Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 1R01DK103598-01A1 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The purpose of this study is to elucidate mechanisms whereby oxidative stress induced by acute reflux esophagitis: 1) activates p38 to regulate proteins that control the G1/S cell cycle checkpoint, and 2) activates HIFs (hypoxia inducible factors) to cause autocrine VEGF (vascular endothelial growth factor) signaling that triggers the EMT (epithelial-mesenchymal-transition) program in Barrett's esophagus.
Gastroesophageal reflux disease (GERD) and its complication, Barrett's esophagus (BE), are risk factors for esophageal adenocarcinoma. In BE, GERD causes inflammation with oxidative DNA damage and genomic instability that contributes to carcinogenesis. In BE, one response to oxidative stress is p38 pathway activation, which might protect against cancer development by initiating G1 arrest and enabling repair of DNA damage. Inflammation and oxidative stress also might induce epithelial-mesenchymal transition (EMT), the process in which epithelial cells acquire mesenchymal characteristics including the ability to migrate. This study will elucidate mechanisms whereby the oxidative stress of acute reflux esophagitis in BE activates p38 to regulate proteins controlling the G1/S cell cycle checkpoint, and activates HIFs to cause autocrine vascular endothelial growth factor (VEGF) signaling that triggers the EMT program.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Barrett's esophagus patients | Experimental | Patients with Barrett's Esophagus will be enrolled. The intervention is cessation of acid-suppressing medications. Biopsies will be taken during endoscopy at Day 0, 7, and 14. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cessation of Acid Suppressing Medications | Other | Acid suppressing medications are stopped for all participants the day after baseline assessment. Subsequent evaluations are performed while the participant is not on acid-suppressing medications. Endoscopy with biopsies will be performed in all patients on day 0, 7, and 14. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in esophageal mucosal inflammation using histopathological assessment from baseline to 14 days | Inflammation of the esophageal mucosa will be measured at baseline, 7 days, and at 14 days. Esophageal mucosal inflammation will be measured using esophageal mucosal biopsy specimens, and histopatholgical grading. Mucosal infiltration with inflammatory cells (neutrophils, eosinophils, and lymphocytes) will be measured. | day 0, day 7, and day 14 |
| Measure | Description | Time Frame |
|---|---|---|
| change in p38 pathway from baseline to 14 days | p38 and components of the p38 pathway will be measured in the esophageal mucosa at baseline, 7 days, and at 14 days | day 0, day 7, and day 14 |
| change in phosoho-p38 from baseline to 14 days |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Stuart J Spechler, MD | Dallas VA Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dallas VA Medical Center | Dallas | Texas | 75216 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38641363 | Derived | Zhang Q, Dunbar KB, Odze RD, Agoston AT, Wang X, Su T, Nguyen AD, Zhang X, Spechler SJ, Souza RF. Hypoxia-inducible factor-1alpha mediates reflux-induced epithelial-mesenchymal plasticity in Barrett's oesophagus patients. Gut. 2024 Jul 11;73(8):1269-1279. doi: 10.1136/gutjnl-2023-331467. |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D001471 | Barrett Esophagus |
| D005764 | Gastroesophageal Reflux |
| ID | Term |
|---|---|
| D011230 | Precancerous Conditions |
| D009369 | Neoplasms |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
phospho-p38 will be measured in the esophageal mucosa at baseline, day 7, and at day 14
| day 0, day 7, and day 14 |
| Show oxidative DNA damage associated with p38 activation | OxiSelect Oxidative DNA Damage ELISA assay of Barrett's mucosa at baseline, day 7, and day 14 | day 0, day 7, and day 14 |
| change in VEGF from baseline to 14 days | VEGF will be measured in the esophageal mucosa at baseline, 7 days, and at day 14 | day 0, day 7, and day 14 |
| change in APE-1 from baseline to 14 days | APE-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14 | day 0, day 7, and day 14 |
| change in NPM1 from baseline to 14 days | NPM-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14 | day 0, day 7, and day 14 |
| change in phospho-NPM1 from baseline to 14 days | phospho-NPM1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14 | day 0, day 7, and day 14 |
| change in miRNA expression from baseline to 14 days | miRNAs will be measured in the esophageal mucosa and in exosomes isolated from the blood at baseline, day 7, and day 14 | day 0, day 7, and day 14 |
| change in HIF expression from baseline to 14 days | HIF expression will be measured in the esophageal mucosa at baseline, day 7, and day 14 | day 0, day 7, and day 14 |
| D004066 |
| Digestive System Diseases |
| D015154 | Esophageal Motility Disorders |
| D003680 | Deglutition Disorders |