No abstract

No abstract

Helicobacter pylori infection induces various gastroduodenal diseases. We examined the role of two genes, vacA and cagE, in the gastric pathogenesis induced by H. pylori using a long-term (62 wk) animal model. Reportedly, both genes are associated with the virulence of H. pylori: vacA encodes vacuolating cytotoxin, and cagE, with other genes in the cag pathogenicity islands, encodes a type IV secretion system. Mongolian gerbils were challenged in this study by a wild-type TN2 strain and its isogenic mutants of cagE or vacA. The wild-type and vacA mutants induced severe gastritis, whereas cagE mutants induced far milder changes. Gastric ulcer was induced at the highest rate (22/23) by the wild-type TN2, followed by the vacA mutant (19/28). No ulcer was found in the gerbils infected with the cagE mutant (0/27) or in controls (0/27). Intestinal metaplasia was also found in the gerbils infected with the wild-type (14/23) or vacA mutant (15/28). Gastric cancer developed in one gerbil with wild-type infection and in one with vacA mutant infection. In conclusion, the knocking out of the cagE gene deprived wild-type H. pylori of the pathogenicity for gastritis and gastric ulcer, suggesting that the secretion system encoded by cag pathogenicity island genes plays an essential role.

No abstract

Background-VacA and CagA proteins have been reported to be major virulence factors of Helicobacter pylori. However, antibodies against these proteins are frequently found in the sera of Japanese patients regardless of their gastroduodenal status. Aim-To evaluate the expression of VacA and CagA proteins by H pylori strains isolated in Japan. Methods-By using specific antibodies raised against recombinant VacA and CagA proteins, the expression of VacA and CagA was evaluated in 68 H pylori strains isolated from Japanese patients; a vacuolating assay and genotyping of the vacA gene were also used in the evaluation. The results were analysed in relation to the gastroduodenal diseases of the hosts. Results-VacA and CagA proteins were expressed in 59/68 (87%) and in 61/68 (90%) isolates respectively. The vacuolating assay was positive in 57/68 (84%) isolates, indicating that most immunologically VacA positive strains produced active cytotoxin. The prevalence of infection with strains expressing CagA and positive for vacuolating activity (Type I) was very high, 54/68 (79%), irrespective of the gastroduodenal status of the host. Conclusion-Most H pylori isolates in Japan are positive for vacuolating cytotoxin and CagA, and thus these virulence factors cannot be used as markers to discern the risk of developing serious gastroduodenal pathologies in the hosts. However, the high prevalence of infection with strains positive for vacuolating cytotoxin and CagA may contribute to the characteristics of H pylori infection in Japan. (Gut 1998;42:338-343)

No abstract

Purpose: Nuclear factor nB (NF-nB) is an important transcription factor in various biological processes. Constitutive NF-nB activation has been noted in many tumors, including colorectal cancers. However, the precise role of this activation in colorectal cancer is unclear. Experimental Design: Constitutive NF-nB activation was evaluated in colorectal cancer tissues and cell lines. To inhibit NF-nB activation, we established cancer cells with stable knockdown of InB kinase g (NF-nB essential modulator), which is the regulatory subunit of the InB kinase complex, by RNA interference. Cell growth and apoptosis were evaluated in wild-type cells (WT) and knocked-down cells (KD). Microarray and protein array analysis were also done. To determine involvement of angiogenesis, human umbilical vein endothelial cells were used. By s.c. transplantation of the cells into nude mice, tumor sizes, vascularity, and chemodrug sensitivity were analyzed. Results: Constitutive NF-nB activation was observed in 40% of colorectal cancer tissues and 67% of cell lines. Cell proliferation was not different between WT and KD in vitro, whereas apoptosis mediated by tumor necrosis factor-a and 5-fluorouracil were increased in KD. Several angiogenic chemokines were decreased in KD. Human umbilical vein endothelial cells incubated in WT supernatant showed more branch points than in KD, suggesting that constitutive NF-nB activation was involved in angiogenesis. Subcutaneous tumor expansion was suppressed to 23% in KD, and vessels were also decreased. By 5-fluoruracil treatment, tumor expansion was suppressed to a greater extent in KD (to 6%) than in WT (to 50%). Conclusion: NF-nB inhibition may represent a potent treatment modality in colorectal cancer, especially in cases with constitutive NF-nB activation.Colorectal cancer is the second leading cause of cancer-related death in industrialized nations (1). The development of colorectal cancer results from the sequential accumulation of activating mutations in oncogenes, such as ras, and mutations, truncations, or deletions in the coding sequences of several tumor suppressor genes, including p53 and adenomatous polyposis coli (APC; ref. 2).Over the last decade, there has been a great deal of progress in the development of new therapies for the treatment of colorectal cancer. The cytotoxic chemotherapy drug 5-fluorouracil (FU) was reformulated, and two new drugs, oxaliplatin and irinotecan, have been investigated as adjunctive therapies. In addition, targeted therapies, including monoclonal antibodies against vascular endothelial growth factor (VEGF; bevacizumab) and the epidermal growth factor receptor (cetuximab), are now standard treatments for metastatic colorectal carcinoma (3, 4). However, many cases show tolerance of such treatments (3, 4). Therefore, it is necessary to develop new approaches to replace or complement current therapies.Nuclear factor nB (NF-nB) transcription factors are key regulators of innate immune responses, inflammation, and cell survival (5), and are assembled...

No abstract