Sheng-Wen Wang

Helicobacter pylori infection: a randomized, controlled study comparing 2 rescue therapies after failure of standard triple therapies.

Antibiotic resistance to amoxicillin in second-line eradication therapy for Helicobacter pylori infection is much less frequent than resistance to metronidazole. We conducted a randomized, controlled study to compare the efficacies of standard quadruple rescue therapy and a new therapy with amoxicillin replacing metronidazole for patients failing first-line eradication treatment. We randomly assigned 120 patients who failed H. pylori eradication using a proton pump inhibitor plus clarithromycin and amoxicillin to undergo a 1-week rescue therapy with esomeprazole, bismuth subcitrate, and tetracycline plus either metronidazole (EBTM group, n = 62) or amoxicillin (EBTA group, n = 58). We used follow-up endoscopy 8 weeks after the end of treatment to assess the treatment response. We also examined and analyzed antibiotic resistances and CYP2C19 genotypes.Intention-to-treat analysis demonstrated that the EBTA group had a significantly lower eradication rate than the EBTM group (62% vs. 81%, respectively, p = 0.02). Per-protocol analysis showed similar results (64% vs. 83%, p = 0.01). However, the EBTA group had less frequency of adverse events than the EBTM group (19% vs. 44%, p < 0.01). Both groups had good drug compliance (both 97%). Antibiotic susceptibility tests showed that the frequency of amoxicillin-resistant strains was much less than that of metronidazole-resistant strains (0% vs. 54%, respectively), and there were no significant differences between H. pylori eradication rates and antibiotic resistances.In conclusion, EBTA quadruple therapy demonstrated a lower eradication rate than standard EBTM therapy in second-line rescue treatment. The discrepancy between in vitro antibiotic susceptibility and in vivo eradication response is probably due to drug interactions between combined antibiotics or some unknown causes, and should not be neglected in H. pylori therapy.Abbreviations: b.d. = twice a day, CI = confidence interval, EBTA = esomeprazole, bismuth subcitrate, tetracycline plus amoxicillin, EBTM = esomeprazole, bismuth subcitrate, tetracycline plus metronidazole, hetEM = heterogeneous extensive metabolizer, homEM = homogeneous extensive metabolizer, ITT = intention-to-treat, PM = poor metabolizer, PP = per-protocol, PPI = proton pump inhibitor, q.d.s. = 4 times a day.

Isolation and characterization of human gastric cell lines with stem cell phenotypes.

Aim:  The aim of this study was to develop an in vitro human gastric stem and/or progenitor cell model that may be used to study the mechanism of gastric carcinogenesis induced by Helicobacter pylori infection.

Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients

The current study was to investigate the interaction between Helicobacter pylori and human dendritic cells (DCs). Whether impaired DC function can influence the outcome of H. pylori infections. Human monocyte-derived DCs (MDDCs) from five gastric cancer patients and nine healthy controls were stimulated with H. pylori. Maturation markers of MDDC were examined by flow cytometry. IL-10 and TNF-α released by MDDCs and IL-17 produced by T cells were measured by ELISA. Regulatory signaling pathways of IL-10 were examined by ELISA, western blotting, and chromatin immunoprecipitation assay. The results showed that as compared with healthy individuals, the maturation marker CD40 in MDDCs, IL-17A expression from T cells, and IL-10 expression from MDDCs were significantly lower in gastric cancer patients. Blocking DC-SIGN, TLR2, and TLR4 could reverse H. pylori-associated IL-10 production. Activation of the p38 MAPK and NF-kB signaling pathways concomitant with decreased tri-methylated H3K9 and increased acetylated H3 accounted for the effect of H. pylori on IL-10 expression. Furthermore, upregulated IL-10 expression was significantly suppressed in H. pylori-pulsed MDDCs by histone acetyltransferase and methyltransferase inhibitors. Taken together, impaired DC function contributes to the less effective innate and adaptive immune responses against H. pylori seen in gastric cancer patients. H. pylori can regulate IL-10 production through Toll-like and DC-SIGN receptors, activates p-p38 MAPK signaling and the transcription factors NF-kB, and modulates histone modification.

A tumorigenic homeobox (HOX) gene expressing human gastric cell line derived from putative gastric stem cell.

Goal Study the mechanism of gastric tumor development. Background We have generated and characterized a novel human gastric cell line, KMU-CS12 (CS12), from an immortal cell line, KMU-CSN (CSN; formerly named as GI2CS−) which was derived from putative human gastric stem cell/progenitor cell clone, KMU-GI2. Study The characterization of the CS12 cell line includes gene expression by immunocytochemical staining, cell proliferation and differentiation potential, cyotogenetic analysis by Giemsa banding and spectral karyotype analysis (SKY), and tumorigenicity in immune-deficient congenic inbred, nude mice (BALB/cAnN-Foxn1nu/CrlNarl). The Agilent Human 1A oligo-array and RT-PCR were also employed to analyze the expression of homeobox (HOX) genes. Results The CS12 gastric cell line showed cancer cell phenotypes, i.e. the ability of anchorage-independent growth high frequency (44%) and to the expression of Oct-4, a transcription factor expressed in embryonic stem cells and many types of cancer cells, and tumor development in immune deficient mice. SKY analysis indicated a characteristic duplication of the short arm of chromosome 7 to chromosome 12. Agilent Human 1A oligo-array analysis showed that the expression of 1145 genes was upregulated while that of 890 genes was downregulated in CS12 cells. RT-PCR revealed that homeobox genes (HOXA4, HOXA5, HOXA7, HOXA9, and HOXA13) were highly expressed in CS12 cells in culture, as well as tumor tissues developed by CS12 cells in immunodeficient mice for six to eight weeks. Conclusion Except for the duplication of the short arm of Chromosome 7 on Chromosome12, the karyotype of the tumorigenic CS12 cells is similar to the parental GI2 cells which are non-tumorigenic and normal in karyotype. This chromosomal change could be the cause for the high expression of HOXA genes and tumorigenicity of these cells found in this study. Thus HOXA genes might play an important role in gastric carcinogenesis.