivo Real-time Imaging. International journal

    Yuki Maruyama, Motoo Araki, Kengo Kidokoro, Yuji Sogawa, Kasumi Yoshinaga, Yosuke Mitsui, Takuya Sadahira, Koichiro Wada, Masami Watanabe, Toyohiko Watanabe, Naoki Kashihara, Yasutomo Nasu

    Transplantation   106 ( 2 )   280 - 288   2021.4

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    BACKGROUND: Neutrophils play a major role in ischemia/reperfusion injury (IRI) in renal transplantation and acute kidney injury. However, it has been difficult to observe changes in neutrophil dynamics over time in living mice kidney. We investigate neutrophil dynamics in IRI in living mice using novel in vivo multiphoton microscope imaging techniques and characterize the renoprotective effects of a selective phosphodiesterase (PDE) 5 inhibitor, tadalafil. METHODS: Wild-type (WT) and eNOS knockout (eNOS-KO) mice, a model of endothelial dysfunction, were used to establish in vivo real-time imaging in living mouse kidneys. Neutrophils were labeled green with Ly-6G monoclonal antibody, and plasma flow was labeled red with bovine serum albumin. Tadalafil was administered orally 1 h before surgery. Both kidney pedicles were reperfused after 37° warm ischemia for 45 min. RESULTS: Our novel approach revealed that neutrophils were trapped in glomerulus within a few minutes after reperfusion. They gradually increased over time and Infiltrated neutrophils were observed in the tubular lumen and peritubular capillary. The neutrophils were clearly visualized rolling on peritubular capillary plexus at 3 μm/min. The administration of tadalafil significantly reduced neutrophil influx into the glomerulus in both WT and eNOS-KO mice. Reduced neutrophil infiltration in tadalafil groups, which was confirmed by flow cytometry, resulted in histopathologically decreased tubular injury. The expression of VCAM-1 and KIM-1 was partially prevented by tadalafil. CONCLUSIONS: Use of a novel technique contributed to elucidation of neutrophil dynamics after reperfusion. Tadalafil has a potential for inhibiting neutrophil infiltration in renal IRI.Supplemental Visual Abstract; http://links.lww.com/TP/C223.

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  • Pancreas preservation with amphotericin B deteriorates islet yield for porcine islet isolation. International journal

    Sayaka Sawada, Chika Miyagi-Shiohira, Kazuho Kuwae, Yoshihito Tamaki, Kai Nishime, Mayuko Sakai-Yonaha, Tasuku Yonaha, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Xenotransplantation   28 ( 4 )   e12690   2021.4

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    BACKGROUND: Amphotericin B is a crucial agent in the management of serious systemic fungal infections. It is also known to be cytotoxic. In this study, we evaluated the effect of amphotericin B added to the preservation solution on islet yield during islet isolation. METHODS: Porcine pancreata were preserved in the preservation solution with or without amphotericin B (0.25 μg/mL) for approximately 18 hours at 4°C, and then islet isolation was performed. An optimized number (1750 IE) of isolated islets from each group were transplanted into streptozotocin-induced diabetic mice. The culture of isolated islets and acinar tissue with amphotericin B was also evaluated. RESULTS: The islet yield before and after purification in the amphotericin B (-) group was significantly higher than that in the amphotericin B (+) group. After islet transplantation into diabetic mice, blood glucose levels reached the normoglycemic range, with 50% and 0% of that of the diabetic mice in the amphotericin B (-) and amphotericin B (+) groups, respectively. In the culture study, amphotericin B was found to be cytotoxic to porcine islets and acinar tissue. CONCLUSIONS: Amphotericin B added to the preservation solution deteriorates islet yield during porcine islet isolation. Thus, the use of amphotericin B should be considered carefully for the preservation of the pancreas for islet isolation and islet culture before islet transplantation.

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  • A second opinion pathology review improves the diagnostic concordance between prostate cancer biopsy and radical prostatectomy specimens

    Takanori Maehara, Takuya Sadahira, Yuki Maruyama, Koichiro Wada, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Hiroyuki Yanai, Yasutomo Nasu

    Urology Annals   13 ( 2 )   119 - 124   2021.4

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    Objectives: The Gleason scoring system is an essential tool for determining the treatment strategy in prostate cancer (PCa). However, the Gleason grade group (GGG) often differs between needle-core biopsy (NCB) and radical prostatectomy (RP) specimens. We investigated the diagnostic value of a second opinion pathology review using NCB specimens in PCa. Materials and Methods: We retrospectively evaluated 882 patients who underwent robot-assisted RP from January 2012 to September 2019. Of these, patients whose original biopsy specimens were obtained from another hospital and reviewed by the urological pathology expert at our institution were included in the study. Patients who received neoadjuvant hormonal therapy were excluded from the study. Weighted kappa (k) coefficients were used to evaluate the diagnostic accuracy of each review. Results: A total of 497 patients were included in this study. Substantial agreement (weighted k = 0.783) in the GGG between initial- and second-opinion diagnoses based on NCB specimens was observed in 310 cases (62.4%). Although diagnoses based on a single opinion showed moderate agreement with the GGG of RP specimens (initial: 35.2%, weighted k = 0.522
    second opinion
    38.8%, weighted k = 0.560), matching initial and second opinion diagnoses improved the concordance (42.9%, 133/310 cases) to substantial agreement (weighted k = 0.626). Conclusions: A second opinion of PCa pathology helps to improve the diagnostic accuracy of NCB specimens. However, over half of diagnoses that matched between the initial and second opinions differed from the diagnosis of RP specimens.

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  • Impact of paclitaxel, cisplatin, and gemcitabine as first-line chemotherapy in cisplatin-fit and -unfit patients with advanced/metastatic urothelial carcinoma. International journal

    Satoshi Katayama, Yasuyuki Kobayashi, Atsushi Takamoto, Kohei Edamura, Takuya Sadahira, Takehiro Iwata, Shingo Nishimura, Tomoko Sako, Koichiro Wada, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Urologic oncology   39 ( 10 )   731.e25-731.e32   2021.3

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    PURPOSE: This study aimed to clarify the efficacy and toxicity of first-line combination treatment with paclitaxel, cisplatin, and gemcitabine (PCG) for advanced/metastatic urothelial carcinoma (UC) in cisplatin-unfit patients compared with cisplatin-fit patients. METHODS: We conducted a retrospective study of patients who received first-line PCG. Using international consensus criteria, patients were classified into cisplatin-fit and -unfit groups. Cisplatin-unfit patients received PCG with adjustment of the cisplatin dose after assessing 24-hour urinary creatinine clearance, without modifying the administration interval. RESULTS: From 2008 to 2017, 50 patients received first-line PCG, of whom 30 and 20 were classified into the cisplatin-fit and -unfit groups. After a median follow-up of 15.0 months, the median overall survival (OS) and progression-free survival (PFS) were 15.0 and 9.8 months in all patients, 15.0 and 10.0 months in the cisplatin-fit group, and 13.2 and 9.3 months in the cisplatin-unfit group, respectively. There was no significant difference in OS (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 0.69-2.54) or PFS (HR: 1.38, 95% CI: 0.74-2.55) between the groups. The overall response rate and complete response rate were 58% (95% CI: 43.2-71.8) and 32% (95% CI: 19.5-46.7) in all patients, and 55% (95% CI: 31.5-76.9) and 35% (95% CI: 15.4-59.2) in the cisplatin-unfit group, respectively. The common grade 3 of 4 adverse events experienced were neutropenia (78%), followed by thrombocytopenia (56%), anemia (46%), and febrile neutropenia (16%). The 24-hour urinary creatinine clearance did not differ significantly between the groups after one, two, or three courses of PCG. CONCLUSIONS: We found no significant difference regarding OS and PFS between the cisplatin-fit patients with a full dose of cisplatin and -unfit patients with cisplatin-dose-adjusted chemotherapy. In select cisplatin-unfit patients, PCG with dose adjustment of cisplatin may be useful for treating advanced/metastatic UC without any significant adverse events or impaired renal function compared with cisplatin-fit patients with a full dose of cisplatin.

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  • Photodynamic diagnostic ureteroscopy using the VISERA ELITE video system for diagnosis of upper-urinary tract urothelial carcinoma: a prospective cohort pilot study. International journal

    Koichiro Wada, Motoo Araki, Ryuta Tanimoto, Takuya Sadahira, Shogo Watari, Yuki Maruyama, Yosuke Mitsui, Hirochika Nakajima, Herik Acosta, Satoshi Katayama, Takehiro Iwata, Shingo Nishimura, Atsushi Takamoto, Tomoko Sako, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    BMC urology   21 ( 1 )   45 - 45   2021.3

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    BACKGROUND: The advantages of photodynamic diagnostic technology using 5-aminolevulinic acid (ALA-PDD) have been established. The aim of this prospective cohort study was to evaluate the usefulness of ALA-PDD to diagnose upper tract urothelial carcinoma (UT-UC) using the Olympus VISERA ELITE video system. METHODS: We carried out a prospective, interventional, non-randomized, non-contrast and open label cohort pilot study that involved patients who underwent ureterorenoscopy (URS) to detect UT-UC. 5-aminolevulinic acid hydrochloride was orally administered before URS. The observational results and pathological diagnosis with ALA-PDD and traditional white light methods were compared, and the proportion of positive subjects and specimens were calculated. RESULTS: A total of 20 patients were enrolled and one patient who had multiple bladder tumors did not undergo URS. Fifteen of 19 patients were pathologically diagnosed with UT-UC and of these 11 (73.3%) were ALA-PDD positive. Fourteen of 19 patients were ALA-PDD positive and of these 11 were pathologically diagnosed with UC. For the 92 biopsy specimens that were malignant or benign, the sensitivity for both traditional white light observation and ALA-PDD was the same at 62.5%, whereas the specificities were 73.1% and 67.3%, respectively. Of the 38 specimens that were randomly biopsied without any abnormality under examination by both white light and ALA-PDD, 11 specimens (28.9%) from 5 patients were diagnosed with high grade UC. In contrast, four specimens from 4 patients, which were negative in traditional white light observation but positive in ALA-PDD, were diagnosed with carcinoma in situ (CIS). CONCLUSIONS: Our results suggest that ALA-PDD using VISERA ELITE is not sufficiently applicable for UT-UC. Nevertheless, it might be better particularly for CIS than white light and superior results would be obtained using VISERA ELITE II video system. TRIAL REGISTRATION: The present clinical study was approved by the Okayama University Institutional Review Board prior to study initiation (Application no.: RIN 1803-002) and was registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (Accession no.: UMIN000031205).

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  • Pancreas preservation in extracellular-type p38 inhibitor-containing solution improves islet yield for porcine islet isolation. International journal

    Tasuku Yonaha, Chika Miyagi-Shiohira, Kazuho Kuwae, Yoshihito Tamaki, Kai Nishime, Mayuko Sakai-Yonaha, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Xenotransplantation   28 ( 2 )   e12661   2021.3

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    BACKGROUND: For islet transplantation, pancreas preservation and islet isolation activate p38, which is a member of the stress-activated group of mitogen-activated protein kinases (MAPKs). In this study, we evaluated an extracellular-type p38 inhibitor-containing (EP) solution with University of Wisconsin (UW) solution, the gold standard for organ preservation. The EP solution has high sodium-low potassium composition with low viscosity compared to UW solution. Moreover, EP solution contains a recently developed p38 inhibitor (11R-p38I110 ) from our laboratory. METHODS: Porcine pancreata were preserved in UW, EP, or EP-P solution (EP solution without 11R-p38I110 ), and then islet isolation was performed. An optimized number (1500 IE) of isolated islets from each group were transplanted into streptozotocin-induced diabetic mice. RESULTS: The islet yield before and after purification was significantly higher in the EP group than in the UW group. The islet yield before and after purification was not significantly different between the EP and EP-P groups; however, the EP solution prevented a reduction in the number of islets during culture. Western blot analysis showed that p38 activation was attenuated by EP solution. For islet transplantation into streptozotocin-induced diabetic mice, pancreas preservation in EP solution improved the outcome of islet transplantation. CONCLUSIONS: Pancreas preservation with EP solution preserved islet function better than with UW solution. The advantages of EP solution over UW solution may include the inhibition of p38 activity as well as the composition of the solution.

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  • Gene Expression in Pancreatic Cancer-Like Cells and Induced Pancreatic Stem Cells Generated by Transient Overexpression of Reprogramming Factors. International journal

    Chika Miyagi-Shiohira, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Journal of clinical medicine   10 ( 3 )   2021.1

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    We previously reported that transient overexpression of reprogramming factors can be used to generate induced pluripotent stem (iPS) cells, induced tissue-specific stem (iTS) cells, and fibroblast-like (iF) cells from pancreatic tissue. iF cells have tumorigenic ability and behave similarly to pancreatic cancer cells. In this study, we analyzed gene expression in iF cells and iTS-P cells (iTS cells from pancreatic tissue) via microarray analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression levels of the Mybl2 and Lyn genes, which are reported to be oncogenes, were significantly higher in iF cells than in iTS-P cells. The expression level of Nestin, which is expressed in not only pancreatic progenitor cells but also pancreatic ductal adenocarcinomas, was also higher in iF cells than in iTS-P cells. Itgb6 and Fgf13, which are involved in the pathogenesis of diseases such as cancer, exhibited higher expression levels in iF cells than in iTS-P cells. Unexpectedly, the expression levels of genes related to epithelial-mesenchymal transition (EMT), except Bmp4, were lower in iF cells than in iTS-P cells. These data suggest that the Mybl2, Lyn, Nestin, Itgb6, and Fgf13 genes could be important biomarkers to distinguish iTS-P cells from iF cells.

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  • The role of Wnt signaling in male reproductive physiology and pathology. International coauthorship International journal

    Ruizhi Xue, Wenfeng Lin, Jingkai Sun, Masami Watanabe, Abai Xu, Motoo Araki, Yasutomo Nasu, Zhengyan Tang, Peng Huang

    Molecular human reproduction   27 ( 1 )   2021.1

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    Accumulating evidence has shown that Wnt signaling is deeply involved in male reproductive physiology, and malfunction of the signal path can cause pathological changes in genital organs and sperm cells. These abnormalities are diverse in manifestation and have been constantly found in the knockout models of Wnt studies. Nevertheless, most of the research solely focused on a certain factor in the Wnt pathway, and there are few reports on the overall relation between Wnt signals and male reproductive physiology. In our review, Wnt findings relating to the reproductive system were sought and summarized in terms of Wnt ligands, Wnt receptors, Wnt intracellular signals and Wnt regulators. By sorting out and integrating relevant functions, as well as underlining the controversies among different reports, our review aims to offer an overview of Wnt signaling in male reproductive physiology and pathology for further mechanistic studies.

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  • The role of Wnt signaling in male reproductive physiology and pathology. International journal

    Ruizhi Xue, Wenfeng Lin, Jingkai Sun, Masami Watanabe, Abai Xu, Motto Akira, Yasutomo Nasu, Zhengyan Tang, Peng Huang

    Molecular human reproduction   2021.1

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    Accumulating evidence has shown that Wnt signaling is deeply involved in male reproductive physiology, and malfunction of the signal path can cause pathological changes in genital organs and sperm cells. These abnormalities are diverse in manifestation and have been constantly found in the knockout models of Wnt studies. Nevertheless, most of the research solely focused on a certain factor in the Wnt pathway, and there are few reports on the overall relation between Wnt signals and male reproductive physiology. In our review, Wnt findings relating to the reproductive system were sought and summarized in terms of Wnt ligands, Wnt receptors, Wnt intracellular signals and Wnt regulators. By sorting out and integrating relevant functions, as well as underlining the controversies among different reports, our review aims to offer an overview of Wnt signaling in male reproductive physiology and pathology for further mechanistic studies.

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  • Long-term ureteroscopic management of upper tract urothelial carcinoma: 28-year single-centre experience. International journal

    Yuki Maruyama, Motoo Araki, Koichiro Wada, Kasumi Yoshinaga, Yosuke Mitsui, Takuya Sadahira, Shingo Nishimura, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Manoj Monga, Yasutomo Nasu, Hiromi Kumon

    Japanese journal of clinical oncology   51 ( 1 )   130 - 137   2021.1

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    BACKGROUND: Long-term survival outcomes of patients who undergo endoscopic management of non-invasive upper tract urothelial carcinoma remain uncertain. The longest mean follow-up period in previous studies was 6.1 years. This study reports the long-term outcomes of patients with upper tract urothelial carcinoma who underwent ureteroscopic ablation at a single institution over a 28-year period. METHODS: We identified all patients who underwent ureteroscopic management of upper tract urothelial carcinoma as their primary treatment at our institution between January 1991 and April 2011. Survival outcomes, including overall survival, cancer-specific survival, upper-tract recurrence-free survival and renal unit survival, were estimated using Kaplan-Meier methodology. RESULTS: A total of 15 patients underwent endoscopic management, with a mean age at diagnosis of 66 years. All patients underwent ureteroscopy, and biopsy-confirmed pathology was obtained. Median (range; mean) follow-up was 11.7 (2.3-20.9, 11.9) years. Upper tract recurrence occurred in 87% (n = 13) of patients. Twenty percent (n = 3) of patients proceeded to nephroureterectomy. The estimated cancer-specific survival rate was 93% at 5, 10, 15 and 20 years. Estimated overall survival rates were 86, 80, 54 and 20% at 5, 10, 15 and 20 years. Only one patient experienced cancer-specific mortality. The estimated mean and median overall survival times were 14.5 and 16.6 years, respectively. The estimated mean cancer-specific survival time was not reached. CONCLUSIONS: Although upper tract recurrence is common, endoscopic management of non-invasive upper tract urothelial carcinoma provides a 90% cancer-specific survival rate at 20 years in selected patients.

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  • Discovery and Validation of Nitroxoline as a Novel STAT3 Inhibitor in Drug-resistant Urothelial Bladder Cancer. International coauthorship International journal

    Wenfeng Lin, Jingkai Sun, Takuya Sadahira, Naijin Xu, Koichiro Wada, Chunxiao Liu, Motoo Araki, Abai Xu, Masami Watanabe, Yasutomo Nasu, Peng Huang

    International journal of biological sciences   17 ( 12 )   3255 - 3267   2021

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    Repeated cycles of first-line chemotherapy drugs such as doxorubicin (DOX) and cisplatin (CIS) trigger frequent chemoresistance in recurrent urothelial bladder cancer (UBC). Nitroxoline (NTX), an antibiotic to treat urinary tract infections, has been recently repurposed for cancer treatment. Here we aimed to investigate whether NTX suppresses drug-resistant UBC and its molecular mechanism. The drug-resistant cell lines T24/DOX and T24/CIS were established by continual exposure of parental cell line T24 to DOX and CIS, respectively. T24/DOX and T24/CIS cells were resistant to DOX and CIS, respectively, but they were sensitive to NTX time- and dose-dependently. Overexpressions of STAT3 and P-glycoprotein (P-gp) were identified in T24/DOX and T24/CIS, which could be reversed by NTX. Western blot revealed that NTX downregulated p-STAT3, c-Myc, Cyclin D1, CDK4, CDK6, Bcl-xL, Mcl-1, and Survivin, which were further confirmed by Stattic, a selective STAT3 inhibitor. In vivo, NTX exhibited the significant anti-tumor effect in T24/DOX and T24/CIS tumor-bearing mice. These results suggested that NTX-induced P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC were mediated by inhibition of STAT3 signaling. Our findings repurpose NTX as a novel STAT3 inhibitor to induce P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC.

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  • Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment. International coauthorship International journal

    Wenfeng Lin, Chaoming Li, Naijin Xu, Masami Watanabe, Ruizhi Xue, Abai Xu, Motoo Araki, Ruifen Sun, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    International journal of nanomedicine   16   2775 - 2787   2021

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    Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9±1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96±1.88)% compared with (0.99±0.10)% in PBS group, revealing the enhanced immune response against PCa. Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.

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  • A Clinical Trial Evaluating the Usefulness of Tailored Antimicrobial Prophylaxis Using Rectal-culture Screening Media Prior to Transrectal Prostate Biopsy: A Multicenter, Randomized Controlled Trial.

    Takuya Sadahira, Yuki Maruyama, Yoshiki Hiyama, Hiroyuki Kitano, Hiroki Yamada, Takayuki Goto, Tsubasa Kondo, Katsumi Shigemura, Yosuke Mitsui, Takehiro Iwata, Kohei Edamura, Motoo Araki, Masami Watanabe, Tadasu Takenaka, Jun Teishima, Yasuyoshi Miyata, Kiyohito Ishikawa, Ei-Ichiro Takaoka, Jun Miyazaki, Satoshi Takahashi, Naoya Masumori, Hiroshi Kiyota, Masato Fujisawa, Shingo Yamamoto, Takafumi Sakuma, Norihiro Kusumi, Takaharu Ichikawa, Toyohiko Watanabe, Yoshitsugu Nasu, Masaya Tsugawa, Yasutomo Nasu, Koichiro Wada

    Acta medica Okayama   75 ( 5 )   663 - 667   2021

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    The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants.

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  • Medical uses for phenol in the urinary tract: A possible forgotten treatment (Review). International journal

    Takuya Sadahira, Yuki Maruyama, Toyohiko Watanabe, Takanori Sekito, Yosuke Mitsui, Koichiro Wada, Motoo Araki, Masami Watanabe

    Medicine international   1 ( 4 )   13 - 13   2021

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    Phenol is a chemical compound that was first used medically as an antiseptic. At low concentrations, phenol exerts local anesthetic effects achieved through denervation; at high concentrations, it exerts a potent protein-denaturing effect that induces apoptosis. Phenol injection therapy has a long history of use in urology. It is reportedly effective for hemorrhagic cystitis, benign prostate hyperplasia, overactive bladder, hydrocele, bladder tumors, interstitial cystitis and other benign urologic diseases, and it is also used as a tool to decrease bleeding during prostate surgery. The present review article summarizes the medical applications of phenol in urological field. The articles available on the medical uses of phenol are primarily older and retrospective, involving small numbers of patients. In the absence of comparative studies with other treatments, it is impossible to determine the relative benefit of phenol. However, the treatment outcomes of phenol injection are fairly well-established. Phenol therapy may be an option for patients who are poor candidates for invasive treatment. Further studies are required, however, as are improvements in the injection technique to reduce the rate of complications.

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  • Novel canine isocitrate dehydrogenase 1 mutation Y208C attenuates dimerization ability. International journal

    Shota Kawakami, Masaki Michishita, Motoharu Sakaue, Masami Morimatsu, Mitsuki Uemura, Nobuaki Kashiwagi, Marika Maeda, Yukino Machida, Daigo Azakami, Ai S Egusa, Eri Onozawa, Katsumi Ishioka, Masami Watanabe, Yoshikazu Tanaka, Toshinori Omi, Kazuhiko Ochiai

    Oncology letters   20 ( 6 )   351 - 351   2020.12

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    Isocitrate dehydrogenase 1 (IDH1) mutations are common in gliomas, acute myeloid leukemia, and chondrosarcoma. The mutation 'hotspot' is a single arginine residue, R132. The R132H mutant of IDH1 produces the 2-hydroxyglutarate (2-HG) carcinogen from α-ketoglutarate (α-KG). The reduction of α-KG induces the accumulation of hypoxia-inducible factor-1α subunit (HIF-1α) in the cytosol, which is a predisposing factor for carcinogenesis. R132H is the most common IDH1 mutation in humans, but mutations at the R132 residue can also occur in tumor tissues of dogs. The current study reported the discovery of a novel Tyr208Cys (Y208C) mutation in canine IDH1 (cIDH1), which was isolated from 2 of 45 canine chondrosarcoma cases. As the genomic DNA isolated from chondrosarcoma tissue was mutated, but that isolated from blood was not, Y208C mutations were considered to be spontaneous somatic mutations. The isocitrate dehydrogenase activity of the Y208C mutant was attenuated compared with that of wild-type (WT) cIDH1, but the attenuation of Y208C was less intense than that of the R132H mutation. The induction of HIF-1α response element activity and cell retention of HIF-1α were not increased by Y208C overexpression. In silico and cell biological analysis of IDH1 dimerization revealed that the Y208C mutation, but not the R132H mutation, attenuated binding activity with WT cIDH1. These data suggested that the attenuation of dimerization by the Y208C mutation may cause tumorigenesis through different mechanisms other than via 2-HG production by the IDH1 R132 mutation.

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  • Low-dose rituximab induction therapy is effective in immunological high-risk renal transplantation without increasing cytomegalovirus infection. International journal

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Haruhito Adam Uchida, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   27 ( 12 )   1136 - 1142   2020.12

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    OBJECTIVES: To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation. METHODS: A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus. RESULTS: There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53 vs 37 years, respectively; P = 0.04), but not in sex (male 64% vs 65%, P = 1.00), focal segmental glomerulosclerosis (3% vs 0%, P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12% vs 18%, P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10% vs 24%, P = 0.22), including fever ≥38°C (5% vs 12%, P = 0.31) and gastrointestinal symptoms (5% vs 12%, P = 0.31), and the 5-year survival rates of death-censored graft loss (90% vs 83%, P = 0.43) did not differ significantly between groups. CONCLUSIONS: Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.

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  • Preservation of pancreas in the University of Wisconsin solution supplemented with AP39 reduces reactive oxygen species production and improves islet graft function. International journal

    Kai Nishime, Chika Miyagi-Shiohira, Kazuho Kuwae, Yoshihito Tamaki, Tasuku Yonaha, Mayuko Sakai-Yonaha, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons   21 ( 8 )   2698 - 2708   2020.11

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    Ischemia-reperfusion injury (IRI) results in increased rates of delayed graft function and early graft loss. It has recently been reported that hydrogen sulfide (H2 S) protects organ grafts against prolonged IRI. Here, we investigated whether the preservation of pancreas in University of Wisconsin (UW) solution supplemented with AP39, which is a mitochondrial-targeted H2 S donor, protected pancreatic islets against IRI and improved islet function. Porcine pancreata were preserved in the UW solution with AP39 (UW + AP39) or the vehicle (UW) for 18 h, followed by islet isolation. The islet yields before and after purification were significantly higher in the UW + AP39 group than in the UW group. The islets isolated from the pancreas preserved in UW + AP39 exhibited significantly decreased levels of reactive oxygen species (ROS) production and a significantly increased mitochondrial membrane potential as compared to the islets isolated from the pancreas preserved in the vehicle. We found that the pancreas preserved in UW + AP39 improved the outcome of islet transplantation in streptozotocin-induced diabetic mice. These results suggest that the preservation of pancreas in UW + AP39 protects the islet grafts against IRI and could thus serve as a novel clinical strategy for improving islet transplantation outcomes.

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  • Kyoto probe-1 reveals phenotypic differences between mouse ES cells and iTS-P cells. International journal

    Chika Miyagi-Shiohira, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Scientific reports   10 ( 1 )   18084 - 18084   2020.10

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    Kyoto probe 1 (KP-1) rapidly distinguishes between human ES/iPS (hES/iPS) cells and their differentiated cells. Recently, we generated induced tissue-specific stem cells from pancreas (iTS-P cells) using reprogramming factors and tissue-specific selection. The iTS-P cells have self-renewal potential, and subcutaneously transplanting them into immunodeficient mice did not generate teratomas. In this study, we applied KP-1 to analyze mouse ES (mES) cells and mouse iTS-P (miTS-P) cells. KP-1 completely stained mES cells in colonies, but only miTS-P cells at the edge of a colony. This difference was caused by cell type-specific expression of different ABC transporters. These finding suggest that KP-1 will be useful for distinguishing between iPS and iTS-P cells.

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  • Dynamin 1 is important for microtubule organization and stabilization in glomerular podocytes. International journal

    The Mon La, Hiromi Tachibana, Shun-Ai Li, Tadashi Abe, Sayaka Seiriki, Hikaru Nagaoka, Eizo Takashima, Tetsuya Takeda, Daisuke Ogawa, Shin-Ichi Makino, Katsuhiko Asanuma, Masami Watanabe, Xuefei Tian, Shuta Ishibe, Ayuko Sakane, Takuya Sasaki, Jun Wada, Kohji Takei, Hiroshi Yamada

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology   34 ( 12 )   16449 - 16463   2020.10

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    Dynamin 1 is a neuronal endocytic protein that participates in vesicle formation by scission of invaginated membranes. Dynamin 1 is also expressed in the kidney; however, its physiological significance to this organ remains unknown. Here, we show that dynamin 1 is crucial for microtubule organization and stabilization in glomerular podocytes. By immunofluorescence and immunoelectron microscopy, dynamin 1 was concentrated at microtubules at primary processes in rat podocytes. By immunofluorescence of differentiated mouse podocytes (MPCs), dynamin 1 was often colocalized with microtubule bundles, which radially arranged toward periphery of expanded podocyte. In dynamin 1-depleted MPCs by RNAi, α-tubulin showed a dispersed linear filament-like localization, and microtubule bundles were rarely observed. Furthermore, dynamin 1 depletion resulted in the formation of discontinuous, short acetylated α-tubulin fragments, and the decrease of microtubule-rich protrusions. Dynamins 1 and 2 double-knockout podocytes showed dispersed acetylated α-tubulin and rare protrusions. In vitro, dynamin 1 polymerized around microtubules and cross-linked them into bundles, and increased their resistance to the disassembly-inducing reagents Ca2+ and podophyllotoxin. In addition, overexpression and depletion of dynamin 1 in MPCs increased and decreased the nocodazole resistance of microtubules, respectively. These results suggest that dynamin 1 supports the microtubule bundle formation and participates in the stabilization of microtubules.

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  • Internalization of AMPA-type Glutamate Receptor in the MIN6 Pancreatic β-cell Line. Reviewed

    The Mon La, Hiroshi Yamada, Sayaka Seiriki, Shun-Ai Li, Kenshiro Fujise, Natsuho Katsumi, Tadashi Abe, Masami Watanabe, Kohji Takei

    Cell structure and function   45 ( 2 )   121 - 130   2020.8

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    The activity of AMPA-type glutamate receptor is involved in insulin release from pancreatic β-cells. However, the mechanism and dynamics that underlie AMPA receptor-mediated insulin release in β-cells is largely unknown. Here, we show that AMPA induces internalization of glutamate receptor 2/3 (GluR2/3), AMPA receptor subtype, in the mouse β-cell line MIN6. Immunofluorescence experiments showed that GluR2/3 appeared as fine dots that were distributed throughout MIN6 cells. Intracellular GluR2/3 co-localized with AP2 and clathrin, markers for clathrin-coated pits and vesicles. Immunoelectron microscopy revealed that GluR2/3 was also localized at plasma membrane. Surface biotinylation and immunofluorescence measurements showed that addition of AMPA caused an approximate 1.8-fold increase in GluR2/3 internalization under low-glucose conditions. Furthermore, internalized GluR2 largely co-localized with EEA1, an early endosome marker. In addition, GluR2/3 co-immunoprecipitated with cortactin, a F-actin binding protein. Depletion of cortactin by RNAi in MIN6 cells altered the intracellular distribution of GluR2/3, suggesting that cortactin is involved in internalization of GluR2/3 in MIN6 cells. Taken together, our results suggest that pancreatic β-cells adjust the amount of AMPA-type GluR2/3 on the cell surface to regulate the receptive capability of the cell for glutamate.Key words: endocytosis, GluR2, AMPA, cortactin, MIN6.

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  • Mutations in the C1 element of the insulin promoter lead to diabetic phenotypes in homozygous mice. International journal

    Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Takao Kinjo, Issei Saitoh, Masami Watanabe

    Communications biology   3 ( 1 )   309 - 309   2020.6

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    Genome editing technologies such as CRISPR-Cas9 are widely used to establish causal associations between mutations and phenotypes. However, CRISPR-Cas9 is rarely used to analyze promoter regions. The insulin promoter region (approximately 1,000 bp) directs β cell-specific expression of insulin, which in vitro studies show is regulated by ubiquitous, as well as pancreatic, β cell-specific transcription factors. However, we are unaware of any confirmatory in vivo studies. Here, we used CRISPR-Cas9 technology to generate mice with mutations in the promoter regions of the insulin I (Ins1) and II (Ins2) genes. We generated 4 homozygous diabetic mice with 2 distinct mutations in the highly conserved C1 elements in each of the Ins1 and Ins2 promoters (3 deletions and 1 replacement in total). Remarkably, all mice with homozygous or heterozygous mutations in other loci were not diabetic. Thus, the C1 element in mice is required for Ins transcription in vivo.

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  • Dkk3/REIC, an N-glycosylated Protein, Is a Physiological Endoplasmic Reticulum Stress Inducer in the Mouse Adrenal Gland.

    Hirofumi Fujita, Tetsuya Bando, Seiichi Oyadomari, Kazuhiko Ochiai, Masami Watanabe, Hiromi Kumon, Hideyo Ohuchi

    Acta medica Okayama   74 ( 3 )   199 - 208   2020.6

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    Dickkopf 3 (Dkk3) is a secreted protein belonging to the Dkk family and encoded by the orthologous gene of REIC. Dkk3/REIC is expressed by mouse and human adrenal glands, but the understanding of its roles in this organ is still limited. To determine the functions of Dkk3 in the mouse adrenal gland, we first identified that the mouse Dkk3 protein is N-glycosylated in the adrenal gland as well as in the brain. We performed proteome analysis on adrenal glands from Dkk3-null mice, in which exons 5 and 6 of the Dkk3 gene are deleted. Twodimensional polyacrylamide gel electrophoresis of adrenal proteins from wild-type and Dkk3-null mice revealed 5 protein spots whose intensities were altered between the 2 genotypes. Mass spectrometry analysis of these spots identified binding immunoglobulin protein (BiP), an endoplasmic reticulum (ER) chaperone. To determine whether mouse Dkk3 is involved in the unfolded protein response (UPR), we carried out a reporter assay using ER-stress responsive elements. Forced expression of Dkk3 resulted in the induction of distinct levels of reporter expression, showing the UPR initiated by the ER membrane proteins of activating transcription factor 6 (ATF6) and inositol-requring enzyme 1 (IRE1). Thus, it is possible that Dkk3 is a physiological ER stressor in the mouse adrenal gland.

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  • Tumor suppressor REIC/Dkk‑3 and its interacting protein SGTA inhibit glucocorticoid receptor to nuclear transport Reviewed

    Takehiro Iwata, Takuya Sadahira, Kazuhiko Ochiai, Hideo Ueki, Takanori Sasaki, Peng Haung, Motoo Araki, Toyohiko Watanabe, Yasutomo Nasu, Masami Watanabe

    Experimental and Therapeutic Medicine   2020.5

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    DOI: 10.3892/etm.2020.8819

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  • Correlation between lumbar skeletal muscle size and urinary incontinence after radical prostatectomy. Reviewed International journal

    Yosuke Mitsui, Takuya Sadahira, Toyohiko Watanabe, Motoo Araki, Yuki Maruyama, Ryota Sato, Acosta Gonzalez Herik Rodrigo, Koichiro Wada, Masami Watanabe, Michael B Chancellor, Yasutomo Nasu

    Lower urinary tract symptoms   12 ( 3 )   245 - 252   2020.5

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    OBJECTIVES: Urinary incontinence is a major concern after radical prostatectomy because it can decrease quality of life. The aim of the present study was to explore the effect of preoperative skeletal muscle on urinary quality of life after robot-assisted radical prostatectomy. METHODS: A total of 762 patients underwent robot-assisted radical prostatectomy. Longitudinal health-related quality of life was evaluated using the Expanded Prostate Cancer Index Composite instrument. The skeletal muscle area at the level of the third lumbar vertebra was assessed preoperatively by computed tomography and was standardized to height to obtain the skeletal muscle index. Reduced skeletal muscle size (RSMS) was defined as a skeletal muscle index ≤ 53 or ≤ 43 cm2 /m2 in patients with a body mass index (BMI) ≥25 or < 25, respectively. RESULTS: A total of 301 patients were included in this study, of whom 91 were classified as having RSMS (30.2%). Non-RSMS patients exhibited better urinary function at 12 months (P = .012) and better urinary continence recovery at 2 weeks and 12 months (P = .033 and P = .014, respectively) after prostatectomy compared with RSMS patients. Univariate and multivariate analyses identified preoperative RSMS as a significant and independent predictor of urinary incontinence (odds ratio = 1.77, P = .028). CONCLUSIONS: Patients with RSMS had a lower urinary quality of life compared with non-RSMS patients after robot-assisted radical prostatectomy, and RSMS, independent of age or BMI, was predictive of postoperative urinary incontinence.

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  • Novel cell-permeable p38-MAPK inhibitor efficiently prevents porcine islet apoptosis and improves islet graft function. International journal

    Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Issei Saitoh, Masami Watanabe

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons   20 ( 5 )   1296 - 1308   2020.5

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    During islet transplantation, mitogen-activated protein kinase (MAPK) p38 is preferentially activated in response to the isolation of islets and the associated inflammation. Although therapeutic effects of p38 inhibitors are expected, the clinical application of small-molecule inhibitors of p38 is not recommended because of their serious adverse effects on the liver and central nervous system. Here we designed peptides to inhibit p38, which were derived from the sites on p38 that mediate binding to proteins such as MAPK kinases. Peptide 11R-p38I110 significantly inhibited the activation of p38. To evaluate the effects of 11R-p38I110 , porcine islets were incubated with 10 µmol/L 11R-p38I110 or a mutant form designated 11R-mp38I110 . After islet transplantation, blood glucose levels reached the normoglycemic range in 58.3% and 0% of diabetic mice treated with 11R-p38I110 or 11R-mp38I110 , respectively. These data suggest that 11R-p38I110 inhibited islet apoptosis and improved islet function. Peptide p38I110 is a noncompetitive inhibitor of ATP and targets a unique docking site. Therefore, 11R-p38I110 specifically inhibits p38 activation, which may avoid the adverse effects that have discouraged the clinical use of small-molecule inhibitors of p38. Moreover, our methodology to design "peptide inhibitors" could be used to design other inhibitors derived from the binding sites of proteins.

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  • Factors predicting pathological upgrading after prostatectomy in patients with Gleason grade group 1 prostate cancer based on opinion-matched biopsy specimens. Reviewed International journal

    Yuki Maruyama, Takuya Sadahira, Motoo Araki, Yosuke Mitsui, Koichiro Wada, Acosta Gonzalez Herik Rodrigo, Kazuaki Munetomo, Yasuyuki Kobayashi, Masami Watanabe, Hiroyuki Yanai, Toyohiko Watanabe, Yasutomo Nasu

    Molecular and clinical oncology   12 ( 4 )   384 - 389   2020.4

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    The present study investigated the concordance between Gleason scores assigned to prostate biopsy specimens by outside pathologists and a urological pathology expert, and determined the risk of upgrading between opinion-matched Gleason grade group (GGG) 1 biopsy specimens and radical prostatectomy specimens. Between January 2012 and May 2018, 733 patients underwent robot-assisted radical prostatectomy. Patients whose original biopsy specimens from outside hospitals were reviewed by a urological pathology expert Okayama University Hospital were included. Patients who had received neoadjuvant hormonal therapy were excluded. Logistic regression analysis was used to identify predictors of upgrading among GGG 1 diagnoses. A total of 403 patients were included in the present study. Agreement in GGG between initial and second-opinion diagnoses was present in 256 cases (63.5%). Although opinion-matched cases improved concordance between biopsy and prostatectomy specimen GGG compared with single-opinion cases (initial, 35.2%; second-opinion, 36.5%; matched, 41.4%), 71% (56/79) of cases classified as GGG 1 were upgraded after prostatectomy. Multivariate analysis revealed that prostate-specific antigen density and Prostate Imaging Reporting and Data System version 2 score were significant predictors of upgrading (odds ratio, 1.10; P=0.01; and odds ratio, 1.88; P=0.03, respectively). In conclusion, the GGG concordance rate between needle-core biopsy and radical prostatectomy specimens was higher in opinion-matched cases; however, 71% of opinion-matched GGG1 cases were upgraded after robot-assisted radical prostatectomy. Urologists should propose treatment strategies or further biopsy rather than active surveillance for patients with GGG1 and a high PSAD and/or PI-RADS score.

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  • Quality of Life and Mental Satisfaction Improve Slowly in Preemptive Kidney Transplantation Compared With Nonpreemptive Kidney Transplantation. Reviewed International journal

    Yosuke Mitsui, Motoo Araki, Yuki Maruyama, Kasumi Yoshinaga, Takuya Sadahira, Koichiro Wada, Katsuyuki Tanabe, Masashi Kitagawa, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Transplantation proceedings   52 ( 3 )   740 - 747   2020.3

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    BACKGROUND AND AIMS: Preemptive kidney transplantation (PEKT) is recognized as the best therapy to avoid dialysis. However, it is not clear whether PEKT recipients experience an improvement in quality of life (QoL) after kidney transplantation (KT) that exceeds that of non-PEKT recipients, since PEKT recipients have not experienced the heavy burden of dialysis. The aim of this study was to compare the changes in QoL for PEKT and non-PEKT recipients following transplantation. METHODS: Patients included in this study underwent living donor KT in our hospital. We excluded patients with incomplete SF-36 scores and with factors that could affect QoL, such as complications or rejection. QoL was assessed by the Short Form 36-Item Health Survey version 2.0 preoperatively and 3 and 12 months postoperatively. RESULTS: Eighty-eight patients underwent living donor KT in our hospital. Twelve PEKT and 20 non-PEKT recipients were enrolled in this retrospective study. In the non-PEKT group, both the physical and mental domain scores dramatically improved from baseline at 3 months, and remained at a similar level at 12 months. In contrast, in the PEKT group, only 1 domain of the physical and mental score improved at 3 months, and the social functioning score gradually improved at 12 months. Although the mental component score showed significant improvement in the non-PEKT group, it did not change in the PEKT group. CONCLUSIONS: The improvement of QoL after transplantation is more evident in the non-PEKT group. PEKT recipients have less mental satisfaction than non-PEKT recipients.

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  • Robotic Renal Autotransplantation: A Feasibility Study in a Porcine Model. Reviewed

    Risa Kubota, Motoo Araki, Koichiro Wada, Kasumi Kawamura, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Yuichi Ariyoshi, Takehiro Iwata, Shingo Nishimura, Atsushi Takamoto, Tomoko Sako, Kohei Edamura, Yasuyuki Kobayashi, Yuzuki Kano, Masashi Kitagawa, Katsuyuki Tanabe, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Acta medica Okayama   74 ( 1 )   53 - 58   2020.2

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    We investigated the feasibility of robotic renal autotransplantation (RAT) in a porcine model to reduce invasiveness of RAT. Five pigs underwent robotic RAT using the da Vinci® robotic system. A robotic left nephrectomy was performed in all cases. Robotic RAT was performed on the left side in all but one case. Four ports were used. In 3 cases, the kidney was taken out through the GelPort® and irrigated on ice with Ringer's solution. In 2 cases, a complete intracorporeal robotic RAT was performed. An end-to-side anastomosis was performed between the renal vein and the external iliac vein and between the renal artery and the external iliac artery. Ureteroneocystostomy was also performed in 2 cases. All cases were performed robotically without open conversion. The median (IQR) console time was 3.1 (0.7) h, and the operative time was 3.8 (1.1) h. The estimated blood loss was 30 (0) ml. The warm ischemia time was 4.0 (0.2) min, and the cold ischemia time was 97 (17) min. Intracorporeal transarterial hypothermic renal perfusion was feasible in the 2 complete intracorporeal robotic RAT cases by using a perfusion catheter through a laparoscopic port. Robotic RAT has the potential to be a new minimally invasive substitute for conventional open surgery.

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  • Promising Gene Therapy Using an Adenovirus Vector Carrying REIC/Dkk-3 Gene for the Treatment of Biliary Cancer. Reviewed International journal

    Emi Tanaka, Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Atsushi Ohyama, Masaya Iwamuro, Masami Watanabe, Hiromi Kumon, Hiroyuki Okada

    Current gene therapy   20 ( 1 )   64 - 70   2020

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    BACKGROUND: We previously demonstrated that the reduced expression in immortalized cells (REIC)/dikkopf-3 (Dkk-3) gene was downregulated in various malignant tumors, and that an adenovirus vector carrying the REIC/Dkk-3 gene, termed Ad-REIC induced cancer-selective apoptosis in pancreatic cancer and hepatocellular carcinoma. OBJECTIVE: In this study, we examined the therapeutic effects of Ad-REIC in biliary cancer using a second- generation Ad-REIC (Ad-SGE-REIC). METHODS: Human biliary cancer cell lines (G-415, TFK-1) were used in this study. The cell viability and apoptotic effect of Ad-SGE-REIC were assessed in vitro using an MTT assay and Hoechst staining. The anti-tumor effect in vivo was assessed in a mouse xenograft model. We also assessed the therapeutic effects of Ad-SGE-REIC therapy with cisplatin. Cell signaling was assessed by Western blotting. RESULTS: Ad-SGE-REIC reduced cell viability, and induced apoptosis in biliary cancer cell lines via the activation of the c-Jun N-terminal kinase pathway. Ad-SGE-REIC also inhibited tumor growth in a mouse xenograft model. This effect was further enhanced in combination with cisplatin. CONCLUSION: Ad-SGE-REIC induced apoptosis and inhibited tumor growth in biliary cancer cells. REIC/Dkk-3 gene therapy using Ad-SGE-REIC is an attractive therapeutic tool for biliary cancer.

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  • Nitroxoline inhibits bladder cancer progression by reversing EMT process and enhancing anti-tumor immunity. International coauthorship International journal

    Naijin Xu, Wenfeng Lin, Jingkai Sun, Takuya Sadahira, Abai Xu, Masami Watanabe, Kai Guo, Motoo Araki, Gonghui Li, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    Journal of Cancer   11 ( 22 )   6633 - 6641   2020

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    Nitroxoline is considered to be an effective treatment for the urinary tract infections. Recently, it has been found to be effective against several cancers. However, few studies have examined the anti-tumor activity of nitroxoline in bladder cancer. The purpose of the study was to reveal the possible mechanisms how nitroxoline inhibited bladder cancer progression. In vitro assay, we demonstrated that nitroxoline inhibited bladder cancer cell growth and migration in a concentration-related manner. Western blot analysis demonstrated that nitroxoline downregulated the expressions of epithelial mesenchymal transition (EMT)-related proteins. Furthermore, treatment with nitroxoline in the C3H/He mice bladder cancer subcutaneous model resulted in significant inhibition of tumor growth. Moreover, the percentage of myeloid-derived suppressor cells (MDSC) in peripheral blood cells significantly decreased after treatment of nitroxoline. Taken together, our results suggested that nitroxoline may be used as a potential drug for bladder cancer.

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  • Preventive efficacy and safety of lactobacillus vaginal suppositories in women with recurrent cystitis: A phase 2 study Reviewed

    Sadahira T, Wada K, Ishii A, Maruyama Y, Iwata T, Araki M, Watanabe M, Watanabe T, Nasu Y

    Eur Urol Open Sci   19 ( 2 )   2036 - 2037   2020

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  • Clinical pharmacokinetics of oral azithromycin in epididymal tissue. Reviewed International journal

    Sadahira T, Wada K, Ikawa K, Morikawa N, Mitsui M, Araki M, Fujiyoshi M, Ishii A, Watanabe M, Watanabe T, Nasu Y

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 10 )   832 - 834   2019.10

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    OBJECTIVES: Chlamydia trachomatis is one of the major pathogens causing acute epididymitis. Azithromycin (AZM) has a good efficacy against C. trachomatis; however, the ability of AZM to penetrate into human epididymal tissue has not yet been fully elucidated. Here, we examined the appropriate dosage of oral AZM for human epididymal tissue by site-specific pharmacokinetic/pharmacodynamic (PK/PD) analysis. METHODS: Patients with prostate cancer who underwent orchiectomy were included in this study. All patients received a 1-g dose of AZM before orchiectomy. Both epididymal tissue and blood samples were collected during surgery, and the drug concentrations were measured by high-performance liquid chromatography. All concentration-time data were analyzed with a three-compartment model with first-order absorption and elimination processes to simulate AZM concentrations in serum and epididymal tissue. RESULTS: A total of 10 patients were enrolled in the current study. For the observed values, the ratio of the epididymal concentration to the serum concentration was 5.13 ± 3.71 (mean ± standard deviation). For the simulated values, the maximum concentrations were 0.64 μg/mL at 2.42 h in serum and 1.96 μg/g at 4.10 h in epididymal tissue. The 24-h concentrations were 0.239 μg/mL in serum and 0.795 μg/g in epididymal tissue. CONCLUSIONS: The penetration of oral AZM into human epididymal tissue was examined to assess the potential application of AZM for the treatment of acute epididymitis. Based on the previous reports mentioning drug-susceptibility of C. trachomatis, multiple doses of oral AZM 1 g would be recommended for epididymitis based on the site-specific PK/PD.

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  • Excellent Islet Yields after 18-h Porcine Pancreas Preservation by Ductal Injection, Pancreas Preservation with MK Solution, Bottle Purification, and Islet Purification Using Iodixanol with UW Solution and Iodixanol with MK Solution. Reviewed International journal

    Kuwae K, Miyagi-Shiohira C, Hamada E, Tamaki Y, Nishime K, Sakai M, Yonaha T, Makishi E, Saitoh I, Watanabe M, Noguchi H

    Journal of clinical medicine   8 ( 10 )   2019.9

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    Successful islet isolation is the key to successful islet transplantation. Our group recently modified the islet isolation protocol to include pancreatic ductal injection of the preservation solution, pancreas storage in modified extracellular-type trehalose-containing Kyoto (MK) solution, and use of an iodixanol-based purification solution and bottle purification. In this study, we applied these methods to porcine islet isolation after 18-h pancreas preservation and compared two solutions with different compositions in bottle purification. Islet yield before purification was 651,661 ± 157,719 islet equivalents (IE) and 5576 ± 1538 IE/g pancreas weight. An IU solution was made by adding iodixanol to University of Wisconsin solution and an IK solution was made by adding iodixanol to MK solution. The efficacy of the two solutions for islet isolation was compared. There were no significant differences between the two purification methods with regard to islet yield, survival rate, purity, score, or stimulation index. These results indicate that our isolation protocol produces efficient islet yields from prolonged cold-stored pancreas and that IU and IK solutions are equally useful for islet purification.

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  • The canine RAD51 mutation leads to the attenuation of interaction with PALB2. Reviewed International journal

    Uemura M, Ochiai K, Morimatsu M, Michishita M, Onozawa E, Azakami D, Uno Y, Yoshikawa Y, Sasaki T, Watanabe M, Omi T

    Veterinary and comparative oncology   18 ( 2 )   247 - 255   2019.9

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    RAD51 forms a complex with BRCA2 and plays a central role in the DNA damage response pathway that is associated with homologous recombination. The structures of RAD51 and its homologues are highly conserved from prokaryotes to higher eukaryotes. Although a large number of BRCA2 mutations have been reported, there are only a few reports on the mutations of RAD51, which have been shown in humans and dogs. However, several mutations of canine RAD51 were identified from mammary gland tumour tissues in a recent study. Some of these mutations seem to have an influence on the homo-oligomerization or interaction with "Partner and localizer of BRCA2" (PALB2). In this study, we cloned the canine PALB2 homologue and investigated the effect on its interaction with the RAD51 mutants to evaluate the alteration in the function of RAD51 mutants. The A209S and T225S mutants of RAD51 show an attenuation of the interaction between RAD51 and PALB2. These results indicate that the canine RAD51 mutations can potentially alter the homologous recombination pathways in response to DNA damage in dogs.

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  • Metastatic ureteral tumor arising from gastrointestinal cancer: A report of two cases

    Kasumi Kawamura, Motoo Araki, Takuya Sadahira, Yuki Maruyama, Yosuke Mitsui, Shingo Nishimura, Atsushi Takamoto, Koichiro Wada, Ryuta Tanimoto, Morito Sugimoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu, Hiroyuki Yanai

    Nishinihon Journal of Urology   81 ( 4 )   461 - 466   2019.8

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    We report two cases where gastrointestinal cancer gave rise to a metastatic ureteral tumor. Case one was a 64-year-old man who was operated on for descending colon cancer in September, 2007. In 2014, he was referred to our hospital because computed tomography (CT) scan showed a tumor of the right ureter. Ureteroscopic biopsy showed a metastatic ureteral tumor arising from descending colon cancer. The patient underwent open tumor resection. Transurethral resection of a bladder tumor (TUR- BT) was required three times for treatment of tumor recurrence from the ureteral stump in an effort to control gross hematuria Case two was a 62-year-old man who underwent pylorus-preserving gastrectomy for gastric cancer in December, 2014. Follow-up CT showed right hydronephrosis and thickening of the right ureteral wall in 2017. Selective urine cytology of the right ureter revealed urothelial carcinoma, class V. Ureteroscopic biopsy of the right ureter revealed invasive urothelial carcinoma. The patient underwent retroperitoneal laparoscopic nephroureterectomy. Histological examination revealed the right ureteral tumor to be metastasis of gastric cancer.

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  • Robotic renal auto transplantation

    Motoo Araki, Koichiro Wada, Shingo Nishimura, Risa Kubota, Kasumi Kawamura, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Atsushi Takamoto, Tomoko Sako, Kohei Edamura, Yasuyuki Kobayashi, Ayano Ishii, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Nishinihon Journal of Urology   81 ( 3 )   314 - 320   2019.6

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    Renal autotransplantation (RAT) is a great surgical procedure for renal preservation, however it is underutilized due to its invasiveness. Robotic RATx has been in use since 2014. We conducted robotic RATx following a feasibility study using a porcine model. A 38-year-old woman with left ureteral stenosis was referred to us for urinary tract reconstruction. She had undergone an emergency Caesarean section for intraperitoneal bleeding secondary to left ovarian rupture four years earlier. After the surgery, she developed hypovolemic shock and disseminated intravascular coagulation (DIC) due to postoperative bleeding. Left internal iliac artery embolization saved her life. However, it resulted in a left ureteral stenosis measuring 2.7 cm that was located 5 cm from the left ureteral orifice, which required chronic ureteral stent exchange. Neither balloon dilation nor laser incision was successful. In addition, retrograde pyelography showed a possible left ureteropelvic junction obstruction. The patient was hesitant about the surgery because of its invasiveness. However, four years later, the patient elected to undergo robotic RATx. To date, only four cases of robotic RATx have been reported, including the current case. The indication of all four cases was extensive ureteral stenosis. Ileal ureter is frequently used for the treatment of extensive ureteral stenosis, but it can entail many problems including urine reabsorption resulting in metabolic acidosis. Ileal ureter is contraindicated for patients with a serum creatinine (sCr) level greater than 2 mg/dl. Even if sCr is less than 2 mg/dl, it is questionable whether sCr will remain less than 2 mg/ dl for the remainder of someone's life. Boari flap can give rise to vesicoureteral reflux causing urinary tract infection. RATx does not have those problems. Robotic RATx is a new, minimally invasive approach to renal preservation.

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  • Comparison of the predictive value among inflammation-based scoring systems for bleomycin pulmonary toxicity in patients with germ cell tumors. Reviewed International journal

    Maruyama Y, Sadahira T, Araki M, Mitsui Y, Wada K, Edamura K, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    International journal of urology : official journal of the Japanese Urological Association   26 ( 8 )   813 - 819   2019.5

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    OBJECTIVE: To compare the predictive value of pretreatment inflammation-based scoring systems in patients with germ cell tumors receiving first-line bleomycin-based chemotherapy. METHODS: Retrospectively, we evaluated 57 patients with germ cell tumors. Bleomycin pulmonary toxicity was defined as the presence of asymptomatic decline in pulmonary function tests, pulmonary symptoms or interstitial pneumonia on computed tomography in the absence of infection. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, albumin-to-globulin ratio, Prognostic Nutritional Index, Glasgow Prognostic Score and C-reactive protein were measured in all patients. To assess the predictive ability of each scoring system, the area under the receiver operating characteristic curve was calculated, and multivariate analysis was carried out to identify the predictive scores associated with bleomycin pulmonary toxicity. RESULTS: Of the 57 patients, 15 patients developed bleomycin pulmonary toxicity. The neutrophil-to-lymphocyte ratio had the highest area under the curve value (0.763) of all inflammation-based scoring systems, followed by the Prognostic Nutritional Index (0.749). In multivariate analysis, the neutrophil-to-lymphocyte ratio (odds ratio 11.5; P = 0.009) and Prognostic Nutritional Index (odds ratio 9.07; P = 0.013) were independently associated with development of bleomycin pulmonary toxicity. As these two independent markers were combined, the area under the curve achieved the highest value (0.822). CONCLUSIONS: The present study shows that the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index are independent risk factors for development of bleomycin pulmonary toxicity. The combination of the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index seems to have superior predictive value compared with other inflammation-based scoring systems.

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  • Comparison of longitudinal health-related quality-of-life outcomes between anterior and posterior surgical approaches to robot-assisted radical prostatectomy. Reviewed International journal

    Maruyama Y, Sadahira T, Araki M, Mitsui Y, Wada K, Tanimoto R, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Journal of robotic surgery   14 ( 2 )   255 - 260   2019.5

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    Increasingly, studies have explored health-related quality-of-life (HRQOL) outcomes after robot-assisted radical prostatectomy (RARP). Nevertheless, no study has compared differences between anterior and posterior surgical approaches. The aim of this study is to assess differences of HRQOL following these two surgical approaches. From January 2012 to September 2017, 653 patients underwent RARP at our institution. We included patients who underwent operations by three experienced surgeons with interchangeability of role as console operator, and who could evaluate preoperatively the Expanded Prostate Cancer Index Composite (EPIC) score. Patients treated with neoadjuvant hormonal therapy were excluded. HRQOL was assessed using the EPIC score, and the questionnaire was administered at 6 timepoints: the baseline survey was conducted within 3 months before the surgery, and follow-up surveys were conducted at 2 weeks, 1, 3, 6, and 12 months after surgery. We defined the minimal clinically important difference (MCID) as half the standard deviation of the baseline score for each domain. A total of 201 patients were included in this retrospective study. Of these, 146 patients underwent RARP using an anterior surgical approach and 55 patients underwent a posterior approach. The clinical characteristics had no significant differences except for median prostate volume between the anterior and posterior groups (27 ml vs 29 ml, p = 0.049). There were no significant differences between the two groups in score decline beyond the MCID in any domain at any timepoint. Our study demonstrates no significant differences in HRQOL between anterior and posterior surgical approaches to RARP.

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  • Identification of Proteins Differentially Expressed by Adipose-derived Mesenchymal Stem Cells Isolated from Immunodeficient Mice. Reviewed International journal

    Yoshiki Nakashima, Saifun Nahar, Chika Miyagi-Shiohira, Takao Kinjo, Naoya Kobayashi, Shinji Kitamura, Issei Saitoh, Masami Watanabe, Jiro Fujita, Hirofumi Noguchi

    International journal of molecular sciences   20 ( 11 )   E2672   2019.5

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    Although cell therapy using adipose-derived mesenchymal stem cells (AdMSCs) regulates immunity, the degree to which cell quality and function are affected by differences in immunodeficiency of donors is unknown. We used liquid chromatography tandem-mass spectrometry (LC MS/MS) to identify the proteins expressed by mouse AdMSCs (mAsMSCs) isolated from normal (C57BL/6) mice and mice with severe combined immunodeficiency (SCID). The protein expression profiles of each strain were 98%-100% identical, indicating that the expression levels of major proteins potentially associated with the therapeutic effects of mAdMSCs were highly similar. Further, comparable levels of cell surface markers (CD44, CD90.2) were detected using flow cytometry or LC MS/MS. MYH9, ACTN1, CANX, GPI, TPM1, EPRS, ITGB1, ANXA3, CNN2, MAPK1, PSME2, CTPS1, OTUB1, PSMB6, HMGB1, RPS19, SEC61A1, CTNNB1, GLO1, RPL22, PSMA2, SYNCRIP, PRDX3, SAMHD1, TCAF2, MAPK3, RPS24, and MYO1E, which are associated with immunity, were expressed at higher levels by the SCID mAdMSCs compared with the C57BL/6 mAdMSCs. In contrast, ANXA9, PCBP2, LGALS3, PPP1R14B, and PSMA6, which are also associated with immunity, were more highly expressed by C57BL/6 mAdMSCs than SCID mAdMSCs. These findings implicate these two sets of proteins in the pathogenesis and maintenance of immunodeficiency.

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  • Upregulation of mobility in pancreatic cancer cells by secreted S100A11 through activation of surrounding fibroblasts. Reviewed International journal

    Mitsui Y, Tomonobu N, Watanabe M, Kinoshita R, Sumardika W, Youyi C, Murata H, Yamamoto KI, Sadahira T, Rodrigo AGH, Takamatsu H, Araki K, Yamauchi A, Yamamura M, Fujiwara H, Inoue Y, Futami J, Saito K, Iioka H, Kondo E, Nishibori M, Toyooka S, Yamamoto Y, Nasu Y, Sakaguchi M

    Oncology research   27 ( 8 )   945 - 956   2019.4

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    S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

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  • Very late relapse and management of clinical stage I seminoma after orchiectomy: A case report

    Shogo Watari, Takuya Sadahira, Atsushi Takamoto, Yuki Maruyama, Yosuke Mitsui, Koichiro Wada, Ryuta Tanimoto, Morito Sugimoto, Yasuyuki Kobayashi, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu, Hiroyuki Yanai

    Nishinihon Journal of Urology   81 ( 1 )   45 - 48   2019.2

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    The patient was a 44-year-old man with a history of right radical orchiectomy for clinical stage I seminoma 14 years earlier followed by 6 years of surveillance, who presented with right lower leg edema. A thorough examination showed high testicular cancer-related tumor marker values, and based on computed tomography, a diagnosis of right pelvic lymph node metastasis was made. Salvage chemotherapy, consisting of bleomycin, etoposide, and cisplatin was administered followed by secondline chemotherapy with vinblastine, ifosfamide, and cisplatin. The tumor markers were confirmed to be negative, and the patient underwent retroperitoneal lymph node dissection. One year after surgery, there was no evidence of recurrence. Recurrence of clinical stage I seminoma more than 10 years after the initial diagnosis is rarely experienced. We report this case and review the management of clinical stage I seminoma.

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  • A Novel Preservation Solution Containing a JNK Inhibitory Peptide Efficiently Improves Islet Yield for Porcine Islet Isolation. Reviewed International journal

    Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Nana Ebi, Eri Hamada, Yoshihito Tamaki, Kazuho Kuwae, Shinji Kitamura, Naoya Kobayashi, Issei Saitoh, Masami Watanabe

    Transplantation   103 ( 2 )   344 - 352   2019.2

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    BACKGROUND: For islet transplantation, pancreas preservation in University of Wisconsin (UW) solution is associated with disadvantages, such as collagenase inhibition, resulting in poor islet yield and islets with poor viability. In this study, we evaluated a novel preservation solution, the extracellular-type c-Jun N-terminal kinase (JNK) inhibitor-containing (EJ) solution. METHODS: The EJ solution has high sodium-low potassium composition with low viscosity compared to UW solution. Moreover, EJ solution contains a recently developed JNK inhibitor from our laboratory. RESULTS: We first compared the performance of EJ solution with that of UW solution. Islet yield before and after purification was significantly higher in the EJ group than in the UW group. Second, we compared the performance of EJ solution with that of EJ solution without the JNK inhibitor (EJ-J solution). After pancreas preservation in EJ solution, JNK activity was maintained at a relatively low level during islet isolation. Islet yield before and after purification was significantly higher in the EJ group than in the EJ-J group. After islet transplantation into streptozotocin-induced diabetic mice, blood glucose levels reached the normoglycemic range in 61.5% and 7.7% of diabetic mice in the EJ and EJ-J groups, respectively. Moreover, EJ solution exhibited reduced inhibition of collagenase digestion compared with UW solution. CONCLUSIONS: Advantages of EJ solution over UW solution were inhibition of JNK activity and reduced collagenase inhibition. EJ solution may therefore be more suitable for islet isolation than UW solution.

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  • Robotic-assisted renal autotransplantation: Preliminary studies and future directions

    Motoo Araki, Koichiro Wada, Kasumi Kawamura, Yuuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Takashi Yoshioka, Yuichi Ariyoshi, Kei Fujio, Atsushi Takamoto, Morito Sugimoto, Katsumi Sasaki, Yasuyuki Kobayashi, Shin Ebara, Amano Hiroyuki, Masashi Inui, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Endourology Progress: Technique, Technology and training   143 - 148   2019.1

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    The indications for renal autotransplantation (RATx) include renal vascular trauma, thrombosis, stenosis, aneurysm, complex ureteral injuries, renal cell carcinoma, urolithiasis, retroperitoneal fibrosis, and loin pain-hematuria syndrome. Unfortunately, RATx is underutilized because of its invasiveness. The current gold standard approach to RATx is laparoscopic nephrectomy and open autotransplantation, which requires a large pelvic incision. Robotic-assisted renal autotransplantation (robotic RATx) is a new, minimally invasive approach that has been used since 2014. The first completely intracorporeal robotic RATx, used to repair a ureteral injury, was reported in 2014. Since then, only three cases have been reported, all from North America. After an initial porcine study, we conducted the fourth robotic RATx procedure. Robotic surgery has multiple advantages, such as providing a three-dimensional magnified view, navigating in narrow spaces, and fine suturing and dissection, which are particularly helpful in cases with desmoplastic changes. Most robotic RATx procedures have been used to repair ureteral injuries. These cases tend to have desmoplastic changes due to previous surgeries. Nephrectomy and RATx are technically challenging, hence robotic surgery may be the best option in patients with complex and severe desmoplastic changes. The disadvantages of robotic RATx include the length of surgery and cost. However, with continued use, both the operative time and the cost should decrease. In conclusion, robotic RATx is a new, minimally invasive approach to renal preservation.

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  • A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of Primary Cultured Cells and Subcultured Cells Using Mouse Adipose-Derived Mesenchymal Stem Cells. Reviewed International journal

    Yoshiki Nakashima, Saifun Nahar, Chika Miyagi-Shiohira, Takao Kinjo, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Jiro Fujita, Hirofumi Noguchi

    Stem cells international   2019   7274057 - 7274057   2019.1

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    Adipose-derived mesenchymal stem cells (MSC-ATs) are representative cell sources for cell therapy. However, how cell stress resulting from passage influences the MSC-AT protein expression has been unclear. In this study, a protein expression analysis was performed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) using mouse primary cultured cells (P0) and cells passaged three times (P3) as samples. A total of 256 proteins were classified as cellular process-related proteins, while 179 were classified as metabolic process-related proteins in P0. These were considered to be adaptive responses of the cells to an in vitro environment. However, seven proteins of growth were identified (Csf1, App, Adam15, Alcam, Tbl1xr1, Ninj1, and Sbds) in P0. In addition, four proteins of antioxidant activity were also identified (Srxn1, Txndc17, Fam213b, and Apoe) in P0. We identified 1139 proteins expressed in both P0 and P3 cells that had their expression decreased to 69.4% in P3 cells compared with P0 cells, but 1139 proteins are very likely proteins that are derived from MSC-AT. The function of MSC-ATs was maintained after three passages. However, the LC-MS/MS analysis data showed that the protein expression was degraded after three passages. MSC-ATs retained about 70% of their protein expression ability in P3 cells.

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  • Induction of Expandable Tissue-Specific Progenitor Cells from Human Pancreatic Tissue through Transient Expression of Defined Factors. Reviewed

    Noguchi H, Miyagi-Shiohira C, Nakashima Y, Kinjo T, Kobayashi N, Saitoh I, Watanabe M, Shapiro AMJ, Kin T

    Mol Ther Methods Clin Dev   13   243 - 252   2019.1

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  • The Novel Combination of Nitroxoline and PD-1 Blockade, Exerts a Potent Antitumor Effect in a Mouse Model of Prostate Cancer. Reviewed International coauthorship International journal

    Naijin Xu, Linglong Huang, Xiezhao Li, Masami Watanabe, Chaoming Li, Abai Xu, Chunxiao Liu, Qiang Li, Motoo Araki, Koichiro Wada, Yasutomo Nasu, Peng Huang

    International journal of biological sciences   15 ( 5 )   919 - 928   2019

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    Programmed cell death protein 1 (PD-1) blockade is a promising therapeutic strategy against prostate cancer. Nitroxoline has been found to have effective anticancer properties in several cancer types. We investigated the efficacy of a combination therapy involving nitroxoline and PD-1 blockade in a prostate cancer mouse model. In our in vitro analysis, we found that nitroxoline inhibited the viability and proliferation of the mouse prostate cancer cell line RM9-Luc-PSA. Additionally, nitroxoline downregulated the expressions of phospho-PI3 kinase, phospho-Akt (Thr308), phospho-Akt (Ser473), phospho-GSK-3β, Bcl-2, and Bcl-xL. Nitroxoline also downregulated programmed death-ligand 1 (PD-L1) expression levels in prostate cancer cell line and tumor tissue. In our murine prostate cancer orthotopic model, nitroxoline plus PD-1 blockade synergistically suppressed tumor growth when compared with nitroxoline or PD-1 blockade alone, leading to reductions in tumor weight, bioluminescence tumor signals, and serum prostate-specific antigen levels. Furthermore, fluorescence-activated cell sorting analysis showed that the combination strategy significantly enhanced antitumor immunity by increasing CD44+CD62L+CD8+ memory T cell numbers and reducing myeloid-derived suppressor cell numbers in peripheral blood. In conclusion, our findings suggest that nitroxoline plus PD-1 blockade may be a promising treatment strategy in patients with prostate cancer.

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  • Pelvic magnetic resonance imaging parameters predict urinary incontinence after robot-assisted radical prostatectomy. Reviewed International journal

    Sadahira T, Mitsui Y, Araki M, Maruyama Y, Wada K, Edamura K, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Lower urinary tract symptoms   11 ( 3 )   122 - 126   2018.12

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    OBJECTIVE: Urinary incontinence (UI) is a major prostate cancer (PCa) treatment-related morbidity. It has been reported that post-prostatectomy UI is related to the width of the pelvic floor muscles (PFM) and the length of the urethra. However, the details of these anatomical parameters are unknown. The aim of this study was to investigate whether preoperative pelvic parameters or anatomical parameters of the urethra, as measured by magnetic resonance imaging (MRI), are correlated with UI. METHODS: Between 2010 and 2017, 571 patients with localized PCa underwent robot-assisted radical prostatectomy (RARP) at Okayama University Hospital. Patients treated by a single experienced surgeon were included in the study. Preoperative prostate volume, obturator internal muscle, anal sphincter muscle, levator ani muscle (LAM), urethra wall thickness (UWT), and membranous urethral length (MUL) were measured by MRI. Patients were divided into two groups depending on leakage status 1 year after RARP using Expanded Prostate Index Composite Item 1. RESULTS: Seventy patients were included in this retrospective study. Based on leakage status, 37 and 33 patients were allocated to the no-leakage and leakage groups, respectively. There were significant differences between the two groups in age (P = 0.03), MUL (P < 0.001), UWT (P = 0.03), and LAM (P = 0.001). Multivariate logistic regression analyses revealed that MUL and LAM predicted UI 1 year after RARP. CONCLUSIONS: Pelvic parameters measured by MRI before RARP may be useful in the prediction of UI. In particular, MUL and LAM can predict postoperative UI by strict definition.

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  • Burned-out Prostate Cancer ? Primary Metastatic Cancer Not Detected on Repeat Biopsy. Reviewed

    Mitsui Y, Sadahira T, Maruyama Y, Wada K, Tanimoto R, Sugimoto M, Araki M, Watanabe M, Yanai H, Watanabe T, Nasu Y

    Acta medica Okayama   72 ( 6 )   605 - 609   2018.12

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    Metastatic prostate cancer (PCa) cases that cannot be detected on repeat prostate biopsy are extremely rare. Our patient was a 51-year-old Japanese man diagnosed as metastatic PCa by histopathological examination of lesions obtained bone biopsy and lymph node dissection. The primary tumor was not detected after repeated prostate biopsy. Metastatic PCa was diagnosed based on immunohistochemical staining: PSA, AR, P504S, and NKX3.1 of bone and lymph node with metastasis. We speculate that the primary PCa was "burned-out," demonstrating remote metastases with no apparent primary tumor in the prostate. Burned-out PCa may be difficult to diagnose and treat due to its rarity.

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  • The 3-D Volumetric Measurement Including Resected Specimen for Predicting Renal Function AfterRobot-assisted Partial Nephrectomy. Reviewed International journal

    Mitsui Y, Sadahira T, Araki M, Maruyama Y, Nishimura S, Wada K, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Urology   125   104 - 110   2018.12

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    OBJECTIVE: To investigate the relationship between postoperative renal function and resected cortex margin volume calculated by a 3-dimensional reconstruction technique based on the resected specimen, and to determine predictors of renal function after robot-assisted partial nephrectomy. METHODS: A total of 114 patients underwent robot-assisted partial nephrectomy from 2014 to 2018. Patients without a 1 mm slice computed tomography or renal scintigraphy were excluded. We identified the margins of the tumor from each resected specimen with 2 mm margin being added as the ischemic margin. The volume of the renal cortex was calculated automatically using 3-dimensional volume analyzer software. The total margin volume was excluded from the ipsilateral cortex volume to calculate the cortex volume split. Predicted estimated glomerular filtration rate (eGFR) was calculated using the change in cortex volume and then compared with the actual eGFR. RESULTS: Eighty-two patients were included in this retrospective study. Sixty-six patients (80%) were cT1a. A strong correlation was observed between renal scintigraphy split and pre- and postoperative cortex volume split (Pearson correlation coefficient r = 0.9330 and 0.8742, respectively). The predicted eGFR correlated strongly with post 1, 3, 6, and 12 months eGFR (r = 0.8929, 0.9294, 0.9320, and 0.8952, respectively). Preoperative relative renal function and total cortex margin volume were independent risk factors for decreasing postoperative renal function. CONCLUSION: This precise volumetric assessment that includes the resected margin is an alternative to renal scintigraphy for predicting postoperative relative renal function. The healthy cortex margin volume calculated by the reconstruction technique is an independent risk factor of decreasing postoperative renal function.

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  • A Comparison of Proteins Expressed between Human and Mouse Adipose-Derived Mesenchymal Stem Cells by a Proteome Analysis through Liquid Chromatography with Tandem Mass Spectrometry. Reviewed International journal

    Saifun Nahar, Yoshiki Nakashima, Chika Miyagi-Shiohira, Takao Kinjo, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi, Jiro Fujita

    International journal of molecular sciences   19 ( 11 )   E3497   2018.11

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    Adipose-derived mesenchymal stem cells (ADSCs) have become a common cell source for cell transplantation therapy. Clinical studies have used ADSCs to develop treatments for tissue fibrosis, such as liver cirrhosis and pulmonary fibroma. The need to examine and compare basic research data using clinical research data derived from mice and humans is expected to increase in the future. Here, to better characterize the cells, the protein components expressed by human ADSCs used for treatment, and mouse ADSCs used for research, were comprehensively analyzed by liquid chromatography with tandem mass spectrometry. We found that 92% (401 type proteins) of the proteins expressed by ADSCs in humans and mice were consistent. When classified by the protein functions in a gene ontology analysis, the items that differed by >5% between human and mouse ADSCs were "biological adhesion, locomotion" in biological processes, "plasma membrane" in cellular components, and "antioxidant activity, molecular transducer activity" in molecular functions. Most of the listed proteins were sensitive to cell isolation processes. These results show that the proteins expressed by human and murine ADSCs showed a high degree of correlation.

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  • Cytokines in adipose-derived mesenchymal stem cells promote the healing of liver disease. Reviewed

    Nahar S, Nakashima Y, Miyagi-Shiohira C, Kinjo T, Toyoda Z, Kobayashi N, Saitoh I, Watanabe M, Noguchi H, Fujita J

    World J Stem Cells   10 ( 11 )   146 - 159   2018.11

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  • Loss of psoas major muscle volume during systemic chemotherapy is related to worse prognosis in testicular cancer. Reviewed International journal

    Mitsui Y, Sadahira T, Araki M, Maruyama Y, Wada K, Tanimoto R, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Japanese journal of clinical oncology   49 ( 2 )   183 - 189   2018.11

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    Objective: In several cancers, the loss of skeletal muscle is well associated with oncological outcome. However, its effect is unknown in testicular cancer. This study evaluated the prognostic impact of psoas major muscle volume loss during systemic chemotherapy. Methods: This was a retrospective study of patients who underwent chemotherapy from 2008 to 2017. Psoas major muscle volume was calculated by volume analyzer software, and its loss was calculated during systemic chemotherapy. The patients were divided according to muscle volume loss: Group 1 (<20%) and Group 2 (≥20%). The losses were compared with Kaplan-Meier curves, and a Cox proportional hazard model was applied to test predictors of poor prognosis. Results: Fifty patients were included. Seventeen were classified into Group 1, and 33 into Group 2. The Kaplan-Meier curves revealed that the progression-free and the overall survival of Group 1 were significantly better than those of Group 2 (P = 0.002, P = 0.03, respectively). A multivariate analysis identified psoas major muscle volume loss as a significant and independent predictor of poor prognosis. Conclusions: Patients with psoas major muscle volume loss during chemotherapy had a significantly worse prognosis than those without loss.

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  • Induction of Expandable Adipose-Derived Mesenchymal Stem Cells from Aged Mesenchymal Stem Cells by a Synthetic Self-Replicating RNA. Reviewed

    Miyagi-Shiohira C, Nakashima Y, Kobayashi N, Kitamura S, Saitoh I, Watanabe M, Noguchi H

    Int J Mol Sci   19 ( 11 )   E3489   2018.11

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  • Induction of Expandable Adipose-Derived Mesenchymal Stem Cells from Aged Mesenchymal Stem Cells by a Synthetic Self-Replicating RNA

    Chika Miyagi-Shiohira, Yoshiki Nakashima, Naoya Kobayashi, Shinji Kitamura, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   19 ( 11 )   2018.11

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    Adipose-derived mesenchymal stem cells (ADSCs) have attracted attention due to their potential for use in the treatment of various diseases. However, the self-renewal capacity of ADSCs is restricted and their function diminishes during passage. We previously generated induced tissue-specific stem cells from mouse pancreatic cells using a single synthetic self-replicating Venezuelan Equine Encephalitis (VEE)-reprogramming factor (RF) RNA replicon (SR-RNA) expressing the reprogramming factors POU class 5 homeobox 1 (OCT4), Krueppel-like factor 4 (KLF4), Sex determining region Y-box 2 (SOX2), and Glis Family Zinc Finger 1 (GLIS1). This vector was used to generate induced pluripotent stem (iPS) cells. Here, we applied this SR-RNA vector to generate human iTS cells from aged mesenchymal stem cells (hiTS-M cells) deficient in self-renewal that were derived from adipose tissue. These hiTS-M cells transfected with the SR-RNA vector survived for 15 passages. The hiTS-M cells expressed cell surface markers similar to those of human adipose-derived mesenchymal stem cells (hADSCs) and differentiated into fat cells and osteoblasts. Global gene expression profiling showed that hiTS-M cells were transcriptionally similar to hADSCs. These data suggest that the generation of iTS cells has important implications for the clinical application of autologous stem cell transplantation.

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  • Red nodular melanoma of the penile foreskin: A case report and literature review. Reviewed International journal

    Maruyama Y, Sadahira T, Mitsui Y, Wada K, Tanimoto R, Kobayashi Y, Araki M, Watanabe M, Watanabe T, Nasu Y

    Molecular and clinical oncology   9 ( 4 )   449 - 452   2018.10

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    The penis is an extremely rare primary site for malignant melanomas, and the clinical presentation may vary greatly. We herein present the case of a 71-year-old male patient who presented with a 6-year history of two slow growing, asymptomatic red macules on the penile foreskin. On physical examination, the mobility of the foreskin was good, and there was no metastasis on computed tomography and magnetic resonance imaging. The patient underwent segmental circumcision for treatment and histological diagnosis, and the histological examination revealed a malignant melanoma. As cancer cells were identified at the edge of the tissue specimen and computed tomography-positron emission tomography revealed increased uptake of 18F-fluorodeoxyglucose in the penis, wider resection and a right sentinel lymph node biopsy were performed; both specimens came back negative. Two years after the surgery, there has been no evidence of locoregional recurrence or distant metastases. The aim of this report is to alert physicians to include melanoma in the differential diagnosis of red-pigmented lesions of the penile foreskin.

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  • A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of the Proteins Secreted by Human Adipose-Derived Mesenchymal Stem Cells. Reviewed International journal

    Yoshiki Nakashima, Saifun Nahar, Chika Miyagi-Shiohira, Takao Kinjo, Zensei Toyoda, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Jiro Fujita, Hirofumi Noguchi

    Cell transplantation   27 ( 10 )   1469 - 1494   2018.10

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    Liquid chromatography using a tandem mass spectrometer (LC-MS/MS) is a method of proteomic analysis. A shotgun analysis by LC-MS/MS comprehensively identifies proteins from tissues and cells with high resolution. The hepatic function of mice with acute hepatitis following the intraperitoneal administration of CCL4 was improved by the tail vein administration of the culture conditional medium (CM) of human mesenchymal stem cells from adipose tissue (hMSC-AT). In this study, a secreted protein expression analysis of hMSC-AT was performed using LC-MS/MS; 128 proteins were identified. LC-MS/MS showed that 106 new functional proteins and 22 proteins (FINC, PAI1, POSTN, PGS2, TIMP1, AMPN, CFAH, VIME, PEDF, SPRC, LEG1, ITGBL, ENOA, CSPG2, CLUS, IBP4, IBP7, PGS1, IBP2, STC2, CTHR1, CD9) were previously reported in hMSC-AT-CMs. In addition, various proteins associated with growth (SAP, SEM7A, PTK7); immune system processes (CO1A2, CO1A1, CATB, TSP1, GAS6, PTX3, C1 S, SEM7A, G3P, PXDN, SRCRL, CD248, SPON2, ENPP2, CD109, CFAB, CATL1, MFAP5, MIF, CXCL5, ADAM9, CATK); and reproduction (MMP2, CATB, FBLN1, SAP, MFGM, GDN, CYTC) were identified in hMSC-AT-CMs. These results indicate that a comprehensive expression analysis of proteins by LC-MS/MS is useful for investigating new factors associated with cellular components, biological processes, and molecular functions.

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  • THE PROMISING USE OF PROBIOTICS AGAINST RECURRENT URINARY TRACT INFECTIONS Reviewed

    定平 卓也, 和田 耕一郎, 三井 將雄, 石井 亜矢乃, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科 = The Nishinihon journal of urology   80 ( 10 )   505 - 509   2018.10

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    尿路感染症に対する治療として中心的な役割を果たしてきた抗菌化学療法は大きな転機を迎えている。世界的な時流として耐性菌の問題や医療経済的にも抗菌薬の使用量を減少させる方向に移行している。尿路感染症においても例外ではなく、そのマネジメントに関して治療法の見直しだけでなく予防の重要性についての議論がなされている。そのうち、これまでに様々な臨床研究において有効性が確認されつつあるプロバイオティクスが抗菌薬とは異なる尿路感染症対策として注目されている。健常な閉経前の女性の腟内においては、基本的に乳酸菌が細菌叢(フローラ)を形成しているが、月経中や閉経後は乳酸菌が減少して腸内細菌が腟内に定着することとなる。その腟がリザーバーとなって細菌を供給し、頻繁に尿路の逆行性感染を引き起こすと考えられている。すなわち、腟内を乳酸菌中心のフローラに保つことで尿路感染症の再発(反復)リスクが低くなることが期待でき、実際にプロバイオティクスを用いた多くの研究が行われている。我々が現在行っている乳酸菌製剤のほか、プロバイオティクスの経口摂取が腟内フローラに与える影響に関しても検証が進んでおり、プロバイオティクスが尿路感染症の予防や治療に寄与することが期待されている。(著者抄録)

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  • A Comparison of the Preservation of Mouse Adipose Tissue-Derived Mesenchymal Stem Cells Using the University of Wisconsin Solution and Hank's Balanced Salt Solution. Reviewed International journal

    Saifun Nahar, Yoshiki Nakashima, Chika Miyagi-Shiohira, Takao Kinjo, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi, Jiro Fujita

    Stem cells international   2018   1625464 - 1625464   2018.9

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    Preservation of adipose tissue before the isolation of cells is one of the most important steps in maintaining the cell viability of adipose tissue-derived mesenchymal stem cells (ADSCs) for clinical use. Hank's balanced salt solution (HBSS) is one of the main ADSC preservation solutions used clinically. However, this step is known to lead to decreased cell viability. The University of Wisconsin (UW) solution is recognized by transplant physicians as an excellent organ preservation solution. We aimed to investigate the effectiveness of UW solution in preservation of the viability of ADSCs. We collected adipose tissue from the inguinal fat pad of mice and compared preservation in UW solution and HBSS overnight by measuring cell viability after isolation. We found that the number of viable cells harvested per gram of adipose tissue mass was higher in UW solution- than HBSS-preserved tissue.

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  • Bufalin suppresses the proliferation and metastasis of renal cell carcinoma by inhibiting the PI3K/Akt/mTOR signaling pathway. Reviewed International journal

    Jinlin Xie, Wenfeng Lin, Linglong Huang, Naijin Xu, Abai Xu, Binshen Chen, Masami Watanabe, Chunxiao Liu, Peng Huang

    Oncology letters   16 ( 3 )   3867 - 3873   2018.9

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    Bufalin, one of the active ingredients of the Chinese drug Chan su, exhibits significant antitumor activity against various cancer types. However, the role of bufalin in renal cell carcinoma (RCC) remains unclear. In the present study, it was demonstrated that bufalin inhibited cell proliferation, blocked the cell cycle in the G2/M phase, and reduced the metastasis of human RCC ACHN cells via the upregulation of p21waf/cip1 and E-cadherin and the downregulation of cyclin dependent kinase 1, cyclin B1, N-cadherin, and hypoxia-inducible factor-1α (HIF-1α). Further mechanistic study revealed that bufalin reduced the expression of phosphorylated (phospho)-Akt and phospho-mammalian target of rapamycin (mTOR). Moreover, HIF-1α expression may be regulated through the inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling pathway. Thus, the present results suggest that bufalin induces cell cycle arrest and suppresses metastasis; this process may be associated with the PI3K/Akt/mTOR signaling pathway. Accordingly, it is suggested that bufalin is a therapeutic agent for RCC.

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  • Clinical impact of abdominal fat distribution measured by 3-D computed tomography volumetry on post-transplant renal function in recipients after living kidney transplantation: a retrospective study. Reviewed

    Mitsui Y, Sadahira T, Araki M, Maruyama Y, Wada K, Tanimoto R, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Clinical and experimental nephrology   23 ( 3 )   415 - 424   2018.9

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    BACKGROUND: Excessive visceral fat may decrease renal function because of metabolic derangements. The aim of this study was to evaluate the impact of abdominal fat distribution on renal function of recipients after kidney transplantation using the visceral adipose tissue (VAT)/subcutaneous adipose tissue (SAT) ratio. METHODS: Seventy-nine patients underwent living kidney transplantation from 2009 to 2017. Patients without a correct measurement of VAT and SAT, follow-up of < 6 months, or with kidney transplant rejection or a virus infection were excluded. VAT and SAT were calculated automatically by 3-D volume analyzer software in recipients prior to living kidney transplantation. Our primary aim was to identify abdominal fat distribution measured by CT associated with renal dysfunction (estimate glomerular filtration rate; eGFR < 45) at 6 month post renal transplantation in recipient. RESULTS: Fifty-eight living kidney recipients were included in this retrospective study: 30 for the high VAT/SAT ratio group; 28 for the VAT/SAT low group. Multiple logistic regression analysis showed the VAT/SAT ratio and pre-donor eGFR were associated with eGFR < 45 ml/min/1.73 m2. An increase in VAT/SAT ratio was associated independently with the incidence of decreased renal function. CONCLUSION: This finding indicates that adipose tissue distribution is an important predictor of the outcome of living kidney transplantation in recipients.

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  • 排尿障害を伴う女性尿道憩室に対して手術治療を行った1例

    松尾 聡子, 杉本 盛人, 佐久間 貴文, 坪井 一朗, 本郷 智拡, 三井 將雄, 河村 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 定平 卓也, 前原 貴典, 大岩 裕子, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 谷本 竜太, 小林 泰之, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友, 中村 あや, 津島 知靖

    西日本泌尿器科   80 ( 9 )   495 - 495   2018.9

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  • 前立腺に発生したSFT(Solitary fibrous tumor)の1例

    本郷 智拡, 高本 篤, 三井 將雄, 松尾 聡子, 坪井 一朗, 佐久間 貴文, 和田里 章悟, 河村 香澄, 丸山 雄樹, 光井 洋介, 前原 貴典, 窪田 理沙, 大岩 裕子, 定平 卓也, 西村 慎吾, 佐古 智子, 和田 耕一郎, 谷本 竜太, 杉本 盛人, 小林 泰之, 石井 亜矢乃, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   80 ( 9 )   497 - 497   2018.9

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  • Comparison Between Modified Extracellular-Type Trehalose-Containing Kyoto Solution and University of Wisconsin Solution in 18-Hour Pancreas Preservation for Islet Transplantation. Reviewed

    Hamada E, Ebi N, Miyagi-Shiohira C, Tamaki Y, Nakashima Y, Kobayashi N, Saitoh I, Watanabe M, Kinjo T, Noguchi H

    Pancreas   47 ( 7 )   e46 - e47   2018.8

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  • Characterization of induced tissue-specific stem cells from pancreas by a synthetic self-replicative RNA. Reviewed International journal

    Chika Miyagi-Shiohira, Yoshiki Nakashima, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Scientific reports   8 ( 1 )   12341 - 12341   2018.8

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    Induced pluripotent stem (iPS) cells have significant implications for overcoming most of the ethical issues associated with embryonic stem (ES) cells. Furthermore, our recent study demonstrated the generation of induced tissue-specific stem (iTS) cells by transient overexpression of the reprogramming factors using a plasmid combined with tissue-specific selection. In this study, we were able to generate RNA-based iTS cells that utilize a single, synthetic, self-replicating VEE-RF RNA replicon expressing four reprogramming factors (OCT4, KLF4, SOX2, and GLIS1). A single VEE-RF RNA transfection into mouse pancreatic tissue resulted in efficient generation of iTS cells from pancreas (iTS-P cells) with genetic markers of endoderm and pancreatic progenitors and differentiation into insulin-producing cells more efficiently than ES cells. Subcutaneous transplantation of iTS-P cells into immunodeficient mice resulted in no teratoma formation. Bisulfite genomic sequencing demonstrated that the promoters of Oct4 and Nanog remained partially methylated in iTS-P cells. We compared the global gene-expression profiles of ES cells, iTS-P cells, and pancreatic islets. Microarray analyses confirmed that the iTS-P cells were similar but not identical to ES cells compared with islets. These data suggest that iTS-P cells are cells that inherit numerous components of epigenetic memory from pancreas cells and acquire self-renewal potential. The generation of iTS cells may have important implications for the clinical application of stem cells.

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  • Endogenous Leu332Gln mutation in p53 disrupts the tetramerization ability in a canine mammary gland tumor cell line Reviewed

    Kazuhiko Ochiai, Daigo Azakami, Masami Morimatsu, Hinako Hirama, Shota Kawakami, Takayuki Nakagawa, Masaki Michishita, Ai S. Egusa, Takanori Sasaki, Masami Watanabe, Toshinori Omi

    Oncology Reports   40 ( 1 )   488 - 494   2018.7

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    Mutations in the p53 gene are associated with more than half of all human cancers. These mutations often cause a disruption of the tumor-suppressor function of p53 and induce genomic instabilities. Wild-type p53 requires tetramerization to function as an initiator of cell cycle arrest and apoptosis. Although alterations in p53 tetramerization caused by mutation have been well studied, there are few cell lines containing an endogenous mutation in the tetramerization domain of p53. Here, we report the discovery of a canine mammary gland tumor cell line CTB-m2, which contains the Leu332Gln (L332Q) mutation corresponding to Leu344 in the tetramerization domain of human p53. Although CTB-m2 cells are genetically heterozygous for the Leu332Gln mutation, the mutant mRNA was almost exclusively expressed. CTB-m2 cells showed enhanced cell proliferation compared to wild-type p53-expressing CTB-m cells of the same lineage. A p53 tetramerization reporter assay showed that the ability of the p53 mutant to form tetramers was signifcantly lower than that of wild-type p53. An immunoblot analysis of cross-linked p53 oligomerized forms demonstrated that the L332Q mutant lacked the ability to form tetramers but retained the ability to form dimers. These data suggest that the p53 mutant cell line CTB-m2 could be a useful tool for analyzing the precise tetramerization mechanisms of p53 and verifying the effects of therapeutic agents against tumors expressing p53 mutants that lack the ability to tetramerize.

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  • Modified cell-permeable JNK inhibitors efficiently prevents islet apoptosis and improves the outcome of islet transplantation Reviewed

    Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Nana Ebi, Nana Ebi Eri Hamada, Yoshihito Tamaki, Kazuho Kuwae, Naoya Kobayashi, Issei Saitoh, Masami Watanabe

    SCIENTIFIC REPORTS   8 ( 1 )   11082   2018.7

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    We previously reported that treatment with a JNK inhibitory peptide (11R-JNKI) prevents islet apoptosis and enhances the islet function in vivo. In the present study, we explored more efficient JNK inhibitors. The inhibition of the JNK activity by five types of deletion peptides in 11R-JNKI was investigated. One of the peptides, 8R-sJNKI(-9), significantly prevented JNK activation. At a concentration of 1 mu M, 8R-sJNKI(-9) inhibited JNK activity similarly to 10 mu M 11R-JNKI and the inhibition of the JNK activity by 10 mu M 8R-sJNKI(-9) was significantly greater than that by 10 mu M 11R-JNK. To evaluate the effects of 8R-sJNKI(-9), porcine islets were cultured with 1 mu M of 8R-sJNKI(-9) or 8R-mutant sJNKI(-9) (8R-mJNKI(-9)). After 1 day of culture, the numbers of islets in the 8R-sJNKI(-9)-treated group was significantly higher than that in the 8R-mJNKI(-9)-treated group. After islet transplantation, the blood glucose levels reached the normoglycemic range in 58.3% of streptozotocin-induced diabetic mice in the 8R-sJNKI(-9) group and 0% of the mice in the 8R-mJNKI(-9)-treated group. These data suggest that 8R-sJNKI(-9) inhibits islet apoptosis and improves islet function.

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  • A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of Cells Cultured in DMEM 10% FBS and Chemically Defined Medium Using Human Adipose-Derived Mesenchymal Stem Cells. Reviewed

    Nakashima Y, Nahar S, Miyagi-Shiohira C, Kinjo T, Kobayashi N, Saitoh I, Watanabe M, Fujita J, Noguchi H

    Int J Mol Sci   19 ( 7 )   E2042   2018.7

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  • 新規抗癌免疫療法としてのAd-REIC遺伝子治療とその臨床効果

    定平 卓也, 渡部 昌実, 那須 保友

    日本がん免疫学会総会プログラム・抄録集   22回   69 - 69   2018.7

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  • 膵がん進展に導く膵がん細胞 間質線維芽細胞クロストークを介在する分泌性S100A11 受容体RAGE連携の役割

    光井 洋介, 山本 健一, Sumardika I Wayan, 木下 理恵, 村田 等, 二見 淳一郎, 高松 仁, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 渡部 昌実, 那須 保友, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   156 - 156   2018.7

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  • A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of Cells Cultured in DMEM 10% FBS and Chemically Defined Medium Using Human Adipose-Derived Mesenchymal Stem Cells

    Yoshiki Nakashima, Saifun Nahar, Chika Miyagi-Shiohira, Takao Kinjo, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Jiro Fujita, Hirofumi Noguchi

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   19 ( 7 )   2018.7

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    Human adipose-derived mesenchymal stem cells (hADSCs) are representative cell sources for cell therapy. Classically, Dulbecco's Modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) has been used as culture medium for hADSCs. A chemically defined medium (CDM) containing no heterologous animal components has recently been used to produce therapeutic hADSCs. However, how the culture environment using a medium without FBS affects the protein expression of hADSC is unclear. We subjected hADSCs cultured in CDM and DMEM (10% FBS) to a protein expression analysis by tandem mass spectrometry liquid chromatography and noted 98.2% agreement in the proteins expressed by the CDM and DMEM groups. We classified 761 proteins expressed in both groups by their function in a gene ontology analysis. Thirty-one groups of proteins were classified as growth-related proteins in the CDM and DMEM groups, 16 were classified as antioxidant activity-related, 147 were classified as immune system process-related, 557 were involved in biological regulation, 493 were classified as metabolic process-related, and 407 were classified as related to stimulus responses. These results show that the trend in the expression of major proteins related to the therapeutic effect of hADSCs correlated strongly in both groups.

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  • Comparison of Tissue Loading Before and After the Creation of a Continuous Density Gradient in Porcine Islet Purification Reviewed

    Miyagi-Shiohira Chika, Nakashima Yoshiki, Ebi Nana, Hamada Eri, Tamaki Yoshihito, Kuwae Kazuho, Kobayashi Naoya, Saitoh Issei, Watanabe Masami, Kinjo Takao, Noguchi Hirofumi

    CELL MEDICINE   10   2018.6

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    The purification step is one of the most important and difficult procedures in islet isolation for pancreatic islet transplantation. We previously reported that a purification method using large plastic bottles effectively achieved a high yield of islets from the porcine pancreas. In this study, we evaluated the impact of the timing of tissue loading on porcine islet purification using large plastic bottles. One method involved loading digested tissue after creating a continuous density gradient (tissue after gradient [TAG]). The other method involved loading digested tissue before creating a continuous density gradient (tissue before gradient [TBG]). There were no significant differences between TAG and TBG in terms of the islet yield, rates of viability and purity, score, and in the stimulation index after purification. Furthermore, there were no marked differences in the attainability or suitability of post-transplantation normoglycemia. Our study shows the equivalency of these two methods of islet purification.

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  • A Comparison of Pancreatic Islet Purification using Iodixanol with University of Wisconsin Solution and with Na-Lactobionate and Histidine Solution Reviewed

    Nakashima Yoshiki, Miyagi-Shiohira Chika, Ebi Nana, Hamada Eri, Tamaki Yoshihito, Kuwae Kazuho, Kobayashi Naoya, Saitoh Issei, Watanabe Masami, Kinjo Takao, Noguchi Hirofumi

    CELL MEDICINE   10   2018.6

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    Purification of pancreatic islets is an important step in islet isolation for islet transplantation. In this study, to investigate how a solution composed mainly of Na-lactobionate and histidine (HL) influences the purification of islets, iodixanol was added to a purified solution for porcine islet isolation. A solution (IU) made by adding iodixanol to University of Wisconsin solution and a solution (IHL) made by adding iodixanol to HL solution were used to evaluate the islet isolation performance. We noted no significant differences between the two purification methods with regard to the islet yield, survival rate or purity, score, or stimulation index. These results show that IHL solution is as useful as IU solution for islet purification.

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  • Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors Reviewed

    Yuki Maruyama, Takuya Sadahira, Yosuke Mitsui, Motoo Araki, Koichiro Wada, Ryuta Tanimoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Medical Oncology   35 ( 6 )   80   2018.6

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    Bleomycin pulmonary toxicity (BPT) has been well described in patients with germ cell tumors treated with bleomycin etoposide and cisplatin chemotherapy (BEP). To assess the prognostic impact of BPT, we retrospectively identified 52 patients who underwent bleomycin etoposide and cisplatin chemotherapy from 2008 to 2017 in our institution, and evaluated the risk factors of BPT and its effect on prognosis. Patients who had received chemotherapy at another institution were excluded. BPT was defined as bleomycin discontinuation in response to pulmonary function test decline, pulmonary symptoms, or interstitial pneumonia on computed tomography without infection. We divided the patients into two groups according to this definition: BPT and non-BPT. Their median age was 34.2 years, and their median body mass index was 22.8 kg/m2. Twenty patients had a smoking history, 37 were diagnosed with non-seminoma, and 20 had lung metastasis. The median cumulative bleomycin dose was 270 mg/body. Fifteen patients were classified into the BPT group and 37 into the non-BPT group. Only body mass index &lt
    22 was identified as a predictor of BPT in multivariable logistic models. Age or use of granulocyte-colony stimulating factor did not have a significant impact. Kaplan–Meier analysis revealed that the presence of BPT had no significant impact on either 5-year overall survival or progression-free survival. Lower body mass index can increase the risk of BPT in patients with germ cell tumors undergoing BEP. However, discontinuation of bleomycin with BPT does not adversely influence the survival outcomes.

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  • The Development of Cancer through the Transient Overexpression of Reprogramming Factors Reviewed

    Miyagi-Shiohira Chika, Nakashima Yoshiki, Kobayashi Naoya, Saitoh Issei, Watanabe Masami, Noguchi Yasufumi, Kinjo Takao, Noguchi Hirofumi

    CELL MEDICINE   10   2018.5

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    Although induced pluripotent stem (iPS) cells have significant implications for overcoming most of the ethical issues associated with embryonic stem cells, several issues related to the use of iPS cells in clinical applications remain unresolved, including the issue of teratoma formation. We previously reported that the induction of induced tissue-specific stem (iTS) cells from the pancreas (iTS-P) or liver (iTS-L) by the transient overexpression of reprogramming factors, combined with tissue-specific selection and the generation of iTS cells, could have important implications for the clinical application of stem cells. At the same time, we also generated "induced fibroblast-like (iF) cells" that were capable of self-renewal, which had a similar morphology to fibroblast cells. In this study, we evaluated iF cells. iF cells are unlikely to show adipogen/costeogenic differentiation. Moreover, iF cells have the ability to form tumors and behave similarly to pancreatic cancer cells. The technology used in the generation of iPSiTS cells is also associated with the risk of generating cancer-like cells.

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  • Role of Egr1 on Pancreatic Endoderm Differentiation Reviewed

    Tsugata Takako, Nikoh Naruo, Kin Tatsuya, Miyagi-Shiohira Chika, Nakashima Yoshiki, Saitoh Issei, Noguchi Yasufumi, Ueki Hideo, Watanabe Masami, Kobayashi Naoya, Shapiro Andrew, M. James, Noguchi Hirofumi

    CELL MEDICINE   10   2018.5

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    The low efficiency of in vitro differentiation of human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (iPSCs) into insulin-producing cells is a crucial hurdle for the clinical implementation of human pluripotent stem cells (PSCs). Our previous investigation into the key factors for the differentiation of PSCs into insulin-producing cells suggested that the expression of GATA binding protein 6 (GATA6) and Gremlin 1 (GREM1) and inhibition of early growth response protein 1 (Egr1) may be important factors. In this study, we investigated the role of Egr1 in pancreas development. The transfection of small interfering RNA (siRNA) of Egr1 in the early phase induced the differentiation of iPSCs derived from fibroblasts (FiPSCs) into pancreatic endoderm and insulin-producing cells. In contrast, the downregulation of Egr1 in the late phase suppressed the differentiation of FiPSCs into pancreatic endoderm and insulin-producing cells. In addition, the overexpression of Egr1 suppressed the differentiation of iPSCs derived from pancreatic cells into pancreatic endoderm and insulin-producing cells. These data suggest that the downregulation of Egr1 in the early phase can efficiently induce the differentiation of iPSCs into insulin-producing cells.

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  • Evaluation of Islet Purification Methods for Making a Continuous Density Gradient and Loading Tissue Reviewed

    Ebi Nana, Miyagi-Shiohira Chika, Hamada Eri, Tamaki Yoshihito, Masamoto Mariko, Makishi Erika, Nakashima Yoshiki, Kobayashi Naoya, Saitoh Issei, Watanabe Masami, Noguchi Yasufumi, Kinjo Takao, Noguchi Hirofumi

    CELL MEDICINE   10   2018.5

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    Islet purification is one of the most important steps of islet isolation for pancreatic islet transplantation. We previously reported that a purification method using large plastic bottles effectively achieved a high yield of islets from porcine pancreas. In this study, we evaluated the methods for making a continuous density gradient and loading tissue. One method involved loading digested tissue on top of a continuous density gradient (top loading). The other method involved mixing digested tissue with low-density solution and then making a continuous gradient (mixed loading). There were no significant differences between the 2 purification methods in terms of the islet yield, rate of viability or purity, score, or in the stimulation index after purification. Furthermore, there were no marked differences in the attainability or suitability of posttransplantation normoglycemia. Our study shows the equivalency of these 2 methods of islet purification.

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  • Gene therapy for prostate cancer: Current status and future prospects

    Yasutomo Nasu, Masami Watanabe

    Hormone Therapy and Castration Resistance of Prostate Cancer   397 - 406   2018.5

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    Prostate is an ideal target organ for gene therapy as a translational research. It has some advantages as follows: prostate is not a life keeping organ, can be approached easily by ultrasound as a routine clinical practice and PSA is a sensitive and useful tumor marker for the evaluation of clinical response. Intraprostatic therapeutic gene transduction (in situ gene therapy) is one of the potent therapeutic options for prostate cancer gene therapy aiming at antimetastatic benefits through the generation of immune cell-mediated cytotoxic activities that affect not only the primary tumor but also metastatic lesion. In this chapter, current outcome and future prospect of prostate cancer gene therapy are discussed.

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  • Adhesion characteristics of porcine pancreatic islets and exocrine tissue to coating materials Reviewed

    Yoshiki Nakashima, Chika Miyagi-Shiohira, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    Islets   10 ( 3 )   2018.5

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    Since the report of the Edmonton protocol in 2000, islet transplantation has been implemented worldwide, and xenotransplantation using porcine islets has also been reported. In addition, many basic experiments using pancreatic islets and exocrine tissue after isolation have been reported. Recently, exocrine cells have been found to be essential for inducing the differentiation of pancreatic islets. Therefore, the importance of the culture conditions for pancreatic tissue when conducting experiments using pancreatic tissue is also increasing. In this study, we focused on the coat material and examined the adhesive properties of porcine pancreatic islets and exocrine tissue after isolation. Porcine islet isolation was performed, and isolated islets (purity ≥95%) and exocrine tissue (purity ≥99%) were used to achieve adhesion to several extracellular matrixes, fibronectin, collagen type I, collagen type IV, laminin I, fibrinogen, and bovine serum albumin (BSA). DMEM with 0.5% FBS was used as the assay medium. For exocrine tissue, the adhesion was promoted in fibronectin, collagen type I, laminin I, and fibrinogen. The adhesive ability to fibronectin was more than twice that to BSA, while the adhesive ability to collagen type I, laminin I, and fibrinogen was less than twice that to BSA. For islets, the adhesive ability to fibronectin was weaker than that of exocrine tissue. Furthermore, the adhesion effect in fibronectin was obtained within 30 minutes and in medium containing little serum for both islets and exocrine tissues. These data suggest that fibronectin may be useful for the adhesion of pancreatic tissue.

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  • Programmed death ligand 1 expression in bladder. Reviewed

    Peng Zhou, Qiongren Wang, Chongshan Wang, Xiezhao L, Wei Du, Chunxiao Liu, Masami Watanabe, Peng Huang, Abai Xu

    Int J Clin Exp Pathol   2018.4

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  • R132 mutations in canine isocitrate dehydrogenase 1 (IDH1) lead to functional changes Reviewed

    Shota Kawakami, Kazuhiko Ochiai, Daigo Azakami, Yuiko Kato, Masaki Michishita, Masami Morimatsu, Toshina Ishiguro-Oonuma, Eri Onozawa, Masami Watanabe, Toshinori Omi

    Veterinary Research Communications   42 ( 1 )   49 - 56   2018.3

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    Glioma is the second most common intracranial neoplasia in dogs, but the pathogenic mechanisms remain unclear. In humans, isocitrate dehydrogenase 1 (IDH1) is frequently mutated in gliomas. Although almost all human IDH1 mutations have been identified as involving the Arg132 codon, few studies have reported structural, functional, and mutational information for canine IDH1. Therefore, in this study, we cloned the canine IDH1 homologue and used PCR mutagenesis to substitute the wildtype (WT) Arg132 with His (R132H) or Ser (R132S). WT and mutated IDH1 were overexpressed in HeLa cells, and their presence was confirmed by immunoblotting and immunocytochemistry using mutation-specific antibodies. The IDH1 activity between WT, R132H, and R132S transfectants was compared by measuring the production of NADH and NADPH. NADPH production in R132H and R132S transfectants was lower than that in WT, but NADH levels were not significantly different. Finally, we detected increased expression of hypoxia inducible factor 1 alpha (HIF-1α) in the R132H and R132S transfectants. These results indicated that the canine IDH1 Arg132 mutation has the potential to induce carcinogenesis in canine somatic cells.

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  • Glaucocalyxin A induces G2/M cell cycle arrest and apoptosis through the PI3K/Akt pathway in human bladder cancer cells. Reviewed International journal

    Wenfeng Lin, Jinlin Xie, Naijin Xu, Linglong Huang, Abai Xu, Hulin Li, Chaoming Li, Yubo Gao, Masami Watanabe, Chunxiao Liu, Peng Huang

    International journal of biological sciences   14 ( 4 )   418 - 426   2018

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    Glaucocalyxin A (GLA), a major component isolated from Rabdosia japonica, has been proven to show anti-bacterial and anti-tumor biological characteristics according to previous studies. However, its potential effect on bladder cancer remains unknown. The present research aims to investigate the underlying mechanism in treating bladder cancer in vivo and in vitro. Cell proliferation was analyzed by CCK-8 assay and colony formation. Flow cytometry was used to measure the cell cycle distribution and apoptosis. The expressions of the cell cycle and apoptosis-related proteins were detected by western blotting and immunofluorescence staining. Meanwhile, the in vivo study was performed to evaluate the anti-tumor effect on a UMUC3 subcutaneous tumor of NOD/SCID mice model. GLA suppressed colony-formation ability, triggered G2/M arrest and promoted apoptosis of UMUC3 cells in a dose-dependent manner. Furthermore, western blotting showed that GLA downregulated the expressions of PI3K p85, p-Akt, Bcl-2, CDK1, Cyclin B1 whereas upregulated the levels of PTEN, Bax, Cleaved Caspase-3. In vivo, GLA at a dosage of 20 mg/kg significantly inhibited tumor growth compared with the control group by intraperitoneal injection. These results suggested that GLA-related G2/M arrest and apoptosis in UMUC3 cells were mediated by a suppressed PI3K/Akt signaling pathway, which regulated p21Waf1/Cip1 as well as intrinsic caspase cascade. Collectively, our observations could help to develop new drugs targeting the PI3K/Akt pathway for the treatment of bladder cancer.

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  • Functional alteration of canine isocitrate dehydrogenase 2 (IDH2) via an R174K mutation Reviewed

    Shota Kawakami, Kazuhiko Ochiai, Yuiko Kato, Masaki Michishita, Hinako Hirama, Ryo Obara, Daigo Azakami, Masami Watanabe, Toshinori Omi

    Journal of Veterinary Medical Science   80 ( 1 )   85 - 91   2018

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    Gliomas are common intracranial neoplasias in dogs. However, the underlying pathogenic mechanisms remain unclear. In humans, isocitrate dehydrogenase 2 (IDH2) is often mutated in gliomas. Although almost human IDH2 mutations have been identified at the Arg172 codon, few studies have reported structural, functional or mutational information for canine IDH2. In this study, we cloned the full-length canine IDH2 (cIDH2) cDNA and substituted wild type Arg174 (cIDH2 WT: corresponding to R172 of human IDH2) with Lys (cIDH2 R174K). The cIDH2 WT and R174K proteins were overexpressed in HeLa cells, and their presence was confirmed using an anti-human IDH2-WT mAb (clone: KrMab-3) and an anti-IDH2-R172K mAb (clone: KMab-1). The IDH2 activity between cIDH2 WT and cIDH2 R174K transfectants was compared by measuring the production of NADH and NADPH. NADPH production was lower for cIDH2 R174K than that for cIDH2 WT transfectants. Finally, we detected increased expression of hypoxia inducible factor-1 alpha (HIF-1α) in cIDH2 R174K transfectants. This indicates that mutations at R174 can potentially induce carcinogenesis in canine somatic cells.

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  • Induction of cells with prostate cancer stem-like properties from mouse induced pluripotent stem cells via conditioned medium. Reviewed International journal

    Naijin Xu, Xiezhao Li, Masami Watanabe, Hideo Ueki, Hao Hu, Na Li, Motoo Araki, Koichiro Wada, Abai Xu, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    American journal of cancer research   8 ( 8 )   1624 - 1632   2018

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    Cancer stem cells (CSCs) that closely correlated with tumor growth, metastasis, provide a plausible explanation for chemoresistance and cancer relapse. CSCs are usually isolated and enriched from carcinoma cells, which is inconvenient, low-efficient, and even unreliable. Here, we converted mouse induced pluripotent stem cells (miPSCs) into prostate cancer stem-like cells with carcinoma microenvironment following exposure to conditioned medium (CM) derived from RM9, a mouse prostate cancer cell line. These transformed cells, termed as miPS-RM9CM, displayed CSCs properties, including spheroids morphology and expression of both stemness genes and cancer stem cells surface markers, such as Oct3/4, Sox2, Nanog, Klf-4, c-Myc, CD44, and CD133. In addition, in vivo transplantation experiment was performed to confirm the tumorigenicity. Furthermore, we used the model to assess conventional chemotherapeutic agent, docetaxel. The results showed that miPS-RM9CM cells exhibited increased resistance to docetaxel, however, high susceptibility to the cancer cell stemness inhibitor I (BBI-608). Our current study demonstrates that CM from cultured RM9 cells play a crucial role in the determination of cell fate from miPSCs to cancer stem-like cells and provide a potentially valuable system for the study of CSCs.

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  • Properties of the feline tumour suppressor reduced expression in immortalized cells (REIC/Dkk-3) Reviewed

    K. Ochiai, H. Oda, S. Shono, Y. Kato, S. Sugihara, S. Nakazawa, D. Azakami, M. Michishita, E. Onozawa, M. Bonkobara, T. Sako, L. Shun-Ai, H. Ueki, M. Watanabe, T. Omi

    VETERINARY AND COMPARATIVE ONCOLOGY   15 ( 4 )   1181 - 1186   2017.12

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    Reduced expression in immortalized cells (REIC/Dkk-3), a member of the human Dickkopf (Dkk) family, is a growth suppressor in human and canine mammary tumours. Mammary gland tumours are common neoplasms with high malignancy in female cats. The purpose of this study was to clone the feline REIC/Dkk-3 homolog, investigate its expression in cell lines established from feline mammary gland tumours, and test its tumour suppressor function. Western blot analysis revealed that expression of the REIC/Dkk-3 protein was reduced in feline mammary carcinoma cell lines. Forced expression of REIC/Dkk-3 induced apoptosis in feline mammary tumour cell lines. These results demonstrate that REIC/Dkk-3 expression, which is downregulated in feline mammary tumour cell lines, results in the induction of apoptosis in these cells. Our findings suggest that feline REIC/Dkk-3 represents a potential molecular target for the development of therapies against feline mammary cancers.

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  • Exogenous DKK-3/REIC inhibits Wnt/beta-catenin signaling and cell proliferation in human kidney cancer KPK1 Reviewed

    Jiaqi Xu, Takuya Sadahira, Rie Kinoshita, Shun-Ai Li, Peng Huang, Koichiro Wada, Motoo Araki, Kazuhiko Ochiai, Hirofumi Noguchi, Masakiyo Sakaguchi, Yasutomo Nasu, Masami Watanabe

    ONCOLOGY LETTERS   14 ( 5 )   5638 - 5642   2017.11

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    The third member of the Dickkopf family (DKK-3), also known as reduced expression in immortalized cells (REIC), is a tumor suppressor present in a variety of tumor cells. Regarding the regulation of the Wnt/beta-catenin signaling pathway, exogenous DKK-1 and DKK-2 are reported to inhibit Wnt signaling by binding the associated effectors. However, whether exogenous DKK-3 inhibits Wnt signaling remains unclear. A recombinant protein of human full-length DKK-3 was used to investigate the exogenous effects of the protein in vitro in KPK1 human renal cell carcinoma cells. It was demonstrated that the expression of phosphorylated (p-)beta-catenin (inactive form as the transcriptional factor) was increased in KPK1 cells treated with the exogenous DKK-3 protein. The levels of non-p-beta-catenin (activated form of beta- catenin) were consistently decreased. It was revealed that the expression of transcription factor (TCF) 1 and c-Myc, the downstream transcription factors of the Wnt/beta-catenin signaling pathway, was inhibited following treatment with DKK-3. A cancer cell viability assay confirmed the anti-proliferative effects of exogenous DKK-3 protein, which was consistent with a suppressed Wnt/beta-catenin signaling cascade. In addition, as low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor of DKK-1 and DKK-2 and their interaction on the cell surface inhibits Wnt/beta-catenin signaling, it was examined whether the exogenous DKK-3 protein affects LRP6-mediated Wnt/beta-catenin signaling. The LRP6 gene was silenced and the effects of DKK-3 on the time course of the upregulation of p-beta-catenin expression were subsequently analyzed. Notably, LRP6 depletion elevated the base level of p-beta-catenin; however, there was no significant effect on its upregulation course or expression pattern. These findings indicate that exogenous DKK-3 upregulates p-beta-catenin and inhibits Wnt/beta-catenin signaling in an LRP6-independent manner. Therefore, exogenous DKK-3 protein may inhibit the proliferation of KPK1 cells via inactivating Wnt/beta-catenin signaling.

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  • Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf-3 expressing adenoviral vector for hepatocellular carcinoma Reviewed

    Hiroaki Sawahara, Hidenori Shiraha, Daisuke Uchida, Hironari Kato, Ryo Kato, Atsushi Oyama, Teruya Nagahara, Masaya Iwamuro, Shigeru Horiguchi, Koichiro Tsutsumi, Mari Mandai, Tetsushige Mimura, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Masami Watanabe, Masakiyo Sakaguchi, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Okada

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   32 ( 10 )   1769 - 1777   2017.10

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    Background and Aim: Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed.
    Methods: Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice.
    Results: REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6).
    Conclusions: Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

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  • Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells Reviewed

    Yuhei Horikawa, Masami Watanabe, Takuya Sadahirai, Yuichi Ariyoshi, Yasuyuki Kobayashi, Motoo Araki, Koichiro Wada, Kazuhiko Ochiai, Shun-Ai Li, Yasutomo Nasu

    ONCOLOGY LETTERS   14 ( 3 )   3223 - 3228   2017.9

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    Our group previously developed an adenoviral vector encoding the REIC/Dkk-3 gene (Ad-REIC), a tumor suppressor, for cancer gene therapy. The Ad-REIC agent induces apoptosis and inhibits invasion in a number of cancer cell lines; however, the molecular mechanisms underlying its effects remain unclear. Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a key molecule that promotes cancer proliferation and invasion. In order to elucidate the therapeutic mechanism of Ad-REIC, its effect on the expression of CD147 in human bladder cancer KK47 cells was investigated. Treatment with Ad-REIC markedly downregulated the expression of CD147 and significantly inhibited cellular proliferation. Since the expression of CD147 is reported to be under the positive control of mitogen-activated protein kinase (MAPK) signaling and the c-Myc protein, the correlations between the expression of CD147 and the activation of MAPKs or the expression of c-Myc were examined. Unexpectedly, no positive correlation was observed between the level of CD147 and the potential regulators that were assessed, indicating that another signaling pathway is responsible for the downregulation of CD147. The results from the present study demonstrate that Ad-REIC treatment can significantly downregulate the expression of CD147 in bladder cancer cells. Downregulation of the cancer-progression factor CD147 may be a novel mechanism that underlies the therapeutic effects of Ad-REIC treatment.

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  • Robust cancer-specific gene expression by a novel cassette with hTERT and CMV promoter elements Reviewed

    Masakiyo Sakaguchi, Takuya Sadahira, Hideo Ueki, Rie Kinoshita, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Yasutomo Nasu, Kazuhiko Ochiai, Hiromi Kumon, Nam-Ho Huh, Masami Watanabe

    ONCOLOGY REPORTS   38 ( 2 )   1108 - 1114   2017.8

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    We developed and validated a novel hTERT/CMV promoter element-driven gene expression cassette that can robustly enhance cancer-specific gene expression. The following gene expressional elements were located in tandem within the plasmid construct: [hTERT core promoter, cytomegalovirus (CMV) minimized promoter, RU5' sequence, an inserted gene, BGH polyA, hTERT enhancer]; this is hereafter referred to as the hT/Cm-R-hT construct. Using various human cancer cell lines and normal cells, the cancer-specific transcription of the green fluorescent protein (GFP) gene was examined by western blotting and fluorescence microscopy. Cancer-specific gene expression was robustly achieved in the hT/Cm-R-hT plasmid in comparison to the other control hT/Cm-driven construct. Notably, the expression level of GFP observed in the hT/Cm-RhT-driven construct was superior to that of the control plasmid with the conventional CMV promoter in HEK293 cells, which are known to possess higher hTERT activity than normal cells. We next examined the availability of hT/Cm-R-hT in detecting the target GFP expressing cancer cells from human peripheral blood mononuclear cells (PBMCs). The hT/Cm-R-hT plasmid successfully induced cancer-specific gene expression; the robust expression of GFP was observed in target HeLa cancer cells, whereas GFP was not visibly expressed in normal PBMCs. The plasmid allowed for the selective visualization of viable HeLa cancer cells in mixed cell cultures containing up to 10000-fold more PBMCs. These findings indicate that the hT/Cm-R-hT expressional system is a valuable tool for detecting viable cancer cells mixed with normal cells. The current system can therefore be applied to the in vitro detection of cancer cells that are disseminated in the blood and other types of body fluid in vivo. Since the current system can also be applied to other types of vectors, including virus vectors, this approach using the hTERT promoter-based construct is expected to become a valuable tool for enhancing cancer specific gene expression.

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  • Robotic Renal Autotransplantation: First Case Outside of North America Reviewed

    Motoo Araki, Koichiro Wada, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Takashi Yoshioka, Yuichi Ariyoshi, Kei Fujio, Atsushi Takamoto, Morito Sugimoto, Katsumi Sasaki, Yasuyuki Kobayashi, Shin Ebara, Hideki Taninishi, Hiroyuki Amano, Masashi Inui, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   71 ( 4 )   351 - 355   2017.8

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    A 38-year-old woman with a 2.7-cm left ureteral stenosis requiring chronic ureteral stent exchange elected to undergo robotic renal autotransplantation. Left ureteropelvic junction obstruction (UPJO) was also suspected. Robotic donor nephrectomy contributed to the fine dissection for desmoplastic changes. The kidney was removed through a Gelport and examined on ice. UPJO was not seen. An end-to-side robotic anastomosis was created between the renal and external iliac vessels. The console time was 507 min, and the warm ischemia time was 4 min 5 sec. She became stent-free. Robotic renal autotransplantation is a new, minimally invasive approach to renal preservation.

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  • The assessment of renal cortex and parenchymal volume using automated CT volumetry for predicting renal function after donor nephrectomy Reviewed

    Yosuke Mitsui, Takuya Sadahira, Motoo Araki, Koichiro Wada, Ryuta Tanimoto, Yuichi Ariyoshi, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Clinical and Experimental Nephrology   22 ( 2 )   1 - 6   2017.7

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    Background: Contrast-enhanced CT is necessary before donor nephrectomy and is usually combined with a Tc-99m-mercapto-acetyltriglycine (MAG3) scan to check split renal function (SRF). However, all transplant programs do not use MAG3 because of its high cost and exposure to radiation. We examined whether CT volumetry of the kidney can be a new tool for evaluating SRF. Methods: Sixty-three patients underwent live donor nephrectomy. Patients without a 1.0 mm slice CT or follow-up for &lt
    12 months were excluded leaving 34 patients’ data being analyzed. SRF was measured by MAG3. Split renal volume (SRV) was calculated automatically using volume analyzer software. The correlation between SRF and SRV was examined. The association between the donor’s postoperative estimated glomerular filtration rate (eGFR) and predicted eGFR calculated by MAG3 or CT volumetry was analyzed at 1, 3, and 12 months post nephrectomy. Results: Strong correlations were observed preoperatively in a Bland–Altman plot between SRF measured by MAG3 and either CT cortex or parenchymal volumetry. In addition, eGFR after donation correlated with SRF measured by MAG3 or CT volumetry. The correlation coefficients (R) for eGFR Mag3 split were 0.755, 0.615, and 0.763 at 1, 3 and 12 months, respectively. The corresponding R values for cortex volume split were 0.679, 0.638, and 0.747. Those for parenchymal volume split were 0.806, 0.592, and 0.764. Conclusion: Measuring kidney by CT volumetry is a cost-effective alternative to MAG3 for evaluating SRF and predicting postoperative donor renal function. Both cortex and parenchymal volumetry were similarly effective.

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  • Expression of tumor suppressor REIC/Dkk-3 by a newly improved adenovirus vector with insertion of a hTERT promoter at the 3'-side of the transgene Reviewed

    Endy Widya Putranto, Rie Kinoshita, Masami Watanabe, Takuya Sadahira, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Ken Kataoka, Yusuke Inoue, I. Made Winarsa Ruma, I. Wayan Sumardika, Chen Youyi, Miyoko Kubo, Yoshihiko Sakaguchi, Kenji Saito, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh, Masakiyo Sakaguchi

    ONCOLOGY LETTERS   14 ( 1 )   1041 - 1048   2017.7

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    Reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3) overexpression, induced using an adenovirus (Ad)-REIC, has been revealed to have a dramatic therapeutic effect on multiple types of cancer. To achieve an improved therapeutic effect from Ad-REIC on cancer, our group previously developed an enhanced gene expression system, the C-TSC cassette [cytomegalovirus (CMV)-RU5' located upstream (C); another promoter unit composed of triple tandem promoters, human telomerase reverse transcriptase (hTERT), simian virus 40 and CMV, located downstream of the cDNA (TSC); plus a polyadenylation (polyA) signal]. When applied to the conventional Ad-REIC, this novel system induced the development of an enhanced product, Ad-C-TSC-REIC, which exhibited a noticeable anticancer effect. However, there were difficulties in terms of Ad-C-TSC-REIC productivity in HEK293 cells, which are a widely used donor cell line for viral production. Productivity of Ad-C-TSC-REIC was significantly reduced compared with the conventional Ad-REIC, as the Ad-C-TSC-REIC had a significantly higher ability to induce apoptotic cell death of not only various types of cancer cell, but also HEK293 cells. The present study aimed to overcome this problem by modifying the C-TSC structure, resulting in an improved candidate: A C-T cassette (C: CMV-RU5' located upstream; T: another promoter unit composed of a single hTERT promoter, located downstream of the cDNA plus a polyA signal), which demonstrated gene expression comparable to that of the C-TSC system. The improved adenovirus REIC/Dkk-3 product with the C-T cassette, named Ad-C-T-REIC, exhibited a higher expression level of REIC/Dkk3, similar to that of Ad-C-TSC-REIC. Notably, the vector mitigated the cell death of donor HEK293 cells, resulting in a higher rate of production of its adenovirus. These results indicated that Ad-C-T-REIC has the potential to be a useful tool for application in cancer gene therapy.

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  • Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. Reviewed

    Suzawa K, Shien K, Peng H, Sakaguchi M, Watanabe M, Hashida S, Maki Y, Yamamoto H, Tomida S, Soh J, Asano H, Tsukuda K, Nasu Y, Kumon H, Miyoshi S, Toyooka S

    Anticancer Res   37 ( 1 )   301 - 307   2017.6

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  • Canine REIC/Dkk-3 interacts with SGTA and restores androgen receptor signalling in androgen-independent prostate cancer cell lines Reviewed

    Yuiko Kato, Kazuhiko Ochiai, Shota Kawakami, Nobuhiro Nakao, Daigo Azakami, Makoto Bonkobara, Masaki Michishita, Masami Morimatsu, Masami Watanabe, Toshinori Omi

    BMC VETERINARY RESEARCH   13 ( 1 )   170   2017.6

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    Background: The pathological condition of canine prostate cancer resembles that of human androgen-independent prostate cancer. Both canine and human androgen receptor (AR) signalling are inhibited by overexpression of the dimerized co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein a (SGTA), which is considered to cause the development of androgen-independency. Reduced expression in immortalised cells (REIC/Dkk-3) interferes with SGTA dimerization and rescues AR signalling. This study aimed to assess the effects of REIC/Dkk-3 and SGTA interactions on AR signalling in the canine androgen-independent prostate cancer cell line CHP-1.
    Results: Mammalian two-hybrid and Halo-tagged pull-down assays showed that canine REIC/Dkk-3 interacted with SGTA and interfered with SGTA dimerization. Additionally, reporter assays revealed that canine REIC/Dkk-3 restored AR signalling in both human and canine androgen-independent prostate cancer cells. Therefore, we confirmed the interaction between canine SGTA and REIC/Dkk-3, as well as their role in AR signalling.
    Conclusions: Our results suggest that this interaction might contribute to the development of a novel strategy for androgen-independent prostate cancer treatment. Moreover, we established the canine androgen-independent prostate cancer model as a suitable animal model for the study of this type of treatment-refractory human cancer.

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  • RCAN-11R peptide provides immunosuppression for fully mismatched islet allografts in mice Reviewed

    Hirofumi Noguchi, Koji Sugimoto, Chika Miyagi-Shiohira, Yoshiki Nakashima, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Yasufumi Noguchi

    SCIENTIFIC REPORTS   7 ( 1 )   3043 - 3043   2017.6

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    Calcineurin inhibitors have been used for transplant therapy. However, the inhibition of calcineurin outside the immune system has a number of side effects. We previously developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system. This peptide (11R-VIVIT) selectively interferes with calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase and provides immunosuppression for fully mismatched islet allografts in mice. However, our recent study showed that 11R-VIVIT affected cell viability in vitro when it was used at higher concentration because of the VIVIT sequence. The aim of this study is to develop a safer NFAT inhibitor (RCAN-11R) that does not affect cell viability, and which is less toxic than calcineurin inhibitors. The minimal sequence of the protein family of regulators of calcineurin (RCAN) that is responsible for the inhibition of calcineurin-NFAT signaling was recently characterized. The peptide could selectively interfere with the calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase, similar to 11R-VIVIT. RCAN-11R did not affect cell viability when it was used at a higher concentration than the toxic concentration of 11R-VIVIT. RCAN-11R could therefore be useful as a therapeutic agent that is less toxic than current drugs or 11R-VIVIT.

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  • The canine prostate cancer cell line CHP-1 shows over-expression of the co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein Reviewed

    D. Azakami, R. Nakahira, Y. Kato, M. Michishita, M. Kobayashi, E. Onozawa, M. Bonkobara, M. Kobayashi, K. Takahashi, M. Watanabe, K. Ishioka, T. Sako, K. Ochiai, T. Omi

    VETERINARY AND COMPARATIVE ONCOLOGY   15 ( 2 )   557 - 562   2017.6

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    Although androgen therapy resistance and poor clinical outcomes are seen in most canine prostate cancer cases, there are only a few tools for analysing canine prostate cancer by using a cell biological approach. Therefore, to evaluate androgen-independent neoplastic cell growth, a new canine prostate cancer cell line (CHP-1) was established in this study. CHP-1 over-expressed the co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein (SGTA), which is over-expressed in human androgen-independent prostate cancer. The CHP-1 xenograft also showed SGTA over-expression. Although CHP-1 shows poor androgen receptor (AR) signalling upon dihydrotestosterone stimulation, forced expression of AR enabled evaluation of AR signalling. Taken together, these results suggest that CHP-1 will be a useful model for investigating the pathogenesis of androgen-dependent and androgen-independent canine prostate cancer.

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  • Clinical pharmacokinetics of oral levofloxacin and sitafloxacin in epididymal tissue Reviewed

    Takuya Sadahira, Koichiro Wada, Kazuro Ikawa, Norifumi Morikawa, Hiroaki Kurahashi, Takashi Yoshioka, Yuichi Ariyoshi, Yasuyuki Kobayashi, Motoo Araki, Ayano Ishii, Masami Watanabe, Shinya Uehara, Toyohiko Watanabe, Yasutomo Nasu

    JOURNAL OF INFECTION AND CHEMOTHERAPY   23 ( 4 )   214 - 217   2017.4

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    Objectives: This study aimed to investigate the penetration of fluoroquinolones into human epididymal tissue.
    Methods: The penetration of levofloxacin (LVFX) 500 mg or sitafloxacin (STFX) 100 mg into epididymal tissue was examined. Patients with prostate cancer who were referred for orchiectomy were included. LVFX 500 mg (n = 9) or STFX 100 mg (n = 9) was administered orally 1 h before orchiectomy, and 0.5 g of epididymal tissue and blood samples were collected simultaneously during surgery. Drug concentrations were measured by high-performance liquid chromatography, and patient characteristics and adverse events were analyzed.
    Results: The mean ratio of the epididymal concentration to the serum concentration was 1.48 +/- 0.45 for LVFX and 1.54 +/- 0.81 for STFX. For LVFX, the simulated curves estimated the following: maximum concentrations (Cmax) of 8.84 mu g/ml in serum and 14.1 mu g/g in epididymal tissue and area under the concentration-time curve for 24 h (AUC(24)) of 68.5 mu g h/ml in serum and 108.9 mu g h/g in epididymal tissue. For STFX, the Cmax was 1.22 mu g/ml in serum and 1.66 mu g/g in epididymal tissue, and the AUC24 was 9.58 mu g h/ml in serum and 13.1 mu g h/g in epididymal tissue. Neither treatment-related adverse events nor postoperative urogenital infections were observed.
    Conclusions: The results of this study suggest that oral administration of LVFX 500 mg or STFX 100 mg achieves effective epididymal concentrations for treatment of epididymitis. (C) 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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  • The Downregulation of the Expression of CD147 by Tumor Suppressor REIC/Dkk-3, and Its Implication in Human Prostate Cancer Cell Growth Inhibition Reviewed

    Akihiro Mori, Masami Watanabe, Takuya Sadahira, Yasuyuki Kobayashi, Yuichi Ariyoshi, Hideo Ueki, Koichiro Wada, Kazuhiko Ochiai, Shun-Ai Li, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   71 ( 2 )   135 - 142   2017.4

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    The cluster of differentiation 147 (CD147), also known as EMMPRIN, is a key molecule that promotes cancer progression. We previously developed an adenoviral vector encoding a tumor suppressor REIC/Dkk-3 gene (Ad-REIC) for cancer gene therapy. The therapeutic effects are based on suppressing the growth of cancer cells, but, the underlying molecular mechanism has not been fully clarified. To elucidate this mechanism, we investigated the effects of Ad-REIC on the expression of CD147 in LNCaP prostate cancer cells. Western blotting revealed that the expression of CD147 was significantly suppressed by Ad-REIC. Ad-REIC also suppressed the cell growth of LNCaP cells. Since other researchers have demonstrated that phosphorylated mitogen-activated protein kinases (MAPKs) and c-Myc protein positively regulate the expression of CD147, we investigated the correlation between the CD147 level and the activation of MAPK and c-Myc expression. Unexpectedly, no positive correlation was observed between CD147 and its possible regulators, suggesting that another signaling pathway was involved in the downregulation of CD147. This is the first study to show the downregulation of CD147 by Ad-REIC in prostate cancer cells. At least some of the therapeutic effects of Ad-REIC may be due to the downregulation of the cancer-progression factor, CD147.

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  • Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma Reviewed

    Xiezhao Li, Peng Xu, Chongshan Wang, Naijin Xu, Abai Xu, Yawen Xu, Takuya Sadahira, Motoo Araki, Koichiro Wada, Eiji Matsuura, Masami Watanabe, Junxia Zheng, Pinghua Sun, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    ONCOTARGET   8 ( 13 )   21177 - 21186   2017.3

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    Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.

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  • Programmed death ligand 1 expression in bladder rhabdomyosarcoma and its association with clinicopathological features Reviewed

    Peng Zhou, Qiongren Wang, Chongshan Wang, Xiezhao Li, Wei Du, Chunxiao Liu, Masami Watanabe, Peng Huang, Abai Xu

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY   10 ( 10 )   10565 - 10570   2017

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    The aim of this study was to detect PD-L1 expression in bladder rhabdomyosarcoma and its association with clinicopathological features and patient prognosis. PD-L1 expression was detected in paraffin-embedded sections obtained from 34 patients with bladder rhabdomyosarcoma via immunohistochemistry. Immunohistochemistry results were statistically analyzed to determine their association with patient clinicopathological features and survival outcomes. PD-L1-positive staining was observed in 47.1% (16/34) of patients. Metastatic tumor cells in the lymph nodes of two patients were positive for PD-L1 expression. PD-L1 expression was significantly different with regard to muscularis invasion, but the expression did not affect patient survival outcomes. We confirmed PD-L1 expression in bladder rhabdomyosarcoma, suggesting that PD-1/PD-L1 inhibitors are potential therapeutic agents for patients with bladder rhabdomyosarcoma.

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  • A proteome analysis of pig pancreatic islets and exocrine tissue by liquid chromatography with tandem mass spectrometry Reviewed

    Yoshiki Nakashima, Chika Miyagi-Shiohira, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi

    ISLETS   9 ( 6 )   159 - 176   2017

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    Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is a proteome analysis method, and the shotgun analysis by LC-MS/MS comprehensively identifies proteins from tissues and cells with high resolving power. In this study, we analyzed the protein expression in pancreatic tissue by LC-MS/MS. Islets isolated from porcine pancreata (purity 95%) and exocrine tissue (purity 99%) were used in this study. LC-MS/MS showed that 13 proteins were expressed in pancreatic islets only (Group I), 43 proteins were expressed in both islets and exocrine tissue (Group I&E), and 102 proteins were expressed in exocrine tissue only (Group E). Proteins involved in islet differentiation and cell proliferation were identified in Group I (e.g. CLUS, CMGA, MIF). In addition, various functional proteins (e.g. SCG2, TBA1A) were identified in islet by using the new method of principal component analysis (PCA)'. However, the function of such proteins on islets remains unclear. EPCAM was identified in Group E. Group E was found to include proteins involved in clinical inflammatory diseases such as pancreatitis (e.g. CBPA1, CGL, CYTB, ISK1 and PA21B). Many of these identified proteins were reported less frequently in previous studies, and HS71B, NEC2, PRAF3 and SCG1 were newly detected in Group I while CPNS1, DPEP1, GANAB, GDIB, GGT1, HSPB1, ICTL, VILI, MUTA, NDKB, PTGR1, UCHL3, VAPB and VINC were newly detected in Group E. These results show that comprehensive expression analysis of proteins by LC-MS/MS is useful as a method to investigate new factors constructing cellular component, biological process, and molecular function.

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  • Efficacy and safety of 3 day versus 7 day cefditoren pivoxil regimens for acute uncomplicated cystitis: Multicentre, randomized, open-label trial Reviewed

    Takuya Sadahira, Okayama Urological Research Group (OURG), Koichiro Wada, Motoo Araki, Ayano Ishii, Atsushi Takamoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon, Teruaki Akaeda, Nobuyuki Akazawa, Naoki Akebi, Daiji Araki, Tohru Araki, Ryoji Arata, Yuichi Ariyoshi, Eiichi Ando, Nobuyoshi Ando, Kazushi Ishii, Tsutomu Ishikawa, Noritaka Ishito, Takaharu Ichikawa, Takaaki Inoue, Miyabi Inoue, Yosuke Inoue, Shin Irie, Takehiro Iwata, Tatsuya Uesugi, Shinya Uehara, Katsutoshi Uematsu, Satoshi Uno, Kohei Edamura, Shin Ebara, Yuko Oiwa, Tadashi Oeda, Teruhisa Ohashi, Yozo Ohashi, Hideo Ozawa, Junzo Ochi, Noriaki Ono, Seiji Kai, Haruki Kaku, Satoshi Katayama, Yasuhiro Katayama, Tetuzo Kaneshige, Keiichiro Kawauchi, Masashi Kawaguchi, Tatsushi Kawada, Taiki Kanbara, Mikio Kishi, Ryo Kishimoto, Nobuyuki Kusaka, Norihiro Kusumi, Kimito Kunitomi, Risa Kubota, Hiroaki Kurahashi, Hironori Kojima, Tomoko Kobayashi, Makoto Kobuke, Katsuyoshi Kondo, Takashi Saika, Kazuma Sakaeda, Koji Sakuramoto, Shinichi Sako, Tomoko Sako, Taketo Sasaoka, Katsumi Sasaki, Yoshimasa Jo, Morito Sugimoto, Yuko Seno, Akira Takao, Kosuke Takamura, Kousuke Takamura, Hitoshi Takamoto, Katsuji Takeda, Tadasu Takenaka, Daisuke Tanaka, Ryuta Tanimoto, Masaya Tsugawa, Tomoyasu Tsushima, Hiromu Tsuboi, Syunji Tojo, Kenji Tokinaga, Yusuke Tominaga, Keisuke Doi, Atsushi Nagai, Hirochika Nakajima, Tetsuya Nakada, Hirokazu Nakatsuka, Aya Nakamura, Yasuki Nakayama, Yoshitsugu Nasu, Daisuke Nishikawa, Jun Nishiguchi, Yoshio Nishitani, Shingo Nishimura, Motoichi Nishimura, Yasuhiro Nishiyama, Hajime Nibuno, Kunihiro Nozaki, Hiroyuki Nose, Gaku Noda, Hideaki Hashimoto, Kazuhiro Hata, Toshihide Hayashi, Nobuki Hayashi, Syunji Hayata, Ryoei Hara, Takeshi Hirata, Tomohiro Fujii, Kei Fujio, Ryuji Fujita, Kensuke Bekku, Takanori Maehara, Yoshio Maki, Yuko Matsumoto, Daisuke Manabe, Yusuke Mayumi, Yuki Maruyama, Yosuke Mitsui, Sadayuki Miyaji, Syuhei Munemasa, Wataru Murao, Takanori Murakami, Tadashi Murata, Akihiro Mori, Akira Morita, Koichi Monden, Tomoya Yamasaki, Masahiro Yamashita, Daiduke Yamada, Toyoko Yamato, Toru Yamane, Tomoaki Yamanoi, Yasuo Yamamoto, Kazuaki Yukari, Teruhiko Yokoyama, Takashi Yoshioka, Yuichi Watanabe

    Journal of Antimicrobial Chemotherapy   72 ( 2 )   529 - 534   2017

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    Background: Fluoroquinolone-non-susceptible Escherichia coli isolated from patients with acute uncomplicated cystitis are a matter of increasing concern. Cefditoren pivoxil is an oral, β-lactamase-stable, extended-spectrum cephalosporin that is effective against fluoroquinolone-non-susceptible bacteria. Objectives: To evaluate the clinical and microbiological efficacies of cefditoren pivoxil against acute uncomplicated cystitis and to determine the optimal duration of cefditoren pivoxil treatment. Methods: We compared 3 and 7 day regimens of cefditoren pivoxil in a multicentre, randomized, open-label study. Results: A total of 104 female patients with acute uncomplicated cystitis were enrolled and randomized into 3 day (n=51) or 7 day (n=53) treatment groups. At first visit, 94 bacterial strains were isolated from the 104 participants of which 81.7% (85/104) were E. coli. Clinical and microbiological efficacies were evaluated 5-9 days following administration of the final dose of cefditoren pivoxil. The clinical efficacies of the 3 and 7 day groups were 90.9% (40/44) and 93.2% (41/44), respectively (P=1.000). The microbiological efficacies of the 3 and 7 day groups were 82.5% (33/40) and 90.2% (37/41), respectively (P=0.349). There were no adverse events due to cefditoren pivoxil treatment, with the exception of a mild allergic reaction in one patient, after which the cefditoren pivoxil was exchanged for another antimicrobial. Conclusions: Cefditoren pivoxil is safe and effective for uncomplicated cystitis, with no significant differences in clinical and microbiological efficacies between 3 and 7 day regimens.

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  • Dynamin2 GTPase contributes to invadopodia formation in invasive bladder cancer cells Reviewed

    Yubai Zhang, Maya Nolan, Hiroshi Yamada, Masami Watanabe, Yasutomo Nasu, Kohji Takei, Tetsuya Takeda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   480 ( 3 )   409 - 414   2016.11

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    Cancer cell invasion is mediated by actin-based membrane protrusions termed invadopodia. Invadopodia consist of "core" F-actin bundles associated with adhesive and proteolytic machineries promoting cell invasion by degrading extracellular matrix (ECM). Formation of the F-actin core in invadopodia is regulated by various actin-binding proteins including Arp2/3 complex and cortactin. Dynamin GTPase localizes to the invadopodia and is implicated in cancer cell invasion, but its precise role at the invadopodia remained elusive.
    In this study, we examined the roles of dynamin at the invadopodia of bladder cancer cells. Although all three dynamin isoforms (dynamin1, 2 and 3) are expressed in human bladder cancer cell line T24, only dynamin2 localizes to the invadopodia. Inhibition of dynamin2 function, using either RNA interference (RNAi) or the dynamin specific inhibitor Dynasore, caused defects in invadopodia formation and suppressed invasive activity of 124 bladder cancer cells. Structure-function analysis using dynamin2 deletion fragments identified the proline/arginine-rich domain (PRD) of dynamin2 as indispensable for invadopodia formation and invasiveness of 124 cells. Thus, dynamin2 contributes to bladder cancer invasion by controlling invadopodia formation in bladder cancer cells and may prove a valuable therapeutic target. (C) 2016 Elsevier Inc. All rights reserved.

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  • Adenovirus vector carrying REICIDKK-3 gene: neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy Reviewed

    H. Kumon, Y. Ariyoshi, K. Sasaki, T. Sadahira, M. Araki, S. Ebara, H. Yanai, M. Watanabe, Y. Nasu

    CANCER GENE THERAPY   23 ( 11 )   400 - 409   2016.11

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    As the First-In-Human study of in situ gene therapy using an adenovirus vector carrying the human REIC (reduced expression in immortalized cell)/Dkk-3 gene (Ad-REIC), we conducted neoadjuvant intraprostatic injections in patients with high-risk localized prostate cancer undergoing radical prostatectomy (RP). Patients with recurrence probability of 35% or more within 5 years following RP, as calculated by Kaftan's nomogram, were enrolled. Patients received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. After confirming the safety of the therapeutic interventions with initially planned three escalating doses of 1.0 x 10(10), 1.0 x 10(11) and 1.0 x 10(12) viral particles (vp) in 1.0-1.2 ml (n=3, 3 and 6), an additional higher dose of 3.0 x 10(12) vp in 3.6 ml (n=6) Was further studied. All four DLs including the additional dose level-4 (DL-4) were feasible with no adverse events, except for grade 1 or 2 transient fever. Laboratory toxicities were grade 1 or 2 elevated aspartate transaminase/alanine transaminase (n=4). Regarding antitumor activities, cytopathic effects (tumor degeneration With cytolysis and pyknosis) and remarkable tumor-infiltrating lymphocytes in the targeted tumor areas were detected in a clear dose-dependent manner. Consequently, biochemical recurrence-free survival in DL-4 was significantly more favorable than in patient groups DL-1+2+2:

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  • Comparison of Purification Solutions With Different Osmolality for Porcine Islet Purification. Reviewed

    Miyagi-Shiohira C, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M, Noguchi H

    Cell Med   9 ( 1月2日 )   53 - 59   2016.9

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  • The Evaluation of Islet Purification Methods That Use Large Bottles to Create a Continuous Density Gradient. Reviewed

    Miyagi-Shiohira C, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M, Noguchi H

    Cell Med   9 ( 1月2日 )   45 - 51   2016.9

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  • Evaluation of Serum-Free, Xeno-Free Cryopreservation Solutions for Human Adipose-Derived Mesenchymal Stem Cells. Reviewed

    Miyagi-Shiohira C, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M, Noguchi H

    Cell Med   9 ( 1月2日 )   15 - 20   2016.9

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  • A super gene expression system enhances the anti-glioma effects of adenovirus-mediated REIC/Dkk-3 gene therapy Reviewed

    Tetsuo Oka, Kazuhiko Kurozumi, Yosuke Shimazu, Tomotsugu Ichikawa, Joji Ishida, Yoshihiro Otani, Toshihiko Shimizu, Yusuke Tomita, Masakiyo Sakaguchi, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Isao Date

    SCIENTIFIC REPORTS   6   2016.9

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    Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and therapeutic gene in many human cancers. Recently, an adenovirus REIC vector with the super gene expression system (Ad-SGE-REIC) was developed to increase REIC/Dkk-3 expression and enhance therapeutic effects compared with the conventional adenoviral vector (Ad-CAG-REIC). In this study, we investigated the in vitro and in vivo effects of Ad-SGE-REIC on malignant glioma. In U87 Delta EGFR and GL261 glioma cells, western blotting confirmed that robust upregulation of REIC/Dkk-3 expression occurred in Ad-SGE-REIC-transduced cells, most notably after transduction at a multiplicity of infection of 10. Cytotoxicity assays showed that Ad-SGE-REIC resulted in a time-dependent and significant reduction in the number of malignant glioma cells attaching to the bottom of culture wells. Xenograft and syngeneic mouse intracranial glioma models treated with Ad-SGE-REIC had significantly longer survival than those treated with the control vector Ad-LacZ or with Ad-CAG-REIC. This study demonstrated the anti-glioma effect of Ad-SGE-REIC, which may represent a promising strategy for the treatment of malignant glioma.

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  • MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-kappa B and ROS formation upon ligand binding Reviewed

    I. Made Winarsa Ruma, Endy Widya Putranto, Eisaku Kondo, Hitoshi Murata, Masami Watanabe, Peng Huang, Rie Kinoshita, Junichiro Futami, Yusuke Inoue, Akira Yamauchi, I. Wayan Sumardika, Chen Youyi, Ken-Ichi Yamamoto, Yasutomo Nasu, Masahiro Nishibori, Toshihiko Hibino, Masakiyo Sakaguchi

    CLINICAL & EXPERIMENTAL METASTASIS   33 ( 6 )   609 - 627   2016.8

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    The dynamic interaction between tumor cells and their microenvironment induces a proinflammatory milieu that drives cancer development and progression. The S100A8/A9 complex has been implicated in chronic inflammation, tumor development, and progression. The cancer microenvironment contributes to the up-regulation of this protein complex in many invasive tumors, which is associated with the formation of pre-metastatic niches and poor prognosis. Changing adhesive preference of cancer cells is at the core of the metastatic process that governs the reciprocal interactions of cancer cells with the extracellular matrices and neighboring stromal cells. Cell adhesion molecules (CAMs) have been confirmed to have high-level expression in various highly invasive tumors. The expression and function of CAMs are profoundly influenced by the extracellular milieu. S100A8/A9 mediates its effects by binding to cell surface receptors, such as heparan sulfate, TLR4 and RAGE on immune and tumor cells. RAGE has recently been identified as an adhesion molecule and has considerably high identity and similarity to ALCAM and MCAM, which are frequently over-expressed on metastatic malignant melanoma cells. In this study, we demonstrated that ALCAM and MCAM also function as S100A8/A9 receptors as does RAGE and induce malignant melanoma progression by NF-kappa B activation and ROS formation. Notably, MCAM not only activated NF-kappa B more prominently than ALCAM and RAGE did but also mediated intracellular signaling for the formation of lung metastasis. MCAM is known to be involved in malignant melanoma development and progression through several mechanisms. Therefore, MCAM is a potential effective target in malignant melanoma treatment.

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  • The Efficacy of Rituximab in High-risk Renal Transplant Recipients Reviewed

    Motoo Araki, Koichiro Wada, Yosuke Mitsui, Risa Kubota, Takashi Yoshioka, Yuichi Ariyoshi, Yasuyuki Kobayashi, Masashi Kitagawa, Katsuyuki Tanabe, Hiroshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Hotta, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   70 ( 4 )   295 - 297   2016.8

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    Although graft survival following renal transplantation (RTx) has improved, outcomes following highrisk RTx are variable. Preexisting antibodies, including donor-specific antibodies (DSA), play an important role in graft dysfunction and survival. We have designed a study to investigate the safety and efficacy of anti-CD20 monoclonal antibodies (rituximab) in high-risk RTx recipients. Major eligibility criteria include: 1) major and minor ABO blood group mismatch, 2) positive DSA. Thirty-five patients will receive 200 mg/body of rituximab. The primary endpoint is the incidence of B cell depletion. This study will clarify whether rituximab is efficacious in improving graft survival in high-risk RTx recipients.

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  • Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer Reviewed

    H. Sawahara, H. Shiraha, D. Uchida, H. Kato, T. Nagahara, M. Iwamuro, J. Kataoka, S. Horiguchi, M. Watanabe, M. Sakaguchi, A. Takaki, K. Nouso, Y. Nasu, H. Kumon, H. Okada

    CANCER GENE THERAPY   23 ( 8 )   278 - 283   2016.8

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    Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3), a tumor suppressor gene, is downregulated in various cancers. We previously reported the tumor-inhibitory effects of the REIC/Dkk-3 gene, delivered by a conventional adenoviral vector (Ad-CAG-REIC) in pancreatic cancer. Here, we developed an Ad-REIC vector with a novel gene expression system, termed the super gene expression (SGE) system, and assessed its therapeutic effects relative to those of Ad-CAG-REIC in pantreatic cancer cells. Human pancreatic cancer cell lines ASPC1 and MIAPaCa2 were used. REIC/Dkk-3 expression was assessed by western blot analysis. Relative cell viability and apoptotic effects were examined in vitro. The anti-tumor effects of Ad-REIC treatment were assessed in the mouse xenograft model. Compared with Ad-CAG-REIC, Ad-SGE-REIC elicited a significant increase in REIC protein expression in the cells studied, Relative to Ad-CAG-REIC, Ad-SGE-REIC reduced cell viability and induced apoptosis in the ASPC1 and MIAPaCa2 cell lines in vitro, and achieved superior tumor growth inhibition in the mouse xenograft model. Compared with conventional Ad-REIC agents, Ad-SGE-REIC provided enhanced inhibitory effects against tumor growth. Our results indicate that Ad-SGE-REIC is an innovative therapeutic tool for pancreatic cancer.

    DOI: 10.1038/cgt.2016.31

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  • A Phase II Clinical Trial Evaluating the Preventive Effectiveness of Lactobacillus Vaginal Suppositories in Patients with Recurrent Cystitis Reviewed

    Koichiro Wada, Shinya Uehara, Ayano Ishii, Takuya Sadahira, Masumi Yamamoto, Ritsuko Mitsuhata, Atsushi Takamoto, Motoo Araki, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Hotta, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   70 ( 4 )   299 - 302   2016.8

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    Urinary tract infections (UTIs) are the most common bacterial infections in women, and many patients experience frequent recurrence. The aim of this report is to introduce an on-going prospective phase II clinical trial performed to evaluate the preventive effectiveness of Lactobacillus vaginal suppositories for prevention of recurrent cystitis. Patients enrolled in this study are administered vaginal suppositories containing the GAI 98322 strain of Lactobacillus crispatus every 2 days or 3 times a week for one year. The primary endpoint is recurrence of cystitis and the secondary endpoints are adverse events. Recruitment began in December 2013 and target sample size is 20 participants.

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  • Study about the Efficacy of Metformin to Immune Function in Cancer Patients. Reviewed

    Watanabe M, Yamamoto H, Eikawa S, Shien K, Shien T, Soh J, Hotta K, Wada J, Hinotsu S, Fujiwara T, Kiura K, Doihara H, Miyoshi S, Udono H, Toyooka S

    Acta medica Okayama   70 ( 4 )   327 - 30   2016.8

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    A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8+ T cells, which produce multiple cytokines.

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  • Synergistic anti-pancreatic cancer immunological effects by treatment with reduced expression in immortalized cells/dickkopf-3 protein and peripheral blood mononuclear cells Reviewed

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Hiroaki Sawahara, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Hiromi Kumon, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   31 ( 6 )   1154 - 1159   2016.6

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    Background and AimReduced expression in immortalized cells/dickkopf-3 (REIC/DKK3) is a reported tumor suppressor gene and has potential to become an innovative therapy for various cancers. We examined the antitumor immunological effects of human REIC/DKK3 protein against pancreatic cancer.
    MethodsActivation of extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 by REIC/DKK3 protein was assessed in human peripheral blood mononuclear cells using immunoblotting. Pancreatic cancer cell lines (AsPC-1 and MIA Paca-2) were cocultured with peripheral blood mononuclear cells, and the anticancer effects of REIC/DKK3 protein were assessed using the methyl thiazole tetrazolium, cytotoxicity, and enzyme-linked immunospot assays. The antitumor immunological effects of the combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells were also assessed in a pancreatic cancer model using non-obese diabetic/severe combined immunodeficiency mice.
    ResultsThe REIC/DKK3 protein activated extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 in peripheral blood mononuclear cells. REIC/DKK3 protein inhibited in vitro cancer cell viability and enhanced cytotoxicity when incubated with peripheral blood mononuclear cells. REIC/DKK3 protein induced significant production of interferon gamma from lymphocytes incubated with pancreatic cancer cells, indicating that CD8+ T cells were activated in the peripheral blood mononuclear cells when cocultured with AsPC-1 and MIA Paca-2 in the presence of REIC/DKK3 protein. Combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells produced in vivo anticancer immunostimulatory effects on pancreatic cancer cells.
    ConclusionsThe REIC/DKK3 protein and peripheral blood mononuclear cells synergistically enhanced anticancer immunological effects against pancreatic cancer cells. The observed immunomodulatory effect of combined treatment likely occurs in adenovirus-mediated REIC/DKK3 gene therapy and provides important clues to the therapeutic mechanisms involving immune cells.

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  • The induction of antigen-specific CTL by in situ Ad-REIC gene therapy Reviewed

    Y. Ariyoshi, M. Watanabe, S. Eikawa, C. Yamazaki, T. Sadahira, T. Hirata, M. Araki, S. Ebara, Y. Nasu, H. Udono, H. Kumon

    GENE THERAPY   23 ( 5 )   408 - 414   2016.5

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    An adenovirus vector carrying the human Reduced Expression in Immortalized Cell (REIC)/Dkk-3 gene (Ad-REIC) mediates simultaneous induction of cancer-selective apoptosis and augmentation of anticancer immunity. In our preclinical and clinical studies, in situ Ad-REIC gene therapy showed remarkable direct and indirect antitumor effects to realize therapeutic cancer vaccines. We herein aimed to confirm the induction of tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs) by Ad-REIC. Using an ovalbumin (OVA), a tumor-associated antigen, expressing E.G7 tumor-bearing mouse model, we investigated the induction and expansion of OVA-specific CTLs responsible for indirect, systemic effects of Ad-REIC. The intratumoral administration of Ad-REIC mediated clear antitumor effects with the accumulation of OVA-specific CTLs in the tumor tissues and spleen. The CD86-positive dendritic cells (DCs) were upregulated in the tumor draining lymph nodes of Ad-REIC-treated mice. In a dual tumor-bearing mouse model in the left and right back, Ad-REIC injection in one side significantly suppressed the tumor growth on both sides and significant infiltration of OVA-specific CTLs into non-injected tumor was also detected. Consequently, in situ Ad-REIC gene therapy is expected to realize a new-generation cancer vaccine via anticancer immune activation with DC and tumor antigen-specific CTL expansion.

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  • [Gene therapy]. Reviewed

    Watanabe M, Sadahira T, Nasu Y

    Nihon rinsho. Japanese journal of clinical medicine   74 Suppl 3   221 - 225   2016.5

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  • Promising Therapeutic Efficacy of a Novel REIC/Dkk-3 Expressing Adenoviral Vector for Hepatocellular Carcinoma Reviewed

    Hiroaki Sawahara, Shiraha Hidenori, Uchida Daisuke, Sakaguchi Masakiyo, Watanabe Masami, Nasu Yasutomo, Kumon Hiromi, Okada Hiroyuki

    GASTROENTEROLOGY   150 ( 4 )   S1153   2016.4

  • Development of a Novel REIC/DKK-3-Encoding Adenoviral Agent: Its Robust and Promising Therapeutic Effects in Pancreatic Cancer Reviewed

    Uchida Daisuke, Shiraha Hidenori, Kato Hironari, Hiroaki Sawahara, Sakaguchi Masakiyo, Watanabe Masami, Nasu Yasutomo, Kumon Hiromi, Okada Hiroyuki

    GASTROENTEROLOGY   150 ( 4 )   S294 - S294   2016.4

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  • Tumor suppressor REIC/DKK-3 and co-chaperone SGTA: Their interaction and roles in the androgen sensitivity Reviewed

    Kazuhiko Ochiai, Masami Morimatsu, Yuiko Kato, Toshina Ishiguro-Oonuma, Chihiro Udagawa, Oumaporn Rungsuriyawiboon, Daigo Azakami, Masaki Michishita, Yuichi Ariyoshi, Hideo Ueki, Yasutomo Nasu, Hiromi Kumon, Masami Watanabe, Toshinori Omi

    ONCOTARGET   7 ( 3 )   3273 - 3286   2016.1

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    REIC/DKK-3 is a tumor suppressor, however, its intracellular physiological functions and interacting molecules have not been fully clarified. Using yeast two-hybrid screening, we found that small glutamine-rich tetratricopeptide repeat-containing protein a (SGTA), known as a negative modulator of cytoplasmic androgen receptor (AR) signaling, is a novel interacting partner of REIC/DKK-3. Mammalian two-hybrid and pull-down assay results indicated that the SGTA-REIC/DKK-3 interaction involved the N-terminal regions of both REIC/DKK-3 and SGTA and that REIC/DKK-3 interfered with the dimerization of SGTA, which is a component of the AR complex and a suppressor of dynein motor-dependent AR transport and signaling. A reporter assay in human prostate cancer cells that displayed suppressed AR signaling by SGTA showed recovery of AR signaling by REIC/DKK-3 expression. Considering these results and our previous data that REIC/DKK-3 interacts with the dynein light chain TCTEX-1, we propose that the REIC/DKK-3 protein interferes with SGTA dimerization, promotes dynein-dependent AR transport and then upregulates AR signaling.

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  • Feasibility of Neoadjuvant Ad-REIC Gene Therapy in Patients with High-Risk Localized Prostate Cancer Undergoing Radical Prostatectomy Reviewed

    Hiromi Kumon, Katsumi Sasaki, Yuichi Ariyoshi, Takuya Sadahira, Motoo Araki, Shin Ebara, Hiroyuki Yanai, Masami Watanabe, Yasutomo Nasu

    CTS-CLINICAL AND TRANSLATIONAL SCIENCE   8 ( 6 )   837 - 840   2015.12

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    In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 x 10(10), 1.0 x 10(11), and 1.0 x 10(12) viral particles (VP) in 1.0-1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 x 10(12) VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan's nomogram, were enrolled. They received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence-free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad-REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199)

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  • Molecular cloning of canine co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) and investigation of its ability to suppress androgen receptor signalling in androgen-independent prostate cancer Reviewed

    Yuiko Kato, Kazuhiko Ochiai, Masaki Michishita, Daigo Azakami, Rei Nakahira, Masami Morimatsu, Toshina Ishiguro-Oonuma, Yasunaga Yoshikawa, Masato Kobayashi, Makoto Bonkobara, Masanori Kobayashi, Kimimasa Takahashi, Masami Watanabe, Toshinori Omi

    VETERINARY JOURNAL   206 ( 2 )   143 - 148   2015.11

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    Although the morbidity of canine prostate cancer is low, the majority of cases present with resistance to androgen therapy and poor clinical outcomes. These pathological conditions are similar to the signs of the terminal stage of human androgen-independent prostate cancer. The co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) is known to be overexpressed in human androgenindependent prostate cancer. However, there is little information about the structure and function of canine SGTA. In this study, canine SGTA was cloned and analysed for its ability to suppress androgen receptor signalling.
    The full-length open reading frame (ORF) of the canine SGTA gene was amplified by RT-PCR using primers designed from canine-expressed sequence tags that were homologous to human SGTA. The canine SGTA ORF has high homology with the corresponding human (89%) and mouse (81%) sequences. SGTA dimerisation region and tetratricopeptide repeat (TPR) domains are conserved across the three species. The ability of canine SGTA to undergo homodimerisation was demonstrated by a mammalian two-hybrid system and a pull-down assay. The negative impact of canine SGTA on androgen receptor (AR) signalling was demonstrated using a reporter assay in androgen-independent human prostate cancer cell lines. Pathological analysis showed overexpression of SGTA in canine prostate cancer, but not in hyperplasia. A reporter assay in prostate cells demonstrated suppression of AR signalling by canine SGTA. Altogether, these results suggest that canine SGTA may play an important role in the acquisition of androgen independence by canine prostate cancer cells. (C) 2015 Elsevier Ltd. All rights reserved.

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  • REIC/Dkk-3遺伝子治療の胸部悪性腫瘍に対する免疫刺激を介する抗腫瘍効果

    諏澤 憲, 枝園 和彦, 阪口 政清, 渡部 昌実, 橋田 真輔, 宗 淳一, 山本 寛斉, 牧 祐歩, 佃 和憲, 那須 保友, 公文 裕巳, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   74回   J - 1224   2015.10

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  • Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies Reviewed

    Suzawa Ken, Shien Kazuhiko, Huang Peng, Sakaguchi Masakiyo, Watanabe Masami, Hashida Shinsuke, Soh Junichi, Yamamoto Hiromasa, Maki Yuho, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Kumon Hiromi, Miyoshi Shinichiro, Toyooka Shinichi

    JOURNAL OF THORACIC ONCOLOGY   10 ( 9 )   S599   2015.9

  • Possible role of cortactin phosphorylation by protein kinase C in actin-bundle formation at growth cone Reviewed

    Hiroshi Yamada, Tatsuya Kikuchi, Toshio Masumoto, Fan-Yan Wei, Tadashi Abe, Tetsuya Takeda, Teiichi Nishiki, Kazuhito Tomizawa, Masami Watanabe, Hideki Matsui, Kohji Takei

    BIOLOGY OF THE CELL   107 ( 9 )   319 - 330   2015.9

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    Background Information. Cortactin contributes to growth cone morphogenesis by forming with dynamin, ring-shaped complexes that mechanically bundle and stabilise F-actin. However, the regulatory mechanism of cortactin action is poorly understood.
    Results. Immunofluorescence microscopy revealed that protein kinase C (PKC) colocalises with cortactin at growth cone filopodia in SH-SY5Y neuroblastoma cells. PKC activation by phorbol 12-myristate 13-acetate causes cortactin phosphorylation, filopodial retraction and F-actin-bundle loss. Moreover, PKC directly phosphorylates cortactin in vitro at S135/T145/S172, mitigating both cortactin's actin-binding and actin-crosslinking activity, whereas cellular expression of a phosphorylation-mimetic cortactin mutant hinders filopodial formation with a significant decrease of actin bundles.
    Conclusions. Our results indicate that PKC-mediated cortactin phosphorylation might be implicated in the maintenance of growth cone.

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  • A novel in situ permeation system and its utility in cancer tissue ablation Reviewed

    Masami Watanabe

    INTERNATIONAL JOURNAL OF ONCOLOGY   47 ( 3 )   875 - 883   2015.9

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    Focal ablation therapy is an emerging treatment modality for localized cancer lesions. It is an attractive strategy for inhibiting tumor progression and preventing morbidity associated with open surgery. As for intratissue drug delivery systems for use in local therapy, the convection-enhanced delivery (CED) of liquid drugs has been utilized, particularly for the treatment of malignant brain tumors. Although the conventional CED system is useful for providing drug/vehicle-based local therapy, there are several reported disadvantages in terms of the ability to control the extent of drug diffusion. We herein developed and validated a novel in situ permeation (ISP)-MW-1 system for achieving intratissue drug diffusion. The ISP system includes a perfusion catheter connected to an injector and aspirator, which enables intratissue perfusion of the solute diluted in the vehicle in the tip-inserted cavity. We subsequently evaluated the utility of the ISP-MW-1 system for in situ permeation in a subcutaneous tumor model in hamsters. Dehydrated ethanol, saline and 50% acetic acid were evaluated as the vehicle, and methylene blue was used as a dissolved substance for evaluating the diffusion of the agent. As a result, almost all of the tumor tissue within the capsule (tumor size: 3 cm) was permeated with the dehydrated ethanol and 50% acetic acid and partially with the saline. We further demonstrated that ISP treatment with 50% acetic acid completely ablated the subcutaneous tumors in all of the treated hamsters (n=3). Therefore, the ISP-MW-1 system is a promising approach for controlling the intratissue diffusion of therapeutic agents and for providing local ablation therapy for cancer lesions. We believe that this system may be applicable to a broad range of medicinal and industrial fields, such as regenerative medicine, drug delivery systems, biochemistry and material technologies as well as cancer therapy.

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  • Islet Culture/Preservation Before Islet Transplantation. Reviewed

    Noguchi H, Miyagi-Shiohira C, Kurima K, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M

    Cell Med.   8 ( 1月2日 )   25 - 29   2015.8

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    Although islet culture prior to transplantation provides flexibility for the evaluation of isolated islets and the pretreatment of patients, it is well known that isolated islets deteriorate rapidly in culture. Human serum albumin (HSA) is used for medium supplementation instead of fetal bovine serum (FBS), which is typically used for islet culture research, to avoid the introduction of xenogeneic materials. However, FBS contains several factors that are beneficial to islet viability and which also neutralize the endogenous pancreatic enzymes or exogenous enzymes left over from the isolation process. Several groups have reported the comparison of cultures at 22 degrees C and 37 degrees C. Recent studies have demonstrated the superiority of 4 degrees C preservation to 22 degrees C and 37 degrees C cultures. We herein review the current research on islet culture/preservation for clinical islet transplantation.

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  • Cryopreservation of Adipose-Derived Mesenchymal Stem Cells. Reviewed

    Miyagi-Shiohira C, Kurima K, Kobayashi N, Saitoh I, Watanabe M, Noguchi Y, Matsushita M, Noguchi H

    Cell Med.   8 ( 1月2日 )   3 - 7   2015.8

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  • Testosterone replacement therapy and cross-sex hormone treatment

    Morito Sugimoto, Hiroaki Kurahashi, Yuko Matsumoto, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Kazushi Ishii, Atsushi Nagai

    Nishinihon Journal of Urology   77 ( 6 )   202 - 206   2015.6

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    Currently, androgen replacement therapy (ART) which is provided clinically in the field of urology is a common treatment for many of the patients with LOH syndrome or gender identity disorder (GID) Female to Male (FTM). We herein describe the current situation and the challenges regarding ART for these two diseases. ART has been provided according to LOH syndrome treatment guidelines. However, the opinion of any individual clinician and/or the patient's own adherence in continuing treatment will be seen as influencing treatment decisions at any particular moment. With regard to ART in our department, cases where ART has been judged to be effective for LOH syndrome comprised 51% of cases (23 out of 45 cases). No significant difference was showen between cases which hoped treatment continuation and didn't hope. Guidelines for correctly evaluating the response to treatment and the feasibility of providing such treatment are awaited. ART provided for GID-FTM is particular in that its therapeutic effect is expected to differ greatly from that obtained when ART is provided for LOH syndrome. Order to obtain a cessation of the expected virilization and physiology of a patient's body, the hormone dose and interval need to be carefully considered. Data accumulated in our department have demonstrated that in most patients, a sufficient therapeutic effect is obtained by the administration of 125 mg testosterone enanthate for 2 weeks, and serious adverse events have not been observed. Guidelines regarding GID androgen replacement therapy are also awaited, in particular with regard to a more detailed evaluation of its predicted therapeutic effect.

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  • The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression Reviewed

    Rie Kinoshita, Masami Watanabe, Peng Huang, Shun-Ai Li, Masakiyo Sakaguchi, Hiromi Kumon, Junichiro Futami

    ONCOLOGY REPORTS   33 ( 6 )   2908 - 2914   2015.6

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    Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell-specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3 beta (GSK-3 beta) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony-stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.

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  • Potential Factors for the Differentiation of ESCs/iPSCs Into Insulin-Producing Cells. Reviewed

    Takako Tsugata, Naruo Nikoh, Tatsuya Kin, Issei Saitoh, Yasufumi Noguchi, Hideo Ueki, Masami Watanabe, Andrew M, James Shapiro, Hirofumi Noguchi

    Cell Medicine   7 ( 2 )   83 - 93   2015.4

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  • A vaccine strategy with multiple prostatic acid phosphatase-fused cytokines for prostate cancer treatment Reviewed

    Kei Fujio, Masami Watanabe, Hideo Ueki, Shun-Ai Li, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    ONCOLOGY REPORTS   33 ( 4 )   1585 - 1592   2015.4

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    Immunotherapy is one of the attractive treatment strategies for advanced prostate cancer. The US Food and Drug Administration (FDA) previously approved the therapeutic vaccine, sipuleucel-T, which is composed of autologous antigen-presenting cells cultured with a fusion protein [prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF)]. Although sipuleucel-T has been shown to prolong the median survival of patients for 4.1 months, more robust therapeutic effects may be expected by modifying the vaccination protocol. In the present study, we aimed to develop and validate a novel vaccination strategy using multiple PAP-fused cytokines for prostate cancer treatment. Using a super gene expression (SGE) system that we previously established to amplify the production of a recombinant protein, significant amounts of PAP-fused cytokines [human GMCSF, interleukin-2 (IL2), IL4, IL7 and mouse GMCSF and IL4] were obtained. We examined the activity of the fusion proteins in vitro to validate their cytokine functions. A significant upregulation of dendritic cell differentiation from monocytes was achieved by PAP-GMCSF when used with the other PAP-fused cytokines. The PAP-fused human IL2 significantly increased the proliferation of lymphocytes, as determined by flow cytometry. We also investigated the in vivo therapeutic effects of multiple PAP-fused cytokines in a mouse prostate cancer model bearing prostate-specific antigen (PSA)- and PAP-expressing tumors. The simultaneous intraperitoneal administration of PAP-GMCSF, -IL2, -IL4 and -IL7 significantly prevented tumor induction and inhibited the tumor growth in the PAP-expressing tumors, yet not in the PSA-expressing tumors. The in vivo therapeutic effects with the multiple PAP-fused cytokines were superior to the effects of PAP-GMCSF alone. We thus demonstrated the advantages of the combined use of multiple PAP-fused cytokines including PAP-GMCSF, and propose a promising prostatic antigen-vaccination strategy to enhance the therapeutic effects.

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  • Polymorphisms of canine BRCA2 BRC repeats affecting interaction with RAD51 Reviewed

    Kazuhiko Ochiai, Toshina Ishiguro-Oonuma, Yasunaga Yoshikawa, Chihiro Udagawa, Yuiko Kato, Masami Watanabe, Makoto Bonkobara, Masami Morimatsu, Toshinori Omi

    BIOMEDICAL RESEARCH-TOKYO   36 ( 2 )   155 - 158   2015.4

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    Mutations in the breast cancer susceptibility gene BRCA2 leading to the failure of interactions with the recombinase RAD51 are associated with an increased risk of cancer in humans. This interaction depends on the eight BRC repeat (BRC1-8) sequences in BRCA2. We previously reported that canine BRC3 has two polymorphisms (T1425P and K1435R) influencing the interaction with RAD51, and 1435R was identified in mammary tumor dog samples. In this study, we investigated the sequence variations of BRC3 and 4 in 236 dogs of five breeds. Allele frequencies of 1425P and 1435R were 0.063 and 0.314, respectively, and there was no other polymorphism in the sequenced region. A mammalian two-hybrid assay using BRC3-4 sequences demonstrated that 1425P allele reduced the binding strength with RAD51 but 1435R had no effect. These results may provide an insight into the functions of not only individual but also multiple BRC repeats of BRCA2 in dogs.

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  • Ad-REIC gene therapy: Promising results in a patient with metastatic CRPC following chemotherapy Reviewed

    Hiromi Kumon, Katsumi Sasaki, Yuichi Ariyoshi, Takuya Sadahira, Shin Ebara, Takao Hiraki, Susumu Kanazawa, Hiroyuki Yanai, Masami Watanabe, Yasutomo Nasu

    Clinical Medicine Insights: Oncology   9   31 - 38   2015.3

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    A 63-year-old man with metastatic castration-resistant prostate cancer (CRPC) was successfully treated for two years with in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk‑3 gene (Ad-REIC), following chemotherapy. Ad-REIC mediates simultaneous induc-tion of cancer-selective apoptosis and augmentation of antitumor immunity, and a Phase I/IIa clinical study on Ad-REIC has been conducted at Okayama University Hospital since January 2011. At the time of enrollment in December 2012, the patient presented with rapid progression of lymph node (LN) metastases. Two scheduled Ad-REIC injections and 10 additional Ad-REIC injections into metastatic pelvic and para-aortic LNs under CT guidance, with an average four weeks’ interval, exhibited the potent direct and indirect effects of Ad-REIC as a therapeutic cancer vaccine. During the next 12 months, three additional injections into para-aortic LNs showing regrowth achieved adequate control of all metastatic LNs with prostate-specific antigen (PSA) decline, without any particular adverse events.

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  • Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma Reviewed

    Y. Shimazu, K. Kurozumi, T. Ichikawa, K. Fujii, M. Onishi, J. Ishida, T. Oka, M. Watanabe, Y. Nasu, H. Kumon, I. Date

    GENE THERAPY   22 ( 2 )   146 - 154   2015.2

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    Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma.

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  • Induction of tissue-specific stem cells by reprogramming factors, and tissue-specific selection Reviewed

    H. Noguchi, I. Saitoh, T. Tsugata, H. Kataoka, M. Watanabe, Y. Noguchi

    CELL DEATH AND DIFFERENTIATION   22 ( 1 )   145 - 155   2015.1

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    Although induced pluripotent stem (iPS) cells have significant implications for overcoming most of the ethical issues associated with embryonic stem (ES) cells, there are still several unresolved issues related to the use of iPS cells for clinical applications, such as teratoma formation. In this study, we were able to generate tissue-specific stem (induced tissue-specific stem; iTS) cells from the pancreas (iTS-P) or liver (iTS-L) by transient overexpression of reprogramming factors, combined with tissue-specific selection. The generation of iTS cells was easier than that of iPS cells. The iTS-P/iTS-L cells express genetic markers of endoderm and pancreatic/hepatic progenitors and were able to differentiate into insulin-producing cells/hepatocytes more efficiently than ES cells. Subcutaneous transplantation of both types of iTS cells into immunodeficient mice resulted in no teratoma formation. The technology used for the transient overexpression of reprogramming factors and tissue-specific selection may be useful for the generation of other tissue-specific stem cells, and the generation of iTS cells could have important implications for the clinical application of stem cells.

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  • Potential Factors for the Differentiation of ESCs/iPSCs Into Insulin-Producing Cells. Reviewed

    Tsugata T, Nikoh N, Kin T, Saitoh I, Noguchi Y, Ueki H, Watanabe M, James Shapiro AM, Noguchi H

    Cell Med   7 ( 2 )   83 - 93   2014.12

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  • Significant association between the Axin2 rs2240308 single nucleotide polymorphism and the incidence of prostate cancer Reviewed

    Chao Ma, Chunxiao Liu, Peng Huang, Haruki Kaku, Jie Chen, Kai Guo, Hideo Ueki, Akiko Sakai, Yasutomo Nasu, Hiromi Kumon, Kenji Shimizu, Masami Watanabe

    ONCOLOGY LETTERS   8 ( 2 )   789 - 794   2014.8

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    The Wnt signaling pathway plays a crucial role in human cancer development, and axis inhibition protein 2 (Axin2) is a master scaffold protein involved in Wnt signaling. Axin2 negatively regulates Wnt signaling and acts as a tumor suppressor protein. The present study evaluated the association between the Axin2 single nucleotide polymorphism (SNP) rs2240308 [guanine (G)/adenine (A)] and the incidence of prostate cancer. In total, 103 patients with prostate cancer and 100 cancer-free control males were included in this case-control study, and were genotyped using the genomic DNA extracted from peripheral blood samples. The results revealed a higher incidence of prostate cancer in the subjects with the homozygous GG genotype and a reduced cancer incidence in the patients with the GA genotype of the rs2240308 SNP (G/A) in the Axin2 gene. T-he adjusted odds ratio for carriers with the GA genotype was 0.377 (95% CI, 0.206-0.688; P=0.001) and that for the AA genotype was 0.830 (95% CI, 0.309-2.232; P=0.712) compared with the GG genotype. Therefore, the GA genotype was found to exhibit a protective effect that decreased the risk of prostate cancer. To the best of our knowledge, this is the first study to demonstrate the significant association between this SNP (rs2240308, G/A) and the risk of prostate cancer. This association indicates the possibility that the variations in the Axin2 gene in this position may play a significant role in promoting the development of cancer in the prostate. We believe that the Axin2 SNP (rs2240308) could be a useful biomarker for the predisposition and early diagnosis of the disease.

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  • Immunological aspects of REIC/Dkk-3 gene therapy : the mechanism of the robust anti-tumor effects. Reviewed

    Masami Watanabe, Peng Huang, Fernando Abarzua, Haruki Kaku, Katsumi Sasaki, Hideo Ueki, Toyohiko Wananabe, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   226 - 227   2014.7

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  • Dramatic Increase in Expression of a Transgene by Insertion of Promoters Downstream of the Cargo Gene Reviewed

    Masakiyo Sakaguchi, Masami Watanabe, Rie Kinoshita, Haruki Kaku, Hideo Ueki, Junichiro Futami, Hitoshi Murata, Yusuke Inoue, Shun-Ai Li, Peng Huang, Endy Widya Putranto, I. Made Winarsa Ruma, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh

    MOLECULAR BIOTECHNOLOGY   56 ( 7 )   621 - 630   2014.7

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    For expression of genes in mammalian cells, various vectors have been developed using promoters including CMV, EF-1 alpha, and CAG promoters and have been widely used. However, such expression vectors sometimes fail to attain sufficient expression levels depending on the nature of cargo genes and/or on host cell types. In the present study, we aimed to develop a potent promoter system that enables high expression levels of cargo genes ubiquitously in many different cell types. We found that insertion of an additional promoter downstream of a cargo gene greatly enhanced the expression levels. Among the constructs we tested, C-TSC cassette (C: CMV-RU5' located upstream; TSC: another promoter unit composed of triple tandem promoters, hTERT, SV40, and CMV, located downstream of the cDNA plus a polyadenylation signal) had the most potent capability, showing far higher efficiency than that of potent conventional vector systems. The results indicate that the new expression system is useful for production of recombinant proteins in mammalian cells and for application as a gene therapeutic measure.

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  • Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer Reviewed

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Takahito Yagi, Hiromi Kumon, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   29 ( 5 )   973 - 983   2014.5

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    Background and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
    MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
    ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
    ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

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  • Establishment of a pancreatic stem cell line from fibroblast-derived induced pluripotent stem cells Reviewed

    Takashi Kuise, Hirofumi Noguchi, Hiroshi Tazawa, Takashi Kawai, Masaya Iwamuro, Issei Saitoh, Hitomi Usui Kataoka, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara

    BIOMEDICAL ENGINEERING ONLINE   13   2014.5

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    Background: For cell therapies to treat diabetes, it is important to produce a sufficient number of pancreatic endocrine cells that function similarly to primary islets. Induced pluripotent stem (iPS) cells represent a potentially unlimited source of functional pancreatic endocrine cells. However, the use of iPS cells for laboratory studies and cell-based therapies is hampered by their high tumorigenic potential and limited ability to generate pure populations of differentiated cell types in vitro. The purpose of this study was to establish a pancreatic stem cell line from iPS cells derived from mouse fibroblasts.
    Methods: Mouse iPS cells were induced to differentiate into insulin-producing cells by a multi-step differentiation protocol, which was conducted as described previously with minor modifications. Selection of the pancreatic stem cell was based on morphology and Pdx1 expression. The pancreatic potential of the pancreatic stem cells was evaluated using a reverse transcription PCR, real-time PCR, immunofluorescence, and a glucose challenge test. To assess potential tumorigenicity of the pancreatic stem cells, the cells were injected into the quadriceps femoris muscle of the left hindlimb of nude mice.
    Results: The iPS-derived pancreatic stem cells expressed the transcription factor -Pdx1- a marker of pancreatic development, and continued to divide actively beyond passage 80. Endocrine cells derived from these pancreatic stem cells expressed insulin and pancreatic genes, and they released insulin in response to glucose stimulation. Mice injected with the pancreatic stem cells did not develop tumors, in contrast to mice injected with an equal number of iPS cells.
    Conclusion: This strategy provides a new approach for generation of insulin-producing cells that is more efficient and safer than using iPS cells. We believe that this approach will help to develop a patient-specific cell transplantation therapy for diabetes in the near future.

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  • リプログラミングファクターの導入による人工膵幹細胞の作成

    野口 洋文, 齊藤 一誠, 片岡 仁美, 渡部 昌実, 野口 寧文, 西郷 健一, 長谷川 正行, 丸山 通広, 大月 和宣, 青山 博道, 松本 育子, 浅野 武秀, 圷 尚武

    糖尿病   57 ( Suppl.1 )   S - 440   2014.4

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  • Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review) Reviewed

    Masami Watanabe, Yasutomo Nasu, Hiromi Kumon

    ONCOLOGY LETTERS   7 ( 3 )   595 - 601   2014.3

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    Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor suppressor and therapeutic gene and has been studied with respect to the application of cancer gene therapy. Our previous studies demonstrated that the intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) suppresses tumor growth in mouse models of prostate, breast and testicular cancer and malignant mesothelioma. The mechanisms underlying these antitumor therapeutic effects have only been clarified recently. It has been demonstrated that Ad-REIC treatment inhibits cancer progression via the upregulation of systemic anticancer immunity. Under experimental conditions, autologous cancer vaccination via cancer-specific apoptosis and anticancer immune activation is a possible therapeutic mechanism. The robust anticancer effects observed in previous preclinical studies support the clinical utility of Ad-REIC. At present, a phase I-IIa study of Ad-REIC gene therapy in prostate cancer patients is ongoing. The current study reviews the observations of previous fundamental studies and summarizes the anticancer mechanisms of intratumoral Ad-REIC treatment in terms of cancer vaccination.

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  • A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector Reviewed

    Masami Watanabe, Masakiyo Sakaguchi, Rie Kinoshita, Haruki Kaku, Yuichi Ariyoshi, Hideo Ueki, Ryuta Tanimoto, Shin Ebara, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Peng Huang, Yasutomo Nasu, Nam-Ho Huh, Hiromi Kumon

    ONCOLOGY REPORTS   31 ( 3 )   1089 - 1095   2014.3

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    Gene expression systems with various promoters, including the cytomegalovirus (CMV) promoter, have been developed to increase the gene expression in a variety of normal and cancer cells. In particular, in the clinical trials of cancer gene therapy, a more efficient and robust gene expression system is required to achieve sufficient therapeutic outcomes. By inserting the triple translational enhancer sequences of human telomerase reverse transcriptase (hTERT), Simian virus 40 (SV40) and CMV downstream of the sequence of the BGH polyA, we were able to develop a novel gene expression system that significantly enhances the expression of the genes of interest. We termed this novel gene expression cassette the super gene expression (SGE) system, and herein verify the utility of the SGE cassette for a replication-deficient adenoviral vector. We newly developed an adenoviral vector expressing the tumor suppressor, reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), based on the CMV promoter-driven SGE system (Ad-SGE-REIC) and compared the therapeutic utility of Ad-SGE-REIC with that of the conventional adenoviral vectors (Ad-CMV-REIC or Ad-CAG-REIC). The results demonstrated that the CMV promoter-SGE system allows for more potent gene expression, and that the Ad-SGE-REIC is superior to conventional adenoviral systems in terms of the REIC protein expression and therapeutic effects. Since the SGE cassette can be applied for the expression of various therapeutic genes using various vector systems, we believe that this novel system will become an innovative tool in the field of gene expression and gene therapy.

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  • Anti-Cancer Effects of REIC/Dkk-3-encoding Adenoviral Vector for the Treatment of Non-small Cell Lung Cancer Reviewed

    Kazuhiko Shien, Norimitsu Tanaka, Masami Watanabe, Junichi Soh, Masakiyo Sakaguchi, Keitaro Matsuo, Hiromasa Yamamoto, Masashi Furukawa, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Nam-Ho Huh, Shinichiro Miyoshi, Hiromi Kumon, Shinichi Toyooka

    PLOS ONE   9 ( 2 )   2014.2

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    Objectives: REIC/Dkk-3 is down-regulated in a broad range of human cancer cells and is considered to function as a tumor suppressor. We previously reported that REIC/Dkk-3-expressing adenovirus vector (Ad-REIC) induced endoplasmic reticulum (ER) stress and cancer-specific apoptosis in human prostate cancer. In this study, we examined the therapeutic impact of Ad-REIC on non-small cell lung cancer (NSCLC).
    Materials and Methods: We examined the anti-tumor effect of Ad-REIC on 25 NSCLC cell lines in vitro and A549 cells in vivo. Two of these cell lines were artificially established as EGFR-tyrosine kinase inhibitor (TKI) resistant sublines.
    Results: Ad-REIC-treatment inhibited the cell viability by 40% or more in 13 (52%) of the 25 cell lines at multiplicity of infection (MOI) of 20 (20 MOI). These cell lines were regarded as being highly sensitive cells. The cell viability of a nonmalignant immortalized cell line, OUMS-24, was not inhibited at 200 MOI of Ad-REIC. The effects of Ad-REIC on EGFR-TKI resistant sublines were equivalent to those in the parental cell lines. Here, we demonstrated that Ad-REIC treatment activated c-Jun N-terminal kinase (JNK) in NSCLC cell lines, indicating the induction of ER stress with GRP78/BiP (GRP78) up-regulation and resulting in apoptosis. A single intratumoral injection of Ad-REIC significantly inhibited the tumorigenic growth of A549 cells in vivo. As predictive factors of sensitivity for Ad-REIC treatment in NSCLC, we examined the expression status of GRP78 and coxsackievirus and adenovirus receptor (CAR). We found that the combination of the GRP78 and CAR expressional statuses may be used as a predictive factor for Ad-REIC sensitivity in NSCLC cells.
    Conclusion: Ad-REIC induced JNK activation and subsequent apoptosis in NSCLC cells. Our study indicated that Ad-REIC has therapeutic potential against NSCLC and that the expression statuses of GRP78 and CAR may predict a potential therapeutic benefit of Ad-REIC.

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  • N '[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide is a dynamin GTPase inhibitor that suppresses cancer cell migration and invasion by inhibiting actin polymerization Reviewed

    Hiroshi Yamada, Tadashi Abe, Shun-Ai Li, Shota Tago, Peng Huang, Masami Watanabe, Satoru Ikeda, Naohisa Ogo, Akira Asai, Kohji Takei

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   443 ( 2 )   511 - 517   2014.1

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    Dynasore, a specific dynamin GTPase inhibitor, suppresses lamellipodia formation and cancer cell invasion by destabilizing actin filaments. In search for novel dynamin inhibitors that suppress actin dynamics more efficiently, dynasore analogues were screened. N'-14-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide (DBHA) markedly reduced in vitro actin polymerization, and dose-dependently inhibited phosphatidylserine-stimulated dynamin GTPase activity. DBHA significantly suppressed both the recruitment of dynamin 2 to the leading edge in U2OS cells and ruffle formation in H1299 cells. Furthermore, DBHA suppressed both the migration and invasion of H1299 cells by approximately 70%. Furthermore, intratumoral DBHA delivery significantly repressed tumor growth. DBHA was much less cytotoxic than dynasore. These results strongly suggest that DBHA inhibits dynamin-dependent actin polymerization by altering the interactions between dynamin and lipid membranes. DBHA and its derivative may be potential candidates for potent anti-cancer drugs. (C) 2013 Elsevier Inc. All rights reserved.

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  • A rare complication: Misdirection of an indwelling urethral catheter into the ureter Reviewed

    Tsutomu Ishikaw, Motoo Araki, Takeshi Hirata, Masami Watanabe, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    Acta Medica Okayama   68 ( 1 )   47 - 51   2014

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    We report 3 patients with the rare complication of an indwelling urethral catheter misdirected into the ureter. This is the largest series to date. Patients were referred to us for a variety of reasons following exchange of their chronic indwelling urinary catheters. CT in all cases demonstrated the urinary catheters residing in the left ureter. The ages of the patients were 37, 67 and 81 years old. All patients suffered from neurogenic bladder. Two patients were female, one was male, and 2 of the 3 had a sensory disorder inhibiting their pain response. The catheters were replaced with open-end Foley catheters. Extensive follow-up CT scans were obtained in one case, demonstrating improvement of hydronephrosis and no evidence of ureteral stenosis. Cystoscopy in this patient demonstrated normally positioned and functioning ureteral orifices. Although the placement of an indwelling urethral catheter is a comparatively safe procedure, one must keep in mind that this complication can occur, particularly in female patients with neurogenic bladder. CT without contrast is a noninvasive, definitive diagnostic tool. © 2014 by Okayama University Medical School.

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  • Comparison of Incubation Solutions Prior to the Purification of Porcine Islet Cells. International journal

    Takashi Kawai, Hirofumi Noguchi, Takashi Kuise, Atsuko Nakatsuka, Akihiro Katayama, Noriko Imagawa, Hitomi Usui Kataoka, Issei Saitoh, Yasufumi Noguchi, Masami Watanabe, Toshiyoshi Fujiwara

    Cell medicine   6 ( 1-2 )   9 - 14   2013.12

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    For pancreatic islet transplantation, one of the most important steps of islet isolation is islet purification. The most common method of islet purification is density gradient centrifugation because there are differences in density between islets and acinar tissue. However, the density of islets/acinar tissue depends on several conditions, such as the incubation time before purification and the osmolality of the preincubation solution. In this study, we evaluated the impact of using two different preincubation solutions before purification. We used the University of Wisconsin (UW) solution and a new preservation solution (HN-1), which we recently developed. There were no significant differences between the two solutions in terms of the islet yield, rate of viability, and purity or stimulation index after purification. There were also no differences in the attainability and suitability of posttransplantation normoglycemia. Our study shows that the HN-1 solution is equivalent to the UW solution for preincubation before islet purification.

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  • Comparison of New Preservation Solutions, HN-1 and University of Wisconsin Solution, in Pancreas Preservation for Porcine Islet Isolation. Reviewed International journal

    Akihiro Katayama, Hirofumi Noguchi, Takashi Kuise, Atsuko Nakatsuka, Daisho Hirota, Hitomi Usui Kataoka, Takashi Kawai, Kentaro Inoue, Noriko Imagawa, Issei Saitoh, Yasufumi Noguchi, Masami Watanabe, Jun Wada, Toshiyoshi Fujiwara

    Cell medicine   6 ( 1-2 )   3 - 8   2013.12

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    For pancreatic islet transplantation, maintaining organ viability after pancreas procurement is critical and a major determinant for better graft function and survival. University of Wisconsin (UW) solution is currently the gold standard for abdominal organ preservation and the pancreas in particular. However, in the use of UW preservation solution for islet transplantation, there are disadvantages to be overcome, such as the inhibition of collagenase activity during pancreatic digestion. In this study, we compared UW solution with HN-1 solution in pancreas preservation for islet isolation. Islet yield was significantly greater in the HN-1 group than the UW group both before and after purification. In the in vitro assay, the adenosine triphosphate content in cultured islets was significantly higher in the HN-1 group than in the UW group. Furthermore, in streptozotocin-induced diabetic nude mice, the islet graft function of the HN-1 group was superior to that of the UW group. We concluded that the use of HN-1 solution is a promising approach for optimal pancreas preservation in islet transplantation.

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  • Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder Reviewed

    Hiroaki Kurahashi, Masami Watanabe, Morito Sugimoto, Yuichi Ariyoshi, Sabina Mahmood, Motoo Araki, Kazushi Ishii, Yasutomo Nasu, Atsushi Nagai, Hiromi Kumon

    ENDOCRINE JOURNAL   60 ( 12 )   1321 - 1327   2013.12

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    Gender identity disorder (GID) results from a disagreement between a person's biological sex and the gender to which he or she identifies. With respect to the treatment of female to male GID, testosterone replacement therapy (TRT) is available. The uric acid (UA) level can be influenced by testosterone; however, the early effects and dose-dependency of TRT on the serum UA concentration have not been evaluated in this population. We herein conducted a dose-response analysis of TRT in 160 patients with female to male GID. The TRT consisted of three treatment groups who received intramuscular injections of testosterone enanthate: 125 mg every two weeks, 250 mg every three weeks and 250 mg every two weeks. Consequently, serum UA elevation was observed after three months of TRT and there was a tendency toward testosterone dose-dependency. The onset of hyperuricemia was more prevalent in the group who received the higher dose. We also demonstrated a positive correlation between increased levels of serum UA and serum creatinine. Since the level of serum creatinine represents an individual's muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass. This is the first study showing an association between serum UA elevation and a TRT-induced increase in muscle mass. The current study provides important information regarding TRT for the follow-up and management of the serum UA levels in GID patients.

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  • Culture Conditions for Mouse Pancreatic Stem Cells. International journal

    Hirofumi Noguchi, Issei Saitoh, Hitomi Usui Kataoka, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara

    Cell medicine   5 ( 2-3 )   63 - 8   2013.11

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    Recently, mouse pancreatic stem cells have been isolated from adult mouse pancreata. However, these pancreatic stem cells could be maintained only under specific culture conditions with lot-limited fetal bovine serum (FBS). For the efficient isolation and maintenance of mouse pancreatic stem cells, it is important to identify culture conditions that can be used independent of the FBS lot. In this study, we evaluated the culture conditions required to maintain mouse pancreatic stem cells. The mouse pancreatic stem cells derived from the pancreas of a newborn mouse, HN#101, were cultured under the following conditions: 1) Dulbecco's modified Eagle's medium (DMEM) with 20% lot-limited FBS, in which mouse pancreatic stem cells could be cultured without changes in morphology and growth activity; 2) complete embryonic stem (ES) cell media; and 3) complete ES cell media on feeder layers of mitomycin C-treated STO cells, which were the same culture conditions used for mouse ES cells. Under culture conditions #1 and #3, the HN#101 cells continued to form a flat "cobblestone" monolayer and continued to divide actively beyond the population doubling level (PDL) 100 without growth inhibition, but this did not occur under culture condition #2. The gene expression profile and differentiated capacity of the HN#101 cells cultured for 2 months under culture condition #3 were similar to those of HN#101 cells at PDL 50. These data suggest that complete ES cell media on feeder layers could be useful for maintaining the undifferentiated state of pancreatic stem cells.

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  • Isolation Efficiency of Mouse Pancreatic Stem Cells Is Age Dependent. International journal

    Takashi Kuise, Hirofumi Noguchi, Issei Saitoh, Hitomi Usui Kataoka, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara

    Cell medicine   5 ( 2-3 )   69 - 73   2013.11

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    Mouse pancreatic stem cells have been isolated from mouse pancreata. This study evaluated the efficacy of isolating mouse pancreatic stem cells using mice of different ages. The pancreata of newborn mice, 8-week-old mice, and 24-week-old mice were harvested and digested by using collagenase. The "duct-like" cells in the digested pancreatic tissue were then inoculated into 96-well plates, cloned by limiting dilution, and cultured in DMEM with 20% FBS. Pancreatic stem cells were isolated from the pancreata of all newborn mice, while cells could only be isolated from 10% of the pancreata of 8-week-old mice and could not be isolated from the pancreata of any 24-week-old mice. These data suggest that young mice may have some pancreatic stem cells and that older mice may only have a few pancreatic stem cells. These data also indicate that it is extremely difficult to isolate pancreatic stem cells from older mice, suggesting that future research focus its efforts on finding methods of isolating pancreatic stem cells from adult mice.

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  • Comparison of incubation solutions prior to the purification of porcine islet cells. Reviewed

    Kawai Takashi, Noguchi Hirofumi, Kuise Takashi, Nakatsuka Atsuko, Katayama Akihiro, Imagawa Noriko, Kataoka, Hitomi Usui, Saitoh Issei, Noguchi Yasufumi, Watanabe Masami, Fujiwara Toshiyoshi

    Cell Medicine   2013.10

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  • Molecular cloning and tumour suppressor function analysis of canine REIC/Dkk-3 in mammary gland tumours Reviewed

    Kazuhiko Ochiai, Masami Watanabe, Daigo Azakami, Masaki Michishita, Yasunaga Yoshikawa, Chihiro Udagawa, Pornphimon Metheenukul, Thippayarat Chahomchuen, Hiroshi Aoki, Hiromi Kumon, Masami Morimatsu, Toshinori Omi

    VETERINARY JOURNAL   197 ( 3 )   769 - 775   2013.9

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    REIC/Dkk-3, a member of the human Dickkopf (Dkk) family, plays a role as a suppressor of growth in several human cancers. In this study, the tumour suppression function of canine REIC/Dkk-3 was investigated. The full-length open reading frame of the canine REIC/Dkk-3 homologue was cloned and the tissue distribution of REIC/Dkk-3 mRNA was determined, along with the subcellular localisation of the REIC/Dkk-3 protein in canine cancer cell lines. Expression of REIC/Dkk-3 was lower in mammary gland tumours and in canine mammary carcinoma cell lines than in normal mammary gland tissue. Overexpression of REIC/Dkk-3 induced apoptosis in canine mammary carcinoma cell lines. These results show that expression of REIC/Dkk-3 is downregulated in canine mammary tumours and that one of the functions of this gene is induction of apoptosis. (C) 2013 Elsevier Ltd. All rights reserved.

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  • Clinical significance of CD24 as a predictor of bladder cancer recurrence Reviewed

    Chunxiao Liu, Shaobo Zheng, Haiyan Shen, Kai Xu, Jie Chen, Hulin Li, Yawen Xu, Abai Xu, Binshen Chen, Haruki Kaku, Yasutomo Nasu, Hiromi Kumon, Peng Huang, Masami Watanabe

    ONCOLOGY LETTERS   6 ( 1 )   96 - 100   2013.7

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    Cluster of differentiation (CD)24 was originally described as a B lymphocyte marker and has recently received considerable attention in cancer research as its overexpression has been observed in several types of carcinoma. The CD24 molecule is a glycosyl-phosphatidylinositol-linked cell surface protein that appears to be associated with aggressive cancers involving invasion and metastasis. However, the expression of CD24 in human bladder cancer and its clinical significance remains largely unknown and no association has been reported between CD24 overexpression and human bladder tumor recurrence. In the present study, the CD24 expression in cancer tissues obtained during transurethral surgery and the subsequent intra-bladder tumor recurrence following surgery were assessed. Immunohistochemical staining was performed and the intensity of CD24 staining was semi-quantitatively evaluated. CD24 expression was observed more frequently in high-grade bladder tumors (G2-G3) than low-grade tumors (G1). Positive CD24 expression was significantly associated with intra-bladder tumor recurrence following surgery and increased staining intensity was also correlated with recurrence. The positive association between CD24 expression and tumor recurrence was observed in each tumor category (stages Ta and Tl, low and high grade). The results demonstrated that CD24 expression is Significantly associated with bladder tumor recurrence. To the best of our knowledge, this is the first study to reveal the significance of CD24 as a predictor of bladder cancer recurrence. These insights may lead to future therapeutic strategies targeting CD24 to prevent the dissemination of bladder cancer cells and tumor recurrence.

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  • Stabilization of actin bundles by a dynamin 1/cortactin ring complex is necessary for growth cone filopodia. Reviewed International journal

    Hiroshi Yamada, Tadashi Abe, Ayano Satoh, Nana Okazaki, Shota Tago, Kinue Kobayashi, Yumi Yoshida, Yoshiya Oda, Masami Watanabe, Kazuhito Tomizawa, Hideki Matsui, Kohji Takei

    The Journal of neuroscience : the official journal of the Society for Neuroscience   33 ( 10 )   4514 - 26   2013.3

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    Dynamin GTPase, a key molecule in endocytosis, mechanically severs the invaginated membrane upon GTP hydrolysis. Dynamin functions also in regulating actin cytoskeleton, but the mechanisms are yet to be defined. Here we show that dynamin 1, a neuronal isoform of dynamin, and cortactin form ring complexes, which twine around F-actin bundles and stabilize them. By negative-staining EM, dynamin 1-cortactin complexes appeared as "open" or "closed" rings depending on guanine nucleotide conditions. By pyrene actin assembly assay, dynamin 1 stimulated actin assembly in mouse brain cytosol. In vitro incubation of F-actin with both dynamin 1 and cortactin led to the formation of long and thick actin bundles, on which dynamin 1 and cortactin were periodically colocalized in puncta. A depolymerization assay revealed that dynamin 1 and cortactin increased the stability of actin bundles, most prominently in the presence of GTP. In rat cortical neurons and human neuroblastoma cell line, SH-SY5Y, both dynamin 1 and cortactin localized on actin filaments and the bundles at growth cone filopodia as revealed by immunoelectron microscopy. In SH-SY5Y cell, acute inhibition of dynamin 1 by application of dynamin inhibitor led to growth cone collapse. Cortactin knockdown also reduced growth cone filopodia. Together, our results strongly suggest that dynamin 1 and cortactin ring complex mechanically stabilizes F-actin bundles in growth cone filopodia. Thus, the GTPase-dependent mechanochemical enzyme property of dynamin is commonly used both in endocytosis and regulation of F-actin bundles by a dynamin 1-cortactin complex.

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  • Dose-response analysis of testosterone replacement therapy in patients with female to male gender identity disorder Reviewed

    Aya Nakamura, Masami Watanabe, Morito Sugimoto, Tomoko Sako, Sabina Mahmood, Haruki Kaku, Yasutomo Nasu, Kazushi Ishii, Atsushi Nagai, Hiromi Kumon

    ENDOCRINE JOURNAL   60 ( 3 )   275 - 281   2013.3

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    Gender identity disorder (GID) is a conflict between a person's actual physical gender and the one they identify him or herself with. Testosterone is the key agent in the medical treatment of female to male GID patients. We conducted a dose-response analysis of testosterone replacement therapy (TRT) in 138 patients to determine the onset of the therapeutic effects. The TRT consisted of intramuscular injection of testosterone enanthate and patients were divided into three groups; 250 mg every two weeks, 250 mg every three weeks and 125 mg every two weeks. The onset of deepening of voice, increase in facial hair and cessation of menses was evaluated in each group. At one month after the start of TRT, the onset of these physical changes was more prevalent in the group receiving the higher dose of testosterone, and there were dose-dependent effects observed between the three treatment groups. On the other hand, at six months after the start of TRT, most of the patients had achieved treatment responses and there were no dose-dependent effects with regard to the percentage of patients with therapeutic effects. No significant side effects were observed in any of the treatment groups. We demonstrated that the early onset of the treatment effects of TRT is dose-dependent, but within six months of starting TRT, all three doses were highly effective. Current study provides useful information to determine the initial dose of TRT and to suggest possible changes that should be made in the continuous dosage for long term TRT.

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  • In Vivo Imaging of Transplanted Islets Labeled with a Novel Cationic Nanoparticle Reviewed

    Koichi Oishi, Yoshitaka Miyamoto, Hiroaki Saito, Katsutoshi Murase, Kenji Ono, Makoto Sawada, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara, Shuji Hayashi, Hirofumi Noguchi

    PLoS ONE   8 ( 2 )   2013.2

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    To monitor pancreatic islet transplantation efficiency, reliable noninvasive imaging methods, such as magnetic resonance imaging (MRI) are needed. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially-available magnetic nanoparticles are not efficiently transduced into cells. We herein report the in vivo detection of transplanted islets labeled with a novel cationic nanoparticle that allowed for noninvasive monitoring of islet grafts in diabetic mice in real time. The positively-charged nanoparticles were transduced into a β-cell line, MIN6 cells, and into isolated islets for 1 hr. MRI showed a marked decrease in the signal intensity on T1- and T2-weighted images at the implantation site of the labeled MIN 6 cells or islets in the left kidneys of mice. These data suggest that the novel positively-charged nanoparticle could be useful to detect and monitor islet engraftment, which would greatly aid in the clinical management of islet transplant patients. © 2013 Oishi et al.

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  • Culture conditions for mouse pancreatic stem cells. Reviewed

    Noguchi H, Saitoh I, Kataoka HU, Watanabe M, Fujiwara T

    Cell Medicine.   5   63 - 68   2013.1

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  • Isolation efficiency of mouse pancreatic stem cells is age-dependent. Reviewed

    Kuise T, Noguchi H, Saitoh I, Kataoka HU, Watanabe M, Fujiwara T

    Cell Medicine.   5   69 - 73   2013.1

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  • Cancer stem cell-like characteristics of a CD133+ subpopulation in the J82 human bladder cancer cell line. Reviewed International journal

    Peng Huang, Masami Watanabe, Haruki Kaku, Hideo Ueki, Hirofumi Noguchi, Morito Sugimoto, Takeshi Hirata, Hiroshi Yamada, Kohji Takei, Shaobo Zheng, Kai Xu, Yasutomo Nasu, Yasuyuki Fujii, Chunxiao Liu, Hiromi Kumon

    Molecular and clinical oncology   1 ( 1 )   180 - 184   2013.1

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    Cancer stem cells (CSCs) are thought to be crucial for understanding the biological roots of cancer, and are of increasing importance as a target for new anticancer agents. According to an expression analysis of the cell surface antigens of various types of cancer, CD133 is considered to be a potential marker of cancer stemness. In this study, a human urinary bladder cancer cell line (J82) was used to analyze the cancer stem cell-like characteristics of CD133+ bladder cancer cells in vitro and in vivo. The CD133 expression in the J82 cells was examined and the cells were immunomagnetically categorized into positive and negative subsets. The CD133- and CD133+ subsets were phenotypically divergent with regard to the cell growth pattern, while CD133+ cells tended to colonize during their growth. In CD133+ cells, the pluripotent stem cell factors Oct-4 and Sox-2 were upregulated, and a statistically significant proliferation increase was observed when compared to CD133- cells. The CD133+ subpopulation was more tolerant to the chemotherapeutic agent cisplatin, and Bacillus Calmette-Guérin (BCG), an agent instilled intravesically to treat bladder cancer. In addition, CD133+ J82 cells were more resistant to radiation treatment when compared to CD133- cells. The in vivo tumorigenesis of the CD133- and CD133+ subsets of J82 cancer cells was also examined by subcutaneously injecting them into nude mice. The tumor growth was more aggressive in the CD133+ subpopulation, showing a significant difference in the tumorigenic potential in these subsets. In conclusion, J82 human bladder cancer cells include CD133- and CD133+ subpopulations, while the CD133 molecule is a potential marker of the potential malignancy of human bladder cancer. In the present study, the CD133+ subpopulation was herein demonstrated to have certain characteristics consistent with those of cancer stem cells.

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  • DIRECT THERAPEUTIC EFFECT OF REIC/DKK-3-ENCODING ADENOVIRAL VECTOR FOR NON-SMALL CELL LUNG CANCER Reviewed

    Yamamoto Hiromasa, Tanaka Norimitsu, Toyooka Shinichi, Watanabe Masami, Sakaguchi Masakiyo, Soh Junichi, Shien Kazuhiko, Furukawa Masashi, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Huh Nam-ho, Kumon Hiromi, Miyoshi Shinichirou

    JOURNAL OF THORACIC ONCOLOGY   7 ( 11 )   S463   2012.11

  • Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy Reviewed

    Morito Sugimoto, Masami Watanabe, Haruki Kaku, Shun-Ai Li, Hirofumi Noguchi, Hideo Ueki, Masakiyo Sakaguchi, Nam-Ho Huh, Yasutomo Nasu, Hiromi Kumon

    ONCOLOGY REPORTS   28 ( 5 )   1645 - 1652   2012.11

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    The biodistribution and safety of adenoviral vectors encoding the human REIC/Dkk-3 tumor suppressor gene (Ad-REIC) were examined in this preclinical study for in situ prostate cancer gene therapy. First, the in vitro apoptotic effects of Ad-REIC in normal and cancer cells derived from the prostate and liver were examined. Significant apoptotic effects were observed at 100 MOI (multiplicity of infection) in prostate cancer cells (LNCaP, PC3) and hepatoma cells (HEP3B and HEPG2); however, no effects were seen in normal cells. To analyze the safety of intraprostatic Ad-REIC administration, the biodistribution and histology after Ad-REIC injection were evaluated in various organs of normal male C57BL6 mice. In a supporting study, vector dissemination following intravenous injection of Ad-REIC into tail veins was determined. To evaluate whether Ad-REIC was present in the collected tissue specimens, human REIC gene detection was performed using DNA-PCR. Intraprostatic treatment administered at lower doses showed vector biodistribution into the colon, urinary bladder and prostate. At higher doses, vector dissemination was observed in tissues more distant from the prostate, including the lung, thymus, heart, liver and adrenal gland. After intravenous injection a: Ad-REIC, dissemination was observed in the liver and spleen. These results indicate that the biodistribution of Ad-REIC is determined by the dose and route of administration. Although acute inflammatory effects were observed in the prostate after intraprostatic administration at higher doses, no abnormal histological findings were noted in the other tissues, including those of intravenously treated mice. Regarding the safety of Ad-REIC administration, no deaths and no signs of toxicity or unusual behavior were observed in the mice in any treatment group. Based on these preclinical experiments, adenovirus-mediated in situ REIC/Dkk-3 gene therapy is considered to be safe for use as a treatment for human prostate cancer.

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  • REIC/Dkk-3-encoding adenoviral vector as a potentially effective therapeutic agent for bladder cancer Reviewed

    Takeshi Hirata, Masami Watanabe, Haruki Kaku, Yasuyuki Kobayashi, Hiroshi Yamada, Masakiyo Sakaguchi, Kohji Takei, Nam-Ho Huh, Yasutomo Nasu, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   41 ( 2 )   559 - 564   2012.8

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    Bladder cancer is one of the most common urogenital malignancies. The intravesical instillation of anticancer agents is an attractive strategy to treat a superficial lesion or floating/disseminated cancer cells after transurethral operation. An adenovirus carrying REIC/Dkk-3, a tumor suppressor gene (Ad-REIC), exhibits cancer-specific apoptotic effects in various types of cancer cells. The aim of the present study was to examine the potential of Ad-REIC as a therapeutic agent for bladder cancer. KK47 and RT4 human bladder cancer cells were sensitive to the Ad-REIC treatment for apoptosis induction, but some human bladder cancer cell lines (T24, J82 and TccSup) were resistant. Significant cell growth inhibition was observed when these resistant cancer cell lines were treated with Ad-REIC in a condition of floating cells, which is clinically observed after transurethral operation and becomes a cause of intravesical cancer dissemination. The therapeutic potential of Ad-REIC for the treatment of multidrug-resistant bladder cancer was investigated. The adriamycin-resistant KK47 bladder cancer cells (KK47/ADM), which also present multidrug resistance, showed induction of significant apoptosis following Ad-REIC treatment. The Ad-REIC treatment induced downregulation of P-glycoprotein in KK47/ADM cells and restored the sensitivity to doxorubicin (adriamycin). Ad-REIC suppressed P-glycoprotein expression in a c-Jun-NH2-kinase (JNK)-dependent manner. Therefore, the current study indicated two therapeutic aspects of the Ad-REIC agent against human bladder cancer cells, as an apoptosis inducer/cell growth inhibitor and as a sensitizer of chemotherapeutic agents in multidrug-resistant cancer cells. The intravesical instillation of Ad-REIC could be an attractive therapeutic method in human bladder cancer where the treatment of superficial lesions and floating/disseminated or multidrug-resistant cancer cells is necessary.

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  • A novel gene expression system for detecting viable bladder cancer cells Reviewed

    Hideo Ueki, Masami Watanabe, Haruki Kaku, Peng Huang, Shun-Ai Li, Kazuhiko Ochiai, Takeshi Hirata, Hirofumi Noguchi, Hiroshi Yamada, Kohji Takei, Yasutomo Nasu, Yuji Kashiwakura, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   41 ( 1 )   135 - 140   2012.7

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    A novel transcriptional system was developed that can robustly enhance cancer-specific gene expression. In the system, hTERT promoter-driven gene expression was enhanced by an advanced two-step transcriptional amplification (TSTA). This construct was used to develop a novel system for detection of bladder cancer cells. The current study evaluated the advanced TSTA system by examining the cancer-specific gene transcription in various bladder cancer cell lines. The system significantly enhanced cancer-specific luciferase gene expression in the bladder cancer cell lines in comparison to the previous expression system of one-step or conventional TSTA. The fold gain of the enhancement was significantly correlated to the telomerase activity of the cell lines. A green fluorescent protein (GFP) gene encoding plasmid vector was constructed where hTERT promoter-driving transcription is enhanced by the advanced TSTA to utilize the system for the imaging and detection of viable bladder cancer cells. The advanced TSTA-hTERT-GFP plasmid successfully induced cancer-specific gene expression, showing robust GFP expression in human bladder cancer cell lines, but no visible GFP expression in normal bladder urothelial cells. The control GFP plasm id with a CMV promoter yielded GFP expression in both normal bladder cells and cancer cells. The advanced TSTA-hTERT-GFP plasmid allowed selective visualization of viable human bladder cancer cells in mixed cell culture containing 10- and 100-fold more normal bladder urothelial cells. These findings indicate that the advanced TSTA-hTERT expressional system is a valuable tool for detecting viable bladder cancer cells. The current system can be applied for in vitro detection of bladder cancer cells in urine and other types of cancer cells disseminated in vivo.

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  • Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence Reviewed

    Peng Huang, Jie Chen, Lei Wang, Yanqun Na, Haruki Kaku, Hideo Ueki, Katsumi Sasaki, Ken Yamaguchi, Kai Zhang, Takashi Saika, Yasutomo Nasu, Masami Watanabe, Hiromi Kumon

    MEDICAL ONCOLOGY   29 ( 2 )   829 - 834   2012.6

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    OCT-4, which is also known as POU5f1, is a key regulator of self-renewal in embryonic stem cells. The new cancer stem cell concept proposes that the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of the cancer behavior, such as recurrence or metastasis. This study investigated the association between OCT-4 expression in cancer tissues obtained by transurethral surgery and the clinical data to clarify the involvement of OCT-4 in human bladder malignancy. Immunohistochemical analysis demonstrated that a positive rate of OCT-4 expression was significantly associated with the higher-grade cancer (G2 and G3) in comparison with that of the lower grade (G1). In addition, positive OCT-4 expression was significantly associated with the intra-bladder tumor recurrence after the operation. The staining intensity of OCT-4 expression was also correlated with tumor recurrence. These data indicate that positive OCT-4 expression may be involved in the development of high-grade bladder cancer and with the bladder cancer recurrence. This is the first study showing a correlation between the expression of OCT-4 and bladder cancer recurrence. OCT-4 may be a valuable clinical marker for the progression of bladder cancer and may be an attractive therapeutic target for the development of new medicines for the treatment of malignancy.

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  • 非小細胞肺癌に対する新たな個別化治療戦略 REIC/Dkk-3遺伝子治療の可能性

    宗 淳一, 豊岡 伸一, 田中 則光, 渡部 昌実, 山本 寛斉, 阪口 政清, 許 南浩, 那須 保友, 公文 裕巳, 三好 新一郎

    日本呼吸器外科学会雑誌   26 ( 3 )   P17 - 01   2012.4

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  • Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1 Reviewed

    Yu Jin, Hitoshi Murata, Masakiyo Sakaguchi, Ken Kataoka, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    ONCOLOGY REPORTS   27 ( 3 )   695 - 699   2012.3

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    REIC/Dkk-3 is a tumor suppressor gene that was first identified as a gene downregulated in association with immortalization of normal human fibroblasts. We have demonstrated that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) showed a tumor-specific killing effect on a wide range of cancers. However, some human cancers, bladder cancers in particular, are resistant to Ad-REIC. In this study, we investigated the combination effect of downregulation of BRPK/PINK1 (PINK1) and Ad-REIC on bladder cancer cells. Five bladder cancer cell lines among six cell lines examined were resistant to Ad-REIC. Among the cell lines, the resistance of two cell lines was probably due to low infection efficiency of the adenovirus. PINK1-specific siRNA remarkably downregulated Bcl-x(L) and TRAP1 proteins and upregulated BAX protein expression. Finally, downregulation of PINK1 partially sensitized the other three cell lines that were resistant to Ad-REIC. This sensitization was associated with increasing production of reactive oxygen species (ROS). These results indicate that PINK1 is one of the key molecules for the mitochondrial protection system and that PINK1 can be a new target molecule to sensitize bladder cancer cells that are resistant to Ad-REIC.

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  • Preclinical Safety and Efficacy of in Situ REIC/Dkk-3 Gene Therapy for Prostate Cancer Reviewed

    Keiichiro Kawauchi, Masami Watanabe, Haruki Kaku, Peng Huang, Kasumi Sasaki, Masakiyo Sakaguchi, Kazuhiko Ochiai, Nam-ho Huh, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   66 ( 1 )   7 - 16   2012.2

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    The preclinical safety and therapeutic efficacy of adenoviral vectors that express the REIC/Dkk-3 tumor suppressor gene (Ad-REIC) was examined for use in prostate cancer gene therapy. The Ad-human (h) and mouse (m) REIC were previously demonstrated to induce strong anti-cancer effects in vitro and in vivo, and we herein report the results of two in vivo studies. First, intra-tumor Ad-hREIC administration was examined for toxicity and therapeutic effects in a subcutaneous tumor model using the PC3 prostate cancer cell line. Second, intra-prostatic Ad-mREIC administration was tested for toxicity in normal mice. The whole-body and spleen weights, hematological and serum chemistry parameters, and histological evaluation of tissues from throughout the body were analyzed. Both experiments indicated that there was no significant difference in the examined parameters between the Ad-REIC-treated group and the control (PBS- or Ad-LacZ-treated) group. In the in vitro analysis using PC3 cells, a significant apoptotic effect was observed after Ad-hREIC treatment. Confirming this observation, the robust anti-tumor efficacy of Ad-hREIC was demonstrated in the in vivo subcutaneous prostate cancer model. Based on the results of these preclinical experiments, we consider the adenovirus-mediated REIC/Dkk-3 in situ gene therapy to be safe and useful for the clinical treatment of prostate cancer.

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  • Single Nucleotide Polymorphism WRN Leu1074Phe Is Associated with Prostate Cancer Susceptibility in Chinese Subjects Reviewed

    Lei Wang, Haruki Kaku, Peng Huang, Kexin Xu, Kai Yang, Jiheng Zhang, Ming Li, Liping Xie, Xiaofeng Wang, Akiko Sakai, Masami Watanabe, Yasutomo Nasu, Kenji Shimizu, Hiromi Kumon, Yanqun Na

    ACTA MEDICA OKAYAMA   65 ( 5 )   315 - 323   2011.10

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    Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR = 0.58, 95% CI: 0.35-0.97, p = 0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age &lt;= 72 yr (OR = 0.27, 95% CI: 0.12-0.61, p = 0.002) and in patients with localized diseases (OR = 0.36, 95% CI: 0.19-0.70, p = 0.003). However, no statistically significant difference was found in the subgroup with age &gt; 72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects.

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  • Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging Reviewed

    Masami Watanabe, Hideo Ueki, Kazuhiko Ochiai, Peng Huang, Yasuyuki Kobayashi, Yasutomo Nasu, Katsumi Sasaki, Haruki Kaku, Yuji Kashiwakura, Hiromi Kumon

    ONCOLOGY REPORTS   26 ( 4 )   769 - 775   2011.10

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    The two-step transcriptional amplification (TSTA) system was previously reported to enhance the tissue-specific gene expression driven by weak promoters, but the enhancement of the gene expression is limited to use in in vitro and in vivo experimental situations. To achieve robust tissue-specific gene expression using the TSTA system, we developed an advanced TSTA system which includes polyglutamines and rat glucocorticoid receptor sequences between the GAL4 and VP16 sequences in the region of the first step of transcription. We evaluated the advanced TSTA system as a method to enhance the human telomerase reverse transcriptase (hTERT) promoter-driving cancer-specific transcription in various cancer cell lines. As a result, the advanced TSTA enhanced cancer-specific luciferase gene expression in all of the examined cancer cell lines, when compared with both the one-step and conventional TSTA systems (an similar to 6- and similar to 17-fold enhancement, respectively). Notably, the enhancement of the hTERT driven expression by the conventional TSTA system was modest and even inferior to the one-step system in several cancer cell lines. We then constructed a luciferase gene encoding the adeno-associated virus vector in which the hTERT promoter-mediated expression was driven by the advanced TSTA or control systems. In an orthotopic liver tumor model, mice were treated with the vector via tail vein injection. An optical imaging device was used to visualize the in vivo luciferase expression in the orthotopic tumor. The advanced TSTA system significantly enhanced the luciferase expression compared with the one-step and conventional TSTA systems (18.0+/-1.0- and 15.9+/-0.85-fold gain, respectively). Therefore, the advanced TSTA system significantly improves hTERT-dependent cancer-specific gene expression both in vitro and in vivo when compared with the previous systems. Since the advanced TSTA method can also be applied to other site-specific gene expression systems using tissue-specific promoters, this approach is expected to become a valuable tool enabling in vivo site-specific targeting in the field of gene therapy and molecular imaging.

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  • Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model Reviewed

    K. Tabata, S. Kurosaka, M. Watanabe, K. Edamura, T. Satoh, G. Yang, E. Abdelfattah, J. Wang, A. Goltsov, D. Floryk, T. C. Thompson

    GENE THERAPY   18 ( 10 )   969 - 978   2011.10

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    We previously identified the mouse and human Glipr1 and GLIPR1/RTVP-1 genes, respectively, as direct p53 targets with proapoptotic activities in various cancer cell lines, including prostate cancer (PCa). Intratumoral injection of an adenoviral vector capable of efficient transduction and expression of Glipr1 (AdGlipr1) yielded promising therapeutic results in an orthotopic, metastatic mouse model of PCa. AdGlipr1-transduced macrophages (M phi/Glipr1) generated greater surface expression of CD40, CD80 and major histocompatibility complex class II molecules and greater production of interleukin 12 (IL-12) and IL-6 in vitro than control macrophages did. Mechanistic analysis indicated that increased production of IL-12 in M phi/Glipr1 depends on activation of the p38 signaling cascade. M phi/Glipr1 injected into orthotopic 178-2BMA tumors in vivo resulted in significantly suppressed prostate tumor growth and spontaneous lung metastases and longer survival relative to those observed in control-treated mice. Furthermore, these preclinical data indicate the generation of systemic natural killer cell activity and tumor-specific cytotoxic T lymphocyte responses. Trafficking studies confirmed that intratumorally injected M phi/Glipr1 could migrate to draining lymph nodes. Overall, our data suggest that this novel gene-modified cell approach is an effective treatment avenue that induces antitumor immune responses in preclinical studies. Gene Therapy (2011) 18, 969-978; doi:10.1038/gt.2011.51; published online 21 April 2011

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  • Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1 Reviewed

    Kazuhiko Ochiai, Masami Watanabe, Hideo Ueki, Peng Huang, Yasuyuki Fujii, Yasutomo Nasu, Hirofumi Noguchi, Takeshi Hirata, Masakiyo Sakaguchi, Nam-ho Huh, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   412 ( 2 )   391 - 395   2011.8

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    REIC/Dkk-3 is a member of the Dickkopf family proteins known as Wnt-antagonists, and REIC/Dkk-3 expression is downregulated in a broad range of cancer types. REIC/Dkk-3 acts as a tumor suppressor in multiple cancer cell lines by inducing apoptosis through endoplasmic reticulum (ER) stress signaling. However, the intracellular interaction partners of REIC/Dkk-3 have not been fully elucidated. By employing yeast two-hybrid screening, we identified the human dynein light chain, Tctex-1, as a novel interaction partner of REIC/Dkk-3. We further disclosed that the interaction involves the 136-157 amino acid region of REIC/Dkk-3 by using the mammalian two-hybrid system. Interestingly, this binding region of REIC/Dkk-3 with Tctex-1 contains an amino acid sequence motif [-(E) under bar -X-(G) under bar-(R) under bar-(R) under bar -X-(H) under bar-] which was previously reported as the Tctex-1 binding domain of dynein intermediate chain (DIC). Immunocytochemistry demonstrated that both REIC/Dkk-3 and Tctex-1 were localized around the ER of human fibroblasts, and the similar distribution pattern of the proteins suggests that their interaction occurs around the ER. This is the first study showing the interaction of a Dickkopf family protein with a dynein motor complex protein. The link between REIC/Dkk-3 and Tctex-1 may be of significance for understanding the molecular functions of the proteins in ER stress signaling and intracellular dynein motor dynamics, respectively. (C) 2011 Elsevier Inc. All rights reserved.

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  • [REIC/Dkk-3 gene therapy]. Reviewed

    Masami Watanabe, Haruki Kaku, Peng Huang, Hiromi Kumon, Yasutomo Nasu

    Nihon rinsho. Japanese journal of clinical medicine   69 Suppl 5   559 - 63   2011.6

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  • A PHASE I/II STUDY OF ADENOVIRUS-MEDIATED INTERLEUKIN-12 GENE THERAPY FOR HORMONE REFRACTORY PROSTATE CANCER; A REPORT OF INITIAL 6 CASES Reviewed

    Sasaki Katsumi, Nasu Yasutomo, Kaku Haruki, Watanabe Masami, Edamura Kohei, Saika Takashi, Kumon Hiromi, Brenner Malcolm K

    JOURNAL OF GENE MEDICINE   12 ( 12 )   1025   2010.12

  • Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development Reviewed

    Kai Zhang, Masami Watanabe, Yuji Kashiwakura, Shun-Al Li, Kohei Edamura, Peng Huang, Ken Yamaguchi, Yasutomo Nasu, Yasuyuki Kobayashi, Masakiyo Sakaguchi, Kazuhiko Ochiai, Hiroshi Yamada, Kohji Takei, Hideo Ueki, Nam-Ho Huh, Ming Li, Haruki Kaku, Yanqun Na, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   37 ( 6 )   1495 - 1501   2010.12

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    The tumor suppressor REIC/Dkk-3 is a secretory protein which was originally identified to be downregulated in human immortalized cells In the present study, we investigated the expression pattern of REIC/Dkk-3 in various cell types to characterize its physiological functions We first examined the expression level of REIC/Dkk-3 in a broad range of cancer cell types and confirmed that it was significantly downregulated in all of the cell types We also examined the tissue distribution pattern in a variety of normal mouse organs Ubiquitous REIC/Dkk-3 protein expression was observed in the organs The expression was abundant in the liver, heart and brain tissue, but was absent in the spleen and peripheral blood mononuclear cells The immunohistochemical analyses revealed that the subcellular localization of REIC/Dkk-3 had a punctate pattern around the nucleus, indicating its association with secretory vesicles In cancer cells stably transfected with REIC/Dkk-3 the protein was predominantly localized to the endoplasmic reticulum (ER) under observation with confocal microscopy Because REIC/ Dkk-3 was found to be abundantly expressed in the acinar epithelial cells of the mouse prostate, we analyzed the effects of recombinant REIC/Dkk-3 protein on the acinar morphogenesis of RWPE-1 cells, which are derived from human normal prostate epithelium Statistically significant acinar growth was observed in the culture condition with 10 mu g/m1 REIC/Dkk-3 protein, implicating the soluble form m prostatic acinar development Current results suggest that REIC/Dkk-3 may play a role in regulating the morphological process of normal tissue architecture through an autocrine and/or paracrine manner

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  • Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma Reviewed

    P. Huang, H. Kaku, J. Chen, Y. Kashiwakura, T. Saika, Y. Nasu, Y. Urata, T. Fujiwara, M. Watanabe, H. Kumon

    CANCER GENE THERAPY   17 ( 7 )   484 - 491   2010.7

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    OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC. Cancer Gene Therapy (2010) 17, 484-491; doi:10.1038/cgt.2010.5; published online 19 February 2010

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  • The role of caveolin-1 in prostate cancer: clinical implications Reviewed

    T. C. Thompson, S. A. Tahir, L. Li, M. Watanabe, K. Naruishi, G. Yang, D. Kadmon, C. J. Logothetis, P. Troncoso, C. Ren, A. Goltsov, S. Park

    PROSTATE CANCER AND PROSTATIC DISEASES   13 ( 1 )   6 - 11   2010.3

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    Caveolin-1 (cav-1) is reportedly overexpressed in prostate cancer cells and is associated with disease progression. Specific oncogenic activities of cav-1 associated with Akt activation also occur in prostate cancer. A membrane-associated protein, cav-1, is nonetheless secreted by prostate cancer cells; results of recent studies showed that secreted cav-1 can stimulate cell survival and angiogenic activities, defining a role for cav-1 in the prostate cancer microenvironment. Serum cav-1 levels were also higher in prostate cancer patients than in control men without prostate cancer, and the preoperative serum cav-1 concentration had prognostic potential in men undergoing radical prostatectomy. Secreted cav-1 is therefore a potential biomarker and therapeutic target for prostate cancer. Prostate Cancer and Prostatic Diseases (2010) 13, 6-11; doi:10.1038/pcan.2009.29; published online 7 July 2009

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  • PP-470 低ゴナドトロピン性男子性腺機能低下症に対するhCG、hMG療法の臨床的検討(発表・討論,第98回日本泌尿器科学会総会)

    石井 和史, 大石 智子, 渡部 昌実, 公文 裕巳, 永井 敦

    日本泌尿器科学会雑誌   101 ( 2 )   486 - 486   2010

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  • Dynasore, a dynamin inhibitor, suppresses lamellipodia formation and cancer cell invasion by destabilizing actin filaments Reviewed

    Hiroshi Yamada, Tadashi Abe, Shun-Ai Li, Yuki Masuoka, Mihoko Isoda, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Akira Asai, Kohji Takei

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   390 ( 4 )   1142 - 1148   2009.12

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    Dynamic remodeling of actin filaments are bases for a variety of cellular events including cell motility and cancer invasion, and the regulation of actin dynamics implies dynamin, well characterized endocytotic protein. Here we report that dynasore, a inhibitor of dynamin GTPase, potently destabilizes F-actin in vitro, and it severely inhibits the formation of pseudopodia and cancer cell invasion, both of which are supported by active F-actin formation. Dynasore rapidly disrupted F-actin formed in brain cytosol in vitro, and the dynasore&apos;s effect on F-actin was indirect. Dynasore significantly suppressed serum-induced lamellipodia formation in U2OS cell. Dynasore also destabilized F-actin in resting cells, which caused the retraction of the plasma membrane. A certain amount of dynamin 2 in U2OS cells localized along F-actin, and co-localized with cortactin, a physiological binding partner of dynamin and F-actin. However. these associations of dynamin were partially disrupted by dynasore treatment. Furthermore, invasion activity of H1080 cell, a lung cancer cell line, was suppressed by approximately 40% with dynasore treatment. These results strongly suggest that dynasore potently destabilizes F-actin, and the effect implies dynamin. Dynasore or its derivative would be suitable candidates as potent anti-cancer drugs. (C) 2009 Elsevier Inc. All rights reserved.

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  • REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells Reviewed

    Jie Chen, Masami Watanabe, Peng Huang, Masakiyo Sakaguchi, Kazuhiko Ochiai, Yasutomo Nasu, Mamoru Ouchida, Nam-Ho Huh, Kenji Shimizu, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE   24 ( 6 )   789 - 794   2009.12

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    The reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3. a member of the Dkk gene family, is a tumor suppressor in a broad range of cancers. REIC/Dkk-3 transfected stable clones of mouse prostate cancer RM9 cells (RM9-REIC) and the empty vector-transfected control clone cells (RM9-EV) were established. Clones were used to evaluate the anti-cancer effects and a proteomics analysis of REIC/Dkk-3 continuous expression was performed. The RM9-REIC cells show a feeble appearance and the cell membrane shows irregular buds known as blebs. In vitro cell proliferation was significantly suppressed in RM9-REIC clones in comparison to the control. The apoptosis assay was done under standard culture conditions and RM9-REIC showed a higher incidence of apoptosis. The RM9-EV and RM9-REIC cells were orthotopically implanted into a C57BL/6 mouse prostate. After 2 weeks, the tumor growth was significantly inhibited in RM9-REIC cells in comparison to the control. Two-dimensional gel electrophoresis was used to examine the modification of protein expression by the gene transfection. The analysis with mass spectrometry disclosed that expression of peroxiredoxin-l, GST-P1. transgelin-2, MRP-L12, ARD, GRP78 and Sorcin were increased and eEF1A-1 and cyclophilin-40 protein were decreased in RM9-REIC cells. Therefore, REIC/Dkk-3 stable transfectants show a reduction of malignancy in mouse prostate cancer RM9 cells in vitro and in vivo. The result of the proteomics analysis might provide important clues to clarify the anti-cancer molecular mechanism of REIC/Dkk-3 gene transfer.

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  • Therapeutic effects of gelatin matrix-embedded IL-12 gene-modified macrophages in a mouse model of residual prostate cancer Reviewed

    K. Tabata, M. Watanabe, K. Naruishi, K. Edamura, T. Satoh, G. Yang, E. Abdel Fattah, J. Wang, A. Goltsov, D. Floryk, S. D. Soni, D. Kadmon, T. C. Thompson

    PROSTATE CANCER AND PROSTATIC DISEASES   12 ( 3 )   301 - 309   2009.9

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    We evaluated the potential use of intraoperative gelatin matrix hemostatic sealant (GMHS; FloSeal; Baxter Healthcare) embedded with macrophages (M phi) transduced with murine interleukin (IL)-12 recombinant adenoviral vector (G/M phi/AdmIL-12) for prevention of recurrence of prostate cancer following radical prostatectomy. Application of G/M phi/AdmIL-12 resulted in significant suppression of tumor growth and spontaneous lung metastases, a statistically significant survival advantage of the G/M phi/AdmIL-12-treated animals, more efficient trafficking of M phi to lymph nodes draining from the prostate and generation of systemic natural killer cell activity and tumor-specific cytolytic T lymphocyte responses compared to the controls in a preclinical mouse model of residual prostate cancer. Our data recommend this treatment as a novel adjuvant for prevention of local recurrence of prostate cancer following radical prostatectomy. Prostate Cancer and Prostatic Diseases (2009) 12, 301-309; doi: 10.1038/pcan.2008.57; published online 23 December 2008

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  • Functional Analysis of Secreted Caveolin-1 in Mouse Models of Prostate Cancer Progression Reviewed

    Masami Watanabe, Guang Yang, Guangwen Cao, Salahaldin A. Tahir, Koji Naruishi, Ken-ichi Tabata, Elmoataz Abdel Fattah, Kartik Rajagopalan, Terry L. Timme, Sanghee Park, Shinji Kurosaka, Kohei Edamura, Ryuta Tanimoto, Francesco J. Demayo, Alexei A. Goltsov, Timothy C. Thompson

    MOLECULAR CANCER RESEARCH   7 ( 9 )   1446 - 1455   2009.9

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    Previously, we reported that caveolin-1 (cav-1) is overexpressed in metastatic prostate cancer and that virulent prostate cancer cells secrete biologically active cav-1. We also showed that cav-1 expression leads to prosurvival activities through maintenance of activated Akt and that cav-1 is taken up by other cav-1-negative tumor cells and/or endothelial cells, leading to stimulation of angiogenic activities through PI-3-K-Akt-eNOS signaling. To analyze the functional consequences of cav-1 overexpression on the development and progression of prostate cancer in vivo, we generated PBcav-1 transgenic mice. Adult male PBcav-1 mice showed significantly increased prostatic wet weight and higher incidence of epithelial hyperplasia compared with nontransgenic littermates. Increased immunostaining for cav-1, proliferative cell nuclear antigen, P-Akt, and reduced nuclear p27(KiP1) staining occurred in PBcav-1 hyperplastic prostatic lesions. PBcav-1 mice showed increased resistance to castration-induced prostatic regression and elevated serum cav-1 levels compared with nontransgenic littermates. Intraprostatic injection of androgen-sensitive, cav-1-secreting RM-9 mouse prostate cancer cells resulted in tumors that were larger in PBcav-1 mice than in nontransgenic littermates (P = 0.04). Tall vein inoculation of RM-9 cells produced significantly more experimental lung metastases in PBcav-1 males than in nontransgenic male littermates (P = 0.001), and in cav-1(+/+) mice than in cav-1(-/-) mice (P = 0.041). Combination treatment with surgical castration and systemic cav-1 antibody dramatically reduced the number of experimental metastases. These experimental data suggest a causal association of secreted cav-1 and prostate cancer growth and progression. (Mol Cancer Res 2009;7(9):1446-55)

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  • Overexpression of REIC/Dkk-3 in Normal Fibroblasts Suppresses Tumor Growth via Induction of Interleukin-7 Reviewed

    Masakiyo Sakaguchi, Ken Kataoka, Fernando Abarzua, Ryuta Tanimoto, Masami Watanabe, Hitoshi Murata, Swe Swe Than, Kaoru Kurose, Yuji Kashiwakura, Kazuhiko Ochiai, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 21 )   14236 - 14244   2009.5

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    We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through a mechanism triggered by endoplasmic reticulum stress. Adenovirus vectors show no target cell specificity and thus may elicit unfavorable side effects through infection of normal cells even upon intra-tumoral injection. In this study, we examined possible effects of Ad-REIC on normal cells. We found that infection of normal human fibroblasts (NHF) did not cause apoptosis but induced production of interleukin (IL)-7. The induction was triggered by endoplasmic reticulum stress and mediated through IRE1 alpha, ASK1, p38, and IRF-1. When Ad-REIC-infected NHF were transplanted in a mixture with untreated human prostate cancer cells, the growth of the cancer cells was significantly suppressed. Injection of an IL-7 antibody partially abrogated the suppressive effect of Ad-REIC-infected NHF. These results indicate that Ad-REIC has another arm against human cancer, an indirect host-mediated effect because of overproduction of IL-7 by mis-targeted NHF, in addition to its direct effect on cancer cells.

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  • Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression Reviewed

    Masami Watanabe, Yuji Kashiwakura, Peng Huang, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Munenori Takaoka, Yasutomo Nasu, Masakiyo Sakaguchi, Nam-Ho Huh, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   34 ( 3 )   657 - 663   2009.3

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    The REIC/Dkk-3 gene has been reported to be a tumor suppressor and the expression is significantly down-regulated in a broad range of cancer cell types. The protein is secretory, but the physiological function remains unclear. This study demonstrated that recombinant REIC/Dkk-3 protein induced the differentiation of human CD14(+) monocytes into a novel cell type ((REIC/Dkx-3)Mo). (REIC/Dkk-3)Mo resembles immature dendritic cells generated with IL-4 and GM-CSF. Both these cell populations exhibit similar proportions of CD11c(+), CD40(+), CD86(+) and HLA-DR(+) cells and endocytic capacity, but (REIC/Dkk-3)Mo is negative for CD1a antigen. An analysis of the signal transducers and activators of transcription (STAT) pathways revealed that REIC/Dkk-3 induces phosphorylation of STAT 1 and STAT 3. Furthermore, intratumoral administration of REIC/Dkk-3 protein significantly suppressed tumor growth with CD11c(+) and CD8(+) (dendritic and killer T cell marker, respectively) cell accumulation and enhanced anticancer cytolytic activity of splenocytes. These data indicated a cytokine-like role of REIC/Dkk-3 protein in monocyte differentiation that might be exploited therapeutically.

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  • REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer Reviewed

    K. Kawasaki, M. Watanabe, M. Sakaguchi, Y. Ogasawara, K. Ochiai, Y. Nasu, H. Doihara, Y. Kashiwakura, N-h Huh, H. Kumon, H. Date

    CANCER GENE THERAPY   16 ( 1 )   65 - 72   2009.1

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    The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH(2)-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.

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  • Dynamin 2 is required for actin assembly in phagocytosis in Sertoli cells Reviewed

    Atsushi Otsuka, Tadashi Abe, Masami Watanabe, Hitoshi Yagisawa, Kohji Takei, Hiroshi Yamada

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   378 ( 3 )   478 - 482   2009.1

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    Dynamin 2 has been reported to be implicated in phagocytosis. However, the mode of action of dynamin is Poorly understood. In this Study, we examined whether dynamin 2 participates in actin assembly during phagocytosis in Sertoli cells. In the presence of dynasore, a dynamin inhibitor, phagocytosis was reduced by 60-70% in Sertoli cells and macrophages. Scanning electron microscopy revealed that Sertoli cells treated with dynasore were unable to form phagocytic cups. In addition, dysfunction of dynamin 2 reduced both actin polymerization and recruitment of actin and dynamin 2 to phosphatidylinositol (4,5) bisphosphate [ PI(4,5)P(2)]-containing liposomes. The formation of dynamin 2-positive ruffles of Sertoli cells was decreased by 60-70% by sequestering PI(4,5)P2 either by expression of PH domain of PLC delta or treatment with neomycin. These results strongly Suggest that dynamin 2 is involved in actin dynamics and the formation of dynamin 2-positive ruffles during phagocytosis. (C) 2008 Elsevier Inc. All rights reserved.

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  • A comparison of proteomic profiles changes during 17β-estradiol treatment in human prostate cancer PC-3 cell line Reviewed

    Jie Chen, Peng Huang, Haruki Kaku, Kai Zhang, Masami Watanabe, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

    Cancer Genomics and Proteomics   6 ( 6 )   331 - 335   2009

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:International Institute of Anticancer Research  

    Human telomerase reverse transcriptase (hTERT) is overexpressed in prostate cancer. Estrogen plays a central role in the development of prostate cancer. hTERT activity has been shown to be increased after estrogen treatment. Although significant efforts have been made to understand the role of estrogen, the telomerase connection with estrogen is poorly understood. In this report, we describe a proteomics approach for investigating the global changes in protein expression in estrogen-treated human prostate cancer PC-3 cells. PC-3 cells were seeded in medium and then treated with estrogen
    the protein extract from these cells was used for two-dimensional (2D) gel electrophoresis. The protein spots were subjected to comparative analysis by liquid chromatography/mass spectrometry (LC/MS). We observed that the expression of 17 proteins, including stress-induced phosphoprotein 1 and lamin-A/C was down-regulated, and that the expression of proteins such as subunit a of T-complex protein 1, tubulin alpha-1B, and other 13 proteins was up-regulated. These proteins may have been closely associated with estrogen-induced hTERT activity. The expression level of these proteins could be a useful parameter for evaluating the estrogen-induced hTERT activity in clinical specimens of human prostate cancer.

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  • PP-125 性同一性障害患者(FTM)に対するテストステロン補充量の検討(性機能障害,一般演題ポスター,第97回日本泌尿器科学会総会)

    大石 智子, 石井 和史, 渡部 昌実, 公文 裕巳, 松本 裕子

    日本泌尿器科学会雑誌   100 ( 2 )   348 - 348   2009

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    DOI: 10.5980/jpnjurol.100.348_1

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  • Dynamin 2 Cooperates with Amphiphysin 1 in Phagocytosis in Sertoli Cells Reviewed

    Akira Nakanishi, Tadashi Abe, Masami Watanabe, Kohji Takei, Hiroshi Yamada

    ACTA MEDICA OKAYAMA   62 ( 6 )   385 - 391   2008.12

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    Testicular Sertoli cells highly express dynamin 2 and amphiphysin 1. Here we demonstrate that dynamin 2 is implicated in phosphatidylserine (PS)-dependent phagocytosis in Sertoli cells. Immunofluorescence and dual-live imaging revealed that dynamin 2 and amphiphysin 1 accumulate simultaneously at ruffles. These proteins are specifically bound in vitro. Over-expression of dominant negative dynamin 2 (K44A) inhibits liposome-uptake and leads to the mis-localization of amphiphysin 1. Thus, the cooperative function of dynamin 2 and amphiphysin 1 in PS-dependent phagocytosis is strongly suggested.

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  • Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3-Induced Apoptosis Reviewed

    Yuji Kashiwakura, Kazuhiko Ochiai, Masami Watanabe, Fernando Abarzua, Masakiyo Sakaguchi, Munenori Takaoka, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Hub, Hiromi Kumon

    CANCER RESEARCH   68 ( 20 )   8333 - 8341   2008.10

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    REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH2 kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional down-regulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed down-regulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM. [Cancer Res 2008;68(20):8333-41]

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  • An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis Reviewed

    Fernando Abarzua, Yuji Kashiwakura, Munenori Takaoka, Masami Watanabe, Kazuhiko Ochiai, Masakiyo Sakaguchi, Takao Iwawaki, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Huh, Hiromi Kumon

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   375 ( 4 )   614 - 618   2008.10

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    Overexpression of REIC/Dkk-3 (a tumor suppressor gene) induces cancer cell apoptosis through endoplasmic reticulum (ER) stress. Therefore, the identification of the portion of REIC/Dkk-3 that causes ER stress may be essential for the development of cancer treatment based on REIC/Dkk-3. Here, we made several truncated forms of REIC/Dkk-3 and investigated their therapeutic potentials against prostate cancer. Among three truncated forms, a variant comprising the N-terminal 78 amino acid region of REIC/Dkk-3 ((1-78) REIC/Dkk-3) most strongly induced ER stress and apoptosis in human prostate cancer cells (PC3). For in vivo gene expression, we coupled a biodegradable polymer with naked DNA, which attained robust trans-gene expression in PC3-derived subcutaneous tumor. In therapeutic experiments, we demonstrated that multiple direct injections of polymer-conjugated (1-78)REIC/Dkk-3 plasmid provoke ER stress and significantly reduced the subcutaneous tumor volume compared with the control group. We suggest this non-viral strategy may be an effective alternative to viral gene therapy. (C) 2008 Elsevier Inc. All rights reserved.

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  • Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model Reviewed

    P. Huang, M. Watanabe, H. Kaku, Y. Kashiwakura, J. Chen, T. Saika, Y. Nasu, T. Fujiwara, Y. Urata, H. Kumon

    CANCER GENE THERAPY   15 ( 5 )   315 - 322   2008.5

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    We previously constructed OBP-301 ( Telomelysin, a telomerase-specific replication-competent adenovirus with human telomerase reverse transcriptase ( hTERT) promoter), which showed a strong anticancer effect by inducing cell lysis of human non-small cell lung cancer and colorectal cancer cells. To investigate the utility of OBP-301 for prostate cancer treatment, we herein evaluate the cell killing and antitumor effects. First, in vitro hTERT-specific adenovirus transduction in human prostate cancer cells ( LNCaP, PC3, DU145) was confirmed using OBP-401 ( Telomelysin-green fluorescent protein ( GFP)). There was no detectable GFP transduction in the human prostate normal cells ( PrEC, PrSC). Consistently, the cell-killing effect of OBP-301 was observed only in the cancer cells. Second, using an in vivo subcutaneous LNCaP tumor model in nude mice, we demonstrated that three intratumoral OBP-301 injections ( 10(7) PFU per tumor x 3 days) were sufficient to eradicate the detectable LNCaP prostate tumor. We also demonstrated that the ispilateral treatment with OBP-301 significantly suppressed contralateral LNCaP tumor growth in both sides of the tumor model. Histological and immunohistochemical analyses revealed diffuse oncolytic degeneration and adenoviral E1A protein expression in both sides of the tumors. Therefore, in situ OBP-301 administration could be a promising therapeutic strategy against prostate cancer and its metastatic lesions.

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  • Adenovirus-mediated REIC/DKK-3 gene transfer prevented mesothelioma tumor progressions in orthotopic mice model Reviewed

    Kashiwakura Yuji, Watanabe Masami, Abarzua Fernando, Sakaguchi Masakiyo, Takaoka Munenori, Tanimoto Ryuta, Nasu Yasutomo, Huh Nam-ho, Kumon Hiromi

    JOURNAL OF GENE MEDICINE   10 ( 4 )   469 - 470   2008.4

  • Tumor cell-secreted caveolin-1 has proangiogenic activities in prostate cancer Reviewed

    Salahaldin A. Tahir, Guang Yang, Alexei A. Goltsov, Masami Watanabe, Ken-ichi Tabata, Josephine Addai, El Moataz Abdel Fattah, Dov Kadmon, Timothy C. Thompson

    CANCER RESEARCH   68 ( 3 )   731 - 739   2008.2

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    Caveolin, a major structural component of specialized plasma membrane invaginations (caveolae) that participate in diverse cellular activities, has been implicated in the pathogenesis of several human diseases, including cancer. We showed in earlier studies that caveolin-1 (cav-1) is consistently and strongly overexpressed in metastatic prostate cancer and is secreted in a biologically active form by virulent prostate cancer cells. Using both in vitro and in vivo model systems, we now present evidence supporting a proangiogenic role for cav-1 in prostate cancer development and progression. Recombinant cav-1 (rcav-1) was taken up by cav-1(-/-) endothelial cells through either a lipid raft/caveolae- or clathrin-dependent mechanism, leading to specific angiogenic activities (tubule formation, cell migration, and nitric oxide production) that were mediated by rcav-1 stimulation of the PI3K-Akt-eNOS signaling module. Pathologic angiogenesis induced by cav-1 in prostate cancer-bearing mice correlated with an increased frequency, number, and size of lung metastases. We propose that in addition to its antiapoptotic role, cav-1 secreted by prostate cancer cells functions critically as a proangiogenic factor in metastatic progression of this tumor. These new insights into cav-1 function in prostate cancer may provide a base for the design of clinically applicable therapeutic strategies.

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  • Amphiphysin 1 is important for actin polymerization During phagocytosis Reviewed

    Hiroshi Yamada, Emiko Ohashi, Tadashi Abe, Norihiro Kusumi, Shun-AI Li, Yumi Yoshida, Masami Watanabe, Kazuhito Tomizawa, Yuji Kashiwakura, Hiromi Kumon, Hideki Matsui, Kohji Takei

    MOLECULAR BIOLOGY OF THE CELL   18 ( 11 )   4669 - 4680   2007.11

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    Amphiphysin 1 is involved in clathrin-mediated endocytosis. In this study, we demonstrate that amphiphysin 1 is essential for cellular phagocytosis and that it is critical for actin polymerization. Phagocytosis in Sertoli cells was induced by stimulating phosphatidylserine receptors. This stimulation led to the formation of actin-rich structures, including ruffles, phagocytic cups, and phagosomes, all of which showed an accumulation of amphiphysin 1. Knocking out amphiphysin 1 by RNA interference in the cells resulted in the reduction of ruffle formation, actin polymerization, and phagocytosis. Phagocytosis was also drastically decreased in amph 1(-/-) Sertoli cells. In addition, phosphatidylinositol-4,5-bisphosphate-induced actin polymerization was decreased in the knockout testis cytosol. The addition of recombinant amphiphysin 1 to the cytosol restored the polymerization process. Ruffle formation in small interfering RNA-treated cells was recovered by the expression of constitutively active Rac1, suggesting that amphiphysin 1 functions upstream of the protein. These findings support that amphiphysin 1 is important in the regulation of actin dynamics and that it is required for phagocytosis.

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  • Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model Reviewed

    K. Edamura, Y. Nasu, M. Takaishi, T. Kobayashi, F. Abarzua, M. Sakaguchi, Y. Kashiwakura, S. Ebara, T. Saika, M. Watanabe, N-H Huh, H. Kumon

    CANCER GENE THERAPY   14 ( 9 )   765 - 772   2007.9

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    We had previously reported that REIC/Dkk-3, a member of the Dickkopf ( Dkk) gene family, works as a tumor suppressor. In this study, we evaluated the therapeutic effects of an intratumoral injection with adenoviral vector encoding REIC/Dkk-3 gene ( Ad-REIC) using an orthotopic mouse prostate cancer model of RM-9 cells. We also investigated the in vivo anti-metastatic effect and in vitro anti-invasion effect of Ad-REIC gene delivery. We demonstrated that the Ad-REIC treatment inhibited prostate cancer growth and lymph node metastasis, and prolonged mice survival in the model. These therapeutic responses were consistent with the intratumoral apoptosis induction and in vitro suppression of cell invasion/migration with reduced matrix metalloprotease-2 activity. We thus concluded that in situ Ad-REIC/Dkk-3 gene transfer may be a promising therapeutic intervention modality for the treatment of prostate cancer.

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  • Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3 Reviewed

    Fernando Abarzua, Masakiyo Sakaguchi, Ryuta Tanimoto, Hiroyuki Sonegawa, Dai-Wei L, Kohei Edamura, Tomoko Kobayashi, Masami Watanabe, Yuji Kashiwakura, Haruki Kaku, Takashi Saika, Keiichiro Nakamura, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE   20 ( 1 )   37 - 43   2007.7

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    We recently showed that overexpression of REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in a tumor cell-specific manner. The aim of the present study was to determine the mechanisms underlying the selective induction of apoptosis. At first, we found a mouse renal carcinoma cell line, RENCA, to be extremely sensitive to an adenovirus carrying REIC/Dkk-3 (Ad-REIC), and we showed that activation of c-Jun N-terminal kinase (JNK) was a critical step in cell death, i.e. a process similar to that in human prostate and testicular cancer observed in our previous studies. Among the proteins interfering with the activation of JNK, heat shock protein (Hsp)70/72 was reduced in expression in RENCA cells compared with that in NIH3T3 cells. An Hsp70/72 inducer protected RENCA cells from Ad-REIC-induced apoptosis, while an Hsp70/72 inhibitor sensitized NIH3T3 cells for apoptosis induction. These results indicate that functionally active Hsp70/72 is a key factor in tumor cell-specific induction of apoptotic cell death and that analyses of the expression levels of Hsp70/72 may be essential in determining the significance of Ad-REIC-based gene therapy against human cancer.

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  • テロメラーゼ特異的複製:前立腺癌に対する選択的ウイルス療法(Telomerase-Specific Replication: Selective Virotherapy for Prostate Cancer) Reviewed

    黄 鵬, 渡部 昌実, 陳 潔, 賀来 春紀, 那須 保友, 雑賀 隆史, 藤原 俊義, 浦田 泰生, 公文 裕巳

    日本泌尿器科学会雑誌   98 ( 2 )   458 - 458   2007.2

  • Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer Reviewed

    T. Fujita, T. L. Timme, K. Tabata, K. Naruishi, N. Kusaka, M. Watanabe, E. Abdelfattah, J. X. Zhu, C. Ren, C. Ren, G. Yang, A. Goltsov, H. Wang, M. T. Vlachaki, B. S. Teh, E. B. Butler, T. C. Thompson

    GENE THERAPY   14 ( 3 )   227 - 236   2007.2

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    We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 1782 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-alpha mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Ad beta gal, Ad beta gal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

    DOI: 10.1038/sj.gt.3302788

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  • Implication of amphiphysin 1 and dynamin 2 in tubulobulbar complex formation and spermatid release Reviewed

    Norihiro Kusumi, Masami Watanabe, Hiroshi Yamada, Shun-Ai Li, Yuji Kashiwakura, Takashi Matsukawa, Atsushi Nagai, Yasutomo Nasu, Hiromi Kumon, Kohji Takei

    CELL STRUCTURE AND FUNCTION   32 ( 2 )   101 - 113   2007

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    Tubulobulbar complexes (TBCs) are composed of several tubular invaginations formed at the plasma membrane of testicular Sertoli cells. TBCs are transiently formed at the contact region with spermatids at spermatogenic stage VII in rat and mouse, and such TBC formation is prerequisite for spermatid release. Since the characteristic structure of TBCs suggests that the molecules implicated in endocytosis could be involved in TBC formation, we here investigated the localization and physiological roles of endocytic proteins, amphiphysin 1 and dynamin 2, at TBCs. We demonstrated by immunofluorescence that the endocytic proteins were concentrated at TBCs, where they colocalized with cytoskeletal proteins, such as actin and vinculin. Immunoelectron microscopy disclosed that both amphiphysin 1 and dynamin 2 were localized on TBC membrane. Next, we histologically examined the testis from amphiphysin 1 deficient {Amph(-/-)} mice. Morphometric analysis revealed that the number of TBCs was significantly reduced in Amph(-/-). The ratio of stage VIII seminiferous tubules was increased, and the ratio of stage IX was conversely decreased in Amph(-/-). Moreover, unreleased spermatids in stage VIII seminiferous tubules were increased in Amph(-/-), indicating that spermatid release and the following transition from stage VIII to IX was prolonged in Amph(-/-) mice. These results suggest that amphiphysin 1 and dynamin 2 are involved in TBC formation and spermatid release at Sertoli cells.

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  • Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer Reviewed

    K. Naruishi, T. L. Timme, N. Kusaka, T. Fujita, G. Yang, A. Goltsov, T. Satoh, X. Ji, W. Tian, E. Abdelfattah, T. Men, M. Watanabe, K. Tabata, T. C. Thompson

    CANCER GENE THERAPY   13 ( 7 )   658 - 663   2006.7

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    We previously identified a novel p53 target gene, RTVP-1, that possesses unique cytotoxic and immunostimulatory activities which make it potentially useful for cancer gene therapy. To test the therapeutic potential of RTVP-1 in a gene- modified tumor cell-based vaccine model, we used an adenoviral vector capable of efficient transduction and expression of RTVP-1 (AdRTVP-1), together with a highly metastatic mouse prostate cancer cell line (178-2 BMA). A vaccine was prepared with 178-2 BMA cells transduced with AdRTVP-1 or a control adenoviral vector expressing beta-galactosidase (Ad beta gal). After irradiation of the cells, syngeneic 129/Sv mice were vaccinated three times at weekly intervals. After 3 weeks, they were challenged with orthotopic 178-2 BMA cells. After 21 days, fewer than 60% of the RTVP-1-cell-vaccinated mice developed tumors compared to 100% of the control mice. The RTVP-1-cell vaccine significantly reduced primary tumor wet weight compared with control Ad beta gal-cell vaccine (P &lt; 0.0001 at 7 and 14 days). Experimental metastasis to lung was also significantly reduced (P = 0.0377), and survival significantly increased (P = 0.0002). In addition, significantly increased NK and CTL activities were demonstrated in the AdRTVP-1-cell-vaccinated mice. These findings indicate that RTVP-1 gene-modified cell-based vaccines may be useful in the prevention of recurrent prostate cancer.

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  • Extensive biopsy using a combined transperineal and transrectal approach to improve prostate cancer detection Reviewed

    M Watanabe, T Hayashi, T Tsushima, S Irie, T Kaneshige, H Kumon

    INTERNATIONAL JOURNAL OF UROLOGY   12 ( 11 )   959 - 963   2005.11

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    Purpose: Previous studies have indicated that 6-core transrectal prostate biopsy misses a considerable number of cancers. We performed an extensive biopsy protocol of 12-core sampling using both transperineal and transrectal approaches to determine the impact on the cancer detection rate.
    Materials and methods: We prospectively evaluated 402 men who underwent 6-core transperineal and 6-core transrectal biopsies simultaneously due to abnormal digital rectal examination (DRE) and/or elevated prostate-specic antigen (PSA) levels of 4.0 ng/mL or greater. Using the transperineal approach we obtained four cores from the bilateral peripheral zone targeting the lateral and parasagittal areas and two cores from the bilateral transition zone. The following transrectal biopsy was performed traditionally. We compared cancer detection rate between the extended 12-core procedure and conventional 6-core transperineal and transrectal groups in terms of total PSA and DRE ndings.
    Results: Using the extensive combined method, prostate cancer was detected in 195 cases (48.5%) and the detection rate signicantly increased 7.2% and 8.5% compared to the transperineal and transrectal groups, respectively. According to PSA levels and DRE ndings, the cancer detection rate by the combined method was signicantly improved in patients with PSA levels of 4-10 ng/mL and negative DRE: 10.3% and 11.6% compared to the transperineal and transrectal groups, respectively.
    Conclusions: The extensive 12-core method signicantly improved the overall cancer detection rate and was especially efcient for men with PSA levels of 4-10 ng/mL accompanied by a negative DRE nding.

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  • Minimal invasiveness and effectivity of subinguinal microscopic varicocelectomy: a comparative study with retroperitoneal high and laparoscopic approaches Reviewed

    M Watanabe, A Nagai, N Kusumi, H Tsuboi, Y Nasu, H Kumon

    INTERNATIONAL JOURNAL OF UROLOGY   12 ( 10 )   892 - 898   2005.10

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    Aim: The standard management of varicocele repair is the subject of ongoing controversy. We retrospectively evaluated three surgical methods of varicocele treatment to determine the minimally invasive and most effective procedure.
    Methods: We performed 144 varicocelectomies on infertile patients with left clinical varicocele. Of the patients, 50 were treated with retroperitoneal high ligation under lumbar anesthesia, 33 with laparoscopic ligation under general anesthesia, and 61 with subinguinal microscopic ligation under local anesthesia. Operative time, hospital days, and clinical outcomes were compared between these techniques.
    Results: The operating time and hospitalization period required for subinguinal microscopic ligation was signicantly shorter compared to those for the other procedures. All patients treated with subinguinal microscopic ligation could achieve normal activity as soon as they returned to their rooms. Postoperative complications were observed in ve (10.0%) cases treated with high ligation and three (9.1%) laparoscopic cases, but were not observed after the subinguinal procedure. There were six cases (12.0%) of recurrence in the high ligation group and six (6.1%) in the laparoscopic group, but none in the subinguinal group. Sperm density was signicantly improved in all procedures postoperatively, but sperm motility was not improved. The two-year pregnancy rate calculated by the Kaplan-Meier method was 35.8% for high ligation, 40.4% for laparoscopic ligation and 50.9% for subinguinal microscopic ligation, although there were no statistical differences between the three groups.
    Conclusion: We concluded that subinguinal microscopic varicocelectomy could be a minimally invasive procedure compared to the other two techniques and a worthy method for treating male infertility due to clinical varicocele.

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  • Adeno-associated virus-mediated human IL-10 gene transfer suppresses the development of experimental autoimmune orchitis Reviewed

    M Watanabe, Y Kashiwakura, N Kusumi, K Tamayose, Y Nasu, A Nagai, T Shimada, H Daida, H Kumon

    GENE THERAPY   12 ( 14 )   1126 - 1132   2005.7

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    Testicular germ cell-induced autoimmune orchitis is characterized by inflammatory cell infiltration followed by disturbance of spermatogenesis. Experimental autoimmune orchitis (EAO) is an animal model for human immunological male infertility; delayed-type hypersensitivity (DTH) response plays a key role in its induction. Interleukin-10 (IL-10) is a regulatory cytokine that is critical in preventing organ-specific autoimmune inflammation. To determine the effects on EAO of human IL-10 (hIL-10) gene transfer, C3H/He mice immunized by unilateral testicular injury were administered intramuscular ( i.m.) injections of adeno-associated viral (AAV) vector-encoding hIL-10 on the day of immunization. Serum hIL-10 was detected beginning at 1 week postinjection, and peaked at 3 weeks. Histological examinations showed a significantly low incidence of orchitis and disturbance of spermatogenesis in AAV hIL-10-treated mice, and the DTH response to autologous testicular cells was significantly suppressed. Immunohistochemical analysis of IFN-gamma and IL-2, T-cell-associated cytokines, in the spleen and testes revealed significantly fewer cytokine-expressing cells after treatment. We conclude that a single i.m. administration of AAV hIL-10 significantly suppresses EAO and hypospermatogenesis by regulating cell-mediated immunity in the testes.

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  • Adeno-associated virus 2-mediated intratumoral prostate cancer gene therapy: Long-term maspin expression efficiently suppresses tumor growth Reviewed

    M Watanabe, Y Nasu, Y Kashiwakura, N Kusumi, K Tamayose, A Nagai, T Sasano, T Shimada, H Daida, H Kumon

    HUMAN GENE THERAPY   16 ( 6 )   699 - 710   2005.6

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    Maspin is a member of the serine protease inhibitors and the maspin gene, a tumor suppressor gene, is down-regulated in a large fraction of prostate cancers. We evaluated the use of adeno-associated virus (AAV, serotype 2) vector encoding maspin as a means for in vivo gene therapy for human prostate cancer. TUNEL assay of subcutaneously formed LNCaP or DU145 tumors in nude mice showed that intratumoral AAV-mediated maspin expression significantly upregulated the number of apoptotic cells compared with AAV-LacZ treatment. Immunofluorescence double staining for maspin protein and apoptosis in LNCaP tumors showed that the percentage of apoptotic cells in AAV-maspin-mediated maspin-expressing cells was significantly high compared with that in AAV-GFP-mediated GFP-expressing cells. Moreover, significantly fewer CD31-positive microvessels were observed in AAV-maspin-treated tumors compared with the control tumors. These therapeutic responses were highly correlated to persistent maspin expression in tumors, confirmed by Western blot analysis until at least day 56 after treatment. Finally, intratumoral delivery of AAV-maspin significantly suppressed growth of LNCaP and DU145 tumors and improved survival of mice. We conclude that AAV-mediated prolonged maspin expression efficiently suppresses human prostate tumor growth in vivo by apoptosis induction and inhibition of angiogenesis.

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  • Varicocele rupture due to sexual intercourse Reviewed

    Y Nishiyama, A Nagai, Y Nasu, M Watanabe, N Kusumi, K Monden, H Kumon

    INTERNATIONAL JOURNAL OF UROLOGY   12 ( 6 )   585 - 587   2005.6

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    Varicocele rupture was diagnosed in a 23-year-old man who presented with swelling and pain in the left scrotum after sexual intercourse. Color Doppler ultrasonography revealed blood flowing into the space surrounding the left testis, a hematoma and reflux of blood in the left spermatic vein. Varicocele rupture is a very rare condition and there have been only five reported cases.

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  • Clinical results of one-stage urethroplasty with parameatal foreskin flap for hypospadias Reviewed

    A Nagai, Y Nasu, M Watanabe, N Kusumi, H Tsuboi, H Kumon

    ACTA MEDICA OKAYAMA   59 ( 2 )   45 - 48   2005.4

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    We investigated the usefulness of one-stage urethroplasty by the parameatal foreskin flap method (OUPF procedure), which is useful for repairing all types of hypospadias. Between June 1992 and March 2001, the OUPF procedure was performed on 18 patients with hypospadias: 10 patients with distal and 8 with proximal hypospadias. The follow-up periods ranged from 33-75 months, with an average of 52 months. The duration of surgery, the catheter indwelling period, and the postoperative complications of each patient were analyzed. The median age of the patients at the time of surgery was 3 years and 8 months. The length of surgery for OUPF II ranged from 150-230 min (average 186 min), and from 190-365 min (average 267 min) for OUPF IV. Postoperative complications were confirmed in 3 of the 18 patients (16.6%). Two patients had fistulas, and one had a meatal regression. The fistulas were successfully closed by the simple multilayered closure method. After adopting DuoDerm dressings instead of elastic bandages for protection of the wound, no fistulization occurred. DuoDerm dressings are useful in the healing of wounds without complications. To date, the longest follow-up period has been 75 months, and during that time there have been no late complications such as urethral stenosis or penile curvature. OUPF is a useful method in the treatment of hypospadias with a low incidence of early and late complications.

    DOI: 10.18926/AMO/31964

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  • Analysis of human ejaculation using color Doppler ultrasonography: A comparison between antegrade and retrograde ejaculation Reviewed

    A Nagai, M Watanabe, Y Nasu, H Iguchi, N Kusumi, H Kumon

    UROLOGY   65 ( 2 )   365 - 368   2005.2

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    Objectives. To observe the phenomenon of human ejaculation dynamically using color Doppler ultrasonography.
    Methods. Human ejaculation was observed using transrectal color Doppler ultrasonography in a healthy man and a patient with retrograde ejaculation. Ejaculation was induced manually with audiovisual sexual stimulation. The ejaculatory phenomenon was analyzed and compared with that of retrograde ejaculation.
    Results. In the healthy man, the prostatic urethra flattened slightly and the bladder neck contracted just before expulsion. The ejaculatory stream spurted from the seminal vesicles to the bulbous urethra through the ejaculatory duct. In the patient with retrograde ejaculation, the ejaculatory stream from the seminal vesicles and inframontanal and distal prostatic urethras distended into a globular-shaped sac filled with semen. No seminal flow toward the bulbous urethra occurred. The semen remaining in the prostatic urethra began flowing slowly into the bladder.
    Conclusions. Differences between antegrade and retrograde ejaculation can be clearly detected by color Doppler ultrasonography, providing a noninvasive method to diagnose ejaculatory disorders. UROLOGY 65: 365-368, 2005. (C) 2005 Elsevier Inc.

    DOI: 10.1016/j.urology.2004.09.016

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  • Hepatocyte growth factor receptor is a coreceptor for adeno-associated virus type 2 infection Reviewed

    Y Kashiwakura, K Tamayose, K Iwabuchi, Y Hirai, T Shimada, K Matsumoto, T Nakamura, M Watanabe, K Oshimi, H Daida

    JOURNAL OF VIROLOGY   79 ( 1 )   609 - 614   2005.1

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    After the first attachment of virus to the cell surface through a primary receptor, efficient entry of virus requires the presence of a coreceptor. For adeno-associated virus type 2 (AAV2) infection, heparan sulfate proteoglycan is supposed as the primary receptor, and alphavbeta5 integrin and FGFR1 are reported to act as coreceptors. In this study, we were able to demonstrate that hepatocyte growth factor receptor, e-Met, is also a coreceptor for AAV2 infection. AAV2-mediated transgene analyses revealed that c-Met expression significantly up-regulated transgene expression without increasing AAV2 cell binding. Moreover, a viral overlay assay elucidated the physical interaction between AAV2 and the beta subunit of c-Met. These data suggest that c-Met plays the role of coreceptor for AAV2 infection by facilitating AAV2 internalization into the cytoplasm.

    DOI: 10.1128/JVI.79.1.609-614.2005

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  • マウス精巣針生検後の造精機能および精細胞に対する遅延型過敏反応の解析(第93回日本泌尿器科学会総会)

    坪井 啓, 渡部 昌実, 久住 倫宏, 永井 敦, 公文 裕巳

    日本泌尿器科学会雑誌   96 ( 2 )   186 - 186   2005

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    DOI: 10.5980/jpnjurol.96.186_2

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  • Cytosolic Ca2+ responses to sub-picomolar and nanomolar PACAP in pancreatic beta-cells are mediated by VPAC2 and PAC1 receptors Reviewed

    H Yamada, M Watanabe, T Yada

    REGULATORY PEPTIDES   123 ( 1-3 )   147 - 153   2004.12

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    Pituitary adenylate cyclase-activating polypeptide (PACAP) potentiates glucose-induced insulin release and increases cytosolic Ca2+ concentration ([Ca2+](i)) in islet beta-cells in a concentration-dependent manner with two peaks at 10(-13) and 10(-9) M. PAC1 receptor (PAC1-R) and VPAC2 receptor (VPAC2-R) are expressed in pancreatic beta-cells and thought to be involved in insulin release. We aimed to determine the receptor types involved in the [Ca-2](i) responses to 10(-13) and 10(-9) M PACAP. We measured [Ca2+](i) in beta-cells and examined comparative effects of PAC1-R-selective agonist maxadilan, its antagonist M65, VPAC2-R-selective agonist Ro25-1553, and native ligands of PACAP and VIP. In the presence of 8.3 mM glucose, maxadilan, Ro25-1553, PACAP, and VIP at 10(-13) and 10(-9) M all increased [Ca2+](i). PACAP and maxadilan elicited greater effects at 10(-9) M than at 10(-13) M both in the incidence and amplitude of [Ca2+](i) responses. For VIP and Ro25-1553, in contrast, the effects at 10(-9) and 10(-13) M were comparable. Furthermore, the amplitude of [Ca2+](i) responses to 10(-9) M PACAP, but not 10(-13) M PACAP, was suppressed by M65. The results suggest that VPAC2-R and PAC1-R contribute equally to [Ca2+](i) responses to sub-picomolar concentrations of PACAP, while PAC1-R has greater contribution to [Ca2+](i) responses to nanomolar concentrations of this peptide. (C) 2004 Elsevier B.V. All rights reserved.

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  • Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice Reviewed

    SA Li, M Watanabe, H Yamada, A Nagai, M Kinuta, K Takei

    CELL STRUCTURE AND FUNCTION   29 ( 4 )   91 - 99   2004.12

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    Klotho mutant mouse (kl-/-), a mouse model for human aging. exhibits various phenotypes in a wide range of organs including arteriosclerosis, neural degeneration. skin and gonadal atrophy, pulmonary emphysema, calcification of soft tissues, and cognition impairment. Klotho mRNA. however. is expressed only in brain, kidney, reproductive organs, pituitary gland, and parathyroid gland. Therefore it remains to be elucidated how lack of Klotho protein in these limited organs leads to the variery of phenotypes. To shed light on mechanisms by which Klotho protein acts on distant targets, we examined localization of Klotho protein in brain. kidney. and reproductive organs, and analyzed brain and kidney in kl-/- mice searching for changes in target regions in these organs. In brain, Klotho proteins were localized at choroid plexus, where the proteins were dominantly localized at the apical plasma membrane of ependymal cells. In kl-/- brain, reduction of synapses was evident in hippocampus, suggesting a role of Klotho as a humoral factor in cerebrospinal fluid. Klotho proteins in kidney localized at distal renal tubules. Interestingly, in kl-/- mice, type IIa Na/phosphate (Pi) cotransporters, which function at the proximal renal tubules in reabsorption of phosphate ions. were translocated. This suggests that Klotho protein in kidney is implicated in calcium homeostasis which regulates localization of type IIa Na/Pi cotransporters via parathyroid hormone (PTH). Klotho proteins in reproductive organs were expressed only in mature germ cells, although in kl-/- mice germ cell maturation was arrested at earlier stages. Thus, Klotho proteins not only function as a humoral factor, but also are implicated in hormonal regulation. which may explain why mutation of klotho gene results in a variety of phenotypes.

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  • Dynamin-2 regulates oxidized low-density lipoprotein-induced apoptosis of vascular smooth muscle cell Reviewed

    Y Kashiwakura, M Watanabe, N Kusumi, K Sumiyoshi, Y Nasu, H Yamada, T Sawamura, H Kumon, K Takei, H Daida

    CIRCULATION   110 ( 21 )   3329 - 3334   2004.11

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    Background-On exposure to oxidized low-density lipoprotein (oxLDL), vascular cells generally undergo apoptosis, which is one of the major pathogenic factors of atherosclerosis. In this study, we examined the role of dynamin ( a crucial GTPase protein in endocytosis) in oxLDL-induced apoptosis of vascular smooth muscle cells (VSMC).
    Methods and Results-After oxLDL stimulation, dynamin-2 colocalized with LOX-1 around the cell surface, as well as oxLDL in the cytoplasm, suggesting that dynamin-2 was involved in scavenger receptor-mediated oxLDL endocytosis. Downregulation of dynamin-2 induced by dynamin-2 dominant negative plasmid (K44A) resulted in a decrease of oxLDL uptake and thereby in a reduction of apoptosis. These data demonstrated that dynamin-2 was involved in oxLDL-induced apoptosis via the oxLDL endocytotic pathway. On the other hand, dynamin-2 wild-type plasmid transfection promoted oxLDL-induced apoptosis without increasing oxLDL uptake. Interestingly, the p53 inhibitor pifithrin-alpha (PFT) significantly reduced apoptosis promoted by wild-type dynamin-2 (78% reduction compared with the PFT[-] condition). These results indicated that dynamin-2 enhanced oxLDL-induced apoptosis of VSMC by participating in the p53 pathway, probably as a signal transducer. Moreover, we demonstrated that, in advanced plaques of apolipoprotein E-/- mice, dynamin-2 expression was often enhanced in apoptotic VSMC, suggesting that dynamin-2 might participate in apoptosis of VSMC even in vivo.
    Conclusions - Our data demonstrated that dynamin-2 at least partially regulated oxLDL-induced apoptosis of VSMC by participating in 2 independent pathways: the oxLDL endocytotic pathway and the p53 pathway. These findings suggest that dynamin-2 may serve as a new research or therapeutic target in vascular disease.

    DOI: 10.1161/01.CIR.0000147828.86593.85

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  • Analysis of retrograde ejaculation using color Doppler ultrasonography before and after transurethral collagen injection Reviewed

    A Nagai, Y Nasu, M Watanabe, M Tsugawa, H Iguchi, H Kumon

    INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH   16 ( 5 )   456 - 458   2004.10

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    Transurethral bladder neck collagen injection therapy was performed in a patient with retrograde ejaculation. The phenomenon of retrograde ejaculation and its correction after the therapy were clearly demonstrated by color Doppler ultrasonography. To our knowledge this is the first report showing successful observation of retrograde ejaculation using color Doppler ultrasonography.

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  • PP3-132 経会陰的および経直腸的前立腺12ヶ所生検の有用性 : 再生検施行症例の検討(一般演題(ポスター))

    秋山 博伸, 林 俊秀, 枝村 康平, 渡部 昌実, 牧 佳男, 入江 伸, 金重 哲三

    日本泌尿器科学会雑誌   95 ( 2 )   506 - 506   2004

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    DOI: 10.5980/jpnjurol.95.506_4

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  • 経会陰的および経直腸的前立腺12ヵ所生検の有用性 : 前立腺全摘標本での癌mappingをふまえて

    渡部 昌実, 林 俊秀, 枝村 康平, 森末 浩一, 入江 伸, 金重 哲三

    日本泌尿器科学会雑誌   94 ( 2 )   145 - 145   2003

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  • Localization of dynamin 2 in rat seminiferous tubules during the spermatogenic cycle Reviewed

    H Iguchi, M Watanabe, A Kamitani, A Nagai, O Hosoya, K Tsutsui, H Kumon

    ACTA MEDICA OKAYAMA   56 ( 4 )   205 - 209   2002.8

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    Dynamin is a protein essential to endocytosis. Dynamin 2, a dynamin isoform, is expressed most intensely in testicular tissue; however, precise localization has never been studied. Therefore, we investigated the expression of dynamin 2 in rat testicular tissue using immunohistochemical methods, and discuss here the physiological function of this protein. Testicular tissues were obtained from Wistar rats at 10, 21 and 63 days of age. Immunohistochemistrical examination and Western blot analysis were conducted using dynamin 2 specific antibody. Western blot analysis showed that expression in 21- and 63-day-old rats was more intense than that in 10-day-old rats. Dynamin 2 expression was observed using immunohistochemical method in the seminiferous tubules of all rats. In the 63-day-old rats, the expression was intense, especially in spermatids in the earlier maturation stages and in spermatocytes, and was observed in Sertoli cells. However, in spermatids, the expression gradually declined as spermatids matured to spermatozoa. In the 21-day-old rats, the expression was evident in spermatocytes and Sertoli cells, but that in the 10-day-old rats was weak. Intense expression of dynamin 2 during spermatogenesis suggests that this protein plays an important role in this process.

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  • Distribution of dynamins in testis and their possible relation to spermatogenesis Reviewed

    A Kamitani, H Yamada, M Kinuta, M Watanabe, SA Li, T Matsukawa, M McNiven, H Kumon, K Takei

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   294 ( 2 )   261 - 267   2002.6

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    Dynamin 2 and dynamin 3 are highly expressed in testis. However, their functions in the tissue remain unclear. Considering that dynamin 1, neuron-specific isoform of dynamin, plays a pivotal role in endocytosis, functions of dynamin 2 and dynamin 3 in testis must be essential. Cellular expression and subcellular localization of dynamin 2 and dynamin 3 in testis were investigated. Dynamin 2 and dynainin 3 were highly expressed in germ cells and Sertoli cells, constituents of seminiferous tubules. By immunofluorescence it was revealed that dynamin 2 colocalizes with clathrin both at the plasmamembrane and at Golgi in a cell line of Sertoli cells. Immuno reactivity for dynamin 3, on the other hand, appeared as finer puncta, which did not colocalize with clathrin, suggesting that these two dynamins have distinct functions in Sertoli cells. In the klotho deficient mouse testis, which demonstrates disorder in spermatogenesis, expression of dynamin 2 and dynamin 3 was drastically reduced indicating possible association of these proteins with spermatogenesis. (C) 2002 Elsevier Science (USA). All rights reserved.

    DOI: 10.1016/S0006-291X(02)00470-9

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  • Norepinephrine triggers Ca2+-dependent exocytosis of 5-hydroxytryptamine from rat pinealocytes in culture Reviewed

    H Yamada, M Hayashi, S Uehara, M Kinoshita, A Muroyama, M Watanabe, K Takei, Y Moriyama

    JOURNAL OF NEUROCHEMISTRY   81 ( 3 )   533 - 540   2002.5

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    5-Hydroxytryptamine (5-HT) is a precursor and a putative modulator for melatonin synthesis in mammalian pinealocytes. 5-HT is present in organelles distinct from L-glutamate-containing synaptic-like microvesicles as well as in the cytoplasm of pinealocytes, and is secreted upon stimulation by norepinephrine (NE) to enhance serotonin N-acetyltransferase activity via the 5-HT2 receptor. However, the mechanism underlying the secretion of 5-HT from pinealocytes is unknown. In this study, we show that NE-evoked release of 5-HT is largely dependent on Ca2+ in rat pinealocytes in culture. Omission of Ca2+ from the medium and incubation of pineal cells with EGTA-tetraacetoxymethyl-ester inhibited by 59 and 97% the NE-evoked 5-HT release, respectively. Phenylephrine also triggered the Ca2+-dependent release of 5-HT, which was blocked by phentolamine, an alpha antagonist, but not by propranolol, a beta antagonist. Botulinum neurotoxin type E cleaved 25 kDa synaptosomal-associated protein and inhibited by 50% of the NE-evoked 5-HT release. Bafilomycin A1, an inhibitor of vacuolar H+-ATPase, and reserpine and tetrabenazine, inhibitors of vesicular monoamine transporter, all decreased the storage of vesicular 5-HT followed by inhibition of the NE-evoked 5-HT release. Agents that trigger L-glutamte exocytosis such as acetylcholine did not trigger any Ca2+-dependent 5-HT release. Vice versa neither NE nor phenylephrine caused synaptic-like microvesicle-mediated L-glutamate exocytosis. These results indicated that upon stimulation of a adrenoceptors pinealocytes secrete 5-HT through a Ca-2-dependent exocytotic mechanism, which is distinct from the exocytosis of synaptic-like microvesicles.

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  • Phosphatidylinositol 4,5-bisphosphate stimulates vesicle formation from liposomes by brain cytosol Reviewed

    M Kinuta, H Yamada, T Abe, M Watanabe, SA Li, A Kamitani, T Yasuda, T Matsukawa, H Kumon, K Takei

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   99 ( 5 )   2842 - 2847   2002.3

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    As a step toward the elucidation of mechanisms in vesicle budding, a cell-free assay that measures cytosol-induced vesicle generation from liposomes was established. This assay then was used to explore the role of phosphoinositides in vesicle formation. Liposomes incubated with brain cytosol in the presence of ATP and GTP massively generated small vesicles, as assessed both quantitatively and qualitatively by a dynamic light-scattering assay. Both ATP and GTP were required. Vesicle formation was inhibited greatly by the immunodepletion of dynamin 1 from the cytosol, indicating a major contribution of this GTPase in this reaction and suggesting that it mimics endocytic vesicle fission. Increasing the concentration Of L-alpha-phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P-2] but not of L-alpha-phosphatidylinositol 4-monophosphate or L-alpha-phosphatidylinositol in the lipid membranes enhanced vesicle formation. Lipid analysis revealed rapid degradation of PtdIns(4,5)P-2 to L-alpha-phosphatidylinositol during the incubation with the reaction reaching a maximum within 5 sec, whereas vesicle formation proceeded with a longer time course. PtdIns(4,5)P-2 degradation was independent of vesicle formation and occurred also in the presence of guanosine 5'-O-(thiotriphosphate), where few vesicle formations occurred. These results suggest that PtdIns(4,5)P-2 plays a critical role in the early step of vesicle formation, possibly in the recruitment of coats and fission factors to membranes.

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  • Primary gastric T-cell lymphoma without human T-lymphotropic virus type 1: Report of a case Reviewed

    M Watanabe, Y Moriyama

    SURGERY TODAY   32 ( 6 )   525 - 530   2002

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    Although primary gastric malignant lymphoma accounts for slightly more than 10% of all lymphomas at extranodular sites, it is relatively rare clinically, representing only 1% of all malignant diseases of the stomach. In addition, most such diseases tend to be B-cell lymphoma, while T-cell lymphoma is extremely rare. We encountered a patient with primary gastric T-cell malignant lymphoma who, although demonstrating a very rare phenomenon, was negative for antihuman T-lymphotropic virus type 1 antibody. A 73-year-old man was admitted to the hospital with the chief complaint of upper abdominal pain. The primary lesion was a type 3 tumor located at the cardia to the posterior wall of the upper body of the stomach, which had invaded the tail of the pancreas and a part of the transverse colon. A total gastrectomy, pancreatosplenectomy, and partial resection of the transverse colon were performed. The surgical section contained a giant ulcerative lesion with its bank cleaved, and a histological examination revealed a diffuse, small cell (Lymphoma Study Group classification) malignant lymphoma. An immunohistochemical analysis of the surgical specimen was positive for LCA/CD45, UCLH-1/CD45RO, and Leu-4/CD3, and negative for L-26/CD20, and it was diagnosed to be primary gastric T-cell malignant lymphoma.

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  • ヒト射精現象の超音波カラードプラによる解析

    永井 敦, 井口 裕樹, 紙谷 章弘, 渡部 昌実, 公文 裕巳

    日本泌尿器科学会雑誌   93 ( 2 )   414 - 414   2002

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    DOI: 10.5980/jpnjurol.93.414_1

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  • Identification and Characterization of a Synaptojanin 2 Splice Isoform Predominantly Expressed in Nerve Terminals Reviewed

    Yasuo Nemoto, Markus R. Wenk, Masami Watanabe, Laurie Daniell, Tomoe Murakami, Niels Ringstad, Hiroshi Yamada, Kohji Takei, Pietro De Camilli

    Journal of Biological Chemistry   276 ( 44 )   41133 - 41142   2001.11

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    We have previously identified synaptojanin 1, a phosphoinositide phosphatase predominantly expressed in the nervous system, and synaptojanin 2, a broadly expressed isoform. Synaptojanin 1 is concentrated in nerve terminals, where it has been implicated in synaptic vesicle recycling and actin function. Synaptojanin 2A is targeted to mitochondria via a PDZ domain-mediated interaction. We have now characterized an alternatively spliced form of synaptojanin 2 that shares several properties with synaptojanin 1. This isoform, synaptojanin 2B, undergoes further alternative splicing to generate synaptojanin 2B1 and 2B2. Both amphiphysin and endophilin, two partners synaptojanin 1, bind synaptojanin 2B2, whereas only amphiphysin binds synaptojanin 2B1. Sequence similar to the endophilin-binding site in synaptojanin 1 is present only in synaptojanin 2B2, and this sequence was capable of affinity purifying endophilin from rat brain. The Sac1 domain of synaptojanin 2 exhibited phosphoinositide phosphatase activity very similar to that of the Sac1 domain of synaptojanin 1. Site-directed mutagenesis further illustrated its functional similarity to the catalytic domain of Sac1 proteins. Antibodies raised against the synaptojanin 2B-specific carboxyl-terminal region identified a 160-kDa protein in brain and testis. Immunofluorescence showed that synaptojanin 2B is localized at nerve terminals in brain and at the spermatid manchette in testis. Active Rac1 GTPase affects the intracellular localization of synaptojanin 2, but not of synaptojanin 1. These results suggest that synaptojanin 2B has a partially overlapping function with synaptojanin 1 in nerve terminals, with additional roles in neurons and other cells including spermatids.

    DOI: 10.1074/jbc.M106404200

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  • Expression of amphiphysin I in sertoli cells and its implication in spermatogenesis Reviewed

    M Watanabe, K Tsutsui, O Hosoya, K Tsutsui, H Kumon, A Tokunaga

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   287 ( 3 )   739 - 745   2001.9

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    Amphiphysin I is a protein concentrated in nerve terminals and involved in the endocytosis of synaptic vesicle membrane. We show here that amphiphysin I is expressed in the rat testis, localized exclusively in the Sertoli cells. In the postnatal testicular development, expression of amphiphysin I was not evident at birth, but became significant at postnatal day 15 (P15), coinciding with the onset of spermatogenesis. The expression level of amphiphysin I increased 10-fold between P15 and P25 to reach the adult level. In adult testes reversibly damaged by ethane dimethane sulphonate administration, expression of amphiphysin I did not change following the damage, whereas the protein was transiently converted into its phosphorylated form. The increase in levels of phosphorylated amphiphysin I was closely associated with the severe histological damage to germ cells. The present findings suggest that amphiphysin I in Sertoli cells is involved in spermatogenesis, probably through endocytic processes. (C) 2001 Academic Press.

    DOI: 10.1006/bbrc.2001.5650

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  • Sertoli cellで発現するシナプスタンパク質Amphiphysin Iと精子形成

    渡部 昌実, 永井 敦, 井口 裕樹, 公文 裕巳, 筒井 公子, 細谷 修, 徳永 叡, 筒井 研

    日本泌尿器科学会雑誌   91 ( 3 )   372 - 372   2000

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    DOI: 10.5980/jpnjurol.91.372_1

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  • 遺伝子治療開発研究ハンドブック 第2版

    ( Role: Joint author ,  第2章第4節1-2)

    2023.7 

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  • LOH症候群における精神症状がテストステロン補充療法に与える影響について

    富永 悠介, 小林 知子, 森分 貴俊, 松本 裕子, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 別宮 謙介, 枝村 康平, 小林 泰之, 佐古 智子, 杉本 盛人, 渡部 昌実, 荒木 元朗

    日本性機能学会雑誌   39 ( 2 )   167 - 167   2024.8

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  • 転移性腎癌に対してPembrolizumab投与中,サイトカイン放出症候群を認めた一例

    川合 裕也, 西村 慎吾, 長崎 直也, 奥村 美紗, 津川 卓士, 井上 翔太, 渡部 智文, 関戸 崇了, 堀井 聡, 森分 貴俊, 吉永 香澄, 山野井 友昭, 河田 達志, 富永 悠介, 定平 卓也, 岩田 健宏, 片山 聡, 別宮 謙介, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科   86 ( 増刊号2 )   193 - 194   2024.6

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  • 上部尿路上皮癌に対するThulium:YAGレーザーとHo:YAGレーザーを用いた内視鏡下レーザー焼灼術の適応と治療成績

    片山 聡, 長崎 直也, 津川 卓士, 奥村 美紗, 川合 裕也, 井上 翔太, 渡部 智文, 関戸 崇了, 堀井 聡, 吉永 香澄, 森分 貴俊, 山野井 友昭, 河田 達志, 富永 悠介, 定平 卓也, 岩田 健宏, 西村 慎吾, 別宮 謙介, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科   86 ( 増刊号2 )   190 - 190   2024.6

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  • グラフト感染が契機と考えられる腎動脈破綻を認めた自家腎移植の一例

    西村 慎吾, 長崎 直也, 奥村 美紗, 尾地 晃典, 原 尚史, 川野 香, 横山 周平, 渡部 智文, 関戸 崇了, 堀井 聡, 吉永 香澄, 丸山 雄樹, 長尾 賢太郎, 山野井 友昭, 河田 達志, 富永 悠介, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗, 枝木 大治, 加藤 源太郎

    西日本泌尿器科   86 ( 増刊号1 )   57 - 57   2024.1

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  • 高度腸骨動脈石灰化を有するレシピエントに対する脳死献腎移植の経験

    吉永 香澄, 西村 慎吾, 長崎 直也, 奥村 美紗, 尾地 晃典, 原 尚史, 川野 香, 横山 周平, 渡部 智文, 関戸 崇了, 堀井 聡, 丸山 雄樹, 長尾 賢太郎, 山野井 友昭, 河田 達志, 富永 悠介, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗, 三浦 望, 加藤 源太郎

    西日本泌尿器科   86 ( 増刊号1 )   56 - 57   2024.1

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  • 生体腎移植レシピエントの周術期尿路感染症リスク因子の検討 Reviewed

    西村 慎吾, 長崎 直也, 奥村 美紗, 原 尚史, 川野 香, 横山 周平, 渡部 智文, 関戸 崇了, 堀井 聡, 吉永 香澄, 丸山 雄樹, 長尾 賢太郎, 山野井 友昭, 河田 達志, 富永 悠介, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科   86 ( 増刊号1 )   56 - 56   2024.1

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  • 腎提供後11年経過の若年ドナーに認めたT3a腎細胞癌の1例 Reviewed

    原 尚史, 西村 慎吾, 長崎 直也, 奥村 美紗, 尾地 晃典, 川野 香, 渡部 智文, 関戸 崇了, 堀井 聡, 吉永 香澄, 丸山 雄樹, 山野井 智昭, 長尾 賢太郎, 河田 達志, 富永 悠介, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科   86 ( 増刊号1 )   24 - 24   2024.1

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  • 性同一性障害に対するフィナステリドの安全性の検討について:中間報告 Reviewed

    富永 悠介, 小林 知子, 松本 裕子, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 枝村 康平, 小林 泰之, 渡部 昌実, 荒木 元朗

    GID(性同一性障害)学会雑誌   16 ( 1 )   165 - 167   2023.12

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    ホルモン療法に伴う男性型脱毛症(AGA)を有する性同一性障害(GID-FTM)に対するフィナステリドの安全性・治療効果を前向きに検討した.選択基準はNorwood-Hamilton(N-H)分類II以上などで,性別適合手術後の症例は除外した.被験者にはフィナステリド0.2mgを3ヵ月経口投与し,継続可能であった症例については,1.0mgに増量しさらに3ヵ月投与した.登録した2例において,フィナステリドに関連した有害事象を認めず,6ヵ月間の内服継続が可能であった.2例ともに多血症の改善およびN-H分類で脱毛の改善を認めた.1例で1度の月経再開を認めた.フィナステリドはホルモン療法中の身体的男性化に影響を与える可能性がある.本試験においては,良好な安全性・有効性を示唆する結果が得られた.(著者抄録)

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  • 閉経後の反復性膀胱炎を有する女性における尿および腟内の大腸菌の相同性の比較

    関戸 崇了, 定平 卓也, 岩田 健宏, 富永 悠介, 片山 聡, 西村 慎吾, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科学会総会抄録集   75回   239 - 239   2023.11

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  • 転移性去勢抵抗性前立腺癌におけるBRCA遺伝子バリアントの検討

    岩田 健宏, 吉永 香澄, 丸山 雄樹, 河田 達志, 定平 卓也, 富永 悠介, 片山 聡, 西村 慎吾, 別宮 謙介, 枝村 康平, 小林 知子, 小林 泰之, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    日本癌治療学会学術集会抄録集   61回   P12 - 5   2023.10

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  • ロボット支援腹腔鏡下膀胱全摘除術における予防的全腟閉鎖術併用の試み

    小林 知子, 西村 慎吾, 富永 悠介, 宇埜 誠, 吉永 香澄, 丸山 雄樹, 定平 卓也, 片山 聡, 岩田 健宏, 枝村 康平, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    日本女性骨盤底医学会プログラム・抄録集   25回   91 - 91   2023.8

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  • RPLND後の難治性リンパ漏に対して開腹リンパ管結紮術が奏功した1例 Reviewed

    鵜川 聖也, 長崎 直也, 原 惇也, 松島 萌希, 奥村 美紗, 渡部 智文, 宇埜 誠, 堀井 聡, 吉永 香澄, 丸山 雄樹, 長尾 賢太郎, 山野井 友昭, 富永 悠介, 定平 卓也, 岩田 健宏, 片山 聡, 西村 慎吾, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科   85 ( 増刊号2 )   148 - 148   2023.6

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  • Staphylococcus saprophyticusによる感染結石の1例 Reviewed

    渡部 智文, 鵜川 聖也, 長崎 直也, 奥村 美紗, 宇埜 誠, 堀井 聡, 吉永 香澄, 丸山 雄樹, 山野井 智昭, 長尾 賢太郎, 富永 悠介, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 枝村 康平, 小林 知子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科   85 ( 増刊号2 )   148 - 148   2023.6

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  • 異所性腎患者に発生したmicropapillary variantを伴う筋層浸潤性膀胱癌に対して,ロボット支援下膀胱全摘除術を施行した一例 Reviewed

    原 惇也, 堀井 聡, 岩田 健宏, 鵜川 聖也, 長崎 直也, 松島 萌希, 奥村 美紗, 渡部 智文, 関戸 崇了, 吉永 香澄, 丸山 雄樹, 長尾 賢太郎, 山野井 友昭, 富永 悠介, 定平 卓也, 片山 聡, 西村 慎吾, 別宮 謙介, 枝村 康平, 小林 知子, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 小林 泰之

    西日本泌尿器科   85 ( 増刊号1 )   46 - 46   2023.1

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  • LOH症候群における各種質問票の有用性について Reviewed

    富永悠介, 小林知子, 松本裕子, 定平卓也, 片山聡, 岩田健宏, 西村慎吾, 枝村康平, 小林泰之, 佐古智子, 杉本盛人, 渡部昌実, 荒木元朗

    日本性機能学会雑誌   38 ( 2 )   2023

  • 横隔膜、腸腰筋、左腎に接する後腹膜脱分化型脂肪肉腫に対して横隔膜合併切除を含めた外科的治療を行った一例

    松島 萌希, 岩田 健宏, 富永 悠介, 定平 卓也, 片山 聡, 西村 慎吾, 別宮 謙介, 枝村 康平, 小林 知子, 小林 泰之, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科学会総会抄録集   74回   190 - 190   2022.11

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  • 再三の細胞診検査で骨盤内再発が判明した膀胱癌の一例

    鵜川 聖也, 岩田 健宏, 富永 悠介, 定平 卓也, 片山 聡, 西村 慎吾, 別宮 謙介, 枝村 康平, 小林 知子, 小林 泰之, 渡部 昌実, 渡邉 豊彦, 荒木 元朗

    西日本泌尿器科学会総会抄録集   74回   227 - 227   2022.11

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  • ステント付着結石により3本尿管ステント留置し2度のECIRSによりstone freeとなった1例 Reviewed

    堀井 聡, 奥村 美紗, 渡部 智文, 関戸 崇了, 徳永 素, 吉永 香澄, 丸山 雄樹, 山野井 友昭, 長尾 賢太郎, 富永 悠介, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 佐古 智子, 枝村 康平, 小林 泰之, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   84 ( 増刊号2 )   168 - 168   2022.6

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  • テキストマイニングによる腎移植に関する症例報告論文の考察

    関戸 崇了, 荒木 元朗, 吉永 香澄, 丸山 雄樹, 山野井 友昭, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 佐古 智子, 枝村 康平, 小林 泰之, 渡部 昌実, 渡邉 豊彦, 田邊 克幸, 竹内 英実, 喜多村 真治, 杉山 斉, 和田 淳, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   55回   227 - 227   2022.2

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  • 待機日数56日で先行的脳死下献腎移植を行った17歳女性の1例 Reviewed

    奥村 美紗, 吉永 香澄, 西村 慎吾, 和田 耕一郎, 荒木 元朗, 渡部 智文, 近藤 崇弘, 関戸 崇了, 堀井 聡, 竹丸 紘史, 和田里 章悟, 丸山 雄樹, 山野井 友昭, 長尾 賢太郎, 河田 達志, 富永 悠介, 定平 卓也, 岩田 健宏, 高本 篤, 佐古 智子, 枝村 康平, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡辺 豊彦, 那須 保友

    西日本泌尿器科   84 ( 増刊号1 )   50 - 51   2022.1

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  • 岡山大学におけるUTUCに対するURSの成績と課題 Reviewed

    和田 耕一郎, 丸山 雄樹, 荒木 元朗, 関戸 崇了, 枝村 康平, 定平 卓也, 林 あずさ, 三宅 修司, 渡部 智文, 吉永 香澄, 和田里 章悟, 長尾 賢太郎, 河田 達志, 富永 悠介, 大岩 裕子, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡辺 豊彦, 那須 保友

    西日本泌尿器科   84 ( 増刊号1 )   48 - 49   2022.1

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  • 全身転移を来たした成人発症の胎児型前立腺横紋筋肉腫の1例 Reviewed

    近藤崇弘, 関戸崇了, 定平卓也, 富永悠介, 高本篤, 奥村美紗, 渡部智文, 堀井聡, 竹丸絋史, 和田里章悟, 吉永香澄, 丸山雄樹, 山野井友昭, 長尾賢太郎, 河田達志, 岩田健宏, 西村慎吾, 佐古智子, 和田耕一郎, 枝村康平, 小林泰之, 荒木元朗, 石井亜矢乃, 渡部昌実, 渡邉豊彦, 那須保友, 田端雅弘, 柳井広之

    西日本泌尿器科(Web)   84   2022

  • 後腹膜リンパ節郭清術後の射精障害の検討 Reviewed

    富永悠介, 佐古智子, 奥村美紗, 渡部智文, 近藤崇弘, 関戸崇了, 竹丸紘史, 堀井聡, 吉永香澄, 丸山雄樹, 山野井友昭, 長尾賢太郎, 片山聡, 定平卓也, 岩田健宏, 西村慎吾, 高本篤, 枝村康平, 小林泰之, 荒本元朗, 石井亜矢乃, 渡部昌実, 渡邉豊彦, 那須保友, 松本裕子, 杉本盛人, 和田耕一郎

    西日本泌尿器科(Web)   84   2022

  • 精巣腫瘍に対し化学療法後に後腹膜リンパ節郭清術を行った症例における射精障害の検討 Reviewed

    富永悠介, 松本裕子, 佐古智子, 小林知子, 倉橋寛明, 杉本盛人, 渡部昌実, 荒木元朗

    日本性機能学会雑誌   37 ( 2 )   2022

  • APCCC JAPAN:今こそ日本人泌尿器科医の常識を問う! M0CRPC診療 M0CRPCに対する新規ホルモン剤はどのような症例に有効か?

    枝村 康平, 河田 達志, 定平 卓也, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 小林 泰之, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本泌尿器科学会総会   109回   SY31 - 3   2021.12

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  • リアルタイムイメージングを用いた腎虚血再灌流後生体マウス腎における好中球動態のタダラフィル投与による変化

    丸山 雄樹, 荒木 元朗, 城所 研吾, 十川 裕史, 吉永 香澄, 光井 洋介, 定平 卓也, 和田 耕一郎, 渡部 昌実, 渡邉 豊彦, 柏原 直樹, 那須 保友

    日本泌尿器科学会総会   109回   AOP13 - 06   2021.12

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  • 腸骨下腹神経ブロックが鼠径部痛の緩和に有効であった、再発性鼠径ヘルニアを合併したミュラー管遺残症候群の1例

    関戸 崇了, 丸山 雄樹, 定平 卓也, 岩田 健宏, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡辺 豊彦, 那須 保友

    日本泌尿器科学会総会   109回   OP05 - 06   2021.12

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  • 浸潤性膀胱癌に対する開腹膀胱全摘除術(ORC)と比較した腹腔鏡下膀胱全摘除術(LRC)の長期治療成績に関する後方視的検討

    和田里 章悟, 小林 泰之, 河田 達志, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 枝村 康平, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   84 ( 2 )   146 - 153   2021.12

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    【目的】腹腔鏡下膀胱全摘除術(LRC)と開腹膀胱全摘除術(ORC)の長期制癌性を検討した本邦からの報告は少数である。当院におけるLRCとORCの周術期成績と長期治療成績を後方視的に比較検討した。【対象】2012年5月から2018年6月までに施行した膀胱全摘症例のうち78例(LRC48例,ORC30例)とした。【結果】観察期間中央値はLRC群30ヵ月,ORC群43.5ヵ月であった。LRC群で男性が多く,回腸導管の割合が高かった。手術時間はLRC群で長く(p=0.038),推定出血量と輸血症例が少なかった(ともにp<0.001)。術後病理結果はLRC群でG2症例が少なかった(p=0.008)が,断端陽性率を含む他の結果に差はなかった。リンパ節郭清領域はORCで内外腸骨動脈分岐部以下,LRCで総腸骨動脈分岐部以下を基本としたが,郭清リンパ節の数とリンパ節陽性症例の割合に差はなかった。LRC群とORC群の5年全生存率,癌特異生存率,無再発生存率は72.2%と54.4%(p=0.249),77.7%と63.4%(p=0.376),71.4%と55.0%(p=0.115)であった。【結語】当院におけるLRC群の周術期成績は出血量,輸血頻度においてORC群より優れていた。制癌性についてもORC群に比しLRC群が優れている傾向を認め,リンパ節郭清領域が制癌性に影響する報告を裏付ける結果となった。(著者抄録)

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  • Tumor suppressor REIC/Dkk-3 and its co-chaperone SGTA: Two aspects of a GR inhibitor and AR activator as a modifier of the steroid signaling(和訳中)

    岩田 健宏, 定平 卓也, 片山 聡, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科学会総会抄録集   73回   175 - 175   2021.11

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  • 腎移植後の尿細胞診で6ヵ月以上持続するDecoy細胞陽性所見はBKウイルス腎症の発症予測に有効である

    関戸 崇了, 荒木 元朗, 吉永 香澄, 丸山 雄樹, 定平 卓也, 西村 慎吾, 和田 耕一郎, 渡部 昌実, 渡邉 豊彦, 田邊 克幸, 竹内 英実, 和田 淳, 柳井 広之, 那須 保友

    移植   56 ( 総会臨時 )   O17 - 3   2021.9

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  • 腎部分切除術を施行した巨大類上皮型腎血管筋脂肪腫の1例

    横山 周平, 富永 悠介, 高本 篤, 定平 卓也, 関戸 崇了, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 柳井 広之, 那須 保友

    西日本泌尿器科   83 ( 3 )   175 - 180   2021.8

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    症例は41歳,女性。2008年に結節性硬化症,両側腎血管筋脂肪腫およびIgA腎症と診断され,経過観察されていた。2015年に右腎血管筋脂肪腫より出血を認め緊急経カテーテル的動脈塞栓術を施行し,左腎血管筋脂肪腫に対しても待機的に経カテーテル的動脈塞栓術を施行した。2017年にCTで右腎尾側に新たに腫瘤を指摘され,2年の経過で12cmから20cm大に急速に増大したため2019年3月にCTガイド下針生検を実施し類上皮型腎血管筋脂肪腫と診断された。2019年5月に術前TAE後に開腹右腎部分切除術を施行した。2019年9月よりエベロリムスを開始したが,腎機能障害とHbA1cの上昇を認めたため中止した。その後,術後12ヵ月まで再発および転移を認めず経過している。(著者抄録)

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  • 腎門部に発生した粘液嚢胞腺癌の1例

    三宅 修司, 岩田 健宏, 長尾 賢太郎, 河田 達志, 富永 悠介, 定平 卓也, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 久保 寿夫, 柳井 広之, 那須 保友

    西日本泌尿器科   83 ( 2 )   100 - 105   2021.6

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    症例は79歳,男性。2年前に検診にて左腎嚢胞と診断され近医で経過観察となっていたが,増大傾向であったため当科紹介となった。造影CT検査でBosniak分類category IVの左嚢胞性腎癌を疑い,腹腔鏡下左腎摘除術を施行した。術後病理結果から,粘液嚢胞腺癌(Mucinous cystadenocarcinoma)と診断した。術後補助化学療法は行わずに経過観察としていたが,術後3ヵ月後に多発肺転移が出現し,化学療法(カルボプラチン+パクリタキセル)を開始した。5コース投与後の肺転移はSDであったため,一旦化学療法中止で経過観察の方針としたが,5ヵ月後に肺転移は増大傾向を認めたため術後14ヵ月目よりニボルマブの投与を開始した。ニボルマブ2コース投与後のCTで肺転移は縮小し,5コース投与後もPRを維持しているため現在も投与継続中である。(著者抄録)

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  • 若年発症の前立腺炎症性偽腫瘍の1例

    佐久間 貴文, 丸山 雄樹, 定平 卓也, 高本 篤, 和田 耕一郎, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡辺 豊彦, 那須 保友

    西日本泌尿器科   83 ( 1 )   54 - 58   2021.4

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    症例は19歳,男性。抗菌薬投与で改善しない排尿障害,排尿時痛を主訴に前医を受診。MRIで前立腺のT1強調像,T2強調像ともに低信号で,造影効果を伴う膀胱内に突出する腫瘤を指摘され当院紹介となった。血液,尿検査では特記事項なく,尿培養,尿細胞診は陰性であった。PSAを含め腫瘍マーカーの有意な上昇を認めなかった。膀胱鏡検査では前立腺部尿道に約35mmの非乳頭状広基性腫瘍を認めた。造影CTでは前立腺部にMRI同様の所見を認め,リンパ節腫大及び遠隔転移は認めなかった。排尿障害改善及び組織検査目的に経尿道的前立腺切除術(TUR-P)を施行した。切除組織は長紡錘形細胞の束状の増殖とリンパ球,形質細胞浸潤を認め,免疫染色でALK(anaplastic lymphoma kinase)陽性,α-smooth muscle actinが少数の細胞で陽性であり,前立腺炎症性偽腫瘍(inflammatory pseudtumor:IPT)と診断した。局所再発の可能性はあるものの,遠隔転移の可能性は低く,排尿状態の改善を得られたため経過観察の方針とした。術後10ヵ月現在で腫瘍の再燃を認めていない。(著者抄録)

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  • Retroperitoneal malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1: A case report

    Daijiro Soda, Takehiro Iwata, Takuya Sadahira, Yusuke Tominaga, Satoshi Katayama, Shingo Nishimura, Atsushi Takamoto, Tomoko Sako, Kohei Edamura, Yasuyuki Kobayashi, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu, Eiji Nakada, Hiroyuki Yanai

    Nishinihon Journal of Urology   82 ( 86 )   596 - 600   2021.2

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    A female patient in her thirties was diagnosed with neurofibroma by left axillary skin biopsy, and neurofibromatosis type 1 (NF-1
    von Recklinghausen disease) was suspected based on characteristic skin findings (cafe-au-lait spots) and her family history. In February X, the patient consulted a doctor for right thigh and back pain. An MRI and contrast CT showed a 13 cm retroperitoneal tumor, which was suspected to have originated from the L2 nerve root and to have invaded the spinal canal. The doctor referred the patient to our department for a surgical procedure. We consulted the Department of Orthopaedic Surgery and performed an MRI-guided biopsy, which suggested the possibility of a malignant peripheral nerve sheath tumor (MPNST). In June X, we resected the right retroperitoneal tumor following arterial embolization. Pathological results confirmed it to be an MPNST. The patient has not experienced any recurrence during the 10 months since the surgery. MPNSTs are extremely rare tumors and there is no standard treatment for them because of their rarity. We experienced a case of retroperitoneal MPNST and we herein report the features of this case and present some review of the literature.

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  • 神経線維腫症1型に合併した後腹膜悪性末梢神経鞘腫瘍の1例

    宗田 大二郎, 岩田 健宏, 定平 卓也, 富永 悠介, 片山 聡, 西村 慎吾, 高本 篤, 佐古 智子, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友, 中田 英二, 柳井 広之

    西日本泌尿器科   82 ( 6 )   596 - 600   2021.2

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    症例は30代,女性。過去に左腋窩皮膚生検で神経線維腫と診断され,特徴的な皮膚所見や家族歴などから神経線維腫症1型(NF-1;von Recklinghausen病)を疑われていたが放置していた。20XX年2月に右大腿部痛,背部痛を主訴に近医を受診しMRI,造影CTで約13cm大の後腹膜腫瘤を指摘され,L2神経根からの発生と脊柱管内の浸潤も疑われ,神経線維腫の疑いとして手術目的に当科紹介された。合同での手術が必要と考えられたため,整形外科に紹介しMRIガイド下生検で悪性末梢神経鞘腫瘍の可能性を示唆された。同年6月に腫瘍の動脈塞栓術施行後に右後腹膜腫瘍摘出術を施行し,病理結果から悪性末梢神経鞘腫瘍と診断された。術後10ヵ月現在再発認めず,外来通院中である。後腹膜原発腫瘍において悪性末梢神経鞘腫瘍は極めて稀な症例であり,有効な治療法は確立されていない。今回,後腹膜原発の悪性末梢神経鞘腫瘍の1例を経験したので,若干の文献的考察を加えて報告する。(著者抄録)

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  • 高血圧・糖尿病に焦点を当てたマージナルドナーからの生体腎移植

    吉永 香澄, 荒木 元朗, 関戸 崇了, 和田里 章悟, 丸山 雄樹, 定平 卓也, 窪田 理沙, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 竹内 英実, 田邉 克幸, 森永 裕士, 杉山 斉, 和田 淳, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   54回   193 - 193   2021.2

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  • 【腎盂・尿管癌の治療を考える】腎盂・尿管癌における腹腔鏡下腎尿管全摘除術の適応

    吉永 香澄, 荒木 元朗, 和田里 章悟, 丸山 雄樹, 光井 洋介, 窪田 理沙, 定平 卓也, 岩田 健宏, 西村 慎吾, 高本 篤, 和田 耕一郎, 佐古 智子, 枝村 康平, 小林 泰之, 渡部 昌実, 渡辺 豊彦, 那須 保友

    泌尿器外科   33 ( 5 )   455 - 461   2020.5

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    切除可能な腎盂・尿管癌において、外科的治療の標準術式は腎尿管全摘除術・膀胱部分切除術である。腹腔鏡手術は開放手術と比較して低侵襲であり、低リスク症例では前者が選択される傾向にあるが、pT3以上やリンパ節転移が疑われる症例では開放手術が推奨されている。また、腎機能に問題がある場合などに腎温存療法や化学療法が選択されることもある。本稿では腎盂・尿管癌における腹腔鏡手術の適応について考察する。(著者抄録)

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  • 後腹膜悪性末梢神経鞘腫の1例

    宗田 大二郎, 高本 篤, 荒木 元朗, 角南 亮輔, 関戸 崇了, 佐久間 貴文, 和田里 章悟, 吉永 香澄, 丸山 雄樹, 光井 洋介, 富永 悠介, 大岩 裕子, 窪田 理沙, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   82 ( 1 )   173 - 173   2020.4

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  • 腎組織由来幹細胞の樹立と解析

    定平卓也, 李順愛, 野口洋文, 那須保友, 渡部昌実, 渡部昌実

    日本再生医療学会総会(Web)   19th   2020

  • The novel in vivo imaging techniques for visualizing neutrophil infiltration following renal ischemia/reperfusion which was reduced by tadalafil.

    丸山雄樹, 荒木元朗, 城所研吾, 十川裕史, 吉永香澄, 吉永香澄, 光井洋介, 定平卓也, 和田耕一郎, 渡部昌実, 渡邉豊彦, 柏原直樹, 那須保友

    西日本泌尿器科   82   2020

  • POLYCYSTIC EMPHYSEMATOUS PYELONEPHRITIS TREATED BY NEPHRECTOMY: A CASE REPORT

    小林宏州, 小林宏州, 高本篤, 定平卓也, 和田耕一郎, 前原貴典, 前原貴典, 大岩裕子, 岩田健宏, 西村慎吾, 杉本盛人, 杉本盛人, 小林泰之, 荒木元朗, 渡部昌実, 渡邉豊彦, 那須保友

    西日本泌尿器科   82 ( 4 )   2020

  • Comparison of open versus laparoscopic radical cystectomy for bladder cancer: a single-center retrospective study.

    和田里章悟, 小林泰之, 定平卓也, 片山聡, 岩田健宏, 西村慎吾, 高本篤, 佐古智子, 枝村康平, 荒木元朗, 渡部昌実, 渡邉豊彦, 那須保友

    日本泌尿器科学会総会(Web)   108th   2020

  • 癌抗原CD147-サイトカイン融合タンパク質を用いた抗癌免疫・再生療法に関する研究

    李順愛, 定平卓也, 那須保友, 渡部昌実, 渡部昌実

    日本再生医療学会総会(Web)   19th   2020

  • 岡山大学病院における進行性尿路上皮癌に対するpembrolizumabの治療経験

    富永 悠介, 高本 篤, 角南 亮輔, 関戸 崇了, 和田里 章悟, 河村 香澄, 丸山 雄樹, 光井 洋介, 大岩 裕子, 窪田 理沙, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   81 ( 6 )   656 - 656   2019.12

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  • S100A11 contributes to tumor progression with cross talking between muscle invasive bladder cancer cells and fibroblasts

    光井 洋介, 定平 卓也, 渡部 昌実, 丸山 雄樹, 荒木 元朗, 渡邉 豊彦, 阪口 政清, 那須 保友

    西日本泌尿器科   81 ( 増刊 )   138 - 138   2019.10

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  • 症例から学ぶ 治療変遷から読み解く腎癌治療 何を、どこまで、どのように? 下大静脈腫瘍塞栓を伴う腎腫瘍の新しい手術アプローチ

    荒木 元朗, 小林 泰之, 枝村 康平, 角南 亮輔, 関戸 崇了, 和田里 章悟, 河村 香澄, 丸山 雄樹, 光井 洋介, 大岩 裕子, 窪田 理沙, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 渡辺 豊彦, 渡部 昌実, 那須 保友, 楳田 佑三, 八木 孝仁

    西日本泌尿器科   81 ( 増刊 )   113 - 113   2019.10

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  • ロボット補助腹腔鏡下前立腺全摘術後尿失禁の予測因子としての骨盤MRIパラメーターの有用性

    定平 卓也, 河村 香澄, 丸山 雄樹, 光井 洋介, 和田 耕一郎, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本排尿機能学会誌   30 ( 1 )   321 - 321   2019.9

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  • 前立腺癌に対するロボット支援前立腺全摘除術における前方・後方アプローチ間での術後QOLの比較

    丸山 雄樹, 定平 卓也, 荒木 元朗, 河村 香澄, 光井 洋介, 和田 耕一郎, 谷本 竜太, 小林 泰之, 渡部 昌実, 渡邊 豊彦, 那須 保友

    日本排尿機能学会誌   30 ( 1 )   255 - 255   2019.9

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  • サルコペニアが前立腺全摘除後の排尿関連QoLに与える影響 Expanded Prostate Cancer Index Compositeを用いた経時的変化

    光井 洋介, 渡邉 豊彦, 定平 卓也, 丸山 雄樹, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 那須 保友

    日本排尿機能学会誌   30 ( 1 )   255 - 255   2019.9

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  • 消化器癌による転移性尿管腫瘍の2例

    河村 香澄, 荒木 元朗, 定平 卓也, 丸山 雄樹, 光井 洋介, 西村 慎吾, 高本 篤, 和田 耕一郎, 谷本 竜太, 杉本 盛人, 小林 泰之, 渡部 昌実, 渡辺 豊彦, 那須 保友, 柳井 広之

    西日本泌尿器科   81 ( 4 )   461 - 466   2019.8

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    消化器癌を原発とする転移性尿管腫瘍の2例を経験したため報告する。【症例1】64歳、男性。2007年9月、下行結腸癌に対して下行結腸切除術を施行した。2014年、術後のCTで右尿管腫瘍を指摘され当科へ紹介となった。右尿管鏡検査時の生検病理結果より下行結腸癌の尿管転移と診断し、開腹腫瘍摘出術を行った。術後4ヵ月の時点で肝転移を認めたためTS-1 120mg内服療法を14ヵ月行い、様々な変更を経て現在はXELIRI + Bevacizumab療法8コース目を行っている。肝転移は緩徐に増大中である。【症例2】62歳、男性。2014年12月、多発胃癌に対して幽門側胃切除術、胆嚢摘出術およびRoux-en-Y再建術を施行し、術後TS-1 100mg内服療法を1年間行った。2017年、CTで右水腎症と尿管壁肥厚を指摘され、右尿管鏡検査を行うも狭窄が強く組織は採取できず、検査時の分腎尿細胞診はclass IVであった。再施行した右尿管鏡検査において狭窄尾側を生検したところ浸潤性尿路上皮癌の診断であったため、後腹膜鏡下右腎尿管摘除術を施行した。右尿管は腹膜およびS状結腸と著しく癒着し、漿膜ごと摘除した。病理結果は胃癌の右尿管転移であった。術後weekly PTX 100mgを開始したが骨転移の出現や腹膜転移の進行を認め、PTX + Ramucirumab 1コース施行した後に抗PD-1抗体180mgを5コース行ったが全身状態は徐々に悪化した。術後7ヵ月で緩和療法に移行し、術後11ヵ月で永眠された。転移性尿管腫瘍は術前生検しても診断が難しい場合がある。予後不良な疾患であり、悪性疾患の既往のある尿管腫瘍は転移性尿管腫瘍も鑑別に挙げる必要がある。(著者抄録)

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  • 当院におけるニボルマブ+イピリムマブの初期経験

    片山 聡, 高本 篤, 関戸 崇了, 角南 亮輔, 佐久間 貴文, 和田里 章悟, 河村 香澄, 丸山 雄樹, 光井 洋介, 窪田 理沙, 大岩 裕子, 定平 卓也, 岩田 健宏, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   81 ( 4 )   483 - 484   2019.8

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  • 消化器癌による転移性尿管腫瘍の2例

    河村 香澄, 荒木 元朗, 定平 卓也, 丸山 雄樹, 光井 洋介, 西村 慎吾, 高本 篤, 和田 耕一郎, 谷本 竜太, 杉本 盛人, 小林 泰之, 渡部 昌実, 渡辺 豊彦, 那須 保友, 柳井 広之

    西日本泌尿器科   81 ( 4 )   461 - 466   2019.8

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    消化器癌を原発とする転移性尿管腫瘍の2例を経験したため報告する。【症例1】64歳、男性。2007年9月、下行結腸癌に対して下行結腸切除術を施行した。2014年、術後のCTで右尿管腫瘍を指摘され当科へ紹介となった。右尿管鏡検査時の生検病理結果より下行結腸癌の尿管転移と診断し、開腹腫瘍摘出術を行った。術後4ヵ月の時点で肝転移を認めたためTS-1 120mg内服療法を14ヵ月行い、様々な変更を経て現在はXELIRI + Bevacizumab療法8コース目を行っている。肝転移は緩徐に増大中である。【症例2】62歳、男性。2014年12月、多発胃癌に対して幽門側胃切除術、胆嚢摘出術およびRoux-en-Y再建術を施行し、術後TS-1 100mg内服療法を1年間行った。2017年、CTで右水腎症と尿管壁肥厚を指摘され、右尿管鏡検査を行うも狭窄が強く組織は採取できず、検査時の分腎尿細胞診はclass IVであった。再施行した右尿管鏡検査において狭窄尾側を生検したところ浸潤性尿路上皮癌の診断であったため、後腹膜鏡下右腎尿管摘除術を施行した。右尿管は腹膜およびS状結腸と著しく癒着し、漿膜ごと摘除した。病理結果は胃癌の右尿管転移であった。術後weekly PTX 100mgを開始したが骨転移の出現や腹膜転移の進行を認め、PTX + Ramucirumab 1コース施行した後に抗PD-1抗体180mgを5コース行ったが全身状態は徐々に悪化した。術後7ヵ月で緩和療法に移行し、術後11ヵ月で永眠された。転移性尿管腫瘍は術前生検しても診断が難しい場合がある。予後不良な疾患であり、悪性疾患の既往のある尿管腫瘍は転移性尿管腫瘍も鑑別に挙げる必要がある。(著者抄録)

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  • 経尿道的砕石術(TUL)を施行した小児腎結石症の1例

    佐久間貴文, 和田耕一郎, 本郷智拡, 前原貴典, 高本篤, 坪井一朗, 松尾聡子, 三井將雄, 和田里章悟, 河村香澄, 丸山雄樹, 光井洋介, 窪田理沙, 大岩裕子, 定平卓也, 西村慎吾, 佐古智子, 枝村康平, 小林泰之, 石井亜矢乃, 荒木元朗, 渡部昌実, 渡邉豊彦, 那須保友

    西日本泌尿器科   81 ( 2 )   243‐244 - 244   2019.4

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  • がん・生殖の現状と今後の展望地域ネットワークにおける泌尿器科医の役割は何か? 岡山大学病院におけるがん生殖医療の現状と課題

    佐古 智子, 杉本 盛人, 高山 修, 中塚 幹也, 和田 耕一郎, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡辺 豊彦, 那須 保友

    日本泌尿器科学会総会   107回   SY20 - 4   2019.4

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  • 前立腺全摘除術前における針生検病理標本second-lookの有用性

    定平 卓也, 丸山 雄樹, 光井 洋介, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本泌尿器科学会総会   107回   PP1 - 070   2019.4

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  • 胚細胞腫瘍におけるブレオマイシン関連薬剤性肺障害の炎症性バイオマーカーの探索

    丸山 雄樹, 定平 卓也, 荒木 元朗, 光井 洋介, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本泌尿器科学会総会   107回   PP1 - 137   2019.4

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  • PNにおける腎機能温存は生命予後に寄与しているのか? 腎部分切除術における腎機能温存と心血管イベントの関連性の検討

    枝村 康平, 窪田 理沙, 大岩 裕子, 定平 卓也, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本泌尿器科学会総会   107回   SY15 - 3   2019.4

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  • ロボット支援腎部分切除術における切除皮質体積の重要性 切除組織からの3D再構築による精密測定を用いて

    光井 洋介, 定平 卓也, 荒木 元朗, 丸山 雄樹, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本泌尿器科学会総会   107回   AOP - 105   2019.4

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  • 腎虚血再灌流障害における好中球動態の2光子励起顕微鏡を用いた解析

    丸山雄樹, 荒木元朗, 城所研吾, 和田耕一郎, 河村香澄, 光井洋介, 定平卓也, 窪田理沙, 西村慎吾, 渡部昌実, 渡邉豊彦, 田邊克幸, 和田淳, 柏原直樹, 那須保友

    日本移植学会総会プログラム抄録集   55th   2019

  • URETHRAL TUMOR INDUCED BY METHOTREXATE‐ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS: A CASE REPORT

    河村香澄, 丸山雄樹, 定平卓也, 光井洋介, 西村慎吾, 高本篤, 甲斐誠二, 和田耕一郎, 谷本竜太, 杉本盛人, 小林泰之, 荒木元朗, 渡部昌実, 渡辺豊彦, 那須保友, 田中健大

    西日本泌尿器科   80 ( 12 )   678‐683 - 683   2018.12

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    症例は64歳、女性。2007年に関節リウマチの診断を受け、2008年よりメトトレキサート(MTX)内服中であった。2015年に繰り返す発熱で近医を受診。CTで子宮頸癌および両肺多発転移を疑われた。当院婦人科で子宮頸部パンチ生検を施行するも悪性所見なく、肺結節も自然消退したため経過観察となっていた。2017年2月、症状が再燃し近医を受診した。CTで左下葉結節影、右肺門リンパ節腫脹、腹腔内リンパ節腫脹および左腎盂拡張を認め、PET-CTで左腎門部リンパ節、尿道、上咽頭に高集積を認めた。MTX関連リンパ増殖性疾患(MTX-LPD)を疑い、施行した上咽頭生検はHodgkinリンパ腫の像を呈し、EBER-ISH陽性であった。MTX中止後は左尿管病変および尿道病変に著変はないものの、肺腫瘤とリンパ節は縮小傾向で現在経過観察中である。(著者抄録)

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  • 超細径HDIGスコープを用いた直視下腎杯穿刺とPCNLの初期成績

    和田耕一郎, 公文裕巳, 谷本竜太, 荒木元朗, 本郷智拡, 三井將雄, 松尾聡子, 坪井一朗, 佐久間貴文, 和田里章悟, 河村香澄, 丸山雄樹, 光井洋介, 前原貴典, 窪田理沙, 大岩裕子, 定平卓也, 岩田健宏, 西村慎吾, 高本篤, 佐古智子, 枝村康平, 杉本盛人, 小林泰之, 石井亜矢乃, 渡部昌実, 渡邉豊彦, 那須保友

    西日本泌尿器科   80 ( 12 )   700 - 700   2018.12

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  • 新規抗癌ウイルス医薬の開発とその局所投与法の最適化

    渡部 昌実

    上原記念生命科学財団研究報告集   32   1 - 4   2018.12

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  • Cytokines in adipose-derived mesenchymal stem cells promote the healing of liver disease

    Saifun Nahar, Yoshiki Nakashima, Chika Miyagi-Shiohira, Takao Kinjo, Zensei Toyoda, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi, Jiro Fujita

    WORLD JOURNAL OF STEM CELLS   10 ( 11 )   146 - 159   2018.11

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    Adipose-derived mesenchymal stem cells (ADSCs) are a treatment cell source for patients with chronic liver injury. ADSCs are characterized by being harvested from the patient's own subcutaneous adipose tissue, a high cell yield (i.e., reduced immune rejection response), accumulation at a disease nidus, suppression of excessive immune response, production of various growth factors and cytokines, angiogenic effects, anti-apoptotic effects, and control of immune cells via cell-cell interaction. We previously showed that conditioned medium of ADSCs promoted hepatocyte proliferation and improved the liver function in a mouse model of acute liver failure. Furthermore, as found by many other groups, the administration of ADSCs improved liver tissue fibrosis in a mouse model of liver cirrhosis. A comprehensive protein expression analysis by liquid chromatography with tandem mass spectrometry showed that the various cytokines and chemokines produced by ADSCs promote the healing of liver disease. In this review, we examine the ability of expressed protein components of ADSCs to promote healing in cell therapy for liver disease. Previous studies demonstrated that ADSCs are a treatment cell source for patients with chronic liver injury. This review describes the various cytokines and chemokines produced by ADSCs that promote the healing of liver disease.

    DOI: 10.4252/wjsc.v10.i11.146

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  • THE PROMISING USE OF PROBIOTICS AGAINST RECURRENT URINARY TRACT INFECTIONS

    定平卓也, 和田耕一郎, 三井將雄, 石井亜矢乃, 荒木元朗, 渡部昌実, 渡邉豊彦, 那須保友

    西日本泌尿器科   80 ( 10 )   505‐509 - 509   2018.10

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    尿路感染症に対する治療として中心的な役割を果たしてきた抗菌化学療法は大きな転機を迎えている。世界的な時流として耐性菌の問題や医療経済的にも抗菌薬の使用量を減少させる方向に移行している。尿路感染症においても例外ではなく、そのマネジメントに関して治療法の見直しだけでなく予防の重要性についての議論がなされている。そのうち、これまでに様々な臨床研究において有効性が確認されつつあるプロバイオティクスが抗菌薬とは異なる尿路感染症対策として注目されている。健常な閉経前の女性の腟内においては、基本的に乳酸菌が細菌叢(フローラ)を形成しているが、月経中や閉経後は乳酸菌が減少して腸内細菌が腟内に定着することとなる。その腟がリザーバーとなって細菌を供給し、頻繁に尿路の逆行性感染を引き起こすと考えられている。すなわち、腟内を乳酸菌中心のフローラに保つことで尿路感染症の再発(反復)リスクが低くなることが期待でき、実際にプロバイオティクスを用いた多くの研究が行われている。我々が現在行っている乳酸菌製剤のほか、プロバイオティクスの経口摂取が腟内フローラに与える影響に関しても検証が進んでおり、プロバイオティクスが尿路感染症の予防や治療に寄与することが期待されている。(著者抄録)

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  • 排尿障害を伴う女性尿道憩室に対して手術治療を行った1例

    松尾 聡子, 杉本 盛人, 佐久間 貴文, 坪井 一朗, 本郷 智拡, 三井 將雄, 河村 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 定平 卓也, 前原 貴典, 大岩 裕子, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 谷本 竜太, 小林 泰之, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友, 中村 あや, 津島 知靖

    西日本泌尿器科   80 ( 9 )   495 - 495   2018.9

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  • 前立腺に発生したSFT(Solitary fibrous tumor)の1例

    本郷 智拡, 高本 篤, 三井 將雄, 松尾 聡子, 坪井 一朗, 佐久間 貴文, 和田里 章悟, 河村 香澄, 丸山 雄樹, 光井 洋介, 前原 貴典, 窪田 理沙, 大岩 裕子, 定平 卓也, 西村 慎吾, 佐古 智子, 和田 耕一郎, 谷本 竜太, 杉本 盛人, 小林 泰之, 石井 亜矢乃, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   80 ( 9 )   497 - 497   2018.9

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  • 尿路感染を契機とした化膿性脊椎炎の3例

    森 聰博, 和田 耕一郎, 定平 卓也, 西村 慎吾, 藤尾 圭, 高本 篤, 堀川 雄平, 谷本 竜太, 杉本 盛人, 小林 泰之, 佐々木 克己, 荒木 元朗, 渡部 昌実, 江原 伸, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   80 ( 8 )   428 - 433   2018.8

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    化膿性脊椎炎は尿路感染症や尿性敗血症(ウロセプシス)が原因の一つとなる。今回、尿路感染症の治療経過中に発症し、保存的加療により治癒した化膿性脊椎炎の3例を経験した。いずれの症例も腎盂腎炎に対する抗菌薬の投与中に腰背部痛が遷延もしくは増強し、発症から9日以上経過した複数回目のMRIで診断し得た。尿路感染症治療中に持続、または増強する背部痛、腰痛には注意が必要であり、化膿性脊椎炎を疑って複数回の画像診断を行う必要があると考えられた。(著者抄録)

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  • Comparison Between Modified Extracellular-Type Trehalose-Containing Kyoto Solution and University of Wisconsin Solution in 18-Hour Pancreas Preservation for Islet Transplantation

    Eri Hamada, Nana Ebi, Chika Miyagi-Shiohira, Yoshihito Tamaki, Yoshiki Nakashima, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Takao Kinjo, Hirofumi Noguchi

    PANCREAS   47 ( 7 )   E46 - E47   2018.8

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    DOI: 10.1097/MPA.0000000000001104

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  • 尿路感染を契機とした化膿性脊椎炎の3例

    森 聰博, 和田 耕一郎, 定平 卓也, 西村 慎吾, 藤尾 圭, 高本 篤, 堀川 雄平, 谷本 竜太, 杉本 盛人, 小林 泰之, 佐々木 克己, 荒木 元朗, 渡部 昌実, 江原 伸, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   80 ( 8 )   428 - 433   2018.8

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    化膿性脊椎炎は尿路感染症や尿性敗血症(ウロセプシス)が原因の一つとなる。今回、尿路感染症の治療経過中に発症し、保存的加療により治癒した化膿性脊椎炎の3例を経験した。いずれの症例も腎盂腎炎に対する抗菌薬の投与中に腰背部痛が遷延もしくは増強し、発症から9日以上経過した複数回目のMRIで診断し得た。尿路感染症治療中に持続、または増強する背部痛、腰痛には注意が必要であり、化膿性脊椎炎を疑って複数回の画像診断を行う必要があると考えられた。(著者抄録)

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  • 膵がん進展に導く膵がん細胞 間質線維芽細胞クロストークを介在する分泌性S100A11 受容体RAGE連携の役割

    光井 洋介, 山本 健一, Sumardika I Wayan, 木下 理恵, 村田 等, 二見 淳一郎, 高松 仁, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 渡部 昌実, 那須 保友, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   156 - 156   2018.7

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  • 岡山大学におけるロボット支援腹腔鏡下前立腺全摘除術の治療成績

    谷本 竜太, 小林 宏州, 河村 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 前原 貴典, 大岩 裕子, 定平 卓也, 岩田 健宏, 西村 慎吾, 高本 篤, 松本 裕子, 甲斐 誠二, 和田 耕一郎, 杉本 盛人, 荒木 元朗, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   80 ( 5 )   246 - 246   2018.5

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  • 転移性尿管腫瘍の2例

    河村 香澄, 杉本 盛人, 小林 宏州, 和田里 章悟, 丸山 雄樹, 光井 洋介, 前原 貴典, 大岩 裕子, 定平 卓也, 岩田 健宏, 西村 慎吾, 高本 篤, 甲斐 誠二, 和田 耕一郎, 谷本 竜太, 荒木 元朗, 小林 泰之, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   80 ( 5 )   242 - 242   2018.5

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  • 岡山大学病院泌尿器科における腹腔鏡下尿膜管摘出術の治療経験

    前原 貴典, 杉本 盛人, 和田里 章悟, 河村 香澄, 小林 宏州, 丸山 雄樹, 光井 洋介, 大岩 裕子, 定平 卓也, 岩田 健宏, 西村 慎吾, 高本 篤, 甲斐 誠二, 和田 耕一郎, 谷本 竜太, 小林 泰之, 石井 亜矢乃, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   80 ( 4 )   181 - 181   2018.4

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  • INDUCTION OF PROSTATE CANCER STEM CELL PROPERTIES IN MOUSE INDUCED PLURIPOTENT STEM CELLS VIA DEFINED CARCINOMA NICHE AND TRACKING DRUG RESPONSE IN PRECLINICAL RESEARCH

    Naijin Xu, Xiezhao Li, Aibai Xu, Masami Watanabe, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    JOURNAL OF UROLOGY   197 ( 4 )   E540 - E540   2017.4

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  • IMMUNE CHECKPOINT INHIBITOR COMBINED WITH THE GROWTH INHIBITOR LYCORINE SYNERGISTICALLY FUNCTION TO MEDIATE ANTI-TUMOR EFFECTS IN A MOUSE MODEL OF RENAL CELL CARCINOMA

    Xiezhao Li, Naijin Xu, Aibai Xu, Masami Watanabe, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    JOURNAL OF UROLOGY   197 ( 4 )   E963 - E963   2017.4

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  • REAL-TIME MONITORING OF TUMOR PROGRESSION AND DRUG RESPONSES IN A PRECLINICAL MOUSE MODEL OF PROSTATE CANCER

    Peng Huang, Peng Xu, Xiezhao Li, Naijin Xu, Abai Xu, Masami Watanabe, Hiromi Kumon, Chunxiao Liu, Yasutomo Nasu

    JOURNAL OF UROLOGY   197 ( 4 )   E598 - E598   2017.4

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  • 後腹膜線維症に対し尿管剥離術および大網ラッピングを施行した1例

    児島 宏典, 荒木 元朗, 藤尾 圭, 吉岡 貴史, 森 聰博, 高本 篤, 堀川 雄平, 杉本 盛人, 和田 耕一郎, 佐々木 克己, 小林 康之, 江原 伸, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   79 ( 1 )   12 - 15   2017.1

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    症例は62歳、男性。全身倦怠感で来院。CT、MRIにて後腹膜線維症による両側水腎症、腹部大動脈瘤(35mm)、左総腸骨動脈瘤(23mm)、右総腸骨動脈瘤(16mm)を認めた。血清Crは5.3mg/dLで腎後性腎不全の状態であったため両側尿管ステントを留置したところ血清Crは1.6mg/dLに低下した。その後3ヵ月ごとの尿管ステント交換を20ヵ月行った。経過中プレドニゾロン内服(30mg/dからの漸減5mg/d、11ヵ月)を行ったがステント抜去不可であった。またステロイド糖尿病を発症した。経過中両側尿管の狭窄が悪化、ガイドワイヤー挿入困難となった。将来的な尿管動脈瘻の出現も懸念されたため右尿管剥離、大網ラッピングを行った。Mag3腎シンチで左腎は無機能腎であったため同時に腎摘した。術後6週で尿管ステント抜去。術後9週において血清Crは1.3mg/dL、腎エコーで水腎grade II、Mag3腎シンチで3相形成が見られた。術後14ヵ月において血清Crは1.5mg/dL、腎エコーで水腎なく経過している。後腹膜線維症による水腎症に尿管剥離、大網ラッピングは有効な外科的治療である。(著者抄録)

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  • URETEROLYSIS WITH OMENTAL WRAP FOR BILATERAL HYDRONEPHROSIS SECONDARY TO RETROPERITONEAL FIBROSIS : A CASE REPORT

    79 ( 1 )   12 - 15   2017

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  • 【新前立腺癌学-最新の基礎研究と診断・治療-】 臨床応用を目指した基礎研究 新規治療開発 遺伝子治療

    渡部 昌実, 定平 卓也, 那須 保友

    日本臨床   74 ( 増刊3 新前立腺癌学 )   221 - 225   2016.5

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  • 2.新規治療開発 (2)遺伝子治療

    渡部昌実, 定平卓也, 那須保友

    新前立腺癌学―最新の基礎研究と診断・治療―   74 ( 3 )   221 - 225   2016.5

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  • ADVANCED TWO-STEP TRANSCRIPTIONAL AMPLIFICATION AS A NOVEL SYSTEM FOR DETECTING VIABLE BLADDER CANCER CELLS

    Takuya Sadahira, Masami Watanabe, Motoo Araki, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu

    JOURNAL OF UROLOGY   195 ( 4 )   E610 - E610   2016.4

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  • ロボット補助腹腔鏡下前立腺全摘除術と前立腺密封小線源永久挿入療法後の排尿関連QOLの検討

    宗政 修平, 定平 卓也, 高本 篤, 藤尾 圭, 和田 耕一郎, 杉本 盛人, 佐々木 克己, 小林 泰之, 荒木 元朗, 渡部 昌実, 江原 伸, 渡辺 豊彦, 那須 保友

    日本泌尿器科学会総会   104回   PP3 - 240   2016.4

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  • 緑色蛍光タンパク質発現プラスミドによる膀胱癌に対する新たな診断の有用性

    定平 卓也, 渡部 昌実, 荒木 元朗, 江原 伸, 渡辺 豊彦, 那須 保友

    日本泌尿器科学会総会   104回   PP2 - 042   2016.4

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  • 精管結紮術27年後に精管精管吻合による精路再建を行い再疎通認められた一例

    杉本 盛人, 石井 和史, 倉橋 寛明, 松本 裕子, 渡部 昌実, 荒木 元朗, 渡邉 豊彦, 那須 保友

    日本生殖医学会雑誌   61 ( 1-2 )   72 - 72   2016.4

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  • ロボット支援・開腹術における腎部分切除の工夫

    荒木 元朗, 小林 泰之, 井上 陽介, 児島 宏典, 光井 洋介, 宗政 修平, 定平 卓也, 吉岡 貴史, 有吉 勇一, 森 聰博, 藤尾 圭, 高本 篤, 松本 裕子, 堀川 雄平, 和田 耕一郎, 杉本 盛人, 佐々木 克己, 石井 亜矢乃, 渡部 昌実, 江原 伸, 渡辺 豊彦, 那須 保友

    西日本泌尿器科   78 ( 4 )   194 - 195   2016.4

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  • 難治性前立腺癌に対するREIC遺伝子医薬の開発

    渡部昌実, 定平卓也, 有吉勇一, 那須保友

    泌尿器外科   29 ( 4 )   361 - 364   2016.4

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  • ロボット自家腎移植の検討

    荒木 元朗, 和田 耕一郎, 有吉 勇一, 平田 武志, 小林 泰之, 吉岡 貴史, 井上 陽介, 児島 宏典, 光井 洋介, 定平 卓也, 森 聰博, 藤尾 圭, 高本 篤, 松本 裕子, 堀川 雄平, 杉本 盛人, 佐々木 克己, 石井 亜矢乃, 渡部 昌実, 江原 伸, 渡辺 豊彦, 那須 保友, 公文 裕巳

    西日本泌尿器科   78 ( 3 )   136 - 136   2016.3

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  • 不完全な尿管ステント留置と移植腎動脈下極枝の閉塞により尿管穿孔を生じた生体腎移植の一例

    和田耕一郎, 荒木元朗, 有森千聖, 有吉勇一, 佐々木克己, 小林泰之, 渡部昌実, 江原 伸, 渡辺豊彦, 那須保友, 公文裕巳, 吉岡貴史

    腎移植・血管外科   26 ( 1 )   82 - 87   2016

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    尿管の血流不全と不完全なステント留置による尿路合併症を経験した。症例は42歳のO型男性。血液透析歴2年。44歳A型の姉をドナーとした血液型不適合生体腎移植を施行した。グラフトに2本の腎動脈が認められ、下極枝は下腹壁動脈と端々吻合し、尿管膀胱吻合に尿管ステントを留置した。術後2日目に下極枝が閉塞、術後5日目のCTでステントの近位ループが腎盂より遠位側に認められた。術後16日目に手術創より尿が流出し、腎瘻を造設した。術後17日目に腎盂尿管移行部近位で移植尿管-自己尿管吻合を施行し、術後22ヵ月でs-Cr:1.49mg/dlで経過良好である。複数腎動脈例では可及的な血行再建と、適切な尿管ステント留置が尿路合併症の予防に重要である。(著者抄録)

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  • 成長円錐におけるPKCαのコルタクチンリン酸化によるアクチン制御の可能性

    山田 浩司, 菊池 達也, 増本 年男, 魏 范研, 阿部 匡史, 竹田 哲也, 西木 禎一, 富澤 一仁, 渡部 昌実, 松井 秀樹, 竹居 孝二

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [1P1328] - [1P1328]   2015.12

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  • 悪性胸膜中皮腫に対するREIC/Dkk-3遺伝子治療

    山本 寛斉, 枝園 和彦, 牧 佑歩, 宗 淳一, 大谷 真二, 三好 健太郎, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 渡部 昌実, 那須 保友, 三好 新一郎, 豊岡 伸一

    肺癌   55 ( 5 )   502 - 502   2015.10

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  • 精嚢造影併用の経尿道的内視鏡手術が診断治療に有用であった射精障害の一例

    杉本 盛人, 石井 和史, 光井 洋介, 吉岡 貴史, 倉橋 寛明, 松本 裕子, 瀬野 祐子, 小林 泰之, 渡部 昌実, 渡邊 豊彦, 那須 保友

    日本性機能学会雑誌   30 ( 2 )   198 - 198   2015.8

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  • テストステロンエナント酸エステル注射液の供給停止状態でのLOH症候群の治療

    倉橋 寛明, 松本 裕子, 杉本 盛人, 石井 和史, 佐々木 克己, 荒木 元朗, 江原 伸, 賀来 春紀, 渡部 昌実, 渡邉 豊彦, 那須 保友, 公文 裕巳

    日本泌尿器科学会総会   103回   479 - 479   2015.4

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  • ハイリスク前立腺癌に対するネオアジュバントREIC遺伝子治療

    有吉 勇一, 定平 卓也, 高本 篤, 平田 武志, 佐々木 克己, 荒木 元朗, 渡部 昌実, 江原 伸, 渡辺 豊彦, 那須 保友, 公文 裕巳

    日本泌尿器科学会総会   103回   502 - 502   2015.4

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  • Adenovirus-Mediated Overexpression of REIC/DKK-3 Inhibits Cell Growth and Induces Apoptosis in Pancreatic Cancer and Hepatocellular Carcinoma

    Sawahara Hiroaki, Hidenori Shiraha, Daisuke Uchida, Hironari Kato, Masami Watanabe, Hiromi Kumon, Yasutomo Nasu, Kazuhide Yamamoto

    GASTROENTEROLOGY   148 ( 4 )   S954 - S954   2015.4

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  • 前立腺癌に対する新規免疫療法としてのREIC/Dkk-3遺伝子治療

    那須保友, 渡部昌実

    泌尿器外科   28 ( 7 )   1187 - 1190   2015

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  • Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer

    Ken Suzawa, Shinichi Toyooka, Kazuhiko Shien, Norimitsu Tanaka, Masami Watanabe, Junichi Soh, Masakiyo Sakaguchi, Keitaro Matsuo, Hiromasa Yamamoto, Masashi Furukawa, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Nam-Ho Huh, Shinichiro Miyoshi, Hiromi Kumon

    CANCER RESEARCH   74 ( 19 )   2014.10

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    DOI: 10.1158/1538-7445.AM2014-2879

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  • 社会的性自認に対して持続的な性別違和感を有し、ジェンダーセンターを受診した性分化疾患の3例

    松本 裕子, 杉本 盛人, 渡部 昌実, 倉橋 寛明, 荒木 元朗, 江原 伸, 渡邉 豊彦, 那須 保友, 公文 裕巳, 石井 和史

    日本性科学会雑誌   32 ( 2 )   152 - 152   2014.9

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  • 勃起障害に対する陰茎海綿体自己注射の初期経験

    松本 裕子, 杉本 盛人, 渡部 昌実, 倉橋 寛明, 荒木 元朗, 江原 伸, 渡邉 豊彦, 那須 保友, 公文 裕巳, 石井 和史

    日本性機能学会雑誌   29 ( 2 )   182 - 182   2014.8

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  • ADENOVIRUS-MEDIATED INTERLEUKIN-12 GENE THERAPY FOR CASTRATION RESISTANT PROSTATE CANCER: REPORT OF A CLINICALLY RESPONDED CASE

    Taiki Kanbara, Yasutomo Nasu, Katsumi Sasaki, Haruki Kaku, Masami Watanabe, Toyohiko Wananabe, Hiromi Kumon, Malcolm K. Brenner

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   240 - 241   2014.7

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  • A PHASE I/II STUDY OF REDUCED EXPRESSION IN IMMORTALIZED CELLS (REIC/DKK-3) GENE THERAPY FOR PROSTATE CANCER; INTERIM REPORT

    Katsumi Sasaki, Yasutomo Nasu, Haruki Kaku, Masami Watanabe, Taiki Kanbara, Toyohiko Wananabe, Hiromi Kumon

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   239 - 240   2014.7

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  • The Efficacy of REIC/DKK-3 Gene Therapy for Pancreatic Cancer

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Sigeru Horiguchi, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Kazuhide Yamamoto

    GASTROENTEROLOGY   146 ( 5 )   S301 - S301   2014.5

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  • A Case Report Showing Dramatic Response With In-Situ Ad-REIC Gene Therapy in a Patient With Metastatic CRPC Following Chemotherapy

    Yuichi Ariyoshi, Kathumi Sasaki, Takao Hiraki, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon

    MOLECULAR THERAPY   22   S103 - S103   2014.5

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  • 超高効率遺伝子発現システムを用いた次世代REIC遺伝子治療の開発

    渡部 昌実, 阪口 政清, 賀来 春紀, 佐々木 克己, 高本 篤, 有吉 勇一, 杉本 盛人, 江原 伸, 渡辺 豊彦, 許 南浩, 那須 保友, 公文 裕巳

    日本泌尿器科学会総会   102回   621 - 621   2014.4

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  • 岡山大学における前立腺癌に対するReduced Expression in Immortalized Cells遺伝子治療臨床研究 CRPC著効例の報告

    佐々木 克己, 有吉 勇一, 高本 篤, 江原 伸, 渡部 昌実, 賀来 春紀, 柳井 広之, 渡辺 豊彦, 那須 保友, 公文 裕巳

    日本泌尿器科学会総会   102回   621 - 621   2014.4

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  • 性同一性障害患者に対するホルモン補充療法における多血症の検討

    倉橋 寛明, 杉本 盛人, 石井 和史, 渡部 昌実, 渡邉 豊彦, 公文 裕巳

    日本泌尿器科学会総会   102回   481 - 481   2014.4

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  • 岡山大学泌尿器科における前立腺癌に対するREIC遺伝子治療臨床研究 CRPC著効例の報告

    有吉 勇一, 高本 篤, 谷本 竜太, 佐々木 克己, 江原 伸, 賀来 春紀, 渡部 昌実, 渡邉 豊彦, 那須 保友, 公文 裕巳

    西日本泌尿器科   76 ( 1 )   33 - 33   2014.1

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  • 小胞体ストレスにより癌細胞アポトーシスを誘導するREIC/Dkk‐3遺伝子治療が抗腫瘍免疫に及ぼす影響の検討

    有吉勇一, 定平卓也, 渡部昌実, 那須保友, 榮川伸吾, 山崎千尋, 一柳朋子, 鵜殿平一郎, 公文裕巳

    臨床ストレス応答学会大会抄録集   9th   55   2014

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  • Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging

    H. Kaku, H. Ueki, Y. Ariyoshi, S. Li, P. Huang, Y. Nasu, H. Kumon, M. Watanabe

    HUMAN GENE THERAPY   24 ( 12 )   A154 - A154   2013.12

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