Osamu Kishida

Cd9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells

CD9, a member of the tetraspanin family, has been shown to be involved in a range of cellular activities, including migration, proliferation and adhesion, but the molecular mechanisms by which it mediates such events is unclear. Here, we found that anti-CD9 monoclonal antibody ALB6 inhibited cell proliferation, reduced cell viability and induced not only morphological changes specific to apoptosis but also molecular changes, as evidenced by TUNEL and annexin-V staining. For the possible mechanism of ALB6-induced apoptosis, ALB6 activated the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 mitogen-activated-protein kinase (MAPK) within 5-15 minutes, as well as caspase-3 within 24-48 hours. It is noteworthy that ALB6 induced tyrosine phosphorylation of the p46 Shc isoform specifically and that the overexpression of its dominant-negative form completely suppressed the ALB6-induced activation of JNK/SAPK, p38 MAPK and caspase-3, resulting in the inhibition of apoptotic cell death. These results suggest that CD9 might regulate apoptosis through the specialized signals in human cancer cell lines.

Comparative study of esomeprazole and lansoprazole in triple therapy for eradication of Helicobacter pylori in Japan

AIM To evaluate the efficacy and safety of esomeprazole-based triple therapy compared with lansoprazole therapy as first-line eradication therapy for patients with Helicobacter pylori (H. pylori) in usual post-marketing use in Japan, where the clarithromycin (CAM) resistance rate is 30%. METHODS For this multicenter, randomized, open-label, non-inferiority trial, we recruited patients (≥ 20 years of age) with H. pylori infection from 20 hospitals in Japan. We randomly allocated patients to esomeprazole therapy (esomeprazole 20 mg, CAM 400 mg, amoxicillin (AC) 750 mg for the first 7 d, with all drugs given twice daily) or lansoprazole therapy (lansoprazole 30 mg, CAM 400 mg, AC 750 mg for the first 7 d, with all drugs given twice daily) using a minimization method with age, sex, and institution as adjustment factors. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. H. pylori eradication was confirmed by a urea breath test from 4 to 8 wk after cessation of therapy. RESULTS ITT analysis revealed the eradication rates of 69.4% (95%CI: 61.2%-76.6%) for esomeprazole therapy and 73.9% (95%CI: 65.9%-80.6%) for lansoprazole therapy (P = 0.4982). PP analysis showed eradication rate of 76.9% (95%CI: 68.6%-83.5%) for esomeprazole therapy and 79.8% (95%CI: 71.9%-86.0%) for lansoprazole therapy (P = 0.6423). There were no differences in adverse effects between the two therapies. CONCLUSION Esomeprazole showed non-inferiority and safety in a 7 day-triple therapy for eradication of H. pylori compared with lansoprazole.

Lower Serum Level of Adiponectin Is Associated with Increased Risk of Endoscopic Erosive Gastritis

BackgroundObesity is recently known as a risk factor for endoscopic gastritis. Adiponectin is an anti-inflammatory cytokine secreted from fat tissue, and its serum concentrations are reduced in obesity. The relation between adiponectin and gastritis remains unclear.AimsThe aim of this study was to determine whether lower serum adiponectin level is associated with the risk of endoscopic gastritis.MethodsWe analyzed medical records of participants of a routine health check-up examination. Association among endoscopic findings, serum adiponectin level, and other clinical factors including age, sex, alcohol habit, smoking habit, body mass index (BMI), blood pressure, cholesterol, triglyceride, glucose, and insulin were investigated. Endoscopic erosive gastritis was defined as a flat or minimally depressed white spot surrounded by a reddish area or small elevation with central umbilications mimicking octopus’ suckers.ResultsA total of 2,400 participants were enrolled. BMI was significantly higher in gastritis-positive participants than in gastritis-negative participants. Serum adiponectin levels were significantly lower in gastritis-positive participants than in gastritis-negative participants. Multivariate logistic regression analysis revealed that lower serum adiponectin level (OR 0.96; 95% CI 0.93–0.99), smoking (OR 0.50; 95% CI 0.30–0.80), higher blood pressure (OR 1.02; 95% CI 1.01–1.03), and duodenitis (OR 1.8; 95% CI 1.00–3.09) were significantly associated with endoscopic erosive gastritis.ConclusionsLower serum level of adiponectin may increase the risk of endoscopic erosive gastritis, independently of BMI. Our findings facilitate further study to clarify the role of hypoadiponectinemia in erosive gastritis.

Adiponectin negatively correlates with alcoholic and non‐alcoholic liver dysfunction: Health check‐up study of Japanese men

Aim:  Central obesity, insulin resistance and alcohol consumption are thought to be major risk factors for fatty liver formation. Adiponectin (APN) prevents fatty liver formation, and its serum levels are lower in subjects with central obesity and/or insulin resistance. The aim of this study was to explore the association among serum APN levels, central obesity, insulin resistance and liver dysfunction with or without fatty liver classified by alcohol consumption in healthy subjects.

Clinical use of molecular targeted agents for primary small bowel adenocarcinoma: A multicenter retrospective cohort study by the Osaka Gut Forum

Primary small bowel adenocarcinoma (SBA) is a rare cancer for which effective treatment strategies have not yet been established. The results of previous retrospective studies suggest that chemotherapy contributes to a longer survival time in patients with SBA. However, there are few case reports about the efficacy of molecular targeted agent-containing chemotherapy for SBA. In the present study, the treatment and follow-up data of patients with SBA who received chemotherapy with or without molecular targeted agents were retrospectively analyzed. Each patient was treated in one of ten hospitals participating in the Osaka Gut Forum between April 2006 and March 2014. The following factors were evaluated: Age, sex, Eastern Cooperative Oncology Group performance status (PS), tumor location, tumor differentiation, chemotherapy regimen, resection of primary tumor, tumor biomarker expression, distant metastasis, best response under chemotherapy, time to disease progression, subsequent treatments, survival status and treatment toxicity. A total of 27 patients (17 males and 10 females; mean age, 63.4 years old; range, 36-83 years old) received chemotherapy due to non-curative tumor resection, unresectable tumor or post-operative recurrence. The median overall survival time was 14.8 months (range, 2-58 months). A univariate analysis revealed a PS of 0 (P=0.0228) and treatment with platinum-based chemotherapy (P=0.0048) were significant factors for an improved prognosis. An age-adjusted multivariate analysis also revealed that a platinum-based regimen was a significant positive prognostic factor (P=0.0373). Molecular targeted agents were administered to 8 patients, for whom it was their first- or second-line therapy. Among the 17 patients who received oxaliplatin-based chemotherapy as a first-line chemotherapy, a PS of 0 (P=0.0255) and treatment with bevacizumab (P=0.0121) were significant positive prognostic factors. Toxicities higher than Grade 3 occurred in 8/27 patients with SBA; however, serious side effects due to the molecular targeted agents were not experienced. The results of the present study indicate that chemotherapy containing molecular targeted agents is a well-tolerated and effective treatment option for SBA.

Tu1064 Esomeprazole Versus Lansoprazole in Triple Therapy for Eradication of Helicobacter pylori in Japan: A Multicenter, Randomized Study by the Osaka Gut Forum

G A A b st ra ct s ethical committee and written informed consent was obtained from all patients. Subjects randomly assigned to three treatment groups for 10 days: Standard triple therapy (STT), Esomeprazole (40 mg b.i.d.) + clarithromycin (500 mg b.id.) + amoxicillin (1,000 mg b.i.d.). Levofloxacin triple therapy (LTT): Esomeprazole (40 mg b.i.d.) + levofloxacin (500 mg once a day) + amoxicillin (1,000 mg b.i.d.) and Levo-Clari triple therapy LCT: Esomeprazole (40 mg b.i.d.) + clarithromycin ((500mg b.i.d.) + levofloxacin (500mg once a day). The allocation was concealed. All were H. pylori positive. Antimicrobial susceptibility was determined by agar dilution and by direct sequencing of PCR products. Post treatment H. pylori status was determined by the 13C-UBT at least 8 weeks after the completion of treatment. The results and analysis of clinical trial was by intention-to-treat (ITT) and per-protocol (PP). Results 240 patients were enrolled between February 2008 and February 2011, 80 patients in each treatment group. ITT results were: STT 71% (95% CI 61% 82%), LTT 75% (95% CI 65% -85%) and LCT 79% (95% CI 70% -91%). PP results were 71%, 75% and 83%, respectively (p = n.s.) The most common mutation resulting in clari resistance was A2143G, and for levofloxacin, mutations D91G, N87K and N871. The relative risk (RR) of failure in relation to specific mutations were: for 23S rRNA in STT 6 and 2.9 for LCT. The (RR) for presence of mutations in both gene gyrA and 23S rRNA in LTT was 14. We performed a logistic regression model to estimate the probability of treatment success. The model variables were associated with the presence of A2143G mutation, N87I, D91G. The probability of treatment success in patients without mutation was 98% compared to 13% for those with mutations in both genes. Adverse events occurred in all three treatment groups and were mild or moderate, with no residual effects. Metallic taste was the most common adverse effect, followed by diarrhea, abdominal pain and nausea. 2 patients required stopping treatment for diarrhea in the LCT group. Conclusion Triple standard therapy and triple therapies containing levofloxacin no provided acceptable cure rates in Bogota because of high rates of clarithromycin and levofloxacin resistance.

Lower Serum Adiponectin Increases the Risk of Endoscopic Gastritis Relevant to Excess Gastric Acid: An Epidemiologic Study of 2400 Japanese Subjects

Lower Serum Adiponectin Increases the Risk of Endoscopic Gastritis Relevant to Excess Gastric Acid: An Epidemiologic Study of 2400 Japanese Subjects Shunsuke Yamamoto, Kenji Watabe, Shusaku Tsutsui, Shinichi Kiso, Toshimitsu Hamasaki, Yoshihiro Kamada, Motohiko Kato, Yuichi Yoshida, Miyuki Umeda, Aiko Furubayashi, Kazuo Kinoshita, Osamu Kishida, Takashi Fujimoto, Akira Yamada, Yoshifumi Tsukamoto, Norio Hayashi, Yuji Matsuzawa