Shinichiro Zushi

STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells.

The oncogenic ras mutation is a common and critical step in gastrointestinal carcinogenesis. In a previous study, we demonstrated that oncogenic ras activated the EGF‐related peptide autocrine loop and that the apoptosis resistance observed in the oncogenic ras‐stimulated cell (IEC‐ras cell) was dependent on this activated EGF‐related peptide autocrine loop. STATs (signal transducers and activators of transcription), first identified as intracellular signal transducers stimulated by cytokines, are known to also be activated by EGF. However, the role of STATs in the survival signal of IEC‐ras cells is not clear. In the present study, we demonstrate that STAT3 is constitutively activated in ras‐stimulated cells and that STAT3 activation is considerably suppressed by the EGF‐specific receptor kinase inhibitor AG1478. We also show that disruption of the STAT3 pathway by introduction of a dominant‐negative STAT3 mutant abolishes the apoptosis resistance against UVC and MMC treatment observed in IEC‐ras cells without affecting proliferation. Moreover, the expression of Bcl‐2 and Bcl‐xL, apoptosis‐suppressive proteins, is reduced in dominant‐negative STAT3‐transfected cells. Thus, STAT3 appears to be an important mediator of the anti‐apoptotic signal in IEC‐ras cells. Int. J. Cancer 78:326–330, 1998.© 1998 Wiley‐Liss, Inc.

Gastrin Induces Heparin-Binding Epidermal Growth Factor-like Growth Factor in Rat Gastric Epithelial Cells Transfected With Gastrin Receptor

BACKGROUND & AIMS Parietal cells express heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF). However, it is unknown whether HB-EGF mediates the trophic action of gastrin. The purpose of this study was to determine whether gastrin modulates the expression of HB-EGF, which mediates the proliferative effects of gastrin on gastric epithelial cells. METHODS RGM1 cells, a rat gastric epithelial cell line, were transfected with a human gastrin receptor complementary DNA. Gastrin induction of messenger RNAs (mRNAs) for EGF-related polypeptides was assayed by Northern blotting. Processing of cell surface-associated proHB-EGF and secretion of HB-EGF were determined by flow cytometry and Western blotting, respectively. Tyrosine phosphorylation of the EGF receptor was assayed by immunoprecipitation and Western blotting with an antiphosphotyrosine antibody. Cell growth was evaluated by [3H]thymidine incorporation. RESULTS Gastrin induced expression of HB-EGF mRNA, processing of proHB-EGF, release of HB-EGF into the medium, and tyrosine phosphorylation of the EGF receptor. The growth-stimulatory effects of gastrin were partly inhibited by anti-rat HB-EGF serum and completely blocked by AG1478, an EGF receptor-specific tyrphostin. CONCLUSIONS The findings suggest that HB-EGF at least partially mediates the proliferative effects of gastrin on gastric epithelial cells.

SHORT-TERM OUTCOMES OF ENDOSCOPIC SUBMUCOSAL DISSECTION (ESD) FOR EARLY GASTRIC NEOPLASM: MULTICENTER SURVEY BY OSAKA UNIVERSITY ESD STUDY GROUP

Background:  Endoscopic submucosal dissection (ESD) was developed for en bloc removal of large and flat gastrointestinal tract neoplasms. In Japan, ESD is performed under conscious sedation. The risks for sedation‐related complications of ESD, such as postoperative pneumonia, have not been evaluated. The aim of this study was to evaluate the incidence of postoperative pneumonia after ESD in a multicenter survey.

Over-expression of bcl-xL gene in human gastric adenomas and carcinomas

The present study was designed to clarify whether bel‐xL is involved in the development of carcinoma in the stomach. Levels of bel‐xL and bc1‐2 mRNA were determined by a reverse‐transcription/polymerase‐chain reaction in endoscopic gastric biopsy specimens from 10 control subjects, 11 patients with adenomas and 14 patients with carcinomas. In 6 of 11 adenomas, 5 of 8 early carcinomas and 3 of 6 advanced carcinomas, the bel‐xL gene was over‐expressed. In carcinomas, overexpression of the bel‐xL gene was observed in 6 of 9 intestinaltype carcinomas and 2 of 5 diffuse‐type carcinomas. No correlation was observed between bel‐xL and bc1‐2 gene expression. In cases in which the bel‐xL gene was over‐expressed, an apparent increase in the protein level of Bcl‐xL was observed by immunoblot analysis and intense Bcl‐x immunoreactivity was detected immunohistochemically within the tumor cells. In conclusion, we showed that bel‐xL is over‐expressed in gastric carcinomas at both the RNA and protein levels, suggesting that overexpression of bel‐xL may play a role in gastric carcinogenesis.

Modulation of apoptosis by endogenous Bcl-xL expression in MKN-45 human gastric cancer cells

This study was designed to clarify the role of endogenous Bcl-xL expression in modulating apoptosis of malignant cells. Administration of bcl-x-antisense oligonucleotides decreased Bcl-xL protein levels in the MKN-45 human gastric cancer cell line. The decrease in Bcl-xL protein content resulted in increased cell death induced by serum deprivation or Fas-antibody administration. Flow cytometric analysis revealed that the increased apoptotic cell death was more prominent in bcl-x-antisense-treated cells as compared to control cells, bcl-x-sense-treated cells, or bcl-x-nonsense-treated cells. To inhibit the effect of intrinsic Bcl-xL protein, we overexpressed Bak, which binds Bcl-xL and inhibits the anti-apoptotic effect of Bcl-xL, by transfection into MKN-45 cells. Bak-overexpressing cells showed increased apoptotic cell death induced by Fas-antibody when compared to parent cells and MKN-neo-transfected cells. Bak-overexpressing cells also showed greater sensitization to 5-fluorouracil and cisplatin than parent cells and MKN-neo-transfected cells.  In conclusion, we demonstrated that administration of bcl-x-antisense oligonucleotides or overexpression of Bak protein induces sensitization to apoptosis in MKN-45 gastric cancer cells, suggesting that endogenous Bcl-xL expression in cancer cells is an important modulator of apoptosis.

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.

Utility of computed tomography fusion imaging for the evaluation of the ablative margin of radiofrequency ablation for hepatocellular carcinoma and the correlation to local tumor progression

To demonstrate the usefulness of the computed tomography (CT) fusion imaging for the evaluation of treatment effect of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).

PHOSPHOLIPASE A2 STIMULATES RAT GASTRIC EPITHELIAL CELL LINE (RGM-1) MIGRATION

Abstract.Objective and Methods: The effect of phospholipase A2 (PLA2) and its phospholipid metabolites on gastric epithelial migration was examined using an in vitro wounding model of confluent monolayers of rat gastric epithelial cell line RGM-1. ¶Results: Lysophosphatidylcholine (lysoPC) (0.01–100 ng/ml) as well as PLA2 (0.01–100 mU/ml) dose-dependently increased the cell migration. Lysophosphatidic acid (10 ng/ml) also increased the migration, but no significant increase in migration was observed when stimulated by lysophosphatidylethanolamine (10 ng/ml) or lysophosphatidylserine (10 ng/ml). Addition of 4-bromophenacyl bromide (BPB), a PLA2 inhibitor, completely blocked the effect of PLA2. However, addition of piroxicam (a cyclooxygenase inhibitor) or nordihydroguaiaretic acid (a lipoxygenase inhibitor) had no significant effect. Combination of PLA2 (10 mU/ml) with lysoPC (10 ng/ml) had no additive effect on migration. Moreover, lysoPC levels were increased in the cells after incubation with PLA2 (10 mU/ml). After pretreatment of RGM-1 cells with replication-inhibiting doses of mitomycin C, PLA2 and lysoPC still increased the cell migration. ¶Conclusions: These data suggest that PLA2 may, independently of proliferation, increase gastric epithelial migration mainly via lysoPC production.

ENDOSCOPIC COAGULATION THERAPY IS USEFUL FOR IMPROVING ENCEPHALOPATHY IN CIRRHOTIC PATIENTS WITH GASTRIC ANTRAL VASCULAR ECTASIA

Background:  Gastric antral vascular ectasia (GAVE) is an uncommon but treatable cause of chronic gastrointestinal bleeding often associated with severe cirrhosis. Efficacy of endoscopic treatment is well known; however, long‐term outcome after endoscopic treatment is not clear.

Percutaneous endoscopic gastrostomy under steady pressure automatically controlled endoscopy: First clinical series

AIM To elucidate the safety of percutaneous endoscopic gastrostomy (PEG) under steady pressure automatically controlled endoscopy (SPACE) using carbon dioxide (CO2). METHODS Nine patients underwent PEG with a modified introducer method under conscious sedation. A T-tube was attached to the channel of an endoscope connected to an automatic surgical insufflator. The stomach was inflated under the SPACE system. The intragastric pressure was kept between 4-8 mmHg with a flow of CO2 at 35 L/min. Median procedure time, intragastric pressure, median systolic blood pressure, partial pressure of CO2, abdominal girth before and immediately after PEG, and free gas and small intestinal gas on abdominal X-ray before and after PEG were recorded. RESULTS PEG was completed under stable pneumostomach in all patients, with a median procedural time of 22 min. Median intragastric pressure was 6.9 mmHg and median arterial CO2 pressure before and after PEG was 42.1 and 45.5 Torr (NS). The median abdominal girth before and after PEG was 68.1 and 69.6 cm (NS). A mild free gas image after PEG was observed in two patients, and faint abdominal gas in the downstream bowel was documented in two patients. CONCLUSION SPACE might enable standardized pneumostomach and modified introducer procedure of PEG.