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Background and Purpose: Colorectal cancer (CRC) is a major health problem worldwide. Dicarbonyl electrophiles, such as iso-levuglandins (isoLGs), are generated from lipid peroxidation and form covalent adducts with amine-containing macromolecules. We have shown high levels of adducts of isoLGs in colonic epithelial cells from patients with CRC. We thus investigated the role of these reactive aldehydes on colon cancer development. Experimental Approach: We investigated the effect of oral treatment with 2-hydroxybenzylamine (2-HOBA), a natural compound derived from buckwheat seeds that acts as a potent scavenger of electrophiles, on colon carcinogenesis using the azoxymethane-dextran sulfate sodium model of colitis-associated carcinogenesis and mice with epithelial-specific deletion of the adenomatous polyposis coli gene, as a model of sporadic cancer. We also tested 2-HOBA in a murine xenograft of human HCT116 CRC cells implanted into the flank of nude mice. Key Results: 2-HOBA is bioavailable in the colon of mice after supplementation in the drinking water and does affect the colonic microbiome. However, it reduced the level of isoLG adducts to lysine as well as tumorigenesis in both models of CRC. In parallel, we found that NRF2 activation and signaling was decreased in the colon of 2-HOBA-treated mice. Last, the growth of human tumors is significantly attenuated by 2-HOBA supplementation. Conclusion and Implications: 2-HOBA, which has been shown to be safe in humans, reduces colon tumorigenesis and growth of tumor cells in three distinct models of CRC. Thus, 2-HOBA represents a promising natural compound for the prevention and treatment of CRC.

In populations with similar prevalence of Helicobacter pylori infection, cancer risk can vary dramatically. Changes in composition or structure of bacterial communities in the stomach, either at the time of exposure or over the course of H. pylori infection, may contribute to gastric pathology. In this study, a population of 37 patients from the low-gastric-cancer-risk (LGCR) region of Tumaco, Colombia, and the high-gastric-cancer-risk (HGCR) region of Túquerres, Colombia, were recruited for gastric endoscopy. Antral biopsy specimens were processed for histology and bacterial isolation. Fifty-nine distinct species among 26 genera were isolated by aerobic, anaerobic, and microaerobic culture and confirmed by 16S rRNA analysis. Urease-positive Staphylococcus epidermidis and Streptococcus salivarius were frequently isolated from gastric biopsy specimens. We asked whether coinfection of H. pylori with urease-positive

// Mohammed Soutto 1, 2 , Judith Romero-Gallo 3 , Uma Krishna 3 , M. Blanca Piazuelo 3 , M. Kay Washington 4 , Abbes Belkhiri 2 , Richard M. Peek Jr 3, 5 , Wael El-Rifai 1, 2, 5 1 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA 2 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA 3 Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA 4 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 5 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA Correspondence to: Wael El-Rifai, e-mail: wael.el-rifai@vanderbilt.edu Keywords: TFF1, Helicobacter pylori, s-catenin, gastric cancer Abbreviations: TFF1; trefoil factor 1, H. pylori; Helicobacter pylori, knockout; KO, TCF/LEF; T cell factor/lymphoid Received: February 18, 2015 Accepted: April 14, 2015 Published: April 27, 2015 ABSTRACT Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori -mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori -induced β-catenin nuclear translocation, as compared to control ( p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes ( CCND1 and c-MYC) , as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori -induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1 -KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1 -KO, as compared to Tff1 -WT mice ( p < 0.05). Only 10% of uninfected Tff1 -KO mice, as opposed to one-third of H. pylori -infected Tff1 -KO mice, developed invasive adenocarcinoma ( p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori -mediated oncogenic activation of β-catenin and gastric tumorigenesis.

Background: TFF1 deficiency induces a mucosal pro-inflammatory phenotype that contributes to gastric tumorigenesis in mouse and human. Methods: We utilized the Tff1-KO mouse model to assess the impact of TFF1 loss on immune cells infiltration in the stomach. We used single cell suspension, flow cytometry, immunohistochemistry, and quantitative PCR (qPCR) assays. Results: The Tff1-KO gastric mucosa demonstrated high chronic inflammatory scores (score: 3-4) at age 2 months, which exacerbated at age 8 months (score: 4-6). We next used single-cell suspensions for flow cytometry analysis of total leukocytes (CD45+ cells), total T lymphocytes (CD45+CD3+cells), T cell subsets (CD4+, CD8+, and CD3+CD4-CD8-cells), and monocytes/macrophages (CD45+F4/80+cells). The results demonstrated an age-dependent (2 → 8 month age) significant increase of leukocytes (p

The aim of this study was to assess the role of add-on devices for the prevention of phlebitis and other complications associated with the use of peripheral catheters. Patients admitted to an infectious diseases ward and requiring the insertion of a peripheral catheter for at least 24h were randomly allocated to be managed with or without add-on devices. Incidence of phlebitis and all complications were the primary outcomes. Extravasation, inadvertent withdrawal, obstruction and rupture were considered to be mechanical complications, and analysis was performed using survival methods. Of 683 evaluated catheters, 351 were allocated to the add-on device arm and 332 to the control arm. Despite randomisation, patients in the add-on device group were older (P=0.048), less likely to have human immunodeficiency virus (P=0.02) and more likely to have received antibiotics (P=0.05). After adjustment for these variables, the hazard ratio for phlebitis remained non-significant (hazard ratio: 0.95; 95% confidence interval: 0.7-1.3), but the risk of mechanical complications became lower in the add-on device arm (0.68; 0.5-0.94). This translated into a trend towards a lower risk of any complication (0.83; 0.67-1.01). The beneficial effect on mechanical or all complications was noticeable after six days of catheterisation. Add-on devices do not reduce the incidence of phlebitis but may prevent mechanical complications. However, the impact of add-on devices on the incidence of all complications is at most small and only apparent after the sixth day of catheter use.