Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway.

Helicobacter pylori (H. pylori) produces vacuolating cytotoxin (VacA), a potent protein toxin, which is associated with gastric inflammation and ulceration. Recent studies demonstrated that connexins (Cxs), which are responsible for intracellular communication at gap junctions (GJs) as well as cell homeostasis, participate in VacA-induced cell death. We now demonstrate in AZ-521 cells that VacA increased cytoplasmic Cx43, accompanied by LC3-II generation in a time- and dose-dependent manner without induction of Cx43 mRNA expression. Inhibition of VacA-induced Rac1 activity prevented ERK phosphorylation and the increase in Cx43. Suppression of ERK activity and addition of N-acetyl-cysteine inhibited VacA-dependent increase in Cx43 and LC3-II. DIDS, an anion-selective inhibitor, suppressed VacA-dependent increase in Cx43, suggesting that VacA channel activity was involved in this pathway. By confocal microscopy, Cx43 increased by VacA was predominately localized in cholesterol-rich, detergent-resistant membranes including GJs, and a fraction of Cx43 was incorporated in endocytotic vesicles and autophagolysosomes. Accumulation of Cx43 was also observed in gastric mucosa from H. pylori-infected patients compared with healthy controls, suggesting that the pathogen caused a similar effect in vivo. Our findings show that VacA-mediated effects on autophagy inhibits turnover of Cx43, resulting in increased levels in the cytoplasm, leading eventually to apoptotic cell death.

Significance of background coloration in endoscopic detection of early esophageal squamous cell carcinoma.

Endoscopic diagnostics of early squamous cell carcinoma (SCC) in the laryngo-esophageal region have dramatically improved together with development of less invasive endoscopic treatment. It is essential for gastrointestinal endoscopists to detect lesions when they are still endoscopically treatable, especially in this region since surgical approach can still be extremely invasive. Pioneers have found some notable fundamental alterations in early SCC and created several classifications. Inoue [Dig Endosc 2001;13(suppl): 40-41] proposed the intrapapillary capillary (IPCL) classification, which focused on the microvascular change of the mucosal surface. One of the significances of this classification is that it clearly distinguished the lesions that require further pathological evaluation by categorizing the diameter change of the IPCLs. On the other hand, Arima et al. [Esophagus 2005;2:191-197] advocated the alteration of microvessels as well as change of the vascular arrangement in the area. Most recently, the Japan Esophageal Society constructed a new classification uniting these two exemplary classifications as the 'Japanese Classification of Magnifying Endoscopy for Early Squamous Cell Carcinoma'. This classification was intended to be simple and easily applicable in general clinical practice. Brownish color change between the IPCLs has reported to be one of the useful findings in distinguishing early SCC from benign changes such as inflammatory change and low-grade intraepithelial neoplasia. Nevertheless, the exact cause of this phenomenon remains unclear. We recently examined the association of color change with hemoglobin (Hb) in cancer tissue, since NBI exclusively detects the wavelength of Hb in superficial vessels in the gastrointestinal tract. This review article also describes our examination of a distinct finding in esophageal cancer, namely, 'background coloration'.

Clinicopathological factors associated with clinical outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) permits removal of colorectal epithelial neoplasms en bloc, but a substantial risk of procedure-related perforation has been reported. We sought to unravel the clinicopathological factors associated with the clinical outcomes of ESD for colorectal epithelial neoplasms in a large series. PATIENTS AND METHODS: ESD was done in 278 patients with 292 colorectal tumors that fulfilled the inclusion criteria. The criteria for ESD were: lesion greater than 20 mm in size, lesion with fibrotic scarring, locally residual colorectal lesion, or invasive carcinoma with slight submucosal penetration. Resection was assessed as en bloc or piecemeal, complete (en bloc with tumor-free lateral and basal margins) or incomplete. Complications including perforation and bleeding were assessed, and factors related to each were analyzed using logistic regression. Patients underwent multiple follow-up endoscopic examinations (mean 4.6; median 4; range 2 - 9; total number 1010). RESULTS: En bloc resection was achieved in 90.1 % of lesions (263/292) and resection was deemed to be complete in 233 (79.8 %). Right-side colonic location and the finding of fibrosis were the significant contributors to incomplete resection. Perforation was seen in 24 cases (8.2 %), and was associated with large tumor size and the presence of fibrosis. When the contributive factors for each were combined, the risks of incomplete resection and perforation were substantially increased. CONCLUSION: The present study provides useful information for predicting risks for incomplete resection and complication in colorectal ESD.

Concentrations of alpha- and beta-defensins in plasma of patients with inflammatory bowel disease.

BACKGROUND: Impaired production/release of defensins, representative endogenous antimicrobial peptides, is associated with the pathogenesis of inflammatory bowel disease (IBD). MATERIAL AND METHODS: Employing in house radioimmunoassay, we examined concentrations of the major forms alpha-defensins, human neutrophil peptides (HNP) 1-3 and human beta-defensin (HBD)-2 in plasma of 55 IBD patients consisting of 29 patients with ulcerative colitis (UC) and 26 with Crohn's disease (CD) and 57 controls. RESULTS: The circulating HNP 1-3, but not HBD-2, levels in IBD patients were significantly higher than those in controls. Plasma HNP 1-3 concentrations in CD patients significantly correlated with Crohn's disease activity index, peripheral white blood cell counts, serum CRP values and TNF-alpha levels. CONCLUSIONS: Elevation of circulating alpha-defensins levels is suggestive of their physiopathological roles in IBD. Plasma HNP 1-3 concentrations may be an indicator for CD activity and their association with CRP and TNF-alpha supports a possible association with the inflammatory process.

Relationship between period of survival and clinicopathological characteristics in patients with colorectal liver metastasis.

AIM: Cancer death in the early period after hepatectomy still occurs in patients with colorectal liver metastasis (CLM). We examined the relationship between clinicopathological parameters and survival periods in 130 CLM patients who underwent hepatectomy. PATIENTS/METHODS: Patients were divided into four groups: Group 1 (5-year survivors without tumor relapse), Group 2 (survivors at 2-5 years), Group 3 (cancer death at 2-5 years), and Group 4 (cancer death within 2 years). RESULTS: A short surgical margin was frequent in Group 4 compared to Group 1 (31 vs. 78%, P<0.05). Primary node-positive status, absence of fibrous pseudo-capsular formation, higher Clinical Risk Score, and tumor recurrence within 12 months were frequent in Group 4 (P<0.05). Multivariate analysis revealed a short surgical margin (HR; 3.5) and early tumor relapse (HR; 5.9) as independently significant related parameters (P<0.05). CONCLUSIONS: Sufficient surgical margins and careful follow-up for early tumor relapse may be important for improving postoperative outcomes for CLM patients.

Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study.

OBJECTIVE: Endoscopic submucosal dissection (ESD) has the advantage over conventional endoscopic mucosa resection, permitting removal of early gastric cancer (EGC) en bloc, but long-term clinical outcomes remain unknown. A follow-up study on tumour recurrence and survival after ESD was conducted. METHOD: ESD was performed for patients with EGC that fulfilled the expanded criteria: mucosal cancer without ulcer findings irrespective of tumour size; mucosal cancer with ulcer findings