IRB 00006477.

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Although Barretts metaplasia of the esophagus (BE) is the only known precursor lesion to esophageal adenocarcinomas (EACs), drivers of the metaplasia->dysplasia->neoplasia cascade in the esophagus remains incompletely understood. Using an AI-guided network transcriptomics approach, in which EAC initiation and progression is modeled as networks to simplify complex multi-cellular processes, we first predict cellular continuum states and disease driving processes with an unprecedented degree of precision. Key AI-guided predictions are subsequently validated in a human organoid model and patient-derived biopsies of BE, a case-control study of genomics of BE progression, and in a cross-sectional study of 113 patients with BE and EACs. We find that all EACs must originate from BE, pinpoint a CXCL8/IL8<-->neutrophil immune microenvironment as a driver of cellular transformation in both EACs and gastroesophageal junction-ACs, and that this driver is prominent in Caucasians (Cau), but notably absent in African Americans (AAs). Network-derived gene signatures, independent signatures of neutrophil processes, CXCL8/IL8, and an absolute neutrophil count (ANC) are associated with risk of progression. SNPs associated with ethnic changes in ANC modify that risk. Thus, findings define a racially influenced immunological basis for cell transformation and suggest that benign ethnic neutropenia in AAs may serve as a deterrent to BE->EAC progression.

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To evaluate the effect of dietary interventions aimed at weight loss in gastroesophageal reflux disease (GERD) symptoms and general health-related quality of life (HRQL) in overweight and obese patients. A population of GERD patients were randomized into two groups: the intervention group received individualized dietary counselling on scheduled appointments throughout 6 months of follow-up (n = 31) and the control group received only informative dietary guidelines on baseline (n = 31). Anthropometric data were monthly collected, and the HRQL score for GERD (GERD-HRQL) and the Health Survey (SF-36) questionnaires were applied on baseline and reevaluated at the end of follow-up. Dietary intervention led to an average weight loss of 4.4 kg (±5.3) and an average BMI reduction of 1.7 kg/m 2 (±2.9) compared to an increase in weight of 2.1 kg (±4.4) (p < .001) and an increase in BMI of 1.3 (±6.3) (p = 0.023) in the control group. Individuals in the intervention group had a mean decrease in symptoms of 6.8 (±5.5) points while the control group had worsening of their symptoms with an increase of 3.3 (±4) points (p < .001) in the disease-specific questionnaire. There was a positive association between weight loss and reduction of symptoms as measured by the GERD-HRQL score (r = .49; p < .001). Dietary intervention for 6 months with an individualized low-calorie diet program produces weight loss and a significant improvement in GERD-related symptoms, as well as in HRQL.