Hypoxic culture enhances the antimicrobial activity of amnion-derived mesenchymal stem cells, thereby reducing bacterial load and promoting wound healing in diabetic mice
Riku Ishii, Shunsuke Ohnishi, Masahiro Hojo, Kosuke Ishikawa, Emi Funayama, Takahiro Miura, Naoto Okubo, Kazufumi Okada, Yuhei Yamamoto, Taku Maeda
Biochemical and Biophysical Research Communications, 150903, 150903, Elsevier BV, 2024年10月
研究論文（学術雑誌）

Positivity of high-sensitivity HBsAg test, not previous HBV infection, indicates poor prognosis in patients with non-HBV-related HCC.
Naohiro Yasuura, Goki Suda, Masatsugu Ohara, Akimitsu Meno, Takuya Sho, Risako Kohya, Takashi Sasaki, Tomoka Yoda, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Osamu Maehara, Shunsuke Ohnishi, Tomoya Saitou, Masaya Sugiyama, Takasuke Fukuhara, Masaru Baba, Takashi Kitagataya, Naoki Kawagishi, Masato Nakai, Mitsuteru Natsuizaka, Koji Ogawa, Akinobu Taketomi, Naoya Sakamoto
Alimentary pharmacology & therapeutics, 2024年09月04日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIMS: The prognostic impact of previous-HBV-infection (pHBV) in non-HBV-related hepatocellular carcinoma (non-HBV-related-HCC) and the prevalence, characteristics and significance of recently developed high-sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps. METHODS: We retrospectively screened patients with newly diagnosed non-HBV-related-HCC (standard HBsAg-test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non-HBV-related-HCC. RESULTS: A total of 401 non-HBV-related-HCC patients were included (288 with pHBV/113 without pHBV). In non-HBV-related-HCC, pHBV did not affect overall survival (OS). Among non-HBV-related-HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non-HBV-related-HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non-HBV-related-HCC patients with non-B-non-C aetiology and advanced HCC. CONCLUSIONS: In non-HBV-related-HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis.

Application of polyglycolic acid sheets and basic fibroblast growth factor to prevent esophageal stricture after endoscopic submucosal dissection in pigs.
Yusuke Nishimura, Masayoshi Ono, Naoto Okubo, Takayuki Sone, Masayuki Higashino, Shogo Matsumoto, Marina Kubo, Keiko Yamamoto, Shoko Ono, Shunsuke Ohnishi, Naoya Sakamoto
Journal of gastroenterology, 58, 11, 1094, 1104, 2023年11月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Endoscopic submucosal dissection (ESD) has been the first-line treatment for early-stage esophageal cancer. However, it often causes postoperative stricture in cases requiring wide dissection. Basic fibroblast growth factor (bFGF) reportedly has anti-scarring effects during cutaneous wound healing. We hypothesized that suppressing myofibroblast activation will prevent stricture after esophageal ESD. METHODS: We resected a complete porcine esophagus circumference section by ESD. To investigate the preventive effect of bFGF on esophageal stricture formation after ESD, we endoscopically applied bFGF-soaked poly-glycolic acid (PGA) sheets onto the wound bed after ESD and fixed them by spraying fibrin glue (PGA + bFGF group), PGA sheets alone onto the wound bed and fixed them by spraying fibrin glue (PGA group), or nothing (control group). After removing the esophagus on day 22, we evaluated the mucosal constriction rate. RESULTS: Compared with those in the control group, esophageal stricture was significantly reduced in the PGA + bFGF group, and the areas stained with α-SMA and calponin-1 antibodies were significantly inhibited in the PGA + bFGF and PGA groups. The thickness of the fibrous layer in the PGA + bFGF group was uniform compared to that of the other groups. Thus, PGA + bFGF inhibited the development of unregulated fibroblasts in the acute phase, leading to uniform wound healing. CONCLUSIONS: Stenosis after esophageal ESD is related to fibrosis in the acute phase. Administration of PGA and bFGF suppresses myofibroblast activation in the acute phase, thereby preventing esophageal constriction in pigs.

Potential Correlation between Changes in Serum FGF21 Levels and Lenvatinib-Induced Appetite Loss in Patients with Unresectable Hepatocellular Carcinoma.
Risako Kohya, Goki Suda, Masatsugu Ohara, Takashi Sasaki, Tomoka Yoda, Naofumi Sakurai, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Osamu Maehara, Shunsuke Ohnishi, Yoshimasa Tokuchi, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto
Cancers, 15, 12, 2023年06月20日, ［国際誌］
英語, 研究論文（学術雑誌）, Lenvatinib, used for unresectable hepatocellular carcinoma (HCC), causes appetite loss, but the underlying mechanisms, clinical impact, and predictive factors have been unclear. The endocrine factor FGF21 modulates appetite and is involved in cachexia. We evaluated the association between FGF21 level changes during lenvatinib treatment for unresectable HCC and appetite loss. Sixty-three eligible unresectable HCC patients who started lenvatinib treatment between 2018 and 2021 were included. We analyzed FGF21 levels at baseline; 1, 2, and 4 weeks after lenvatinib initiation, and before the onset of appetite loss. Grade ≥ 2 lenvatinib-induced appetite loss led to liver functional reserve deterioration at disease progression and a poor prognosis. Baseline characteristics and serum FGF21 levels were similar between patients with and without appetite loss. However, the serum FGF21 change rate increased significantly at 4 weeks post-lenvatinib initiation in patients with grade ≥ 2 appetite loss, as compared to those without appetite loss. Similar significant increases in the serum FGF21 level change rate were observed prior to grade ≥ 2 appetite loss onset. This suggests that changes in FGF21 levels can be used to predict patients with a greater risk of marked appetite loss and provides insights into the mechanisms underlying lenvatinib-induced appetite loss in patients with HCC.

Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan.
Takashi Sasaki, Goki Suda, Masatsugu Ohara, Shunichi Hosoda, Naoki Kawagishi, Risako Kohya, Tomoka Yoda, Osamu Maehara, Shunsuke Ohnishi, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Yoshimasa Tokuchi, Takashi Kitagataya, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Sho Komukai, Koji Ogawa, Naoya Sakamoto
Hepatology research : the official journal of the Japan Society of Hepatology, 2023年06月18日, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: Although hepatitis delta virus (HDV) coinfection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. We aimed to investigate the recent prevalence of HDV infections in Japan. METHODS: We screened 1264 consecutive patients with HBV infection at Hokkaido University Hospital between 2006 and 2022. Patients' serums were preserved and subsequently tested for HDV antibody (immunoglobulin-G). Available clinical information was collected and analyzed. We compared the changes in liver fibrosis using the Fibrosis-4 (FIB-4) index between propensity-matched patients with and without the evidence of anti-HDV antibodies and corrected for baseline FIB-4 index, nucleoside/nucleotide analog treatment, alcohol intake, sex, HIV coinfection, liver cirrhosis, and age. RESULTS: After excluding patients without properly stored serums and those lacking appropriate clinical information, 601 patients with HBV were included. Of these, 1.7% of patients had detectable anti-HDV antibodies. Patients with anti-HDV antibody serum positivity had a significantly higher prevalence of liver cirrhosis, significantly lower prothrombin time, and a higher prevalence of HIV coinfection than those who demonstrated serum anti-HDV antibody negativity. A propensity-matched longitudinal analysis revealed that liver fibrosis (FIB-4 index) progressed more rapidly in patients with positive results for anti-HDV antibody tests. CONCLUSIONS: The recent prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.

Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment.
Shunichi Hosoda, Goki Suda, Takuya Sho, Koji Ogawa, Megumi Kimura, Zijian Yang, Sonoe Yoshida, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Takuto Miyagishima, Naoya Sakamoto
Liver cancer, 12, 2, 156, 170, 2023年06月, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial. METHODS: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib. RESULTS: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without. CONCLUSION: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

Hepatitis C virus eradication by direct-acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low-density lipoprotein cholesterolemia without an increase in body weight.
Yoshimasa Tokuchi, Goki Suda, Naoki Kawagishi, Masatsugu Ohara, Risako Kohya, Takashi Sasaki, Tomoka Yoda, Osamu Maehara, Shunsuke Ohnishi, Akinori Kubo, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Takashi Kitagataya, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto
Hepatology research : the official journal of the Japan Society of Hepatology, 53, 7, 595, 606, 2023年03月21日, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: Hepatitis C virus (HCV) infection has been reported to cause liver steatosis. Thus, eradicating HCV with direct-acting antivirals (DAAs) is expected to reduce liver steatosis. We aimed to clarify long-term changes in the prevalence of fatty liver and hyper-low-density lipoprotein (LDL) cholesterolemia and their associations in patients who achieve successful HCV eradication using DAAs. METHODS: This retrospective study included patients with HCV who achieved sustained virologic response after interferon-free DAA and analyzed the changes in the prevalence of fatty liver diagnosed with controlled attenuation parameter (CAP), hyper-LDL cholesterolemia, and their relationships at baseline (n = 100) and 24 weeks (SVR24, n = 100), 96 weeks (SVR96, n = 100), and 144 weeks (SVR144, n = 90) after DAA. RESULTS: In 100 participants, the prevalence of fatty liver (19% vs. 32%, p = 0.0349) and hyper-LDL cholesterolemia (6% vs. 15%, p = 0.0379) significantly increased without changes in body weight at SVR96. Median total cholesterol, low-density lipoprotein cholesterol (LDL-C), and small-dense-LDL (sdLDL) levels and CAP values were significantly greater at SVR24, SVR96, and SVR144 than at baseline. Baseline CAP values and changes in CAP values were significantly negatively correlated at every observation point: r = -0.5305, p < 0.0001 at SVR24; r = -0.3617, p = 0.0005 at SVR96; and r = -0.4735, p < 0.0001 at SVR144. A similar relationship was observed in cholesterol levels. Unlike at baseline, CAP values were significantly positively correlated with LDL-C and sdLDL-C levels at all observation points after DAAs. CONCLUSIONS: Direct-acting antivirals may cause an increased prevalence of fatty liver accompanying hyper-LDL cholesterolemia without increased body weight. As post-SVR liver steatosis could cause HCC, careful follow-up may be required.

Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma.
Zijian Yang, Goki Suda, Osamu Maehara, Masatsugu Ohara, Tomoka Yoda, Takashi Sasaki, Risako Kohya, Sonoe Yoshida, Shunichi Hosoda, Yoshimasa Tokuchi, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
Cancers, 15, 3, 2023年01月18日, ［国際誌］
英語, 研究論文（学術雑誌）, The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies.

Serum Angiopoietin-2 Predicts the Occurrence and Recurrence of Hepatocellular Carcinoma after Direct-Acting Antiviral Therapy for Hepatitis C.
Naoki Kawagishi, Goki Suda, Yoshiya Yamamoto, Masaru Baba, Ken Furuya, Osamu Maehara, Shunsuke Ohnishi, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Yoshimasa Tokuchi, Takashi Kitagataya, Masatsugu Ohara, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto
Viruses, 15, 1, 2023年01月07日, ［国際誌］
英語, 研究論文（学術雑誌）, Progressive liver fibrosis after anti-HCV treatment is a risk factor for HCC. Angiopoietin-2 (Ang2) is associated with non-regression of liver fibrosis after direct-acting antiviral (DAA). This study evaluated the predictive value of serum Ang2 levels for HCC occurrence or recurrence after DAA administration. In this retrospective study, 310 HCV-infected patients treated with DAAs in 2014-2020 were screened and evaluated for HCC occurrence or recurrence every three-six months. Multivariate Cox regression analysis revealed that age ≥ 75 years (HR: 2.92, 95% CI: 1.34-6.33; p = 0.007) and baseline Ang2 level ≥ 464 pg/mL (HR: 2.75, 95% CI: 1.18-6.37; p = 0.019) were significantly associated with HCC occurrence after DAA therapy. A high or low risk of HCC after DAA therapy could be distinguished by the combination of age and baseline Ang2 level. The cumulative incidences of de-novo HCC at two and four years were 0.8% and 3.8% in the low-risk group and 22.6% and 27.1% in the high-risk group, respectively. Baseline Ang2 level ≥ 402 pg/mL was significantly associated with HCC recurrence in patients who achieved sustained virological response with DAAs (HR: 3.68). In conclusion, serum Ang2 levels can predict HCC occurrence and recurrence after successful HCV eradication by DAAs.

Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation-related hepatitis.
Goki Suda, Masaru Baba, Yoshiya Yamamoto, Takuya Sho, Koji Ogawa, Megumi Kimura, Shunichi Hosoda, Sonoe Yoshida, Akinori Kubo, Qingjie Fu, Zijian Yang, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Tomoe Kobayashi, Izumi Tsunematsu, Naoya Sakamoto
Journal of medical virology, 95, 2, e28452, 2023年01月04日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing HBV reactivation has yet been reported. METHODS: This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF. RESULTS: Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months. CONCLUSION: TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis. This article is protected by copyright. All rights reserved.

Coexistence of muscle atrophy and high subcutaneous adipose tissue radiodensity predicts poor prognosis in hepatocellular carcinoma.
Masatsugu Ohara, Goki Suda, Risako Kohya, Takashi Sasaki, Tomoka Yoda, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Osamu Maehara, Shunsuke Ohnishi, Yoshimasa Tokuchi, Takashi Kitagataya, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto
Frontiers in nutrition, 10, 1272728, 1272728, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: We aimed to assess the prognostic implications of muscle atrophy and high subcutaneous adipose tissue (SAT) radiodensity in patients with hepatocellular carcinoma (HCC). METHODS: In this retrospective study, muscle atrophy was assessed using the psoas muscle index (PMI) obtained from computed tomography. SAT radiodensity was evaluated based on radiodensity measurements. Survival and multivariate analyses were performed to identify factors associated with prognosis. The impact of muscle atrophy and high SAT radiodensity on prognosis was determined through survival analysis. RESULTS: A total of 201 patients (median age: 71 years; 76.6% male) with HCC were included. Liver cirrhosis was observed in 72.6% of patients, and the predominant Child-Pugh grade was A (77.1%). A total of 33.3% of patients exhibited muscle atrophy based on PMI values, whereas 12.9% had high SAT radiodensity. Kaplan-Meier survival analysis demonstrated that patients with muscle atrophy had significantly poorer prognosis than those without muscle atrophy. Patients with high SAT radiodensity had a significantly worse prognosis than those without it. Muscle atrophy, high SAT radiodensity, the Barcelona Clinic Liver Cancer class B, C, or D, and Child-Pugh score ≥ 6 were significantly associated with overall survival. Further classification of patients into four groups based on the presence or absence of muscle atrophy and high SAT radiodensity revealed that patients with both muscle atrophy and high SAT radiodensity had the poorest prognosis. CONCLUSION: Muscle atrophy and high SAT radiodensity are significantly associated with poor prognosis in patients with HCC. Identifying this high-risk subgroup may facilitate the implementation of targeted interventions, including nutritional therapy and exercise, to potentially improve clinical outcomes.

Serum IL-1β predicts de novo hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C, not during anti-cancer/immunosuppressive therapy
Naoki Kawagishi, Goki Suda, Ryotaro Sakamori, Takeshi Matsui, Masahiro Onozawa, Zijian Yang, Sonoe Yoshida, Masatsugu Ohara, Megumi Kimura, Akinori Kubo, Osamu Maehara, Qingjie Fu, Shunichi Hosoda, Yoshimasa Tokuchi, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Kenichi Morikawa, Mitsuteru Natsuizaka, Koji Ogawa, Hajime Sakai, Shunsuke Ohnishi, Masaru Baba, Tetsuo Takehara, Naoya Sakamoto
Scientific Reports, 12, 1, Springer Science and Business Media LLC, 2022年10月07日
研究論文（学術雑誌）, Abstract

De novo hepatitis B virus (HBV) reactivation occurs during direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-infected patients with resolved HBV infection. We evaluated the predictive factors, mechanical insight, and differences of cytokine levels during anti-cancer/immunosuppressive and DAA. Eleven, 35, and 19 HCV-infected patients with previous HBV infection with HBV reactivation during DAA treatment, previous HBV infection without HBV reactivation during DAA treatment, and without HBV infection resolution receiving DAA treatment, respectively, were enrolled. Clinical data and baseline cytokine levels were analyzed. Low baseline serum interleukin (IL)-1β levels predicted de novo HBV reactivation during DAA treatment (odds ratio: 47.6, 95% confidence interval: 6.94–333.3). HCV-infected patients with the IL-1β gene single nucleotide polymorphism rs16944 AA allele had significantly higher IL-1β levels; no HCV-infected patient with the IL-1β AA allele experienced HBV reactivation during DAA treatment. Compared to HCV-infected patients with HBV infection resolution, non-HCV infected patients with or without HBV reactivation during anti-cancer/immunosuppressive therapy or bone marrow transplantation had remarkably lower baseline IL-1β levels. Low IL-1β levels were not associated with HBV reactivation. IL-1β levels before DAA for HCV-infected patients with resolved HBV infection could predict HBV reactivation during DAA treatment.

Efficacy and Effect on Liver Functional Reserve of Atezolizumab and Bevacizumab for Unresectable Hepatocellular Carcinoma in Patients Who Do Not Meet Eligibility Criteria of IMbrave150
Takuya Sho, Goki Suda, Yoshiya Yamamoto, Ken Furuya, Masaru Baba, Koji Ogawa, Akinori Kubo, Yoshimasa Tokuchi, Qingjie Fu, Zijian Yang, Megumi Kimura, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Tomofumi Takagi, Jun Ito, Tomoe Kobayashi, Takuto Miyagishima, Naoya Sakamoto
Cancers, 14, 16, 3938, 3938, MDPI AG, 2022年08月15日
研究論文（学術雑誌）, The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 × 109/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 ± 0.43 vs. −2.18 ± 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed.

Small-molecule inhibitor cocktail promotes the proliferation of pre-existing liver progenitor cells.
Qingjie Fu, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto
Stem cell reports, 17, 7, 1589, 1603, 2022年06月13日, ［国際誌］
英語, 研究論文（学術雑誌）, A recent study showed that a cocktail of three small molecules, Y-27632, A83-01, and CHIR99021 (YAC), converts mature hepatocytes (MHs) into proliferative bipotent cells that can be induced into MHs and cholangiocytes in rats. However, when we reproduced these experiments, it was found that bipotent cells may be derived from resident liver progenitor cells (LPCs), whose proliferative activity was promoted by YAC. A simple and efficient sorting scheme was also developed in this study to harvest high-purity and high-yield LPCs. The inducible bipotency of purified LPCs was verified; in addition, they were found to spontaneously differentiate into hepatocytes and cholangiocytes due to changes in proliferative status even without induction. Moreover, during the differentiation process, some hepatocytes spontaneously reconverted to LPCs under certain conditions, such as the release of contact inhibition. These findings may improve our understanding of LPCs and provide a cell source for regenerative medicine.

The potential of soluble CD14 in discriminating nonalcoholic steatohepatitis from nonalcoholic fatty liver disease.
Akihisa Nakamura, Koji Yamamoto, Rei Takeda, Ren Yamada, Akinori Kubo, Kenichi Morikawa, Sayaka Ando, Tomoe Shimazaki, Takaaki Izumi, Machiko Umemura, Takashi Kitagataya, Taku Shigesawa, Kazuharu Suzuki, Megumi Kimura, Masato Nakai, Takuya Sho, Goki Suda, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Toshiro Sugiyama, Hiroshi Takeda, Naoya Sakamoto
Hepatology research : the official journal of the Japan Society of Hepatology, 52, 6, 508, 521, 2022年06月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIMS: Although various noninvasive markers and prediction formulas for nonalcoholic steatohepatitis (NASH) have been reported, they are of value only in the diagnosis of the advanced fibrosis stage of NASH. In this study, we evaluated soluble CD14 (sCD14) as a diagnostic marker for discriminating NASH from nonalcoholic fatty liver disease (NAFLD) using an animal model and clinical specimens. METHODS: Serum sCD14 levels were measured in samples derived from mice with diet-induced NASH and patients using an enzyme-linked immunosorbent assay. Our cohort enrolled 126 patients with liver needle biopsy-proven NAFLD. RESULTS: The intestinal defense mechanism in NASH model mice was altered as a consequence of the unique gut environment. Elevated serum levels of sCD14 were observed in mice with diet-induced NASH, and the condition of the liver was exacerbated as a result of exposure to gut-derived endotoxin. We confirmed that the serum sCD14 levels in NAFL patients significantly differed from those in NASH patients. The area under the curve for distinguishing between NAFL and NASH was 0.891. Moreover, we found that serum sCD14 levels were weakly correlated with the inflammation grade based on the NAFLD activity score (NAS), the grade of fibrosis according to the Brunt fibrosis classification, and a positive correlation with the grade of ballooning based on NAS in patients with NAFLD. CONCLUSION: sCD14 could be a useful pathophysiological marker and diagnostic adjunct distinguishing NASH from NAFLD. The use of sCD14 may allow the screening and identification of high-risk groups for NASH development and support early therapeutic interventions.

Overestimated Renal Function in Patients with Liver Cirrhosis Predicts Poor Prognosis.
Sonoe Yoshida, Goki Suda, Masatsugu Ohara, Megumi Kimura, Zijian Yang, Osamu Maehara, Qingjie Fu, Shunichi Hosoda, Kubo Akinori, Yoshimasa Tokuchi, Ren Yamada, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
Hepatology research : the official journal of the Japan Society of Hepatology, 52, 7, 603, 613, 2022年03月30日, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: A high prevalence of overestimated renal function in patients with liver cirrhosis (LC) has been reported; nonetheless, its impact on prognosis remains unclear. We aimed to evaluate the impact of overestimated renal function on prognosis in patients with LC. METHODS: An overestimated renal function was defined as a >20% increase in the creatinine-based estimated glomerular filtration rate (eGFR), compared with cystatin C-based eGFR. LC patients with conserved serum, who were evaluated for muscle atrophy and had proper clinical information were included, and their prognostic factors were analyzed. RESULTS: A total of 215 consecutive patients with LC were included. The prevalence of overestimated renal function was 29.8% (64/215). Kaplan-Meier survival analysis revealed that patients with overestimated renal function had a poorer prognosis than those without overestimated renal function (hazard ratio [HR]: 2.217 95% confidence interval [CI]: 1.290-3.810; P=0.001). Subgroup analysis showed that overestimated renal function was a significant prognostic factor, irrespective of sex and the presence of hepatocellular carcinoma (HCC). Multivariate Cox regression analyses revealed that overestimated renal function was a significant and independent factor predictive of poor prognosis in the entire cohort (HR: 2.050; 95% CI: 1.041-4.037; P=0.038) and in subgroups classified by Child-Pugh class A (HR: 2.131; 95% CI: 1.019-4.458; P=0.044), Model for End-Stage Liver Disease score <9 (HR: 2.303; 95% CI: 1.038-5.109; P=0.04), and presence of HCC (HR: 2.290; 95% CI: 1.128-4.651; P=0.022). CONCLUSION: Overestimated renal function is a significant and independent prognostic factor in patients with LC. This article is protected by copyright. All rights reserved.

Changes in Serum Growth Factors during Lenvatinib Predict the Post Progressive Survival in Patients with Unresectable Hepatocellular Carcinoma.
Zijian Yang, Goki Suda, Osamu Maehara, Masatsugu Ohara, Sonoe Yoshida, Shunichi Hosoda, Megumi Kimura, Akinori Kubo, Yoshimasa Tokuchi, Qingjie Fu, Ren Yamada, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
Cancers, 14, 1, 2022年01月04日, ［国際誌］
英語, 研究論文（学術雑誌）, Serum growth factor changes and their effect on prognosis during lenvatinib for unresectable hepatocellular carcinoma (HCC) remain underexplored. The sequential changes in serum growth factors during lenvatinib for unresectable HCC were evaluated in 58 patients using complete clinical data, and preserved serum was used to investigate changes in FGF-19, ANG-2, HGF, VEGF, and EGF. Patients with a complete response (CR), partial response (PR), and stable disease (SD) were evaluated for growth factor changes between the best response and progressive disease (PD) points, classified based on these changes, and evaluated by post progression survival (PPS). A total of 8, 24, 18, and 8 patients showed CR, PR, SD, and PD, respectively. Multivariate analysis revealed that age, relative dose intensity, and baseline ANG-2 were significantly associated with treatment response. Growth factor changes between the best response and PD points revealed that patients could be classified into four groups based on the EGF, ANG-2, and HGF changes. Although patient characteristics at baseline and PD, their response to lenvatinib, and PFS were similar among those groups, patients with an increase in all growth factors had significantly shorter PPS (median PPS was 553, 323, and 316 versus 173 days in groups 1-4 p = 0.032). We revealed that the evaluation of the changes in growth factors during lenvatinib could predict PPS.

Possible correlation between increased serum free carnitine levels and increased skeletal muscle mass following HCV eradication by direct acting antivirals
Yoshimasa Tokuchi, Goki Suda, Megumi Kimura, Osamu Maehara, Takashi Kitagataya, Akinori Kubo, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Masatsugu Ohara, Ren Yamada, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
Scientific Reports, 11, 1, Springer Science and Business Media LLC, 2021年12月
研究論文（学術雑誌）, We aimed to evaluate factors associated with changes in skeletal muscle mass in hepatitis C virus (HCV)-infected patients after treatment with direct-acting antivirals (DAAs). Consecutive HCV-infected patients after treatment with DAA were recruited into the study. Patients who achieved sustained virological response (SVR); and had complete clinical information, preserved serum samples at baseline and SVR48, and skeletal muscle mass evaluations based on the psoas muscle mass index (PMI) on computed tomography at baseline and ≥ 12 months were included. Altogether, 70.7% of patients (41/58) showed increased PMI after DAA therapy, and mean relative PMI was significantly higher after DAA therapy than at baseline. There were no significant associations between baseline clinical factors routinely examined in clinical practice and increased PMI. Among factors reported to be associated with skeletal muscle loss in patients with chronic liver disease, serum zinc levels and total and free carnitine levels increased significantly after DAA therapy and only changes in serum free carnitine levels were significantly associated with an increased PMI (r = 0305, P = 0.020). In conclusion, increased skeletal muscle mass after successful HCV eradication by DAAs was significantly associated with increased serum-free carnitine levels. l-carnitine supplementation may be beneficial in patients with low skeletal muscle mass after DAA.

Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria.
Takuya Sho, Goki Suda, Koji Ogawa, Megumi Kimura, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Taku Shigesawa, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Takuto Miyagishima, Naoya Sakamoto
Hepatology research : the official journal of the Japan Society of Hepatology, 51, 9, 979, 989, 2021年09月, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real-world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria. METHODS: In this multicenter study, patients with unresectable HCC treated with atezolizumab plus bevacizumab between October 2020 and May 2021 were screened. In patients who did not meet IMbrave150 eligibility criteria, treatment responses and safety at 6 and 12 weeks were evaluated. RESULTS: Atezolizumab plus bevacizumab was initiated in 64 patients, including 46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of these patients had a history of systemic therapy (44/46). The objective response rate and disease control rate observed using Response Evaluation Criteria in Solid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, respectively; these rates were similar between patients who met and did not meet the IMbrave150 criteria. Ten patients experienced progressive disease (PD) at 6 weeks. Portal vein tumor thrombosis was significantly associated with PD (p = 0.039); none of the 15 patients with hepatitis B virus-related HCC experienced PD (p = 0.050). The most common adverse events of grade 3 or higher were aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile was similar between patients who met and did not meet the IMbrave150 criteria. CONCLUSION: Most patients treated with atezolizumab plus bevacizumab did not meet the IMbrave150 criteria; however, the combination therapy showed good safety and efficacy at the early treatment phase.

The TLR4–TRIF–type 1 IFN–IFN-γ pathway is crucial for gastric MALT lymphoma formation after Helicobacter suis infection
Koji Yamamoto, Yasuyuki Kondo, Shunsuke Ohnishi, Masaru Yoshida, Toshiro Sugiyama, Naoya Sakamoto
iScience, 24, 9, 103064, 103064, Elsevier {BV}, 2021年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Helicobacter suis, a zoonotic infection-related bacterium, can induce gastric mucosa-associated lymphoid tissue (MALT) lymphoma in humans and animals. Recently, we reported that the formation of gastric MALT lymphoma after H. suis infection is induced by interferon (IFN)-γ activation. Here, we revealed that activation of the Toll-like receptor (TLR) 4-Toll/IL-1 receptor domain-containing adapter-inducing interferon-β (TRIF) pathway after H. suis infection is associated with the production of type 1 IFNs (IFN-α, IFN-β) by gastric epithelial cells. Additionally, these type 1 IFNs interact with type 1 IFN receptors on gastric B cells, facilitating the secretion of IFN-γ and the activation of which is enhanced by positive feedback regulation in B cells. These results suggest that the TLR4-TRIF-type 1 IFN-IFN-γ pathway is crucial in the development of gastric MALT lymphoma after H. suis infection and may, therefore, represent a therapeutic target for the prevention of this condition.

Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI
Akinori Kubo, Goki Suda, Megumi Kimura, Osamu Maehara, Yoshimasa Tokuchi, Takashi Kitagataya, Masatsugu Ohara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
Cancers, 13, 14, 2021年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, In hepatocellular carcinoma (HCC), CTNNB-1 mutations, which cause resistance to immune checkpoint inhibitors, are associated with HCC with iso-high intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in resectable HCC; however, analyses on unresectable HCC are lacking. This study analyzed the prevalence, characteristics, response to lenvatinib, and CTNNB-1 mutation frequency in unresectable HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI. In 52 patients with unresectable HCC treated with lenvatinib, the prevalence of iso-high intensity in the hepatobiliary phase of EOB-MRI was 13%. All patients had multiple HCCs, and 3 patients had multiple HCCs with iso-high intensity in the hepatobiliary phase of EOB-MRI. Lenvatinib response to progression-free survival and overall survival were similar between patients with or without iso-high intensity in the hepatobiliary phase of EOB-MRI. Seven patients (three and four patients who had unresectable HCC with or without iso-high intensity in the hepatobiliary phase of EOB-MRI, respectively) underwent genetic analyses. Among these, two (67%, 2/3) who had HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI carried a CTNNB-1 mutation, while all four patients who had HCC without iso-high intensity in the hepatobiliary phase of EOB-MRI did not carry the CTNNB-1 mutation. This study's findings have clinical implications for the detection and treatment of HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI.

Frequency and Characteristics of Overestimated Renal Function in Japanese Patients with Chronic Liver Disease and Its Relation to Sarcopenia
Sonoe Yoshida, Goki Suda, Masatsugu Ohara, QingJie Fu, Zijian Yang, Shunichi Hosoda, Megumi Kimura, Kubo Akinori, Yoshimasa Tokuchi, Ren Yamada, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Osamu Maehara, Shunsuke Ohnishi, Naoya Sakamoto
Nutrients, 13, 7, 2021年07月, ［国際誌］
英語, 研究論文（学術雑誌）, Renal dysfunction and sarcopenia are important prognostic factors in patients with chronic liver disease (CLD). Muscle atrophy can cause the overestimation of renal function based on serum creatinine. However, the frequency of overestimated renal function in Japanese patients with CLD and its relationship with sarcopenia are unclear. In present study, we evaluated the frequency of overestimated renal function, defined as a >20% higher eGFR using creatinine than using cystatin C, in 307 patients with CLD as well as its relationship with indicators of sarcopenia. In total, 24.8% of patients had overestimated renal function. In a multivariate regression analysis, liver cirrhosis (p = 0.004) and psoas muscle mass index (p = 0.049) were significantly associated with overestimated renal function. Loss of skeletal muscle mass was significantly more frequent in both male and female patients with overestimated renal function than without. In males, the loss of muscle strength and rate of sarcopenia, defined as loss of muscle mass and strength, were significantly higher in patients with than without overestimated renal function. The high frequency of overestimated renal function in Japanese patients suggests that indicators of renal function should be carefully considered; furthermore, monitoring and interventions for both renal function and sarcopenia are needed in patients with CLD.

FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma.
Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Taku Shigesawa, Gouki Kanbe, Megumi Kimura, Masaya Sugiyama, Masashi Mizokami, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Naoto Okubo, Shunsuke Ohnishi, Hiroshi Takeda, Naoya Sakamoto
Cancer biology & therapy, 22, 5-6, 372, 380, 2021年06月03日, ［国際誌］
英語, 研究論文（学術雑誌）, Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important for signaling to maintain cancer stem-like cells (CSCs) in esophageal squamous cell carcinoma (ESCC). However, which FGF receptor, 1, 2, 3, 4, and L1, is essential or whether FGFRs have distinct different roles in ESCC-CSCs is still in question. This study shows that FGFR2, particularly the IIIb isoform, is highly expressed in non-CSCs. Non-CSCs have an epithelial phenotype, and such cells are more differentiated in ESCC. Further, FGFR2 induces keratinocyte differentiation through AKT but not MAPK signaling and diminishes CSC populations. Conversely, knockdown of FGFR2 induces epithelial-mesenchymal transition (EMT) and enriches CSC populations in ESCC. Finally, data analysis using The Cancer Genome Atlas (TCGA) dataset shows that expression of FGFR2 significantly correlated with cancer cell differentiation in clinical ESCC samples. The present study shows that each FGFR has a distinct role and FGFR2-AKT signaling is a key driver of keratinocyte differentiation in ESCC. Activation of FGFR2-AKT signaling could be a future therapeutic option targeting CSC in ESCC.

Topical Application of Conditioned Medium from Hypoxically Cultured Amnion-Derived Mesenchymal Stem Cells Promotes Wound Healing in Diabetic Mice.
Hiroko Takahashi, Shunsuke Ohnishi, Yuhei Yamamoto, Toshihiko Hayashi, Naoki Murao, Masayuki Osawa, Taku Maeda, Kosuke Ishikawa, Naoya Sakamoto, Emi Funayama
Plastic and reconstructive surgery, 147, 6, 1342, 1352, 2021年06月01日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Mesenchymal stem cells or their conditioned medium improve chronic wound healing, and their effect is enhanced by hypoxia. Diabetic foot ulcers are chronic wounds characterized by abnormal and delayed healing, which frequently require amputation. The authors evaluated the effect of topical application of conditioned medium from hypoxically cultured amnion-derived mesenchymal stem cells on wound healing in diabetic mice. METHODS: Amnion-derived mesenchymal stem cells were cultured under 21% oxygen to prepare normoxic conditioned medium and under 1% oxygen to prepare hypoxic conditioned medium. Hydrogels containing standard medium, normoxic conditioned medium, or hypoxic conditioned medium were topically applied to excisional wounds of mice with streptozotocin-induced diabetes. Ulcer tissues were harvested on day 9; immunohistochemical and quantitative polymerase chain reaction analyses were performed to analyze angiogenesis, inflammatory cell infiltration, and expression levels of inflammation-related genes. RESULTS: Hypoxic conditioned medium significantly enhanced wound closure, increased capillary density and epithelization, and reduced macrophage infiltration. It also tended to reduce the infiltration of neutrophils and enhance the infiltration of regulatory T cells; it showed a tendency to downregulate the expression of the inflammation-related genes interleukin-1β, interleukin-6, chemokine ligand 1, and chemokine ligand 2. Normoxic conditioned medium exhibited similar effects, although they were of lesser magnitude than those of hypoxic conditioned medium. CONCLUSIONS: Hydrogels containing hypoxically cultured, amnion-derived mesenchymal stem cell conditioned medium accelerated wound healing in diabetic mice by enhancing angiogenesis, accelerating epithelization, and suppressing inflammation. Therefore, topical application of amnion mesenchymal stem cell-derived hypoxic conditioned medium could be a novel treatment for diabetic foot ulcers.

A protocol for efficacy of rikkunshito on chemotherapy-induced nausea and vomiting in patients with uterine corpus or cervical cancer treated with cisplatin-based regimen -placebo-controlled, double-blind, randomized confirmatory study (efficacy of rikkunshito on chemotherapy-induced nausea and vomiting)
Shunsuke Ohnishi, Keisuke Ariyoshi, Shunsuke Oyamada, Kota Kihara, Yosuke Konno, Hidemichi Watari
Medicine: Case Reports and Study Protocols, 2, 6, e0109, e0109, Ovid Technologies (Wolters Kluwer Health), 2021年06月
研究論文（学術雑誌）

Experiment on endoscopic balloon dilation for esophageal stenosis after endoscopic submucosal dissection in pigs
Sayoko Kinowaki, Yuichi Shimizu, Masayoshi Ono, Yang ZiJian, Ikko Tanaka, Yoshihiko Shimoda, Masaki Inoue, Marin Ishikawa, Keiko Yamamoto, Shoko Ono, Shunsuke Ohnishi, Naoya Sakamoto
Journal of Gastroenterology, 56, 6, 527, 536, Springer Science and Business Media LLC, 2021年06月
研究論文（学術雑誌）

Comprehensive Glycomic Approach Reveals Novel Low-Molecular-Weight Blood Group-Specific Glycans in Serum and Cerebrospinal Fluid
Jun-ichi Furukawa, Hisatoshi Hanamatsu, Ikuko Yokota, Megumi Hirayama, Tomohiro Ando, Hiroyuki Kobayashi, Shunsuke Ohnishi, Nobuaki Miura, Kazue Okada, Shota Sakai, Kohei Yuyama, Yasuyuki Igarashi, Makoto Ito, Yasuro Shinohara, Naoya Sakamoto
Journal of Proteome Research, American Chemical Society (ACS), 2021年03月10日
研究論文（学術雑誌）

Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling.
Taku Shigesawa, Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Megumi Kimura, Tomoe Shimazaki, Koji Yamamoto, Ren Yamada, Takashi Kitagataya, Akihisa Nakamura, Kazuharu Suzuki, Masatsugu Ohara, Naoki Kawagishi, Machiko Umemura, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Masaya Sugiyama, Masashi Mizokami, Hiroshi Takeda, Naoya Sakamoto
Carcinogenesis, 42, 1, 58, 69, 2021年02月11日, ［国際誌］
英語, 研究論文（学術雑誌）, In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1-4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1-3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1-3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.

Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection.
Kazuharu Suzuki, Goki Suda, Yoshiya Yamamoto, Ken Furuya, Masaru Baba, Akinobu Nakamura, Hideaki Miyoshi, Megumi Kimura, Osamu Maehara, Ren Yamada, Takashi Kitagataya, Koji Yamamoto, Taku Shigesawa, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
Journal of gastroenterology, 56, 2, 168, 180, 2021年02月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Entecavir and tenofovir-disoproxil-fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. METHODS: A retrospective study was performed on HBV patients administered entecavir or tenofovir-disoproxil-fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6-12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir-disoproxil-fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. RESULTS: Administration of tenofovir-disoproxil-fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir-disoproxil-fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir-disoproxil-fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir-disoproxil-fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir-disoproxil-fumarate on CD36. CONCLUSIONS: Tenofovir-disoproxil-fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.
Takashi Kitagataya, Goki Suda, Kazunori Nagashima, Takehiko Katsurada, Koji Yamamoto, Megumi Kimura, Osamu Maehara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Yoshito Komatsu, Hiroo Hata, Satoshi Takeuchi, Takashige Abe, Jun Sakakibara-Konishi, Takanori Teshima, Akihiro Homma, Naoya Sakamoto
Journal of gastroenterology and hepatology, 35, 10, 1782, 1788, 2020年10月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

生体ブタ全周性食道ESD施行後のバルーン拡張時の病理組織学的検討　　　　　　　　　　　　　　　
木脇 佐代子, 清水 勇一, 大西 俊介, 大野 正芳, 楊 子健, 霜田 佳彦, 井上 雅貴, 田中 一光, 石川 麻倫, 山本 桂子, 小野 尚子, 坂本 直哉
Gastroenterological Endoscopy, 62, Suppl.1, 1320, 1320, (一社)日本消化器内視鏡学会, 2020年08月
日本語

Oleoylethanolamide Ameliorates Dextran Sulfate Sodium-Induced Colitis in Rats
Shinsuke Otagiri, Shunsuke Ohnishi, Masatsugu Ohara, Qingjie Fu, Koji Yamamoto, Keiko Yamamoto, Takehiko Katsurada, Naoya Sakamoto
FRONTIERS IN PHARMACOLOGY, 11, FRONTIERS MEDIA SA, 2020年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Oleoylethanolamide (OEA) is an endogenous fatty acid ethanolamide known for its anti-inflammatory effects and its influence on gut microbiota composition; however, the effects of OEA in inflammatory bowel disease (IBD) remain unknown. Duringin vitroexperiments, OEA downregulated the expression of tumor necrosis factor (TNF)-alpha and reduced phosphorylation of inhibitor of kappa (I kappa) B alpha induced by lipopolysaccharide in human embryonic kidney cells. Moreover, OEA downregulated the expression of interleukin (IL)-8 and IL-1 beta and inhibited the phosphorylation of I kappa B alpha and p65 induced by TNF-alpha in human enterocytes (Caco-2). The effect of OEA in reducing the expression of IL-8 was blocked by the peroxisome proliferator-activated receptor (PPAR)-alpha antagonist. Duringin vivoexperiments on rats, colitis was induced by the oral administration of 8% dextran sulfate sodium from day 0 through day 5, and OEA (20 mg/kg) was intraperitoneally injected once a day from day 0 for 6 days. OEA administration significantly ameliorated the reduction in body weight, the increase in disease activity index score, and the shortening of colon length. In rectums, OEA administration reduced the infiltration of macrophages and neutrophils and tended to reduce the histological score and the expression of inflammatory cytokines. Administration of OEA produced significant improvement in a colitis model, possibly by inhibiting the nuclear factor kappa B signaling pathway through PPAR-alpha receptors. OEA could be a potential new treatment for IBD.

OLEOYLETHANOLAMIDE AMELIORATES DEXTRAN SULFATE SODIUM-INDUCED COLITIS IN RATS
Shinsuke Otagiri, Shunsuke Ohnishi, Masatsugu Ohara, Qingjie Fu, Koji Yamamoto, Takehiko Katsurada, Naoya Sakamoto
GASTROENTEROLOGY, 158, 6, S275, S275, W B SAUNDERS CO-ELSEVIER INC, 2020年05月
英語, 0

Detection of early adenocarcinoma of the esophagogastric junction by spraying an enzyme-activatable fluorescent probe targeting Dipeptidyl peptidase-IV
Keikokw Yamamoto, Shunsuke Ohnishi, Takeshi Mizushima, Junichi Kodaira, Masayoshi Ono, Yutaka Hatanaka, Kanako C. Hatanaka, Yugo Kuriki, Mako Kamiya, Nobuyuki Ehira, Keisuke Shinada, Hiroaki Takahashi, Yuichi Shimizu, Yasuteru Urano, Naoya Sakamoto
BMC CANCER, 20, 1, BMC, 2020年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Background It is still difficult to detect and diagnose early adenocarcinoma of the esophagogastric junction (EGJ) using conventional endoscopy or image-enhanced endoscopy. A glutamylprolyl hydroxymethyl rhodamine green (EP-HMRG) fluorescent probe that can be enzymatically activated to become fluorescent after the cleavage of a dipeptidyl peptidase (DPP)-IV-specific sequence has been developed and is reported to be useful for the detection of squamous cell carcinoma of the head and neck, and esophagus; however, there is a lack of studies that focuses on detecting EGJ adenocarcinoma by fluorescence molecular imaging. Therefore, we investigated the visualization of early EGJ adenocarcinoma by applying EP-HMRG and using clinical samples resected by endoscopic submucosal dissection (ESD). Methods Fluorescence imaging with EP-HMRG was performed in 21 clinical samples resected by ESD, and the fluorescence intensity of the tumor and non-tumor regions of interest was prospectively measured. Immunohistochemistry was also performed to determine the expression of DPP-IV. Results Fluorescence imaging of the clinical samples showed that the tumor lesions were visualized within a few minutes after the application of EP-HMRG, with a sensitivity, specificity, and accuracy of 85.7, 85.7, and 85.7%, respectively. However, tumors with a background of intestinal metaplasia did not have a sufficient contrast-to-background ratio since complete intestinal metaplasia also expresses DPP-IV. Immunohistochemistry measurements revealed that all fluorescent tumor lesions expressed DPP-IV. Conclusions Fluorescence imaging with EP-HMRG could be useful for the detection of early EGJ adenocarcinoma lesions that do not have a background of intestinal metaplasia.

Gastrointestinal: Endoscopic balloon dilations for an intestinal stricture in a patient with X‐linked inhibitor of apoptosis deficiency
S Otagiri, R Sugiura, T Katsurada, K Yamanashi, K Nagashima, J Sugita, S Ohnishi, N Sakamoto
Journal of Gastroenterology and Hepatology, Wiley, 2019年11月07日, ［査読有り］
研究論文（学術雑誌）

Safety and efficacy of amnion-derived mesenchymal stem cells (AM01) in patients with steroid-refractory acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: a study protocol for a phase I/II Japanese trial
Kenichi Yamahara, Akiko Hamada, Toshihiro Soma, Rika Okamoto, Masaya Okada, Satoshi Yoshihara, Kyoko Yoshihara, Kazuhiro Ikegame, Hiroya Tamaki, Katsuji Kaida, Takayuki Inoue, Yuko Ohsugi, Hiroki Nishikawa, Hiroshi Hayashi, Yoichi M. Ito, Hiroaki Iijima, Shunsuke Ohnishi, Daigo Hashimoto, Toshiyuki Isoe, Takanori Teshima, Hiroyasu Ogawa, Norihiro Sato, Yoshihiro Fujimori
BMJ OPEN, 9, 7, e026403, BMJ PUBLISHING GROUP, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Introduction Regenerative medicine and cell therapies have been gaining much attention among clinicians. Therapeutic infusion of mesenchymal stromal cells (MSCs) is now a leading investigational strategy for the treatment of acute graft-versus-host disease (aGVHD). Bone marrow MSCs are approved for manufacture and marketing as a cell therapy for aGVHD. Our non-clinical studies confirmed that human amnion-derived MSCs had immunomodulatory activity equal to or higher than that of human bone marrow MSCs. This study will aim to evaluate the safety and efficacy of amnion-derived MSCs (AM01) in patients with steroid-refractory aGVHD.Methods and analysis This study will be a multicentre, single-arm, open-label trial (an interventional study). This clinical trial will begin with a low-dose group, and when safety has been confirmed in at least three cases in the low-dose group, treatment will begin for the high-dose group, for which the safety will also be verified. The primary endpoint is to assess the safety of intravenous infusion therapy of AM01 within 24 hours after intravenous infusion of AM01. The secondary endpoint is to explore the efficacy of intravenous infusion therapy with AM01.Ethics and dissemination The institutional review boards of all participating hospitals approved this study protocol (latest V3.3.0, 3 August 2018). Final data will be publicly announced. A report releasing the study results will be submitted for publication to an appropriate peer-reviewed journal.

FLUORESCENCE IMAGING OF EARLY ADENOCARCINOMA OF THE ESOPHAGOGASTRIC JUNCTION BY TOPICALLY SPRAYING PROBE TARGETING DIPEPTIDYLPEPTIDASE-IV
Keiko Yamamoto, Shunsuke Ohnishi, Takeshi Mizushima, Junichi Kodaira, Masayoshi Ono, Yutaka Hatanaka, Kanako Hatanaka, Nobuyuki Ehira, Keisuke Shinada, Hiroaki Takahashi, Yugo Kuriki, Mako Kamiya, Yuichi Shimizu, Yasuteru Urano, Naoya Sakamoto
GASTROINTESTINAL ENDOSCOPY, 89, 6, AB624, AB624, MOSBY-ELSEVIER, 2019年06月, ［査読有り］
英語

Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines.
Maehara O, Ohnishi S, Asano A, Suda G, Natsuizaka M, Nakagawa K, Kobayashi M, Sakamoto N, Takeda H
Neoplasia (New York, N.Y.), 21, 6, 545, 556, 2019年06月, ［査読有り］

Evaluation of amnion-derived mesenchymal stem cells for treatment-resistant moderate Crohn's disease: study protocol for a phase I/II, dual-centre, open-label, uncontrolled, dose-response trial
Shinsuke Otagiri, Shunsuke Ohnishi, Arisa Miura, Hiroshi Hayashi, Izumi Kumagai, Yoichi M. Ito, Takehiko Katsurada, Shiro Nakamura, Rika Okamoto, Kenichi Yamahara, Kyu Yong Cho, Toshiyuki Isoe, Norihiro Sato, Naoya Sakamoto
BMJ OPEN GASTROENTEROLOGY, 5, 1, e000206, BMJ PUBLISHING GROUP, 2018年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction The medical treatment options for patients with Crohn's disease (CD) are limited and patients resistant to those therapies are left requiring surgical operations that usually only achieve some symptomatic relief. Mesenchymal stem cells (MSC) have been shown to be effective for the treatment of CD, and we have demonstrated in animal experiments that human amnion-derived MSCs (AMSC) are a potential new therapeutic strategy. Therefore, we designed this study to investigate the safety and efficacy of AMSCs in patients with treatment-resistant CD.Methods and analysis This is the protocol for an ongoing phase I/II, dual-centre, open-label, uncontrolled, dose-response study. The estimated enrolment is 6-12 patients with treatment-resistant, moderate CD. A dose of 1.0 x 10(6) cells/kg will be administered intravenously in the low-dose group at days 0 and 7. After confirming the safety of low-dose administration, a dose of 4.0 x 10(6) cells/ kg will be administered intravenously in the high-dose group on days 0 and 7. The primary endpoint will measure the occurrence of adverse events related to acute infusion toxicity, and secondary endpoints will include long-term adverse events and efficacy of AMSC administration.Ethics and dissemination The Institutional Review Board of Hokkaido University Hospital approved this study protocol (approval number H29-6). A report releasing study results will be submitted to an appropriate journal.Discussion This study is the first to investigate the safety and efficacy of AMSC use for CD treatment. Our results will advance studies on more efficient and convenient methods to overcome the limits of available CD treatments.

Preventive effect of mesenchymal stem cell culture supernatant on luminal stricture after endoscopic submucosal dissection in the rectum of pigs
Momoko Tsuda, Shunsuke Ohnishi, Takeshi Mizushima, Hidetaka Hosono, Kenichi Yamahara, Marin Ishikawa, Satoshi Abiko, Takehiko Katsurada, Yuichi Shimizu, Naoya Sakamoto
ENDOSCOPY, 50, 10, 1001, 1016, GEORG THIEME VERLAG KG, 2018年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Background Mesenchymal stem cells (MSCs) are valuable in regenerative medicine, and MSC culture supernatant (MSC-CS) reportedly inhibits inflammation and fibrosis. We investigated whether colorectal luminal stricture develops after circumferential endoscopic submucosal dissection (ESD) in the colorectum, and whether the development of luminal stricture could be prevented by using MSC-CS enema.Methods In the first experiment, we performed circumferential ESD in the rectums or distal colons of pigs (n=4 in each group). We sacrificed the pigs on Day22 and measured the degree of luminal stricture. In the second experiment, we performed circumferential ESD in the rectums of pigs and administered an MSC-CS gel or a control gel enema after ESD for 4days. We sacrificed the pigs on Day8 (n=3 in each group) or 22 (n=3 in each group) to measure the degree of luminal stricture, and performed histological analysis.Results Severe luminal stricture was observed in the rectum but not in the distal colon. Moreover, fiber accumulation in the submucosa and hypertrophy of the muscularis propria were observed in the rectum but not in the distal colon. The degree of luminal stricture in the rectum was significantly lower in the MSC-CS group than in the control group.Furthermore, MSC-CS attenuated myofibroblast activation and hypertrophy of the muscularis propria on Day22, and reduced inflammatory cell infiltration on Day8.Conclusions Luminal stricture after ESD developed only in the rectum because of the difference in myofibroblast activation and fiber accumulation. In addition, MSC-CS enema prevented luminal stricture after ESD, possibly by inhibiting the inflammatory reaction and fibrosis.

PREVENTIVE EFFECT OF MESENCHYMAL STEM CELL-CULTURE SUPERNATANT ON LUMINAL STRICTURE AFTER ENDOSCOPIC SUBMUCOSAL DISSECTION IN THE RECTUM OF PIGS
Ohnishi Shunsuke, Tsuda Momoko, Mizushima Takeshi, Ishikawa Marin, Abiko Satoshi, Shimizu Yuichi, Sakamoto Naoya
GASTROINTESTINAL ENDOSCOPY, 87, 6, AB501, 2018年06月, ［査読有り］

Conditioned Medium Obtained from Amnion-Derived Mesenchymal Stem Cell Culture Prevents Activation of Keloid Fibroblasts
Chigusa Sato, Yuhei Yamamoto, Emi Funayama, Hiroshi Furukawa, Akihiko Oyama, Naoki Murao, Hidetaka Hosono, Kazumichi Kawakubo, Naoya Sakamoto, Shunsuke Ohnishi
PLASTIC AND RECONSTRUCTIVE SURGERY, 141, 2, 390, 398, LIPPINCOTT WILLIAMS & WILKINS, 2018年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium obtained from mesenchymal stem cells reportedly inhibits inflammation. Keloids are characterized by abnormal fibrosis, caused by fibroblasts in response to inflammation. In this study, the authors evaluated whether conditioned medium obtained from amnion-derived mesenchymal stem cells suppressed activation of keloid fibroblasts.Methods: Keloid (n = 7), mature (n = 5), and normal (n = 5) fibroblasts were harvested from patients. Fibroblasts were stimulated with transforming growth factor (TGF)-beta, and the effects of conditioned medium obtained from amni-on-derived mesenchymal stem cells on cell proliferation, activation, and expression of extracellular matrix-related genes were analyzed. The effect of concentrating the conditioned medium by ultrafiltration on fibroblast activation was also analyzed.Results: Conditioned medium obtained from amnion-derived mesenchymal stem cells significantly up-regulated proliferation of mature fibroblasts but tended to suppress that of keloid fibroblasts. Conditioned medium obtained from amnion-derived mesenchymal stem cells significantly suppressed the TGF-ss-induced up-regulation of a-smooth muscle actin in keloid and normal fibroblasts and collagen I in keloid fibroblasts, but not in mature fibroblasts. The conditioned medium obtained from amnion-derived mesenchymal stem cells concentrated by ultrafiltration and the filtrate significantly suppressed TGF-ss-induced a-smooth muscle actin expression.Conclusion: Conditioned medium obtained from amnion-derived mesenchymal stem cells prevents proliferation and activation of keloid fibroblasts and is a promising keloid treatment for administration as a topical agent.

L-Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis
Naoya Sakamoto, Shunsuke Ohnishi, Kenichi Morikawa, Mitsuteru Natsuizaka, Takuya Sho, Masato Nakai, Naoki Kawagishi, Takaaki Izumi, Machiko Umemura, Akihisa Nakamura, Kazuharu Suzuki, Tomoe Shimazaki, Osamu Maehara, Megumi Kimura, Goki Suda, Koji Ogawa, Masatsugu Ohara
Hepatology Communications, 2, 8, 906, 918, Wiley, 2018年, ［査読有り］
研究論文（学術雑誌）

Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats
Naoya Sakamoto, Goki Suda, Osamu Maehara, Qingjie Fu, Hideki Nakamura, Kohei Yuyama, Koji Yamamoto, Hidetaka Hosono, Shunsuke Ohnishi, Masatsugu Ohara
Stem Cells International, 2018, 3212643, 3212643, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: There are no approved drug treatments for liver fibrosis and nonalcoholic steatohepatitis (NASH), an advanced stage of fibrosis which has rapidly become a major cause of cirrhosis. Therefore, development of anti-inflammatory and antifibrotic therapies is desired. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We herein investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. Methods: NASH was induced by a 4-week high-fat diet (HFD), and liver fibrosis was induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15 μg/kg) and at week 3 in rats with liver fibrosis (20 μg/kg). The extent of inflammation and fibrosis was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The effect of AMSC-EVs on inflammatory and fibrogenic response was investigated in vitro. Results: AMSC-EVs significantly decreased the number of Kupffer cells (KCs) in the liver of rats with NASH and the mRNA expression levels of inflammatory cytokines such as tumor necrosis factor- (Tnf-) α, interleukin- (Il-) 1β and Il-6, and transforming growth factor- (Tgf-) β. Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. In vitro, AMSC-EVs significantly inhibited KC and HSC activation and suppressed the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway. Conclusions: AMSC-EVs ameliorated inflammation and fibrogenesis in a rat model of NASH and liver fibrosis, potentially by attenuating HSC and KC activation. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease.

Detection of Superficial Head and Neck Squamous Cell Carcinoma by Topically Spraying Fluorescent Probe Targeting DPP-IV
Ohnishi Shunsuke, Mizushima Takeshi, Shimizu Yuichi, Hatanaka Yutaka, Hatanaka Kanako, Yamamoto Keiko, Homma Akihiro, Kuriki Yugo, Kamiya Mako, Urano Yasuteru, Sakamoto Naoya
CANCER SCIENCE, 109, 730, 2018年01月, ［査読有り］

Mesenchymal stem cell therapy for acute and chronic pancreatitis
Sakamoto, Naoya, Kuwatani, Masaki, Ohnishi, Shunsuke, Kawakubo, Kazumichi
Journal of Gastroenterology, 53, 1, 1, 5, Springer Tokyo, 2018年, ［査読有り］
英語, 研究論文（学術雑誌）, Mesenchymal stem cells (MSCs) have attracted attention as a cell source for regenerative medicine. In particular, MSCs have an anti-inflammatory effect by secreting several kinds of bioactive molecules. MSC therapy is now being applied to various gastrointestinal diseases, such as graft-versus-host disease, inflammatory bowel disease, and liver cirrhosis. Therefore, MSC therapy has the potential to be a novel treatment for acute and chronic pancreatitis by suppressing inflammation. Several studies have investigated the effect of MSC therapy on acute and chronic pancreatitis, but the underlying mechanisms remain unknown. In this review, we summarize the present status of MSC therapy for acute and chronic pancreatitis.

Potential role of extracellular vesicle-mediated antigen presentation in Helicobacter pylori hypersensitivity during eradication therapy
Riichiro Abe, Hiroshi Shimizu, Takeshi Tomonaga, Masahiro Asaka, Mototsugu Kato, Shuji Terai, Yuichi Sato, Yasuyuki Fujita, Hideyuki Ujiie, Akito Hasegawa, Katsuhiro Mabe, Shotaro Suzuki, Shunsuke Ohnishi, Takashi Shiromizu, Takamasa Ito
Journal of Allergy and Clinical Immunology, 142, 2, 672, 676, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Rapid detection of superficial head and neck squamous cell carcinoma by topically spraying fluorescent probe targeting dipeptidyl peptidase-IV
Shouko Ono, Keiko Yamamoto, Naoya Sakamoto, Yasuteru Urano, Akihiro Homma, Mako Kamiya, Yugo Kuriki, Yuichi Shimizu, Kanako C. Hatanaka, Shunsuke Ohnishi, Takeshi Mizushima
Head & Neck, 40, 7, 1466, 1475, Wiley, 2018年, ［査読有り］
研究論文（学術雑誌）

Palmitoylethanolamide Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis in Rats
Goki Suda, Qingjie Fu, Naoya Sakamoto, Osamu Maehara, Koji Yamamoto, Hidetaka Hosono, Shunsuke Ohnishi, Masatsugu Ohara
Frontiers in Pharmacology, 9, 709, 709, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Liver fibrosis is a complex inflammatory and fibrogenic process, and the progression of fibrosis leads to cirrhosis. The only therapeutic approaches are the removal of injurious stimuli and liver transplantation. Therefore, the development of anti-fibrotic therapies is desired. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamines family and contained in foods such as egg yolks and peanuts. PEA has therapeutic anti-inflammatory, analgesic, and neuroprotective effects. However, the effects and roles of PEA in liver fibrosis remain unknown. Here we investigated the therapeutic effects of PEA in rats with liver fibrosis. Methods: We conducted in vitro experiments to investigate the effects of PEA on the activation of hepatic stellate cells (HSCs, LX-2). Liver fibrosis was induced by an intraperitoneal injection of 1.5 mL/kg of 50% carbon tetrachloride twice a week for 4 weeks. Beginning at 3 weeks, PEA (20 mg/kg) was intraperitoneally injected thrice a week for 2 weeks. Then rats were sacrificed and we performed histological and quantitative reverse-transcription polymerase chain reaction analyses. Results: The expression of α-smooth muscle actin (SMA) induced by transforming growth factor (TGF)-β1 in HSCs was significantly downregulated by PEA. PEA treatment inhibited the TGF-β1-induced phosphorylation of SMAD2 in a dose-dependent manner, and upregulated the expression of SMAD7. The reporter gene assay demonstrated that PEA downregulated the transcriptional activity of the SMAD complex upregulated by TGF-β1. Administration of PEA significantly reduced the fibrotic area, deposition of type I collagen, and activation of HSCs and Kupffer cells in rats with liver fibrosis. Conclusion: Activation of HSCs was significantly decreased by PEA through suppression of the TGF-β1/SMAD signaling pathway. Administration of PEA produced significant improvement in a rat model of liver fibrosis, possibly by inhibiting the activation of HSCs and Kupffer cells. PEA may be a potential new treatment for liver fibrosis.

Effects of human amnion-derived mesenchymal stem cells and conditioned medium in rats with sclerosing cholangitis
Ryo Sugiura, Shunsuke Ohnishi, Masatsugu Ohara, Marin Ishikawa, Shuichi Miyamoto, Reizo Onishi, Koji Yamamoto, Kazumichi Kawakubo, Masaki Kuwatani, Naoya Sakamoto
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 10, 7, 2102, 2114, E-CENTURY PUBLISHING CORP, 2018年, ［査読有り］
英語, 研究論文（学術雑誌）, Mesenchymal stem cells (MSCs) represent a valuable cell source in regenerative medicine, and large numbers of MSCs can be isolated from the amnion noninvasively. Sclerosing cholangitis is a chronic cholestatic disease and characterized by progressive biliary destruction leading to cirrhosis. Many factors are involved in the development of sclerosing cholangitis; however, effective medical therapy is not established. We investigated the effects of human amnion-derived MSCs (hAMSCs) and conditioned medium (CM) obtained from hAMSC cultures in rats with sclerosing cholangitis. Sclerosing cholangitis was induced via the intragastric administration of 100 mg/kg alpha-naphthylisothiocyanate (ANIT) twice weekly for 4 weeks. One million hAMSCs or 200 mu L of CM were intravenously administered on days 15 and 22. Rats were sacrificed on day 29 and evaluated via histological, immunohistochemical, and mRNA expression analyses. hAMSC transplantation and CM administration significantly improved the histological score. In addition, these two interventions significantly improved biliary hyperplasia, peribiliary fibrosis, and inflammation in Glisson's sheath. Accordingly, CK19, MMP-9, and TNF-alpha, and MCP-1 expression in the liver was also decreased by hAMSC and CM administration. In conclusion, hAMSC and CM administration ameliorated biliary hyperplasia, peribiliary fibrosis, and inflammation in a rat model of sclerosing cholangitis. hAMSCs and CM may represent new modalities for treating sclerosing cholangitis.

Conditioned Medium from Human Amnion-Derived Mesenchymal Stem Cells Regulates Activation of Primary Hepatic Stellate Cells
Naoya Sakamoto, Shunsuke Ohnishi, Qingjie Fu
Stem Cells International, 2018, 4898152, 4898152, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Mesenchymal stem cells (MSCs), or multipotent mesenchymal stromal cells, are present in almost all organs and tissues, including the amnion. Human amnion-derived mesenchymal stem cell (hAMSC) transplantation has been reported to ameliorate liver fibrosis in animal models. However, the mechanism for the prevention of liver fibrosis is poorly understood. In this study, we investigated the effects, and underlying mechanisms, of a conditioned medium obtained from hAMSC cultures (hAMSC-CM) on a primary culture of rat hepatic stellate cells (HSCs). We observed that in routine culture, hAMSC-CM in HSCs significantly inhibited the expression of alpha-smooth muscle actin (α-SMA), an activation marker of HSCs, and the production of collagen type 1 (COL1), a dominant component of the extracellular matrix (ECM) in the culture medium. In addition, hAMSC-CM upregulated the expression of ECM degradation-related genes, such as metalloproteinase- (Mmp-) 2, Mmp-9, Mmp-13, and tissue inhibitor of metalloproteinase- (Timp-) 1; however, it did not affect the expression of collagen type 1α1 (Col1a1). These regulatory effects on HSCs were concentration-dependent. A cell proliferation assay indicated that hAMSC-CM significantly suppressed HSC proliferation and downregulated the expression of cyclin B (Ccnb), a proliferation-related gene. Transforming growth factor-beta (TGF-β) treatment further activated HSCs and hAMSC-CM significantly inhibited the upregulation of α-Sma and Col1a1 induced by TGF-β. These findings demonstrated that hAMSC-CM can modulate HSC function via secretory factors and provide a plausible explanation for the protective role of hAMSCs in liver fibrosis.

Dipeptidylpeptidase-IVの酵素活性により蛍光を発するプローブによる頭頸部表在癌の検出　　　　　　　　　　　　　　　
大西 俊介, 水島 健, 清水 勇一, 畑中 豊, 畑中 佳奈子, 山本 桂子, 本間 明宏, 栗木 優五, 神谷 真子, 浦野 泰照, 坂本 直哉
日本癌学会総会記事, 76回, P, 2320, 日本癌学会, 2017年09月
英語

Anti-Adipogenic and Antiviral Effects of L-Carnitine on Hepatitis C Virus Infection
Yoko Tsukuda, Goki Suda, Seiji Tsunematsu, Jun Ito, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Takuya Sho, Osamu Maehara, Tomoe Shimazaki, Megumi Kimura, Kenichi Morikawa, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Makoto Chuma, Naoya Sakamoto
JOURNAL OF MEDICAL VIROLOGY, 89, 5, 857, 866, WILEY, 2017年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Hepatitis C virus (HCV) has been reported to hijack fatty acid metabolism in infected hepatocytes, taking advantage of lipid droplets for virus assembly. In this study, we analyzed the anti-HCV activity of L-carnitine, a substance involved in the transport of fatty acids into mitochondria. JFH-1 or HCV replicontransfected Huh7.5.1 cells were treated with or without L-carnitine to examine its anti-HCV effects. The effects of L-carnitine on HCV entry, HCV-induced adipogenesis and lipid droplet formation, and HCV-induced oxidative stress were examined. Treatment of JFH1-infected cells with L-carnitine inhibited HCV propagation in a concentration-dependent manner. In contrast, L-carnitine had no antiHCV activity in the HCV replicon system, which is lacking viral assembly. In addition, Lcarnitine did not affect HCV entry. However, Lcarnitine treatment decreased intracellular lipid droplets, which are crucial for HCV assembly in JFH-1-infected cells. The expression level of CPT-1 was decreased in JFH-1-infected cells, and L-carnitine treatment restored this expression. HCV-infected cells exhibited increased production of reactive oxygen species and glutathione oxidation. L-carnitine decreased oxidative stress induced by JFH-1-infection, as shown by glutathione/glutathione disulfide assays and MitoSOX staining. L-carnitine exhibited anti-HCV activity, possibly by inhibiting HCV assembly and through its anti-adipogenic activity in HCV-infected cells. Moreover, L-carnitine has antioxidant properties in HCVinfected hepatocytes. Overall, these results indicated that L-carnitine may be an effective adjunctive agent in antiviral therapies to treat chronic hepatitis C. (C) 2016 Wiley Periodicals, Inc.

Rapid Detection of Superficial Head and Neck Squamous Cell Carcinoma by Topically Spraying Fluorescent Probe Targeting Dipeptidylpeptidase-Iv
Shunsuke Ohnishi, Takeshi Mizushima, Yuichi Shimizu, Yutaka Hatanaka, Kanako Hatanaka, Keiko Yamamoto, Akihiro Homma, Yugo Kuriki, Mako Kamiya, Yasuteru Urano, Naoya Sakamoto
GASTROINTESTINAL ENDOSCOPY, 85, 5, AB530, AB530, MOSBY-ELSEVIER, 2017年05月, ［査読有り］
英語

Fibroblast growth factor-2–mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma
Naoya Sakamoto, Hiroshi Takeda, Hiroshi Nakagawa, Kelly A Whelan, Seiji Naganuma, Hideaki Kinugasa, Shingo Kagawa, Shinya Ohashi, Yoshiyuki Fujimoto, Ayaka Asano, Megumi Kimura, Tomoe Shimazaki, Koji Ogawa, Kenichi Morikawa, Takuya Sho, Masato Nakai, Fumiyuki Sato, Yoshito Komatsu, Shunsuke Ohnishi, Mitsuteru Natsuizaka, Goki Suda, Osamu Maehara
Carcinogenesis, 38, 11, 1073, 1083, OXFORD UNIV PRESS, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchym al-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.

Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02)
Satoru Iwase, Yasuhito Uezono, Takuhiro Yamaguchi, Noriaki Sakuragi, Masahiro Asaka, Toru Sugiyama, Hidenori Kato, Eiji Nomura, Shunsuke Oyamada, Tempei Miyaji, Satoshi Takeuchi, Yoko Ohba, Maki Kanno, Hidemichi Watari, Shunsuke Ohnishi
Journal of Gynecologic Oncology, 28, 5, Asian Society of Gynecologic Oncology$\mathsemicolon$ Korean Society of Gynecologic Oncology and Colposcopy ({KAMJE}), 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: Rikkunshito, an herbal medicine, is widely prescribed in Japan for the treatment of anorexia and functional dyspepsia, and has been reported to recover reductions in food intake caused by cisplatin. We investigated whether rikkunshito could improve chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients treated with cisplatin.
Methods: Patients with uterine cervical or corpus cancer who were to receive cisplatin (50 mg/m(2) day 1) and paclitaxel (135 mg/m2 day 0) as first-line chemotherapy were randomly assigned to the rikkunshito group receiving oral administration on days 0-13 with standard antiemetics, or the control group receiving antiemetics only. The primary endpoint was the rate of complete control (CC: no emesis, no rescue medication, and no significant nausea) in the overall phase (0-120 hours). Two-tailed p<0.20 was considered significant in the planned analysis.
Results: The CC rate in the overall phase was significantly higher in the rikkunshito group than in the control group (57.9% vs. 35.3%, p=0.175), as were the secondary endpoints: the CC rate in the delayed phase (24-120 hours), and the complete response (CR) rates (no emesis and no rescue medication) in the overall and delayed phases (63.2% vs. 35.3%, p=0.095; 84.2% vs. 52.9%, p=0.042; 84.2% vs. 52.9%, p=0.042, respectively), and time to treatment failure (p=0.059). Appetite assessed by visual analogue scale (VAS) appeared to be superior in the rikkunshito group from day 2 through day 6.
Conclusion: Rikkunshito provided additive effect for the prevention of CINV and anorexia.

Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs
Naoya Sakamoto, Masahiro Asaka, Mototsugu Kato, Yuichi Shimizu, Momoko Tsuda, Kenichi Yamahara, Hidetaka Hosono, Shunsuke Ohnishi, Takeshi Mizushima
Gastrointestinal Endoscopy, 86, 3, 542, 552.e1, Elsevier {BV}, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, Background and Aims: Endoscopic submucosal dissection (ESD) for esophageal cancer often causes postoperative stricture when more than three fourths of the circumference of the esophagus is dissected. Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium (CM) obtained from mesenchymal stem cells reportedly inhibits inflammation. In this study we evaluated whether CM could prevent esophageal stricture after ESD.
Methods: We resected a semi-circumference of pig esophagus by ESD. We prepared CM gel by mixing with 5% carboxymethyl cellulose and endoscopically applied it onto the wound bed immediately after ESD and on days 8 and 15 (weekly CM group) or administered it orally from days 1 to 4 (daily CM group). We also injected triamcinolone acetonide into the remaining submucosa immediately after ESD (steroid group). We killed the pigs on day 8 or day 22 to measure the stricture rate and to perform histologic analysis.
Results: Stricture rate in weekly and daily CM groups and steroid groups were significantly lower than in the control group on day 22. Moreover, CM significantly attenuated the number of activated myofibroblasts and fiber thickness on day 22. CM also significantly decreased the infiltration of neutrophils and macrophages compared with the control group on day 8.
Conclusions: CM gel prevents esophageal stricture formation by suppressing myofibroblast activation and fibrosis after the infiltration of neutrophils and macrophages. Oral administration of CM gel is a promising treatment for the prevention of post-ESD stricture.

Therapeutic effects of human amnion-derived mesenchymal stem cell transplantation and conditioned medium enema in rats with trinitrobenzene sulfonic acid-induced colitis
Sakamoto N, Takeda H, Yamahara K, Katsurada T, Hosono H, Tsuchiya I, Onishi R, Ohnishi S, Miyamoto S
American Journal of Translational Research, 9, 3, 940, 952, E-CENTURY PUBLISHING CORP, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, Cell therapy with mesenchymal stem cells (MSCs) is expected to provide a new strategy for the treatment of inflammatory bowel disease (IBD). Large amounts of MSCs can be obtained from human amnion. Therefore, we investigated the effect of transplantation of human amnion-derived MSCs (hAMSCs) or enema of conditioned medium (CM) from hAMSCs into rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. In the first experiment, 10-week-old male Sprague-Dawley rats were intravenously injected with hAMSCs (1 x 10(6) cells) 3 h after rectal administration of TNBS (45 mg/kg). In the second experiment, rats with TNBS-induced colitis received CM by enema into the colon for 3 days. Colitis was investigated by endoscopy, histology, immunohistochemistry, and by measuring mRNA expression of inflammatory mediators. Administration of hAMSCs or CM enema significantly improved the endoscopic score. In addition, these two interventions resulted in significantly decreased infiltration of neutrophils and monocytes/macrophages and decreased expression levels of TNF-alpha, CXCL1, and CCL2. In conclusion, transplantation of hAMSCs and CM enema provided significant improvement in rats with TNBS-induced colitis. CM from hAMSCs and hAMSCs may be new strategies for the treatment of IBD.

Prevention of Subsequent Stricture Formation After Esophageal Endoscopic Submucosal Dissection Using Conditioned Medium Obtained From Amnion-Derived Mesenchymal Stem Cell Culture
Takeshi Mizushima, Shunsuke Ohnishi, Hidetaka Hosono, Momoko Tsuda, Masayoshi Ono, Reizo Onishi, Mototsugu Kato, Naoya Sakamoto
GASTROINTESTINAL ENDOSCOPY, 83, 5, AB583, AB583, MOSBY-ELSEVIER, 2016年05月, ［査読有り］
英語

Rikkunshito and ghrelin
Hiroshi Takeda, Shunsuke Ohnishi, Koji Nakagawa, Naoto Okubo, Chihiro Yamada, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori
Methods in Pharmacology and Toxicology, 135, 163, Humana Press Inc., 2016年, ［査読有り］
英語, 論文集(書籍)内論文, Rikkunshito is a kampo herbal medicine which is widely used in Japan for the treatment of the upper gastrointestinal symptoms of patients with functional dyspepsia (FD), gastroesophageal reflux disease (GERD), dyspeptic symptoms of postgastrointestinal surgery patients, and chemotherapy-induced dyspepsia in cancer patients. Recently, very unique characteristics of rikkunshito have been unveiled
oral administration of rikkunshito potentiates orexigenic action of ghrelin through several different mechanisms. In addition, several lines of evidence obtained from both animal and human studies indicate that rikkunshito can be an attractive and promising therapeutic option for the anorectic conditions including cisplatin-induced dyspepsia, anorexia of aging, stress-induced hypophagia, cancer cachexia-anorexia syndrome, and drug-related anorexia. We will highlight what is known about the orexigenic effect of rikkunshito with a special focus on an interaction with ghrelin signaling system.

Feasibility of Using an Enzymatically Activatable Fluorescence Probe for the Rapid Evaluation of Pancreatic Tissue Obtained Using Endoscopic Ultrasound-Guided Fine Needle Aspiration: a Pilot Study
Sakamoto, Naoya, Urano, Yasuteru, Kawakami, Hiroshi, Kuwatani, Masaki, Kamiya, Mako, Kubota, Yoshimasa, Hosono, Hidetaka, Hatanaka, Kanako C., Hatanaka, Yutaka, Ohnishi, Shunsuke, Kawakubo, Kazumichi
Molecular Imaging and Biology, 18, 3, 463, 471, SPRINGER, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the most reliable method for the histological diagnosis of pancreatic tumors. Rapid on-site fluorescence-guided histological diagnosis was evaluated by topically applying an enzymatically activatable probe onto the EUS-FNA samples; the probe fluoresces in the presence of gamma-glutamyltranspeptidase (GGT).
We evaluated GGT expression in pancreatic cancer cell lines in vitro. EUS-FNA was performed in 10 pancreatic tumors. After topical application of the probe, signal intensity was measured using a fluorescence imaging system for 13 min.
GGT was expressed in Panc-1, AsPC-1, and AR42J, but not in KP4 cells. In samples from six cases, several regions of the specimens fluoresced and contained adequate tissue for pathological diagnosis. The remaining four non-fluorescent samples contained very small amounts of carcinoma, normal epithelial cells, or no epithelial cells. The signal intensity at 5 min was 25.5 +/- 7.7 and 7.7 +/- 0.5 in fluorescent and non-fluorescent regions, respectively (p < 0.05).
Application of enzymatically activatable probe onto EUS-FNA samples would be feasible for the rapid evaluation of tissues suitable for histological diagnosis.

Fluorescent imaging of superficial head and neck squamous cell carcinoma using a Upsilon-glutamyltranspeptidase-activated targeting agent: a pilot study
Urano, Yasuteru, Sakamoto, Naoya, Kato, Mototsugu, Homma, Akihiro, Ono, Shouko, Kamiya, Mako, Natsuizaka, Mitsuteru, Kubota, Yoshimasa, Hosono, Hidetaka, Hatanaka, Kanako C., Hatanaka, Yutaka, Shimizu, Yuichi, Ohnishi, Shunsuke, Mizushima, Takeshi
BMC Cancer, 16, BIOMED CENTRAL LTD, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Detecting superficial head and neck squamous cell carcinoma (HNSCC) by endoscopy is challenging because of limited morphological hallmarks, and iodine cannot be applied to head and neck lesions due to severe mucosal irritation. Upsilon-glutamyltranspeptidase (GGT), a cell surface enzyme, is overexpressed in several cancers, and it has been reported that Upsilon-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent targeting agent which can be enzymatically activated and becomes fluorescent after cleavage of a GGT-specific sequence, can be activated within a few minutes after application to animal models. We investigated whether early HNSCC can be detected by applying gGlu-HMRG to clinical samples.
Methods: gGlu-HMRG was applied to four HNSCC cell lines, and fluorescence was observed by fluorescence microscopy and flow cytometry. Immunohistological examination was performed in three recent cases of endoscopic submucosal dissection (ESD) to investigate GGT expression. Fluorescence imaging with gGlu-HMRG in eight clinical samples resected by ESD or surgery was performed, and fluorescence intensity of tumor and normal mucosa regions of interest (ROI) was prospectively measured.
Results: All four gGlu-HMRG-applied cell lines emitted green fluorescence. Immunohistological examination demonstrated that GGT was highly expressed in HNSCC of the recent three ESD cases but barely in the normal mucosa. Fluorescence imaging showed that iodine-voiding lesions became fluorescent within a few minutes after application of gGlu-HMRG in all eight resected tumors. Tumor ROI fluorescence intensity was significantly higher than in the normal mucosa five minutes after gGlu-HMRG application.
Conclusions: Fluorescence imaging with gGlu-HMRG would be useful for early detection of HNSCC.

Effect of Fetal Membrane-Derived Mesenchymal Stem Cell Transplantation in Rats With Acute and Chronic Pancreatitis
Naoya Sakamoto, Hiroshi Takeda, Atsushi Masamune, Reizo Onishi, Masaki Kuwatani, Hirotoshi Fujita, Shunsuke Ohnishi, Kazumichi Kawakubo
Pancreas, 45, 5, 707, 713, LIPPINCOTT WILLIAMS & WILKINS, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Objectives: Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine and can be isolated from fetal membranes (FMs), particularly amniotic membranes. We investigated the effect of rat FM-derived MSCs (rFM-MSCs) and human amnion-derived MSCs (hAMSCs) on the inflammatory reaction in vitro and therapeutic effects in rats with acute and chronic pancreatitis.
Methods: Effect of rFM-MSCs or hAMSC-conditioned medium was investigated in vitro. Acute pancreatitis was induced by intraductal injection of 4% taurocholate, and rFM-MSCs were transplanted intravenously. Chronic pancreatitis was induced by intravenous injection of 5 mg/kg dibutyltin dichloride, and hAMSCs were transplanted intravenously.
Results: The inflammatory reaction of macrophages induced by lipopolysaccharide and trypsin was significantly suppressed by rFM-MSC coculture. Pancreatic acinar cell injury induced by cerulein was significantly ameliorated by hAMSC-conditioned medium. Pancreatic stellate cell activation induced by tumor necrosis factor-a was significantly decreased by hAMSC-conditioned medium. Transplantation of rFM-MSCs significantly reduced the histological score and infiltration of CD68-positive macrophages in the rat pancreas. The hAMSC transplantation significantly decreased the expression of MCP-1 and attenuated the downregulation of amylase expression in the pancreas.
Conclusions: Transplantation of FM-MSCs and AMSCs suppressed the inflammatory reaction of acute and chronic pancreatitis in rats.

Effects of human amnion-derived mesenchymal stromal cell transplantation in rats with radiation proctitis
Masayoshi Ono, Shunsuke Ohnishi, Minori Honda, Marin Ishikawa, Hidetaka Hosono, Reizo Onishi, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
CYTOTHERAPY, 17, 11, 1545, 1559, ELSEVIER SCI LTD, 2015年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Background aims. Mesenchymal stromal cells (MSCs) have been reported to be a promising cell source in cell therapy, and large amounts of MSCs can easily be isolated from human amnion. Therapeutic irradiation for intra-pelvic cancer often causes radiation proctitis; however, there is currently no effective treatment. We therefore investigated the effect of transplantation of human amnion derived MSCs (AMSCs) in rats with radiation proctitis. Methods. Amnion was obtained at cesarean delivery, and AMSCs were isolated and expanded. Sprague-Dawley rats were gamma-irradiated (5 Gy/d) at the rectum for 5 days. On day 5, AMSCs (1 x 10(6) cells) were intravenously transplanted. Rats were killed on day 8. Histological analyses were performed, and messenger RNA expression of inflammatory mediators was measured. In vitro, after gamma-irradiation of rat intestinal epithelial cells (IEC-6), the cells were cultured with AMSC-conditioned medium (CM). The effect of AMSC-CM was evaluated by measurement of caspase-3/7 activity, p53 transcription activity and quantitative reverse-transcription polymerase chain reaction for p53-target genes. Results. Histological examination demonstrated that epithelial injury and infiltration of inflammatory cells in the rectum were significantly suppressed by transplantation of AMSCs. In vitro, the cell injury in IEC-6 cells induced by gamma-irradiation was inhibited by AMSC-CM, which also inhibited the upregulation of p53 transcription activity, caspase-3/7 activity and p21 expression. Conclusions. Transplantation of AMSCs improved radiation proctitis, possibly through inhibition of cell injury and inflammatory reactions. AMSC transplantation should be considered as a new treatment for radiation proctitis.

Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions
Goki Suda, Yoshiya Yamamoto, Astushi Nagasaka, Ken Furuya, Mineo Kudo, Yoshimichi Chuganji, Yoko Tsukuda, Seiji Tsunematsu, Fumiyuki Sato, Katsumi Terasita, Masato Nakai, Hiromasa Horimoto, Takuya Sho, Mitsuteru Natsuizaka, Kouji Ogawa, Shunsuke Ohnishi, Makoto Chuma, Yasuyuki Fujita, Riichiro Abe, Miki Taniguchi, Mina Nakagawa, Yasuhiro Asahina, Naoya Sakamoto
HEPATOLOGY RESEARCH, 45, 8, 837, 845, WILEY-BLACKWELL, 2015年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Aim: Telaprevir-based therapy for chronic hepatitis C patients is effective; however, the high prevalence of dermatological reactions is an outstanding issue. The mechanism and characteristics of such adverse reactions are unclear; moreover, predictive factors remain unknown. Granulysin was recently reported to be upregulated in the blisters of patients with Stevens-Johnson syndrome (SJS). Therefore, we investigated the risk factors for severe telaprevir-induced dermatological reactions as well as the association between serum granulysin levels and the severity of such reactions.Methods: A total of 89 patients who received telaprevir-based therapy and had complete clinical information were analyzed. We analyzed the associations between dermatological reactions and clinical factors. Next, we investigated the time-dependent changes in serum granulysin levels in five and 14 patients with grade 3 and non-grade 3 dermatological reactions, respectively.Results: Of the 89 patients, 57 patients had dermatological reactions, including nine patients with grade 3. Univariate analysis revealed that grade 3 dermatological reactions were significantly associated with male sex. Moreover, serum granulysin levels were significantly associated with the severity of dermatological reactions. Three patients with grade 3 dermatological reaction had severe systemic manifestations including SJS, drug-induced hypersensitivity syndrome, and systemic lymphoid swelling and high-grade fever; all were hospitalized. Importantly, among the three patients, two patients' serum granulysin levels exceeded 8ng/mL at onset and symptoms deteriorated within 6 days.Conclusion: Male patients are at high risk for severe telaprevir-induced dermatological reactions. Moreover, serum granulysin levels are significantly associated with the severity of dermatological reactions and may be a predictive factor in patients treated with telaprevir-based therapy.

EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition
Fumiyuki Sato, Yoshimasa Kubota, Mitsuteru Natsuizaka, Osamu Maehara, Yutaka Hatanaka, Katsuji Marukawa, Katsumi Terashita, Goki Suda, Shunsuke Ohnishi, Yuichi Shimizu, Yoshito Komatsu, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Kelly A. Whelan, Hiroshi Nakagawa, Naoya Sakamoto
CANCER BIOLOGY & THERAPY, 16, 6, 933, 940, TAYLOR & FRANCIS INC, 2015年06月, ［査読有り］
英語, 研究論文（学術雑誌）, There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44. A novel therapy targeting these cancer stem-like cells (CSCs) is needed to improve prognosis of ESCC. CSCs of ESCC have a mesenchymal phenotype and epithelial-mesenchymal transition (EMT) is critical to enrich and maintain CSCs. EGFR, frequently overexpressed in ESCC, has pivotal roles in EMT induced by TGF- in invasive fronts. Thus, EMT in invasive fronts of ESCC might be important for CSCs and EGFR could be a target of a novel therapy eliminating CSCs. However, effects of EGFR inhibitors on CSCs in ESCC have not been fully examined. EGFR inhibitors, erlotinib and cetuximab, significantly suppressed enrichment of CSCs via TGF-1-mediated EMT. Importantly, EGFR inhibitors sharply suppressed ZEB1 that is essential for EMT in ESCC. Further, EGFR inhibitors activated Notch1 and Notch3, leading to squamous cell differentiation. EGFR inhibition may suppress expression of ZEB1 and induce differentiation, thereby blocking EMT-mediated enrichment of CSCs. In organotypic 3D culture, a form of human tissue engineering, tumor cells in invasive nests showed high expression of CD44. Erlotinib significantly blocked invasion into the matrix and CD44 high expressing CSCs were markedly suppressed by erlotinib in organotypic 3D culture. In conclusion, EMT is a critical process for generation of CSCs and the invasive front of ESCC, where EMT occurs, might form a CSC niche in ESCC. EGFR inhibitors could suppress EMT in invasive fronts and be one therapeutic option targeting against generation of CSCs in ESCC.

Serotonin 2C receptor contributes to gender differences in stress-induced hypophagia in aged mice
Chihiro Yamada, Chiharu Sadakane, Miwa Nahata, Yayoi Saegusa, Koji Nakagawa, Naoto Okubo, Shunsuke Ohnishi, Tomohisa Hattori, Hiroshi Takeda
PSYCHONEUROENDOCRINOLOGY, 55, 81, 93, PERGAMON-ELSEVIER SCIENCE LTD, 2015年05月, ［査読有り］
英語, 研究論文（学術雑誌）, The combination of depression and anorexia may influence morbidity and progressive physical disability in the elderly. Gender differences exist in hypothalamic pituitary adrenal axis activation following stress exposure. The objective of this study was to investigate gender differences in feeding behavior under novelty stress in aged mice. Food intake measurement, immunohistochemical assessment, and mRNA expression analysis were conducted to investigate the role of serotonin 2C receptor (5-HT2CR) and its relationship with ghrelin in stress-induced suppression of feeding behavior in aged mice. After exposure to novelty stress, a 21-fold increase in plasma corticosterone and remarkable suppression of food intake were observed in aged male mice. Furthermore, a 5-HT2CR agonist suppressed food intake in aged mate mice. Novelty stress induced a 7-fold increase in 5-HT2CR and c-Fos co-expressing cells in the paraventricular nucleus of the hypothalamus in aged male mice but caused no change in aged female mice. Plasma acylated ghrelin levels decreased in stressed aged mate mice and administration of the 5-HT2CR antagonist inhibited this decrease. The 5-HT2CR antagonist also reversed the suppression of food intake in estrogen receptor a agonist-treated aged male mice. Therefore, conspicuously suppressed feeding behavior in novelty stress-exposed aged male mice may be mediated by 5-HT2CR hypersensitivity, leading to hypoghrelinemia. The hypersensitivity may partly be due to estrogen receptor activation in aged male mice. (C) 2015 The Authors. Published by Elsevier Ltd.

A Novel Technique for the Detection of Endoscopic Ultrasound-Guided Fine Needle Pancreatic Tissue Acquisition by an Enzymatically Rapid-Activatable Fluorescent Probe
Kazumichi Kawakubo, Shunsuke Ohnishi, Yasuteru Urano, Yutaka Hatanaka, Kanako C. Hatanaka, Hiroshi Kawakami, Masaki Kuwatani, Shuhei Kawahata, Yoko Abe, Yoshimasa Kubota, Kimitoshi Kubo, Naoya Sakamoto
GASTROINTESTINAL ENDOSCOPY, 81, 5, AB536, AB537, MOSBY-ELSEVIER, 2015年05月, ［査読有り］
英語

The Hypophagia After Psychological Stress in Aged Male Mice Is Mediated by an Interaction of Activation of Estrogen Receptor a With Serotonin 2C Receptor
Shunsuke Ohnishi, Koji Nakagawa, Naoto Okubo, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Naoya Sakamoto, Hiroshi Takeda
GASTROENTEROLOGY, 148, 4, S25, S26, W B SAUNDERS CO-ELSEVIER INC, 2015年04月, ［査読有り］
英語

Different Response to Chronic Isolation Stress Between Young and Aged Mice
Hiroshi Takeda, Shunsuke Ohnishi, Koji Nakagawa, Naoto Okubo, Chihiro Yamada, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Naoya Sakamoto
GASTROENTEROLOGY, 148, 4, S26, S26, W B SAUNDERS CO-ELSEVIER INC, 2015年04月, ［査読有り］
英語

KLF5 Promotes Tumorigenicity of Hepatocellular Carcinoma by Upregulation of Cancer Stem-Like Cells
Fumiyuki Sato, Mitsuteru Natsuizaka, Osamu Maehara, Ayaka Asano, Yoshimasa Kubota, Jun Itoh, Seiji Tsunematsu, Yoko Tsukuda, Katsumi Terashita, Masato Nakai, Takuya Sho, Goki Suda, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
GASTROENTEROLOGY, 148, 4, S43, S43, W B SAUNDERS CO-ELSEVIER INC, 2015年04月, ［査読有り］
英語

Association of Peripheral Total and Differential Leukocyte Counts with Obesity-Related Complications in Young Adults
Aya Yoshimura, Shunsuke Ohnishi, Chieko Orito, Yukako Kawahara, Hiroyo Takasaki, Hiroshi Takeda, Naoya Sakamoto, Satoshi Hashino
OBESITY FACTS, 8, 1, 1, 16, KARGER, 2015年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: Obesity has been demonstrated to be associated with elevated leukocytes in adults and children. This study assessed the associations between peripheral total and differential leukocyte counts and obesity-related complications in young adults. Methods: 12 obese (median age 21.5 (range 19-28) years, median BMI 35.7 (range 32.0-44.9) kg/m 2) and 11 normal (median age 23 (range 18-27) years, median BMI 19.5 (range 18.1-21.7) kg/m 2) adults were enrolled. Complete blood count and serum levels of liver enzymes, fasting blood glucose, insulin and lipids were measured, and the homeostasis model assessment of insulin resistance was calculated. Fat mass was calculated using a bioimpedance analysis device, and ultrasonography was performed to measure fat thickness and to detect fatty change of the liver. Results: Total leukocyte and monocyte counts were significantly increased in obese young adults. Total leukocyte count was associated with liver enzyme levels, insulin resistance as well as visceral and subcutaneous fat thickness. Neutrophil count was associated with insulin resistance. Lymphocyte count was associated with serum liver enzymes, insulin resistance, and dyslipidemia. Monocyte count was associated with serum liver enzyme, insulin resistance, visceral and subcutaneous fat thickness, body fat mass, and percentage body fat. Conclusion: The results of this study suggest that chronic low-grade systemic inflammation is associated with obesity-related complications such as nonalcoholic fatty liver disease, insulin resistance, and dyslipidemia in young adults. (C) 2015 S. Karger GmbH, Freiburg

A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma
Naoya Sakamoto, Hiroshi Takeda, Kelly A Whelan, Yoshito Komatsu, Shunsuke Ohnishi, Koji Nakagawa, Makoto Chuma, Koji Ogawa, Kenichi Morikawa, Goki Suda, Takuya Sho, Masato Nakai, Yoko Tsukuda, Katsumi Terashita, Seiji Tsunematsu, Jun Itoh, Yoshimasa Kubota, Ayaka Asano, Mitsuteru Natsuizaka, Fumiyuki Sato, Osamu Maehara
Cancer Biology & Therapy, 16, 10, 1453, 1461, TAYLOR & FRANCIS INC, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, In hepatocellular carcinoma (HCC), there exists a highly tumorigenic subset of cells defined by high expression of CD44 and CD133 that has been reported to contain cancer stem-like cells (CSCs). Kruppel-like factor 5 (KLF5) regulates many factors involved in cell cycle, migration, inflammation, angiogenesis and stemness and has cancer-promoting effects in some cancers. While some reports have indicated that KLF5 may have important roles in regulation of CSCs, what role, if any, KLF5 plays in regulation of CSCs in HCC remains to be elucidated. Flow cytometric analysis of CD44 and CD133 in HCC cell lines revealed subpopulations of CD44(High)/CD133(High) and CD44(Low)/CD133(Low) cells. We subsequently sorted these subpopulations and identified KLF5 as a gene that is significantly upregulated in CD44(High)/CD44(High) cells via RNA sequencing using next generation sequencing technology. Moreover, KLF5 overexpression enriched the CD44(High)/CD133(High) subpopulation and, consistent with the up-regulation of CD44(High)/CD133(High) cells, KLF5 overexpressing cells were more resistant to anti-cancer drugs and displayed enhanced colony-formation capacity. By contrast, knock-down of KLF5 by siRNA diminished the CD44(High)/CD133(High) subpopulation. When KLF5 was acetylated by TGF-1, the KLF5-mediated CD44(High)/CD133(High) subpopulation enrichment was abrogated. Oppositely, ectopic expression of an acetylation-deficient KLF5 mutant further increased CD44(High)/CD133(High) subpopulations as compared to cell expressing wild-type KLF5. These findings provide novel mechanistic insight into a pivotal role for KLF5 in the regulation of CSCs in HCC.

Chromoendoscopy With Iodine Staining, as Well as Narrow-Band Imaging, Is Still Useful and Reliable for Screening of Early Esophageal Squamous Cell Carcinoma
Yuichi Shimizu, Masakazu Takahashi, Takeshi Mizushima, Shouko Ono, Katsuhiro Mabe, Shunsuke Ohnishi, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto
AMERICAN JOURNAL OF GASTROENTEROLOGY, 110, 1, 193, 194, NATURE PUBLISHING GROUP, 2015年01月, ［査読有り］
英語, 研究論文（学術雑誌）

Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Dextran Sulfate Sodium-Induced Severe Colitis in Rats
Naoya Sakamoto, Hiroshi Takeda, Mitsuteru Natsuizaka, Goki Suda, Takehiko Katsurada, Koji Nakagawa, Naoto Okubo, Kenichi Yamahara, Michiko Watari, Ryosuke Higashi, Shunsuke Ohnishi, Reizo Onishi
Cell Transplantation, 24, 12, 2601, 2614, COGNIZANT COMMUNICATION CORP, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of human amnion-derived MSCs (AMSCs) in rats with severe colitis. Colitis was induced by the administration of 8% dextran sulfate sodium (DSS) from day 0 to day 5, and AMSCs (1 x 10(6) cells) were transplanted intravenously on day 1. Rats were sacrificed on day 5, and the colon length and histological colitis score were evaluated. The extent of inflammation was evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. The effect of AMSCs on the inflammatory signals was investigated in vitro. AMSC transplantation significantly ameliorated the disease activity index score, weight loss, colon shortening, and the histological colitis score. mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and migration inhibitory factor (MIF) were significantly decreased in the rectums of AMSC-treated rats. In addition, the infiltration of monocytes/macrophages was significantly decreased in AMSC-treated rats. In vitro experiments demonstrated that activation of proinflammatory signals induced by TNF-alpha or lipopolysaccharide (LPS) in immortalized murine macrophage cells (RAW264.7) was significantly attenuated by coculturing with AMSCs or by culturing with a conditioned medium obtained from AMSCs. Although the phosphorylation of I kappa B induced by TNF-alpha or LPS was not inhibited by the conditioned medium, nuclear translocation of NF-kappa B was significantly inhibited by the conditioned medium. Taken together, AMSC transplantation provided significant improvement in rats with severe colitis, possibly through the inhibition of monocyte/macrophage activity and through inhibition of NF-kappa B activation. AMSCs could be considered as a new cell source for the treatment of severe colitis.

Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Liver Fibrosis in Rats
Naoya Sakamoto, Hiroshi Takeda, Kenichi Yamahara, Takahiro Yamada, Reizo Onishi, Ryosuke Higashi, Ayano Kameya, Moto Fukai, Hidetaka Hosono, Shunsuke Ohnishi, Kimitoshi Kubo
Transplantation Direct, 1, 4, e16, 2015年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, UNLABELLED: Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of transplantation of human amnion-derived MSCs (hAMSCs) in rats with liver fibrosis. METHODS: Liver fibrosis was induced by an intraperitoneal injection of 2 mL/kg of 50% carbon tetrachloride twice a week for 6 weeks. At 3 weeks, hAMSCs (1 × 10(6) cells) were transplanted intravenously. Rats were sacrificed at 7 weeks, and histological analyses and quantitative reverse-transcription polymerase chain reaction were performed. In vitro experiments were conducted to investigate the effect of hAMSCs on the activation of Kupffer cells. RESULTS: Transplantation of hAMSCs significantly reduced the fibrotic area, deposition of type-I collagen, the number of α-smooth muscle actin-positive hepatic stellate cells, and CD68-positive Kupffer cells in the livers. messenger RNA expression of α-smooth muscle actin and tissue inhibitor of metalloproteinase-1 was significantly decreased and the expression of matrix metalloproteinase-9 and hepatocyte growth factor was significantly increased in the liver of hAMSC-treated rats. Transplantation of hAMSCs at 3 weeks plus 5 weeks did not have an additive effect. In vitro experiments demonstrated that Kupffer cell activation induced by lipopolysaccharide was significantly decreased by culturing with conditioned medium obtained from hAMSCs. CONCLUSIONS: Transplantation of hAMSCs provided significant improvement in a rat model of liver fibrosis, possibly through the inhibition of Kupffer cell and hepatic stellate cell activation. hAMSCs may be a potential new treatment for liver fibrosis.

TGF-beta in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma
Mitsuteru Natsuizaka, Shingo Kagawa, Kelly Whelan, Shinya Ohashi, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto, Anil K. Rustgi, Hiroshi Nakagawa
CANCER RESEARCH, 75, 1, AMER ASSOC CANCER RESEARCH, 2015年01月, ［査読有り］
英語

Herbal medicines for the treatment of cancer chemotherapy-induced side effects
Hiroshi Takeda, Shunsuke Ohnishi
Frontiers in Pharmacology, 6, FRONTIERS MEDIA SA, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, Accumulating evidence suggests that Japanese herbal medicines, called Kampo, have beneficial effects on cancer chemotherapy induced side effects. Rikkunshito ameliorates cisplatin-induced anorexia through an antagonistic effect on the 5-HT receptors and by increasing the serum ghrelin levels. Hangeshashinto improves irinotecan-induced diarrhea and chemotherapy-induced mucositis by inhibiting the activity of beta-glucuronidase as well as the synthesis of prostaglandin E2. Goshajinkigan prevents oxaliplatin-induced neurotoxicity, possibly through suppressing functional alterations of the transient receptor potential channels. In this review, we will summarize the currently available literature regarding the clinical efficacy and potential mechanisms of Kampo medicines in the treatment of cancer chemotherapy induced side effects.

TRANSPLANTATION OF HUMAN AMNIOTIC MEMBRANE-DERIVED MESENCHYMAL STEM CELLS IMPROVES RADIATION ENTERITIS
Minori Honda, Shunsuke Ohnishi, Masayoshi Ono, Kenichi Yamahara, Jun Yoshimatsu, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
PLACENTA, 35, 10, A7, A7, W B SAUNDERS CO LTD, 2014年10月, ［査読有り］
英語

THE ANTI-INFLAMMATORY EFFECT OF HUMAN AMNION-DERIVED MESENCHYMAL STEM CELLS
Reizo Onishi, Shunsuke Ohnishi, Ryosuke Higashi, Kenichi Yamahara, Jun Yoshimatsu, Takehiko Katsurada, Naoto Okubo, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
PLACENTA, 35, 10, A23, A23, W B SAUNDERS CO LTD, 2014年10月, ［査読有り］
英語

[Sensitization to laboratory animal allergens among students and researchers exposed to laboratory rodents in Hokkaido university].
Yoshimura A, Musashi M, Kaneko T, Ohnishi S, Orito C, Kawahara Y, Hashino S, Morimatsu M, Konno S, Arikawa J, Ishii T, Sawamura M, Ueda I
Arerugi = [Allergy], 63, 8, 1132, 1139, 一般社団法人 日本アレルギー学会, 2014年09月, ［査読有り］
日本語, 【目的】北海道大学で発生したマウス咬傷によるアナフィラキシー事例を踏まえ,アレルギー予防対策の構築を目的として,動物実験を実施する学生及び職員の動物アレルギーの感作状況を調査した.【方法】齧歯類等の取扱者で同意を得た555名を対象に問診票と実験動物5種に対する特異的IgE抗体と好酸球数測定によるアレルギー健診を実施した.【結果】特異的IgE抗体陽性率(陽性者数/取扱者数)は,マウス14.1% (62/441名),ラット17.9% (50/279名),ハムスター18.8% (6/32名),モルモット17.4% (4/23名),ウサギ11.3% (12/106名)であった.マウス取扱者においては,動物に接触した時に何らかのアレルギー症状が現れる場合は,抗マウスIgE抗体陽性率が有意に高いことも判明した(38.1% vs 8.8%, p<0.01).【結論】動物取扱者の感作状況を把握するために,特異的IgE抗体検査を含む健診を実施することが有用であることが示された.

Rikkunshito, a Traditional Japanese Kampo Medicine, Ameliorates the Decrease in Feeding Behavior in Aged Mice Exposed to Stress via Enhancement of Endogenous Ghrelin Production
Shuichi Muto, Shunsuke Ohnishi, Koji Nakagawa, Chihiro Yamada, Yayoi Saegusa, Miwa Nahata, Chiharu Sadakane, Tomohisa Hattori, Naoya Sakamoto, Hiroshi Takeda
GASTROENTEROLOGY, 146, 5, S848, S849, W B SAUNDERS CO-ELSEVIER INC, 2014年05月, ［査読有り］
英語

Gender Difference Influences Food Intake Under an Emotional Stress via 5-HT2CR Activation in Aged Mice
Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chihiro Yamada, Yayoi Saegusa, Miwa Nahata, Chiharu Sadakane, Tomohisa Hattori, Naoya Sakamoto, Hiroshi Takeda
GASTROENTEROLOGY, 146, 5, S498, S499, W B SAUNDERS CO-ELSEVIER INC, 2014年05月, ［査読有り］
英語

The Possibility of Rikkunshito As a Treatment for Anorexia: a Proposal From a Basic Research Perspective
Hiroshi Takeda, Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Naoya Sakamoto
GASTROENTEROLOGY, 146, 5, S899, S899, W B SAUNDERS CO-ELSEVIER INC, 2014年05月, ［査読有り］
英語

Association of Abnormal Ghrelin Dynamics With Delayed Gastric Emptying in Acute Restraint-Stressed Mice
Hiroshi Takeda, Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Naoya Sakamoto
GASTROENTEROLOGY, 146, 5, S658, S658, W B SAUNDERS CO-ELSEVIER INC, 2014年05月, ［査読有り］
英語

EGFR Inhibitors Eliminate Esophageal Cancer Stem Cells by Suppressing Epithelial-Mesenchymal Transition
Mitsuteru Natsuizaka, Bongani Kaimila, Yoshimasa Kubota, Yutaka Hatanaka, Katsuji Marukawa, Katsumi Terashita, Fumiyuki Satou, Shunsuke Ohnishi, Goki Suda, Shinya Ohashi, Shingo Kagawa, Kelly A. Whelan, Anil K. Rustgi, Hiroshi Nakagawa, Naoya Sakamoto
GASTROENTEROLOGY, 146, 5, S821, S821, W B SAUNDERS CO-ELSEVIER INC, 2014年05月, ［査読有り］
英語

Comparison of Angiogenic, Cytoprotective, and Immunosuppressive Properties of Human Amnion- and Chorion-Derived Mesenchymal Stem Cells
Kenichi Yamahara, Kazuhiko Harada, Makiko Ohshima, Shin Ishikane, Shunsuke Ohnishi, Hidetoshi Tsuda, Kentaro Otani, Akihiko Taguchi, Toshihiro Soma, Hiroyasu Ogawa, Shinji Katsuragi, Jun Yoshimatsu, Mariko Harada-Shiba, Kenji Kangawa, Tomoaki Ikeda
PLOS ONE, 9, 2, PUBLIC LIBRARY SCIENCE, 2014年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Although mesenchymal stem cells (MSCs) can be obtained from the fetal membrane (FM), little information is available regarding biological differences in MSCs derived from different layers of the FM or their therapeutic potential. Isolated MSCs from both amnion and chorion layers of FM showed similar morphological appearance, multipotency, and cell-surface antigen expression. Conditioned media obtained from amnion-and chorion-derived MSCs inhibited cell death caused by serum starvation or hypoxia in endothelial cells and cardiomyocytes. Amnion and chorion MSCs secreted significant amounts of angiogenic factors including HGF, IGF-1, VEGF, and bFGF, although differences in the cellular expression profile of these soluble factors were observed. Transplantation of human amnion or chorion MSCs significantly increased blood flow and capillary density in a murine hindlimb ischemia model. In addition, compared to human chorion MSCs, human amnion MSCs markedly reduced T-lymphocyte proliferation with the enhanced secretion of PGE2, and improved the pathological situation of a mouse model of acute graft-versus-host disease. Our results highlight that human amnion-and chorion-derived MSCs, which showed differences in their soluble factor secretion and angiogenic/immuno-suppressive function, could be ideal cell sources for regenerative medicine.

Administration of exogenous acylated ghrelin or rikkunshito, an endogenous ghrelin enhancer, improves the decrease in postprandial gastric motility in an acute restraint stress mouse model
H. Takeda, N. Sakamoto, T. Hattori, S. Ohnishi, N. Okubo, K. Nakagawa, C. Yamada, C. Sadakane, Y. Saegusa, M. Nahata
Neurogastroenterology and Motility, 26, 6, 821, 831, Blackwell Publishing Ltd, 2014年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Physical or psychological stress causes functional disorders in the upper gastrointestinal tract. This study aims to elucidate the ameliorating effect of exogenous acylated ghrelin or rikkunshito, a Kampo medicine which acts as a ghrelin enhancer, on gastric dysfunction during acute restraint stress in mice. Methods: Fasted and postprandial motor function of the gastric antrum was wirelessly measured using a strain gauge force transducer and solid gastric emptying was detected in mice exposed to restraint stress. Plasma corticosterone and ghrelin levels were also measured. To clarify the role of ghrelin on gastrointestinal dysfunction in mice exposed to stress, exogenous acylated ghrelin or rikkunshito was administered, then the mice were subjected to restraint stress. Key Results: Mice exposed to restraint stress for 60 min exhibited delayed gastric emptying and increased plasma corticosterone levels. Gastric motility was decreased in mice exposed to restraint stress in both fasting and postprandial states. Restraint stress did not cause any change in plasma acylated ghrelin levels, but it significantly increased the plasma des-acyl ghrelin levels. Administration of acylated ghrelin or rikkunshito improved the restraint stress-induced delayed gastric emptying and decreased antral motility. Ameliorating effects of rikkunshito on stress-induced gastric dysfunction were abolished by simultaneous administration of a ghrelin receptor antagonist. Conclusions &
Inferences: Plasma acylated/des-acyl ghrelin imbalance was observed in acute restraint stress. Supplementation of exogenous acylated ghrelin or enhancement of endogenous ghrelin signaling may be useful in the treatment of decreased gastric function caused by stress. © 2014 The Authors. Neurogastroenterology &
Motility published by John Wiley &
Sons Ltd.

Altered levels of serum sphingomyelin and ceramide containing distinct acyl chains in young obese adults
Hanamatsu Hisatoshi, Ohnishi Shunsuke, Sakai Shota, Yuyama Kohei, Mitsutake S., Takeda Hiroshi, Hashino Satoshi, Igarashi Yasuyuki
Nutrition & diabetes, 4, e141, Nature Publishing Group, 2014年, ［査読有り］
英語, 研究論文（学術雑誌）, OBJECTIVE: Recent studies indicate that sphingolipids, sphingomyelin (SM) and ceramide (Cer) are associated with the development of metabolic syndrome. However, detailed profiles of serum sphingolipids in the pathogenesis of this syndrome are lacking. Here we have investigated the relationship between the molecular species of sphingolipids in serum and the clinical features of metabolic syndrome, such as obesity, insulin resistance, fatty liver disease and atherogenic dyslipidemia. SUBJECTS: We collected serum from obese (body mass index, BMI >= 35, n = 12) and control (BMI = 20 - 22, n = 11) volunteers (18 - 27 years old), measured the levels of molecular species of SM and Cer in the serum by liquid chromatography-mass spectrometry and analyzed the parameters for insulin resistance, liver function and lipid metabolism by biochemical blood test. RESULTS: The SM C18:0 and C24:0 levels were higher, and the C20:0 and C22:0 levels tended to be higher in the obese group than in the control group. SM C18:0, C20:0, C22:0 and C24:0 significantly correlated with the parameters for obesity, insulin resistance, liver function and lipid metabolism, respectively. In addition, some Cer species tended to correlate with these parameters. However, SM species containing unsaturated acyl chains and most of the Cer species were not associated with these parameters. CONCLUSIONS: The present results demonstrate that the high levels of serum SM species with distinct saturated acyl chains (C18:0, C20:0, C22:0 and C24:0) closely correlate with the parameters of obesity, insulin resistance, liver function and lipid metabolism, suggesting that these SM species are associated with the development of metabolic syndrome and serve as novel biomarkers of metabolic syndrome and its associated diseases.

A pivotal role of KLF5 in regulation of cancer stem-like cells in hepatocellular carcinoma
Mitsuteru Natsuizaka, Osamu Maehara, Fumiyuki Sato, Yoshimasa Kubota, Goki Suda, Jun Itoh, Seiji Tsunematsu, Yoko Tsukuda, Katsumi Terashita, Masato Nakai, Takuya Sho, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
HEPATOLOGY, 60, 825A, 825A, WILEY-BLACKWELL, 2014年, ［査読有り］
英語

Pathophysiologic Basis of Anorexia: Focus on the Interaction between Ghrelin Dynamics and the Serotonergic System
Hiroshi Takeda, Koji Nakagawa, Naoto Okubo, Mie Nishimura, Shuichi Muto, Shunsuke Ohnishi, Naoya Sakamoto, Hidetaka Hosono, Masahiro Asaka
BIOLOGICAL & PHARMACEUTICAL BULLETIN, 36, 9, 1401, 1405, PHARMACEUTICAL SOC JAPAN, 2013年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Anorexia is an important issue in the management of elderly patients with cancer because it contributes to the development of malnutrition, increases morbidity and mortality, and negatively affects patients' quality of life. This review summarizes the potential mechanisms of the development of anorexia in three animal models that mimic the situations commonly seen in elderly patients receiving chemotherapy. Cisplatin-induced anorexia is attributable to a decrease in peripheral and central ghrelin secretion caused by the stimulation of serotonin (5-hydroxytryptamine; 5-HT)(2B) and 5-HT2C receptors via 5-HT secretion. Age-associated anorexia is caused by an increase in plasma leptin, which results from disturbed reactivity of ghrelin in the hypothalamus and regulation of ghrelin secretion. Environmental change causes the activation of central 5-HT1B and 5-HT2C receptors and the melanocortin-4 receptor system, resulting in a decrease in circulating ghrelin levels which lowers food intake. New therapeutic approaches based on these pathophysiological mechanisms are warranted for the treatment of anorexia in cancer patients, especially elderly ones.

Activation of Corticotropin-Releasing Factor 2 and Melanocortin-4 Receptors Mediates the Persistent Loss of Appetite Induced by Stress Loading in Advanced Age
Hiroshi Takeda, Shuichi Muto, Shunsuke Ohnishi, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 144, 5, S712, S713, W B SAUNDERS CO-ELSEVIER INC, 2013年05月, ［査読有り］
英語, 0

Involvement of Ghrelin Signaling Dysfunction in Acute Restraint Stress-Induced Delayed Gastric Emptying
Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Masahiro Asaka, Naoya Sakamoto, Hiroshi Takeda
GASTROENTEROLOGY, 144, 5, S542, S542, W B SAUNDERS CO-ELSEVIER INC, 2013年05月, ［査読有り］
英語

Serotonin 2C Receptor Antagonism Improves Stress-Induced Anorexia in Aged Mice
Muto Shuichi, Ohnishi Shunsuke, Nakagawa Koji, Sadakane Chiharu, Saegusa Yayoi, Nahata Miwa, Yamada Chihiro, Hattori Tomohisa, Asaka Masahiro, Takeda Hiroshi
GASTROENTEROLOGY, 144, 5, S714, 2013年05月, ［査読有り］

Transplantaion of Human Fetal Membrane-Derived Mesenchymal Stem Cells Improves Severe Colitis Induced by Dextran Sulfate Sodium in Rats
Reizo Onishi, Shunsuke Ohnishi, Ryosuke Higashi, Michiko Watari, Waka Kobayashi, Takehiko Katsurada, Hiroshi Takeda, Naoya Sakamoto
GASTROENTEROLOGY, 144, 5, S811, S812, W B SAUNDERS CO-ELSEVIER INC, 2013年05月, ［査読有り］
英語

Gender Differences in the Action Mechanisms of Rikkunshito, a Ghrelin Signaling Enhancer, on the Improvement of Food Intake After Exposure to a Novel Environmental Stress in Aged Mice
Chihiro Yamada, Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka, Hiroshi Takeda
GASTROENTEROLOGY, 144, 5, S512, S513, W B SAUNDERS CO-ELSEVIER INC, 2013年05月, ［査読有り］
英語, 0

Hypoxia-Inducible Factors Activate CD133 Promoter through ETS Family Transcription Factors
Kikuko Takagi, Ryosuke Higashi, Hiroshi Takeda, Masanobu Kobayashi, Naoya Sakamoto, Masahiro Asaka, Hirotoshi Fujita, Kanako Otaki, Ayano Kameya, Koji Nakagawa, Osamu Maehara, Shunsuke Ohnishi
Plos One, 8, 6, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, CD133 is a cellular surface protein that has been reported to be a cancer stem cell marker, and thus it is considered to be a potential target for cancer treatment. However, the mechanism regulating CD133 expression is not yet understood. In this study, we analyzed the activity of five putative promoters (P1-P5) of CD133 in human embryonic kidney (HEK) 293 cells and colon cancer cell line WiDr, and found that the activity of promoters, particularly of P5, is elevated by overexpression of hypoxia-inducible factors (HIF-1α and HIF-2α). Deletion and mutation analysis identified one of the two E-twenty six (ETS) binding sites (EBSs) in the P5 region as being essential for its promoter activity induced by HIF-1α and HIF-2α. In addition, a chromatin imunoprecipitation assay demonstrated that HIF-1α and HIF-2α bind to the proximal P5 promoter at the EBSs. The immunoprecipitation assay showed that HIF-1α physically interacts with Elk1
however, HIF-2α did not bind to Elk1 or ETS1. Furthermore, knockdown of both HIF-1α and HIF-2α resulted in a reduction of CD133 expression in WiDr. Taken together, our results revealed that HIF-1α and HIF-2α activate CD133 promoter through ETS proteins. © 2013 Ohnishi et al.

Rikkunshito, a Japanese Kampo Medicine, Ameliorates Decreased Feeding Behavior via Ghrelin and Serotonin 2B Receptor Signaling in a Novelty Stress Murine Model
Chihiro Yamada, Yayoi Saegusa, Koji Nakagawa, Shunsuke Ohnishi, Shuichi Muto, Miwa Nahata, Chiharu Sadakane, Tomohisa Hattori, Naoya Sakamoto, Hiroshi Takeda
BIOMED RESEARCH INTERNATIONAL, 2013, HINDAWI LTD, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, We investigated the effects of rikkunshito (RKT), a ghrelin signal enhancer, on the decrease in food intake after exposure to novelty stress in mice. RKT administration (500 mg/kg, per os) improved the decrease in 6 h cumulative food intake. In control mice, the plasma acylated ghrelin levels significantly increased by 24 h fasting. In contrast, the acylated ghrelin levels did not increase by fasting in mice exposed to the novelty stress. RKT administration to the novelty stress mice showed a significant increase in the acylated ghrelin levels compared with that in the distilled-water-treated control mice. Food intake after administering serotonin 2B (5-HT2B) receptor antagonists was evaluated to clarify the role of 5-HT2B receptor activation in the decrease in feeding behavior after novelty stress. SB215505 and SB204741, 5-HT2B receptor antagonists, significantly improved the decrease in food intake after exposure to novelty stress. A component of RKT, isoliquiritigenin, prevented the decrease in 6 h cumulative food intake. Isoliquiritigenin showed 5-HT2B receptor antagonistic activity in vitro. In conclusion, the results suggested that RKT improves the decrease in food intake after novelty stress probably via 5-HT2B receptor antagonism of isoliquiritigenin contained in RKT.

Serotonin 2C receptor antagonism ameliorates novelty-induced hypophagia in aged mice
Hiroshi Takeda, Masahiro Asaka, Tomohisa Hattori, Seiichi Iizuka, Yayoi Saegusa, Chiharu Sadakane, Shunsuke Ohnishi, Koji Nakagawa, Shuichi Muto, Miwa Nahata
Psychoneuroendocrinology, 38, 10, 2051, 2064, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, This study was conducted to clarify the role of serotonin (5-hydroxytryptamine, 5-HT) 2C receptor (5-HT2CR) signaling during novelty-induced hypophagia in aged mice. Male C57BL/6J mice [6-week-old (young) and 79-80-week-old (aged) mice] were exposed to a novel environment, and its effects on feeding behavior, stress hormones, and appetite-related factors were examined. Exposure of aged mice to a novel environment suppressed food intake and increased corticosterone secretion. These responses were marked compared with those in young mice. The expression in hypothalamic corticotropin-releasing factor (CRF), pituitary CRF1R and proopiomelanocortin mRNA in aged mice exposed to a novel environment was increased or tended to increase, compared to control mice. 5-HT2CR antagonist, SB242084 or rikkunshito administration attenuated the decrease in food intake and increased stress hormone levels in aged mice exposed to the environmental change. The 5-HT2CR mRNA expression in paraventricular nucleus was significantly enhanced, when aged mice was exposure to the novel environment. Thus, novelty-induced hypophagia in aged mice resulted, at least in part, from up-regulated hypothalamic 5-HT2CR function. In conclusion, 5-HT2CR signaling enhancement and the subsequent activation of the CRF neuron were involved in novelty-induced hypophagia in aged mice, and the 5-HT2CR antagonists offer a promising therapeutic option for depression. © 2013 Elsevier Ltd.

Rikkunshito and Ghrelin Secretion
Hiroshi Takeda, Shuichi Muto, Koji Nakagawa, Shunsuke Ohnishi, Masahiro Asaka
CURRENT PHARMACEUTICAL DESIGN, 18, 31, 4827, 4838, BENTHAM SCIENCE PUBL LTD, 2012年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Rikkunshito is a kampo herbal medicine which is widely used in Japan for the treatment of the upper gastrointestinal symptoms of patients with functional dyspepsia (FD), gastroesophageal reflux disease (GERD), dyspeptic symptoms of postgastrointestinal surgery patients, and chemotherapy-induced dyspepsia in cancer patients. Recently, very unique characteristics of rikkunshito have been unveiled; oral administration of rikkunshito potentiates orexigenic action of ghrelin through several different mechanisms. In addition, several lines of evidence obtained from both animal and human studies indicate that rikkunshito can be an attractive and promising therapeutic option for the anorectic conditions including cisplatin-induced dyspepsia, anorexia of aging, stress-induced hypophagia, cancer cachexia-anorexia syndrome. In this review, we will highlight what is known about the orexigenic effect of rikkunshito with a special focus on an interaction with ghrelin signaling system.

Potential New Treatment to Alleviate Stress-Induced Anorexia
Shuichi Muto, Hiroshi Takeda, Shunsuke Ohnishi, Koji Nakagawa, Yayoi Saegusa, Miwa Nahata, Chiharu Sadakane, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 142, 5, S293, S293, W B SAUNDERS CO-ELSEVIER INC, 2012年05月, ［査読有り］
英語

The Ghrelin Enhancer Rikkunshito Improves Gastric Dysmotility in Restraint Stress Mice
Hiroshi Takeda, Shuichi Muto, Shunsuke Ohnishi, Koji Nakagawa, Miwa Nahata, Yayoi Saegusa, Chiharu Sadakane, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 142, 5, S891, S891, W B SAUNDERS CO-ELSEVIER INC, 2012年05月, ［査読有り］
英語

A Study on Gender Differences in Feeding Behavior and Plasma Acyl Ghrelin Levels in Aged Mice Following Exposure to a Novel Environmental Stress
Shunsuke Ohnishi, Hiroshi Takeda, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Miwa Nahata, Yayoi Saegusa, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 142, 5, S559, S559, W B SAUNDERS CO-ELSEVIER INC, 2012年05月, ［査読有り］
英語

Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease
Hiroshi Takeda, Masahiro Asaka, Tomohisa Hattori, Yayoi Saegusa, Chiharu Sadakane, Koji Nakagawa, Nobuhiko Oridate, Shunsuke Ohnishi, Shuichi Muto, Miwa Nahata
AJP: Gastrointestinal and Liver Physiology, 303, 1, G42, G53, AMER PHYSIOLOGICAL SOC, 2012年, ［査読有り］
英語, 研究論文（学術雑誌）, Nahata M, Muto S, Oridate N, Ohnishi S, Nakagawa K, Sadakane C, Saegusa Y, Hattori T, Asaka M, Takeda H. Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease. Am J Physiol Gastrointest Liver Physiol 303: G42-G53, 2012. First published April 19, 2012; doi:10.1152/ajpgi.00462.2011.-Gastroesophageal reflux disease (GERD) is often associated with decreased upper gastrointestinal motility, and ghrelin is an appetite-stimulating hormone known to increase gastrointestinal motility. We investigated whether ghrelin signaling is impaired in rats with GERD and studied its involvement in upper gastrointestinal motility. GERD was induced surgically in Wistar rats. Rats were injected intravenously with ghrelin (3 nmol/rat), after which gastric emptying, food intake, gastroduodenal motility, and growth hormone (GH) release were investigated. Furthermore, plasma ghrelin levels and the expression of ghrelin-related genes in the stomach and hypothalamus were examined. In addition, we administered ghrelin to GERD rats treated with rikkunshito, a Kampo medicine, and examined its effects on gastroduodenal motility. GERD rats showed a considerable decrease in gastric emptying, food intake, and antral motility. Ghrelin administration significantly increased gastric emptying, food intake, and antral and duodenal motility in sham-operated rats, but not in GERD rats. The effect of ghrelin on GH release was also attenuated in GERD rats, which had significantly increased plasma ghrelin levels and expression of orexigenic neuropeptide Y/agouti-related peptide mRNA in the hypothalamus. The number of ghrelin-positive cells in the gastric body decreased in GERD rats, but the expression of gastric preproghrelin and GH secretagogue receptor mRNA was not affected. However, when ghrelin was exogenously administered to GERD rats treated with rikkunshito, a significant increase in antral motility was observed. These results suggest that gastrointestinal dysmotility is associated with impaired ghrelin signaling in GERD rats and that rikkunshito restores gastrointestinal motility by improving the ghrelin response.

Ghrelin Treatment of Cachectic Patients with Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
Kenji Kangawa, Kenichi Yamahara, Masanori Yoshikawa, Nobuhiro Matsumoto, Yasuji Arimura, Yoshitaka Tateishi, Kenji Yoshimura, Seigo Kitada, Toru Hiraga, Shunsuke Ohnishi, Shinsuke Murakami, Hiroshi Kimura, Masamitsu Nakazato, Ryoji Maekura, Noritoshi Nagaya, Keisuke Miki
Plos One, 7, 5, PUBLIC LIBRARY SCIENCE, 2012年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Pulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated.
Methodology/Principal Findings: In a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 mg/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p = 0.033) and was maintained at Week 7 (+47 m, within-group p = 0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p = 0.026), in MRC (between-group p = 0.030), and in maximal expiratory pressure (MEP; between-group p = 0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p = 0.049) and MEP (p = 0.021). Ghrelin treatment was well tolerated.
Conclusions/Significance: In cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD.

Rikkunshito as a Ghrelin Enhancer
Hiroshi Takeda, Shuichi Muto, Koji Nakagawa, Shunsuke Ohnishi, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka
GHRELIN, 514, 333, 351, ELSEVIER ACADEMIC PRESS INC, 2012年, ［査読有り］
英語, 論文集(書籍)内論文, Rikkunshito is a kampo herbal medicine which is widely used in Japan for the treatment of the upper gastrointestinal symptoms of patients with functional dyspepsia, gastroesophageal reflux disease, dyspeptic symptoms of postgastrointestinal surgery patients, and chemotherapy-induced dyspepsia in cancer patients. Recently, very unique characteristics of rikkunshito have been unveiled; oral administration of rikkunshito potentiates orexigenic action of ghrelin through several different mechanisms. In addition, several lines of evidence obtained from both animal and human studies indicate that rikkunshito can be an attractive and promising therapeutic option for the anorectic conditions including cisplatin-induced dyspepsia, anorexia of aging, stress-induced hypophagia, and cancer cachexia anorexia syndrome. In this chapter, we highlight the orexigenic effect of rikkunshito with a special focus on its interaction with ghrelin signaling system.

Decreased plasma ghrelin contributes to anorexia following novelty stress
Yayoi Saegusa, Hiroshi Takeda, Shuichi Muto, Koji Nakagawa, Shunsuke Ohnishi, Chiharu Sadakane, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 301, 4, E685, E696, AMER PHYSIOLOGICAL SOC, 2011年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Saegusa Y, Takeda H, Muto S, Nakagawa K, Ohnishi S, Sadakane C, Nahata M, Hattori T, Asaka M. Decreased plasma ghrelin contributes to anorexia following novelty stress. Am J Physiol Endocrinol Metab 301: E685-E696, 2011. First published June 28, 2011; doi:10.1152/ajpendo.00121.2011.-We hypothesized that anorexia induced by novelty stress caused by exposure to a novel environment may be due to activation of corticotropin-releasing factor (CRF) and subsequently mediated by decreasing peripheral ghrelin concentration via serotonin (5-HT) and melanocortin-4 receptors (MC4R). Each mouse was transferred from group-housed cages to individual cages to establish the novelty stress. We observed the effect of changes in feeding behavior in a novel environment using the method of transferring group-housed mice to individual cages. We investigated the effect of an intracerebroventricular injection of antagonists/agonists of CRF1/2 receptors (CRF1/2Rs), 5-HT(1B/2C) receptors (5-HT(1B/2C)R), and MC4R to clarify the role of each receptor on the decrease in food intake. Plasma ghrelin levels were also measured. The novelty stress caused a reduction in food intake that was abolished by administering a CRF1R antagonist. Three hours after the novelty stress, appetite reduction was associated with reduced levels of neuropeptide Y/agouti-related peptide mRNA, increased levels of proopiomelanocortin mRNA in the hypothalamus, and a decrease in plasma ghrelin level. Administering a CRF1R antagonist, a 5-HT(1B/2C)R antagonist, an MC4R antagonist, exogenous ghrelin, and an enhancer of ghrelin secretion, rikkunshito, resolved the reduction in food intake 3 h after the novelty stress by enhancing circulating ghrelin concentrations. We showed that anorexia during a novelty stress is a process in which CRF1R is activated at the early stage of appetite loss and is subsequently activated by a 5-HT(1B/2C)R and MC4R stimulus, leading to decreased peripheral ghrelin concentrations.

10-Gingerol, a component of rikkunshito, improves cisplatin-induced anorexia by inhibiting acylated ghrelin degradation
Chiharu Sadakane, Shuichi Muto, Koji Nakagawa, Shunsuke Ohnishi, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka, Hiroshi Takeda
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 412, 3, 506, 511, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Rikkunshito (RKT), a Japanese traditional medicine, has been shown to stimulate food intake in rats with cisplatin-induced anorexia: however, the underlying mechanisms remain unknown. In this study, we investigated whether RKT is involved in the degradation of peripheral ghrelin. RKT inhibited decreases in plasma ghrelin level and enhanced acyl- to desacyl-ghrelin (A/D) ratio in cisplatin-treated rats. Several components of RKT demonstrated inhibitory activity against ghrelin deacylating enzymes. In addition, 10-gingerol, a component of RKT, inhibited exogenous ghrelin deacylation. Therefore, RKT may enhance plasma acyl-ghrelin level, at least in part, by inhibiting the circulating ghrelin degrading enzyme. (C) 2011 Elsevier Inc. All rights reserved.

Novelty Stress-Induced Anorexia is Due to the Decrease in the Plasma Ghrelin Level via 5-HT1b/(2c)-Melanocortin4 System Activation
Shuichi Muto, Hiroshi Takeda, Shunsuke Ohnishi, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 140, 5, S833, S833, W B SAUNDERS CO-ELSEVIER INC, 2011年05月, ［査読有り］
英語

Potential New Treatment to Alleviate Chemotherapy Anorexia
Shunsuke Ohnishi, Hiroshi Takeda, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 140, 5, S861, S861, W B SAUNDERS CO-ELSEVIER INC, 2011年05月, ［査読有り］
英語

Stress-Related Differences in Appetite-Related Genes Between Advanced-Age Male and Female Mice
Shuichi Muto, Hiroshi Takeda, Shunsuke Ohnishi, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 140, 5, S358, S358, W B SAUNDERS CO-ELSEVIER INC, 2011年05月, ［査読有り］
英語

Influence of Gender on Peripheral Ghrelin Secretion. -Examination in the Aging Mice-
Shunsuke Ohnishi, Hiroshi Takeda, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 140, 5, S357, S357, W B SAUNDERS CO-ELSEVIER INC, 2011年05月, ［査読有り］
英語

Impaired Gastric Emptying in Gastroesophageal Reflux Disease Rat Models is Caused by a Reduced Response to Ghrelin
Hiroshi Takeda, Shuichi Muto, Nobuhiko Oridate, Shunsuke Ohnishi, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Tomohisa Hattori, Masahiro Asaka
GASTROENTEROLOGY, 140, 5, S481, S482, W B SAUNDERS CO-ELSEVIER INC, 2011年05月, ［査読有り］
英語

Gene and protein expression analysis of mesenchymal stem cells derived from rat adipose tissue and bone marrow
Masakazu Yamagishi, Toshinari Tsubokawa, Masa-aki Kawashiri, Kenshi Hayashi, Tetsuo Konno, Shu Takabatake, Kenichi Yamahara, Shunsuke Ohnishi, Noritoshi Nagaya, Chiaki Nakanishi
Circulation Journal: Official Journal of the Japanese Circulation Society, 75, 9, 2260, 2268, JAPANESE CIRCULATION SOC, 2011年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Mesenchymal stem cells (MSC) are multipotent and reside in bone marrow (BM), adipose tissue and many other tissues. However, the molecular foundations underlying the differences in proliferation, differentiation potential and paracrine effects between adipose tissue-derived MSC (ASC) and BM-derived MSC (BM-MSC) are not well-known. Therefore, we investigated differences in the gene and secretory protein expressions of the 2 types of MSC.
Methods and Results: ASC and BM-MSC were obtained from subcutaneous adipose tissue and BM of adult Lewis rats. ASC proliferated as rapidly as BM-MSC, and had expanded 200-fold in approximately 2 weeks. On microarray analysis of 31,099 genes, 571 (1.8%) were more highly (>3-fold) expressed in ASC, and a number of these genes were associated with mitosis and immune response. On the other hand, 571 genes (1.8%) were more highly expressed in BM-MSC, and some of these genes were associated with organ development and morphogenesis. In secretory protein analysis, ASC secreted significantly larger amounts of growth factor and inflammatory cytokines, such as vascular endothelial growth factor, hepatocyte growth factor and interleukin 6, whereas BM-MSC secreted significantly larger amounts of stromal-derived factor-1 alpha.
Conclusions: There are significant differences between ASC and BM-MSC in the cytokine secretome, which may provide clues to the molecule mechanisms associated with tissue regeneration and alternative cell sources. (Circ J 2011; 75: 2260-2268)

Macrophage migration inhibitory factor contributes to development of nonsteroidal anti-inflammatory drugs-induced gastric injury in mice
Masahiro Asaka, Jun Nishihira, Mototsugu Kato, Shunsuke Ohnishi, Hiroshi Takeda, Tatsuya Ohkawara
International Immunopharmacology, 11, 4, 418, 423, ELSEVIER SCIENCE BV, 2011年, ［査読有り］
英語, 研究論文（学術雑誌）, Macrophage migration inhibitory factor (MIF) plays an important role in the development of inflammation. In this study, we evaluated the role of MIF in gastric injury induced by non-steroidal anti-inflammatory drugs (NSAIDs) in mice. To induce gastric injury, mice were intraperitnoneally injected with 35 mg/kg of indomethacin. The level of MIF protein was up-regulated and severe gastric injury with inflammatory infiltrate was observed in the stomach of wild-type (WT) mice treated with indomethacin. The severity of gastric injury in MIF-deficient mice was less than that in WT mice. Increase in TNF-alpha in gastric tissue of mice treated with indomethacin was suppressed in MIF-deficient mice. The expression of HSP70, which has a cytoprotective role, was remarkably up-regulated in the stomach of MIF-deficient mice compared with WT mice after indomethacin treatment. Our results suggest that MIF is essential for the development of gastric injury-induced by NSAIDs. (C) 2010 Elsevier B.V. All rights reserved.

Sustained-release adrenomedullin ointment accelerates wound healing of pressure ulcers
Tomoaki Ikeda, Noritoshi Nagaya, Kenji Kangawa, Naoto Minamino, Hatsue Ishibashi-Ueda, Hirohisa Kanoh, Kentaro Otani, Shunsuke Ohnishi, Kenichi Yamahara, Kazuhiko Harada
Regulatory Peptides, 168, 1-3, 21, 26, ELSEVIER SCIENCE BV, 2011年, ［査読有り］
英語, 研究論文（学術雑誌）, Pressure ulcers are one of the most common complications in elderly, incontinent or paralyzed patients. For the healing of pressure ulcers, the development of granulation tissue and reepithelialization is required. Adrenomedullin (AM), an endogenous vasodilator peptide, is reported to stimulate the proliferation and migration of various cells including endothelial cells, fibroblasts and keratinocytes. Therefore, we hypothesized that AM might accelerate the healing process of pressure ulcers in which these cells were involved. We developed a sustained-release ointment containing human recombinant AM, and applied it in a mouse model of pressure ulcer twice a day for 14 days. Human AM was efficiently absorbed in wound area, but its blood concentration was negligible. AM ointment significantly reduced the wound area on day 5 to 7 after injury. In addition, AM ointment accelerated the formation of granulation tissue and angiogenesis as well as lymphangiogenesis after 7 days of treatment. Immunological analysis revealed that Ki-67-positive proliferating cells in granulation tissue expressed AM receptors. In summary, sustained-release AM significantly improved wound healing of pressure ulcers through acceleration of granulation and induction of angiogenesis and lymphangiogenesis. Therefore, sustained-release AM ointment may be a novel therapeutic agent for pressure ulcers. (C) 2011 Elsevier B.V. All rights reserved.

[Repetition of Helicobacter cinaedi infections during chemotherapy for malignant lymphoma].
Masayoshi Ono, Shunsuke Ohnishi, Reizo Onishi, Shojiro Takahashi, Yoshimitsu Kobayashi, Mio Suzuki, Kimitoshi Kubo, Masayoshi Dazai, Junji Yamamoto, Hisashi Oda, Kenji Tada, Tatsuro Takahashi, Takuto Miyagishima
[Rinsho ketsueki] The Japanese journal of clinical hematology, 51, 12, 1781, 5, 2010年12月, ［国内誌］
日本語, 研究論文（学術雑誌）, A 70-year-old male, who had undergone resection of gastric malignant lymphoma in 1992, presented with cervical lymph node swelling in January 2008. Pathological examination of the lymph node biopsy demonstrated recurrence of malignant lymphoma, and he was treated with the R-CHOP regimen. Although he did not develop fever during the first through third course of R-CHOP, from the fourth course, he repeatedly demonstrated fever over 38°C for about one week after each course of chemotherapy, despite the absence of neutropenia. Helicobacter cinaedi infection was confirmed by blood culture each time. Although it is difficult to diagnose Helicobacter cinaedi infection by the standard culture method, increased numbers of recent reports especially in immunocompromised patients have emphasized the importance of diagnosing Helicobacter cinaedi infection.

Undiagnosed collecting duct carcinoma presenting as meningeal carcinomatosis and multiple bone metastases
Takuto Miyagishima, Tatsuro Takahashi, Kazufumi Tsuzaka, Yoshinori Iwasaki, Masayoshi Dazai, Shunsuke Ohnishi
Internal medicine (Tokyo, Japan), 49, 15, 1541, 1544, JAPAN SOC INTERNAL MEDICINE, 2010年, ［査読有り］
英語, 研究論文（学術雑誌）, A 54-year-old woman presented with blepharoptosis, numbness in the lower lip, dysgeusia and pain in the extremities and back. MRI showed marked meningeal thickening and multiple bone lesions accompanying a prominent enhancing effect. CT scan of the chest and abdomen appeared to be unremarkable for primary cancer. She died 3 months after the admission, and postmortem autopsy showed a mass of about 2.5 cm in diameter in the renal medulla. Histological examination including immunohistochemistry confirmed the presence of a collecting duct carcinoma (CDC). This case is of particular interest because it emphasizes the possible fulminate clinical course of a small CDC.

Pulmonary Sequestration Diagnosed by Three-dimensional Reconstruction Computed Tomography
Ryo Takemura, Shunsuke Ohnishi, Shojiro Takahashi, Takuto Miyagishima
INTERNAL MEDICINE, 49, 15, 1683, 1684, JAPAN SOC INTERNAL MEDICINE, 2010年, ［査読有り］
英語, 研究論文（学術雑誌）

POEMS syndrome complicated by follicular lymphoma.
Takahide SASAKI, Shunsuke OHNISHI, Reizo ONISHI, Ryou TAKEMURA, Yoshimitsu KOBAYASHI, Mio SUZUKI, Masayoshi DAZAI, Tamotsu HATA, Junji YAMAMOTO, Hisashi ODA, Tatsuro TAKAHASHI, Kazuhiro OGASAWARA, Takuto MIYAGISHIMA
[Rinsho ketsueki] The Japanese journal of clinical hematology, 50, 11, 1621, 5, 2009年11月, ［国内誌］
英語, 研究論文（学術雑誌）, A 59-year-old woman presented with ascites and intraperitoneal lymph node swelling. Pathological examination of the lymph node revealed follicular lymphoma. After a lymph node biopsy, she developed atypical genital bleeding, multiple endocrine disorders, polyneuropathy with a high plasma level of vascular endothelial growth factor (VEGF), and was diagnosed with POEMS syndrome. Following administration of methyl prednisolone, ascites immediately decreased and her performance status improved; however, about 18 months later, renal failure occurred, and she died despite increased steroid dosage. Lymph node swelling is often found in POEMS syndrome; however, its histological appearance is not well known, and it is very rare to be concomitant with malignant lymphoma. Therefore, it is important to perform a lymph node biopsy and investigate it in relation with VEGF.

Selective Delivery of siRNA Nanoparticles Targeting MEK Attenuates Experimental Pulmonary Hypertension
Hiroaki Obata, Nobuhiro Yagi, Shunsuke Ohnishi, Kenichi Yamahara, Toshihito Hosokawa, Ichiro Manabe, Makoto Kodama, Yoshifusa Aizawa, Ryozo Nagai, Noritoshi Nagaya
CIRCULATION, 120, 18, S841, S841, LIPPINCOTT WILLIAMS & WILKINS, 2009年11月, ［査読有り］
英語

Involvement of tazarotene-induced gene 1 in proliferation and differentiation of human adipose tissue-derived mesenchymal stem cells
N. Nagaya, S. Kitamura, H. Ogino, S. Ishikane, K. Otani, H. Obata, K. Okabe, S. Ohnishi
Cell Proliferation, 42, 3, 2009年, ［査読有り］
研究論文（学術雑誌）

Nonviral delivery of siRNA into mesenchymal stem cells by a combination of ultrasound and microbubbles
Kentaro Otani, Kenichi Yamahara, Shunsuke Ohnishi, Hiroaki Obata, Soichiro Kitamura, Noritoshi Nagaya
JOURNAL OF CONTROLLED RELEASE, 133, 2, 146, 153, ELSEVIER SCIENCE BV, 2009年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Cell therapy is a promising therapeutic strategy for regenerative medicine. However, its current efficacy is insufficient, because of the short lifetime and low engraftment of transplanted cells. Transplantation of genetically modified stem cells has been reported to improve the efficacy of cell therapy. The aim of this Study was to elucidate the feasibility of a combination Of ultrasound and microbubbles (US-MB) for delivery of small interfering RNA (siRNA) into mesenchymal stem cells (MSC). Although cell damage was observed after US-MB treatment, the transfection efficiency determined using fluorescent-labeled siRNA was significantly increased after US-MB. Furthermore, the intracellular delivery of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) siRNA by US-MB resulted in significant knockdown of PTEN mRNA expression and activation of Akt, a mediator of a survival signaling pathway. Our results indicate that US-MB could serve as a nonviral delivery method of siRNA into MSC. The transplantation of genetically modified MSC by US-MB Could be a useful strategy for regenerative medicine in the future. (C) 2008 Elsevier B.V. All rights reserved.

CONTRAST SONOGRAPHY ENABLES NONINVASIVE AND QUANTITATIVE ASSESSMENT OF NEOVASCULARIZATION AFTER STEM CELL TRANSPLANTATION
Kentaro Otani, Shunsuke Ohnishi, Hiroaki Obata, Osamu Ishida, Soichiro Kitamura, Noritoshi Nagaya
ULTRASOUND IN MEDICINE AND BIOLOGY, 34, 12, 1893, 1900, ELSEVIER SCIENCE INC, 2008年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Stem cell transplantation is one of the attractive therapeutic strategies for the treatment of hindlimb ischemia. However, few studies have quantitatively assessed perfusion noninvasively in deep tissues after cell transplantation. In this study, we examined the feasibility of contrast sonography for the assessment of perfusion after bone marrow-derived mesenchymal stem cell (MSC) transplantation by using a rat unilateral hindlimb ischemia model. The quantitative parameters derived from contrast sonography were compared with the colored microspheres-derived blood flow and the capillary density. Nine rats were assigned each to a control (saline injection) or a treated (MSC transplantation) group. Video intensity vs. pulsing interval plots were acquired with ultraharmonic imaging of SONOS5500 during IV infusion of Levovist. The left-to-right ratio of hindlimb blood volume (beta-ratio). microbubble velocity (beta-ratio) and hindlimb blood flow (A beta-ratio) were calculated. The MS-ratio, the ratio of the left to the right hindlimb blood flow determined using colored microspheres, was also calculated. Although A-ratio did not change, beta- and A beta-ratio in the treated group were significantly higher than those in the control group. In addition, MS-ratio and capillary density in the treated group were significantly higher than those in the control group. Compared with A- and A beta-ratio, beta-ratio had the highest correlation with MS-ratio and capillary density (vs. MS-ratio: r = 0.66, p < 0.01; vs. capillary density: r = 0.52, p < 0.05). The results of our study imply that the contrast sonography-derived beta-ratio is a useful parameter that reflects the perfusion after cell transplantation in ischemic hindlimb. (E-mail: nnagaya@ri.ncvc.go.jp) (C) 2008 World Federation for Ultrasound in Medicine & Biology.

Adrenomedullin Induces Lymphangiogenesis and Ameriolates Secondary Lymphedema
DongHao Jin, Kenich Yamahara, Kazuhiko Harada, Shunsuke Ohnishi, Kenji Kangawa, Noritosh Nagoya
CIRCULATION, 118, 18, S507, S507, LIPPINCOTT WILLIAMS & WILKINS, 2008年10月, ［査読有り］
英語

Therapeutic Potential of Mesenchymal Stem Cells Derived from Three Different Layers of Human Fetal Membrane In Hindlimb Ischemia Model
Kazuhiko Harada, Shunsuke Ohnishi, Kenichi Yamahara, Masaharu Sada, Shin Ishikane, Kenichi Mishima, Katsunori Iwasaki, Michihiro Fujiwara, Kenji Kangawa, Soichiro Kitamura, Noritoshl Nagaya, Tomoaki Ikeda
CIRCULATION, 118, 18, S381, S382, LIPPINCOTT WILLIAMS & WILKINS, 2008年10月, ［査読有り］
英語

Novel sustained-release prostacyclin analog attenuates pulmonary hypertension in rats
Hiroaki Obata, Yoshiki Sakai, Shunsuke Ohnishi, Makoto Kodama, Yoshifusa Aizawa, Noritoshi Nagaya
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 45, S26, S26, ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2008年10月, ［査読有り］
英語

Real-time intraoperative assessment of the extrahepatic bile ducts in rats and pigs using invisible near-infrared fluorescent light
Eiichi Tanaka, Hak Soo Choi, Valerie Humblet, Shunsuke Ohnishi, Rita G. Laurence, John V. Frangioni
SURGERY, 144, 1, 39, 48, MOSBY-ELSEVIER, 2008年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Background. Currently, only x-ray fluoroscopy is available for visualization of the extrahepatic bile ducts intraoperatively. We hypothesized that with an appropriate fluorophore and imaging system, invisible near-infrared (NIR) light could be used for image-guided procedures on the extrahepatic bile ducts.Methods. We quantified the Performance of three 800 nm NIR fluorophores, differing primarily in their degree of hydrophilicity, for real-time imaging of the extrahepatic bile ducts in rats and pigs: IR-786, indocyanine green (ICG), and the carboxylic form of IRDye (TM) 800CW (CW800-CA). The signal-to-background ratio (SBR) of the common bile duct relative to liver and pancreas was measured as a function of the dose of contrast agent, injection site, and kinetics using an intraoperative NIR fluorescence imaging system described previously. Bile samples were examined by high performance liquid chromatography tandem mass spectrometry (HPLC/MS) to determine the chemical form of fluorophores in bile.Results. Non-sulfonated (IR-786) and di-sulfonated (ICG) NIR fluorophores had Poor efficiency and kinetics of excretion into bile. Tetra-sulfonated CW800-CA, however, provided sensitive, specific, and real-time visualization. of the extrahepatic bile ducts after a single low-dose given either intraportally or intravenously via systemic vein. A SBR >= 2 provided sensitive assessment of extrahepatic bile duct anatomy and function for over 30 min post-injection, including them detection of millimeter-sized, radiolucent inclusions in Pigs. CW800-CA remained intact chemically after secretion into bile.Conclusion. The combination of invisible NIR light and an TV injection of CW800-CA provides prolonged, real-time visualization of the extrahepatic bile duct, without ionizing radiation and without changing the look of the operative field.

Paracrine cytoprotective effects of inner chorion-derived human mesenchymal stem cells
Kazuhiko Harada, Noritoshi Nagaya, Shunsuke Ohnishi, Shin Ishikane, Michihiro Fujiwara, Tomoaki Ikeda
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 51, 10, A187, A187, ELSEVIER SCIENCE INC, 2008年03月, ［査読有り］
英語

Transplantation of Mesenchymal Stem Cells Improves Atrioventricular Conduction in a Rat Model of Complete Atrioventricular Block
Miki Yokokawa, Shunsuke Ohnishi, Hatsue Ishibashi-Ueda, Hiroaki Obata, Kentaro Otani, Yoshinori Miyahara, Koichi Tanaka, Wataru Shimizu, Kazuo Nakazawa, Kenji Kangawa, Shiro Kamakura, Soichiro Kitamura, Noritoshi Nagaya
CELL TRANSPLANTATION, 17, 10-11, 1145, 1155, SAGE PUBLICATIONS INC, 2008年, ［査読有り］
英語, 研究論文（学術雑誌）, Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into a variety of lineages including myocytes and vascular endothelial cells. However, little information is available regarding the therapeutic potential of MSCs in patients with atrioventricular block (AVB). We investigated whether local implantation of MSCs improves AV conduction in a rat model of complete AVB. Complete AVB was achieved by injection of ethanol into the AV nodal region of Lewis rats. Five days after ethanol injection, 2 x 10(6) of MSCs (MSC group) or vehicle (Control group) were injected into the AV nodal region. Animals were monitored by electrocardiograms for 14 days, and physiological and histological examinations were performed. The 1:1 AV conduction was recovered in 5 of 15 rats (33670) in the MSC group during the follow-up period, whereas no improvement was observed in the control group. MSC transplantation significantly decreased collagen deposition in the AV node, which was associated with a marked decrease in transforming growth factor-beta 1 expression. In vitro experiments demonstrated that MSCs secreted a large amount of antifibrotic factors such as hepatocyte growth factor and interleukin-10, and MSC conditioned medium inhibited the growth of adult cardiac fibroblasts. In addition, local injection of MSC conditioned medium recovered AV conduction in 2 of 15 rats (13670). MSC transplantation improved AV conduction in a rat model of complete AVB, at least in part through antifibrotic paracrine effects.

Single Injection of a Sustained-release Prostacyclin Analog Improves Pulmonary Hypertension in Rats
Noritoshi Nagaya, Yoshifusa Aizawa, Makoto Kodama, Kenji Kangawa, Hidezo Mori, Satoshi Takeshita, Shunsuke Ohnishi, Yoshiki Sakai, Hiroaki Obata
American Journal of Respiratory and Critical Care Medicine, 177, 2, 195, 201, AMER THORACIC SOC, 2008年, ［査読有り］
英語, 研究論文（学術雑誌）, Rationale: Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. Therefore, we developed a new drug delivery system for prostacyclin. We prepared ONO-1301MS, a novel sustained-release prostacyclin analog polymerized with poly(D, L-lactic-co-glycolic acid) (PLGA) microspheres.
Objectives: We examined whether ONO-1301MS attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats, and attempted to elucidate the underlying mechanisms responsible for the beneficial effects of ONO-1301MS.
Methods: After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle.
Measurements and Main Results: We prepared ONO-1301MS, which was polymerized with PLGA to release ONO-1301 for 3 weeks. A single administration of ONO-1301MS achieved sustained elevation of its circulating level and plasma cyclic adenosine 3',5'-monophosphate level for 3 weeks, and attenuated an increase in a metabolite of thromboxane A(2) level. Rats had developed pulmonary hypertension 3 weeks after MCT injection; however, treatment with ONO-1301MS significantly attenuated the increases in right ventricular systolic pressure and right ventricular weight to body weight ratio. ONO-1301MS significantly inhibited hypertrophy of pulmonary arteries. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the lung was significantly increased in the control group, whereas this increase was markedly attenuated by treatment.
Conclusions: We developed a new drug delivery system for prostacyclin using PLGA and ONO-1301. A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension, partly through its antiproliferative effect on vascular smooth muscle cells via inhibition of ERK phosphorylation.

Allogeneic Injection of Fetal Membrane-Derived Mesenchymal Stem Cells Induces Therapeutic Angiogenesis in a Rat Model of Hind Limb Ischemia
Tomoaki Ikeda, Noritoshi Nagaya, Soichiro Kitamura, Michihiro Fujiwara, Katsunori Iwasaki, Kenichi Mishima, Kazuhiko Harada, Masaharu Sada, Kenichi Yamahara, Shunsuke Ohnishi, Shin Ishikane
Stem Cells, 26, 10, 2625, 2633, ALPHAMED PRESS, 2008年, ［査読有り］
英語, 研究論文（学術雑誌）, Bone marrow-derived mesenchymal stem cells (BM-MSC) have been demonstrated to be an attractive therapeutic cell source for tissue regeneration and repair. However, it remains unknown whether or not allogeneic transplantation of mesenchymal stem cells (MSC) derived from fetal membranes (FM), which are generally discarded as medical waste after delivery, has therapeutic potential. FM-MSC were obtained from Lewis rats and had surface antigen expression and multipotent potential partly similar to those of BM-MSC. Compared with BM-MSC, FM-MSC secreted a comparable amount of hepatocyte growth factor despite a small amount of vascular endothelial growth factor. FM-MSC and BM-MSC both expressed major histocompatibility complex (MHC) class I but not MHC class II antigens and did not elicit allogeneic lymphocyte proliferation in mixed lymphocyte culture. FM-MSC or BM-MSC obtained from Lewis rats were injected into a MHC-mismatched August-Copenhagen-Irish rat model of hind limb ischemia. Three weeks after injection, blood perfusion and capillary density were significantly higher in the FM-MSC and BM-MSC groups than in the phosphate-buffered saline group, and allogeneic FM-MSC and BM-MSC were still observed. In nonischemic hind limb tissues, allogeneic FM-MSC and BM-MSC injection were associated with a comparatively small amount of T lymphocyte infiltration, compared with the injection of allogeneic splenic lymphocytes. In conclusion, allogeneic FM-MSC injection did not elicit a lymphocyte proliferative response and provided significant improvement in a rat model of hind limb ischemia, comparable to the response to BM-MSC. Thus, allogeneic injection of FM-MSC may be a new therapeutic strategy for the treatment of severe peripheral vascular disease. STEM CELLS 2008; 26: 2625-2633

Adrenomedullin induces lymphangiogenesis and ameliorates secondary lymphoedema
N. Nagaya, K. Kangawa, K. Yamahara, S. Ohnishi, K. Harada, D. Jin
Cardiovascular Research, 80, 3, 339, 345, OXFORD UNIV PRESS, 2008年, ［査読有り］
英語, 研究論文（学術雑誌）, Adrenomedullin (AM) is a multifunctional peptide hormone that plays a significant role in vasodilation and angiogenesis. Lymphoedema is a common but refractory disorder that is difficult to be treated with conventional therapy. We therefore investigated whether AM promotes lymphangiogenesis and improves lymphoedema.
The effects of AM on lymphatic endothelial cells (LEC) were investigated. AM promoted proliferation, migration, and network formation of cultured human lymphatic microvascular endothelial cells (HLMVEC). AM increased intracellular cyclic adenosine monophosphate (cAMP) level in HLMVEC. The cell proliferation induced by AM was inhibited by a cAMP antagonist and mitogen-activated protein kinase kinase (MEK) inhibitors. Phosphorylated extracellular signal-regulated kinase (ERK) in HLMVEC was increased by AM. Continuous administration of AM (0.05 mu g/kg/min) to BALB/c mice with tail lymphoedema resulted in a decrease in lymphoedema thickness. AM treatment increased the number of lymphatic vessels and blood vessels in the injury site.
AM promoted LEC proliferation at least in part through the cAMP/MEK/ERK pathway, and infusion of AM induced lymphangiogenesis and improved lymphoedema in mice.

Real-time intraoperative ureteral guidance using invisible near-infrared fluorescence
Eiichi Tanaka, Shunsuke Ohnishi, Rita G. Laurence, Hak Soo Choi, Valerie Humblet, John V. Frangioni
JOURNAL OF UROLOGY, 178, 5, 2197, 2202, ELSEVIER SCIENCE INC, 2007年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: Invisible near-infrared light is safe and it penetrates relatively deeply through tissue and blood without altering the surgical field. Our hypothesis was that near-infrared fluorescence imaging would enable visualization of the ureteral anatomy and flow intraoperatively and in real time.Materials and Methods: CW800-CA (LI-COR, Lincoln, Nebraska), the carboxylic acid form of near-infrared fluorophore IRDye(TM) 800CW, was injected intravenously, and its renal clearance kinetics and imaging performance were quantified in 350 g-m rats and 35 kg pigs. High performance liquid chromatography and electrospray time-of-flight mass spectrometry were used to characterize CW800-CA metabolism in urine. The clinically available near-infrared fluorophore indocyanine green was also used via retrograde injection into the ureter. Using the 2 near-infrared fluorophores the ureters were imaged under the conditions of steady state, intraluminal foreign bodies and injury.Results: In rat models the highest signal-to-background ratio for visualization occurred after intravenous injection of 7.5 mu g/kg CW800-CA with values of 4.0 or greater and 2.3 or greater at 10 and 30 minutes, respectively. In pig models 7.5 mu g/kg CW800-CA clearly visualized the normal ureter and intraluminal. foreign bodies as small as 2.5 mm. in diameter. Retrograde injection of 10 mu M indocyanine green also permitted the detection of normal ureter and pinpointed urine leakage caused by injury. Electrospray time-of-flight mass spectrometry, and absorbance and fluorescence spectral analysis confirmed that the fluorescent material in urine was chemically identical to CW800-CA.Conclusions: A convenient intravenous injection of CW800-CA or direct injection of indocyanine green permits high sensitivity visualization of the ureters under steady state and abnormal conditions using invisible light.

Clinical trial of autologous bone marrow mesenchymal stem cell transplantation for severe chronic heart failure
Noritoshi Nagaya, Hajime Ohgushi, Wataru Shimizu, Masakazu Yamagishi, Teruo Noguchi, Takashi Noda, Kaori Doi, Yoshio Ishida, Shunsuke Ohnishi, Masafumi Kitakaze, Takeshi Nakatani, Hidezo Mori, Shiro Kamakura, Kenji Kangawa, Kunio Miyatake, Hitonobu Tomoike, Soichiro Kitamura
CIRCULATION, 116, 16, 453, 453, LIPPINCOTT WILLIAMS & WILKINS, 2007年10月, ［査読有り］
英語

Infusion of adrenomedullin improves acute myocarditis via attenuation of myocardial inflammation and edema
Bobby Yanagawa, Masaharu Kataoka, Shunsuke Ohnishi, Makoto Kodama, Koichi Tanaka, Yoshinori Miyahara, Hatsue Ishibashi-Ueda, Yoshifusa Aizawa, Kenji Kangawa, Noritoshi Nagaya
CARDIOVASCULAR RESEARCH, 76, 1, 110, 118, OXFORD UNIV PRESS, 2007年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: Our aim was to assess whether adrenomedullin (AM), a potent vasodilator peptide with a variety of cardioprotective effects, has a therapeutic potential for the treatment of acute myocarditis in a rat model.Methods: One week after myosin injection, rats received a continuous infusion of AM or vehicle for 2 weeks, and pathological and physiological investigations were performed.Results: AM treatment significantly reduced the infiltration of inflammatory cells in myocarditic hearts, and decreased the expressions of macrophage chemoattractant protein-1, matrix metalloproteinase-2 and transforming growth factor-beta. Myocardial edema indicated by increased heart weight to body weight ratio and wall thickness was attenuated by AM infusion (5.7 +/- 0.5 vs. 6.5 +/- 0.4 g/kg, and 1.9 +/- 0.3 vs. 2.8 +/- 0.5 mm, respectively). Infusion of AM significantly improved left ventricular maximum dP/dt and fractional shortening of myocarditic hearts (4203 640 vs. 3450 607 mm Hg/s, and 21.3 +/- 4.1 vs. 14.7 +/- 5.1%, respectively).Conclusion: Infusion of AM improved cardiac function and pathological findings in a rat model of acute myocarditis. Thus, infusion of AM may be a potent therapeutic strategy for acute myocarditis. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Lymphatic drainage of the peritoneal space: A pattern dependent on bowel lymphatics
Cherie P. Parungo, David I. Soybel, Yolonda L. Colson, Sang-Wook Kim, Shunsuke Ohnishi, Alec M. DeGrand, Rita G. Laurence, Edward G. Soltesz, Fredrick Y. Chen, Lawrence H. Cohn, Moungi G. Bawendi, John V. Frangioni
ANNALS OF SURGICAL ONCOLOGY, 14, 2, 286, 298, SPRINGER, 2007年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Understanding lymph drainage patterns of the peritoneum could assist in staging and treatment of gastrointestinal and ovarian malignancies. Sentinel lymph nodes (SLNs) have been identified for solid organs and the pleural space. Our purpose was to determine whether the peritoneal space has a predictable lymph node drainage pattern.Methods: Rats received intraperitoneal injections of near-infrared (NIR) fluorescent tracers: namely, quantum dots (designed for retention in SLNs) or human serum albumin conjugated with IRDye800 (HSA800; designed for lymphatic flow beyond the SLN). A custom imaging system detected NIR fluorescence at 10 and 20 minutes and 1, 4, and 24 hours after injection. To determine the contribution of viscera to peritoneal lymphatic flow, additional cohorts received bowel resection before NIR tracer injection. Associations with appropriate controls were assessed with the chi(2) test.Results: Quantum dots drained to the celiac, superior mesenteric, and periportal lymph node groups. HSA800 drained to these same groups at early time points but continued flowing to the mediastinal lymph nodes via the thoracic duct. After bowel resection, both tracers were found in the thoracic, not abdominal, lymph node groups. Additionally, HSA800 was no longer found in the thoracic duct but in the anterior chest wall and diaphragmatic lymphatics.Conclusions: The peritoneal space drains to the celiac, superior mesenteric, and periportal lymph node groups first. Lymph continues via the thoracic duct to the mediastinal lymph nodes. Bowel lymphatics are a key determinant of peritoneal lymph flow, because bowel resection shifts lymph flow directly to the intrathoracic lymph nodes via chest wall lymphatics.

Sentinel lymph node mapping with type-II quantum dots
Frangioni JV, Kim SW, Ohnishi S, Kim S, Bawendi MG
Methods Mol. Biol., 374, 147, 160, 2007年, ［査読有り］
研究論文（学術雑誌）

Mesenchymal Stem Cells for the Treatment of Heart Failure
Noritoshi Nagaya, Soichiro Kitamura, Hajime Ohgushi, Shunsuke Ohnishi
International Journal of Hematology, 86, 1, 17, 21, SPRINGER TOKYO, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, Heart failure is one of the most important cardiovascular health problems throughout the world and has high mortality, and there is a need to develop more effective therapeutic strategies to replace such specialized treatment as mechanical circulatory support and cardiac transplantation. Mesenchymal stem cells (MSC) are multipotent plastic-adherent cells obtained from bone marrow, adipose tissue, and other tissues and can be easily expanded in culture. The ability of MSC to differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells, make them an attractive therapeutic tool for heart failure. Recent in vitro and in vivo studies have revealed the underlying mechanisms of MSC in cardiac repair. MSC exert their role in cardiac regeneration not only by differentiating into specific cell types such as cardiomyocytes and vascular endothelial cells but also through paracrine effects via secretion of a variety of angiogenic, antiapoptotic, and mitogenic factors. Endogenous MSC as well as exogenously administered MSC have also been suggested to migrate and participate in cardiac repair. On the basis of information obtained from basic and translational research, several clinical trials have recently been started to evaluate the safety and efficacy of autologous MSC for heart failure.

CNP infusion attenuates cardiac dysfunction and inflammation in myocarditis
Shunsuke Ohnishi
Biochemical and Biophysical Research Communications, 356, 1, 60, 66, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, Myocarditis is an acute inflammatory disease of the myocardium for which there is currently no specific therapy. We investigated the therapeutic potential of C-type natriuretic peptide (CNP) in acute experimental autoimmune myocarditis. One week after injection of porcine myosin into male Lewis rats, CNP (0.05 mu g/kg/min) was continuously administered for 2 weeks. CNP infusion significantly increased maximum dP/dt, decreased left ventricular end-diastolic pressure, and improved fractional shortening compared with vehicle administration. In vehicle-treated hearts, severe necrosis and marked infiltration of CD68-positive inflammatory cells were observed. Myocardial and serum levels of monocyte chemoattractant protein-1 were elevated in myocarditis. However, these changes were attenuated by CNP infusion. In addition, treatment with CNP significantly increased myocardial capillary density. Guanylyl cyclase-B, a receptor for CNP, was expressed in myocarditic heart, and cyclic guanosine monophosphate was elevated by CNP infusion. In conclusion, CNP infusion attenuated cardiac function in acute myocarditis through anti-inflammatory and angiogenic effects. (c) 2007 Elsevier Inc. All rights reserved.

Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis
Nagaya, Noritoshi, Kitamura, Soichiro, Kangawa, Kenji, Ishibashi-Ueda, Hatsue, Kodama, Makoto, Kataoka, Masaharu, Obata, Hiroaki, Miyahara, Yoshinori, Tanaka, Koichi, Yanagawa, Bobby, Ohnishi, Shunsuke
Journal of Molecular and Cellular Cardiology, 42, 1, 88, 97, ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, Acute myocarditis is a non-ischemic inflammatory disease of the myocardium for which there is currently no specific treatment. We have previously shown that mesenchymal stem cells'(MSC) can ameliorate heart injury during acute ischemia and in dilated cardiomyopathy; however, the therapeutic potential in acute myocarditis is unclear. In this study, we investigated the ability of MSC to attenuate myocardial injury and dysfunction during the acute phase of experimental myocarditis. Ten-week-old male Lewis rats were injected with porcine myosin to induce myocarditis. Cultured MSC (3 x 10(6) cells/rat) were injected intravenously 7 days after myosin injection. At 3 weeks, myosin injection resulted in severe inflammation and significant deterioration of cardiac function. MSC transplantation attenuated increases in CD68-positive inflammatory cells and monocyte chemoattractant protein-1 (MCP-1) expression in myocardium, and improved cardiac function in this model. Furthermore, myocardial capillary density was higher in myocarditis tissue, and was further increased by MSC transplantation. In vitro, cultured adult rat cardiomyocytes were injured in response to MCP-1, whereas this effect was attenuated by MSC-derived conditioned medium, suggesting cardioprotective effects of MSC acting in a paracrine manner. MSC transplantation attenuated myocardial injury and dysfunction in a rat model of acute myocardifis, at least in part through paracrine effects of MSC. (c) 2006 Elsevier Inc. All rights reserved.

Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions
Noritoshi Nagaya, Soichiro Kitamura, Hideaki Sumiyoshi, Shunsuke Ohnishi
FEBS Letters, 581, 21, 3961, 3966, ELSEVIER SCIENCE BV, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, Mesenchymal stem cells (MSC) transplantation has been shown to decrease fibrosis in the heart; however, whether MSC directly influence the function of cardiac fibroblasts (CFB) remains unknown. MSC-conditioned medium significantly attenuated proliferation of CFB compared with CFB-conditioned medium. MSC-conditioned medium upregulated antiproliferation-related genes such as elastin, myocardin and DNA-damage inducible transcript 3, whereas CFB-conditioned medium upregulated proliferation-related genes such as alpha-2-macrogrobulin and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog. MSC-conditioned medium significantly downregulated type I and III collagen expression, and significantly suppressed type III collagen promoter activity. MSC may exert paracrine anti-fibrotic effects at least in part through regulation of CFB proliferation and collagen synthesis. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Gene expression profiles of endothelial progenitor cells by oligonucleotide microarray analysis
Ohnami, Shumpei, Yoshida, Teruhiko, Sakamoto, Hiromi, Sasaki, Hiroki, Aoyagi, Kazuhiko, Ohnishi, Shunsuke, Aoki, Kazunori, Oki, Masayuki, Ando, Kiyoshi, Furuhata, Souichi
Molecular and Cellular Biochemistry, 298, 1-2, 125, 138, SPRINGER, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, Among the many tissue stem or progenitor cells recently being unveiled, endothelial progenitor cells (EPCs) have attracted particular attention, not only because of their cardinal role in vascular biology and embryology but also because of their potential use in the therapeutic development of a variety of postnatal diseases, including cardiovascular and peripheral vascular disorders and cancer. The aim of this study is to provide some basic and comprehensive information on gene expression of EPCs to characterize the cells in molecular terms. Here, we focus on EPCs derived from CD34-positive mononuclear cells of human umbilical cord blood. The EPCs were purified and expanded in culture and analyzed by a high-density oligonucleotide microarray and real-time RT-PCR analysis. We identified 169 up-regulated and 107 down-regulated genes in the EPCs compared with three differentiated endothelial cells of human umbilical vein endothelial cells (HUVEC), human lung microvascular endothelial cells (LMEC) and human aortic endothelial cells (AoEC). It is expected that the obtained list include key genes which are critical for EPC function and survival and thus potential targets of EPC recognition in vivo and therapeutic modulation of vasculogenesis in cancer as well as other diseases, in which de novo vasculogenesis plays a crucial role. For instance, the list includes Syk and galectin-3, which encode protein tyrosine kinase and beta-galactoside-binding protein, respectively, and are expressed higher in EPCs than the three control endothelial cells. In situ hybridization showed that the genes were expressed in isolated cells in the fetal liver at E11.5 and E14.5 of mouse development.

Prepare cells to repair the heart: Mesenchymal stem cells for the treatment of heart failure
Nagaya, Noritoshi, Ohnishi, Shunsuke
American Journal of Nephrology, 27, 3, 301, 307, KARGER, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, Heart failure is one of the most important cardiovascular diseases, with high mortality, and invasive treatment such as mechanical circulatory support and cardiac transplantation is sometimes required for severe heart failure. Therefore, the development of less invasive and more effective therapeutic strategies is desired. Cell therapy is attracting growing interest as a new approach for the treatment of heart failure. As a cell source, various kinds of stem/progenitor cells such as bone marrow cells, endothelial progenitor cells, mesenchymal stem cells ( MSC) and cardiac stem cells have been investigated for their efficacy and safety. Especially, bone marrow-derived MSC possess multipotency and can be easily expanded in culture, and are thus an attractive therapeutic tool for heart failure. Recent studies have revealed the underlying mechanisms of MSC in cardiac repair: MSC not only differentiate into specific cell types such as cardiomyocytes and vascular endothelial cells, but also secrete a variety of paracrine angiogenic and cytoprotective factors. It has also been suggested that endogenous MSC as well as exogenously transplanted MSC migrate and participate in cardiac repair. Based on these findings, several clinical trials have just been started to evaluate the safety and efficacy of MSC for the treatment of heart failure. Copyright (C) 2007 S. Karger AG, Basel.

Effect of Hypoxia on Gene Expression of Bone Marrow-Derived Mesenchymal Stem Cells and Mononuclear Cells
Noritoshi Nagaya, Soichiro Kitamura, Takeshi Yasuda, Shunsuke Ohnishi
Stem Cells, 25, 5, 1166, 1177, ALPHAMED PRESS, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, MSC have self-renewal and multilineage differentiation potential, including differentiation into endothelial cells and vascular smooth muscle cells. Although bone marrow-derived mononuclear cells ( MNC) have been applied for therapeutic angiogenesis in ischemic tissue, little information is available regarding comparison of the molecular foundation between MNC and their MSC subpopulation, as well as their response to ischemic conditions. Thus, we investigated the gene expression profiles between MSC and MNC of rat bone marrow under normoxia and hypoxia using a microarray containing 31,099 genes. In normoxia, 2,232 (7.2%) and 2,193 genes (7.1%) were preferentially expressed more than threefold in MSC and MNC, respectively, and MSC expressed a number of genes involved in development, morphogenesis, cell adhesion, and proliferation, whereas various genes highly expressed in MNC were involved in inflammatory response and chemotaxis. Under hypoxia, 135 (0.44%) and 49 (0.16%) genes were upregulated (> threefold) in MSC and MNC, respectively, and a large number of those upregulated genes were involved in glycolysis and metabolism. Focusing on genes encoding secretory proteins, the upregulated genes in MSC under hypoxia included several molecules involved in cell proliferation and survival, such as vascular endothelial growth factor-D, placenta growth factor, pre-B-cell colony-enhancing factor 1, heparin-binding epidermal growth factor-like growth factor, and matrix metalloproteinase-9, whereas the upregulated genes in MNC under hypoxia included proinflammatory cytokines such as chemokine (CXC motif) ligand 2 and interleukin-1 alpha. Our results may provide information on the differential molecular mechanisms regulating the properties of MSC and MNC under ischemic conditions.

Novel expansion/shrinkage modulation of 2D layered MOF triggered by clathrate formation with CO2 molecules
Atsushi Kondo, Hiroshi Noguchi, Shunsuke Ohnishi, Hiroshi Kajiro, Aya Tohdoh, Yoshiyuki Hattori, Wei-Chun Xu, Hideki Tanaka, Hirofumi Kanoh, Katsumi Kaneko
NANO LETTERS, 6, 11, 2581, 2584, AMER CHEMICAL SOC, 2006年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Crystal-to-crystal transformation from a 3D interpenetrated-type MOF {[Cu(BF4)(2)(bpy)(H2O)(2)](bpy)}(1) to a 2D square-grid-type [Cu(BF4)(2)-(bpy)2](2)(bpy=4,4'-bipyridine) was observed. It was derived from dehydration and confirmed by in situ FT-IR, TG, and elemental analysis. Moreover, we elucidate the novel expansion/shrinkage dynamic modulation of 2 triggered by clathrate formation with gas molecules.

Radiolabeled and near-infrared fluorescent fibrinogen derivatives create a system for the identification and repair of obscure gastrointestinal bleeding
Shunsuke Ohnishi, Evan S. Garfein, Seth J. Karp, John V. Frangioni
SURGERY, 140, 5, 785, 792, MOSBY, INC, 2006年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Background. Gastrointesintal hemorrhage is often difficult to localize. A test that does not depend on active bleeding might prove clinically useful. We tested 2 novel fibrinogen (FBG)-based contrast agents for their ability to localize gastrointestinal (GI) hemorrhage after bleeding stopped. I-125-FBG permits gamma ray-based preoperative or intraoperative scanning, and near-inftared (NIR) flourescent FBG (FBG800) permits real-time intraoperative visualization of active clot.
Methods. Bovine FBG was radiolabeled with 1251 or conjugated to the NIR fluorophore CW800. Sites of bleeding were created bygastrotomy, mucosal resection of the stomach, or laceration of a mesenteric vessel; then 1.7 mg/kg FBG800 or 15 mu Ci/kg I-125-FBG was injected intravenously into mice, rabbits, or pigs 30 minutes before or after injury. Sites Of active clot were quantified by using gamma counting and were also imaged by using invisible NIR light intraoperatively, for up to 3 hours postinjection.
Results. After an injection of either I-125-FBG or FBG800, sites of prior bleeding could be identified in the absence of active bleeding. Blood clearance was such that a signal-to-background ratio of 2.0 or greater could be achieved within 20 minutes after injection. A similarly labeled human serum albumin did not accumulate at any site, with an SBR of 1.0 or less.
Conclusions. Both radiolabeled (preoperative gamma scanning) and NIR fluorescent (intraoperative real-time imaging) FBG can be used in experimental situations to identify the location of prior bleeding in the absence of active bleeding. Taken together, these contrast agents create a system for the identification and control of obscure GI bleeding.

Transplantation of mesenchymal stem cells improves atrioventricular conduction in a rat model of complete atrioventricular block
Miki Yokokawa, Shunsuke Ohnishi, Hatsue Ishibashi-Lieda, Masashi Inagaki, Hiroaki Obata, Yoshinori Miyahara, Koichi Tanaka, Wataru Shimizu, Kenji Kangawa, Shiro Kamakura, Soichiro Kitamura, Noritoshi Nagaya
CIRCULATION, 114, 18, 80, 80, LIPPINCOTT WILLIAMS & WILKINS, 2006年10月, ［査読有り］
英語, 研究論文（学術雑誌）

Single administration of a novel sustained-release prostacyclin analogue attenuates monocrotaline-induced pulmonary hypertension in rats
Hiroaki Obata, Yoshiki Sakai, Shunsuke Ohnishi, Satoshi Takeshita, Hidezo Mori, Makoto Kodama, Yoshifusa Aizawa, Noritoshi Nagaya
CIRCULATION, 114, 18, 83, 83, LIPPINCOTT WILLIAMS & WILKINS, 2006年10月, ［査読有り］
英語

Overexpression of the oncoprotein prothymosin α triggers a p53 response that involves p53 acetylation
Takahiko Kobayashi, Ting Wang, Masaji Maezawa, Masanobu Kobayashi, Shunsuke Ohnishi, Kazuteru Hatanaka, Shuhei Hige, Yuichi Shimizu, Mototsugu Kato, Masahiro Asaka, Junji Tanaka, Masahiro Imamura, Kiminori Hasegawa, Yoshiyuki Tanaka, Rainer K. Brachmann
Cancer Research, 66, 6, 3137, 3144, 2006年03月15日, ［査読有り］
英語, 研究論文（学術雑誌）, Activation of the tumor suppressor protein p53 is a critical cellular response to various stress stimuli and to inappropriate activity of growth-promoting proteins, such as Myc, Ras, E2F, and β-catenin. Protein stability and transcriptional activity of p53 are modulated by protein-protein interactions and post-translational modifications, including acetylation. Here, we show that inappropriate activity of prothymosin α (PTMA), an oncoprotein overexpressed in human cancers, triggers a p53 response. Overexpression of PTMA enhanced p53 transcriptional activity in reporter gene assays for p53 target gene promoters hdm2, p21, and cyclin G. Overexpressed PTMA resulted in increased mRNA and protein levels for endogenous p53 target genes, hdm2 and p21, and in growth suppression. In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity. Histone acetyltransferases (HATs) act as p53 coactivators and acetylate p53. PTMA, known to interact with HATs, led to increased levels of acetylated p53. PTMA did not increase the transcriptional activity of an acetylation-deficient p53 mutant, suggesting that p53 acetylation is an indispensable part of the p53 response to PTMA. Chromatin immunoprecipitation assays showed that excess PTMA associates with the p21 promoter and results in increased levels of acetylated p53 at the p21 promoter. Our findings indicate that overexpressed PTMA elicits a p53 response that involves p53 acetylation. ©2006 American Association for Cancer Research.

Engineering InAsxP1-x/InP/ZnSe III-V alloyed core/shell quantum dots for the near infrared
Sang-Wook Kim, John P. Zimmer, Shunsuke Ohnishi, Joseph B. Tracy, John V. Frangioni, Moungi G. Bawendi
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 231, AMER CHEMICAL SOC, 2006年03月, ［査読有り］
英語

Beraprost sodium enhances neovascularization in ischemic myocardium by mobilizing bone marrow cells in rats
Miyahara, Yoshinori, Ohnishi, Shunsuke, Obata, Hiroaki, Ishino, Kozo, Sano, Shunji, Mori, Hidezo, Kangawa, Kenji, Kitamura, Soichiro, Nagaya, Noritoshi
Biochemical and Biophysical Research Communications, 349, 4, 1242, 1249, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2006年, ［査読有り］
英語, 研究論文（学術雑誌）, Beraprost sodium, an orally active prostacyclin analogue, has vasoprotective effects such as vasodilation and antiplatelet activities. We investigated the therapeutic potential of beraprost for myocardial ischemia. Immediately after coronary ligation of Sprague-Dawley rats, beraprost (200 mu g/kg/day) or saline was subcutaneously administered for 28 days. Four weeks after coronary ligation, administration of beraprost increased capillary density in ischemic myocardium, decreased infarct size, and improved cardiac function in rats with myocardial infarction. Beraprost markedly increased the number of CD34-positive cells and e-kit-positive cells in plasma. Also, four weeks after coronary ligation of chimeric rats with GFP-expressing bone marrow, bone marrow-derived cells were incorporated into the infarcted region and its border zone. Treatment with beraprost increased the number of GFP/von Willebrand factor-double-positive cells in the ischemic myocardium. These results suggest that beraprost has beneficial effects on ischemic myocardium partly by its ability to enhance neovascularization in ischemic myocardium by mobilizing bone marrow cells. (c) 2006 Elsevier Inc. All rights reserved.

Organic Alternatives to Quantum Dots for Intraoperative Near-Infrared Fluorescent Sentinel Lymph Node Mapping
Shunsuke Ohnishi, Stephen J. Lomnes, Rita G. Laurence, Andrew Gogbashian, Giuliano Mariani, John V. Frangioni
MOLECULAR IMAGING, 4, 3, 172, 181, B C DECKER INC, 2005年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Intraoperative near-infrared (NIR) fluorescence imaging provides the surgeon with real-time image guidance during cancer and other surgeries. We have previously reported the use of NIR fluorescent quantum dots (QDs) for sentinel lymph node (SLN) mapping. However, because of concerns over potential toxicity, organic alternatives to QDs will be required for initial clinical studies. We describe a family of 800 nm organic heptamethine indocyanine-based contrast agents for SLN mapping spanning a spectrum from 775 Da small molecules to 7 MDa nanocolloids. We provide a detailed characterization of the optical and physical properties of these contrast agents and discuss the advantages and disadvantages of each. We present robust methods for the covalent conjugation, purification, and characterization of proteins with tetra-sulfonated heptamethine indocyanines, including mass spectroscopic site mapping of highly substituted molecules. One contrast agent, NIR fluorescent human serum albumin (HSA800), emerged as the molecule with the best overall performance with respect to entry to lymphatics, flow to the SLN, retention in the SLN, fluorescence yield and reproducibility. This preclinical study, performed on large animals approaching the size of humans, should serve as a foundation for future clinical studies. Mol Imaging (2005) 4, 172-181.

Hyperammonemic encephalopathy in a patient with ureterosigmoidostomy and acute hepatitis: A specific case of fulminant hepatic failure
Shunsuke Ohnishi, Takeshi Yoshida, Hiroaki Makiyama, Katsuya Usui, Mayumi Kudo, Takahiko Kobayashi, Shuhei Hige, Masahiro Asaka
Digestive Diseases and Sciences, 48, 4, 821, 823, 2003年04月01日
英語, 研究論文（学術雑誌）

Developmental expression of mouse Krüppel-like transcription factor KLF7 suggests a potential role in neurogenesis
Friedrich Laub, Rafael Aldabe, Victor Friedrich Jr., Shunsuke Ohnishi, Teruhiko Yoshida, Francesco Ramirez
Developmental Biology, 233, 2, 305, 318, Academic Press Inc., 2001年05月15日, ［査読有り］
英語, 研究論文（学術雑誌）, To identify potential functions for the Krüppel-like transcription factor KLF7, we have determined the spatiotemporal pattern of gene expression during embryogenesis and in the adult organism. We show that the profile of Klf7 expression predominantly involves the central and peripheral nervous systems and is broadly identified by three separate phases. The first phase occurs early in embryogenesis with increasingly strong expression in the spinal cord, notably in motor neurons of the ventral horn, in dorsal root ganglia, and in sympathetic ganglia. The second robust phase of Klf7 expression is confined to the early postnatal cerebral cortex and is downregulated thereafter. The third phase is characterized by high and sustained expression in the adult cerebellum and dorsal root ganglia. Functionally, these three phases coincide with establishment of neuronal phenotype in embryonic spinal cord, with synaptogenesis and development of mature synaptic circuitry in the postnatal cerebral cortex, and with survival and/or maintenance of function of adult sensory neurons and cerebellar granule cells. Consistent with Klf7 expression in newly formed neuroblasts, overexpression of the gene in cultured fibroblasts and neuroblastoma cells repressed cyclin D1, activated p21, and led to G1 growth arrest. Based on these data, we argue for multiple potential functions for KLF7 in the developing and adult nervous system
they include participating in differentiation and maturation of several neuronal subtypes and in phenotypic maintenance of mature cerebellar granule cells and dorsal root ganglia. © 2001 Academic Press.

Developmental expression of the mouse gene coding for the Kruppel-like transcription factor KLF5
Shunsuke Ohnishi, Friedrich Laub, Nobuyuki Matsumoto, Masahiro Asaka, Francesco Ramirez, Teruhiko Yoshida, Masaaki Terada
Developmental Dynamics, 217, 4, 421, 429, 2000年, ［査読有り］
英語, 研究論文（学術雑誌）, The mammalian Kruppel-like transcription factors are key regulators of multiple morphogenetic programs. Here, we examined the developmental expression of the mouse Klf5 gene and compared it to the established pattern of the Klf4 gene. The results revealed that the two genes are expressed in both overlapping and mutually exclusive patterns. Unlike Klf4, Klf5 mRNA is detected in the E15.5 meninges and in the E.16.5 epithelium of trachea and bronchi. Both genes are co-expressed in the outer layer of the tongue, as well as in the developing epidermis and gut with interesting temporal differences. Klf4 expression in the skin gradually decreases from E15.5 on, whereas Klf5 transcripts continue to accumulate at a fairly high rate in the basal layer of the epidermis. The same sustained activity of Klf5 is already seen in the gastrointestinal tract of the 10.5 day embryo, and is later confined to the base of the intestinal crypts. Maximal Klf4 expression in the gastrointestinal tract is limited to a narrower window of time during the late phase of development. (C) 2000 Wiley-Liss, Inc.

A case of G-CSF producing malignant fibrous histiocytoma of the small intestine
Makoto Chuma, Hiroki Nakaya, Hisashi Oda, Shigeki Hatakeyama, Shunsuke Ohnishi, Kenichi Kumagai, Gong Heun Choi, Takahiko Kobayashi, Kiichiro Kamiya, Takuto Miyagishima, Tatsuro Takahashi
Japanese Journal of Gastroenterology, 94, 5, 340, 345, 1997年05月, ［査読有り］
日本語, 研究論文（学術雑誌）

当科で経験した羊水過多症例の周産期予後の検討　　　　　　　　　　　　　　　
大西 俊介, 福井 陽介, 植田 陽子, 三宅 龍太, 山中 彰一郎, 竹田 善紀, 中野 和俊, 市川 麻祐子, 丸山 祥代, 赤坂 珠理晃, 成瀬 勝彦, 川口 龍二, 日本産科婦人科学会雑誌, 73, 臨増, S, 289, 2021年03月
(公社)日本産科婦人科学会, 日本語

妊娠中に胎児脳室拡大を指摘された児の予後についての検討　　　　　　　　　　　　　　　
市川 麻祐子, 三宅 龍太, 山中 彰一郎, 竹田 善紀, 大西 俊介, 中野 和俊, 吉元 千陽, 赤坂 珠理晃, 成瀬 勝彦, 馬淵 誠士, 川口 龍二, 小林 浩, 日本産科婦人科学会雑誌, 72, 臨増, S, 499, 2020年03月
(公社)日本産科婦人科学会, 日本語

【一般・消化器外科医のための できる! 漢方】がん化学療法完遂のための漢方 食欲不振,嘔気,嘔吐
大西 俊介, 臨床外科, 75, 3, 328, 333, 2020年03月
＜文献概要＞ポイント ◆がん化学療法に伴う嘔気・嘔吐・食欲不振に対する現在の標準的な支持療法はいまだ十分とはいえない.◆六君子湯(りっくんしとう)はセロトニン受容体に対する拮抗作用およびグレリンを介した食欲増進作用が明らかとなっている.◆六君子湯は標準制吐療法に対する上乗せ効果が期待されているが,プラセボを用いた質の高い臨床試験の結果が待たれる., (株)医学書院, 日本語

生体ブタ全周性食道ESD施行後のバルーン拡張時の病理組織学的検討
木脇佐代子, 清水勇一, 大西俊介, 大野正芳, 楊子健, 霜田佳彦, 井上雅貴, 田中一光, 石川麻倫, 山本桂子, 小野尚子, 坂本直哉, Gastroenterological Endoscopy (Web), 62, Supplement1, 2020年

FGFR阻害剤およびMEK阻害剤は食道扁平上皮癌(ESCC)がん幹細胞を減少させる　　　　　　　　　　　　　　　
前原 経, 夏井坂 光輝, 須田 剛生, 大西 俊介, 坂本 直哉, 武田 宏司, 日本消化管学会雑誌, 4, Suppl., 301, 301, 2020年01月
(一社)日本消化管学会, 日本語

【肝胆膵の線維化up-to-date】肝臓の線維化 基礎研究 間葉系幹細胞による肝線維化治療　　　　　　　　　　　　　　　
大原 正嗣, 大西 俊介, 坂本 直哉, 肝・胆・膵, 79, 5, 853, 859, 2019年11月
(株)アークメディア, 日本語

消化器疾患と再生医療 Tissue Engineering技術を利用した臓器復元
宮澤 光男, 合川 公康, 大西 俊介, 日本消化器病学会雑誌, 116, 臨増大会, A522, A522, 2019年11月
(一財)日本消化器病学会, 日本語

腹腔鏡下胆道再建術の工夫と治療成績 術後吻合部狭窄を招かない腹腔鏡下胆道再建法の検討 生体吸収性材料を用いた胆管再生モデルより　　　　　　　　　　　　　　　
宮澤 光男, 合川 公康, 大西 俊介, 胆道, 33, 3, 449, 449, 2019年10月
日本胆道学会, 日本語

消化管外科手術における縫合不全対策について考える1 生体吸収性材料を用いた新規吻合部縫合不全対策法の開発　　　　　　　　　　　　　　　
宮澤 光男, 合川 公康, 岡田 克也, 渡邉 幸博, 大西 俊介, 小林 宏寿, 谷口 桂三, 日本臨床外科学会雑誌, 80, 増刊, 342, 342, 2019年10月
日本臨床外科学会, 日本語

肝細胞癌細胞株においてメトホルミンはAMPK-CEBPβ経路を介してCD133の発現を制御する(Metformin regulates the expression of CD133 through the AMPK-CEBPβ pathway in hepatocellular carcinoma cell lines)　　　　　　　　　　　　　　　
前原 経, 大西 俊介, 夏井坂 光輝, 坂本 直哉, 日本癌学会総会記事, 78回, P, 3258, 2019年09月
日本癌学会, 英語

【漢方の今、これから】漢方療法のランダム化研究やビッグデータ解析 シスプラチン/パクリタキセル併用療法を受ける子宮頸癌・体癌患者における嘔気・嘔吐に対する六君子湯の効果
大西 俊介, 渡利 英道, 産科と婦人科, 86, 8, 947, 950, 2019年08月
化学療法誘発悪心・嘔吐に対する標準制吐療法はいまだ十分ではない。われわれは、シスプラチンを初回の化学療法として施行される子宮頸癌・体癌患者を対象として、六君子湯のCINVに対する有効性を明らかにするための探索試験を実施した。標準制吐療法のみの群に対して、標準制吐療法+六君子湯投与群は有意に嘔吐完全制御率ならびに嘔吐完全抑制率が改善しており、嘔気ならびに食欲のvisual analogue scaleも改善していた。今後、プラセボを用いた検証試験を実施する予定である。(著者抄録), (株)診断と治療社, 日本語

消化器内視鏡診療におけるトランスレーショナルリサーチ DPP-IV活性により蛍光を発するプローブによる食道胃接合部腺癌の検出　　　　　　　　　　　　　　　
山本 桂子, 大西 俊介, 坂本 直哉, Gastroenterological Endoscopy, 61, Suppl.1, 822, 822, 2019年05月
(一社)日本消化器内視鏡学会, 日本語

ヒト羊膜由来間葉系幹細胞を用いた再生医療研究
山本 幸司, 大西 俊介, 遺伝子医学, 9, 2, 74, 76, 2019年04月
間葉系幹細胞は、出産後に廃棄される胎児付属組織にも存在し、侵襲を伴わず大量の細胞を得られるため、新しい細胞ソースとして期待されている。また、間葉系幹細胞からは抗炎症作用や組織修復に寄与する多くの液性因子が分泌されるが、その細胞が疾患に対して治療効果を発揮するかの詳細は不明であった。近年われわれは、ヒト羊膜由来間葉系幹細胞を用いて炎症性腸疾患や肝硬変などの消化器疾患において治療効果を発揮することを動物実験において明らかにし、実際にクローン病を対象にしたfirst-in-human臨床試験を開始している。(著者抄録), (株)メディカルドゥ, 日本語

消化器領域における幹細胞研究とその応用 間葉系幹細胞から分泌される生理活性脂質の抗炎症・抗線維化効果
小田切 信介, 大西 俊介, 坂本 直哉, 日本消化器病学会雑誌, 116, 臨増総会, A87, A87, 2019年03月
(一財)日本消化器病学会, 日本語

動物実験従事者におけるアレルギー健診5年分の経年的解析　　　　　　　　　　　　　　　
吉村 彩, 武藏 学, 折戸 智恵子, 川原 由佳子, 横田 卓, 大西 俊介, 橋野 聡, CAMPUS HEALTH, 56, 1, 239, 241, 2019年03月
実験動物取り扱い関係者においてみられる職業性アレルギーである実験動物アレルギーについて、本学(大学)では、平成22年度に実験中にマウスに咬まれてアナフィラキシーショックを起こした事例が発生したことを機に、23年度より毎年、動物実験従事者のうち希望者に対し取り扱い動物の特異的IgE抗体検査を含むアレルギー健診を実施しており、今回、23年度から5年間連続してアレルギー健診を受診した21名(男性10名、女性11名、平均年齢42.0±10.6歳)を対象に、経年的解析を行った。その結果、5年間連続して同種の抗体検査を実施した者は、マウスIgE抗体19名、ラットIgE抗体10名、ウサギIgE抗体3名で、マウス、ラットのIgE抗体陽性率は有意差はなく横ばい状態であった。また、個人間での抗体価の変動についても、マウス、ラットともに受診者の約60%は陰性のまま推移していた。, (公社)全国大学保健管理協会, 日本語

DPP-IV活性により蛍光を発するプローブによる頭頸部扁平上皮表在がんの検出
山本 桂子, 大西 俊介, 水島 健, 清水 勇一, 坂本 直哉, 耳鼻咽喉科展望, 62, 1, 42, 43, 2019年02月
耳鼻咽喉科展望会, 日本語

羊膜間葉系幹細胞由来細胞外小胞の慢性肝障害モデルに対する抗炎症・抗線維化効果
大原正嗣, 大西俊介, 山本幸司, 付慶傑, 前原経, 須田剛生, 坂本直哉, 日本再生医療学会総会(Web), 18th, 2019年

サイトカインリッチな成牛多血小板血漿由来血清「NeoSERA」を用いた高品質羊膜MSCの製剤化と急性GVHD・クローン病向け医師主導治験
山原 研一, 浜田 彰子, 黒田 将子, 岡田 昌也, 吉原 哲, 大西 俊介, 相馬 俊裕, 豊嶋 崇徳, 小川 啓恭, 藤盛 好裕, 日本内分泌学会雑誌, 94, 4, 1573, 1573, 2018年12月
(一社)日本内分泌学会, 日本語

ポリグリコール酸(PGA)不織布は自動縫合器の吻合部補強材として最適か?　　　　　　　　　　　　　　　
宮澤 光男, 合川 公康, 岡田 克也, 渡邉 幸博, 谷口 桂三, 藤野 昇三, 大西 俊介, 日本内視鏡外科学会雑誌, 23, 7, OS36, 5, 2018年12月
(一社)日本内視鏡外科学会, 日本語

創傷治癒を補助する細胞療法 炎症を標的とした細胞治療による創傷治癒戦略　　　　　　　　　　　　　　　
大西 俊介, 日本創傷治癒学会プログラム・抄録集, 48回, 101, 101, 2018年11月
(一社)日本創傷治癒学会, 日本語

羊膜由来間葉系幹細胞の治療応用　　　　　　　　　　　　　　　
大西 俊介, 日本創傷治癒学会プログラム・抄録集, 48回, 143, 143, 2018年11月
(一社)日本創傷治癒学会, 日本語

長期予後改善をめざす自己免疫性肝疾患の基礎と臨床 薬剤誘発硬化性胆管炎ラットに対するヒト羊膜由来間葉系幹細胞の治療効果　　　　　　　　　　　　　　　
杉浦 諒, 大西 俊介, 坂本 直哉, 日本消化器病学会雑誌, 115, 臨増大会, A606, A606, 2018年10月
(一財)日本消化器病学会, 日本語

Tissue engineeringによる人工臓器作成 Tissue engineeringにより臓器復元が可能である　　　　　　　　　　　　　　　
宮澤 光男, 合川 公康, 岡田 克也, 渡邉 幸博, 大西 俊介, 人工臓器, 47, 2, S, 16, 2018年10月
(一社)日本人工臓器学会, 日本語

【消化器病漢方治療-理論と実践】理論 漢方薬作用機序の科学的解明 六君子湯
武田 宏司, 大久保 直登, 中川 宏治, 大西 俊介, 藤塚 直樹, 服部 智久, 臨床消化器内科, 33, 11, 1349, 1356, 2018年09月
＜文献概要＞六君子湯は上部消化管症状や食欲不振に対して使用されている漢方薬であるが,近年その作用機序が明らかになりつつある.六君子湯は5-HT2B/5-HT2C受容体の阻害によるグレリン分泌亢進あるいは分解阻害により血中グレリン濃度を上昇させる.また,ホスホジエステラーゼ3阻害およびグレリン受容体の感受性亢進などを介してグレリン抵抗性を解除する.さらに,5-HT2Cなど複数の受容体の阻害により抗ストレス作用を示す.最近の研究で,六君子湯がサーチュイン1活性化などを介してマウスの寿命延長をもたらすことが明らかになった.六君子湯は,脳腸軸を構成する複数の標的に作用し,グレリンシステムを増強して生体の機能異常を改善する薬剤と考えられる., (株)日本メディカルセンター, 日本語

動物実験従事者におけるアレルギー健診5年分の経年的解析　　　　　　　　　　　　　　　
吉村 彩, 武藏 学, 折戸 智恵子, 川原 由佳子, 横田 卓, 大西 俊介, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 56回, 70, 70, 2018年09月
(公社)全国大学保健管理協会, 日本語

傷害肝の修復を目指す抗線維化・肝再生研究の展望 羊膜間葉系幹細胞由来細胞外小胞の慢性肝障害モデルに対する抗炎症・抗線維化効果　　　　　　　　　　　　　　　
大原 正嗣, 大西 俊介, 坂本 直哉, 肝臓, 59, Suppl.2, A625, A625, 2018年09月
(一社)日本肝臓学会, 日本語

酵素活性により蛍光を発するプローブの局所散布による早期胃食道接合部癌の検出(Detection of carcinoma of the esophagogastric junction by topically spraying enzymatically activatable fluorescent probe)　　　　　　　　　　　　　　　
大西 俊介, 山本 桂子, 清水 勇一, 水島 健, 畑中 豊, 畑中 佳奈子, 栗木 優五, 神谷 真子, 浦野 泰照, 坂本 直哉, 日本癌学会総会記事, 77回, 786, 786, 2018年09月
日本癌学会, 英語

急性GVHD・クローン病に対する羊膜由来間葉系幹細胞の医師主導治験 兵庫医科大学発・初認定ベンチャーによる開発をめざして
山原 研一, 濱田 彰子, 大西 俊介, 相馬 俊裕, 岡本 里香, 中村 志郎, 岡田 昌也, 吉原 哲, 吉原 享子, 橋本 大吾, 磯江 敏幸, 豊嶋 崇徳, 佐藤 典宏, 藤盛 好啓, 兵庫医科大学医学会雑誌, 43, 1, 41, 45, 2018年09月
我々は免疫調整作用を有する間葉系幹細胞(MSC)の中でも、(1)幹細胞数が多く、(2)増殖能も高く、(3)採取に侵襲性のない羊膜由来MSCに着目し、既存治療抵抗性の急性GVHDやクローン病といった難治性免疫関連疾患を対象とし、細胞治療研究を進めている。2017年、我々は世界で初めて羊膜MSCの治験製剤化に成功し、急性GVHDやクローン病に対する医師主導治験を開始し、現在は兵庫医科大学が羊膜MSCの治験製品(治験製品名:AM01)を提供し、兵庫医科大学病院・北海道大学病院を実施医療機関とした急性GVHD・クローン病に対する第I/II相医師主導治験を進めている。今後の更なる治験の加速化を目指し、兵庫医科大学発・初認定ベンチャーを立ちあげており、羊膜MSC AM01を再生医療等製品として早期の製造販売承認取得を目指す。(著者抄録), 兵庫医科大学医学会, 日本語

術後狭窄 良性胆管狭窄治療のための必要条件 人工胆管を用いた胆管再生モデルによる検討
宮澤 光男, 合川 公康, 大西 俊介, 胆道, 32, 3, 498, 498, 2018年08月
日本胆道学会, 日本語

【間葉系幹細胞移植のupdate】羊膜由来間葉系幹細胞による急性GVHD治療
山原 研一, 濱田 彰子, 大西 俊介, 黒田 将子, 相馬 俊裕, 岡本 里香, 岡田 昌也, 吉原 哲, 吉原 享子, 橋本 大吾, 磯江 敏幸, 豊嶋 崇徳, 佐藤 典宏, 小川 啓恭, 藤盛 好啓, 臨床免疫・アレルギー科, 70, 1, 18, 24, 2018年07月
(有)科学評論社, 日本語

DPP-IV活性により蛍光を発するプローブによる食道胃接合部腺癌の検出　　　　　　　　　　　　　　　
山本 桂子, 大西 俊介, 坂本 直哉, Gastroenterological Endoscopy, 60, Suppl.1, 715, 715, 2018年04月
(一社)日本消化器内視鏡学会, 日本語

Palmitoylethanolamideの星細胞活性化抑制およびラット肝線維症モデルにおける抗線維化効果
大原 正嗣, 大西 俊介, 須田 剛生, 坂本 直哉, 肝臓, 59, Suppl.1, A528, A528, 2018年04月
(一社)日本肝臓学会, 日本語

血清中のスフィンゴ糖脂質および遊離オリゴ糖鎖に特異的なABO式血液型抗原の解析　　　　　　　　　　　　　　　
岡田 和恵, 横田 育子, 花松 久寿, 三浦 信明, 大西 俊介, 湯山 耕平, 酒井 祥太, 伊東 信, 五十嵐 靖之, 坂本 直哉, 篠原 康郎, 古川 潤一, 生命科学系学会合同年次大会, 2017年度, [2P, 0021], 2017年12月
生命科学系学会合同年次大会運営事務局, 日本語

「それぞれの生」支持療法の工夫 嘔気対策・栄養管理 シスプラチン/パクリタキセル療法による嘔気・嘔吐・食欲不振に対する六君子湯の効果　　　　　　　　　　　　　　　
大西 俊介, 渡利 英道, 勘野 真紀, 大場 洋子, 竹内 聡, 宮路 天平, 小山田 隼佑, 野村 英司, 加藤 秀則, 杉山 徹, 浅香 正博, 櫻木 範明, 山口 拓洋, 上園 保仁, 岩瀬 哲, 日本癌治療学会学術集会抄録集, 55回, WS5, 5, 2017年10月
(一社)日本癌治療学会, 日本語

重症妊娠高血圧腎症術後に周産期心筋症をきたした1例　　　　　　　　　　　　　　　
大西 俊介, 常見 泰平, 橋口 康弘, 山尾 佳穂, 中野 和俊, 赤坂 珠理晃, 藤井 絵里子, 佐道 俊幸, 小林 浩, 産婦人科の進歩, 69, 4, 512, 512, 2017年10月
「産婦人科の進歩」編集室, 日本語

「それぞれの生」支持療法の工夫 嘔気対策・栄養管理 シスプラチン/パクリタキセル療法による嘔気・嘔吐・食欲不振に対する六君子湯の効果　　　　　　　　　　　　　　　
大西 俊介, 渡利 英道, 勘野 真紀, 大場 洋子, 竹内 聡, 宮路 天平, 小山田 隼佑, 野村 英司, 加藤 秀則, 杉山 徹, 浅香 正博, 櫻木 範明, 山口 拓洋, 上園 保仁, 岩瀬 哲, 日本癌治療学会学術集会抄録集, 55回, WS5, 5, 2017年10月
(一社)日本癌治療学会, 日本語

大腸ESD/EMRの課題と将来展望 ブタ大腸ESD後狭窄モデルに対する羊膜間葉系幹細胞由来培養上清の注腸投与による狭窄予防効果　　　　　　　　　　　　　　　
津田 桃子, 大西 俊介, 坂本 直哉, Gastroenterological Endoscopy, 59, Suppl.2, 2019, 2019, 2017年09月
(一社)日本消化器内視鏡学会, 日本語

粘膜下局注併用APCと標準的APCの生体ブタ組織に対する焼灼効果の検討　　　　　　　　　　　　　　　
安孫子 怜史, 清水 勇一, 大西 俊介, 水島 健, 加藤 麻倫, 松田 可奈, 宮本 秀一, 津田 桃子, 山本 桂子, 小野 尚子, 工藤 俊彦, 坂本 直哉, Gastroenterological Endoscopy, 59, Suppl.2, 2223, 2223, 2017年09月
(一社)日本消化器内視鏡学会, 日本語

Dipeptidylpeptidase-IVの酵素活性により蛍光を発するプローブによる頭頸部表在癌の検出　　　　　　　　　　　　　　　
大西 俊介, 水島 健, 清水 勇一, 畑中 豊, 畑中 佳奈子, 山本 桂子, 本間 明宏, 栗木 優五, 神谷 真子, 浦野 泰照, 坂本 直哉, 日本癌学会総会記事, 76回, P, 2320, 2017年09月
日本癌学会, 英語

Innovative therapeutic endoscopy 大腸ESD/EMRの課題と将来展望 ブタ大腸ESD後狭窄モデルに対する羊膜間葉系幹細胞由来培養上清の注腸投与による狭窄予防効果　　　　　　　　　　　　　　　
津田 桃子, 大西 俊介, 坂本 直哉, 日本消化器病学会雑誌, 114, 臨増大会, A557, A557, 2017年09月
(一財)日本消化器病学会, 日本語

大腸ESD/EMRの課題と将来展望 ブタ大腸ESD後狭窄モデルに対する羊膜間葉系幹細胞由来培養上清の注腸投与による狭窄予防効果　　　　　　　　　　　　　　　
津田 桃子, 大西 俊介, 坂本 直哉, Gastroenterological Endoscopy, 59, Suppl.2, 2019, 2019, 2017年09月
(一社)日本消化器内視鏡学会, 日本語

粘膜下局注併用APCと標準的APCの生体ブタ組織に対する焼灼効果の検討　　　　　　　　　　　　　　　
安孫子 怜史, 清水 勇一, 大西 俊介, 水島 健, 加藤 麻倫, 松田 可奈, 宮本 秀一, 津田 桃子, 山本 桂子, 小野 尚子, 工藤 俊彦, 坂本 直哉, Gastroenterological Endoscopy, 59, Suppl.2, 2223, 2223, 2017年09月
(一社)日本消化器内視鏡学会, 日本語

介護保険施設・事業所における生活環境構築のための課題と工夫 認知症介護実践研修受講者に対する自由記述回答の分析　　　　　　　　　　　　　　　
宮野 順子, 相良 二朗, 北川 博巳, 大森 清博, 大西 俊介, 中園 正吾, 三谷 信之, 老年社会科学, 39, 2, 255, 255, 2017年06月
日本老年社会科学会, 日本語

腰椎麻酔下帝王切開術後における高アミラーゼ血症に対する予測因子の後方視的検討　　　　　　　　　　　　　　　
大西 俊介, 藤本 佳克, 今中 聖悟, 丸山 祥代, 山下 健, 日本周産期・新生児医学会雑誌, 53, 1, 83, 87, 2017年05月
当院で腰椎麻酔下に帝王切開術を施行した370例を対象に、術後の高アミラーゼ血症に関与する因子について検討した。その結果、術後の高アミラーゼ血症は94例で認められた。術後の高アミラーゼ血症には術中の血圧低下、嘔気・嘔吐による唾液腺の機械的刺激や胸腔内圧の上昇が関与する可能性が示唆された。, (一社)日本周産期・新生児医学会, 日本語

食道狭窄の内視鏡治療 羊膜由来間葉系幹細胞の培養上清を用いた内視鏡的食道粘膜下層剥離術後狭窄に対する新規治療法の開発　　　　　　　　　　　　　　　
水島 健, 大西 俊介, 坂本 直哉, Gastroenterological Endoscopy, 59, Suppl.1, 910, 910, 2017年04月
(一社)日本消化器内視鏡学会, 日本語

DPP-IV活性により蛍光を発するプローブによる頭頸部扁平上皮表在がんの検出　　　　　　　　　　　　　　　
山本 桂子, 大西 俊介, 坂本 直哉, 日本消化器病学会雑誌, 114, 臨増総会, A253, A253, 2017年03月
(一財)日本消化器病学会, 日本語

大量胸・腹水を契機に診断された純粋型卵巣原発扁平上皮癌の一例　　　　　　　　　　　　　　　
藤本 佳克, 丸山 祥代, 大西 俊介, 山下 健, 日本産科婦人科学会雑誌, 69, 2, 813, 813, 2017年02月
(公社)日本産科婦人科学会, 日本語

血清中のスフィンゴ糖脂質および遊離オリゴ糖鎖に特異的な血液型抗原の解析
横田育子, 花松久寿, 大西俊介, 岡田和恵, 湯山耕平, 酒井祥太, 伊東信, 五十嵐靖之, 坂本直哉, 篠原康郎, 古川潤一, 日本糖質学会年会要旨集, 36th, 2017年

【臨床応用を見据えた肝線維化研究の新展開】治療 羊膜由来間葉系幹細胞投与による肝線維化治療
大西 俊介, 久保 公利, 坂本 直哉, 肝・胆・膵, 74, 1, 95, 98, 2017年01月
(株)アークメディア, 日本語

頭頸・口腔 頭頸部がんの集学的治療 表在性頭頸部扁平上皮癌のGGT活性化標的薬を用いた蛍光イメージング(Fluorescent imaging of superficial head and neck squamous cell carcinoma using a GGT-Activated targeting agent)　　　　　　　　　　　　　　　
大西 俊介, 水島 健, 清水 勇一, 畑中 豊, 畑中 佳奈子, 本間 明宏, 浦野 泰照, 坂本 直哉, 日本癌治療学会学術集会抄録集, 54回, WS81, 6, 2016年10月
(一社)日本癌治療学会, 英語

消化器領域における再生医療・幹細胞研究の現状 羊膜由来間葉系幹細胞を用いた消化器疾患の再生医療　　　　　　　　　　　　　　　
大西 俊介, 水島 健, 坂本 直哉, 日本消化器病学会雑誌, 113, 臨増大会, A480, A480, 2016年09月
(一財)日本消化器病学会, 日本語

高度肥満男子学生における末梢血リンパ球サブセット解析　　　　　　　　　　　　　　　
吉村 彩, 大西 俊介, 川原 由佳子, 折戸 智恵子, 柏崎 晴彦, 本間 理央, 加納 崇裕, 横田 卓, 橋野 聡, 肥満研究, 22, Suppl., 229, 229, 2016年09月
(一社)日本肥満学会, 日本語

血清中に含まれる血液型特異的スフィンゴ糖脂質および遊離オリゴ糖鎖の同定　　　　　　　　　　　　　　　
横田 育子, 古川 潤一, 花松 久寿, 大西 俊介, 岡田 和恵, 湯山 耕平, 酒井 祥太, 伊東 信, 五十嵐 靖之, 坂本 直哉, 篠原 康郎, 日本生化学会大会プログラム・講演要旨集, 89回, [1P, 056], 2016年09月
(公社)日本生化学会, 日本語

当科における卵巣癌に対するベバシズマブの使用経験
藤本 佳克, 丸山 祥代, 大西 俊介, 山下 健, 産婦人科の進歩, 68, 3, 298, 299, 2016年08月
卵巣癌・腹膜癌・卵管癌の計11例を対象に、ベバシズマブ(BEV)使用経験を報告した。11例中初発治療例は5例(卵巣癌4例、腹膜癌1例)で、年齢は51〜79歳、進行期はIIIC〜IVA期、全例術後化学療法に併用してBEVを使用し、治療効果はCR:3例、SD、PD:各1例であった。再発治療例は6例(卵巣癌4例、腹膜癌、卵巣癌各1例)で、年齢は49〜81歳、進行期は1A〜IIIc期、前治療は主にddTC療法が行われた。プラチナ感受性再発4例、抵抗性再発2例にBEVを使用し、治療効果はCR:4例、PR、PD:各1例であった。全体での奏効率は約8割に達し、奏効例の無再発生存期間は初発例で11〜12ヵ月、再発例で7〜20ヵ月であった。全11例の有害事象は高血圧6例、蛋白尿、鼻出血各3例で、重篤な合併症は認めなかった。高血圧と蛋白尿はBEV投与を重ねるにつれ悪化する傾向を認め、高血圧はやや早期に発症する傾向であった。, 「産婦人科の進歩」編集室, 日本語

知的・発達障害者の聴覚過敏に関する実態調査　　　　　　　　　　　　　　　
大西 俊介, 中園 正吾, 大森 清博, リハ工学カンファレンス講演論文集, 31回, np179, np180, 2016年08月
(一社)日本リハビリテーション工学協会, 日本語

喫煙妊婦の喫煙状況、喫煙の害についての認知度や喫煙ステージに関する調査　　　　　　　　　　　　　　　
山下 健, 藤本 佳克, 丸山 祥代, 大西 俊介, 日本周産期・新生児医学会雑誌, 52, 2, 584, 584, 2016年06月
(一社)日本周産期・新生児医学会, 日本語

胎内診断し得た頭蓋部の羊膜索症候群の1例　　　　　　　　　　　　　　　
大西 俊介, 藤本 佳克, 丸山 祥代, 山下 健, 夫 律子, 日本周産期・新生児医学会雑誌, 52, 2, 655, 655, 2016年06月
(一社)日本周産期・新生児医学会, 日本語

間葉系幹細胞を用いた細胞治療 羊膜由来間葉系幹細胞を用いた消化器疾患治療 first-in-human臨床試験へ向けて　　　　　　　　　　　　　　　
大西 俊介, 日本輸血細胞治療学会誌, 62, 2, 218, 218, 2016年04月
(一社)日本輸血・細胞治療学会, 日本語

上部消化管におけるAdvanced Diagnostic endscopy for treatment 頭頸部扁平上皮がん早期発見に関する蛍光イメージングの有用性の検討　　　　　　　　　　　　　　　
水島 健, 大西 俊介, 坂本 直哉, Gastroenterological Endoscopy, 58, Suppl.1, 458, 458, 2016年04月
(一社)日本消化器内視鏡学会, 日本語

高度肥満学生における高感度CRPの測定意義について　　　　　　　　　　　　　　　
吉村 彩, 大西 俊介, 川原 由佳子, 折戸 智恵子, 柏崎 晴彦, 本間 理央, 川久保 和道, 加納 崇裕, 横田 卓, 橋野 聡, CAMPUS HEALTH, 53, 1, 106, 108, 2016年03月
(公社)全国大学保健管理協会, 日本語

肥満学生における簡易型自記式食事調査票(BDHQ)の意義について　　　　　　　　　　　　　　　
折戸 智恵子, 大西 俊介, 川原 由佳子, 吉村 彩, 柏崎 晴彦, 本間 理央, 川久保 和道, 加納 崇裕, 横田 卓, 橋野 聡, CAMPUS HEALTH, 53, 1, 201, 203, 2016年03月
本学の2014年定期健診で肥満と判定された学生22名にBDHQ調査を行い、コントロール群11名と比較した。結果、「摂取エネルギー」「炭水化物」「脂質」などの栄養素に有意な群間差はなかったが、食品では「緑黄色野菜」「漬物」「アイスクリーム」「果物」「洋菓子」の摂取量が肥満群で有意に少なかった。BDHQの結果報告には、おおよその信頼度を示す数値として摂取エネルギーの推定申告誤差が表示されており、±30%の範囲であれば、ある程度信頼度が高いとされる。今回の調査では、両群ともに過少申告者が存在したが、肥満群は-30%以上の割合がコントロール群より多く、信頼度が低かった(過少申告率が高かった)。肥満群には栄養・保健指導を行い、4ヵ月後に再度BDHQ調査を行ったところ、過少申告率は更に高くなっていた。, (公社)全国大学保健管理協会, 日本語

消化管疾患における再生医療の最前線 羊膜由来間葉系幹細胞を用いた難治性腸炎に対する新規治療法の開発　　　　　　　　　　　　　　　
大野 正芳, 大西 俊介, 坂本 直哉, 日本消化器病学会雑誌, 113, 臨増総会, A117, A117, 2016年03月
(一財)日本消化器病学会, 日本語

腹壁浸潤および肝転移をきたした原発性卵管癌に対しcomplete surgeryを行った一例　　　　　　　　　　　　　　　
丸山 祥代, 藤本 佳克, 大西 俊介, 山下 健, 日本産科婦人科学会雑誌, 68, 2, 645, 645, 2016年02月
(公社)日本産科婦人科学会, 日本語

妊娠経過中に薬剤性味覚障害をきたした1例　　　　　　　　　　　　　　　
大西 俊介, 藤本 佳克, 丸山 祥代, 山下 健, 日本産科婦人科学会雑誌, 68, 2, 944, 944, 2016年02月
(公社)日本産科婦人科学会, 日本語

エタノール沈殿法による血液型特異的スフィンゴ糖脂質および遊離オリゴ糖鎖の血液型抗原の同定
岡田和恵, 古川潤一, 横田育子, 花松久寿, 大西俊介, 湯山耕平, 酒井祥太, 伊東信, 五十嵐靖之, 坂本直哉, 篠原康郎, 日本糖質学会年会要旨集, 35th, 2016年

P3-41-6 妊娠経過中に薬剤性味覚障害をきたした1例(Group106 合併症妊娠8,一般演題,公益社団法人日本産科婦人科学会第68回学術講演会)
大西 俊介, 藤本 佳克, 丸山 祥代, 山下 健, 日本産科婦人科學會雜誌, 68, 2, 944, 944, 2016年
日本産科婦人科学会, 日本語

【H.pylori除菌後の諸問題】 H.pylori除菌がGERD発症にどのように影響するのか　　　　　　　　　　　　　　　
加藤 元嗣, 小野 尚子, 中川 学, 中川 宗一, 安孫子 怜史, 宮本 秀一, 水島 健, 津田 桃子, 大野 正芳, 大西 俊介, 清水 勇一, 坂本 直哉, 間部 克裕, The GI Forefront, 11, 2, 106, 109, 2016年01月
H.pylori感染は胃酸分泌との関わりからGERDの影響因子である。実際、H.pylori感染率とGERD有病率については相反する関係にあり、H.pylori感染がGERD発症に防御的に作用している可能性がある。一方、H.pylori除菌がGERDの発症を増加させるかについては、いくつかのメタ解析の結果から否定的である。むしろ、GERD症状はH.pylori除菌によって軽減する傾向がある。したがって、GERDの存在がH.pylori除菌の妨げとはならない。(著者抄録), (株)メディカルレビュー社, 日本語

【慢性胃炎を見直す】 胃炎の内視鏡診断 通常光観察　　　　　　　　　　　　　　　
加藤 元嗣, 小野 尚子, 中川 学, 中川 宗一, 安孫子 怜史, 宮本 秀一, 水島 健, 津田 桃子, 大野 正芳, 大西 俊介, 清水 勇一, 坂本 直哉, 間部 克裕, 胃と腸, 51, 1, 42, 51, 2016年01月
組織学的所見と内視鏡所見が一致しないために,慢性胃炎はこれまで組織学的に診断されてきた.しかし,最近の内視鏡機器の進歩により,組織学的胃炎と一致する内視鏡所見が次第に明らかになった.胃粘膜におけるH. pylori感染状態は,H. pylori未感染,H. pylori感染,H. pylori既感染・除菌後に分けることができる.新たな内視鏡による胃炎分類である京都分類では,19の胃炎所見を定義して,H. pylori感染状態との関連性を整理した.RAC,びまん性発赤,地図状発赤は,それぞれH. pylori未感染,H. pylori感染,H. pylori除菌後の特徴的な所見である.H. pylori感染状態によって,発生胃癌のリスクや特徴は異なるため,胃炎の診断は胃癌スクリーニングにおいても重要である.(著者抄録), (株)医学書院, 日本語

医療イノベーション創出ネットワークの現状と展望 新しいフェーズに入ったアカデミアのシーズ開発 シーズ発表・再生医療等製品 羊膜由来間葉系幹細胞を用いた肝硬変の治療法の開発 羊膜由来間葉系幹細胞の再生医療製品化と急性GVHDに対する治療応用 重症クローン病に対する同種卵膜間葉系幹細胞による新規治療法の開発　　　　　　　　　　　　　　　
坂本 直哉, 山原 研一, 大西 俊介, 臨床評価, 43, Suppl.XXXV, 221, 224, 2015年12月
(株)臨床評価刊行会, 日本語

肝細胞癌におけるKLF5による癌幹細胞制御機構　　　　　　　　　　　　　　　
佐藤 史幸, 夏井坂 光輝, 前原 経, 浅野 彩華, 久保田 良政, 出水 孝章, 梅村 真知子, 伊藤 淳, 常松 聖司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 大西 俊介, 坂本 直哉, 肝臓, 56, Suppl.3, A1002, A1002, 2015年11月
(一社)日本肝臓学会, 日本語

喫煙妊婦のアンケート調査からわかったこと　　　　　　　　　　　　　　　
山下 健, 藤本 佳克, 丸山 祥代, 大西 俊介, 赤井 律子, 脇田 真紀, 吉井 瑞希, 日本禁煙学会学術総会プログラム・抄録集, 9回, 206, 206, 2015年11月
(一社)日本禁煙学会, 日本語

当科における卵巣癌に対するベバシズマブの使用経験　　　　　　　　　　　　　　　
藤本 佳克, 丸山 祥代, 大西 俊介, 山下 健, 産婦人科の進歩, 67, 4, 510, 510, 2015年10月
「産婦人科の進歩」編集室, 日本語

γ-Glutamyltranspeptidaseにより蛍光を発するprobeによる早期頭頸部がんの検出　　　　　　　　　　　　　　　
大西 俊介, 清水 勇一, 水島 健, 畑中 豊, 畑中 佳奈子, 久保田 良政, 夏井坂 光輝, 神谷 真子, 本間 明宏, 加藤 元嗣, 浦野 泰照, 坂本 直哉, 日本癌学会総会記事, 74回, P, 3308, 2015年10月
日本癌学会, 英語

高度肥満学生に対する保健指導前後の血液学的変化および体組成変化の検討　　　　　　　　　　　　　　　
吉村 彩, 大西 俊介, 川原 由佳子, 折戸 智恵子, 柏崎 晴彦, 本間 理央, 川久保 和道, 加納 崇裕, 横田 卓, 橋野 聡, 肥満研究, 21, Suppl., 154, 154, 2015年09月
(一社)日本肥満学会, 日本語

発達障害児と認知症高齢者を対象としたタップ課題による認知機能評価システムの開発 (福祉情報工学)
中園 正吾, 大西 俊介, 北川 博巳, 電子情報通信学会技術研究報告 = IEICE technical report : 信学技報, 115, 193, 1, 6, 2015年08月25日
電子情報通信学会, 日本語

当院における子宮体癌および子宮内膜異型増殖症に対する妊孕性温存療法の治療成績
山田 有紀, 大西 俊介, 杉本 ひとみ, 森岡 佐知子, 伊東 史学, 重富 洋志, 棚瀬 康仁, 春田 祥治, 川口 龍二, 吉田 昭三, 古川 直人, 小林 浩, 産婦人科の進歩, 67, 3, 326, 328, 2015年08月
2009年4月〜2014年7月に類内膜腺癌G1または複雑型子宮内膜異型増殖症(AEH)に対し高用量medroxyprogesterone(MPA)療法を施行した7例(年齢中央値34歳)の奏効率、再発の有無、治療後の妊娠出産の有無を後ろ向きに検討した。MPA投与量の中央値は600mg/日であった。MPA療法の効果判定は、子宮内膜全面掻爬による病理組織診断で行い、奏効率は85.7%、再発率は83.3%であった。再発までの期間の中央値は7ヵ月であり、そのうちMPAの再投与を行った症例が4例、最終的に手術を施行した症例が4例であった。出産に至ったのは1例のみであった。AEHおよび類内膜腺癌に対する高用量MPA療法は、奏効率は高いが再発率も高く、挙児希望があれば可及的早期の妊娠を考慮することが望ましいと考えられた。, 「産婦人科の進歩」編集室, 日本語

高度肥満学生における高感度CRPの測定意義について　　　　　　　　　　　　　　　
吉村 彩, 大西 俊介, 川原 由佳子, 折戸 智恵子, 本間 理央, 川久保 和道, 加納 崇裕, 横田 卓, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 53回, 36, 36, 2015年08月
(公社)全国大学保健管理協会, 日本語

高度肥満学生における簡易式自記式食事歴調査票の意義について　　　　　　　　　　　　　　　
折戸 智恵子, 大西 俊介, 川原 由佳子, 吉村 彩, 本間 理央, 川久保 和道, 加納 崇裕, 横田 卓, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 53回, 58, 58, 2015年08月
(公社)全国大学保健管理協会, 日本語

帝王切開術後の高アミラーゼ血症に関与する因子の検討　　　　　　　　　　　　　　　
大西 俊介, 藤本 佳克, 丸山 祥代, 山下 健, 今中 聖悟, 日本周産期・新生児医学会雑誌, 51, 2, 901, 901, 2015年06月
(一社)日本周産期・新生児医学会, 日本語

広汎子宮全摘術後にクリーゼを来した重症筋無力症の1症例
竹田 善紀, 大西 俊介, 棚瀬 康仁, 岩井 加奈, 山田 有紀, 重富 洋志, 春田 祥治, 川口 龍二, 吉田 昭三, 古川 直人, 小林 浩, 産婦人科の進歩, 67, 2, 192, 192, 2015年05月
「産婦人科の進歩」編集室, 日本語

Meckel憩室軸捻転合併妊娠の1例　　　　　　　　　　　　　　　
大西 俊介, 藤本 佳克, 丸山 祥代, 山下 健, 今中 聖悟, 産婦人科の進歩, 67, 2, 238, 238, 2015年05月
「産婦人科の進歩」編集室, 日本語

前置癒着胎盤における予防的な大動脈閉塞バルン(IAB)留置効果の検討　　　　　　　　　　　　　　　
重光 愛子, 岩井 加奈, 山田 有紀, 赤坂 珠理晃, 常見 泰平, 杉本 ひとみ, 大西 俊介, 中野 和俊, 成瀬 勝彦, 小林 浩, 日本産婦人科・新生児血液学会誌, 25, 1, S, 29, 2015年05月
日本産婦人科・新生児血液学会, 日本語

厚生労働省による積極的勧奨中止後に子宮頸がんワクチン接種を受けた大学生への意識調査　　　　　　　　　　　　　　　
川原 由佳子, 齋藤 暢一朗, 大西 俊介, 吉村 彩, 石原 可愛, 横田 卓, 橋野 聡, 日本看護学会論文集: ヘルスプロモーション, 45, 89, 92, 2015年03月
子宮頸がんワクチン接種は、2013年4月から予防接種法改正で定期接種となったが、副反応により安全性が問われ、同年6月14日に厚労省は積極的勧奨を中止した。A大学保健センターでは、2013年6月上旬から子宮頸がんワクチン未接種の1年生を対象に自費でのワクチン接種を開始し、希望者は当初25名いたが、厚労省からの通達後、途中キャンセルが相次ぎ、ワクチン接種全3回の実施に至ったのは18名であった。今回、この18名のうち同意が得られた12名を対象としてワクチン接種に関する半構造化インタビューを行い、語られた内容をカテゴリー化した。結果、『接種行動を妨げる不安』『実施の動機づけとなった要因』という2つのコアカテゴリーが抽出された。前者を構成するカテゴリーとして【様々な情報の不確かさ】【成長過程にある思春期の影響】【実施に至るまでの葛藤】があり、後者を構成するカテゴリーとして【病気の心配から必要性を判断】【家族との話し合い】【安心できる環境が重要】【安心・安全なワクチン接種の実際】があった。, 日本看護学会, 日本語

本学での子宮頸がんワクチン接種実施報告 不安と疼痛の影響から考えられたこと　　　　　　　　　　　　　　　
川原 由佳子, 折戸 智恵子, 吉村 彩, 石原 可愛, 大西 俊介, 横田 卓, 橋野 聡, CAMPUS HEALTH, 52, 1, 231, 233, 2015年03月
本学保健センターでは、子宮頸がんワクチン接種を希望する新入生女子24名に対して平成25年6月上旬に1回目の接種をしていたが、同年6月14日に厚労省が積極的勧奨を差し控えたため、7名が途中キャンセルした。今回、キャンセルした学生を含む24名の接種に対する不安について、接種前後の収縮期血圧を指標に調査するとともに、接種時の疼痛についてVAS(0〜10)で調査した。結果、収縮期血圧の平均値は、1回目の接種前が114.3、接種後107、2回目の接種前103.5、接種後99、3回目の接種前105.1、接種後105.6であり、1回目の接種前が最も高く、1回目と2回目は接種前が接種後より高値であったが、3回目は接種前後で差異を認めなかった。VASは、1回目が「0」7名、「1」1名、「2」1名、「3」2名、「5」12名、「6」1名、2回目(19名)が「2」1名、「3」3名、「4」1名、「5」9名、「6」5名、3回目(18名)が「1」4名、「2」2名、「4」2名、「5」7名、「6」2名、「7」1名であった。, (公社)全国大学保健管理協会, 日本語

動物実験従事者におけるアレルギー健診3年分の経年的解析　　　　　　　　　　　　　　　
吉村 彩, 武藏 学, 折戸 智恵子, 川原 由佳子, 横田 卓, 大西 俊介, 橋野 聡, CAMPUS HEALTH, 52, 1, 443, 445, 2015年03月
本学では平成22年度に、実験中マウスに噛まれてアナフィラキシーショックを起こした事例があったため、平成23年度から予防対策の一環として、動物実験従事者のうち希望者に対し、取扱動物の特異的IgE抗体検査を含む健診を毎年実施している。昨年度に3回目が終了したので、3年間継続受診した者に着目して経年的な解析を行った。対象者は86名で、3年間継続して同種の抗体検査を実施したものは、マウスIgE抗体65名、ラットIgE抗体44名、ハムスターIgE抗体6名、モルモット2名、ウサギ14名であった。動物別にみた特異的IgE抗体陽性率の経年的変化は、マウスが平成23年度18.5%、24年度23.1%、25年度27.7%、ラットがそれぞれ15.9%、20.5%、22.7%であり、両者とも増加傾向にあるものの有意差はなかった。対象者に対して問診票による調査を行い、抗体陽性率との関連について検討した結果、「眼の症状」「蕁麻疹」がマウスIgE抗体陽性率と有意な関連を示したが、「ペット飼育」「親族のアレルギー歴」「喫煙」「気管支炎」「花粉症」「アトピー性皮膚炎」などはマウス・ラットとも有意な関連は示さなかった。, (公社)全国大学保健管理協会, 日本語

ストレスと消化器疾患 ストレスによる老齢動物の摂食低下には性差が存在する　　　　　　　　　　　　　　　
大西 俊介, 武藤 修一, 武田 宏司, 日本消化器病学会雑誌, 112, 臨増総会, A93, A93, 2015年03月
(一財)日本消化器病学会, 日本語

消化管ホルモンの役割を見直す 摂食行動と栄養代謝調節 セロトニンによるグレリン分泌の調節機構　　　　　　　　　　　　　　　
武藤 修一, 大西 俊介, 武田 宏司, 日本消化器病学会雑誌, 112, 臨増総会, A98, A98, 2015年03月
(一財)日本消化器病学会, 日本語

シスプラチンの副作用に対するKampoのメカニズム (特集 臨床"Kampo" : 各科領域におけるエビデンス)
武田 宏司, 武藤 修一, 大西 俊介, 医薬ジャーナル, 51, 2, 75, 80, 2015年02月
医薬ジャーナル社, 日本語

【臨床"Kampo"〜各科領域におけるエビデンス〜】 シスプラチンの副作用に対するKampoのメカニズム　　　　　　　　　　　　　　　
武田 宏司, 武藤 修一, 大西 俊介, 医薬ジャーナル, 51, 2, 705, 710, 2015年02月
六君子湯は、各種消化管機能低下症状に対して使用される代表的な漢方方剤であり、基礎研究においては、ラットにおける胃排出能の亢進作用などが明確となっている。最近、シスプラチンによる遅発性嘔吐および食欲不振に対する六君子湯の効果が、動物モデルを用いた基礎検討および消化器癌化学療法を施行された患者を対象とした臨床研究の両面から、急速に明らかにされてきている。六君子湯は摂食ホルモンであるグレリンの分泌を促進することで、食欲不振や悪心・嘔吐に効果を示すという、極めてユニークな作用を有している。本稿では、シスプラチンによる食欲不振に対する六君子湯の効果に焦点を当てて概説したい。(著者抄録), (株)医薬ジャーナル社, 日本語

重篤なヒトパルボB19ウイルス胎内感染を起こすも後遺症なく出生発達した一例　　　　　　　　　　　　　　　
河原 直紀, 成瀬 勝彦, 大西 俊介, 岩井 加奈, 重光 愛子, 常見 泰平, 小林 浩, 日本産科婦人科学会雑誌, 67, 2, 606, 606, 2015年02月
(公社)日本産科婦人科学会, 日本語

高度救命救急センターとの連携により救命しえた産科危機的出血の4例と文献的考察　　　　　　　　　　　　　　　
森岡 佐知子, 大西 俊介, 河原 直紀, 岩井 加奈, 重光 愛子, 常見 泰平, 成瀬 勝彦, 小林 浩, 日本産科婦人科学会雑誌, 67, 2, 782, 782, 2015年02月
(公社)日本産科婦人科学会, 日本語

自動データ送信可能な血圧計による産後家庭血圧の新たな遠隔管理　　　　　　　　　　　　　　　
大西 俊介, 成瀬 勝彦, 小池 奈月, 赤坂 珠理晃, 重光 愛子, 岩井 加奈, 常見 泰平, 小林 浩, 日本産科婦人科学会雑誌, 67, 2, 924, 924, 2015年02月
(公社)日本産科婦人科学会, 日本語

統合失調症合併妊娠の転帰と周産期予後に関する検討　　　　　　　　　　　　　　　
重光 愛子, 成瀬 勝彦, 大西 俊介, 河原 直紀, 岩井 加奈, 森岡 佐知子, 常見 泰平, 小林 浩, 日本産科婦人科学会雑誌, 67, 2, 928, 928, 2015年02月
(公社)日本産科婦人科学会, 日本語

帝王切開術後肺血栓塞栓症撲滅をめざした抗凝固薬による血栓症予防　　　　　　　　　　　　　　　
春田 祥治, 川口 龍二, 大西 俊介, 河原 直紀, 森岡 佐知子, 岩井 加奈, 重光 愛子, 常見 泰平, 成瀬 勝彦, 小林 浩, 日本産科婦人科学会雑誌, 67, 2, 935, 935, 2015年02月
(公社)日本産科婦人科学会, 日本語

脳腸相関の新展開 脳腸相関からみた六君子湯の食欲改善作用　　　　　　　　　　　　　　　
武田 宏司, 大西 俊介, 武藤 修一, 日本東洋心身医学研究, 29, 1-2, 16,103, 20,103, 2014年12月
日本東洋心身医学研究会, 日本語

当院における子宮体癌および子宮内膜異型増殖症に対する妊孕性温存療法の治療成績　　　　　　　　　　　　　　　
山田 有紀, 大西 俊介, 杉本 ひとみ, 森岡 佐知子, 伊東 史学, 重富 洋志, 棚瀬 康仁, 春田 祥治, 川口 龍二, 吉田 昭三, 古川 直人, 小林 浩, 産婦人科の進歩, 66, 4, 476, 476, 2014年10月
「産婦人科の進歩」編集室, 日本語

大学生における末梢血白血球数および白血球分画と肥満関連合併症との関連についての検討　　　　　　　　　　　　　　　
吉村 彩, 大西 俊介, 川原 由佳子, 折戸 智恵子, 橋野 聡, 肥満研究, 20, Suppl., 160, 160, 2014年10月
(一社)日本肥満学会, 日本語

若年性肥満群血清におけるセラミド及びスフィンゴミエリン分子種の解析　　　　　　　　　　　　　　　
花松 久寿, 大西 俊介, 酒井 祥太, 湯山 耕平, 光武 進, 五十嵐 靖之, 日本生化学会大会プログラム・講演要旨集, 87回, [2P, 487], 2014年10月
(公社)日本生化学会, 日本語

北海道大学における動物実験実施者等の実験動物への感作状況
吉村 彩, 武藏 学, 金子 壮朗, 大西 俊介, 折戸 智恵子, 川原 由佳子, 橋野 聡, 森松 正美, 今野 哲, 有川 二郎, 石井 哲也, 澤村 正也, 上田 一郎, アレルギー, 63, 8, 1132, 1139, 2014年09月
【目的】北海道大学で発生したマウス咬傷によるアナフィラキシー事例を踏まえ,アレルギー予防対策の構築を目的として,動物実験を実施する学生及び職員の動物アレルギーの感作状況を調査した.【方法】齧歯類等の取扱者で同意を得た555名を対象に問診票と実験動物5種に対する特異的IgE抗体と好酸球数測定によるアレルギー健診を実施した.【結果】特異的IgE抗体陽性率(陽性者数/取扱者数)は,マウス14.1%(62/441名),ラット17.9%(50/279名),ハムスター18.8%(6/32名),モルモット17.4%(4/23名),ウサギ11.3%(12/106名)であった.マウス取扱者においては,動物に接触した時に何らかのアレルギー症状が現れる場合は,抗マウスIgE抗体陽性率が有意に高いことも判明した(38.1% vs 8.8%,p<0.01).【結論】動物取扱者の感作状況を把握するために,特異的IgE抗体検査を含む健診を実施することが有用であることが示された.(著者抄録), (一社)日本アレルギー学会, 日本語

EGFR阻害剤を用いた食道扁平上皮癌幹細胞を標的とした新規治療法の開発(EGFR inhibitors suppress EMT and diminish cancer stem-like cells in esophageal squamous cell carcinoma)　　　　　　　　　　　　　　　
佐藤 史幸, 夏井坂 光輝, 大橋 真也, 賀川 真吾, 桑谷 将城, 河上 洋, 大西 俊介, 小松 嘉人, 加藤 元嗣, 坂本 直哉, 日本癌学会総会記事, 73回, J, 1034, 2014年09月
日本癌学会, 英語

本学での子宮頸がんワクチン接種実施報告 不安と疼痛の影響から考えられたこと　　　　　　　　　　　　　　　
川原 由佳子, 折戸 智恵子, 吉村 彩, 石原 可愛, 大西 俊介, 横田 卓, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 52回, 58, 58, 2014年08月
(公社)全国大学保健管理協会, 日本語

動物実験従事者におけるアレルギー健診3年分の経年的解析　　　　　　　　　　　　　　　
吉村 彩, 折戸 智恵子, 川原 由佳子, 横田 卓, 大西 俊介, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 52回, 103, 103, 2014年08月
(公社)全国大学保健管理協会, 日本語

マルチディスプレイによるオンスクリーンキーボードの課題解消に向けた取り組み　　　　　　　　　　　　　　　
大西 俊介, 中園 正吾, 原 良昭, 杉本 義己, リハ工学カンファレンス講演論文集, 29回, np51, np52, 2014年08月
(一社)日本リハビリテーション工学協会, 日本語

NAFLDおよびインスリン抵抗性の発症におけるスフィンゴミエリン代謝系の関与　　　　　　　　　　　　　　　
大西 俊介, 光武 進, 湯山 耕平, 酒井 祥太, 花松 久寿, 折戸 智恵子, 川原 由佳子, 吉村 彩, 高崎 裕代, 武田 宏司, 五十嵐 靖之, 橋野 聡, 坂本 直哉, 肝臓, 55, Suppl.1, A320, A320, 2014年04月
(一社)日本肝臓学会, 日本語

保健センターでの子宮頸がんワクチン接種実施報告 接種勧奨中止に伴う影響　　　　　　　　　　　　　　　
折戸 智恵子, 大西 俊介, 川原 由佳子, 吉村 彩, 小西 剛, 今野 康二, 渡邉 昌也, 橋野 聡, CAMPUS HEALTH, 51, 1, 237, 239, 2014年03月
子宮頸がんワクチン定期接種導入前の新入生のワクチン接種率を把握し、どのようなニーズがあるか検討した。入学前接種率は57.1%で、今後接種を考えていると答えた未接種者は71.8%であった。接種を考えない理由では「価格」が一番多く(34%)、「副反応」を理由に挙げたのは11%であった。ワクチンについての情報源は、女子は学校と家族が多く、男子は学校の他にTVが多かった。1回目の接種直後に「積極的勧奨の中止」の報道があり、25例の申込みのうち、最終の1例が未接種で辞退、5例が2回目以降の接種を辞退した。ワクチンを接種する際、保護者特に母親の理解が必要で、今回の調査でも中止という選択も母親の意向が強かったことが窺えた。, (公社)全国大学保健管理協会, 日本語

定期健康診断の血圧測定における本学の取り組み 高血圧の偽陽性の学生を少なくするために　　　　　　　　　　　　　　　
川原 由佳子, 谷 忍, 小西 剛, 折戸 智恵子, 吉村 彩, 横田 卓, 渡辺 昌也, 大西 俊介, 橋野 聡, CAMPUS HEALTH, 51, 1, 268, 270, 2014年03月
(公社)全国大学保健管理協会, 日本語

留学生の尿検査有所見の傾向 陽性率からみる健診対策　　　　　　　　　　　　　　　
吉村 彩, 折戸 智恵子, 川原 由佳子, 小西 剛, 谷 忍, 前野 由紀子, 渡邉 昌也, 横田 卓, 大西 俊介, 橋野 聡, CAMPUS HEALTH, 51, 1, 297, 299, 2014年03月
定期健康診断時(定健)の尿検査や再検査の結果について、一般学生(日本国籍)と比較し、留学生における尿検査有所見の傾向について検討した。定健尿検査を受診した学生31555例を一般学生と留学生に分けて検討した。定健尿検査(1回目)の再検該当者は、一般学生は平均3.2%であったが、留学生平均7.7%と高かった。さらに、男女別では、女性の留学生に高い傾向が見られた。再検該当項目別の陽性率は、尿潜血賜性は留学生及び男女、特に女性で高かった。再検受診者のうち、他医療機関へ紹介した紹介率は、留学生が平均5割と高いが、医療機閣からの返信が来た返信率は、一般学生の方が高かった。医療機関からの返信内容では、異常なしと血尿が多い傾向にあった。留学生の受診者数でもっとも多いのがアジアで、再検該当率、受診率最多は中国で次いで韓国、インドネシアに多く多かった。, (公社)全国大学保健管理協会, 日本語

FGIDの病態生理学と脳腸相関研究の進歩 ストレスによる胃機能異常にはグレリンシグナルの異常が関与する　　　　　　　　　　　　　　　
武藤 修一, 大西 俊介, 武田 宏司, 日本消化器病学会雑誌, 111, 臨増総会, A164, A164, 2014年03月
(一財)日本消化器病学会, 日本語

肝炎ウイルスの複製増殖および病原性発現機構と薬剤感受性の解析 LカルニチンによるHCV増殖抑制,脂肪化抑制,酸化ストレス抑制効果の検討
大西俊介, 須田剛生, 肝炎ウイルスの複製増殖および病原性発現機構と薬剤感受性の解析 平成25年度 総括・分担研究報告書, 48‐49, 2014年
日本語

卵膜由来間葉系幹細胞を用いた急性膵炎の新規治療法の開発　　　　　　　　　　　　　　　
大西 俊介, 日本膵臓病研究財団研究報告書, 20回, 101, 105, 2013年12月
(公財)日本膵臓病研究財団, 日本語

【Cachexiaと栄養管理】 抗癌剤に伴うcachexiaとその治療　　　　　　　　　　　　　　　
武田 宏司, 武藤 修一, 大西 俊介, 河野 透, 栄養-評価と治療, 30, 4, 283, 286, 2013年11月
シスプラチンによる急性の嘔吐にはセロトニン3(5-HT3)受容体が、遅延性の嘔吐にはニューロキニン1(NK1)受容体が関与することが明らかにされ、それぞれの拮抗薬が臨床応用されている。一方、シスプラチンによる食欲不振は、5-HT2B/5-HT2C受容体を介したグレリン分泌の低下によって生じることが最近明らかにされ、その対策としてグレリンや六君子湯に期待が寄せられている。(著者抄録), (株)メディカルレビュー社, 日本語

消化管の新たな映像(第11回) 術中近赤外蛍光イメージング　　　　　　　　　　　　　　　
大西 俊介, 田中 栄一, 芦立 嘉智, Frangioni John V, Frontiers in Gastroenterology, 18, 4, 334, 339, 2013年10月
(株)メディカルレビュー社, 日本語

保健センターでの子宮頸がんワクチン接種実施報告 接種勧奨中止に伴う影響　　　　　　　　　　　　　　　
折戸 智恵子, 大西 俊介, 川原 由佳子, 吉村 彩, 小西 剛, 今野 康二, 渡邉 昌也, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 51回, 82, 82, 2013年10月
(公社)全国大学保健管理協会, 日本語

定期健康診断における高血圧の偽陽性率を低下させるための取り組み　　　　　　　　　　　　　　　
川原 由佳子, 谷 忍, 小西 剛, 折戸 智恵子, 吉村 彩, 渡邉 昌也, 大西 俊介, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 51回, 85, 85, 2013年10月
(公社)全国大学保健管理協会, 日本語

留学生の尿検査有所見の傾向 陽性率からみる健診対策　　　　　　　　　　　　　　　
吉村 彩, 折戸 智恵子, 川原 由佳子, 小西 剛, 谷 忍, 前野 由紀子, 渡邉 昌也, 大西 俊介, 橋野 聡, 全国大学保健管理研究集会プログラム・抄録集, 51回, 88, 88, 2013年10月
(公社)全国大学保健管理協会, 日本語

食道扁平上皮癌におけるTGF-βおよびNotch1による癌幹細胞維持機構(TGF-β changes a switch of Notch1-mediated signaling to maintain tumor-initiating cells in esophageal SCC(ESCC))　　　　　　　　　　　　　　　
夏井坂 光輝, 大橋 真也, 長沼 誠二, 大西 俊介, 桑谷 将城, 河上 洋, 中馬 誠, 小松 嘉人, 加藤 元嗣, 坂本 直哉, 日本癌学会総会記事, 72回, 137, 137, 2013年10月
日本癌学会, 英語

HIFによる低酸素非依存的なCD133プロモーター活性の制御(Hypoxia-inducible factors regulate CD133 promoter activity independently of hypoxia)　　　　　　　　　　　　　　　
大西 俊介, 中川 宏治, 坂本 直哉, 小林 正伸, 武田 宏司, 日本癌学会総会記事, 72回, 334, 334, 2013年10月
日本癌学会, 英語

消化器疾患と栄養代謝ネットワーク 基礎から臨床まで ストレスによる老齢動物の摂食低下には5-HT2C受容体の機能亢進が関与する　　　　　　　　　　　　　　　
大西 俊介, 武藤 修一, 武田 宏司, 日本消化器病学会雑誌, 110, 臨増大会, A582, A582, 2013年09月
(一財)日本消化器病学会, 日本語

携帯型情報端末を用いた知的障害児の二者択一場面を支援するアプリケーションの開発　　　　　　　　　　　　　　　
杉本 義己, 大森 清博, 大西 俊介, リハ工学カンファレンス講演論文集, 28回, 177, 178, 2013年08月
(一社)日本リハビリテーション工学協会, 日本語

社会的ストレスと消化器症状
武田 宏司, 武藤 修一, 大西 俊介, 消化器心身医学, 20, 1, 6, 9, 2013年08月
環境変化ストレスにともなう摂食低下の機序を明らかにするため、6週齢のC57BL/6J雄性マウスに新奇環境ストレスを負荷し、ストレス応答、セロトニン(5-HT)1B/2C受容体、メラノコルチン4(MC4)受容体およびグレリンの関係について検討した。新奇環境ストレスでは、血清コルチコステロンが増加し、血漿アシルグレリンおよび摂食量が低下した。グレリンの投与は摂食量を回復させ、CRF1受容体拮抗薬(NBI27914)、5-HT1B受容体拮抗剤(SB224289)、5-HT2C受容体拮抗剤(SB242084)、メラノコルチン4受容体拮抗剤(HS014)は血漿アシルグレリンの低下を抑制し、摂食量を回復させた。新奇環境ストレスでは、CRF1受容体活性化に引き続いて5-HT1B/2C-MC4システムが活性化され、血漿アシルグレリンが低下すると考えられた。(著者抄録), 消化器心身医学研究会, 日本語

光の臨床応用 近赤外蛍光イメージングとBlue LASER Imaging　　　　　　　　　　　　　　　
大西 俊介, 田中 栄一, 小野 尚子, 加藤 元嗣, JSMI Report, 6, 2, 59, 59, 2013年05月
日本分子イメージング学会, 日本語

動物実験従事者の動物アレルギー　　　　　　　　　　　　　　　
吉村 彩, 武藏 学, 金子 壮朗, 大西 俊介, 折戸 智恵子, 川原 由佳子, 森松 正美, 今野 哲, 有川 二郎, CAMPUS HEALTH, 50, 1, 316, 316, 2013年03月
(公社)全国大学保健管理協会, 日本語

【摂食制御と消化管】 六君子湯による摂食不振・悪液質の改善　　　　　　　　　　　　　　　
武田 宏司, 中川 宏治, 西村 三恵, 大久保 直登, 細野 秀崇, 浅香 正博, 武藤 修一, 大西 俊介, 坂本 直哉, G.I.Research, 21, 1, 48, 58, 2013年02月
六君子湯は心窩部不快感や胃もたれ感、食欲不振などに対して広く使用されている漢方薬である。六君子湯はグレリンの分泌を亢進させ、さまざまな病態における食欲不振を改善する。シスプラチンは5-HT2B受容体および5-HT2C受容体を活性化してアシルグレリンを低下させ、食欲不振を引き起こすが、六君子湯は5-HT2B/5-HT2C受容体を阻害することにより、アシルグレリン分泌を回復させる。高齢動物では高濃度のレプチンにより視床下部弓状核ニューロペプチドY(NPY)/アグーチ関連ペプチド(AgRP)ニューロンでグレリンシグナルがブロックされているが、六君子湯はPDE3を阻害してグレリン抵抗性を解除し、食欲を回復させる。癌悪液質モデルでは、5-HT2C受容体の関与やグレリン抵抗性の存在が示唆されているが、六君子湯は5-HT2C受容体を阻害し、グレリン受容体の感受性を改善することにより食欲不振を改善させる。(著者抄録), (株)先端医学社, 日本語

消化器領域における幹細胞研究の進歩 食道がん幹細胞におけるTGF-β/Notchシグナルを標的とした新規治療法の創出　　　　　　　　　　　　　　　
夏井坂 光輝, 大西 俊介, 坂本 直哉, 日本消化器病学会雑誌, 110, 臨増総会, A82, A82, 2013年02月
(一財)日本消化器病学会, 日本語

当科における虚血性大腸炎診断の取り組み　　　　　　　　　　　　　　　
武藤 修一, 武田 宏司, 大西 俊介, 小西 康平, 江藤 和範, 宮本 秀一, 日本消化器病学会雑誌, 110, 臨増総会, A309, A309, 2013年02月
(一財)日本消化器病学会, 日本語

ICT機器を活用した知的障害児、発達障害児のコミュニケーション支援に関する研究
大森 清博, 大西 俊介, 中園 正吾, 兵庫県立福祉のまちづくり研究所報告集, 49, 56, 2013年
兵庫県社会福祉事業団総合リハビリテーションセンター兵庫県立福祉のまちづくり研究所, 日本語

【消化管疾患に対する漢方医学からのアプローチ-現状と展望】 消化管疾患に対する漢方医療の実際 消化器癌に対する補助療法 食欲不振　　　　　　　　　　　　　　　
武田 宏司, 武藤 修一, 大西 俊介, 臨床消化器内科, 28, 2, 209, 214, 2013年01月
六君子湯は,各種消化管機能低下症状に対して使用される代表的な漢方薬であり,基礎研究においては,ラットにおける胃排出能の亢進作用などが明確となっている.最近,シスプラチンによる遅発性嘔吐および食欲不振に対する六君子湯の効果が,動物モデルを用いた基礎検討および消化器癌化学療法を施行された患者を対象とした臨床研究の両面から急速に明らかにされてきている.六君子湯は摂食ホルモンであるグレリンの分泌を促進することで,食欲不振や悪心・嘔吐に効果を示すという,きわめてユニークな作用を有している.本稿では,シスプラチンによる食欲不振に対する六君子湯の効果に焦点を当てて概説したい.(著者抄録), (株)日本メディカルセンター, 日本語

健康診断の血液検査で発見されたサラセミアの9例
吉村 彩, 武藏 学, 大西 俊介, 奈良部 正子, 折戸 智恵子, 山城 安啓, 服部 幸夫, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 87, 6, 2012年11月01日
日本語

【有効性・安全性・経済性を考慮した「漢方薬」提案のヒント】 こんな時には漢方薬 方剤単位で学ぶ「漢方薬」提案のヒント 六君子湯　　　　　　　　　　　　　　　
武田 宏司, 武藤 修一, 大西 俊介, 薬局, 63, 11, 3290, 3299, 2012年10月
＜Key Points＞◎六君子湯は虚証の患者に使用される代表的な方剤であり、心窩部不快感や胃もたれ感、食欲不振などに対して使用される。◎六君子湯は機能性ディスペプシアのうち食後愁訴症候群に対する第1選択薬である。◎プロトンポンプ阻害薬抵抗性胃食道逆流症に対する有効性も期待される。◎最近では証にこだわらず西洋医学的な手法で六君子湯の有効性を証明した研究が増えている。◎六君子湯はグレリンの分泌を亢進させるというユニークな作用を有する。(著者抄録), (株)南山堂, 日本語

大腸癌における造影超音波検査と再発予測について　　　　　　　　　　　　　　　
武藤 修一, 大西 俊介, 小西 康平, 江藤 和範, 宮本 秀一, 高橋 亜希, 福島 拓, 高橋 一宏, 石津 明洋, 武田 宏司, 日本癌治療学会誌, 47, 3, 2250, 2250, 2012年10月
(一社)日本癌治療学会, 日本語

機能性消化管障害の病態と治療 グレリンシグナルの低下がGERDにおける胃排出低下に関与する　　　　　　　　　　　　　　　
武田 宏司, 武藤 修一, 大西 俊介, 日本消化器病学会雑誌, 109, 臨増大会, A433, A433, 2012年09月
(一財)日本消化器病学会, 日本語

大腸癌における術前超音波検査結果とその後の予後の検討　　　　　　　　　　　　　　　
武藤 修一, 武田 宏司, 大西 俊介, 福島 拓, 高橋 一宏, 宮本 秀一, 石津 明洋, 浅香 正博, 日本消化器病学会雑誌, 109, 臨増大会, A822, A822, 2012年09月
(一財)日本消化器病学会, 日本語

動物実験従事者の動物アレルギー　　　　　　　　　　　　　　　
吉村 彩, 武藏 学, 金子 壮朗, 大西 俊介, 折戸 智恵子, 川原 由佳子, 森松 正美, 今野 哲, 有川 二郎, CAMPUS HEALTH, 49, 4, 89, 89, 2012年09月
(公社)全国大学保健管理協会, 日本語

新奇環境ストレスによる食欲低下に対する六君子湯の効果　　　　　　　　　　　　　　　
三枝 弥生, 武藤 修一, 中川 宏治, 大西 俊介, 定金 千春, 名畑 美和, 服部 智久, 浅香 正博, 武田 宏司, Journal of Traditional Medicines, 29, Suppl., 94, 94, 2012年08月
(一社)和漢医薬学会, 日本語

HIFによるEts結合部位を介したCD133プロモーター活性の制御(Hypoxia-inducible factors activate CD133 promoter through Ets-binding sites)　　　　　　　　　　　　　　　
大西 俊介, 中川 宏治, 坂本 直哉, 小林 正伸, 日本癌学会総会記事, 71回, 245, 245, 2012年08月
日本癌学会, 英語

健康診断の血液検査で発見されたサラセミアの9例　　　　　　　　　　　　　　　
吉村 彩, 武藏 学, 大西 俊介, 奈良部 正子, 折戸 智恵子, 山城 安啓, 服部 幸夫, CAMPUS HEALTH, 49, 3, 9, 14, 2012年05月
我々は、2004年から2010年までの6年間に実施したRI健診および学生特殊健康診断で9例のサラセミアを発見したので報告する。血算検査で鉄欠乏性貧血を除外しサラセミアを疑った8例の精査を山口大学へ依頼した。血色素異常症スクリーニング・遺伝子分析より、3例がαサラセミア、5例がβサラセミア(HbE 1例)と診断された。7名が留学生であり、出身国別留学生数に占めるサラセミア頻度は、中国2名(1.7%)、フィリピン1名(11.1%)、パキスタン1名(50%)、インド1名(9.1%)、カンボジア1名(100%)、エジプトは、サラセミア疑い1名(9.1%)、日本2名(0.03%)であった。本学では、留学生の増加に伴い、2004年度、2006年度に1例ずつ、2007年度に3例、2009年度には4例とサラセミア診断例が増加していた。小球性赤血球症を認めた場合、鉄欠乏性貧血との鑑別にサラセミアも念頭に置く必要がある。MCVが70fl以下、Mentzer index(MCV/RBC)が13.0以下で、血清鉄減少を認めない場合にはサラセミアを強く疑って精査する必要があると考えられた。今回のサラセミア例は全例軽症であり、治療は要しなかったが、遺伝子型によっては子供に重度のサラセミアが生じる可能性があるため、精密検査結果について、本人に十分な説明を行って熟知させておくこと、場合によっては配偶者のスクリーニング検査を勧めることが重要と思われた。(著者抄録), (公社)全国大学保健管理協会, 日本語

栄養代謝制御における消化管生理活性ペプチドの役割 性差が末梢グレリン分泌に与える影響 老化マウスにおける検討　　　　　　　　　　　　　　　
大西 俊介, 武藤 修一, 武田 宏司, 日本消化器病学会雑誌, 109, 臨増総会, A142, A142, 2012年03月
(一財)日本消化器病学会, 日本語

虚血性腸炎の診断における腹部エコー検査の有用性についての検討　　　　　　　　　　　　　　　
武藤 修一, 福島 拓, 高橋 一宏, 宮本 秀一, 大西 俊介, 武田 宏司, 日本消化器病学会雑誌, 109, 臨増総会, A323, A323, 2012年03月
(一財)日本消化器病学会, 日本語

本学における学生生活実態調査30年のまとめ 経済状況、食生活および健康状況の変化について　　　　　　　　　　　　　　　
折戸 智恵子, 大西 俊介, 武藏 学, CAMPUS HEALTH, 49, 1, 111, 112, 2012年02月
(公社)全国大学保健管理協会, 日本語

健康診断の血液検査で発見されたサラセミアの9例　　　　　　　　　　　　　　　
吉村 彩, 武藏 学, 大西 俊介, 奈良部 正子, 折戸 智恵子, 山城 安啓, 服部 幸夫, CAMPUS HEALTH, 49, 1, 181, 181, 2012年02月
(公社)全国大学保健管理協会, 日本語

急性上気道炎に対する抗生剤投与は学生の再診率低下に寄与するのか?　　　　　　　　　　　　　　　
大西 俊介, 金子 壮朗, 小西 剛, 吉田 和絵, 折戸 智恵子, 武藏 学, CAMPUS HEALTH, 49, 1, 394, 396, 2012年02月
(公社)全国大学保健管理協会, 日本語

Stage4消化器癌患者の入院時Alb値とCRP値の評価　　　　　　　　　　　　　　　
武藤 修一, 武田 宏司, 大西 俊介, 福島 拓, 高橋 一宏, 宮本 秀一, 日本内科学会雑誌, 101, Suppl., 159, 159, 2012年02月
(一社)日本内科学会, 日本語

本学における学生生活実態調査30年のまとめ 経済状況、食生活および健康状況の変化　　　　　　　　　　　　　　　
折戸 智恵子, 大西 俊介, 武藏 学, CAMPUS HEALTH, 48, 3, 61, 61, 2011年10月
(公社)全国大学保健管理協会, 日本語

急性上気道炎に対する抗生剤投与は学生の再診率低下に寄与するのか?　　　　　　　　　　　　　　　
大西 俊介, 金子 壮朗, 小西 剛, 吉田 和絵, 折戸 智恵子, 武蔵 学, CAMPUS HEALTH, 48, 3, 91, 91, 2011年10月
(公社)全国大学保健管理協会, 日本語

【神経消化器病学の進歩】 内分泌ペプチドと消化器の生理 神経内分泌ペプチドを介した悪心・嘔吐の制御機構　　　　　　　　　　　　　　　
武田 宏司, 中川 宏治, 大西 俊介, 医学のあゆみ, 238, 10, 997, 1001, 2011年09月
癌化学療法剤による嘔吐は、消化管粘膜で増加したセロトニン(5-HT)が迷走神経求心性線維末端の5-HT3受容体を刺激することによって引き起されることが明らかにされ、現在ではシスプラチンによる即時性嘔吐を抑えるために5-HT3拮抗薬が汎用されている。シスプラチンによる遅延性嘔吐ならびに予測性嘔吐に対しては、中枢に存在するニューロキニン1(NK1)受容体の役割が明らかにされ、NK1受容体拮抗薬がわが国でも使用可能となっている。内分泌系では以前よりアルギニンバゾプレシンの役割が注目されてきたが、最近ではグレリンの応用に期待が寄せられている。(著者抄録), 医歯薬出版(株), 日本語

大腸癌に対するFDG-PET/CT検査の有用性　　　　　　　　　　　　　　　
武藤 修一, 大西 俊介, 福島 拓, 高橋 一宏, 宮本 秀一, 武田 宏司, 日本消化器病学会雑誌, 108, 臨増大会, A868, A868, 2011年09月
(一財)日本消化器病学会, 日本語

【高齢者の消化と吸収と老化制御】 加齢による食欲不振のメカニズムとその対策 六君子湯の効果とその作用機序
武藤 修一, 大西 俊介, 浅香 正博, 武田 宏司, 消化器内科, 53, 3, 247, 251, 2011年09月
(有)科学評論社, 日本語

成分栄養剤エレンタールにより、消化管粘膜障害が軽快した大腸癌化学療法の1症例　　　　　　　　　　　　　　　
武藤 修一, 福島 拓, 高橋 一宏, 宮本 秀一, 大西 俊介, 武田 宏司, 日本癌治療学会誌, 46, 2, 842, 842, 2011年09月
(一社)日本癌治療学会, 日本語

【実践!!薬効モニタリング】 薬効モニタリングの実践 過敏性腸症候群　　　　　　　　　　　　　　　
武田 宏司, 中川 宏治, 桂田 武彦, 平山 剛, 大西 俊介, 細野 秀崇, 浅香 正博, 薬局, 62, 9, 3191, 3197, 2011年08月
＜Key Points＞◎IBSの薬効評価において、プライマリー・エンドポイントとしてもっともよく用いられているのは、患者による治療満足度である。◎セカンダリー・エンドポイントとしては、症状の全般改善度の変化、主症状重症度の変化などが用いられる。◎健康関連QOLの変化なども、セカンダリー・エンドポイントとしてしばしば用いられる。(著者抄録), (株)南山堂, 日本語

Helicobacterと内視鏡技術(第23回) 近赤外2波長蛍光イメージング装置の開発　　　　　　　　　　　　　　　
大西 俊介, 田中 栄一, 楢崎 肇, 加藤 元嗣, Frangioni John V, Helicobacter Research, 15, 3, 194, 198, 2011年06月
近赤外領域(700〜900nm)は、自家蛍光をほとんど認めず、光の組織透過性が高いため、生体の蛍光イメージングに適していると考えられる。われわれは、近赤外領域の2波長で観察可能な術中イメージング装置を開発し、臨床応用を開始している。現在のところ、臨床現場で使用可能な近赤外領域の蛍光色素はインドシアニングリーンとメチレンブルーしかないため適応も限られているが、今後、目的の分子を標的とした蛍光プローブが開発されれば、術中リアルタイムに病理学的評価が可能になってくると期待される。(著者抄録), (株)先端医学社, 日本語

【消化器癌をめぐる栄養療法】 消化器癌化学療法に伴う食欲不振のメカニズムとその対策
武藤 修一, 大西 俊介, 浅香 正博, 武田 宏司, 消化器内科, 52, 6, 559, 565, 2011年06月
(有)科学評論社, 日本語

【明日の診療に漢方をいかす 西洋医学と漢方医学の融合】 日常診療でまず使ってみたい漢方ベストチョイス15 IBS(便秘型) 大建中湯
武田 宏司, 中川 宏治, 武藤 修一, 大西 俊介, 浅香 正博, 細野 秀崇, 診断と治療, 99, 5, 817, 822, 2011年05月
(株)診断と治療社, 日本語

大腸癌における術前の超音波検査の意義　　　　　　　　　　　　　　　
武藤 修一, 高橋 亜希, 大西 俊介, 武田 宏司, 超音波医学, 38, Suppl., S414, S414, 2011年04月
(一社)日本超音波医学会, 日本語

下部消化管内視鏡検査手技に伴う術者顔面の汚染リスクについての検討
小林 良充, 大西 俊介, 大西 礼造, 竹村 龍, 鈴木 美櫻, 佐々木 尚英, 太宰 昌佳, 幡 有, 山本 純司, 小田 寿, 宮城島 拓人, Gastroenterological Endoscopy, 53, 3, 1117, 1121, 2011年03月
下部消化管内視鏡検査に伴う術者の汚染リスクについて検討するため、術者11名にフェースガード付マスクを着用させ、内視鏡検査102例実施後の水滴付着の有無および面積、個数を調べた。その結果、18例で水滴付着を認め、うち17例は検査経験3年以下の術者によるものであった。検査状況でみると、鉗子口の操作回数に伴って水滴付着陽性率は増加し、水滴面積も増大する傾向にあった。鉗子口の操作数を、鉗子を入れた回数と注射器を用いた水の注入回数の和とし、4回以下の群と5回以上の群で比較したところ、5回以上群で有意に水滴数が多く、水滴面積も大きかった。水滴は全30滴中、20滴がフェースガードの左側に付着していた。検査時間(30分未満/以上)、検査形態(通常検査/緊急検査/EMR・ポリペクトミー)、液体吸引量(200ml未満/以上)と水滴数、水滴面積に有意差はなく関係は認めなかった。また、術者の身長(170cm未満/以上)とも関係は認めなかった。, (一社)日本消化器内視鏡学会, 日本語

消化器病における漢方治療のエビデンスを目指して 六君子湯は社会的隔離による食欲不振を改善する　　　　　　　　　　　　　　　
武田 宏司, 武藤 修一, 大西 俊介, 日本消化器病学会雑誌, 108, 臨増総会, A142, A142, 2011年03月
(一財)日本消化器病学会, 日本語

遺伝性血管性浮腫(HAE)症例の診断と経過、治療について　　　　　　　　　　　　　　　
武藤 修一, 武田 宏司, 大西 俊介, 大西 礼造, 上畠 寧子, 小原 俊央, 日本消化器病学会雑誌, 108, 臨増総会, A337, A337, 2011年03月
(一財)日本消化器病学会, 日本語

急速に進行した低酸素血症と肺高血圧症を呈し、Pulmonary Tumor Thrombotic Microangiopathy(PTTM)が疑われた胆管癌の1症例　　　　　　　　　　　　　　　
武藤 修一, 武田 宏司, 大西 俊介, 大西 礼造, 上畠 寧子, 小原 俊央, 日本消化器病学会雑誌, 108, 臨増総会, A377, A377, 2011年03月
(一財)日本消化器病学会, 日本語

胸膜中皮腫と酷似した肺腺癌の1剖検例　　　　　　　　　　　　　　　
大西 礼造, 大西 俊介, 佐々木 尚英, 大野 正芳, 鈴木 美櫻, 久保 公利, 山本 純司, 小田 寿, 宮城島 拓人, 高橋 達郎, 岡本 賢三, 日本職業・災害医学会会誌, 59, 2, 90, 95, 2011年03月
症例はビル等の解体作業に従事していた61歳の男性。主訴は呼吸困難感。画像上左胸水貯留を認め、明らかな腫瘍性病変は認めなかったが、胸膜肥厚を疑う所見を認め、胸水細胞診では胸膜中皮腫疑いとの結果であった。診断確定のための更なる精査および積極的な治療は望まなかったため、胸膜癒着術を行い一時退院となった。しかし、著明な呼吸困難感、左側大量胸水を認めたため当科再入院となり、永眠された。剖検上、肉眼的には胸膜中皮腫が考えられたが、免疫染色を含めた組織学的検査により偽中皮腫性肺癌と診断された。胸膜中皮腫の鑑別疾患として偽中皮腫性肺癌が挙げられるが、鑑別に難渋する場合もあると考えられた。胸膜病変を有する悪性疾患を考慮した場合は、胸膜生検などにより十分な組織を採取し、精度の高い病理検査を行うことが必要であると考えられた。(著者抄録), (一社)日本職業・災害医学会, 日本語

脳腸相関 消化器内科領域における漢方　　　　　　　　　　　　　　　
武田 宏司, 中川 宏治, 武藤 修一, 大西 俊介, 浅香 正博, 日本東洋心身医学研究, 25, 1-2, 37, 41, 2011年03月
日本東洋心身医学研究会, 日本語

食道平滑筋腫上に発生した食道癌に対し内視鏡的粘膜下層剥離術を施行した1例
鈴木 美櫻, 大西 俊介, 大野 正芳, 大西 礼造, 小林 良充, 久保 公利, 太宰 昌佳, 山本 純司, 小田 寿, 宮城島 拓人, 高橋 達郎, Gastroenterological Endoscopy, 53, 1, 22, 27, 2011年01月
50歳代男。主訴は食道腫瘍の増大で、腫瘍は20年前の検診で指摘され、15年前の生検にて食道平滑筋腫と診断され経過観察中であった。食道バリウム造影および上部消化管内視鏡検査では胸部中部食道後壁になだらかな隆起性病変を認め、隆起部のヨード不染帯からの生検では強い異型を認めた。超音波内視鏡では第二層由来の内部均一な低エコー腫瘤を認めたため、食道癌と食道平滑筋腫の合併と考え内視鏡的粘膜下層剥離術により一括切除した。病理組織学的に平滑筋腫の直上上皮粘膜にcarcinoma in situを認めT1a-EP食道癌と診断した。, (一社)日本消化器内視鏡学会, 日本語

悪性リンパ腫の化学療法中に繰り返し発症したHelicobacter cinaedi感染症
大野 正芳, 大西 俊介, 大西 礼造, 高橋 正二郎, 小林 良充, 鈴木 美櫻, 久保 公利, 太宰 昌佳, 山本 純司, 小田 寿, 多田 憲司, 高橋 達郎, 宮城島 拓人, 臨床血液, 51, 12, 1781, 1785, 2010年12月
症例は70歳男性。平成4年に胃悪性リンパ腫(Diffuse large B-cell lymphoma)に対し,胃全摘術を施行されていた。平成20年1月に頸部リンパ節腫大を認めリンパ節生検を施行し,悪性リンパ腫の再発と診断しR-CHOP療法を施行した。1?3コース目までは発熱はみられなかったが,4コース以降は化学療法開始約1週間後に,白血球減少を認めないにもかかわらず38℃台の発熱が繰り返し認められた。その都度施行した血液培養でHelicobacter cinaediが検出された。Helicobacter cinaediは培養に長時間を要し,形態観察や同定が難しいとされているが,最近易感染者の菌血症の原因菌としての報告が増加している。(著者抄録), (一社)日本血液学会-東京事務局, 日本語

【消化器の生理と漢方】 機能性ディスペプシアおよび食欲不振に対する漢方治療
武田 宏司, 武藤 修一, 大西 俊介, 浅香 正博, 日本消化器病学会雑誌, 107, 10, 1586, 1591, 2010年10月
機能性ディスペプシア(FD)治療に用いられる代表的な方剤である六君子湯は、食欲不振に対する効果を手がかりとして、そのユニークな作用機序の解明が進んでいる。六君子湯の作用機序としては、従来、胃排出促進および胃適応弛緩の改善が知られていたが、摂食促進ホルモンであるグレリンの分泌を亢進させることがごく最近明らかとなった。シスプラチンや選択的セロトニントランスポーター阻害薬(SSRI)投与は、消化管粘膜や脳内のセロトニンを増加させ、セロトニン2Bあるいは2C受容体を介してグレリン分泌を抑制することがその副作用の発現に関わっているが、六君子湯はセロトニン2Bあるいは2C受容体に拮抗してグレリン分泌を改善する。六君子湯のグレリン分泌促進作用は、FDに対する効果に関わっている可能性も示唆されている。また、六君子湯は高齢動物の視床下部でレプチンの作用と拮抗することにより食欲を改善させる機序も有しており、今後さらに多くの作用点が見出される可能性が高い。(著者抄録), (一財)日本消化器病学会, 日本語

機能性ディスペプシアおよび食欲不振に対する漢方治療
武田 宏司, 武藤 修一, 大西 俊介, 浅香 正博, 日本消化器病學會雜誌 = The Japanese journal of gastro-enterology, 107, 10, 1586, 1591, 2010年10月
機能性ディスペプシア（FD）治療に用いられる代表的な方剤である六君子湯は，食欲不振に対する効果を手がかりとして，そのユニークな作用機序の解明が進んでいる．六君子湯の作用機序としては，従来，胃排出促進および胃適応弛緩の改善が知られていたが，摂食促進ホルモンであるグレリンの分泌を亢進させることがごく最近明らかとなった．シスプラチンや選択的セロトニントランスポーター阻害薬（SSRI）投与は，消化管粘膜や脳内のセロトニンを増加させ，セロトニン2Bあるいは2C受容体を介してグレリン分泌を抑制することがその副作用の発現に関わっているが，六君子湯はセロトニン2Bあるいは2C受容体に拮抗してグレリン分泌を改善する．六君子湯のグレリン分泌促進作用は，FDに対する効果に関わっている可能性も示唆されている．また，六君子湯は高齢動物の視床下部でレプチンの作用と拮抗することにより食欲を改善させる機序も有しており，今後さらに多くの作用点が見出される可能性が高い．, 財団法人 日本消化器病学会, 日本語

濾胞性リンパ腫を合併したPOEMS症候群
佐々木 尚英, 大西 俊介, 大西 礼造, 竹村 龍, 小林 良充, 鈴木 美櫻, 太宰 昌佳, 幡 有, 山本 純司, 小田 寿, 高橋 達郎, 小笠原 和宏, 宮城島 拓人, 臨床血液, 50, 11, 1621, 1625, 2009年11月
症例は59歳女性。アルカリホスファターゼ上昇および大量の腹水と腹腔内リンパ節腫大を認め,生検にて濾胞性リンパ腫と診断した。生検後に不正性器出血を認め,多系統の内分泌異常,多発神経障害,血清VEGF高値を認めたため,POEMS症候群の合併と診断した。ステロイド療法により腹水が減少し全身状態も改善したため,外来にて経過観察となったが,発症から18ヵ月後に腎不全にて再燃し,ステロイドを増量したが一時的な反応を示したのみで,発症から23ヵ月後に永眠した。POEMS症候群はリンパ節腫大を多く認める一方で,リンパ節の組織像については十分な検討はなされておらず,また悪性リンパ腫との合併の報告は非常に稀である。両疾患の合併が病因や予後にどのように関係するかは明らかでないが,リンパ節腫大を伴うPOEMS症候群に対して,積極的にリンパ節生検を行ないVEGFとの関連についてさらに検討する必要があると考えられた。(著者抄録), (一社)日本血液学会-東京事務局, 日本語

ESD症例に対するアルギン酸ナトリウムパウダーの改良撒布法とその治療成績　　　　　　　　　　　　　　　
山本 純司, 小田 寿, 大西 俊介, 幡 有, 太宰 昌佳, 佐々木 尚英, 小林 良充, 鈴木 美櫻, 竹村 龍, 大西 礼造, 大野 正芳, 廣瀬 孝則, 五明 秀能, Gastroenterological Endoscopy, 51, Suppl.2, 2200, 2200, 2009年09月
(一社)日本消化器内視鏡学会, 日本語

組織学的に分枝型膵管内乳頭粘液性腫瘍(IPMN)からの進展と考えられた膵管内腫瘍由来の浸潤癌の一例　　　　　　　　　　　　　　　
大野 正芳, 大西 礼造, 竹村 龍, 鈴木 美櫻, 小林 良充, 佐々木 尚英, 太宰 昌佳, 幡 有, 山本 純司, 大西 俊介, 小田 寿, 宮城島 拓人, 河合 朋昭, 高橋 達郎, 日本消化器病学会雑誌, 106, 臨増大会, A945, A945, 2009年09月
(一財)日本消化器病学会, 日本語

Bevacizumabの有用性を検討するレトロスペクティブ調査(HGCSG0801) 年齢別の解析　　　　　　　　　　　　　　　
小松 嘉人, 結城 敏志, 曽我部 進, 大西 俊介, 宮城島 拓人, 畑中 一映, 成瀬 宏仁, 加藤 貴司, 目黒 高志, 鎌田 豪, 上林 実, 中村 路夫, 細川 歩, 久須美 貴哉, 浅香 正博, 日本癌治療学会誌, 44, 2, 422, 422, 2009年09月
(一社)日本癌治療学会, 日本語

【色素内視鏡を見直す 画像強調観察法との比較】 分子イメージングを目的とした近赤外蛍光プローブの開発　　　　　　　　　　　　　　　
大西 俊介, 浅香 正博, Frangioni John V, 臨床消化器内科, 24, 10, 1411, 1417, 2009年08月
近赤外領域は自家蛍光がほとんど認められず,かつ組織透過性が高いため,生体の蛍光イメージングにもっとも適していると考えられる.現在,臨床で使用できる近赤外領域の蛍光色素はインドシアニン・グリーン(ICG)のみであるが,ICGは蛍光強度が低く,目的の分子を標識することはできない.最近,蛍光強度が高く目的の分子を標識できる蛍光色素が開発されてきている.実際に,標的分子を蛍光標識して病変を検出する方法を,いくつかの動物モデルを用いて開発した.これにより,病変の蛍光分子イメージングが可能となり,通常の観察では同定できないような微小な病変の検出,およびリアルタイムな病理診断が可能になると期待される.(著者抄録), (株)日本メディカルセンター, 日本語

遺伝子修飾幹細胞療法としての間葉系幹細胞に対する新規siRNA導入法の開発(Development of a novel siRNA delivery system into stem cells for genetically modified stem cell therapy)　　　　　　　　　　　　　　　
大西 俊介, 大谷 健太郎, 日本癌学会総会記事, 68回, 412, 412, 2009年08月
日本癌学会, 英語

【がん転移・浸潤に対する新たな治療戦略】 がんの転移・浸潤を見極める新しい臨床診断ツール　　　　　　　　　　　　　　　
大西 俊介, ジョン・V・フランジオーニ, Medical Bio, 6, 3, 22, 25, 2009年05月
(株)オーム社, 日本語

下部消化管内視鏡検査における糞口感染リスクの検討　　　　　　　　　　　　　　　
小林 良充, 大西 礼造, 竹村 龍, 鈴木 美櫻, 佐々木 尚英, 太宰 昌佳, 幡 有, 山本 純司, 小田 寿, 大西 俊介, 宮城島 拓人, Gastroenterological Endoscopy, 51, Suppl.1, 817, 817, 2009年04月
(一社)日本消化器内視鏡学会, 日本語

腹膜中皮腫の2例　　　　　　　　　　　　　　　
大西 礼造, 大西 俊介, 竹村 龍, 小林 良充, 鈴木 美櫻, 佐々木 尚英, 太宰 昌佳, 幡 有, 山本 純司, 小田 寿, 宮城嶋 拓人, 高橋 達郎, 日本消化器病学会雑誌, 106, 臨増総会, A423, A423, 2009年03月
(一財)日本消化器病学会, 日本語

【内視鏡イメージングの進化】 近赤外光を用いた蛍光分子イメージング法の開発　　　　　　　　　　　　　　　
大西 俊介, 浅香 正博, Frangioni John V, 消化器内視鏡, 21, 2, 303, 309, 2009年02月
近赤外光を用いた蛍光イメージングは、最近注目を集めている新しい手法である。現在臨床で使用できる近赤外領域の蛍光色素は、インドシアニン・グリーン(ICG)のみであるが、ICGは量子効率が低く、目的の分子を標識することができない。最近、量子効率が高く、かつ目的の分子を標識できる蛍光色素が開発されてきている。蛍光色素はICGに代表される有機化合物と、量子ドットに代表される無機化合物に分けられる。筆者らは新規に開発された有機蛍光色素を用いて、幾つかの分子を標識して病変を検出する方法を開発した。また、人体への安全性が懸念される量子ドットについても、最近腎排泄型のものを開発した。一方、イメージング装置としては、白色光画像と近赤外蛍光画像、および両者の重ね合わせ画像の3画像を同時に、かつリアルタイムに観察できるシステムを開発した。新たな蛍光プローブとイメージングシステムの開発により、病変の術中蛍光分子イメージングが可能になってきた。(著者抄録), (株)東京医学社, 日本語

肝再生 基礎と臨床のBridge研究 胎児付属物由来間葉系幹細胞の新しい再生医療材料としての可能性　　　　　　　　　　　　　　　
大西 俊介, 原田 和彦, 池田 智明, 肝臓, 49, Suppl.2, A490, A490, 2008年09月
(一社)日本肝臓学会, 日本語

分子イメージングを目的とした近赤外蛍光プローブの開発　　　　　　　　　　　　　　　
大西 俊介, 田中 栄一, 清水 勇一, 宮城島 拓人, 加藤 元嗣, 浅香 正博, Frangioni J, Gastroenterological Endoscopy, 50, Suppl.2, 2293, 2293, 2008年09月
(一社)日本消化器内視鏡学会, 日本語

内視鏡観察の新展開(特殊光、拡大、超拡大観察) 近赤外光を応用した"Image-Guided Surgery"の開発　　　　　　　　　　　　　　　
田中 栄一, 大西 俊介, 近藤 哲, 日本消化器病学会雑誌, 105, 臨増大会, A718, A718, 2008年09月
(一財)日本消化器病学会, 日本語

ヒト卵膜由来間葉系幹細胞による心血管再生保護効果の検討
原田 和彦, 山原 研一, 大西 俊介, 佐田 正晴, 石兼 真, 藤原 道弘, 寒川 賢治, 北村 惣一郎, 永谷 憲歳, 池田 智明, 日本内分泌学会雑誌, 84, 2, 687, 687, 2008年09月
(一社)日本内分泌学会, 日本語

超音波と微小気泡の併用による間葉系幹細胞への核酸導入法の開発
大谷 健太郎, 山原 研一, 大西 俊介, 小幡 裕明, 北村 惣一郎, 永谷 憲歳, 日本内分泌学会雑誌, 84, 2, 689, 689, 2008年09月
(一社)日本内分泌学会, 日本語

近赤外光を用いた術中リアルタイム蛍光分子イメージング法の開発(Intra-Operative Real-Time Molecular Imaging using Near-Infrared Fluorescent Contrast Agents)　　　　　　　　　　　　　　　
大西 俊介, 田中 栄一, 藤井 博史, フランジオーニ・ジョン, 日本癌学会総会記事, 67回, 485, 485, 2008年09月
日本癌学会, 英語

超音波と微小気泡を併用した間葉系幹細胞への核酸導入法の開発
大谷 健太郎, 山原 研一, 大西 俊介, 小幡 裕明, 北村 惣一郎, 永谷 憲歳, 超音波医学, 35, Suppl., S290, S290, 2008年04月
(一社)日本超音波医学会, 日本語

OJ-033 Capability of Contrast-enhanced Sonography in the Assessment of Neovascularization after Mesenchymal Stem Cell Transplantation in Rat Model of Hindlimb Ischemia(Echo/Doppler(03)(I),Oral Presentation(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)
Otani Kentaro, Ohnishi Shunsuke, Obata Hiroaki, Ishida Osamu, Kitamura Soichiro, Nagaya Noritoshi, Circulation journal : official journal of the Japanese Circulation Society, 72, 296, 296, 2008年03月01日
社団法人日本循環器学会, 英語

Tissue regeneration as next-generation therapy for COPD--potential applications
Ohnishi, S., Nagaya, N., Int J Chron Obstruct Pulmon Dis, 3, 4, 509, 514, 2008年, ［査読有り］
COPD is a major cause of chronic morbidity and mortality worldwide, and there is a need to develop more effective therapeutic strategies to replace specialized treatment such as lung transplantation. Recent studies suggest that recognition of apoptotic lung epithelial or endothelial cells may result in growth factors to stimulate cell replacement, and defects in these processes may contribute to the pathogenesis of COPD. Furthermore, recent animal and human studies have revealed that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for activation of endogenous stem/progenitor cells may be a potent next-generation therapy for COPD. © 2008 Dove Medical Press Limited. All rights reserved., 英語

グレリンと心血管疾患　　　　　　　　　　　　　　　
大西 俊介, 寒川 賢治, 永谷 憲歳, 血管, 30, 3, 77, 80, 2007年10月
日本心脈管作動物質学会, 日本語

メタボリックシンドロームにおける脂肪組織血管内皮機能障害 共培養系における検討
山原 研一, 大西 俊介, 永谷 憲歳, 日本内分泌学会雑誌, 83, 2, 587, 587, 2007年09月
(一社)日本内分泌学会, 日本語

脂肪組織由来と骨髄由来間葉系幹細胞の遺伝子発現、分泌タンパク質の差異の検討　　　　　　　　　　　　　　　
中西 千明, 山岸 正和, 大西 俊介, 北村 惣一郎, 永谷 憲歳, 日本内分泌学会雑誌, 83, 2, 602, 602, 2007年09月
(一社)日本内分泌学会, 日本語

内側絨毛膜由来間葉系幹細胞による心血管細胞の保護と血管再生効果の検討　　　　　　　　　　　　　　　
原田 和彦, 永谷 憲歳, 大西 俊介, 佐田 正晴, 藤原 道弘, 北村 惣一郎, 池田 智明, 日本内分泌学会雑誌, 83, 2, 602, 602, 2007年09月
(一社)日本内分泌学会, 日本語

ラット下肢虚血モデルにおける微細針刺入刺激による血管新生療法の検討　　　　　　　　　　　　　　　
石田 治, 大西 俊介, 大谷 健太郎, 北村 惣一郎, 永谷 憲歳, 日本内分泌学会雑誌, 83, 2, 602, 602, 2007年09月
(一社)日本内分泌学会, 日本語

間葉系細胞の心線維芽細胞に対するパラクライン効果　　　　　　　　　　　　　　　
大西 俊介, 北村 惣一郎, 永谷 憲歳, 日本内分泌学会雑誌, 83, 2, 603, 603, 2007年09月
(一社)日本内分泌学会, 日本語

褥瘡に対するアドレノメデュリンの効果
原田 和彦, 大西 俊介, 山原 研一, 池田 智明, 藤原 道弘, 北村 惣一郎, 寒川 賢治, 永谷 憲歳, 日本内分泌学会雑誌, 83, 2, 603, 603, 2007年09月
(一社)日本内分泌学会, 日本語

【ペプチドと創薬】 新規機能と創薬ターゲット カヘキシアとグレリン　　　　　　　　　　　　　　　
大西 俊介, 永谷 憲歳, 寒川 賢治, 遺伝子医学MOOK, 8, 132, 136, 2007年07月
(株)メディカルドゥ, 日本語

【心不全 最新の基礎・臨床研究の進歩】 成因・病態に関する基礎的研究 不全心の分子機構に関する最新の基礎研究 神経体液性因子の活性化の分子機構と作用 グレリン
大西 俊介, 永谷 憲歳, 寒川 賢治, 日本臨床, 65, 増刊4 心不全(上), 186, 190, 2007年04月
(株)日本臨床社, 日本語

FRS-055 Transplantation of Mesenchymal Stem Cells Improves Atrioventricular Conduction in Rat Model of Complete Atrioventricular Block(Regeneration, The 71st Annual Scientific Meeting of the Japanese Circulation Society)
Yokokawa Miki, Ohnishi Shunsuke, Ueda Hatsue, Obata Hiroaki, Miyahara Yoshinori, Tanaka Koichi, Shimizu Wataru, Kamakura Shiro, Nagaya Noritoshi, Circulation journal : official journal of the Japanese Circulation Society, 71, 132, 132, 2007年03月01日
社団法人日本循環器学会, 英語

病因と病態 グレリンの心血管系への作用　　　　　　　　　　　　　　　
大西 俊介, 永谷 憲歳, 寒川 賢治, Annual Review循環器, 2007, 55, 59, 2007年01月
(株)中外医学社, 日本語

長期作用型プロスタサイクリンアゴニストの開発と肺高血圧モデルに対する効果の検討　　　　　　　　　　　　　　　
小幡 裕明, 酒井 芳紀, 大西 俊介, 竹下 聡, 盛 英三, 小玉 誠, 相澤 義房, 永谷 憲歳, 日本内分泌学会雑誌, 82, 2, 511, 511, 2006年09月
(一社)日本内分泌学会, 日本語

胎児付属物由来間葉系幹細胞の分離・培養法の確立とパラクライン効果の検討　　　　　　　　　　　　　　　
原田 和彦, 永谷 憲歳, 大西 俊介, 白石 修一, 小幡 裕明, 中西 千明, 三島 健一, 江頭 伸昭, 岩崎 克典, 藤原 道弘, 北村 惣一郎, 池田 智明, 日本内分泌学会雑誌, 82, 2, 512, 512, 2006年09月
(一社)日本内分泌学会, 日本語

急性心筋炎に対するアドレノメデュリンの効果　　　　　　　　　　　　　　　
大西 俊介, Yanagawa Bobby, 片岡 雅晴, 小玉 誠, 寒川 賢治, 永谷 憲歳, 日本内分泌学会雑誌, 82, 2, 514, 514, 2006年09月
(一社)日本内分泌学会, 日本語

骨髄間葉系細胞と骨髄単核球の遺伝子発現の差異の検討　　　　　　　　　　　　　　　
大西 俊介, 永谷 憲歳, 安田 剛, 北村 総一郎, 日本内分泌学会雑誌, 82, 2, 514, 514, 2006年09月
(一社)日本内分泌学会, 日本語

コントラストエコー法を用いた新生血管評価 ラット下肢虚血モデルによる検討　　　　　　　　　　　　　　　
大谷 健太郎, 永谷 憲歳, 石田 治, 小幡 裕明, 大西 俊介, 北村 惣一郎, 日本内分泌学会雑誌, 82, 2, 515, 515, 2006年09月
(一社)日本内分泌学会, 日本語

【高血圧 最新の研究動向】 基礎編 血圧調節因子 循環生理活性物質 グレリン　　　　　　　　　　　　　　　
大西 俊介, 永谷 憲歳, 寒川 賢治, 日本臨床, 64, 増刊5 高血圧(上), 151, 155, 2006年07月
(株)日本臨床社, 日本語

Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer.
Shunsuke Ohnishi, Sumiko Ohnami, Friedrich Laub, Kazunori Aoki, Koichi Suzuki, Yae Kanai, Kazunori Haga, Masahiro Asaka, Francesco Ramirez, Teruhiko Yoshida, Biochemical and biophysical research communications, 308, 2, 251, 6, 2003年08月22日, ［国際誌］
Krüppel-like factors (KLFs) are key transcriptional regulators of cell differentiation and proliferation. Among the KLF family, the expression of KLF4 (GKLF) and KLF5 (IKLF) is highly restricted in the epithelial cells of several organs such as the gut and skin, and it has been reported that these epithelial-type KLF genes may be involved in colon carcinogenesis. Recently we found that Klf4 and Klf5 genes were significantly expressed in the developmental bladder epithelium of mice as well. Therefore, in this report we studied the involvement of the KLF4 and KLF5 genes in bladder carcinogenesis. First, we analyzed the expression of KLF4 and KLF5 in a variety of human bladder cancer cell lines and surgical specimens by RNA blot and in situ hybridization analyses. Both genes were highly expressed in the normal bladder epithelium, whereas KLF4, but not KLF5, was frequently downregulated in bladder cancer cell lines and cancer tissues. We then transduced the KLF4 and KLF5 genes into the bladder cancer cell lines using adenoviral vectors to examine the biological activities of the genes on those cells. The transduction of KLF4, but not KLF5, suppressed cell growth and induced apoptosis. Our study suggests that inactivation of KLF4 is one of the frequent steps towards bladder carcinogenesis., 英語

CTHAで低吸収域を示す肝結節性病変　　　　　　　　　　　　　　　
髭 修平, 関口 真弓, 大西 俊介, 小林 隆彦, 浅香 正博, 北海道医学雑誌, 77, 6, 588, 588, 2002年11月
北海道医学会, 日本語

ラミブジン投与の効果と問題点 B型慢性肝炎ラミブジン治療例の投与中止後の検討　　　　　　　　　　　　　　　
中西 満, 髭 修平, 畑中 一映, 大西 俊介, 中馬 誠, 小林 隆彦, 浅香 正博, 松嶋 喬, 肝臓, 43, Suppl.3, A451, A451, 2002年11月
(一社)日本肝臓学会, 日本語

prothymosin-αによるp53の転写活性制御　　　　　　　　　　　　　　　
小林 隆彦, 大西 俊介, 浅香 正博, 日本癌学会総会記事, 61回, 234, 234, 2002年10月
日本癌学会, 日本語

ラミブジン耐性株が出現したB型肝炎症例の検討　　　　　　　　　　　　　　　
髭 修平, 中西 満, 中馬 誠, 大西 俊介, 小林 隆彦, 浅香 正博, 肝臓, 43, Suppl.1, A53, A53, 2002年05月
(一社)日本肝臓学会, 日本語

ラミブジン投与例に対するIFNあるいはHBワクチン併用の検討　　　　　　　　　　　　　　　
髭 修平, 関口 真弓, 大西 俊介, 中馬 誠, 小林 隆彦, 浅香 正博, 日本消化器病学会雑誌, 99, 臨増総会, A276, A276, 2002年03月
(一財)日本消化器病学会, 日本語

B型肝炎におけるラミブジン耐性株出現例の検討　　　　　　　　　　　　　　　
関口 真弓, 髭 修平, 大西 俊介, 小林 隆彦, 浅香 正博, 肝臓, 42, Suppl.2, A412, A412, 2001年09月
(一社)日本肝臓学会, 日本語

Cyclophosphamide大量間欠投与が奏効した特発性寒冷凝集素症
中川 雅夫, 宮城島 拓人, 鎌田 崇宏, 新井 尚子, 三浦 慶昭, 大西 俊介, 岸本 篤人, 神島 雄一郎, 崔 公賢, 工藤 峰生, 岡部 實裕, 臨床血液, 42, 9, 713, 715, 2001年09月
55歳女.貧血を指摘されたが放置,感冒様症状および全身倦怠感が出現したため受診し,特発性寒冷凝集素症と診断され,プレドニゾロン(PSL)療法,シクロスポリン療法を施行されたが治療抵抗性であった.眼瞼結膜には貧血がみられ,眼球結膜にも黄染が認められ,白血球と好中球は高値で,PSL投与の影響と思われた.さらに末梢血は大小不同があり,赤芽球も出現し,末梢血塗抹標本においては赤血球の著明な凝集が認められ,また網状赤血球とビリルビンは上昇,LDHは高値であったが,アイソザイムには異常が認められなかった.血清学的検査では寒冷凝集素512倍,エリスロポイエチン上昇,ハプトグロビン低下,直接・間接クームス試験陽性も認められた.以上の経過から,シクロフォスファミド大量間欠療法を4週間隔で行ったが,患者のHbは速やかな上昇をし,自覚症状も著明に改善していった, (一社)日本血液学会-東京事務局, 日本語

【血管新生】 抗血管新生薬の開発
大西 俊介, 臨床検査, 44, 13, 1643, 1645, 2000年12月
(株)医学書院, 日本語

Kruppel型転写因子KLF4/GKLFのがんにおける発現と機能解析　　　　　　　　　　　　　　　
大西 俊介, 青木 一教, Ramirez Francesco, 金井 弥栄, 芳賀 一徳, 小柳 知彦, 浅香 正博, 寺田 雅昭, 吉田 輝彦, 日本癌学会総会記事, 59回, 513, 513, 2000年09月
日本癌学会, 日本語

Kruppel型転写因子BTEB2の各種がん細胞における発現の検討　　　　　　　　　　　　　　　
大西 俊介, 松本 伸行, Francesco Ramirez, 寺田 雅昭, 吉田 輝彦, 日本癌学会総会記事, 58回, 485, 485, 1999年08月
日本癌学会, 日本語

がん細胞におけるKruppel型転写因子UKLF及びCPBPの発現　　　　　　　　　　　　　　　
松本 伸行, 大西 俊介, 佐々木 一樹, Ramirez Frencesco, 寺田 雅昭, 吉田 輝彦, 日本癌学会総会記事, 58回, 535, 535, 1999年08月
日本癌学会, 日本語

強化療法として自己造血幹細胞移植併用大量化学療法を施行した予後不良ユーイング肉腫の2例　　　　　　　　　　　　　　　
大西 俊介, 中川 学, 小林 直樹, 小笠原 正浩, 木山 善雄, 直原 徹, 比嘉 敏夫, 佐藤 利宏, 笠井 正晴, 武田 直樹, 癌の臨床, 44, 9, 925, 929, 1998年09月
症例1は23歳女,左大腿骨原発であり,症例2は12歳男,Th5〜7の硬膜外原発であった.大量化学療法はIfosphamide 10g/m2,Carboplatin 1,000mg/m2,Etoposide 1,250mg/m2(ICE療法)を行い,ASCTを施行した.2例とも重篤な非血液毒性を認めず,安全に施行可能であった.ASCT施行後,1年以上の無病生存を得ている, (株)篠原出版新社, 日本語

再生不良性貧血に対するcyclosporine併用anti-thymocyte globulin療法の検討
大西 俊介, 中川 学, 小林 直樹, 小笠原 正浩, 木山 善雄, 直原 徹, 比嘉 敏夫, 笠井 正晴, 臨床血液, 39, 9, 640, 644, 1998年09月
再生不良性貧血に対してシクロスポリンを併用した抗ヒト胸腺細胞グロブリン(ATG)療法を試みた9例を対象とし,その有効性,Tリンパ球の変動,合併症について検討した.対象は男4例,女5例で年齢中央値は55歳.重症が8例,中等症が1例.初回治療例が3例,治療抵抗例が6例.投与直後から急速に著明なTリンパ球の減少,消失がみられ,CD4,CD8陽性細胞共に減少した.1例は肺出血で死亡,6ヵ月以上の観察期間で著効は3例,やや有効は2例,無効は3例.ATGによる薬物有害反応としては,一過性の発熱,掻痒感,皮疹等がみられたが,重篤な症状は認められなかった.シクロスポリンを併用したATG療法は有用であり,安全に施行しうる, (一社)日本血液学会-東京事務局, 日本語

慢性骨髄性白血病の同種末梢血幹細胞移植後の細胞遺伝学的再発に対するドナーリンパ球輸血の試み　　　　　　　　　　　　　　　
大西 俊介, 中川 学, 大川原 辰也, 中川 宗一, 依田 有生, 大泉 弘子, 小林 直樹, 小笠原 正浩, 木山 善雄, 直原 徹, 日本輸血学会雑誌, 44, 4, 586, 586, 1998年08月
(一社)日本輸血・細胞治療学会, 日本語

縦隔原発NK細胞性リンパ腫/白血病の一例　　　　　　　　　　　　　　　
大西 俊介, International Journal of Hematology, 67, Suppl.1, 161, 161, 1998年04月
(一社)日本血液学会, 日本語

透析患者におけるHelicobacter pyloli感染の検討　　　　　　　　　　　　　　　
大泉 弘子, 斎藤 雅雄, 中川 宗一, 大川原 辰也, 依田 有生, 中川 学, 大西 俊介, 小林 直樹, 木山 善雄, 小笠原 正浩, 日本消化器病学会雑誌, 95, 臨増, 181, 181, 1998年03月
(一財)日本消化器病学会, 日本語

自家末梢血造血幹細胞移植症例の検討 : 日本アフェレシス学会第17回北海道地方会
直原 徹, 中川 学, 大西 俊介, 小林 直樹, 小笠原 正浩, 木山 善雄, 比嘉 敏夫, 笠井 正晴, 日本アフェレシス学会雑誌, 17, 2, 154, 154, 1998年
日本アフェレシス学会, 日本語

再生不良性貧血に対するシクロスポリン併用ATG療法の検討　　　　　　　　　　　　　　　
大西 俊介, 臨床血液, 38, 10, 1039, 1039, 1997年10月
(一社)日本血液学会-東京事務局, 日本語

強化療法として自己末梢血幹細胞移植(PBSCT)併用大量化学療法を施行したユーイング肉腫の2症例　　　　　　　　　　　　　　　
大西 俊介, 日本癌治療学会誌, 32, 5, 688, 688, 1997年08月
(一社)日本癌治療学会, 日本語

多発性筋炎に併発した非Hodgkinリンパ腫
大西 俊介, 小田 寿, 仲屋 裕樹, 臨床血液, 38, 7, 582, 586, 1997年07月
67歳男多発性筋炎(PM)と診断され,プレドニンを投与されていた.その後鼻閉が出現し,CTにて上咽頭に充実性の腫瘍を認めた.同部の生検にて非Hodgkin悪性リンパ腫(diffuse medium,B cell type)と診断された.骨髄浸潤を認め臨床病期IVであった.CHOP療法を6コース施行し,完全寛解を得たが,1ヵ月後に中枢神経浸潤を認め,嚥下性肺炎を併発し死亡した, (一社)日本血液学会-東京事務局, 日本語

Hodgkin病とT cell lymphomaのcomposite lymphomaが疑われた1例　　　　　　　　　　　　　　　
大西 俊介, 日本リンパ網内系学会会誌, 37, 2, 67, 67, 1997年05月
(一社)日本リンパ網内系学会, 日本語

多発性筋炎に併発し,中枢神経浸潤を認め死亡した悪性リンパ腫の1例　　　　　　　　　　　　　　　
大西 俊介, 臨床血液, 37, 2, 186, 186, 1996年02月
(一社)日本血液学会-東京事務局, 日本語

十二指腸原発早期悪性リンパ腫の1例
宮城島 拓人, 大村 卓味, 大西 俊介, Gastroenterological Endoscopy, 37, 12, 2761, 2767,2781, 1995年
A 71-year-old female was admitted to our hospital for the evaluation of duodenal tumor, which was incidentally detected by endoscopic examination. The hypotonic duodenography demonstrated flat elevating lesion (2 × 2 cm) in the duodenal second portion. Endoscopic examination showed the mufti-nodular protruding lesion, which was covered with thick whitish mucosa. Biopsy specimens taken from this lesion revealed marked infiltration of atypical lymphocytes, suspected non-Hodgkin's lymphoma (NHL). Endoscopic ultrasonography showed that the tumor located within the submucosa. Local resection of the duodenum was performed. Histologically the tumor was diagnosed as NHL (follicular, medium-sized cell type) spread involving the submucosa, and immunohistological study revealed tumor cells were B-cell origin. Furthermore, gene examination showed the rearrangement of Ig (JH). Adjuvant chemotherapy is now on going. This case, early nan-Hodgkin's lymphoma of the duodenum, was exceedingly rare. © 1995, Japan Gastroenterological Endoscopy Society. All rights reserved., (一社)日本消化器内視鏡学会, 英語

精索原発悪性リンパ腫の1例　　　　　　　　　　　　　　　
大西 俊介, 臨床血液, 35, 12, 1392, 1392, 1994年12月
(一社)日本血液学会-東京事務局, 日本語

肝線維化機構に関連する宿主因子の網羅的探索と新規治療法の開発
科学研究費助成事業
2022年04月01日 - 2025年03月31日
坂本 直哉, 大西 俊介, 須田 剛生
日本学術振興会, 基盤研究(B), 北海道大学, 22H03050

ゲル化されたMSC由来エクソソームの内視鏡的粘膜下層剥離術後食道狭窄に対する効果
科学研究費助成事業
2022年04月01日 - 2025年03月31日
小野 尚子, 大西 俊介, 黒川 孝幸, 大野 正芳
日本学術振興会, 基盤研究(C), 北海道大学, 22K08001

胆管疾患に対する生体吸収性胆管代替物を用いた新規低侵襲治療法の開発
科学研究費助成事業
2021年04月01日 - 2024年03月31日
宮澤 光男, 大西 俊介, 高島 順平
本研究の目的は、胆管欠損部に生体吸収性胆管代替物（Bioabsorbable bile duct substitute: BBDS）を移植し、その部位に胆管を再生させる新規低侵襲治療法の開発である。現在、外科治療の方向性は機能温存および低侵襲にあるが、肝外胆管欠損の治療法は、乳頭部機能を廃絶した胆管―腸再建が通常行われ、機能温存の方向にはない。この再建法では、逆行性胆管炎が起こり理想的ではなく、他の治療法が求められている。本研究では、胆管欠損部を直接修復可能で、その部位に狭窄なく胆管再生が可能な胆管再建用BBDSの開発を目指す。具体的には、BBDSを用い、肝門部領域胆管癌手術の低侵襲化を目指し、Y字（左右肝管を模倣）に胆管を再生させること、さらに内視鏡的に胆管欠損部を修復させること（腹腔鏡下胆嚢摘出術時の胆管損傷治療を想定）が可能かを検討し、胆管系疾患に対する新規低侵襲治療法を開発する。
本年度は、BBDSを用いて、Y字に胆管を再生させる手技の実験研究を行った。（外部の動物実験施設にて）。本BBDSにて、肝外胆管を再生させることは可能となったが、確実にY字に再生させることにおいては、さらなる改善が必要である段階である（時々、再生胆管の狭窄が認められた）。内視鏡を用いた、胆管修復、再生の研究は、順調に進行しており、論文作成の段階である。
生体吸収性材料の消化器系疾患への応用は、一部、吻合部組織補強材として用いられているが、始まったばかりであり、本BBDSの臨床研究施行のための実験を重ねていく予定である。
日本学術振興会, 基盤研究(C), 帝京大学, 21K08786

羊膜MSC由来HSPB6陽性エクソソームを用いた炎症性腸疾患への治療効果の検討
科学研究費助成事業
2021年04月01日 - 2024年03月31日
桂田 武彦, 山本 幸司, 大西 俊介, 武井 則雄
本研究では、羊膜MSCから産生されるHSPB6陽性エクソソームを用いた抗炎症効果の詳細を細胞実験ならびに炎症性腸疾患誘導性動物モデルを用いて、未だ適切な治療法がないヒト炎症性腸疾患に対する臨床応用への基盤を整える。本研究では、以下の通り、HSPB6過剰発現ならびにHSPB6欠損羊膜MSCの作成およびそれらエクソソームの樹立することを明らかにした。羊膜MSCのHSPB6過剰発現株ならびに遺伝子欠損株を樹立する。HSPB6過剰発現株の作成には、CMVプロモーター下にHSPB6遺伝子を挿入したプラスミドをMSCに導入後、薬剤選択による選別を行い、得られたクローンはウエスタンブロット法による野生型およびmockコントロールとの比較解析から、有意に発現増加の認められるクローンを選別することで樹立した。HSPB6欠損株の作成にはCRISPR/Cas9システムを採用し、ヒトHSPB6エクソン領域に特異的なgRNAを設計し、CAGプロモーター下でCas9およびT3プロモーター下でgRNAを発現するプラスミドを構築、MSCに導入し、genotypingによる標的遺伝子座での塩基の欠損が認められ、ウエスタンブロット法で標的分子の翻訳消失が認められるクローンを選別した。結果、20個のクローン中4～5個程度の目的クローンが選別することができた。さらに、その細胞からエクソソームを精製し、HSPB6の発現について確認したところ、HSPB6過剰発現株ではMOCKに比べてHSPB6の発現が増加していた一方、HSPB6欠損株では、HSPB6の発現が消失していることを確認した。これらのことから、本研究において、HSPB6過剰発現株ならびにHSPB6欠損発現株が樹立され、さらに両株から産生される目的となるエクソソームも精製することができた。
日本学術振興会, 基盤研究(C), 北海道大学, 21K07952

脊髄損傷急性期に対する間葉系幹細胞静脈投与に対する脊髄腸相関に関する研究
科学研究費助成事業
2020年04月01日 - 2023年03月31日
関 俊隆, 大西 俊介, 川堀 真人
【背景】脊髄損傷に対する再生治療・細胞治療は多くの基礎研究において有効性が報告され始めているが, その作用機序は全身の炎症制御や損傷部位への幹細胞生着によるネットワークの回復など多岐にわたると考えられている. 近年, 全身の免疫センターとしての機能を有する腸管と他臓器の関連が注目されており, 脊髄損傷においても腸管との関連（脊髄-腸相関）が報告されているが, 幹細胞投与がこの相関にどのように関与しているかは未だ明らかになっていない. 本研究では, 急性期脊髄損傷に対する羊膜由来間葉系幹細胞（AMSC）静脈投与が, “脊髄-腸相関”に与える影響を検討した.
【方法】SDラットを用い, Th6/7高位で, クリップ圧挫脊髄損傷モデルを作成した. 脊髄損傷の翌日, 一定以上の麻痺を認めたラットに対し, 無作為にヒトAMSC（1x107個, A群）または生理食塩水（C群）を尾静脈投与した. AMSCの分布は, XenoLight DiRで標識し, Fusionでin-vivo imagingを行った. 腸管評価は3日後と2週間後に, 運動機能評価は4週間後まで行い, その後に病理学的検討を加えた.
【結果】AMSCは1週間後まで主に肺と肝臓に集積していたが, 急性期には脊髄内にも確認された. A群はC群に比較し, 脊髄損傷3日後以降で回腸の絨毛構造の改善を認めた. 運動機能は2週以降, A群で有意に改善し, 病理学的評価においても, 損傷部位の縮小および炎症細胞浸潤が減少していた.
【考察・結語】本研究の結果から, 脊髄損傷により回腸絨毛構造が悪化するが, 羊膜細胞投与により, 運動機能回復に先立って回腸絨毛構造が改善することが明らかとなった. 今後、bacterial translocationの関与を検討する
日本学術振興会, 基盤研究(C), 北海道大学, 20K09361

ヒト羊膜MSCが持つ新規抗炎症物質の同定ならびに治療効果の検討
科学研究費助成事業
2020年04月01日 - 2023年03月31日
山本 桂子, 大西 俊介, 山本 幸司, 和泉 自泰
間葉系幹細胞は、出産時に廃棄される羊膜にも存在していることが知られており、次世代の再生医療材料として期待されている。申請者らは、ヒト卵膜から短期 間で簡便に間葉系幹細胞 を分離培養する技術を確立し、腸炎、肝炎、膵炎などの複数の炎症性疾患動物モデルに対して、細胞ならびにその培養上清を投与した ところ、いずれも高い治療効果を発揮することを明らかにしてきた。本研究では、羊膜由来間葉系幹細胞のもつ新規抗炎症因子の同定を行い、難治性として知られる炎症性腸疾患における新規治療効果の検討を探索することを目的としている。そこで本研究では、羊膜MSC由来新規物質の抗炎症効果の検証するために培養細胞を用いて検証を行った。具体的には以下の通り実施した。
マウス由来マクロファージを用いて、LPSで刺激後、羊膜MSC由来新規物質を処理し、LPS刺激後に産生される複数の炎症性サイトカインをELISA法で検証した。結果、LPS刺激後のマクロファージに羊膜MSC由来新規物質処理するとTNF-αやIL-6などの炎症性サイトカインの発現が著しく低下したほか、培養上清中の炎症性サイトカインの産生も低下していた。さらに、ウエスタンブロット法を用いて、炎症性サイトカインの産生に重要な転写因子であるNF-kBやIkBなどの活性化を確認した。結果、LPS刺激後のマクロファージではNF-kBやIkBなどの活性化が確認されたが、羊膜MSC由来新規物質を処理するとこれら転写因子の活性化が抑制されていることが明らかとなった。これらのことから、in vitroの系を用いた細胞培養実験において羊膜MSC由来新規物質の抗炎症効果が明らかとなった。
日本学術振興会, 基盤研究(C), 北海道大学, 20K08347

羊膜由来間葉系幹細胞を用いた放射線性口内炎の治療法の開発
科学研究費助成事業
2019年04月01日 - 2022年03月31日
結城 敏志, 大西 俊介
有効な治療法のない放射線性口内炎の新規治療法として、羊膜由来間葉系幹細胞の培養上清の有効性ならびにその作用機序について、動物実験ならびに細胞実験により明らかにすることを目的として研究を行なった。
羊膜由来間葉系幹細胞の培養上清をゲル化し、ラット放射線性口内炎モデルの舌に塗布して評価したところ、治療群において体重減少の抑制傾向がみられたが、対照群に比して有意差は認めなかった。また、舌の病理組織においても、病理スコアに改善は認められず、舌における種々の炎症性サイトカインの発現も治療群において改善傾向を認めなかった。
日本学術振興会, 基盤研究(C), 北海道大学, 19K08192

肝硬変の組織学的進展・軽快を担う間質微小環境因子の包括的解析
科学研究費助成事業
2019年04月01日 - 2022年03月31日
坂本 直哉, 須田 剛生, 古川 潤一, 森川 賢一, 大西 俊介
1. 血清糖鎖修飾構造の網羅的解析を行い、NASHの肝線維化進展例でA2F bisect 糖鎖の発現が上昇することを見いだした。2. A2F bisect糖鎖のキャリア蛋白としてIgAをはじめとする複数の蛋白を同定した。3. 培養肝星細胞活性化に関連するmicro RNAの包括的解析を施行し、miR-29a、miR-449a、その他特定のmiRNAが活性化星細胞で高発現しており、Pathway解析で細胞骨格、細胞外マトリックス、chemotaxis関連経路の蛋白の発現を調節していた。4. C型肝炎SVR後発癌症例では血清中のAng2が有意に高値であった。
日本学術振興会, 基盤研究(B), 北海道大学, 19H03630

羊膜由来間葉系幹細胞がもつEPA-レゾルビン産生と早産予防効果の検討
科学研究費助成事業
2018年04月01日 - 2021年03月31日
大西 俊介, 山本 幸司
間葉系幹細胞（MSC）は、骨髄、脂肪などに存在する体性幹細胞であり、骨、軟骨、脂肪などに分化する多分化能を有し、再生医療における有望な細胞として注目されている。本研究では、羊膜MSCから分泌される液性因子の解析から、エイコサペンタエン酸の代謝産物であるレゾルビンE1を同定した。また、LPS誘発早産ラットモデルに対してEPAを投与したところ、早産が抑制され、羊水中のEPAならびにレゾルビンE1の濃度も回復していた。以上のことから、EPAがレゾルビンE1を介して早産を予防している可能性が示唆された。
日本学術振興会, 基盤研究(C), 北海道大学, 18K09214

生体吸収性材料による消化管穿孔予防および穿孔部閉鎖を目的とした新規治療法の開発
科学研究費助成事業
2017年04月01日 - 2020年03月31日
宮澤 光男, 合川 公康, 平能 康充, 大西 俊介
本研究の目的は、生体吸収性材料を利用し消化管を再生させることにより、食道、胃、大腸の内視鏡的粘膜下層剥離術（以下ESD）後の穿孔予防および穿孔部閉鎖を目的とした新規治療法を開発することにあった。研究期間の途中から北海道大学にて、動物実験を施行し、十二指腸のESD後の穿孔における手技の確立がほぼ開発されたのは本研究の成果である。この研究で用いる新規生体吸収性材料は、現在、臨床研究が施行可能な施設を検討中である。
日本学術振興会, 基盤研究(C), 帝京大学, 17K09481

早期食道腺癌・接合部腺癌の蛍光プローブによる検出に関する多施設共同研究
科学研究費助成事業
2017年04月01日 - 2020年03月31日
山本 桂子, 大西 俊介, 畑中 豊
近年の内視鏡診断学および治療法の進歩にともない、消化管癌が早期に発見され、内視鏡的に切除できるようになってきた。しかしBarrett食道腺癌を含む食道胃接合部腺癌は、画像強調内視鏡による観察を用いても、しばしばその正確な診断が難しいことがある。最近、がんの表面に発現するDPP-IVと特異的に反応して蛍光を発する、Glutamylprolyl hydroxymethyl rhodamine green (EP-HMRG）という蛍光物質が、開発された。この研究では、内視鏡的に切除された早期食道胃接合部腺癌にEP-HMRGを散布すると数分で蛍光を発することを証明し、早期発見に寄与する可能性を示した。
日本学術振興会, 基盤研究(C), 北海道大学, 17K09343

間葉系幹細胞の培養上清を用いた内視鏡的粘膜下層剥離術後の食道狭窄予防
科学研究費助成事業
2017年04月01日 - 2020年03月31日
小野 尚子, 大西 俊介
近年の内視鏡治療技術の進歩により、食道がん患者に対して低侵襲の治療法が提供できる時代になってきた。しかしながら、内視鏡的に広範囲に切除すると、合併症として狭窄が高頻度に生じることが明らかになってきため、新規治療法の開発がのぞまれている。本研究では、羊膜由来間葉系幹細胞の炎症抑制作用に着目し、その培養上清が食道内視鏡的粘膜下層切除術 (ESD)後の狭窄に有効かどうかをブタで検討した。その結果、培養上清の経口投与によってESD後急性期の炎症を抑制することにより、線維芽細胞の活性化を抑制して狭窄を予防することが明らかとなった。引き続き、食道狭窄に対するバルーン拡張後の再狭窄の予防効果を検討している。
日本学術振興会, 基盤研究(C), 北海道大学, 17K09342

肝硬変の組織病態を修復する新規細胞薬物治療法の探索
科学研究費助成事業
2016年04月01日 - 2019年03月31日
坂本 直哉, 大西 俊介, 須田 剛生, 森川 賢一
本研究は，肝線維化の組織修復を促進する候補分子の探索とその作用機構を解析することを目的として遂行した。(1)ヒト羊膜膜由来間葉系幹細胞(AM-MSC)培養上清由来エクソソームの肝線維化抑制，炎症抑制を確認した。(2)palmitoylethanolamide (PEA)の、PPAR非依存的な星細胞活性化抑制作用を示した。(3)血清蛋白の網羅的糖鎖修飾構造解析により、血清蛋白のフコシル化修飾がNAFLからNASH、肝線維化の進展と密接に関連することを見いだした。(4)培養肝星細胞活性化に関連するmicro RNAの包括的解析を施行し、活性化星細胞で発現上昇・低下するmiRNAを抽出した。
日本学術振興会, 基盤研究(B), 北海道大学, 16H05282

卵膜由来間葉系幹細胞の分泌する低分子生理活性物質を用いた再生医療の開発
科学研究費助成事業
2014年04月01日 - 2017年03月31日
大西 俊介, 森 政寛
本研究では、ヒト卵膜由来間葉系幹細胞が産生する低分子の生理活性物質に着目し、再生医療に有効な生理活性物質を同定して、細胞を用いない新規の再生医療へ向けて臨床応用の基盤を整えることを目標とした。卵膜由来間葉系幹細胞の培養上清の低分子分画に抗炎症作用があることが明らかとなり、新規に低分子生理活性脂質を同定することができた。また、非アルコール性脂肪性肝炎モデルに対する効果を確認できた。
日本学術振興会, 基盤研究(C), 北海道大学, 26501001

がん特異的蛍光プローブの散布による新規の頭頸部がん検出法の開発
科学研究費助成事業
2014年04月01日 - 2017年03月31日
小野 尚子, 浦野 泰照, 清水 勇一, 大西 俊介, 畑中 佳奈子
多くのがん細胞表面にはGGTという酵素が発現しており，GGTにより蛍光を発する色素(gGlu-HMRG)が最近開発された.そこで、早期頭頚部扁平上皮がん切除標本にgGlu-HMRGを散布して蛍光観察を行い，がんの検出に有用であるかを検討した。
局所切除した頭頸部扁平上皮がん7病変に蛍光イメージングを行ったところ，全ての病変においてgGlu-HMRG散布後数分以内にヨード不染部とほぼ一致して緑色の蛍光が認められた．また，がん部位ではGGTの発現を認め，蛍光イメージングの結果とほぼ一致していた．gGlu-HMRGによる蛍光イメージングは頭頚部扁平上皮がんの早期発見に有用である．
日本学術振興会, 基盤研究(C), 北海道大学, 26461043

非アルコール性脂肪肝炎におけるＭＩＦの役割とその制御による治療応用
科学研究費助成事業
2013年04月01日 - 2016年03月31日
大川原 辰也, 武田 宏司, 大西 俊介
非アルコール性脂肪性肝炎においてマクロファージ遊走阻止因子の役割を解析した。非アルコール性脂肪性肝炎モデルとしてメチオニン・コリン欠損食を用い発症させた。マウスの肝臓において脂肪滴が発生しマクロファージ遊走阻止因子の発現増強がみられた。マクロファージ遊走阻止因子活性阻害剤であるISO-1を継続投与したが肝炎所見の軽減はみられなかった。アセトアミノフェン投与による肝炎にISO-1を投与したところ肝炎の著明な改善を認めた。非アルコール性脂肪性肝炎においてマクロファージ遊走阻止因子は免疫・脂質代謝ではその病態に対して複雑な関与が示唆された。
日本学術振興会, 基盤研究(C), 北海道大学, 25460968

卵膜由来間葉系幹細胞を用いた急性膵炎に対する新規治療法の開発
科学研究費助成事業
2012年04月01日 - 2015年03月31日
桑谷 将城, 川久保 和道, 大西 俊介
目的：ラット卵膜由来間葉系幹細胞(MSC)およびヒト羊膜由来MSCの急性膵炎および慢性膵炎に対する効果について、動物モデルを用いて検討した。
方法および結果：急性膵炎モデルはラット膵管にタウロコール酸を注入して作成し、ラット卵膜由来MSCを投与したところ、膵臓における病理スコアおよびマクロファージの浸潤が改善した。また、慢性膵炎モデルは5% dibutyltin dichloride(DBTC)を静注して作成し、ヒト羊膜由来MSCを投与したところ、膵臓におけるMCP-1の発現上昇とアミラーゼの発現低下が改善した。
結論；以上のことから、卵膜由来MSCは膵炎における炎症抑制に寄与すると考えられた。
日本学術振興会, 若手研究(B), 北海道大学, 24790670

放射線化学療法後の消化管障害に対する同種卵膜間葉系幹細胞移植による治療法の開発
科学研究費助成事業
2011年 - 2013年
大西 俊介
放射線腸炎は担がん患者の放射線治療や原発事故の被曝によって生じる可能性がある難治性の疾患である．本研究では，放射線腸炎に対する新規治療法の開発を目的として，卵膜由来間葉系幹細胞の効果を動物実験で検討し，その機序を明らかにすることを目標とした．
ラット放射線腸炎モデルに対し，ヒト羊膜由来間葉系幹細胞を投与したところ，病理所見が改善され，炎症性サイトカインの発現が抑制された．また，in vitroの実験においても，腸上皮細胞の放射線照射による障害を保護することが明らかとなった．
以上のことから，卵膜由来間葉系幹細胞は放射線腸炎に対する新規治療法として有用である可能性が示唆された．
日本学術振興会, 基盤研究(C), 北海道大学, 23618001

siRNAを用いた肺高血圧治療法の開発
科学研究費助成事業
2007年 - 2008年
永谷 憲歳, 佐田 正晴, 大西 俊介, 山原 研一
肺動脈性肺高血圧症は、肺血管内皮細胞の機能障害により肺動脈の収縮や肺血管内皮・平滑筋細胞の増殖を来たす難治性疾患である。既存の治療薬は血管拡張を主な作用点としており、治療抵抗例が存在するため、我々は治療のターゲットを主たる病因である肺動脈の血管内皮・血管平滑筋細胞の増殖へ転換する必要があると考えた。肺高血圧症では、細胞増殖・分化を制御するMAPKシグナリングが病態へ関与していると考えられており、まずこのシグナル蛋白であるMEKを標的としたsiRNAをデサインし、その効果を確認した。ラットMEK1および2の双方に相同性をもつ21merのsiRNAを合成し、培養ラット血管平滑筋細胞(A7r5)にリポフェクションさせ、標的遺伝子、蛋白の抑制効率をそれぞれ定量的Real time PCR法、Western blotting法により検討したところ、siRNA濃度が1nMの低濃度でも85%以上の抑制効率を示し、また濃度10nMにおける経時的検討では少なくとも96時間以上その抑制効果が持続していた。次に、このsiRNAの血管平滑筋細胞に対する増殖抑制効果を、MAPKカスケードを下流とする増殖因子であるPDGF-BB刺激下にMTS assayを用いて検討したところ、siRNA濃度依存的に血管平滑筋細胞の増殖が抑制されていた。さらに、アポトーシス誘導効果をカスパーゼ3および7の細胞内活性を測定し検討したところ、やはり濃度依存的にアポトーシス誘導が起こっていた。以上より、我々のデザインした合成siRNAはラノト血管平滑筋細胞の標的蛋白合成を効率的に阻害し、期待された増殖抑制およびアポトーシス誘導の表現型を示すことが証明された。現在、このsiRNAを脂質化合物を用いて生体内での安定性を確保した薬物送達システムを開発中であり、ラット肺高血圧モデルを用いて標的となる肺動脈への導入効率を検討する予定である。
日本学術振興会, 基盤研究(C), 国立循環器病センター(研究所), 19590927