Influence of Living Environment during Childhood on Helicobacter pylori Infection in Japanese Young Adults.

INTRODUCTION: Helicobacter pylori infection is usually established during childhood, for which certain responsible environmental factors have been identified. However, the details of the infection routes remain unclear. OBJECTIVE: To determine the relation between H. pylori infection statuses and living environment of Japanese young adult. METHODS: The subjects were 449 healthy young adult medical students of Tsukuba University (299 men and 150 women, mean age: 22.8 years). The H. pylori infection statuses were investigated using the rapid urease test or urine antibody. Questionnaires regarding sanitary conditions including usage of pit toilet or well water and experience of living with one's grandparents during childhood were surveyed. Each item was compared between the H. pylori-positive and -negative groups. RESULTS: Among all participants, 33 (7.3%) were H. pylori-positive. The usage rates of pit toilets were 12.1 and 3.1% for the H. pylori-positive and -negative groups respectively (p = 0.03; OR 4.35, 95% CI 1.33-14.22). The usage rates of well water were 24.2 and 13.7% for the H. pylori-positive and -negative groups respectively (p = 0.07; OR 2.12, 95% CI 0.91-4.98). The proportion of participants with a history of living with their grandparents was significantly greater in the H. pylori-positive group (46.7%) than in the -negative group (20.9%; p = 0.03; OR 3.28, 95% CI 1.13-9.54). Only a history of living with one's grandparents during childhood showed statistical significance in the multivariate regression analysis (p = 0.04; OR 3.20, 95% CI 1.08-9.49). CONCLUSIONS: These results suggest that H. pylori infection is more strongly related to living with one's grandparents than living in a hygienic environment.

Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.

Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.

Effectiveness of an endoscopic biopsy procedure using EUS-FNA and EMR-C for diagnosing adenocarcinoma arising from ectopic pancreas: two case reports and a literature review.

Adenocarcinomas arising from the ectopic pancreas in the gastrointestinal wall are rarely described in the literature. In addition, obtaining an accurate preoperative diagnosis is difficult in most cases because these adenocarcinomas occur primarily in the submucosal layer and form submucosal tumors. Endoscopic ultrasonography-guided fine-needle aspiration and endoscopic mucosal resection with a transparent plastic cap-fitted panendoscope followed by a biopsy are useful for histological typing and making the differential diagnosis of adenocarcinoma, gastrointestinal stromal tumor, malignant lymphoma or other. These procedures represent the first step toward diagnosing ectopic pancreatic adenocarcinoma. We herein report two such cases with a review of the pertinent literature.

MDM4 expression as an indicator of TP53 reactivation by combined targeting of MDM2 and MDM4 in cancer cells without TP53 mutation.

MDM2 and MDM4, a structurally related MDM2 homolog, negatively regulates expression and functions of TP53 tumor suppressor gene. To explore the precise expression patterns and function of MDM2 and MDM4 in wild-type (wt) TP53 cancer cells, we analyzed 11 various cancer cell lines with wt TP53. All cell lines exhibited deregulated expression of MDM2 and MDM4, and were divided into two distinct types; the one expressing high levels of MDM4 and another expressing low levels of MDM4. The low MDM4 type expressed higher MDM2 levels than the high MDM4 type. In cells with high MDM4 expression, knockdown of MDM4 or MDM2 reactivated TP53, and simultaneous knockdown of MDM2 and MDM4 synergistically reactivated TP53. In contrast, in cells with low MDM4 expression, knockdown of only MDM2 reactivated TP53. These results suggest that both MDM2 and MDM4 are closely involved in TP53 inactivation in cancer cells with high MDM4 expression, whereas only MDM2, and not MDM4, is a regulator of TP53 in cells with low MDM4 expression. MDM4 expression in wt TP53-tumors is a potential indicator for TP53 reactivation cancer therapy by simultaneous targeting of MDM4 and MDM2. Specific knockdown of MDM2 and MDM4 might be applicable for TP53 restoration therapy.

Predicting skin toxicity according to EGFR polymorphisms in patients with colorectal cancer receiving antibody against EGFR.

BACKGROUND/AIM: Monoclonal antibodies against epidermal growth factor receptor (EGFR) can extend progression-free survival (PFS) and overall survival (OS) in patients with unresectable colorectal cancer; however, skin toxicity often interferes with therapy continuation. PATIENTS AND METHODS: We analyzed the polymorphisms in EGFR and IgG fragment C receptor (FCGR) genes and determined their associations with clinical outcomes including PFS, OS, and skin toxicity. Five polymorphisms in EGFR and FCGR genes in 32 patients with unresectable colorectal cancer who were treated with antibodies against EGFR were examined. RESULTS: Patients carrying the C/C genotype of the EGFR D994D polymorphism displayed significantly less skin toxicity than those with other genotypes, although no significant differences in PFS and OS were noted and no significant interactions were detected for other gene polymorphisms. CONCLUSION: These results suggest that the EGFR D994D polymorphism is a useful biomarker for predicting the severity of skin toxicity in patients receiving antibody against EGFR.

The sirtuin inhibitor tenovin-6 upregulates death receptor 5 and enhances cytotoxic effects of 5-fluorouracil and oxaliplatin in colon cancer cells.

It has been reported that upregulated SIRT1 (NAD(+)-dependent class III histone deacetylase) deacetylates the p53 protein, represses its function, and allows for tumor cell growth in various cancers. Here we investigated antitumor effects of tenovin-6, a small-molecule inhibitor of SIRT1 and SIRT2, in various colon cancer cell lines. Tenovin-6 induced apoptosis in all five colon cancer cell lines investigated (two cell lines with wild-type p53 and three with mutant p53) regardless of the p53 mutation status. This effect was accompanied by accumulation of death receptor 5 (DR5) in most cell lines. DR5 silencing in HCT116 cells strongly attenuated tenovin-6-induced apoptosis. We investigated the effect of combining tenovin-6 with conventional anticancer agents 5-fluorouracil (5-FU), SN-38 (an active metabolite of irinotecan), and oxaliplatin. Synergistic antitumor effects of tenovin-6 were observed in combination with either 5-FU or oxaliplatin in vitro. The combination of tenovin-6 and oxaliplatin exhibited potent growth inhibition of HCT116 xenograft tumors in vivo. In conclusion, tenovin-6 induced apoptosis in human colon cancer cells through the activation of the DR5 signaling pathway and enhanced the antitumor properties of 5-FU and oxaliplatin. These results may help develop a novel treatment option for colorectal cancer using a SIRT inhibitor.