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久保田 英嗣クボタ エイジ

所属部署医学研究科共同研究教育センター
職名准教授
メールアドレスekubotamed.nagoya-cu.ac.jp
ホームページURL
生年月日
Last Updated :2019/07/06

研究者基本情報

基本情報

    科研費研究者番号:30405188

学位

  • 医学博士

所属学協会

  • 日本神経消化器病学会
  • 日本潰瘍学会
  • 日本消化器癌発生学会
  • 日本癌学会
  • 日本消化管学会
  • 日本消化器内視鏡学会
  • 日本消化器病学会
  • 日本内科学会

経歴

  •   2015年05月 - 現在, 名古屋市立大学, 消化器代謝内科, 講師
  •   2014年07月 - 2015年04月, 名古屋市立大学, 消化器代謝内科, 病院講師
  •   2013年04月 - 2014年06月, 名古屋市立大学, 消化器代謝内科, 助教
  •   2010年07月 - 2013年, カルガリー大学, 分子生物腫瘍学, 研究員

研究活動情報

研究分野

  • 内科系臨床医学, 消化器内科学

研究キーワード

    消化器内科

MISC

  • Combination Therapy With Intensive Granulocyte and Monocyte Adsorptive Apheresis Plus Ustekinumab in Patients With Refractory Crohn's Disease, Satoshi Tanida, Tsutomu Mizoshita, Keiji Ozeki, Takahito Katano, Mamoru Tanaka, Hirotada Nishie, Takaya Shimura, Yasuyuki Okamoto, Eiji Kubota, Hiromi Kataoka, Takashi Joh, Therapeutic Apheresis and Dialysis, 22,   2018年06月01日, © 2018 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Ustekinumab is applied to induce clinical remission in patients with Crohn's disease. Granulocyte and monocyte absorptive apheresis depletes activated myeloid lineage leukocytes and has been applied for active Crohn's disease. This study retrospectively examined the efficacy and safety of combining intensive granulocyte and monocyte absorptive apheresis and ustekinumab for remission induction therapy in refractory Crohn's disease. Between June and September 2017, three consecutive cases (two females) with refractory Crohn's disease were treated with intensive granulocyte and monocyte absorptive apheresis plus ustekinumab. Crohn's disease activity index, and simple endoscopic score for Crohn's disease at baseline and 10 weeks were applied as treatment efficacy outcomes. In all three cases, at week 10, clinical remission was achieved, while simple endoscopic score for Crohn's disease reflected no improvement. Thus, combination therapy with intensive granulocyte and monocyte absorptive apheresis plus ustekinumab appeared to represent a safe and effective intervention for inducing clinical remission.
  • Refractory gastric antral ulcers without Helicobacter pylori infection and non-steroidal anti-inflammatory drugs, Hirotada Nishie, Hiromi Kataoka, Hiroyuki Kato, Taketo Suzuki, Hiroshi Ichikawa, Yu Nojiri, Mika Kitagawa, Yusuke Inagaki, Hiroyasu Iwasaki, Mamoru Tanaka, Takahito Katano, Yasuyuki Okamoto, Keiji Ozeki, Tsutomu Mizoshita, Takaya Shimura, Eiji Kubota, Satoshi Tanida, Takashi Joh, Clinical Journal of Gastroenterology, 11,   2018年06月01日, © 2018, Japanese Society of Gastroenterology. Herein, we describe a rare case of refractory gastric antral ulcers. A woman in her 50 s was admitted to Nagoya City University Hospital with epigastric pain after being diagnosed with gastric antral submucosal tumor at another hospital. Findings from esophagogastroduodenoscopy and endoscopic ultrasound examination revealed that the lesion was a gastric ulcer. The patient had no Helicobacter pylori infection and no recent history of using non-steroidal anti-inflammatory drugs. On the basis of these findings, we diagnosed this as a case of refractory gastric antral ulcer (RGAU). RGAU is considered a new disease concept and detailed analyses are expected in the future.
  • Excellent antitumor effects for gastrointestinal cancers using photodynamic therapy with a novel glucose conjugated chlorin e6, Hirotada Nishie, Hiromi Kataoka, Shigenobu Yano, Shigenobu Yano, Shigenobu Yano, Hiroaki Yamaguchi, Akihiro Nomoto, Mamoru Tanaka, Akihisa Kato, Takaya Shimura, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Takashi Joh, Biochemical and Biophysical Research Communications, 496,   2018年02月19日, © 2018 Elsevier Inc. Background: Photodynamic therapy (PDT) exploits the reaction between photosensitizer and irradiated light to generate potentially therapeutic reactive oxygen species such as singlet oxygen in cancer cells. We have reported several sugar-conjugated chlorins that express stronger antitumor effects in PDT than talaporfin sodium (TS), a second-generation photosensitizer clinically used in Japan. In this study, we developed a novel glucose-conjugated chlorin e6 (G-chlorin e6) and evaluated its antitumor effects. Methods: G-chlorin e6 was synthesized with a core photosensitizer chlorin e6 conjugated to glucose. We measured the half maximal inhibitory concentration (IC50) to compare the PDT effects of G-chlorin e6 and TS, and flow cytometry was performed to examine the accumulation of G-chlorin e6 in cancer cells. We also compared the accumulation of G-chlorin e6 between normal immortalized esophageal epithelial cells and esophageal cancer cells. Antitumor effects of G-chlorin e6 PDT were finally analyzed in allograft tumor mouse models. Results: PDT in vitro using G-chlorin e6 elicited 9, 000–34,000 times stronger antitumor effects than TS, and there was 70–190 times more G-chlorin e6 accumulated than TS by flow cytometry. G-chlorin e6 accumulated more selectively in esophageal cancer cells than in esophageal immortalized epithelial cells, and in an allograft model, PDT with G-chlorin e6 showed very strong antitumor effects and a 40% complete response (CR) rate. Conclusions: G-chlorin e6 showed excellent tumor selectivity, and PDT using G-chlorin e6 revealed the strongest anti-tumor effects among all sugar-conjugated chlorins that we have studied. G-chlorin e6 is considered to be the best photosensitizer for next-generation PDT.
  • Glucagon promotes colon cancer cell growth via regulating AMPK and MAPK pathways, Takashi Yagi, Eiji Kubota, Hiroyuki Koyama, Tomohiro Tanaka, Hiromi Kataoka, Kenro Imaeda, Takashi Joh, Oncotarget, 9,   2018年01月01日, © Yagi et al. Cancer is one of the major causes of death in diabetic patients, and an association between antidiabetic drugs and cancer risk has been reported. Such evidence implies a strong connection between diabetes and cancer. Recently, glucagon has been recognized as a pivotal factor implicated in the pathophysiology of diabetes. Glucagon acts through binding to its receptor, glucagon receptor (GCGR), and crosstalk between GCGR-mediated signals and signaling pathways that regulate cancer cell fate has been unveiled. In the current study, expression of GCGR in colon cancer cell lines and colon cancer tissue obtained from patients was demonstrated. Glucagon significantly promoted colon cancer cell growth, and GCGR knockdown with small interfering RNA attenuated the proliferation-promoting effect of glucagon on colon cancer cells. Molecular assays showed that glucagon acted as an activator of cancer cell growth through deactivation of AMPK and activation of MAPK in a GCGRdependent manner. Moreover, a stable GCGR knockdown mouse colon cancer cell line, CMT93, grew significantly slower than control in a syngeneic mouse model of type 2 diabetes with glycemia and hyperglucagonemia. The present observations provide experimental evidence that hyperglucagonemia in type 2 diabetes promotes colon cancer progression via GCGR-mediated regulation of AMPK and MAPK pathways.
  • Cullin-3 and its adaptor protein ANKFY1 determine the surface level of integrin β1 in endothelial cells, Masashi Maekawa, Masashi Maekawa, Kazufumi Tanigawa, Kazufumi Tanigawa, Tomohisa Sakaue, Tomohisa Sakaue, Hiromi Hiyoshi, Eiji Kubota, Takashi Joh, Yuji Watanabe, Tomohiko Taguchi, Tomohiko Taguchi, Shigeki Higashiyama, Shigeki Higashiyama, Biology Open, 6,   2017年11月15日, © 2017, Company of Biologists Ltd. All rights reserved. Angiogenesis, the formation of new blood vessels from the preexisting vasculature, is related to numerous pathophysiological events. We previously reported that a RING ubiquitin ligase complex scaffold protein, cullin-3 (CUL3), and one of its adaptor proteins, BAZF, regulated angiogenesis in the mouse retina by suppressing Notch signaling. However, the degree of inhibition of angiogenesis was made greater by CUL3 depletion than by BAZF depletion, suggesting other roles of CUL3 in angiogenesis besides the regulation of Notch signaling. In the present study, we found that CUL3 was critical for the cell surface level of integrin β1, an essential cell adhesion molecule for angiogenesis in HUVECs. By siRNA screening of 175 BTBPs, a family of adaptor proteins for CUL3, we found that ANKFY1/Rabankyrin-5, an early endosomal BTBP, was also critical for localization of surface integrin β1 and angiogenesis. CUL3 interacted with ANKFY1 and was required for the early endosomal localization of ANKFY1. These data suggest that CUL3/ ANKFY1 regulates endosomal membrane traffic of integrin β1. Our results highlight the multiple roles of CUL3 in angiogenesis, which are mediated through distinct CUL3-adaptor proteins.
  • Expression and subcellular localization of at motif binding factor 1 in colon tumours, Hiromi Kataoka, Yutaka Miura, Makoto Kawaguchi, Shugo Suzuki, Yasuyuki Okamoto, Keiji Ozeki, Takaya Shimura, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Satoru Takahashi, Kiyofumi Asai, Takashi Joh, Molecular Medicine Reports, 16,   2017年09月01日, AT motif binding factor 1 (ATBF1) is a transcriptional regulator that functions as a tumour suppressor to negatively affect cancer cell growth. In the present study four specific polyclonal antibodies against ATBF1 were generated, and the expression and intracellular localization of ATBF1 in colonic mucosae, polyps, adenoma and adenocarcinoma tissue samples were investigated. The four polyclonal antibodies produced were as follows: MB34 and MB49, which recognize the N-and C-terminal fragments of ATBF1, respectively; and D1-120 and MB44, which recognize the middle fragments of ATBF1 that contain three nuclear localization signals (NLS). In total, 191 colon samples were examined by immunohistochemical analysis. In addition, colon cancer cells were transfected with four ATBF1 expression vectors, and the subcellular localization of each fragment was examined. Normal colon mucosal cells were not observed to express ATBF1. However, a small number of hyperplastic polyps, serrated adenomas and tubular adenomas expressed ATBF1. Colon cancer cells were observed to express D1-120-and MB44-reactive middle fragments of ATBF1 in their cell nuclei. However, the N-and C-terminal fragments of ATBF1 did not translocate to the nucleus. Transfection of ATBF1 fragments revealed cleavage of the ATBF1 protein and nuclear translocation of the cleaved middle portion containing the NLS. A positive correlation between the cytoplasmic localization of the N-and C-termini of ATBF1, nuclear localization of the middle portion of ATBF1 and malignant cancer cell invasion was observed. In conclusion, the results of the present study suggest that alterations in the expression and subcellular localization of ATBF1, as a result of post-transcriptional modifications, are associated with malignant features of colon tumours.
  • Adalimumab therapy in a patient with Crohn’s disease with a giant pelvic paraganglioma after chemotherapy, Tsutomu Mizoshita, Masashi Ando, Hiroyuki Sagawa, Yoshinori Mori, Takahito Katano, Keiji Ozeki, Satoshi Tanida, Yasuyuki Okamoto, Takaya Shimura, Eiji Kubota, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Clinical Journal of Gastroenterology, 10,   2017年06月01日, © 2017, Japanese Society of Gastroenterology. A 23-year-old man was diagnosed with a giant pelvic paraganglioma in September 2013, and a 6-month chemotherapy course was performed. The chemotherapy resulted in stable disease of the tumor for about 1 year. However, in April 2015, the patient complained of fever and diarrhea of more than ten times a day. Endoscopy showed serpiginous (snake-like) ulcers in the cecum, ascending, descending, and sigmoid colons, with granulomas without caseation histologically. The patient was diagnosed with the active stage of Crohn’s disease (CD) in June 2015. Oral mesalazine (3000 mg/day) and an elemental diet (900 kcal/day) led to temporary clinical remission. At the beginning of January in 2016, an abdominal abscess and fistula were detected by computed tomography, which needed surgical treatment. Adalimumab administration was started at the beginning of February, since active lesions were detected endoscopically. A second endoscopy showed improvement of the inflammatory lesions 3 months after induction therapy with adalimumab. Clinical remission has been maintained with adalimumab administration, with stable disease of the tumor and no adverse events. To the best of our knowledge, this is the first report of a patient with a paraganglioma who developed CD after chemotherapy. The patient was successfully treated with adalimumab after surgery for his CD.
  • Ectopic Gastric and Intestinal Phenotypes, Neuroendocrine Cell Differentiation, and SOX2 Expression Correlated With Early Tumor Progression in Colorectal Laterally Spreading Tumors, Takahito Katano, Tsutomu Mizoshita, Hironobu Tsukamoto, Hirotada Nishie, Yusuke Inagaki, Noriyuki Hayashi, Satoshi Nomura, Keiji Ozeki, Yasuyuki Okamoto, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Hiromi Kataoka, Toshiya Kuno, Satoru Takahashi, Takashi Joh, Clinical Colorectal Cancer, 16,   2017年06月01日, © 2016 Elsevier Inc. We analyzed 105 colorectal laterally spreading tumors (LSTs) resected by endoscopic submucosal dissection and investigated clinicopathologic differences among LST subtypes to identify factors indicative of malignant transformation and invasion. Ectopic gastric and intestinal phenotypes, neuroendocrine cell differentiation, and SOX2 expression differ according to tumor grade in colorectal LSTs, and these markers are correlated with early tumor progression in each LST subtype. Introduction The significance of the ectopic gastric phenotype remains unclear in patients with colorectal laterally spreading tumors (LSTs). We investigated clinicopathologic differences among LST subtypes, aiming to identify factors indicative of malignant transformation and invasion that are linked to ectopic gastric phenotype and tumor progression. Materials and Methods We analyzed the morphologic characteristics of 105 colorectal LSTs resected by endoscopic submucosal dissection. LSTs were classified into 2 subtypes: granular (G-LST) and nongranular (NG-LST). Resected LSTs were analyzed histologically and were immunohistochemically stained for MUC5AC, MUC6, chromogranin A, CD10, and SOX2. Results The 105 LSTs included 60 G-LSTs and 45 NG-LSTs. By histology, G-LSTs comprised 5 adenomas with low-grade dysplasia (LAs), 45 adenomas with high-grade dysplasia (HAs), and 10 adenocarcinomas invading the submucosa (SMs). NG-LSTs comprised 8 LAs, 25 HAs, and 12 SMs. MUC5AC positivity was significantly higher in G-LSTs compared to NG-LSTs (P = .002), and MUC5AC positivity in HA lesions was significantly higher than in LA lesions (P = .01). MUC6 and SOX2 positivity in SM G-LSTs, and chromogranin A positivity in SM NG-LSTs were significantly higher than in HAs (P = .01, .01, and .03, respectively). CD10 positivity in SM NG-LSTs was significantly higher than in HAs and LAs (P = .02 and .01, respectively). Conclusion Ectopic gastric and intestinal phenotypes, neuroendocrine cell differentiation, and SOX2 expression differ according to tumor grade in colorectal LSTs, and these markers are correlated with early tumor progression in each LST subtype.
  • The CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells, Tomohisa Sakaue, Tomohisa Sakaue, Iori Sakakibara, Takahiro Uesugi, Ayako Fujisaki, Koh Ichi Nakashiro, Hiroyuki Hamakawa, Eiji Kubota, Takashi Joh, Yu Ki Imai, Hironori Izutani, Shigeki Higashiyama, Shigeki Higashiyama, Scientific Reports, 7,   2017年02月20日, © The Author(s) 2017. Vascular endothelial cell growth factor receptor 2 (VEGFR2) is an essential receptor for the homeostasis of endothelial cells. In this study, we showed that NEDD8-conjugated Cullin3 (CUL3)-based ubiquitin E3 (UbE3) ligase plays a crucial role in VEGFR2 mRNA expression. Human umbilical vein endothelial cells treated with MLN4924, an inhibitor of NEDD8-activating enzyme, or with CUL3 siRNA drastically lost their response to VEGF due to the intense decrease in VEGFR2 expression. Moreover, speckle-type POZ protein (SPOP) and death-domain associated protein (DAXX) were involved in the CUL3 UbE3 ligase complex as a substrate adaptor and a substrate, respectively. Knockdown of SPOP and CUL3 led to the upregulation of DAXX protein and downregulation of VEGFR2 levels. These levels were inversely correlated with one another. In addition, simultaneous knockdown of SPOP and DAXX completely reversed the downregulation of VEGFR2 levels. Moreover, the CUL3-SPOP-DAXX axis had the same effects on NOTCH1, DLL4 and NRP1 expression. Taken together, these findings suggest that the CUL3-SPOP-DAXX axis plays a very important role in endothelial cell function by targeting key angiogenic regulators.
  • Neddylated Cullin 3 is required for vascular endothelial-cadherin-mediated endothelial barrier function, Tomohisa Sakaue, Tomohisa Sakaue, Ayako Fujisaki, Hironao Nakayama, Hironao Nakayama, Masashi Maekawa, Masashi Maekawa, Hiromi Hiyoshi, Eiji Kubota, Takashi Joh, Hironori Izutani, Shigeki Higashiyama, Shigeki Higashiyama, Cancer Science, 108,   2017年02月01日, © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Vascular endothelial (VE)-cadherin, a major endothelial adhesion molecule, regulates vascular permeability, and increased vascular permeability has been observed in several cancers. The aim of this study was to elucidate the role of the NEDD8-Cullin E3 ligase, in maintaining barrier permeability. To this end, we investigated the effects of the inhibition of Cullin E3 ligases, by using inhibitors and knockdown techniques in HUVECs. Furthermore, we analyzed the mRNA and protein levels of the ligases by quantitative RT-PCR and Western blotting, respectively. The results revealed that NEDD8-conjugated Cullin 3 is required for VE-cadherin-mediated endothelial barrier functions. Treatment of HUVECs with MLN4924, a chemical inhibitor of the NEDD8-activating enzyme, led to high vascular permeability due to impaired cell–cell contact. Similar results were obtained when HUVECs were treated with siRNA directed against Cullin 3, one of the target substrates of NEDD8. Immunocytochemical staining showed that both treatments equally depleted VE-cadherin protein localized at the cell–cell borders. However, quantitative RT-PCR showed that there was no significant difference in the VE-cadherin mRNA levels between the treatment and control groups. In addition, cycloheximide chase assay revealed that the half-life of VE-cadherin protein was dramatically reduced by Cullin 3 depletion. Together, these findings suggest that neddylated Cullin 3 plays a crucial role in endothelial cell barrier function by regulating VE-cadherin.
  • Anti-tumor efficacy of oncolytic reovirus against gastrointestinal stromal tumor cells, Yusuke Inagaki, Eiji Kubota, Yoshinori Mori, Mineyoshi Aoyama, Hiromi Kataoka, Randal N. Johnston, Takashi Joh, Oncotarget, 8,   2017年01月01日, © Inagaki et al. Imatinib, a multitargeted receptor tyrosine kinase inhibitor, is used as the standard initial therapy against inoperable gastrointestinal stromal tumor (GIST). However, GIST can acquire resistance to imatinib within several years of therapy. The development of oncolytic reovirus as an anticancer agent has expanded to many clinical trials for various tumors. Here, we investigated whether reovirus has antitumor activity against GIST cells in the setting of imatinib sensitivity in vitro and in vivo. Cell proliferation and apoptosis assays were performed using a human GIST cell line, GIST-T1, and imatinib-resistant GIST (GIST-IR) cells that we established. The molecular pathways responsible for cell damage by reovirus were explored using PCR-arrays and Western blots. Reovirus significantly induced apoptotic cell death in GIST-T1 and GIST-IR cells in vitro, despite differences in the activation of receptor tyrosine kinase pathways between GIST-T1 and GIST-IR. Molecular assays indicated the possibility that reovirus induces apoptotic cell death via Fas signaling. Furthermore, in vivo mouse tumor xenograft models demonstrated a significant antitumor effect of reovirus on both GIST-T1 and GIST-IR cells. Our results demonstrate the therapeutic potential of reovirus against GIST.
  • A multicenter randomized trial comparing rabeprazole and itopride in patients with functional dyspepsia in Japan: The NAGOYA study, Takeshi Kamiya, Michiko Shikano, Eiji Kubota, Tsutomu Mizoshita, Tsuneya Wada, Tsuneya Wada, Satoshi Tanida, Hiromi Kataoka, Hiroshi Adachi, Makoto Hirako, Noriaki Okuda, Takashi Joh, Journal of Clinical Biochemistry and Nutrition, 60,   2017年01月01日, © 2017 JCBN. The aims of this study were to compare the therapeutic effects of a proton pump inhibitor (PPI), rabeprazole (RPZ), and a prokinetic agent, itopride (ITO), and to investigate the role of PPI in the treatment strategy for Japanese functional dyspepsia (FD) patients. We randomly assigned 134 patients diagnosed by Rome III criteria to 4 weeks treatment with RPZ 10 mg/day (n = 69) or ITO 150 mg/day (n = 65). Dyspeptic symptoms were evaluated using FD scores at baseline and after 1, 2 and 4 weeks of treatment. We also divided subjects into predominantly epigastric pain syndrome (EPS) or postprandial distress syndrome (PDS), and evaluated the efficacy of RPZ and ITO respectively. RPZ showed a significant decrease in the Rate of Change (RC) in FD score within 1 week, which was maintained until after 4 weeks, with RPZ a significant effect compared with ITO at all evaluation points. In addition, RPZ showed a significant decrease in FD score in subjects with both EPS and PDS, whereas a significant decrease in the RC with ITO was only shown in those with predominant PDS. Acid-suppressive therapy with RPZ is useful for PDS as well EPS in Japanese FD patients (UMIN Clinical Trials Registry number: UMIN 000013962).
  • Anticancer effects of a new aminosugar-conjugated platinum complex agent against cisplatin-resistant gastric cancer, Noriyuki Hayashi, Hiromi Kataoka, Shigenobu Yano, Shigenobu Yano, Jun Ichi Kikuchi, Mamoru Tanaka, Hirotada Nishie, Yuma Kinoshita, Miki Hatano, Akihiro Nomoto, Akiya Ogawa, Masahiro Inoue, Tsutomu Mizoshita, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Takashi Joh, Anticancer Research, 36,   2016年11月01日, Background/Aim: Resistance against cisplatin is a problem for the success of gastric cancer chemotherapy. Herein, we evaluated the antitumor effect of a new aminosugar-conjugated, mono-functional platinum complex (Pt-Oqn), which forms a single covalent bond with DNA. Materials and Methods: We compared the cytotoxicity of Pt-Oqn to that of cisplatin (CDDP), oxaliplatin (L-OHP) and carboplatin (CBDCA). We also compared Pt-Oqn and cisplatin for DNA double-strand breaks based on phosphorylated histone H2AX levels in cancer cells and antitumor effects in xenograft models. Results: The resistance factor (RF) for Pt-Oqn was low among the four drugs, indicating the potential of Pt-Oqn for overcoming CDDP-induced resistance. In MKN45-R cells, γ-H2AX protein increased following treatment with Pt-Oqn, but not with cisplatin. Finally, Pt-Oqn, but not cisplatin, showed significant antitumor effects in MKN45-R xenografts. Conclusion: This new aminosugar-conjugated platinum complex is a promising candidate agent for overcoming the drug resistance of cisplatin-resistant stomach cancer.
  • Persistent reflux symptoms cause anxiety, depression, and mental health and sleep disorders in gastroesophageal reflux disease patients, Yoshihide Kimura, Takeshi Kamiya, Kyouji Senoo, Kenji Tsuchida, Atsuyuki Hirano, Hisayo Kojima, Hiroaki Yamashita, Yoshihiro Yamakawa, Nobuhiro Nishigaki, Tomonori Ozeki, Masatsugu Endo, Kazuhisa Nakanishi, Motoki Sando, Yusuke Inagaki, Michiko Shikano, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Hiromi Kataoka, Kohei Katsumi, Takashi Joh, Journal of Clinical Biochemistry and Nutrition, 59,   2016年07月01日, ©2016 JCBN. Some patients with gastroesophageal reflux disease experience persistent reflux symptoms despite proton pump inhibitor therapy. These symptoms reduce their health-related quality of life. Our aims were to evaluate the relationship between proton pump inhibitor efficacy and health-related quality of life and to evaluate predictive factors affecting treatment response in Japanese patients. Using the gastroesophageal reflux disease questionnaire, 145 gastroesophageal reflux disease patients undergoing proton pump inhibitor therapy were evaluated and classified as responders or partial-responders. Their health-related quality of life was then evaluated using the 8-item Short Form Health Survey, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale questionnaires. Sixty-nine patients (47.6%) were partial responders. These patients had significantly lower scores than responders in 5/8 subscales and in the mental health component summary of the 8-item Short Form Health Survey. Partial responders had significantly higher Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale scores, including anxiety and depression scores, than those of responders. Non-erosive reflux disease and double proton pump inhibitor doses were predictive factors of partial responders. Persistent reflux symptoms, despite proton pump inhibitor therapy, caused mental health disorders, sleep disorders, and psychological distress in Japanese gastroesophageal reflux disease patients.
  • Questionnaire-Based Survey on Diagnostic and Therapeutic Endoscopies and H. pylori Eradication for Elderly Patients in East Asian Countries, Juntaro Matsuzaki, Ryoma Hayashi, Tetsuo Arakawa, Fumiaki Ueno, Yoshikazu Kinoshita, Takashi Joh, Shinichi Takahashi, Yuji Naito, Shin Fukudo, Francis K.L. Chan, Ki Baik Hahm, Udom Kachintorn, Kwong Ming Fock, Ari Fahrial Syam, Abdul Aziz Rani, Jose D. Sollano, Qi Zhu, Yasuhiro Fujiwara, Eiji Kubota, Hiromi Kataoka, Kengo Tokunaga, Kazuhiko Uchiyama, Hidekazu Suzuki, Digestion, 93,   2016年01月01日, © 2016 © 2016 S. Karger AG, Basel. Background: Gastrointestinal endoscopy and Helicobacter pylori(H. pylori) eradication therapy are commonly performed even among the elderly population. The aim of this study was to understand the way endoscopists viewed the application of endoscopy and H. pylori eradication in the elderly of East Asian countries. Methods: Self-administered questionnaires containing 13 questions on endoscopy and H. pylori eradication in the elderly were distributed to major institutions in Japan, South Korea, China, Indonesia, and the Philippines. Results: Two hundred and fifteen endoscopists (111 in Japan, 39 in China, 24 in Korea, 21 in Indonesia, and 20 in the Philippines) participated in this study. In the institutions where these endoscopists were associated, around 50% of patients undergoing endoscopy were above the age of 60 years. The participating endoscopists indicated that the necessity of screening esophagogastroduodenoscopy and colonoscopy was lower in populations aged over 81 than the other age groups. They hesitated to perform therapeutic endoscopy, such as endoscopic submucosal dissection or endoscopic retrograde cholangiopancreatography, more often in patients over 85. They also hesitated to perform H. pylori eradication in patients aged over 81, especially in Japan. Conclusion: Endoscopists had significantly different attitudes regarding the indications for screening or therapeutic endoscopy and H. pylori eradication therapy in younger and elderly populations in East Asian countries.
  • Immunogenic cell death due to a new photodynamic therapy (PDT) with glycoconjugated chlorin (G-chlorin), Mamoru Tanaka, Hiromi Kataoka, Shigenobu Yano, Takuya Sawada, Haruo Akashi, Masahiro Inoue, Shugo Suzuki, Yusuke Inagaki, Noriyuki Hayashi, Hirotada Nishie, Takaya Shimura, Tsutomu Mizoshita, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Satoru Takahashi, Takashi Joh, Oncotarget, 7,   2016年01月01日, Both the pre-apoptotic exposure to calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death. Photodynamic therapy (PDT) uses non-toxic photosensitizers and visible light at a specific wavelength in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumor microvasculature, and stimulate the host immune system. We have previously shown that glycoconjugated chlorin (G-chlorin) has superior cancer cell selectivity and effectively suppresses the growth of xenograft tumors. In the present study, we evaluated the immunogenicity of PDT with G-chlorin treatment in colon cancer cells. PDT with G-chlorin suppressed CT26 (mouse colon cancer cells) tumor growth considerably more efficiently in immunocompetent mice (wild-type mice, allograft model) than in immune-deficient mice (nude mice, xenograft model), although control treatments were not different between the two. This treatment also induced CRT translocation and HMGB1 release in cells, as shown by western blot and immunofluorescence staining. To evaluate the use of PDT-treated cells as a tumor vaccine, we employed a syngeneic mouse tumor model (allograft model). Mice inoculated with PDT-treated CT26 cells were significantly protected against a subsequent challenge with live CT26 cells, and this protection was inhibited by siRNA for CRT or HMGB1. In conclusion, PDT with G-chlorin treatment induced immunogenic cell death in a mouse model, where the immunogenicity of this treatment was directed by CRT expression and HMGB1 release.
  • Long-Term Clinical Remission in Biologically Naïve Crohn's Disease Patients with Adalimumab Therapy, Including Analyses of Switch from Adalimumab to Infliximab, Tsutomu Mizoshita, Satoshi Tanida, Keiji Ozeki, Takahito Katano, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Case Reports in Gastroenterology, 10,   2016年01月01日, © 2016 The Author(s). There is little evidence regarding the maintenance of long-term clinical remission by adalimumab (ADA) therapy in Crohn's disease (CD) patients naïve to anti-tumor necrosis factor treatment (naïve CD patients), since most CD patients are treated with ADA after infliximab (IFX) therapy. The long-term clinical response to ADA was retrospectively analyzed in 17 naïve CD patients for at least 24 months, and the serum trough IFX levels were evaluated in patients switching from ADA to IFX. Of the 17 naïve CD patients, 14 (82.4%) maintained long-term clinical remission with ADA therapy for at least 24 months, without serious adverse events. The clinical condition of 7 patients was observed for more than 36 months, and 3, 1, 1, and 2 cases maintained remission at months 42, 48, 54, and 60 after ADA therapy, respectively. Three patients (17.6%) switched from ADA to IFX less than 24 months after the start of ADA therapy, and they had remission, retaining trough levels of IFX higher than 1 μg/ml, occasionally by dose escalation. In conclusion, maintenance ADA therapy achieves long-term clinical remission in naïve CD patients. Switching from ADA to IFX is an important therapeutic option in CD patients showing loss of response to ADA, occasionally with dose escalation, based on the analysis of serum IFX trough levels.
  • A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis, Hirotada Nishie, Hiromi Kataoka, Shigenobu Yano, Jun ichi Kikuchi, Noriyuki Hayashi, Atsushi Narumi, Akihiro Nomoto, Eiji Kubota, Takashi Joh, Oncotarget, 7,   2016年01月01日, Photodynamic therapy (PDT) exploits light interactions and photosensitizers to induce cytotoxic reactive oxygen species. Photodynamic diagnosis (PDD) uses the phenomenon of photosensitizer emitting fluorescence to distinguish some tumors from normal tissue. The standard photosensitizer used for PDD is 5-aminolevulinic acid (5-ALA), although it is not entirely satisfactory. We previously reported glucoseconjugated chlorin (G-chlorin) as a more effective photosensitizer than another widely used photosensitizer, talaporfin sodium (TS); however, G-chlorin is hydrophobic. We synthesized oligosaccharide-conjugated chlorin (O-chlorin) with improved watersolubility. We report herein on its accumulation and cytotoxicity. O-chlorin was synthesized and examined for solubility. Flow cytometric analysis was performed to evaluate O-chlorin accumulation in cancer cells. To evaluate the intracellular localization of photosensitizer, cells were stained with O-chlorin and organelle-specific fluorescent probes. We then measured the in vitro fluorescence of various photosensitizers and the half-maximal inhibitory concentrations to evaluate effects in PDD and PDT, respectively. Xenograft tumor models were established, and antitumor and visibility effects were analyzed. O-chlorin was first shown to be hydrophilic. Flow cytometry then revealed a 20- to 40-times higher accumulation of O-chlorin in cancer cells than of TS, and a 7- to 23-times greater fluorescence than 5-ALA. In vitro, the cytotoxicity of O-chlorin PDT was stronger than that of TS PDT, and O-chlorin tended to accumulate in lysosomes. In vivo, O-chlorin showed the best effect in PDT and PDD compared to other photosensitizers. O-chlorin was hydrophilic and showed excellent tumor accumulation and fluorescence. O-chlorin is promising as a next-generation bifunctional photosensitizer candidate for both PDT and PDD.
  • A novel photodynamic therapy targeting cancer cells and tumor-associated macrophages, Noriyuki Hayashi, Hiromi Kataoka, Shigenobu Yano, Shigenobu Yano, Mamoru Tanaka, Kazuhiro Moriwaki, Haruo Akashi, Shugo Suzuki, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Satoru Takahashi, Takashi Joh, Molecular Cancer Therapeutics, 14,   2015年02月01日, © 2014 AACR. Tumor-associated macrophages (TAM) in cancer stroma play important roles for cancer cell growth, invasion, angiogenesis, and metastases. We synthesized a novel photosensitizer, mannose-conjugated chlorin (M-chlorin), designed to bind mannose receptors highly expressed on TAMs. We evaluated the newly available photodynamic therapy (PDT) with M-chlorin against gastric and colon cancer. We evaluated PDT with M-chlorin for in vitro cytotoxicity and apoptosis induction in cancer cells compared with chlorin alone and glucose-conjugated chlorin (G-chlorin). The subcellular localization of M-chlorin was observed by confocal microscopy, and the M-chlorin PDT effects against TAMs including THP-1-induced M2-polarized macrophages were evaluated. Anticancer effects were also investigated in an allograft model where cytotoxic effects against TAMs in the cancer cell stroma were analyzed by immunohistochemistry. M-chlorin PDT strongly induced cell death in cancer cells to almost the same extent as G-chlorin PDT by inducing apoptosis. M-chlorin was incorporated into cancer cells where it localized mainly in lysosomes and endoplasmic reticula. M-chlorin PDT revealed strong cytotoxicity for M2 macrophages induced from THP-1 cell lines, and it induced stronger cytotoxicity than G-chlorin PDT in the allograft model through killing both cancer cells and TAMs in the cancer stroma. The M-chlorin PDT produced strong cytotoxicity against cancer tissue by inducing apoptosis of both cancer cells and TAMs in the cancer stroma. This novel PDT thus stands as a new candidate for very effective, next-generation PDT.
  • Oncolytic reovirus combined with trastuzumab enhances antitumor efficacy through TRAIL signaling in human HER2-positive gastric cancer cells, Shingo Hamano, Shingo Hamano, Yoshinori Mori, Mineyoshi Aoyama, Hiromi Kataoka, Mamoru Tanaka, Masahide Ebi, Eiji Kubota, Tsutomu Mizoshita, Satoshi Tanida, Randal N. Johnston, Kiyofumi Asai, Takashi Joh, Cancer Letters, 356,   2015年01月01日, © 2014 Elsevier Ireland Ltd. The human epidermal growth factor receptor 2 (HER2)-targeting agent, trastuzumab, is effective for HER2-overexpressing gastric cancer therapy. As oncolytic reovirus is currently undergoing clinical trials internationally, we wanted to explore whether combination therapy using trastuzumab and reovirus might provide a novel, more effective therapeutic option for gastric cancer. Cell proliferation and cell apoptosis were examined in vitro, while molecular analysis of pathways responsible for cell damage was examined using polymerase chain reaction array. Activation of the proteins related to apoptosis, cell growth and survival was detected by Western blotting. Mouse tumor xenograft models were used to examine antitumor activity in vivo. Reovirus sensitized HER2-overexpressing gastric cancer cells to undergo apoptosis. Both in vitro and in vivo studies provided evidence that the combination therapy is a more powerful modality against HER2-overexpressing gastric cancer cells than treatment using a single agent. Molecular analysis indicated that combination therapy induced significantly higher levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in cancer cells. Antibody against TRAIL strongly inhibited cell toxicity caused by the combined treatment. These data suggest that reovirus may augment trastuzumab-induced cytotoxicity in gastric cancer cells.
  • Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines, Eiji Kubota, Eiji Kubota, Eiji Kubota, Christopher T. Williamson, Christopher T. Williamson, Christopher T. Williamson, Ruiqiong Ye, Ruiqiong Ye, Anifat Elegbede, Anifat Elegbede, Lars Peterson, Lars Peterson, Susan P. Lees-Miller, Susan P. Lees-Miller, D. Gwyn Bebb, D. Gwyn Bebb, Cell Cycle, 13,   2014年07月01日, Small-molecule inhibitors of poly (ADP-ribose) polymerase (PARP) have shown considerable promise in the treatment of homologous recombination (HR)-defective tumors, such as BRCA1- and BRCA2-deficient breast and ovarian cancers. We previously reported that mantle cell lymphoma cells with deficiency in ataxia telangiectasia mutated (ATM) are sensitive to PARP-1 inhibitors in vitro and in vivo. Here, we report that PARP inhibitors can potentially target ATM deficiency arising in a solid malignancy. We show that ATM protein expression varies between gastric cancer cell lines, with NUGC4 having significantly reduced protein levels. Significant correlation was found between ATM protein expression and sensitivity to the PARP inhibitor olaparib, with NUGC4 being the most sensitive. Moreover, reducing ATM kinase activity using a small-molecule inhibitor (KU55933) or shRNA-mediated depletion of ATM protein enhanced olaparib sensitivity in gastric cancer cell lines with depletion or inactivation of p53. Our results demonstrate that ATM is a potential predictive biomarker for PARP-1 inhibitor activity in gastric cancer harboring disruption of p53, and that combined inhibition of ATM and PARP-1 is a rational strategy for expanding the utility of PARP-1 inhibitors to gastric cancer with p53 disruption. © 2014 Landes Bioscience.
  • Management of systolic blood pressure after endoscopic submucosal dissection is crucial for prevention of post-ESD gastric bleeding, Masahide Ebi, Takaya Shimura, Takaya Shimura, Takaya Shimura, Hirotaka Nishiwaki, Mamoru Tanaka, Hironobu Tsukamoto, Keiji Ozeki, Takeshi Sawada, Tsutomu Mizoshita, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Hiromi Kataoka, Takashi Joh, European Journal of Gastroenterology and Hepatology, 26,   2014年01月01日, Objective: Endoscopic submucosal dissection (ESD) is a useful technique for early gastric neoplasms without lymph node metastasis. However, a critical complication is unpredictable post-ESD bleeding. Some risk factors for post-ESD bleeding have been reported previously, although those risk factors have not directly contributed toward prevention of post-ESD bleeding. Materials and Methods: We retrospectively identified 186 gastric neoplasms in 183 consecutive patients treated with ESD from 2005 to 2012 at Nagoya City University Hospital, and divided them into two groups on the basis of the presence or absence of post-ESD bleeding. Results: Of the 186 lesions, eight lesions (4.2%) developed post-ESD bleeding. Univariate analysis identified hypertension (38.8% in nonbleeding vs. 87.5% in bleeding; P=0.009) and depressed-type tumors (26.4% in nonbleeding vs. 62.5% in bleeding; P=0.040) as significantly related to the incidence of post-ESD bleeding. On multivariate analysis, hypertension (odds ratio, 11.55; 95% confidence interval, 1.20-111.66; P=0.034) and depressed-type tumors (odds ratio, 5.36; 95% confidence interval, 1.12-25.73; P=0.036) were independent risk factors for post-ESD bleeding. Systolic blood pressure (SBP) after ESD was significantly higher in the post-ESD bleeding group than in the post-ESD non-bleeding group (P=0.021), with the comorbidity of hypertension significantly correlating with SBP after ESD (ρ=0.332, P<0.001). Conclusion: Control of SBP after ESD is important for the prevention of post-ESD bleeding because hypertension as a comorbidity, which is associated positively with SBP after ESD, is a significant risk factor for post-ESD bleeding. © Lippincott Williams and Wilkins.
  • Antitumor effects in gastrointestinal stromal tumors using photodynamic therapy with a novel glucose-conjugated chlorin, Mamoru Tanaka, Hiromi Kataoka, Shigenobu Yano, Shigenobu Yano, Hiromi Ohi, Kazuhiro Moriwaki, Haruo Akashi, Takahiro Taguchi, Noriyuki Hayashi, Shingo Hamano, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Takashi Joh, Molecular Cancer Therapeutics, 13,   2014年01月01日, Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Except for surgical resection, no effective treatment strategies have been established. Photodynamic therapy (PDT) consists of intravenous administration of a photosensitizer, activated by a specific wavelength of light, which produces reactive oxygen species that directly kill tumor cells. We analyzed the efficacy of PDT using a newly developed photosensitizer, 5,10,15,20-tetrakis [4-[β-D-glucopyranosylthio- 2,3,5,6-tetrafluorophenyl]- 2,3,[methano[N-methyl] iminomethano] chlorin(H2TFPC-SGlc), for the GISTtreatment. Various photosensitizers were administered in vitro to GIST (GIST-T1) and fibroblast (WI-38) cells, followed by irradiation, after which cell death was compared. We additionally established xenograft mouse models with GIST-T1 tumors and examined the accumulation and antitumor effects of these photosensitizers in vivo. In vitro, the expression of the glucose transportersGLUT1,GLUT3,andGLUT4,the cellular uptake ofH2TFPC-SGlc,and apoptosis mediated by PDT withH2TFPC-SGlc were significantly higher in GIST-T1 than in WI-38 cells. In vivo, H2TFPC-SGlc accumulation was higher in xenograft tumors of GIST-T1 cells than in the adjacent normal tissue, and tumor growth was significantly suppressed following PDT. PDT with novel H2TFPC-SGlc is potentially useful for clinical applications about the treatment of GIST. Mol Cancer Ther; 13(4); 767-75. © 2014 AACR.
  • Therapeutic effects of biobran, modified arabinoxylan rice bran, in improving symptoms of diarrhea predominant or mixed type irritable bowel syndrome: A pilot, randomized controlled study, Takeshi Kamiya, Michiko Shikano, Mamoru Tanaka, Keiji Ozeki, Masahide Ebi, Takahito Katano, Shingo Hamano, Hirotaka Nishiwaki, Hironobu Tsukamoto, Tsutomu Mizoshita, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Hiromi Kataoka, Noriaki Okuda, Takashi Joh, Evidence-based Complementary and Alternative Medicine, 2014,   2014年01月01日, © 2014 Takeshi Kamiya et al. Background. Recently, it was revealed that low grade mucosal inflammation and/or immune imbalance of the lower digestive tract is one of the mechanisms involved in symptom generation in patients with irritable bowel syndrome (IBS). Biobran, arabinoxylan compound derived from rice bran, has been reported to have several biological actions such as anti-inflammatory and immune modulatory effects. So we investigated the therapeutic effects of Biobran in patients with IBS. Method. Forty patients with diarrhea predominant or mixed type IBS were randomly assigned to either a Biobran group for treatment with Biobran or a placebo group. Therapeutic efficacy and IBS symptoms were assessed subjectively by the patients after 4 weeks of administration. Results. The global assessment was effective in 63.2% of the Biobran group and in 30% of the placebo group (P < 0.05, Biobran group versus placebo group). Biobran group showed a significant decrease in the score of diarrhea and constipation and in CRP value. However, no significant changes were observed in the placebo group. Conclusion. The administration of Biobran improved IBS symptoms. It is likely that anti-inflammatory and/or immune modulatory effects of Biobran might be useful in IBS patients.
  • Adalimumab treatment in biologically naïve Crohn's disease: Relationship with ectopic MUC5AC expression and endoscopic improvement, Tsutomu Mizoshita, Satoshi Tanida, Hironobu Tsukamoto, Keiji Ozeki, Takahito Katano, Hirotaka Nishiwaki, Masahide Ebi, Yoshinori Mori, Eiji Kubota, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Gastroenterology Research and Practice, 2014,   2014年01月01日, Background. Adalimumab (ADA) is effective for patients with Crohn's disease (CD). However, there have been few reports on ADA therapy with respect to its relationship with pathologic findings and drug efficacy in biologically naïve CD cases. Methods. Fifteen patients with active biologically naïve CD were treated with ADA. We examined them clinically and pathologically with ectopic MUC5AC expression in the lesions before and after 12 and 52 weeks of ADA therapy, retrospectively. Results. Both mean CD activity index scores and serum C-reactive protein values were significantly lower after ADA therapy (P < 0.001). In the MUC5AC negative group, all cases exhibited clinical remission (CR) and endoscopic improvement at 52 weeks. In MUC5AC positive groups, loss of MUC5AC expression was detected in cases having CR and endoscopic improvement at 52 weeks, while remnant ectopic MUC5AC expression was observed in those exhibiting no endoscopic improvement and flare up after 52 weeks. Conclusions. ADA leads to CR and endoscopic improvement in biologically naïve CD cases. In addition, ectopic MUC5AC expression may be a predictive marker of flare up and endoscopic improvement in the intestines of CD patients. © 2014 Tsutomu Mizoshita et al.
  • Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53, Chris T. Williamson, Chris T. Williamson, Chris T. Williamson, Eiji Kubota, Eiji Kubota, Jeffrey D. Hamill, Alexander Klimowicz, Alexander Klimowicz, Alexander Klimowicz, Ruiqiong Ye, Ruiqiong Ye, Huong Muzik, Huong Muzik, Michelle Dean, Michelle Dean, Michelle Dean, Liren Tu, David Gilley, Anthony M. Magliocco, Anthony M. Magliocco, Anthony M. Magliocco, Anthony M. Magliocco, Anthony M. Magliocco, Bruce C. Mckay, D. Gwyn Bebb, D. Gwyn Bebb, D. Gwyn Bebb, Susan P. Lees-Miller, Susan P. Lees-Miller, Susan P. Lees-Miller, EMBO Molecular Medicine, 4,   2012年06月01日, Poly-ADP ribose polymerase (PARP) inhibitors have shown promise in the treatment of human malignancies characterized by deficiencies in the DNA damage repair proteins BRCA1 and BRCA2 and preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting ataxia-telangiectasia mutated (ATM)-deficient tumours. Here, we show that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone. In ATM-deficient MCL cells, olaparib induced DNA-PK-dependent phosphorylation and stabilization of p53 as well as expression of p53-responsive cell cycle checkpoint regulators, and inhibition of DNA-PK reduced the toxicity of olaparib in ATM-deficient MCL cells. Thus, both DNA-PK and p53 regulate the response of ATM-deficient MCL cells to olaparib. In addition, small molecule inhibition of both ATM and PARP was cytotoxic in normal human fibroblasts with disruption of p53, implying that the combination of ATM and PARP inhibitors may have utility in targeting p53-deficient malignancies. © 2012 EMBO Molecular Medicine.
  • Effects of transglucosidase on diabetes, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled trial, M. Sasaki, K. Imaeda, N. Okayama, T. Mizuno, H. Kataoka, T. Kamiya, E. Kubota, N. Ogasawara, Y. Funaki, M. Mizuno, A. Iida, C. Goto, S. Koikeda, K. Kasugai, T. Joh, Diabetes, Obesity and Metabolism, 14,   2012年04月01日, In this 12-week, randomized, double-blind, placebo-controlled trial, the efficacy and safety of transglucosidase (TGD) were compared with placebo in patients with type 2 diabetes mellitus (T2DM). At 12 weeks, TGD 300 mg/day and TGD 900 mg/day significantly reduced HbA1c (0.18 and 0.21%) and insulin concentration (19.4 and 25.0 pmol/l), respectively, vs. placebo. TGD 300 mg/day and TGD 900 mg/day also significantly reduced low-density lipoprotein cholesterol (0.22 and 0.17 mmol/l, respectively). TGD 900 mg/day significantly reduced triglyceride by 0.24 mmol/l and diastolic blood pressure by 8 mmHg. Placebo was associated with a significant increase from baseline in body mass index, alanine aminotransferase and aspartate aminotransferase (0.17 kg/m2, 3 and 2 U/l, respectively), whereas TGD was not. TGD 300 mg/day significantly increased high-molecular-weight adiponectin by 0.6 μg/ml. Adverse events did not differ significantly between the groups. TGD resulted in lowering of HbA1c and blood insulin level and improvements in metabolic and cardiovascular risk factors in T2DM. © 2011 Blackwell Publishing Ltd.
  • Efficacy of twice-daily rabeprazole for reflux esophagitis patients refractory to standard once-daily administration of PPI: The Japan-based TWICE study, Yoshikazu Kinoshita, Michio Hongo, Shinya Mitsui, Takeshi Hagiwara, Takeaki Kobayashi, Gakuyo Karasawa, Yukinari Yoshida, Gen Tominaga, Masafumi Komatsu, Harufumi Oizumi, Tadayuki Igarashi, Toshiro Kamoshida, Hironori Masuyama, Motoyasu Kusano, Osamu Kawamura, Yasuyuki Shimoyama, Kazuyoshi Watanabe, Akira Matsukura, Akitaka Takamori, Hideki Hamashima, Kazuharu Misaka, Shin Tsunomiya, Junko Kikuchi, Atsushi Sano, Takayoshi Nishino, Keiko Shiratori, Naomi Uemura, Junichi Akiyama, Naoyoshi Nagata, Keita Sasajima, Katsuhiko Iwakiri, Katsutoshi Yoshida, Jun Miwa, Yasushi Kuyama, Tomofumi Murakami, Shoichi Suemori, Seiji Otsuka, Kuniharu Akita, Masaru Shimizu, Yasufumi Ito, Noriyoshi Yamakita, Toshihiro Murai, Tadashi Kitamura, Takahisa Furuta, Masayoshi Kajimura, Naohito Shirai, Yasuo Takeuchi, Tomohiko Wada, Takahiro Okazaki, Hiroyuki Kubota, Muneji Morishita, Yasuhiko Maruyama, Yasumasa Niwa, Takafumi Ando, Takashi Joh, Makoto Sasaki, Takeshi Kamiya, Tsuneya Wada, Hiromi Kataoka, Naotaka Ogasawara, Eiji Kubota, Satoshi Tanida, Kunio Kasugai, Yasushi Funaki, Shigeki Koyama, Kenjiro Yasuda, Norimasa Yoshida, Takama Maekawa, Yasuhiro Fujiwara, Shujiro Yazumi, Kiyoshi Ashida, Yasuki Habu, Hiroshi Morikawa, Hiroto Miwa, Eijiro Hayashi, Naohisa Hashimoto, Hideyuki Hirakawa, Kazuyo Fujimura, Tomoo Fujisawa, Kazuhiko Inoue, Kyoichi Adachi, Kenji Furuta, Tomonori Imaoka, Yoichi Miyaoka, Yoshinori Fujimura, Akira Tari, Shinichiro Obata, Toyokazu Kawano, Tomoki Inaba, Shuji Inoue, Nobutoshi Kuniyoshi, Hiroto Kumemura, Toshiyuki Matsui, Yasuhiro Takaki, Kyota Higashi, Ryuichiro Maekawa, Hirofumi Fukushima, Shinichi Ogata, Kazuma Fujimoto, Hiroyuki Sakata, American Journal of Gastroenterology, 107,   2012年04月01日, OBJECTIVES: Approximately 10% of patients with reflux esophagitis (RE) are not cured with the standard 8-week q.d. regimen with a proton pump inhibitor (PPI). Thus, b.i.d. dosing is often used in refractory RE (rRE) patients, although there has been no report of endoscopically confirmed healing with b.i.d. dosing of PPIs. This study aimed to assess the efficacy and safety of 8-week therapy with rabeprazole (RPZ) sodium at 20 mg b.i.d. or 10 mg b.i.d. as compared with RPZ at 20 mg q.d. in patients with RE refractory to the standard PPI regimen in Japan. METHODS: Endoscopically confirmed rRE patients (Los Angeles grade A-D) who had received a standard PPI regimen for at least 8 weeks were randomized in a double-blind manner into groups receiving RPZ at 20 and 10 mg b.i.d. or 20 mg q.d. (control) daily for up to 8 weeks. The primary efficacy endpoint was the rate of endoscopically confirmed healing after week 8. RESULTS: A total of 337 rRE patients treated at 71 sites were randomized. The rate of endoscopically confirmed healing after 8 weeks was significantly higher in those who received RPZ at 20 mg b.i.d. (77.0%, P=0.003) and 10 mg b.i.d. (78.4%, P=0.001) as compared with 20 mg q.d. (58.8%), and the rates of resolution of heartburn after week 8 were 80.0%, 74.0%, and 56.4%, respectively. All treatment regimens were well tolerated. CONCLUSIONS: Regimens of RPZ at 20 and 10 mg b.i.d. for 8 weeks were more effective than 20 mg q.d. with regard to endoscopically confirmed healing and symptom resolution of RE refractory to a standard PPI regimen. © 2012 by the American College of Gastroenterology.
  • ERas enhances resistance to CPT-11 in gastric cancer, Eiji Kubota, Hiromi Kataoka, Mamoru Tanaka, Yasuyuki Okamoto, Masahide Ebi, Yoshikazu Hirata, Kenji Murakami, Tsutomu Mizoshita, Takaya Shimura, Oshinori Mori, Satoshi Tanida, Takeshi Kamiya, Mineyoshi Aoyama, Kiyofumi Asai, Takashi Joh, Anticancer Research, 31,   2011年10月01日, Background/Aim: We have reported that embryonic stem cell-expressed Ras (ERas) is expressed in human gastric cancer and is associated with its tumorigenicity. Here, we asked whether ERas plays a role in resistance to chemotherapy in gastric cancer. Materials and Methods: To assess the cytotoxicity of chemotherapeutic agents, ERas-overexpressing human gastric cancer GCIY cells were exposed to anticancer agents, including CPT-11 and inhibitor of mammalian target of rapamycin (mTOR). We also investigated the mechanisms by which ERas induces chemoresistance. Results: ERas-overexpressing clones were significantly more resistant to CPT-11 than were the control (p<0.001). Administration of rapamycin was significantly cytotoxic to the ERas-overexpressing clones compared with the control (p<0.01). Electrophoresis mobility shift assay revealed that ERas enhanced nuclear factor (NF)-κB activity. PCR array demonstrated that ERas up-regulated several multidrug efflux transporter genes, including ABCG2. Conclusion: ERas induces chemoresistance to CPT-11 via activation of phosphatidylinositol-3 kinase-protein kinase β mTOR pathway and NF-κB, and consequently results in upregulation of ABCG2.
  • Metastatic colorectal cancer with severe liver dysfunction successfully treated using FOLFOX therapy, Takaya Shimura, Hiromi Kataoka, Yoshikazu Hirata, Takashi Mizushima, Kenji Murakami, Motoshi Mabuchi, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Takeshi Kamiya, Takashi Joh, Journal of Gastrointestinal Cancer, 42,   2011年03月01日, Introduction: The liver is the most frequent site of metastases from colorectal cancer (CRC), and extensive liver metastases often cause severe secondary liver dysfunction. However, whether chemotherapy for metastatic CRC with severe liver dysfunction offers any clinical benefit is unclear since patients in this setting are typically excluded from clinical trials. Discussion: We report herein a case of metastatic sigmoid colon cancer with severe liver dysfunction that was successfully treated using infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). FOLFOX was effective and well tolerated in the present case, and subsequent addition of bevacizumab to FOLFOX after disease progression was similarly feasible. © 2010 Springer Science+Business Media, LLC.
  • Cardiovascular tolerance and autonomic nervous responses in unsedated upper gastrointestinal small-caliber endoscopy: A comparison between transnasal and peroral procedures with newly developed mouthpiece, Hiromi Kataoka, Junichiro Hayano, Takashi Mizushima, Mamoru Tanaka, Eiji Kubota, Takaya Shimura, Tsutomu Mizoshita, Satoshi Tanida, Takeshi Kamiya, Shunsuke Nojiri, Seiji Mukai, Kiyoshi Mizuno, Takashi Joh, Digestive Endoscopy, 23,   2011年01月01日, Background: Transnasal esophagogastroduodenoscopy (EGD) with small-caliber endoscopy appears to be less stressful to the cardiovascular system and has good patient tolerance. ENDO LEADER, a newly developed mouthpiece for peroral EGD with small-caliber endoscopy, is expected to reduce patient stress. We compared the patient acceptance, cardiovascular tolerance and autonomic nervous responses between transnasal EGD and peroral EGD with ENDO LEADER. Patients and Methods: A total of 130 patients (transnasal group, 77; peroral group, 53) were enrolled. Pulse rate (P), blood pressure (BP), and peripheral blood oxygen saturation (SpO2) were monitored. Acceptance of EGD was also assessed. Autonomic nervous responses were evaluated through analysis of heart rate variability using amplitude of the high-frequency component (HF) and low-frequency-to-high- frequency power ratio (LF/HF) as indices of cardiac vagal activity and sympathetic activity, respectively. Results: Analysis of patient acceptance showed no differences between the two groups, except with regard to nasal pain. Increases in BP and P between before and during EGD examination were significantly higher in the peroral group. Although throat pain and overall tolerance scores were significantly correlated with ΔBP and ΔP, no correlations with nasal pain score were noted. Heart rate variability analysis revealed that heart rate increased significantly in the peroral group, but there were no differences in ΔHF or ΔLF/HF between the two groups. Conclusions: Patient acceptance was not significantly different between the transnasal and peroral with ENDO LEADER groups; however, transnasal EGD appears to be less stressful to the sympathetic nervous system, leading to smaller elevations in BP, P and heart rate. © 2010 Japan Gastroenterological Endoscopy Society.
  • TGFβ induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells, Masahide Ebi, Hiromi Kataoka, Takaya Shimura, Eiji Kubota, Yoshikazu Hirata, Takashi Mizushima, Tsutomu Mizoshita, Mamoru Tanaka, Motoshi Mabuchi, Hironobu Tsukamoto, Satoshi Tanida, Takeshi Kamiya, Shigeki Higashiyama, Takashi Joh, Biochemical and Biophysical Research Communications, 402,   2010年11月19日, Background and aims: Transforming growth factor-beta (TGFβ) is known to potently inhibit cell growth. Loss of responsiveness to TGFβ inhibition on cell growth is a hallmark of many types of cancer, yet its mechanism is not fully understood. Membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) ectodomain is cleaved by a disintegrin and metalloproteinase (ADAM) members and is implicated in epidermal growth factor receptor (EGFR) transactivation. Recently, nuclear translocation of the C-terminal fragment (CTF) of pro-HB-EGF was found to induce cell growth. We investigated the association between TGFβ and HB-EGF signal transduction via ADAM activation. Materials and methods: The CCK-8 assay in two gastric cancer cell lines was used to determine the effect for cell growth by TGFβ. The effect of two ADAM inhibitors was also evaluated. Induction of EGFR phosphorylation by TGFβ was analyzed and the effect of the ADAM inhibitors was also examined. Nuclear translocation of HB-EGF-CTF by shedding through ADAM activated by TGFβ was also analyzed. EGFR transactivation, HB-EGF-CTF nuclear translocation, and cell growth were examined under the condition of ADAM17 knockdown. Result: TGFβ-induced EGFR phosphorylation of which ADAM inhibitors were able to inhibit. TGFβ induced shedding of proHB-EGF allowing HB-EGF-CTF to translocate to the nucleus. ADAM inhibitors blocked this nuclear translocation. TGFβ enhanced gastric cancer cell growth and ADAM inhibitors suppressed this effect. EGFR phosphorylation, HB-EGF-CTF nuclear translocation, and cell growth were suppressed in ADAM17 knockdown cells. Conclusion: HB-EGF-CTF nuclear translocation and EGFR transactivation from proHB-EGF shedding mediated by ADAM17 activated by TGFβ might be an important pathway of gastric cancer cell proliferation by TGFβ. © 2010 Elsevier Inc.
  • Resistance to chemotherapeutic agents and promotion of transforming activity mediated by embryonic stem cell-expressed Ras (ERas) signal in neuroblastoma cells, Mineyoshi Aoyama, Hiromi Kataoka, Eiji Kubota, Toyohiro Tada, Kiyofumi Asai, International Journal of Oncology, 37,   2010年10月01日, Neuroblastoma is a common childhood tumor derived from neural crest precursor cells. In the present study, we investigated the expression and function of embryonic stem cell-expressed Ras (ERas), a novel Ras family protein previously reported as the specific expression gene in embryonic stem cells (ES cells), in neuroblastoma cell lines. Our results showed that the expressions of ERas were detected in neuroblastoma cell lines by RT-PCR and Western blotting. Therefore, we transfected a full length ERas expression vector into the neuroblastoma cell line SH-SY5Y, which has weak endogenous expression of ERas, and obtained clones with higher levels of expression. Overexpression of ERas did not increase the growth rate of the ERas transfectants but promoted their transforming activity. The ERas transfectants were more resistant to all the chemotherapy agents than the parental cell line. The ability of ERas to rescue cells from the toxic effect of chemotherapeutic agents was inhibited by the phosphatidylinositol 3′-kinase (PI3K) inhibitor PD294002. These results show that the ERas/PI3K pathway may provide resistance to chemotherapy and promote transforming activity in neuroblastoma.
  • Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt domain transcription factor 3 (RUNX3) in response to TGF-β signal transduction, Motoshi Mabuchi, Motoshi Mabuchi, Hiromi Kataoka, Yutaka Miura, Tae Sun Kim, Makoto Kawaguchi, Masahide Ebi, Mamoru Tanaka, Yoshinori Mori, Eiji Kubota, Takashi Mizushima, Takaya Shimura, Tsutomu Mizoshita, Satoshi Tanida, Takeshi Kamiya, Kiyofumi Asai, Takashi Joh, Biochemical and Biophysical Research Communications, 398,   2010年07月01日, Background and aims: AT motif binding factor 1 (ATBF1), a homeotic transcription factor, was identified as a tumor suppressor, and loss of heterozygosity at ATBF1 locus occurs frequently in gastric cancers. We previously showed that ATBF1 expression inversely correlated with the malignant character of gastric cancer and that ATBF1 enhanced the promoter activity of p21Waf1/Cip1. We also found that ATBF1 moves between cytoplasm and nucleus, but the precise mechanism of translocation is unknown. In this study, we investigated the mechanism of ATBF1 translocation to the nucleus with the runt domain transcription factor 3 (RUNX3) in cooperation with TGF-β signal transduction. Materials and methods: To analyze the expression of ATBF1 and RUNX3 in gastric cancer cells, we performed immunohistochemistry on 98 resected gastric cancer tissue samples and scored the nuclear staining intensity as grade 0 to grade 5. Co-immunoprecipitation (co-IP) of ATBF1 and RUNX3 was performed. Dual luciferase assays were performed by transfecting ATBF1 and RUNX3 with a p21Waf1/Cip1reporter vector. To investigate the nuclear translocation of endogenous ATBF1 and RUNX3 in response to TGF-β signal, we examined the subcellular localization of ATBF1 and RUNX3 in gastric cancer cells treated with recombinant TGF-β1 using confocal laser scanning microscopy. Results: Strong immunohistochemical nuclear staining of ATBF1 was observed in 37 (37.8%) of the gastric cancer tissue samples, and RUNX3 nuclear staining was observed in 15 (15.3%). There was a statistically significant correlation between ATBF1 and RUNX3 nuclear localization (rs=0.433, p<0.001). Co-IP revealed a physical association between ATBF1 and RUNX3. ATBF1 and RUNX3 up-regulated p21Waf1/Cip1promoter activity synergistically. In SNU16 gastric cancer cells, ATBF1 and RUNX3 were cytoplasmic before TGF-β1 stimulation, but after 24h of TGF-β1 stimulation, endogenous ATBF1 and RUNX3 translocated to the nucleus. Conclusion: ATBF1 associates with RUNX3 and translocates to the nucleus in response to TGF-β signal transduction and might function in the nucleus as tumor suppressor and transcriptional regulator. © 2010 Elsevier Inc.
  • Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis, Takashi Mizushima, Makoto Sasaki, Tomoaki Ando, Tsuneya Wada, Mamoru Tanaka, Yasuyuki Okamoto, Masahide Ebi, Yosikazu Hirata, Kenji Murakami, Tsutomu Mizoshita, Takaya Shimura, Eiji Kubota, Naotaka Ogasawara, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, J. S. Alexander, Takashi Joh, American Journal of Physiology - Gastrointestinal and Liver Physiology, 298,   2010年02月01日, Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to α4β7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R-/-) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-α, but did not inhibit phosphorylation of p38 MAPK or of IκB that modulate MAdCAM-1 expression. However, NF-κB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R-/- than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R-/- than in wild-type mice. These results suggest that AT1R regulates the expression of MAd-CAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-κB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1. Copyright © 2010 the American Physiological Society.
  • Role of ES cell-expressed Ras (ERas) in tumorigenicity of gastric cancer, Eiji Kubota, Hiromi Kataoka, Mineyoshi Aoyama, Tsutomu Mizoshita, Yoshinori Mori, Takaya Shimura, Mamoru Tanaka, Makoto Sasaki, Satoru Takahashi, Kiyofumi Asai, Takashi Joh, American Journal of Pathology, 177,   2010年01月01日, ERas, a unique member of the Ras family, was initially found only in embryonic stem (ES) cells, where it plays a crucial role in the transformation of transplanted ES cells to teratomas. ERas is involved in ES cell survival, and unlike other Ras family members, is constitutively active without any mutations. The aim of this study was to investigate the expression and role of ERas in human gastric cancer. To test whether ERas played a significant role in human cancer cells, we examined its expression and function in gastric cancer. ERas was expressed in gastric cancer cell lines at different levels. Induction of ERas expression activated the phosphatidylinositol 3 kinase (PI3K)/Akt axis and then enhanced anchorage-independent growth and ERas knockdown by siRNA suppressed cell invasion. Immunohistochemical analyses revealed that ERas was expressed in 38.7% (55/142) of human gastric carcinoma tissues, and its expression was significantly associated with metastasis to the liver (P < 0.0001) and lymph nodes (P < 0.05). ERas up-regulated transcription regulatory factors including ZFHX1A, ZFHX1B, and TCF3, which repress E-cadherin. These data suggest that ERas is activated in a significant population of gastric cancer, where it may play a crucial role in gastric cancer cell survival and metastases to liver via down-regulation of E-cadherin. Copyright © American Society for Investigative Pathology.
  • An endocrine cell carcinoma with gastric-and-intestinal mixed phenotype adenocarcinoma component in the stomach: Case report, Tsutomu Mizoshita, Hiromi Kataoka, Eiji Kubota, Takaya Shimura, Yoshinori Mori, Tsuneya Wada, Naotaka Ogasawara, Makoto Sasaki, Takeshi Kamiya, Masaki Sakamoto, Yoshimi Akamo, Takashi Joh, Digestive Endoscopy, 21,   2009年10月01日, A 77-year-old man complained of bodyweight loss, and a Borrmann 3 type lesion was observed endoscopically in the anterior wall of angular region of the stomach. The endocrine cell carcinoma (ECC) having the cytoplasmic staining of chromogranin A (CgA) was detected pathologically in the biopsy samples. The patient underwent distal gastrectomy plus systemic lymph node (LN) dissection (D2 LN dissection), and pathological examination revealed ECC invading the subserosa, and no LN metastasis (pT2N0M0). None of the gastric and intestinal endocrine cell marker expression was apparent in the ECC cells. The lesion also contained a moderately differentiated type tubular adenocarcinoma component, which was judged to be gastric-and-intestinal mixed (GI type) phenotype, using gastric and intestinal exocrine cell markers. After the surgery, he left the hospital and started oral doxifluridine (600 mg/day). The patient now (March 2008, about 19 months since the surgery) continues this chemotherapy with no recurrence. In conclusion, we experienced ECC with a GI type adenocarcinoma component. The ECC cases with the GI type adenocarcinoma component may have a relatively good prognosis, being similar to the results of advanced gastric cancers from the viewpoint of gastric and intestinal phenotypic expression. © 2009 Japan Gastroenterological Endoscopy Society.
  • Gastric schwannoma with adjacent external progression harbored aberrant nf2 gene, Naotaka Ogasawara, Makoto Sasaki, Makoto Sasaki, Hideyuki Ishiguro, Yukimi Itoh, Syunsuke Nojiri, Eiji Kubota, Tsuneya Wada, Hiromi Kataoka, Yoshiyuki Kuwabara, Talkashi Joh, Digestive Endoscopy, 21,   2009年07月01日, Gastric schwannomas are rare benign mesenchymal tumors. We describe a schwannoma of gastric origin with adjacent external progression. Sections showed a spindle cell tumor arranged in interlaced bundles and fascicles that was S-100 and CD34 positive but c-KIT protein negative. Histology and immunohistochemistry revealed the typical appearance of a gastric schwannoma. Genetic evaluation revealed that the tumor harbored a point mutation in exon 6 of the tumor suppressor neurofibromatosis 2 (NF2) gene, which resulted in an amino acid substitution of NF2 protein, and no mutation in exon 4b of the NF1 gene. In conclusion, we identified a rare mutation of the NF2 gene in gastric schwannoma. A diagnosis can only be definitive when based on histological and immunohistochemical findings. Digestive tract schwannomas are rare mesenchymal tumors that are differentiated from gastrointestinal stromal tumors by the absence of KIT protein. Follow up suggested that complete resection is an effective long-term treatment strategy. © 2009 Japan Gastroenterological Endoscopy Society.
  • Combination chemotherapy with cisplatin and gemcitabine in malignant peritoneal mesothelioma, Satoshi Tanida, Hiromi Kataoka, Eiji Kubota, Yoshinori Mori, Makoto Sasaki, Naotaka Ogasawara, Tsuneya Wada, Tsutomu Mizoshita, Takaya Shimura, Kenji Murakami, Takashi Mizushima, Yoshikazu Hirata, Yasuyuki Okamoto, Motoshi Mabuchi, Masahide Ebi, Mamoru Tanaka, Takeshi Kamiya, Satoru Takahashi, Takashi Joh, International Journal of Clinical Oncology, 14,   2009年06月01日, Malignant peritoneal mesothelioma is a rare neoplasm with a rapidly fatal course. The response of this disease to treatment is poor because it tends to be advanced at diagnosis and tends to have inherent resistance to chemotherapeutic treatment. We describe three patients with malignant peritoneal mesothelioma who received combination chemotherapy with cisplatin and gemcitabine. After a histopathological diagnosis of epithelial-type malignant peritoneal mesothelioma, all patients underwent systemic chemotherapy because of the advanced disease stage. Moreover, one patient would have been at high risk of cardiac events, because of congenital heart malformation if complete surgical resection had been performed. This chemotherapy achieved a partial response in two patients, but had no effect in one. Combination chemotherapy with cisplatin and gemcitabine may prove to be one of the recommended treatments for patients with malignant peritoneal mesothelioma in the near future. © 2009 Japan Society of Clinical Oncology.
  • Gastric-and-intestinal mixed endocrine cell phenotypic expression of carcinoid tumors in the rectum, Yoshikazu Hirata, Tsutomo Mizoshita, Takashi Mizushima, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Tsuneya Wada, Naotaka Ogasawara, Satoshi Tanida, Hiromi Kataoka, Makoto Sasaki, Takeshi Kamiya, Tetsuya Tsukamoto, Masae Tatematsu, Takashi Joh, Oncology Reports, 21,   2009年04月23日, We have previously demonstrated that gastric and intestinal endocrine cell (End-cell) marker expression is important for assessment of the histogenesis of endocrine cell tumors. However, the End-cell phenotypes of carcinoid tumors in the rectum remain largely unclear. We therefore examined marker expression of rectal carcinoid tumors. We evaluated 20 rectal carcinoid tumors (as well as 8 from the stomach for comparison) phenotypically, using gastrin, gastric inhibitory polypeptide (GIP) and glucagons-like peptide-1 (GLP-1) as End-cell markers. Rectal carcinoid tumors were divided into 3 endocrine-gastric (e-G), 16 endocrine-gastric-and-intestinal mixed (e-GI), 1 endocrine-intestinal (e-I), and 0 endocrine-null (e-N) types, thus 19 (e-G+ e-GI types, 95%) had gastric phenotypic expression, while 17 (e-GI+ e-I types, 85%) harbored intestinal elements. Stomach carcinoid tumors were classified as 6 e-G and 2 e-N types, respectively. In conclusion, most rectal carcinoid tumors exhibited the e-GI type, suggesting the importance of gastric End-cell marker expression for histogenesis of the rectal carcinoid tumors. Further studies of pathological and biological analyses are needed to clarify the histogenesis of the carcinoid tumors.
  • BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers, Y. Hirata, N. Ogasawara, M. Sasaki, T. Mizushima, T. Shimura, T. Mizoshita, Y. Mori, E. Kubota, T. Wada, S. Tanida, H. Kataoka, T. Kamiya, S. Higashiyama, T. Joh, British Journal of Cancer, 100,   2009年04月21日, BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT-PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression. © 2009 Cancer Research UK.
  • Lentinan with S-i and paclitaxel for gastric cancer chemotherapy improve patient quality of life, Hiromi Kataoka, Hiromi Kataoka, Takaya Shimura, Tsutomu Mizoshita, Eiji Kubota, Yoshinori Moni, Takashi Mizushima, Tsuneya Wada, Naotaka Ogasawara, Satoshi Tanida, Makoto Sasaki, Shozo Togawa, Hitoshi Sano, Yoshikazu Hirata, Yoshikazu Hirata, Masahiro Ikai, Hisato Mochizuki, Kyoji Seno, Sachie Itoh, Takashi Kawai, Takashi Joh, Hepato-Gastroenterology, 56,   2009年03月01日, Background/Aims: Lentinan (I241), a purified 3- glucan, is a biological and immunological modifier and has been used as an anticancer drug in combination with 5-fluorouracil for gastric cancer in Japan. In this prospective randomized study, we evaluated the effects of LNT combination with regard to quality of life (QOL) and LNT binding ratio in monocytes. Methodology: Twenty patients were evaluated for 12 weeks. One cycle was 3weeks and S-i (dayi-i4) and Pacitaxel (daysi and 8) were administered. LNT was used once a week (days 1, 8 and 15) and it was used for all 12 weeks in the LNT i2-wk group and only for the last 6 weeks in the LNT 6-wk group. QOL was evaluated weekly by QOL-ACD, and binding of LNT to monocytes was measured by flow cytometry. Results: There were individual variations in the binding ratio of LNT to monocytes from 0.16% to 11.95%. Toxicity with chemotherapy was not improved in the LNT 12-wk group, however, the total QOL score was significantly elevated in the LNT 12- wk group (p = 0.018) but not in the LNT 6-wk group. Conclusion: LNT combination from the beginning of the chemotherapy may be an important factor for the improvement of patient QOL. © H.G.E. Update Medical Publishing SA., Athens-Stuttgart.
  • Gastric phenotypic expression and histogenesis of metachronous gastric cancers endoscopically resected, Tsutomu Mizoshita, Hiromi Kataoka, Satoshi Tanida, Makoto Sasaki, Naotaka Ogasawara, Eiji Kubota, Tsuneya Wada, Tomonori Yamada, Yoshinori Mon, Takaya Shimura, Tetsuya Tsukamoto, Masae Tatematsu, Takashi Joh, Hepato-Gastroenterology, 56,   2009年03月01日, Background/Aims: Endoscopic Resection (ER) has been performed for early gastric cancers, and metachronous gastric cancers (MGCs) were occasionally observed. Most MGCs were classified histologically as the differentiated type. However, there have been no data on the gastric and intestinal phenotypic classification of MGCs. In our previous study, Hp-infection in MG may trigger intestinalization of gastric cancers. We therefore speculate the phenotype shift in MGC lesions under Hp- chronic-infection. Methodology: We examined the 17 MGC lesions phenotypieally and histologically by using several gastric and intestinal epithelial cell markers, MUC5AC, MUC6, MUC2 and villin. Results: Most lesions (16/17) exhibited the differentiated type. In 8 first cancers, the lesions were divided phenotypically into 2 0, 4 01, 1 I, and 1 N types. In 9 second/third cancers, the lesions were divided phenotypically into 3 G, 1 01, 4 I, and 1 N types. The first lesions (6/8) had more gastric phenotypic expression compared with the second/third ones (4/9) in the MGCs, although there was no significant difference between two groups (1O.28). Conclusion: Our present data suggest the possibility that the cancer retaining G type is detected endoscopically earlier than that obtaining the intestinal phenotypic expression by the phenotypic shift, which may partially explain the MGC occurrence. © H.G.E. Update Medical Publishing.
  • Advanced stomach and pancreas cancer successfully treated with combination chemotherapy with S-1/paclitaxel/lentinan, Eiji Kubota, Hiromi Kataoka, Kazuki Hayashi, Takeshi Kamiya, Makoto Sasaki, Naotaka Ogasawara, Tomonori Yamada, Tsuneya Wada, Yoshinori Mori, Tsutomu Mizoshita, Takaya Shimura, Takashi Mizushima, Yasuyuki Okamoto, Hirotaka Ohara, Takashi Joh, Hepato-Gastroenterology, 56,   2009年01月01日, We report a case of stomach and pancreas cancers that showed marked responses to combination chemotherapy consisting of S-1, paclitaxel (PTX), and lentinan (LNT). A 67-year-old Japanese man was referred to our hospital in July 2005, diagnosed with advanced gastric cancer. Subsequent examination revealed the existence of cancers in the stomach and pancreas, with lymph nodes and peritoneal metastasis and ascites. The patient received combined chemotherapy (one course comprised 3 weeks) with S-1 (100mg/body, day1-14 followed by withdrawal for 1 week), PTX (50mg/m2, day 1 and day 8), and LNT (2 mg/m2, day 1, day 8 and day 15). After completion of 4 courses, the patient achieved partial response (PR), with complete disappearance of the primary gastric tumor and ascites. He maintained in PR for 17 months. We analyzed Th1/Th2 ratio and LNT binding rate to monocytes by flow cytometry. Combination chemotherapy with S-1/PTX/LNT can be an effective treatment for unresectable advanced gastric carcinoma. © H.G.E. Update Medical Publishing S.A., Athens-Stuttgart.
  • Feasibility of self-expandable metallic stent plus chemotherapy for metastatic gastric cancer with pyloric stenosis, Takaya Shimura, Hiromi Kataoka, Makoto Sasaki, Tomonori Yamada, Tomonori Yamada, Kazuki Hayashi, Shozo Togawa, Fumihiro Okumura, Fumihiro Okumura, Eiji Kubota, Hirotaka Ohara, Takashi Joh, Journal of Gastroenterology and Hepatology (Australia), 24,   2009年01月01日, Background and Aim: Self-expandable metallic stent placement is accepted as palliative therapy for advanced gastric cancer with gastric outlet obstruction, but data are lacking for chemotherapy after self-expandable metallic stent insertion. This study retrospectively compared results between surgery plus chemotherapy and stenting plus chemotherapy for metastatic gastric cancer with pyloric stenosis. Methods: Subjects comprised 26 patients who received chemotherapy after surgery or endoscopic stenting for metastatic gastric cancer with pyloric stenosis between April 2000 and December 2007 in four Japanese hospitals. Patients were categorized into two groups: 15 patients who received chemotherapy after surgery for pyloric stenosis (Surgery group); and 11 patients who received chemotherapy after self-expandable metallic stent placement for pyloric stenosis (Stent group). Results: Median survival time and median time to treatment failure were 284 days and 226 days in the Surgery group and 337 days and 247 days in the Stent group, respectively. No significant differences were noted between survival and time to treatment failure. No significant differences were found in median oral intake rate (Surgery, 93.1%; Stent, 93.2%) or median hospital stay rate (Surgery, 24.6%; Stent, 23.7%) during survival. Response rate was 45.5% in the Surgery group and 50% in the Stent group, with no significant difference. Likewise, no significant differences were noted between groups for frequencies of toxicity or complications. Conclusions: The present results suggest that chemotherapy after stenting is as effective and safe as chemotherapy after surgery. Stents may replace surgery in combination therapy with chemotherapy for metastatic gastric cancer with gastric outlet obstruction. © 2009 The Authors.
  • Rectal inflammatory fibroid polyp resected with endoscopic submucosal dissection, Takaya Shimura, Hiromi Kataoka, Makoto Sasaki, Eiji Kubota, Shigehiro Shiraki, Kei Matsusako, Yoshihide Nakayama, Tsutomu Mizohita, Takashi Mizushima, Takashi Joh, Internal Medicine, 47,   2008年12月01日, Inflammatory fibroid polyp (IFP) is a rare benign tumor originating from the submucosa of the gastrointestinal tract. Most are found in the stomach, with only one previous case reported in the rectum. IFPs are typically larger than 1 cm in diameter and present symptoms. Colonoscopic examination of an asymptomatic 66-year-old man revealed a small submucosal tumor, 3 mm in diameter, in the rectum. The lesion was completely resected by endoscopic submucosal dissection (ESD) and was histopathologically diagnosed as IFP. We report herein a very rare rectal IFP that could be treated and diagnosed with ESD. © 2008 The Japanese Society of Internal Medicine.
  • Gastric phenotype signet-ring cell carcinoma of the stomach with multiple bone metastases effectively treated with sequential methotrexate and 5-fluorouracil, Tsutomu Mizoshita, Hiromi Kataoka, Eiji Kubota, Yasuyuki Okamoto, Takaya Shimura, Yoshinori Mori, Tsuneya Wada, Naotaka Ogasawara, Makoto Sasaki, Takeshi Kamiya, Takashi Joh, International Journal of Clinical Oncology, 13,   2008年08月01日, A 63-year-old woman presented with an abnormal serum alkaline phosphatase (ALP) level. Computed tomography (CT) scan of the abdomen and pelvis and radioisotope (RI) examination led to a strong suspicion of systemic bone metastatic tumors, although the origin was not known. Biopsies from bone metastatic lesions in the left ilium were performed under CT scan, and signet-ring cell carcinoma cells were detected pathologically. Also, a 0-IIc-like lesion was observed endoscopically in the stomach, and signet-ring cell carcinoma cells were also detected histologically. The patient's platelet (Plt) levels were reduced and slight bleeding from the gingiva was detected when she brushed her teeth. Both the stomach and the bone metastatic lesions exhibited a gastric phenotype (G type) phenotypically. From these findings, we diagnosed the patient as having advanced (inoperable) stomach cancer with multiple bone metastases; she also exhibited disseminated intravascular coagulation (DIC). We treated her with sequential methotrexate and 5-fluorouracil (sequential MTX/5-FU) therapy after obtaining her informed consent. After six cycles of the chemotherapy, the abnormal ALP and Plt levels were alleviated. At present, she is receiving weekly sequential MTX/5-FU therapy at the outpatient oncology unit; she has been receiving the therapy for about 7 months since the detection of the bone metastases and has had a total of 17 cycles. In conclusion, sequential MTX/5-FU therapy was effective for a patient with G-type signet-ring cell carcinoma of the stomach with bone metastases, suggesting that the phenotypic classification may be one of the useful markers for prediction of the effectiveness of chemotherapy in patients with inoperable advanced stomach cancer. © 2008 Japan Society of Clinical Oncology.
  • Suppression of proHB-EGF carboxy-terminal fragment nuclear translocation: A new molecular target therapy for gastric cancer, Takaya Shimura, Hiromi Kataoka, Hiromi Kataoka, Naotaka Ogasawara, Eiji Kubota, Makoto Sasaki, Satoshi Tanida, Takashi Joh, Clinical Cancer Research, 14,   2008年06月15日, Purpose: Inactivation of epidermal growth factor (EGF) receptor (EGFR) represents a promising strategy for the development of selective therapies against epithelial cancers and has been extensively studied as a molecular target for cancer therapy. However, little attention has been paid to remnant cell-associated domains created by cleavage of EGFR ligands. The present study focused on recent findings that cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF), an EGFR ligand, induces translocation of the carboxyl-terminal fragment (CTF) of HB-EGF from the plasma membrane to the nucleus and regulates cell cycle. Experimental Design: Two gastric cancer cell lines, MKN28 and NUGC4, were used. KB-R7785, an inhibitor of proHB-EGF shedding, was used to suppress HB-EGF-CTF nuclear translocation with cetuximab, which inhibits EGFR phosphorylation. Cell growth was analyzed using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl)-2H- tetrazolium, inner salt assay, apoptosis was evaluated by assay of caspase-3 and caspase-7, and cell cycle was investigated by flow cytometry. Results: Immunofluorescence study confirmed that KB-R7785 inhibited HB-EGF-CTF nuclear translocation under conditions of proHB-EGF shedding induction by 12-O-tetradecanoylphor-bol-13-acetate in gastric cancer cells. KB-R7785 inhibited cell growth in a dose-dependent manner and high-dose KB-R7785 induced apoptosis. Moreover, KB-R7785 induced cell cycle arrest and increased sub-G 1 DNA content. KB-R7785 suppressed cyclin A and c-Myc expression. All effects of KB-R7785 were reinforced by combination with cetuximab. Conclusions: These results suggest that both inhibition of EGFR phosphorylation and inhibition of HB-EGF-CTF nuclear translocation play crucial roles in inhibitory regulation of cancer cell growth. Suppression of HB-EGF-CTF nuclear translocation might offer a new strategy for treating gastric cancer. © 2008 American Association for Cancer Research.
  • Effect of plaunotol in combination with clarithromycin against clarithromycin-resistant Helicobacter pylori in vitro and in vivo, Makoto Sasaki, Tsutomu Mizoshita, Takashi Mizushima, Harumi Inoue, Takeshi Kamiya, Hiromi Kataoka, Naotaka Ogaswara, Tsuneya Wada, Eiji Kubota, Yoshinori Mori, Takaya Shimura, Hirokazu Hirata, Kenji Ando, Yasuyuki Okamoto, Hirotaka Ohara, Haruhisa Nakao, Takashi Joh, Journal of Antimicrobial Chemotherapy, 60,   2007年11月01日, Objectives: Recently, there has been a decrease in the eradication rate of Helicobacter pylori due to the increase in antibiotic resistance of this bacterium. Plaunotol, a cytoprotective anti-ulcer agent, exhibits antibacterial activity against H. pylori. The purpose of the present study was to investigate the effect of plaunotol in combination with clarithromycin against clarithromycin-resistant H. pylori clinical isolates. Methods and results: In the chequerboard titration method, the combination of plaunotol and clarithromycin showed a synergistic effect against 67% (10/15) clarithromycin-resistant strains and an additive effect against the other strains. No indifferent and antagonistic effects were observed against any of the strains tested. In a gastritis model of Mongolian gerbils infected with clarithromycin-resistant H. pylori, the plaunotol (40 mg/kg) and clarithromycin (66.6 mg/kg) combination exhibited synergistic effects; however, neither plaunotol nor clarithromycin alone showed bactericidal effects. Conclusions: These results suggest that plaunotol may play a useful role in combination with anti- H. pylori drugs in the treatment of diseases associated with clarithromycin-resistant H. pylori. © The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
  • Endoscopic submucosal dissection is useful and safe for intramucosal gastric neoplasms in the elderly, Takaya Shimura, Takaya Shimura, T. Joh, M. Sasaki, H. Kataoka, S. Tanida, N. Ogasawara, T. Yamada, E. Kubota, T. Wada, M. Inukai, N. Yoshioka, Y. Saida, Acta Gastro-Enterologica Belgica, 70,   2007年10月01日, Background and study aims : Endoscopic submucosal dissection (ESD) has recently gained popularity for use against intramucosal gastric neoplasms in Japan, but few studies have examined whether ESD is feasible for elderly patients. This study aims are to evaluate the efficacy and safety of ESD according to age in consecutive elderly patients treated with ESD. Patients and methods : Subjects comprised 116 patients (90 men, 26 women) with 125 lesions treated using ESD from November 2002 to March 2006 at Nagoya City University Hospital and Iwata Municipal Hospital, Japan. Patients were categorized into : Group A, < 65-years-oId (n = 34) ; Group B, ≥ 65-years-oId but < 75-years-old (n = 41) ; and Group C, ≥ 75-years-old (n = 41). En bloc resection rate and treatment time were examined according to age, tumour size and location, and frequency of complications was examined according to age. Results : Rate of concomitant disease was significantly higher in Group C than in the other groups. En bloc resection rates and median treatment times were 91.4% and 80 min in Group A, 91.1% and 97 min in Group B and 86.7% and 110 min in Group C, respectively. No significant differences were noted between groups, or for en bloc resection rate and treatment time according to tumour size and location, or between groups for frequency of complications. Conclusions : ESD for gastric neoplasms is effective and safe in elderly patients, and may be positively recommended to elderly patients with intramucosal gastric neoplasms.
  • Subcellular localization of ATBF1 regulates MUC5AC transcription in gastric cancer, Yoshinori Mori, Hiromi Kataoka, Hiromi Kataoka, Yutaka Miura, Makoto Kawaguchi, Eiji Kubota, Naotaka Ogasawara, Tadayuki Oshima, Satoshi Tanida, Makoto Sasaki, Hirotaka Ohara, Tsutomu Mizoshita, Masae Tatematsu, Kiyofumi Asai, Takashi Joh, International Journal of Cancer, 121,   2007年07月15日, Human gastric epithelium has a unique mucin gene expression pattern, which becomes markedly altered in gastrointestinal disorder. This alteration in mucin expression, including the mucin MUC5AC, may be related to the development and prognosis of gastric cancers, and MUC5AC-positive gastric cancer has been reported to be poor prognosis. However, the molecular mechanism of MUC5AC transcriptional regulation has not been fully elucidated. AT motif-binding factor 1 (ATBF1) is a homeotic transcriptional regulatory factor recently identified as a tumor suppressor gene, and its subcellular localization suggests a link to cell proliferation and differentiation. We investigated the mechanism of MUC5AC transcriptional regulation by ATBF1. In 123 gastric cancer lesions, ATBF1 expressed in the nucleus significantly suppressed MUC5AC expression, as determined by immunohistochemistry. In addition, analysis of the MUC5AC promoter region revealed an AT motif-like element. This element was found to be essential for ATBF1 suppression of MUC5AC promoter activity as shown in a dual luciferase-reporter assay. Over-expressed ATBF1 also significantly suppressed endogenous MUC5AC protein expression in gastric cancer cells. Chromatin immunoprecipitation demonstrated that ATBF1 binds to the AT motif-like element in the MUC5AC promoter. These results indicate that ATBF1 in the nucleus negatively regulates the MUC5AC gene in gastric cancer by binding to an AT motif-like element in the MUC5AC promoter. © 2007 Wiley-Liss, Inc.
  • Advantages of endoscopic submucosal dissection over conventional endoscopic mucosal resection, Takaya Shimura, Makoto Sasaki, Hiromi Kataoka, Satoshi Tanida, Tadayuki Oshima, Naotaka Ogasawara, Tsuneya Wada, Eiji Kubota, Tomonori Yamada, Yoshinori Mori, Fumitaka Fujita, Haruhisa Nakao, Hirotaka Ohara, Masami Inukai, Kunio Kasugai, Takashi Joh, Takashi Joh, Journal of Gastroenterology and Hepatology (Australia), 22,   2007年01月01日, Background: Endoscopic mucosal resection is an established method for treating intramucosal gastric neoplasms. Conventional endoscopic mucosal resection has predominantly been performed using strip biopsy, but local recurrence sometimes occurs due to such piecemeal resection. Endoscopic submucosal dissection has recently been performed in Japan using new devices such as an insulation-tip diathermic knife. The efficacy and problems associated with endoscopic submucosal dissection were evaluated by comparison with conventional endoscopic mucosal resection. Methods: Treatment consisted of conventional endoscopic mucosal resection for 48 lesions from January 1999 to October 2002, and endoscopic submucosal dissection for 59 lesions from November 2002 to June 2005. Endoscopic submucosal dissection was performed using an insulation-tip diathermic knife and flex and hook knives, as appropriate. Results: For lesions ≥11 mm in size, en bloc resection rates were significantly higher with endoscopic submucosal dissection than with conventional endoscopic mucosal resection, but treatment time was significantly longer. En bloc resection rates were higher with endoscopic submucosal dissection than with conventional endoscopic mucosal resection in all areas. Treatment of lesions in the upper one-third of the stomach took a long time using endoscopic submucosal dissection, and intraoperative bleeding was frequent. However, en bloc resection rates and intraoperative bleeding with endoscopic submucosal dissection were improved using various knives. Conclusions: Endoscopic submucosal dissection can take a long time, but is superior to conventional endoscopic mucosal resection for treating intramucosal gastric neoplasms. © 2006 The Authors.
  • Contribution of Helicobacter pylori infection and obesity on heartburn in a Japanese population, Eiji Kubota, Satoshi Tanida, Makoto Sasaki, Hiromi Kataoka, Tadayuki Oshima, Naotaka Ogasawara, Tsuneya Wada, Tomonori Yamada, Yoshinori Mori, Fumitaka Fujita, Takaya Shimura, Hirotaka Ohara, Tamaki Yamada, Takashi Joh, Journal of Clinical Biochemistry and Nutrition, 39,   2006年12月01日, Heartburn is the main symptom of gastro-oesophageal reflux disease (GORD) which is a common disorder and is detrimental to health-related quality of life. The aim of the present study is to investigate the role of both Helicobacter pylori (H. pylori) infection and obesity to heartburn in a Japanese population. This was a cross-sectional study of 7386 (3789 male, mean age 52.5 yr), performed in 2002. Age, sex, smoking, drinking status, and presence/absence of heartburn were recorded. Body mass index (BMI) was calculated and anti-H. pylori antibodies were measured. For subjects aged 30-39 years and aged 50-59 years, heartburn reported by 7.8% and 9.1%, respectively, and antibodies to H. pylori were detected in 20.2% and 63.3%, respectively. Among younger individuals (≤39 years) with H. pylori infection, the adjusted odds ratio (OR) for having heartburn was 2.41, compared with those without infection. Overall, 21.3% were obese (BMI ≥25). Among middle-aged individuals (40-59 years) who were obese, the adjusted OR for having heartburn was 1.41, compared who were not obese. In conclusion, H. pylori infection and obesity are independently associated with increased risk of heartburn in the younger-aged and the middle-aged Japanese population, respectively.
  • Oral vaccination against Helicobacter pylori with recombinant cholera toxin B-subunit, Eiji Kubota, Takashi Joh, Satoshi Tanida, Makoto Sasaki, Hiromi Kataoka, Katsushi Watanabe, Keisuke Itoh, Tadayuki Oshima, Naotaka Ogasawara, Shouzo Togawa, Tsuneya Wada, Tomonori Yamada, Yoshinori Mori, Fumitaka Fujita, Takaya Shimura, Hirotaka Ohara, Masanori Isaka, Yoko Yasudat, Makoto Itoh, Helicobacter, 10,   2005年08月17日, Background. The innocuous pure recombinant cholera toxin B-subunit (rCTB) is very attractive as a strong adjuvant for host immunization, but little is known about rCTB's gastric mucosal immunoadjuvanticity against Helicobacter pylori. The immunoadjuvanticity of rCTB against H. pylori was tested. Material and methods. Mice were immunized with sonicated H. pylori and rCTB orally or intranasally and sacrificed on day 42 after immunization. Passive cutaneous anaphylaxis (PCA) test was performed to evaluate IgE-mediated anaphylaxis with serum from mice to which H. pylori-antigen with rCTB had been administered. Immunoglobulin titer specific to H. pylori in serum, lavation of the gastrointestinal tracts and feces were examined. Gastritis in vaccinated mice after a challenge was assessed with the scoring defined from grading of gastric inflammation. H. pylori proliferation after immunization was investigated by counting colony forming units (CFU) per gram of stomach tissue. Results. PCA test exhibited no reactions against the serum from mice immunized with H. pylori-antigen with rCTB administered orally and intranasally. Oral and nasal coadministrations of rCTB significantly raised systemic and mucosal immunities against H. pylori and suppressed proliferation of H. pylori in gastric mucosa. The score of gastritis in mice immunized orally was significantly higher than that of mice immunized nasally due to postimmunization gastritis. Only oral administration of rCTB suppressed H. pylori proliferation as compared with intranasal administration and without rCTB. Conclusions. The present study indicated that rCTB has systemic and mucosal immunoadjuvanticities against H. pylori and that oral vaccination with rCTB might additively support antibiotic eradication. © 2005 Blackwell Publishing Ltd.
  • Efficacy of famotidine and omeprazole in healing symptoms of non-erosive gastro-oesophageal reflux disease: Randomized-controlled study of gastro-oesophageal reflux disease, T. Wada, M. Sasaki, H. Kataoka, S. Tanida, K. Itoh, N. Ogasawara, T. Oshima, S. Togawa, E. Kubota, T. Yamada, Y. Mori, F. Fujita, H. Ohara, H. Nakao, S. Sobue, T. Joh, T. Joh, M. Itoh, Alimentary Pharmacology and Therapeutics, Supplement, 21,   2005年06月01日, Background: The epidemiology and pathophysiology of non-erosive gastro-oesophageal reflux disease differs from erosive gastro-oesophageal reflux disease. There is a possibility that non-erosive gastro-oesophageal reflux disease treatment requires a different regimen/approach but it is not yet acknowledged. Aim: To investigate the efficacy of famotidine and omeprazole in the treatment of gastro-oesophageal reflux disease, especially non-erosive gastro-oesophageal reflux disease. Patients and methods: A randomized, open-label trial was conducted. Fifty-four gastro-oesophageal reflux disease patients were assigned to treatment with famotidine at a dosage of 20 mg twice daily; or omeprazole, 20 mg once daily, for a period of 8 weeks. The Short Form-36 Health Survey and Gastrointestinal Symptom Rating Scale administered at baseline and after 8 weeks of treatment as well as a symptom questionnaire were conducted daily. Results: Short Form-36 revealed that gastro-oesophageal reflux disease has severe impact on health-related quality of life. Thirty-nine subjects (77%) were endoscopically diagnosed as non-erosive gastro-oesophageal reflux disease. The mean Gastrointestinal Symptom Rating Scale abdominal pain, and indigestion score of non-erosive gastro-oesophageal reflux disease significantly improved in famotidine-treated patients (P < 0.05). but not in the omeprazole. There was no significant change regarding improved heartburn symptoms of non-erosive gastro-oesophageal reflux disease between treatments in the daytime or night-time. Conclusion: Famotidine and omeprazole were both effective in improving symptoms of gastro-oesophageal reflux disease, particularly non-erosive gastro-oesophageal reflux disease. © 2005 Blackwell Publishing Ltd.
  • Biliary cystadenocarcinoma followed up as benign cystadenoma for 10 years, Eiji Kubota, Kohei Katsumi, Masayuki Iida, Akihiko Kishimoto, Yoshimitsu Ban, Koutaroh Nakata, Nobuo Takahashi, Kunio Kobayashi, Kenji Andoh, Shinichi Takamatsu, Takashi Joh, Journal of Gastroenterology, 38,   2003年03月01日, We describe a case of biliary cystadenocarcinoma that showed a longterm clinical course. A 69-year-old Japanese man was admitted to our hospital because of abdominal discomfort. The patient had been diagnosed with benign cystadenoma of the liver at another hospital in 1987 and had been followed up for 10 years. Abdominal ultrasonography (US) and computed tomography (CT) scan demonstrated a unilocular cystic lesion, which included multiple conspicuous papillary protrusions in the left hepatic lobe. Left lateral segmentectomy was performed, and intraoperative cholangiography revealed a communication between the cystic tumor and intrahepatic bile duct. The tumor contained clear mucinous fluid and enfolded multiple yellowish papillary projections on the cystic wall. Histological examination showed the tumor to be biliary cystadenocarcinoma. The patient is doing well 4 years after the operation.

受賞

  •   2014年, 内視鏡医学研究振興財団, 平成25年度研究助成
  •   2010年, United European Gastroenterology, Travel Grant to UEGW for Basic scientist

競争的資金

  • DNA修復機構を標的とした新規消化器癌治療の開発, 日本学術振興会, 科研費 基盤研究(C),   2016年 - 2018年, 久保田英嗣
  • マスターモデュレーターとしてのCUL3システムを標的とした血管新生制御法の開発とがん治療応用, 日本医療研究開発機構, 次世代がん医療創生研究事業,   2016年 - 2017年, 東山繁樹
  • 臨床応用のための新規光感受性糖鎖連結クロリンを用いた癌細胞超選択的次世代光線力学療法の開発, 文部科学省, 橋渡し研究加速ネットワークプログラム・シーズB,   2014年 - 2016年, 片岡洋望
  • 消化器癌におけるATM発現とPARP阻害剤感受性の検討, 日本学術振興会, 科研費 基盤研究(C),   2013年 - 2015年, 久保田英嗣
  • ES細胞特異的Ras, ERasを標的とした新規胃癌治療の基礎的解析, 日本学術振興会, 科研費 基盤研究(C),   2012年 - 2010年, 久保田英嗣
  • 胃癌の新規診断,化学療法を目指したES細胞特異的Ras, ERasの機能解析, 日本学術振興会, 科研費 挑戦的萌芽研究,   2008年 - 2009年, 久保田英嗣


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