研究者詳細 - 渡部　昌実

論文 - 渡部　昌実

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Impact of Early Detection and Varying Duration of Chemoprophylaxis on Venous Thromboembolism After Robot-Assisted Radical Cystectomy. 査読国際誌

Yuki Maruyama, Takuya Sadahira, Takanori Sekito, Yuta Iwasaki, Yosuke Mitsui, Tatsushi Kawada, Yusuke Tominaga, Takehiro Iwata, Satoshi Katayama, Shingo Nishimura, Kensuke Bekku, Kohei Edamura, Tomoko Kobayashi, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Motoo Araki

International journal of urology : official journal of the Japanese Urological Association 32 ( 7 ) 839 - 847 2025年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Venous thromboembolism (VTE) is one of the serious complications after robot-assisted radical cystectomy (RARC). This study aims to investigate the optimal duration of VTE prophylaxis and the predictive value of D-dimer measurement on the early detection of VTE. METHODS: Retrospectively, we evaluated 86 RARC patients from July 2020 to September 2023. Thromboprophylaxis was modified two times (July 2020-; no-enoxaparin administration, June 2021-; enoxaparin for one week postoperatively, December 2022-; for two weeks), and patients were divided into three groups according to the duration. For early detection of VTE, D-dimer was measured postoperatively over time. In cases of D-dimer exceeding 10 μg/mL, contrast-enhanced CT was performed. The incidence of VTE was analyzed, and multivariate analysis was performed to identify the predictive factors. RESULTS: Of the 40 patients who experienced postoperative D-dimer levels > 10 μg/mL, 37 underwent CT or ultrasound. VTE was observed in 10/26 cases (38%) in the no-enoxaparin group, 8/36 cases (22%) in the one-week group, and 1/24 cases (4%) in the two-week group, with a significant difference in incidence between the no-enoxaparin and 2-week groups (p = 0.005). Symptomatic VTE was observed in only one case in the no-enoxaparin group. Multivariate analyses of VTE predictive factors showed significant differences in D-dimer levels ≥ 12 on postoperative day 1 (OR = 14.2, 95% CI 2.47-81.1, p = 0.003) and enoxaparin administration for two weeks (OR = 0.10, 95% CI 0.01-0.96, p = 0.046). CONCLUSION: Chemoprophylaxis for 2 weeks significantly reduces the risk of VTE after RARC. In addition, routine measurement of D-dimer enables early detection of asymptomatic VTE, helping to prevent the development of symptomatic VTE.

DOI： 10.1111/iju.70066

A Canine c-kit Novel Mutation Isolated from a Gastrointestinal Stromal Tumor (GIST) Retains the Ability to Form Dimers but Lacks Autophosphorylation. 査読国際誌

Kei Shimakawa, So Doge, Masaki Michishita, Eri Tanabe, Tsuyoshi Tajima, Masato Kobayashi, Makoto Bonkobara, Masami Watanabe, Kazuhiko Ochiai, Yoshikazu Tanaka

Animals : an open access journal from MDPI 15 ( 10 ) 2025年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that develop in the gastrointestinal tract; KIT mutations are present in both canine and human GISTs. In this study, genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) sections of 55 canine GIST cases, and mutation searches were performed for exons 8, 9, and 11. The results revealed novel mutations, A434T and F436S, in exon 8. In contrast to the A434T mutation without functional changes, the F436S mutant retained its dimerization ability, but lost its phosphorylation function and attenuated downstream Akt signaling, which is reflected in wound healing and migration activities. A comparison of the subcellular localization of WT KIT and the F436S mutant revealed no differences. In silico simulations indicated that the F436S mutation alters the structure of the near-membrane region and that its effects may extend to the transmembrane and intracellular domains compared to the WT. F436S is a point mutation that affects the entire molecule because co-mutation with the F436S mutation and the known autophosphorylation mutation reduces the autophosphorylation abilities.

DOI： 10.3390/ani15101444

Vesicular Glutamate Transporter 3 Is Involved in Glutamatergic Signalling in Podocytes. 査読国際誌

Naoko Nishii, Tomoko Kawai, Hiroki Yasuoka, Tadashi Abe, Nanami Tatsumi, Yuika Harada, Takaaki Miyaji, Shunai Li, Moemi Tsukano, Masami Watanabe, Daisuke Ogawa, Jun Wada, Kohji Takei, Hiroshi Yamada

International journal of molecular sciences 26 ( 6 ) 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glomerular podocytes act as a part of the filtration barrier in the kidney. The activity of this filter is regulated by ionotropic and metabotropic glutamate receptors. Adjacent podocytes can potentially release glutamate into the intercellular space; however, little is known about how podocytes release glutamate. Here, we demonstrated vesicular glutamate transporter 3 (VGLUT3)-dependent glutamate release from podocytes. Immunofluorescence analysis revealed that rat glomerular podocytes and an immortal mouse podocyte cell line (MPC) express VGLUT1 and VGLUT3. Consistent with this finding, quantitative RT-PCR revealed the expression of VGLUT1 and VGLUT3 mRNA in undifferentiated and differentiated MPCs. In addition, the exocytotic proteins vesicle-associated membrane protein 2, synapsin 1, and synaptophysin 1 were present in punctate patterns and colocalized with VGLUT3 in MPCs. Interestingly, approximately 30% of VGLUT3 colocalized with VGLUT1. By immunoelectron microscopy, VGLUT3 was often observed around clear vesicle-like structures in differentiated MPCs. Differentiated MPCs released glutamate following depolarization with high potassium levels and after stimulation with the muscarinic agonist pilocarpine. The depletion of VGLUT3 in MPCs by RNA interference reduced depolarization-dependent glutamate release. These results strongly suggest that VGLUT3 is involved in glutamatergic signalling in podocytes and may be a new drug target for various kidney diseases.

DOI： 10.3390/ijms26062485

Erratum: Induction of cells with prostate cancer stem-like properties from mouse induced pluripotent stem cells via conditioned medium. 査読国際誌

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 15 ( 5 ) 2449 - 2450 2025年

Investigating the fate of Zirconium-89 labelled antibody in cynomolgus macaques. 査読国際誌

Takanori Sasaki, Sadaaki Kimura, Akihiro Noda, Yoshihiro Murakami, Sosuke Miyoshi, Masaru Akehi, Kazuhiko Ochiai, Masami Watanabe, Takahiro Higuchi, Eiji Matsuura

Nuclear medicine and biology 144-145 109001 - 109001 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Preclinical pharmacokinetic studies of therapeutic antibodies in non-human primates are desired because of the difficulty in extrapolating ADME data from animal models to humans. We evaluated the pharmacokinetics of 89Zr (Zirconium-89) -labelled anti-KLH human IgG and its metabolites to confirm their non-specific/physiological accumulation in healthy cynomolgus macaques. The anti-KLH antibody was used as a negative control, ensuring that the observed distribution reflected general IgG behavior rather than antigen-specific accumulation. This provides a valuable reference for comparing the biodistribution of targeted antibodies. METHODS: Selected IgG was conjugated to desferrioxamine (DFO), labelled with 89Zr, and injected into healthy cynomolgus macaques. PET/CT images at the whole-body level were acquired at different time points, and standard uptake values (SUV) in regions of interest, such as the heart, liver, spleen, kidneys, bone, and muscles, were calculated. The distribution of a shortened antibody variant, 89Zr-labelled Fab, as well as that of [89Zr]Zr-DFO and [89Zr]Zr-oxalate, the expected metabolites of 89Zr- labelled IgG, was also assessed. RESULTS: After 89Zr-labelled IgG injection, the SUV in the heart, vertebral body, and muscle decreased, in line with the 89Zr concentration decrease in the circulation, whereas radioactivity increased over time in the kidneys and liver. Autoradiography of the renal sections indicated that most of the 89Zr- labelled IgG radioactivity accumulated in the renal cortex. Relatively high accumulation in the kidneys was also observed in 89Zr- labelled Fab-injected macaques, and renal autoradiographs of these animals showed that the renal cortex was the preferred accumulation site. However, [89Zr]Zr-DFO was rapidly excreted into the urine, whereas [89Zr]Zr-oxalate was highly accumulated in the epiphysis of the long bones and vertebral body. CONCLUSION: In the non-human primate cynomolgus macaque, 89Zr- labelled IgG accumulated in the kidneys and the liver. However, [89Zr]Zr-DFO and 89Zr did not accumulate in these organs. This preclinical pharmacokinetic study performed with human IgG in a non-human primate model using PET is of great significance as it sheds light on the basic fate and distribution of 89Zr- labelled IgG.

DOI： 10.1016/j.nucmedbio.2025.109001

Significance of targeted antimicrobial prophylaxis using rectal-culture selective screening media prior to transrectal prostate biopsy: A multicenter, randomized controlled trial. 査読国際誌

Takuya Sadahira, Takanori Sekito, Yuki Maruyama, Takaharu Ichikawa, Yuki Kurihara, Hiromasa Shiraishi, Takafumi Sakuma, Moto Tokunaga, Yosuke Mitsui, Norihiro Kusumi, Yusuke Tominaga, Satoshi Katayama, Takehiro Iwata, Shingo Nishimura, Kohei Edamura, Tomoko Kobayashi, Masami Watanabe, Yoshiki Hiyama, Hiroki Yamada, Hiroki Kurata, Tsubasa Kondo, Masao Mitsui, Tadasu Takenaka, Hiroshi Kiyota, Motoo Araki, Jun Miyazaki, Satoshi Takahashi, Shingo Yamamoto, Koichiro Wada

Urology 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: To examine whether antimicrobial prophylaxis based on screening rectal cultures using selective media prevented acute bacterial prostatitis following transrectal prostate biopsy (TRPB). METHODS: In this multicenter, randomized controlled trial, we enrolled 403 patients undergoing TRPB with low risks of infectious complications. Patients were randomized into a cultured group (CG) or no cultured group (NCG). In the CG, patients with positive culture results for fluoroquinolone (FQ)-resistant or extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (E. coli) used piperacillin/tazobactam as prophylaxis, and those with negative culture results and in the NCG used levofloxacin. The primary endpoint was the incidence of acute prostatitis after TRPB. The secondary endpoint was the accuracy of the selective media. RESULTS: Of 373 patients (CG, 187; NCG, 186), 67 were positive, and 120 were negative for rectal culture in the CG. The overall incidence of prostatitis after TRPB was 1.1% (n=4). The incidences in the CG and the NCG were 1.6% (n=3, all negative-culture cases) and 0.5% (n=1), respectively, without significant difference (P=0.3). No prostatitis occurred in the positive-culture group. The sensitivity and specificity of the levofloxacin-insusceptible selective media were 98.1% and 94.7%, respectively. CONCLUSION: Screening with selective media before TRPB in patients with low infectious risks may provide additive value to preventing post-biopsy prostatitis. Piperacillin/tazobactam can be considered when FQ-resistant or ESBL-producing E. coli is detected.

DOI： 10.1016/j.urology.2024.12.018

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

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年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：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

その他リンク： 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. 査読国際誌

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年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

Cell Transplantation 2024年1月

Exploration of the protein-dependent mechanism of Lactobacillus crispatus GAI98322 to prevent recurrent cystitis. 査読国際誌

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年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

J Cell Sci 136 ( 10 ) 2023年5月

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

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

Antibiotics 12 ( 3 ) 522 - 522 2023年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：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

Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. 査読国際誌

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年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Etiology of recurrent cystitis in postmenopausal women based on vaginal microbiota and the role of Lactobacillus vaginal suppository. 査読国際誌

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年

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Canine Mammary Tumor Cell Lines Derived from Metastatic Foci Show Increased RAD51 Expression but Diminished Radioresistance via p21 Inhibition. 査読国際誌

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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Protocol for the generation of human induced hepatic stem cells using Sendai virus vectors. 査読国際誌

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

STAR protocols 3 ( 4 ) 101884 - 101884 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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年12月

Induced hepatic stem cells are suitable for human hepatocyte production. 査読国際誌

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

iScience 25 ( 10 ) 105052 - 105052 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

AP39, a Mitochondrial-Targeted H2S Donor, Improves Porcine Islet Survival in Culture. 査読国際誌

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Pancreas Preservation in Modified Histidine-lactobionate Solution Is Superior to That in University of Wisconsin Solution for Porcine Islet Isolation. 査読国際誌

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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