Helicobacter pylori causes epigenetic dysregulation of FOXD3 to promote gastric carcinogenesis.

BACKGROUND & AIMS: Deregulation of forkhead box (Fox) proteins, an evolutionarily conserved family of transcriptional regulators, leads to tumorigenesis. Little is known about their regulation or functions in the pathogenesis of gastric cancer. Promoter hypermethylation occurs during Helicobacter pylori-induced gastritis. We investigated whether the deregulated genes contribute to gastric tumorigenesis. METHODS: We used integrative genome-wide scans to identify concomitant hypermethylated genes in mice infected with H pylori and human gastric cancer samples. We also analyzed epigenetic gene silencing in gastric tissues from patients with H pylori infection and gastritis, intestinal metaplasia, gastric tumors, or without disease (controls). Target genes were identified by chromatin immunoprecipitation microarrays and expression and luciferase reporter analyses. RESULTS: Methylation profile analyses identified the promoter of FOXD3 as the only genomic region with increased methylation in mice and humans during progression of H pylori-associated gastric tumors. FOXD3 methylation also correlated with shorter survival times of patients with gastric cancer. Genome demethylation reactivated FOXD3 expression in gastric cancer cell lines. Transgenic overexpression of FOXD3 significantly inhibited gastric cancer cell proliferation and invasion, and reduced growth of xenograft tumors in mice, at least partially, by promoting tumor cell apoptosis. FOXD3 bound directly to the promoters of, and activated transcription of, genes encoding the cell death regulators CYFIP2 and RARB. Levels of FOXD3, CYFIP2, and RARB messenger RNAs were reduced in human gastric tumor samples, compared with control tissues. CONCLUSIONS: FOXD3-mediated transcriptional control of tumor suppressors is deregulated by H pylori infection-induced hypermethylation; this could perturb the balance between cell death and survival. These findings identify a pathway by which epigenetic changes affect gastric tumor suppression.

Exposure assessment of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in temporary municipal-waste-incinerator maintenance workers before and after annual maintenance.

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) have been found in ambient air around municipal waste incinerators (MWIs), and elevated serum levels in incinerator workers have also been observed in some studies. However, few studies have focused on temporary employees who work intermittently through the annual maintenance and clean-up around different incinerators. The present study aimed to assess the change in serum PCDD/F levels of temporary employees between the beginning of periodic incinerator maintenance and one month the work was completed. Thirty-five volunteer workers, most of them transient and temporary maintenance staff, were recruited from a contractor that provided annual maintenance for four incinerators in this study. Information about each participant was obtained by questionnaire at the beginning of annual maintenance. The questionnaire asked for work history, health status, and diet information. As measured by the PCDD/F levels in blood, a significant increase was observed in workers after a month of maintenance work. The increase was greater in workers who had never done this type of maintenance than in those with previous experience, especially for 2,3,4,6,7,8-HxCDF levels. The data also showed that the laborers and employers need to pay more attention to occupational health issues even for short-term incinerator maintenance workers.

Evaluation of PCDD/Fs patterns emitted from incinerator via direct ambient sampling and indirect serum levels assessment of Taiwanese.

The aim of this study was to evaluate the PCDD/Fs patterns in ambient air based on data information emitted from incinerator generated from ambient air measurements and those in serum. Four circular zones, namely A, B, C, and D, were identified based on simulated ambient annual average PCDD/Fs concentrations, from a selected municipal waste incinerator. Sixteen ambient samples were taken from the 4 circular zones across 4-seasons. Eighty-nine volunteers were recruited according to the demographic distribution within each zone. PCDD/Fs profiles were documented both for air and serum samples collected. Comparing to the congener patterns from ambient air and serum samples, we found that OCDD, OCDF, 1,2,3,4,6,7,8-HpCDD, and 1,2,3,4,6,7,8-HpCDF were the predominant groups among 17 congeners from both the ambient air and serum sample. And, factor analysis showed the distribution patterns of PCDD/Fs from ambient air and serum samples are almost identical across different zones, except for congener patterns of serum samples from residents in zone C. In addition, the average PCDD/Fs level significantly reduced for about 10 folds than those of the other three seasons when the incinerator was shut down in one of sampling periods. We might conclude that ambient air exposure was the most important contributor to PCDD/Fs levels in ambient air but not the single in serum. Therefore, another or more powerful source, such as occupational exposure, dietary intake or the consumption of local food, should be further investigated at the same time.

Evaluation of the string test for the detection of Helicobacter pylori.

AIM: Helicobacter pylori can be diagnosed by invasive or non-invasive tests but to obtain bacteria for culture and antibiotic susceptibility testing, an upper GI endoscopy is often required. The string test may be a minimally-invasive alternative method of obtaining H. pylori samples. This study evaluates the sensitivity and specificity of the string test in the diagnosis of H. pylori in comparison with endoscopic means of diagnosis. METHODS: This was a prospective open comparative study of patients with dyspepsia with endoscopy-based tests as gold standard (defined as a positive CLO test and antral histology). Fasting patients swallowed the encapsulated-string (Entero-test Hp), which was withdrawn after 1 hour. The gastric juice from the string was plated onto H. pylori-selective media for culture. Helicobacter pylori was identified by typical colony morphology, gram stain and biochemical test results. RESULTS: Thirty dyspeptic patients were recruited of whom 21 (70 %) were positive for H. pylori according to the gold standard. The sensitivity, specificity, positive predictive value, and negative predictive value for the string test were 38 %, 100 %, 100 % and 41 % respectively, and for endoscopic biopsies 81 %, 100 %, 100 %, 69 % respectively (P=0.004). Logistic regression showed that only abundant growth density from endoscopic biopsy cultures to be a predictor of a positive string test (P=0.018). CONCLUSION: The string test is an alternative method to endoscopy in obtaining H. pylori but has a low sensitivity compared to endoscopic biopsies.