Toshifumi Hibi

Publications (441)1408.62 Total impact

• Article: Innate immunity in the pathogenesis of inflammatory bowel disease.

  Tadakazu Hisamatsu, Toshifumi Hibi
  Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 05/2013; 110(5):753-63.
• Article: Ulcerative colitis: prevention of relapse.

  Makoto Naganuma, Atsushi Sakuraba, Toshifumi Hibi
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  ABSTRACT: The clinical management of ulcerative colitis (UC) involves first treating the acute symptoms to induce remission, and then successfully maintaining it. Oral 5-aminosalicylic acids are safe and useful for maintaining remission in patients with UC. In terms of adherence, a once-daily form of 5-aminosalicylic acid is superior in maintaining remission as compared with split dosing. Patients at high risk of relapse may be candidates for treatment with thiopurines and/or biologics in the early stages of UC. Calcineurin inhibitors, such as cyclosporine and tacrolimus, are effective for severe, steroid-refractory UC patients. It is suggested that these patients use thiopurines as their maintenance therapy once they achieve remission with calcineurin inhibitors. Recent studies have confirmed that biologics are effective for inducing clinical and endoscopic remission of UC, and thus they may improve long-term prognosis of UC.
  Expert review of gastroenterology & hepatology 05/2013; 7(4):341-51.
• Article: TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease.

  Kazuaki Yoneno, Tadakazu Hisamatsu, Katsuyoshi Shimamura, Nobuhiko Kamada, Riko Ichikawa, Mina T Kitazume, Maiko Mori, Michihide Uo, Yuka Namikawa, Katsuyoshi Matsuoka, Toshiro Sato, Kazutaka Koganei, Akira Sugita, Takanori Kanai, Toshifumi Hibi
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  ABSTRACT: Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mϕs) and dendritic cells. Mϕs differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mϕs), which are similar to the human intestinal lamina propria CD14(+) Mϕs that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mϕs stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14(+) intestinal Mϕs from patients with CD expressed TGR5. In isolated intestinal CD14(+) Mϕs, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.
  Immunology 05/2013; 139(1):19-29. · 3.32 Impact Factor
• Article: C-reactive protein is an indicator of serum infliximab level in predicting loss of response in patients with Crohn's disease.

  Toshifumi Hibi, Atsushi Sakuraba, Mamoru Watanabe, Satoshi Motoya, Hiroaki Ito, Noriko Sato, Toru Yoshinari, Kenta Motegi, Yoshitaka Kinouchi, Masakazu Takazoe, Yasuo Suzuki, Takayuki Matsumoto, Kazuhiko Kawakami, Ichiro Hirata, Shinji Tanaka, Toshifumi Ashida, Toshiyuki Matsui
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  ABSTRACT: BACKGROUND: The ability of serum infliximab level to predict clinical outcome in infliximab therapy in Crohn's disease is unclear. Here, we aimed to clarify the correlation between the timing of loss of response (LOR) to treatment and a decrease in serum infliximab level, and, in addition, to identify an indicator of infliximab level. METHODS: The study used data from a previous clinical study of infliximab for Crohn's disease, in which infliximab was initially given at 0, 2, 6 weeks at 5 mg/kg, and then at 8-week intervals to 62 week-10 responders. Of these 62, here we analysed data from 57 in whom Crohn's disease activity index and serum infliximab level were evaluated at week 14. RESULTS: Twelve patients showed a clinical response despite an infliximab level <1 μg/mL at week 14; of these, 8 (67 %) experienced LOR by week 54. A decrease in infliximab level preceded LOR in 6 (75 %). In receiver operating characteristic curve analysis, C-reactive protein (CRP) showed better performance in detecting an infliximab level <1 μg/mL. Infliximab level was <1 μg/mL in 60-80 % of patients with CRP >0.5 mg/dL. Time to LOR (median: 22.0 weeks) was significantly longer than that to a decrease in infliximab level to <1 μg/mL (14.0 weeks, p < 0.05) or to an increase in CRP to >0.5 mg/dL (14.0 weeks, p < 0.01). CONCLUSIONS: A decrease in serum infliximab level preceded LOR, and was easily detected by an increase in CRP. The CRP may be an indicator of serum infliximab level in predicting LOR.
  Journal of Gastroenterology 04/2013; · 4.16 Impact Factor
• Article: Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier.

  Shinta Mizuno, Yoshiyuki Yamagishi, Hirotoshi Ebinuma, Nobuhiro Nakamoto, Mai Katahira, Aya Sasaki, Michiie Sakamoto, Hidekazu Suzuki, Takanori Kanai, Toshifumi Hibi
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  ABSTRACT: A 58-year-old man was diagnosed as a hepatitis B virus (HBV) carrier approximately 30 years ago. He was diagnosed with renal cell carcinoma when he was 57 years old. Radical nephrectomy was performed, and everolimus was administered to treat his lung metastasis. After beginning the everolimus, intermittent fever, general fatigue, and jaundice developed. He was admitted under a diagnosis of flare (acute exacerbation) of chronic B hepatitis due to HBV reactivation. Despite intensive care, he died of hepatic failure and fungus infection. The autopsy findings were compatible with hepatic failure due to HBV reactivation by everolimus. Antiviral prophylaxis must be taken into consideration before beginning immunosuppressive therapy such as everolimus in HBV carriers.
  Clinical Journal of Gastroenterology 04/2013; 6(2):188-192.
• Article: Applicability of second generation colon capsule endoscope to ulcerative colitis: A clinical feasibility study.

  Naoki Hosoe, Katsuyoshi Matsuoka, Makoto Naganuma, Yosuke Ida, Yuka Ishibashi, Kayoko Kimura, Kazuaki Yoneno, Shingo Usui, Kazuhiro Kashiwagi, Tadakazu Hisamatsu, Nagamu Inoue, Takanori Kanai, Hiroyuki Imaeda, Haruhiko Ogata, Toshifumi Hibi
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  ABSTRACT: BACKGROUND AND AIM: Colon capsule endoscopy has already been used for colon visualization and detection of polyps but its applicability to inflammatory bowel disease is still unconfirmed. To assess the feasibility of evaluating the severity of mucosal inflammation in patients with ulcerative colitis (UC) using a second generation colon capsule endoscope (CCE-2). METHODS: Forty patients with histological confirmed diagnosis of UC were enrolled. Low volume (2L) polyethylene glycol solution (PEG) with prokinetics (mosapride citrate and metoclopramide) regimen were used for the bowel preparation. In Phase 1, consisting of 10 patients, to confirm appropriate CCE-2 bowel preparation for UC. In Phase 2, consisting of 30 patients, CCE-2 was performed with a fixed bowel preparation regimen. CCE-2 findings were recorded for 8 hours starting from capsule ingestion and conventional colonoscopy was subsequently performed on the same day. CCE-2 procedure completion rate and the colon cleansing level with a 4-point grading scale (poor, fair, good, and excellent) were evaluated in Phase 2. Correlations between Matts endoscopic scores as judged by CCE-2 and conventional colonoscopy were calculated. RESULTS: CCE-2 procedure was completed within 8 hours in 69% of the patients. The proportion of patients with good or excellent cleansing level was below 50%. However, Matts endoscopic scores determined by CCE-2 showed a strong correlation with scores obtained by conventional colonoscopy (average ρ = 0.797). CONCLUSIONS: Though modifications in bowel preparation are needed, CCE-2 might be feasible for assessing the severity of mucosal inflammation in patients with UC.
  Journal of Gastroenterology and Hepatology 03/2013; · 2.87 Impact Factor
• Article: Suppressive Effect of the Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), on Hepatitis C Virus Replication via Epigenetic Changes in Host Cells.

  Ayami Sato, Yoshimasa Saito, Kazuo Sugiyama, Noriko Sakasegawa, Toshihide Muramatsu, Shinya Fukuda, Mikiko Yoneya, Masaki Kimura, Hirotoshi Ebinuma, Toshifumi Hibi, Hidetsugu Saito
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  ABSTRACT: The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has a clinical promise for treatment of cancer including hepatocellular carcinoma (HCC). To investigate effect of SAHA on hepatitis C virus (HCV) replication, we treated the HCV replicon cell OR6 with SAHA. HCV replication was significantly inhibited by SAHA at concentrations below 1 μM with no cellular toxicity. Another HDAC inhibitor, tricostatin A, also showed reduction of HCV replication. The microarray analysis and quantitative RT-PCR demonstrated up-regulation of osteopontin (OPN) and down-regulation of apolipoprotein-A1 (Apo-A1) after SAHA treatment. Direct gene induction of OPN and knockdown of Apo-A1 also showed reduction of HCV replication. The liver specific microRNA-122, which is involved in HCV replication, was not affected by SAHA treatment. These results suggest that SAHA has suppressive effect on HCV replication through alterations of gene expression such as OPN and Apo-A1 in host cells. Epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for diseases associated with HCV infection such as chronic hepatitis, liver cirrhosis, and HCC. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
  Journal of Cellular Biochemistry 03/2013; · 2.87 Impact Factor
• Article: C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice.

  Po-Sung Chu, Nobuhiro Nakamoto, Hirotoshi Ebinuma, Shingo Usui, Keita Saeki, Atsuhiro Matsumoto, Yohei Mikami, Kazuo Sugiyama, Kengo Tomita, Takanori Kanai, Hidetsugu Saito, Toshifumi Hibi
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  ABSTRACT: Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. We recently demonstrated that C-C motif chemokine receptor (CCR) 9+ macrophages are crucial in the pathogenesis of acute liver inflammation. However, the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed tumor necrosis factor (TNF)-α-producing CCR9+ macrophages accumulated during the initiation of carbon tetrachloride (CCl4 )-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9+ macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9-/- mice compared with wild-type (WT) mice, assessed by α-smooth muscle actin (α-SMA) immunostain, sirius red staining and mRNA expression levels of α-SMA, collagen 1α1, transforming growth factor (TGF)-β1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b+ macrophages in CCl4 -treated WT mice showed marked increases in TNF, NO synthase-2 and TGF-β1 mRNA expression compared with CCR9-/- mice, implying pro-inflammatory and profibrogenic properties. Hepatic CD11b+ macrophages from CCl4 -treated WT mice (i.e. CCR9+ macrophages), but not CD8+ T lymphocytes or non-CD11b+ cells, significantly activated HSCs in vitro compared with those from CCR9-/- mice. TNF-α or TGF-β1 antagonism attenuated CCR9+ macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. Conclusion: Accumulated CD11b+ macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis. (HEPATOLOGY 2013.).
  Hepatology 03/2013; · 11.66 Impact Factor
• Article: Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy.

  Kenro Hirata, Hidekazu Suzuki, Juntaro Matsuzaki, Tatsuhiro Masaoka, Yoshimasa Saito, Toshihiro Nishizawa, Eisuke Iwasaki, Seiichiro Fukuhara, Sawako Okada, Toshifumi Hibi
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  ABSTRACT: The relationship between Helicobacter pylori (H. pylori) eradication therapy and the risk of developing gastroesophageal reflux disease (GERD) is controversial. We investigated the influence of H. pylori eradication on the risk of GERD by focusing on the quality of life (QOL) and evaluating reflux symptoms. Patients with H. pylori infection were administered triple therapy for H. pylori eradication. At 3 months and 1 year after the eradication therapy, surveys were conducted to determine the health-related QOL by quality of life in reflux and dyspepsia-Japanese version, (QOLRAD-J) and the severity of GERD symptoms by Carlsson-Dent questionnaire (CDQ). Forty patients were included in the analysis. Although no significant changes of these scores were apparent 3 months after H. pylori eradication, the QOLRAD-J and CDQ scores were significantly improved after 1 year. The degree of improvement was even more marked in cases with initially low scores. In conclusion, improved GERD-related QOL and reflux symptoms were noted 1 year after H. pylori eradication therapy. In addition, the degree of improvement was more marked in cases with severe reflux symptoms.
  Journal of Clinical Biochemistry and Nutrition 03/2013; 52(2):172-8. · 1.98 Impact Factor
• Article: CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion.

  Yuji Nakamura, Takanori Kanai, Keita Saeki, Miho Takabe, Junichiro Irie, Jun Miyoshi, Yohei Mikami, Toshiaki Teratani, Takahiro Suzuki, Naoteru Miyata, Tadakazu Hisamatsu, Nobuhiro Nakamoto, Yoshiyuki Yamagishi, Hajime Higuchi, Hirotoshi Ebinuma, Shigenari Hozawa, Hidetsugu Saito, Hiroshi Itoh, Toshifumi Hibi
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  ABSTRACT: Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanisms of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b+Gr-1low macrophages and pancreatic inflammation, and significantly upregulated insulin secretion compared with the paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b+Gr-1- and CD11b+Gr-1high cells, but not CD11b+Gr-1low cells, in pancreas with severe inflammation, and significantly decreased insulin secretion compared to the WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, the level of GLP-1 receptor in the pancreas of chronic cerulein-administered CCR2-KO mice was significantly lower than in the paired WT mice. Nevertheless, the significantly higher level of hyperglycemia in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b+-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.
  AJP Gastrointestinal and Liver Physiology 02/2013; · 3.43 Impact Factor
• Article: Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice.

  Tango Handa, Takanori Kanai, Toshiro Sato, Yohei Mikami, Tomohisa Sujino, Atsushi Hayashi, Shinta Mizuno, Atsuhiro Matsumoto, Tadakazu Hisamatsu, Toshifumi Hibi
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  ABSTRACT: Intestinal lamina propria dendritic cells (LPDCs) in mice are known to extend dendrites between the intestinal epithelia and the luminal side when processing luminal antigens. We conducted intrarectal cell transfer experiments of bone marrow-derived dendritic cells (BMDCs) in mice to assess dendritic cell penetration of the intestine. Intrarectally administered GFP(+) BMDCs localized in the colonic LP within 3h and the spleen within 12h after administration. 72h after administration, recipient C57BL/6 mice showed acute diarrhea, and administration of BMDCs (once weekly for 3 wk) induced intestinal inflammation with increased numbers of recipient macrophages and CD4(+) T cells exhibiting a Th2-mediated immune response. These results demonstrate that DCs actively communicate across the intestinal barrier, and highlight a potential technique for controlling colonic immune tolerance. (119 words).
  Immunology letters 01/2013; · 2.91 Impact Factor
• Article: IL-22-Producing RORγt-Dependent Innate Lymphoid Cells Play a Novel Protective Role in Murine Acute Hepatitis.

  Atsuhiro Matsumoto, Takanori Kanai, Yohei Mikami, Po-Sung Chu, Nobuhiro Nakamoto, Hirotoshi Ebinuma, Hidetsugu Saito, Toshiro Sato, Hideo Yagita, Toshifumi Hibi
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  ABSTRACT: Retinoid-related orphan receptor (ROR) γt is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORγt-expressing cells in mouse acute hepatitis model using RORγt deficient (RORγt(-/-)) mice and RAG-2 and RORγt double deficient (RAG-2(-/-) × RORγt(-/-)) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by RORγt-expressing cells. We detected RORC expression in three compartments, CD4(+) T cells, NKT cells, and lineage marker-negative SCA-1(+)Thy1(high) ILCs, of the liver of wild type (WT) mice. CCl4-treated RORγt(-/-) mice developed liver damage in spite of lack of RORγt-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2(-/-) × RORγt(-/-) mice that lacked T and NKT cells. Surprisingly, RAG-2(-/-) × RORγt(-/-) mice developed significantly severer CCl4-induced hepatitis compared with RAG-2(-/-) mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti-asialo GM1 Ab administration exacerbated liver damage in RAG-2(-/-) mice with the depletion of liver ILCs. Collectively, hepatic RORγt-dependent ILCs play a part of protective roles in hepatic immune response in mice.
  PLoS ONE 01/2013; 8(4):e62853. · 4.09 Impact Factor
• Article: Second-line chemotherapy for refractory small cell neuroendocrine carcinoma of the esophagus that relapsed after complete remission with irinotecan plus cisplatin therapy: Case report and review of the literature.

  Shinsuke Funakoshi, Akinori Hashiguchi, Kana Teramoto, Naoteru Miyata, Satoshi Kurita, Masayuki Adachi, Yasuo Hamamoto, Hajime Higuchi, Hiromasa Takaishi, Toshifumi Hibi
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  ABSTRACT: Small cell esophageal carcinoma is a type of small cell neuroendocrine carcinoma (SCNEC). SCNEC follows an aggressive clinical course and has a poor prognosis despite multidisciplinary therapies. A standard therapeutic strategy, including surgery, radiation and first-/second-line chemotherapy, has not yet been established for SCNEC. We present a case of SCNEC of the esophagus. A 66-year-old male with SCNEC as extensive disease was treated with 60 mg/m(2) cisplatin on day 1 plus 60 mg/m(2) irinotecan on days 1, 8 and 15 every 4 weeks (IP) with successful complete remission. After the sixth course of IP, increasing pro-gastrin-releasing peptide (ProGRP) and nonspecific enolase (NSE) levels and intense fluorodeoxyglucose (FDG) avidity in a lymph node around the celiac artery (SUV(max), 8.3) indicated a refractory relapse of the disease. The patient was treated with three courses of amrubicin (AMR, 35 mg/m(2)) administered intravenously for 3 consecutive days every 3 weeks as a second-line chemotherapy. The ProGRP and NSE levels returned to the normal range 1 month after the initiation of second-line chemotherapy. However, the ProGRP and NSE levels were elevated after the third course of AMR, and PET-CT revealed progressive disease with liver metastasis and extended lymph node metastasis. As the patient remained asymptomatic, paclitaxel (100 mg/m(2)) was started as third-line chemotherapy. Patients with SCNEC of the esophagus with extensive disease should be treated with aggressive chemotherapy rather than surgery or radiation monotherapy. In the present case, tumor markers such as ProGRP and NSE were predictive of relapse and PET-CT was used to detect relapse. Further research is required to identify and exploit promising agents for resistant SCNEC.
  Oncology letters 01/2013; 5(1):117-122. · 0.11 Impact Factor
• Article: Musashi-1 Post-Transcriptionally Enhances Phosphotyrosine-Binding Domain-Containing m-Numb Protein Expression in Regenerating Gastric Mucosa.

  Tetsufumi Takahashi, Hidekazu Suzuki, Takao Imai, Shinsuke Shibata, Yoshiaki Tabuchi, Kanji Tsuchimoto, Hideyuki Okano, Toshifumi Hibi
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  ABSTRACT: Upregulation of the RNA-binding protein Musashi-1 (Msi1) has been shown to occur in rat gastric corpus mucosa after ethanol-induced mucosal injury. However, there is no direct evidence linking Msi1 with gastric regeneration. We examined the process of tissue repair after acute gastric mucosal injury with Msi1-knock-out (KO) mice to clarify the role of Msi1 and Msi1-dependent regulation of m-Numb expression in regenerating gastric mucosa. Acute gastric injury was induced in Msi1-KO and wild-type ICR mice by administering absolute ethanol. Expression of the splicing variants of m-Numb mRNA and protein in the gastric mucosa were analyzed by quantitative RT-PCR and western blotting, respectively. We demonstrated that phosphotyrosine-binding domain-containing m-Numb expression was significantly upregulated at both the mRNA and protein levels in wild-type mice at 3 h after ethanol-induced acute gastric injury. In contrast, in Msi1-KO mice, the m-Numb protein was expressed weakly, and was associated with delayed regeneration of the injured gastric mucosal epithelium. In the Msi1-KO mouse, the ratio of m-Numb mRNA to total m-Numb mRNA in the heavy polysome fractions was lower than that in the wild-type mouse. Further, we showed that m-Numb-enhancement in gastric mucous cells induced the expression of prostate stem cell antigen and metallothionein-2. Under the m-Numb enhancing condition, the gastric cells exhibited enhanced cell proliferation and were significantly more resistant to H(2)O(2)-induced cell death than control cells. Msi1-dependent post-transcriptional enhancement of m-Numb is crucial in gastric epithelial regeneration.
  PLoS ONE 01/2013; 8(1):e53540. · 4.09 Impact Factor
• Article: Reactive Oxygen Species-Induced Autophagic Degradation of Helicobacter pylori CagA Is Specifically Suppressed in Cancer Stem-like Cells.

  Hitoshi Tsugawa, Hidekazu Suzuki, Hideyuki Saya, Masanori Hatakeyama, Toshiya Hirayama, Kenro Hirata, Osamu Nagano, Juntaro Matsuzaki, Toshifumi Hibi
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  ABSTRACT: Sustained expression of CagA, the type IV secretion effector of Helicobacter pylori, is closely associated with the development of gastric cancer. However, we observed that after translocation, CagA is degraded by autophagy and therefore short lived. Autophagy and CagA degradation are induced by the H. pylori vacuolating cytotoxin, VacA, which acted via decreasing intracellular glutathione (GSH) levels, causing reactive oxygen species (ROS) accumulation and Akt activation. Investigating this further, we found that CagA specifically accumulated in gastric cells expressing CD44, a cell-surface marker associated with cancer stem cells. The autophagic pathway in CD44-positive gastric cancer stem-like cells is suppressed because of their resistance to ROS, which is supported by increased intracellular GSH levels. These findings provide a molecular link between H. pylori and gastric carcinogenesis through the specific accumulation of CagA in gastric cancer stem-like cells.
  Cell host & microbe 12/2012; 12(6):764-77. · 13.02 Impact Factor
• Article: Relationship between non-adherence to aminosalicylate medication and the risk of clinical relapse among Japanese patients with ulcerative colitis in clinical remission: a prospective cohort study.

  Aki Kawakami, Makoto Tanaka, Masakazu Nishigaki, Makoto Naganuma, Yasushi Iwao, Toshifumi Hibi, Hiromi Sanada, Noriko Yamamoto-Mitani, Keiko Kazuma
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  ABSTRACT: BACKGROUND: Thirty to forty-five percent of ulcerative colitis (UC) patients show non-adherence to aminosalicylates, and non-adherence has been reported to increase the risk of clinical relapse. Because Japan differs from Western countries in terms of health care and drugs administered, adherence to aminosalicylates in Japan may differ from that elsewhere. Therefore, we examined aminosalicylate adherence and its relationship to the risk of clinical relapse of UC in Japan. METHODS: A 1-year, prospective cohort study was conducted in 104 outpatients with UC in remission who had taken aminosalicylates >6 months. Aminosalicylate adherence was evaluated using data from a self-administered questionnaire and medical records. Non-adherence was defined as taking <80 % of the prescribed dose of aminosalicylates. The primary outcome was the record of clinical relapse in medical charts. RESULTS: Twenty-nine patients (27.9 %) were evaluated as showing non-adherence. Among all subjects, 24 patients (23.1 %) relapsed. The non-adherence group had a higher rate of 1-year relapse than did the adherence group (41.3 vs. 16.0 %). Multiple Cox regression analysis showed that non-adherence increased the risk of clinical relapse 2.3-fold (hazard ratio 2.3, 95 % confidence interval 1.004-5.24, p = 0.04). CONCLUSIONS: Although the adherence rate in this study was slightly higher than that in previous studies, Japanese patients with UC who were not adherent to their medications had a twofold greater risk of relapse than those who were. These results indicate the importance of early identification of patients with non-adherence. A program to support medication taking behavior is needed to prevent UC relapse.
  Journal of Gastroenterology 12/2012; · 4.16 Impact Factor
• Article: Biliary Findings Assist in Predicting Enlargement of Intraductal Papillary Mucinous Neoplasms of the Pancreas.

  Juntaro Matsuzaki, Hidekazu Suzuki, Shigeo Okuda, Akihiro Tanimoto, Keiko Asakura, Seiichiro Fukuhara, Sawako Okada, Kenro Hirata, Hideki Mori, Tatsuhiro Masaoka, Hajime Higuchi, Shigenari Hozawa, Sachio Kuribayashi, Toru Takebayashi, Toshifumi Hibi
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  ABSTRACT: BACKGROUND & AIMS: There is controversy over the optimal management strategy for patients with branch-duct type intraductal papillary mucinous neoplasms of the pancreas (BD-IPMN), precursors to pancreatic cancer. We aimed to identify factors associated with the presence of BD-IPMN and changes in their diameter. METHODS: Two separate analyses were conducted in a cohort of patients who underwent magnetic resonance cholangiopancreatography (MRCP) in a single year (2006). MRCP findings and clinical outcomes of these patients were followed for a maximum of 6 years. We evaluated initial MRCP findings and demographics associated with the presence of BD-IPMN at baseline, and increase in BD-IPMN diameter over time. RESULTS: Over the follow-up period, 154 patients developed BD-IPMN and 322 patients did not. Older age, diabetes mellitus, gallbladder adenomyomatosis, and absence of gallstones were associated with the presence of BD-IPMN at baseline. Increases in diameter of BD-IPMNs were associated with 3 baseline factors: BD-IPMN diameter greater than 17 mm, gallbladder adenomyomatosis, and a common bile duct (CBD) diameter less than 5.5 mm. Patients with BD-IPMN could be stratified into 4 groups with varying risk for the enlargement of BD-IPMN over time: those with 3 risk factors (hazard ratio [HR] 11.4; 95% confidence interval [CI], 3.4-37.8), 2 risk factors (HR 4.7; 95% CI, 1.7-12.8), or 1 risk factor (HR 3.1; 95% CI, 1.2-8.2) compared to those without risk factors. CONCLUSIONS: For patients with BD-IPMN, careful follow-up evaluation is particularly important for those with BD-IPMN>17 mm in size, CBD diameter <5.5 mm, or gallbladder adenomyomatosis.
  Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2012; · 5.64 Impact Factor
• Article: Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells.

  Atsushi Nishida, Kiyotaka Nagahama, Hirotsugu Imaeda, Atsuhiro Ogawa, Cindy W Lau, Taku Kobayashi, Tadakazu Hisamatsu, Frederic I Preffer, Emiko Mizoguchi, Hiroki Ikeuchi, Toshifumi Hibi, Minoru Fukuda, Akira Andoh, Richard S Blumberg, Atsushi Mizoguchi
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  ABSTRACT: Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4(+) T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4(+) T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4(+) T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4(+) T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4(+) T cells in intestinal inflammation such as that seen in inflammatory bowel disease.
  Journal of Experimental Medicine 12/2012; · 13.85 Impact Factor
• Article: Molecular Approaches and Modern Clinical Strategies for the Management of Helicobacter pylori Infection in Japan.

  Hidekazu Suzuki, Toshihiro Nishizawa, Hitoshi Tsugawa, Toshifumi Hibi
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  ABSTRACT: Thirty years have passed since Warren and Marshall's discovery of Helicobacter pylori (H.pylori). Since then, not only peptic ulcer diseases and chronic gastritis but also non-cardia gastric cancers have been recognized as diseases originating from H. pylori infection. Several combination therapies consisting of multiple antibiotics have been developed as first- or second-line regimens to eradicate H. pylori infection. Our extensive experience in the field of anti-H. pylori medicine suggests that clinicians should consider a possible role for unidentified, invisible pathogens to elucidate the pathogenesis and improve the treatment of refractory diseases of unknown etiology.
  The Keio Journal of Medicine 12/2012; 61(4):109-19.
• Article: Mesenchymal Stem Cells Regulate Epithelial-to-Mesenchymal Transition and Tumor Progression of Pancreatic Cancer Cells.

  Ayano Kabashima-Niibe, Hajime Higuchi, Hiromasa Takaishi, Yohei Masugi, Yumi Matsuzaki, Yo Mabuchi, Shinsuke Funakoshi, Masayuki Adachi, Yasuo Hamamoto, Shigeyuki Kawachi, Koichi Aiura, Yuko Kitagawa, Michiie Sakamono, Toshifumi Hibi
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  ABSTRACT: Cancer-associated fibroblasts (CAFs) contribute to cancer progression that is caused by epithelial-to- mesenchymal transition (EMT). Recently, mesenchymal stem cells (MSCs) were found to be the major candidate involved in the development of tumor-promoting cancer stroma. Here we report that alpha-smooth muscle actin (α-SMA)-positive myofibroblast-like cells originating from MSCs contribute to inducing EMT in Side Population (SP) cells of pancreatic cancer. More importantly, MSCs-derived myofibroblasts function to maintain tumor-initiating stem cell-like cells (TISCs)-like characteristics, including augmenting expression levels of various stemness-associated genes, enhancing sphere- forming activity, promoting tumor formation in a mouse xenograft model, and exhibiting resistance to anticancer drugs. Furthermore, both γ-secretase inhibitor and small interfering RNA (siRNA) directed against Jagged-1 attenuated MSCs-associated E-cadherin suppression and sphere formation in pancreatic cancer SP cells. Thus, our results suggest that MSCs-derived myofibroblasts play important roles in regulating EMT and TISCs-like properties of pancreatic cancer cells through an intermediating Notch signal.
  Cancer Science 11/2012; · 3.33 Impact Factor