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Gastroesophageal Reflux Induces Protein Adducts in the Esophagus.
Caspa Gokulan R, Adcock JM, Zagol-Ikapitte I, Mernaugh R, Williams P, Washington KM, Boutaud O, Oates JA, Dikalov SI, Zaika AI
(2019) Cell Mol Gastroenterol Hepatol 7: 480-482.e7
MeSH Terms: Acetylcysteine, Animals, Benzylamines, Bile Acids and Salts, Cell Line, Cyclic N-Oxides, Esophagus, Gastroesophageal Reflux, Humans, Lipids, Mice, Spin Labels, Tumor Suppressor Protein p53
Added March 26, 2019
0 Communities
1 Members
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13 MeSH Terms
Activation of NADPH oxidases leads to DNA damage in esophageal cells.
Bhardwaj V, Gokulan RC, Horvat A, Yermalitskaya L, Korolkova O, Washington KM, El-Rifai W, Dikalov SI, Zaika AI
(2017) Sci Rep 7: 9956
MeSH Terms: Barrett Esophagus, Bile Acids and Salts, Cells, Cultured, DNA Damage, Epithelial Cells, Humans, NADPH Oxidase 1, NADPH Oxidase 2, Reactive Oxygen Species
Show Abstract · Added March 26, 2019
Gastroesophageal reflux disease (GERD) is the strongest known risk factor for esophageal adenocarcinoma. In the center of tumorigenic events caused by GERD is repeated damage of esophageal tissues by the refluxate. In this study, we focused on a genotoxic aspect of exposure of esophageal cells to acidic bile reflux (BA/A). Analyzing cells generated from patients with Barrett's esophagus and human esophageal specimens, we found that BA/A cause significant DNA damage that is mediated by reactive-oxygen species. ROS originate from mitochondria and NADPH oxidases. We specifically identified NOX1 and NOX2 enzymes to be responsible for ROS generation. Inhibition of NOX2 and NOX1 with siRNA or chemical inhibitors significantly suppresses ROS production and DNA damage induced by BA/A. Mechanistically, our data showed that exposure of esophageal cells to acidic bile salts induces phosphorylation of the p47 subunit of NOX2 and its translocation to the cellular membrane. This process is mediated by protein kinase C, which is activated by BA/A. Taken together, our studies suggest that inhibition of ROS induced by reflux can be a useful strategy for preventing DNA damage and decreasing the risk of tumorigenic transformation caused by GERD.
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9 MeSH Terms
Prevention of DNA damage in Barrett's esophageal cells exposed to acidic bile salts.
Bhardwaj V, Horvat A, Korolkova O, Washington MK, El-Rifai W, Dikalov SI, Zaika AI
(2016) Carcinogenesis 37: 1161-1169
MeSH Terms: Acetophenones, Acids, Adenocarcinoma, Antioxidants, BRCA1 Protein, Barrett Esophagus, Bile Acids and Salts, Cell Line, Tumor, DNA Damage, DNA Repair, Esophageal Neoplasms, Gastric Acid, Gastroesophageal Reflux, Humans, Reactive Oxygen Species
Show Abstract · Added March 26, 2019
Esophageal adenocarcinoma (EA) is one of the fastest rising tumors in the USA. The major risk factor for EA is gastroesophageal reflux disease (GERD). During GERD, esophageal cells are exposed to refluxate which contains gastric acid frequently mixed with duodenal bile. This may lead to mucosal injury and Barrett's metaplasia (BE) that are important factors contributing to development of EA. In this study, we investigated DNA damage in BE cells exposed to acidic bile salts and explored for potential protective strategies. Exposure of BE cells to acidic bile salts led to significant DNA damage, which in turn, was due to generation of reactive oxygen species (ROS). We found that acidic bile salts induce a rapid increase in superoxide radicals and hydrogen peroxide, which were determined using electron paramagnetic resonance spectroscopy and Amplex Red assay. Analyzing a panel of natural antioxidants, we identified apocynin to be the most effective in protecting esophageal cells from DNA damage induced by acidic bile salts. Mechanistic analyses showed that apocynin inhibited ROS generation and increases the DNA repair capacity of BE cells. We identified BRCA1 and p73 proteins as apocynin targets. Downregulation of p73 inhibited the protective effect of apocynin. Taken together, our results suggest potential application of natural compounds such as apocynin for prevention of reflux-induced DNA damage and GERD-associated tumorigenesis.
© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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MeSH Terms
APE1-mediated DNA damage repair provides survival advantage for esophageal adenocarcinoma cells in response to acidic bile salts.
Hong J, Chen Z, Peng D, Zaika A, Revetta F, Washington MK, Belkhiri A, El-Rifai W
(2016) Oncotarget 7: 16688-702
MeSH Terms: Adenocarcinoma, Barrett Esophagus, Bile Acids and Salts, Cell Line, Tumor, Cell Survival, DNA Damage, DNA Repair, DNA-(Apurinic or Apyrimidinic Site) Lyase, Esophageal Neoplasms, Gastroesophageal Reflux, Humans
Show Abstract · Added April 8, 2016
Chronic Gastroesophageal Reflux Disease (GERD) is the main risk factor for the development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC). Accordingly, EAC cells are subjected to high levels of oxidative stress and subsequent DNA damage. In this study, we investigated the expression and role of Apurinic/apyrimidinic endonuclease 1 (APE1) protein in promoting cancer cell survival by counteracting the lethal effects of acidic bile salts (ABS)-induced DNA damage. Immunohistochemistry analysis of human tissue samples demonstrated overexpression of APE1 in more than half of EACs (70 of 130), as compared to normal esophagus and non-dysplastic BE samples (P < 0.01). To mimic in vivo conditions, we treated in vitro cell models with a cocktail of ABS. The knockdown of endogenous APE1 in EAC FLO-1 cells significantly increased oxidative DNA damage (P < 0.01) and DNA single- and double-strand breaks (P < 0.01), whereas overexpression of APE1 in EAC OE33 cells reversed these effects. Annexin V/PI staining indicated that the APE1 expression in OE33 cells protects against ABS-induced apoptosis. In contrast, knockdown of endogenous APE1 in FLO-1 cells increased apoptosis under the same conditions. Mechanistic investigations indicated that the pro-survival function of APE1 was associated with the regulation of stress response c-Jun N-terminal protein kinase (JNK) and p38 kinases. Pharmacological inhibition of APE1 base excision repair (BER) function decreased cell survival and enhanced activation of JNK and p38 kinases by ABS. Our findings suggest that constitutive overexpression of APE1 in EAC may be an adaptive pro-survival mechanism that protects against the genotoxic lethal effects of bile reflux episodes.
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11 MeSH Terms
Modifiable Risk Factors for Barrett's Esophagus and Esophageal Adenocarcinoma: Still a Shot in the Dark.
Yachimski P
(2016) Clin Gastroenterol Hepatol 14: 773-4
MeSH Terms: Adenocarcinoma, Barrett Esophagus, Humans, Risk Factors
Added May 11, 2016
0 Communities
1 Members
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4 MeSH Terms
Dietary magnesium, calcium:magnesium ratio and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma: a population-based case-control study.
Dai Q, Cantwell MM, Murray LJ, Zheng W, Anderson LA, Coleman HG, FINBAR study group
(2016) Br J Nutr 115: 342-50
MeSH Terms: Adenocarcinoma, Aged, Alcohol Drinking, Barrett Esophagus, Body Mass Index, Calcium, Dietary, Case-Control Studies, Diet, Diet Records, Educational Status, Esophageal Neoplasms, Esophagitis, Peptic, Humans, Ireland, Magnesium, Middle Aged, Northern Ireland, Odds Ratio, Risk Factors, Smoking
Show Abstract · Added May 6, 2016
Evidence suggests a role of Mg and the ratio of Ca:Mg intakes in the prevention of colonic carcinogenesis. The association between these nutrients and oesophageal adenocarcinoma - a tumour with increasing incidence in developed countries and poor survival rates - has yet to be explored. The aim of this investigation was to explore the association between Mg intake and related nutrients and risk of oesophageal adenocarcinoma and its precursor conditions, Barrett's oesophagus and reflux oesophagitis. This analysis included cases of oesophageal adenocarcinoma (n 218), Barrett's oesophagus (n 212), reflux oesophagitis (n 208) and population-based controls (n 252) recruited between 2002 and 2005 throughout the island of Ireland. All the subjects completed a 101-item FFQ. Unconditional logistic regression analysis was applied to determine odds of disease according to dietary intakes of Mg, Ca and Ca:Mg ratio. After adjustment for potential confounders, individuals consuming the highest amounts of Mg from foods had significant reductions in the odds of reflux oesophagitis (OR 0·31; 95 % CI 0·11, 0·87) and Barrett's oesophagus (OR 0·29; 95 % CI 0·12, 0·71) compared with individuals consuming the lowest amounts of Mg. The protective effect of Mg was more apparent in the context of a low Ca:Mg intake ratio. No significant associations were observed for Mg intake and oesophageal adenocarcinoma risk (OR 0·77; 95 % CI 0·30, 1·99 comparing the highest and the lowest tertiles of consumption). In conclusion, dietary Mg intakes were inversely associated with reflux oesophagitis and Barrett's oesophagus risk in this Irish population.
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20 MeSH Terms
Phase Ib Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Patients with Barrett's Esophagus.
Joe AK, Schnoll-Sussman F, Bresalier RS, Abrams JA, Hibshoosh H, Cheung K, Friedman RA, Yang CS, Milne GL, Liu DD, Lee JJ, Abdul K, Bigg M, Foreman J, Su T, Wang X, Ahmed A, Neugut AI, Akpa E, Lippman SM, Perloff M, Brown PH, Lightdale CJ
(2015) Cancer Prev Res (Phila) 8: 1131-7
MeSH Terms: Aged, Aged, 80 and over, Barrett Esophagus, Biopsy, Catechin, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Double-Blind Method, Esophagoscopy, Female, Humans, Male, Middle Aged, Phytotherapy
Show Abstract · Added March 10, 2016
This study was conducted to determine the safety and efficacy of the green tea-derived Polyphenon E (Poly E) in patients with Barrett's Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200, 400, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase II dose was 600 mg twice daily. The most common treatment-related adverse events (AE) in Poly E-treated subjects were grade I and II nausea, grade I belching, and grade I lactate dehydrogenase (LDH) elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade I laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, on the basis of an intention-to-treat analysis, there was a significant relationship between Poly E dose and esophageal EGCG level--mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); P = 0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and treatment with Poly E (400 and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa.
©2015 American Association for Cancer Research.
1 Communities
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14 MeSH Terms
Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma.
Taylor C, Loomans HA, Le Bras GF, Koumangoye RB, Romero-Morales AI, Quast LL, Zaika AI, El-Rifai W, Andl T, Andl CD
(2015) Oncotarget 6: 34228-44
MeSH Terms: Activins, Adenocarcinoma, Barrett Esophagus, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Enzyme-Linked Immunosorbent Assay, Esophageal Neoplasms, Fluorescent Antibody Technique, Humans, Neoplasm Invasiveness
Show Abstract · Added October 13, 2015
TGFβ signaling has been implicated in the metaplasia from squamous epithelia to Barrett's esophagus and, ultimately, esophageal adenocarcinoma. The role of the family member Activin A in Barrett's tumorigenesis is less well established. As tumorigenesis is influenced by factors in the tumor microenvironment, such as fibroblasts and the extracellular matrix, we aimed to determine if epithelial cell-derived Activin affects initiation and progression differently than Activin signaling stimulation from a mimicked stromal source. Using Barrett's esophagus cells, CPB, and the esophageal adenocarcinoma cell lines OE33 and FLO-1, we showed that Activin reduces colony formation only in CPB cells. Epithelial cell overexpression of Activin increased cell migration and invasion in Boyden chamber assays in CPB and FLO-1 cells, which exhibited mesenchymal features such as the expression of the CD44 standard form, vimentin, and MT1-MMP. When grown in organotypic reconstructs, OE33 cells expressed E-cadherin and Keratin 8. As mesenchymal characteristics have been associated with the acquisition of stem cell-like features, we analyzed the expression and localization of SOX9, showing nuclear localization of SOX9 in esophageal CPB and FLO-1 cells.In conclusion, we show a role for autocrine Activin signaling in the regulation of colony formation, cell migration and invasion in Barrett's tumorigenesis.
0 Communities
3 Members
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12 MeSH Terms
Quality indicators for the management of Barrett's esophagus, dysplasia, and esophageal adenocarcinoma: international consensus recommendations from the American Gastroenterological Association Symposium.
Sharma P, Katzka DA, Gupta N, Ajani J, Buttar N, Chak A, Corley D, El-Serag H, Falk GW, Fitzgerald R, Goldblum J, Gress F, Ilson DH, Inadomi JM, Kuipers EJ, Lynch JP, McKeon F, Metz D, Pasricha PJ, Pech O, Peek R, Peters JH, Repici A, Seewald S, Shaheen NJ, Souza RF, Spechler SJ, Vennalaganti P, Wang K
(2015) Gastroenterology 149: 1599-606
MeSH Terms: Adenocarcinoma, Barrett Esophagus, Consensus, Consensus Development Conferences as Topic, Disease Management, Disease Progression, Esophageal Neoplasms, Esophagoscopy, Esophagus, Gastroenterology, Humans, United States
Show Abstract · Added February 5, 2016
The development of and adherence to quality indicators in gastroenterology, as in all of medicine, is increasing in importance to ensure that patients receive consistent high-quality care. In addition, government-based and private insurers will be expecting documentation of the parameters by which we measure quality, which will likely affect reimbursements. Barrett's esophagus remains a particularly important disease entity for which we should maintain up-to-date guidelines, given its commonality, potentially lethal outcomes, and controversies regarding screening and surveillance. To achieve this goal, a relatively large group of international experts was assembled and, using the modified Delphi method, evaluated the validity of multiple candidate quality indicators for the diagnosis and management of Barrett's esophagus. Several candidate quality indicators achieved >80% agreement. These statements are intended to serve as a consensus on candidate quality indicators for those who treat patients with Barrett's esophagus.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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1 Members
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12 MeSH Terms
Randomized controlled trial comparing esophageal dilation to no dilation among adults with esophageal eosinophilia and dysphagia.
Kavitt RT, Ates F, Slaughter JC, Higginbotham T, Shepherd BD, Sumner EL, Vaezi MF
(2016) Dis Esophagus 29: 983-991
MeSH Terms: Adult, Deglutition Disorders, Dexlansoprazole, Dilatation, Eosinophilic Esophagitis, Esophageal Stenosis, Esophagoplasty, Esophagoscopy, Esophagus, Female, Fluticasone, Glucocorticoids, Humans, Male, Proton Pump Inhibitors, Single-Blind Method, Treatment Outcome, Young Adult
Show Abstract · Added September 28, 2015
The role of esophageal dilation in patients with esophageal eosinophilia with dysphagia remains unknown. The practice of dilation is currently based on center preferences and expert opinion. The aim of this study is to determine if, and to what extent, dysphagia improves in response to initial esophageal dilation followed by standard medical therapies. We conducted a randomized, blinded, controlled trial evaluating adult patients with dysphagia and newly diagnosed esophageal eosinophilia from 2008 to 2013. Patients were randomized to dilation or no dilation at time of endoscopy and blinded to dilation status. Endoscopic features were graded as major and minor. Subsequent to randomization and endoscopy, all patients received fluticasone and dexlansoprazole for 2 months. The primary study outcome was reduction in overall dysphagia score, assessed at 30 and 60 days post-intervention. Patients with severe strictures (less than 7-mm esophageal diameter) were excluded from the study. Thirty-one patients were randomized and completed the protocol: 17 randomized to dilation and 14 to no dilation. Both groups were similar with regard to gender, age, eosinophil density, endoscopic score, and baseline dysphagia score. The population exhibited moderate to severe dysphagia and moderate esophageal stricturing at baseline. Overall, there was a significant (P < 0.001) but similar reduction in mean dysphagia score at 30 and 60 days post-randomization compared with baseline in both groups. No significant difference in dysphagia scores between treatment groups after 30 (P = 0.93) or 60 (P = 0.21) days post-intervention was observed. Esophageal dilation did not result in additional improvement in dysphagia score compared with treatment with proton pump inhibitor and fluticasone alone. In patients with symptomatic esophageal eosinophilia without severe stricture, dilation does not appear to be a necessary initial treatment strategy.
© 2015 International Society for Diseases of the Esophagus.
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18 MeSH Terms