Potential role of fructose on human colon DNA methylation in racial disparities observed for colorectal cancer risk.

Background and aims: An increasing body of observational studies has linked fructose intake to colorectal cancer (CRC). African Americans (AAs) are significantly more likely than European Americans to consume greater quantities of fructose and to develop right-side colon cancer. Yet, a mechanistic link between these two associations remains poorly defined. We aimed to identify differentially methylated regions (DMRs) associated with dietary fructose consumption measures obtained from food frequency questionnaires in a cohort of normal colon biopsies derived from AA men and women (n=79). Methods: DNA methylation data from this study was obtained using the Illumina Infinium MethylationEPIC kit and is housed under accession GSE151732. DMR analysis was carried out using DMRcate in right and matched left colon, separately. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Differential expression analysis was carried out on CRC tumors from TCGA-COAD using DESeq2 . Results: We identified 4,263 right-side fructose-DMRs. In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. To identify targets by which dietary fructose drives CRC risk, we overlaid these findings with data from three CRC tumor datasets. Remarkably, almost 50% of right-side fructose-DMRs overlapped regions associated with CRC in at least one of three datasets. TNXB and CDX2 ranked among the most significant fructose risk DMRs in right and left colon respectively that also displayed altered gene expression in CRC tumors. Conclusions: Our mechanistic data support the notion that fructose has a greater CRC-related effect in right than left AA colon, alluding to a potential role for fructose in contributing to racial disparities in CRC.

Assessment of Colorectal Cancer Risk Factors through the Application of Network-Based Approaches in a Racially Diverse Cohort of Colon Organoid Stem Cells.

Numerous demographic factors have been associated with colorectal cancer (CRC) risk. To better define biological mechanisms underlying these associations, we performed RNA sequencing of stem-cell-enriched organoids derived from the healthy colons of seven European Americans and eight African Americans. A weighted gene co-expression network analysis was performed following RNA sequencing. Module-trait relationships were determined through the association testing of each module and five CRC risk factors (age, body mass index, sex, smoking history, and race). Only modules that displayed a significantly positive correlation for gene significance and module membership were considered for further investigation. In total, 16 modules were associated with known CRC risk factors (p < 0.05). To contextualize the role of risk modules in CRC, publicly available RNA-sequencing data from TCGA-COAD were downloaded and re-analyzed. Differentially expressed genes identified between tumors and matched normal-adjacent tissue were overlaid across each module. Loci derived from CRC genome-wide association studies were additionally overlaid across modules to identify robust putative targets of risk. Among them, MYBL2 and RXRA represented strong plausible drivers through which cigarette smoking and BMI potentially modulated CRC risk, respectively. In summary, our findings highlight the potential of the colon organoid system in identifying novel CRC risk mechanisms in an ancestrally diverse and cellularly relevant population.

Insights into barriers that prevent African Americans from seeking colorectal screenings: a qualitative study.

African Americans have disproportionally higher rates of colorectal cancer and higher morbidly. Colorectal cancer screening has been shown to decrease mortality form this largely preventable disease. Despite this fact, preventive screening, particularly colonoscopy, has been underutilized by the general population, especially by African Americans. Identifying barriers to preventive screening among African Americans in central Virginia is an important first step toward increasing the rates of colorectal cancer screening in our community.

Does gender affect career satisfaction and advancement in gastroenterology? Results of an AGA institute-sponsored survey.

BACKGROUND & AIMS: Women comprise 19% of the American Gastroenterological Association (AGA) membership. We performed a prospective study to determine whether female gastroenterologists were less likely to achieve career advancement and satisfaction. METHODS: We administered an online survey to AGA members from 2004-2006. The survey contained questions regarding effects of gender on career advancement, satisfaction with career, promotional policies, and integration of family and career. RESULTS: A total of 457 individuals (response rate 9% after 2 major invitations) completed the survey, including 262 (57%) women (20% in private practice, 53% in academic careers, and 27% trainees) and 195 men (23% in private practice, 58% in academic careers, and 19% trainees). The male gastroenterologists were significantly older (P < .005) and in their careers for significantly more years (P = .002). There were no significant differences with respect to marital status, number of children, or number of hours worked between the genders. Men were more likely to achieve the rank of full professor (P = .035), and significantly more women reported that gender affected their career advancement (47% vs 9%; P < .001). Women in academic careers reported less satisfaction with their careers (P = .01) and perceived more difficulty in achieving promotion and tenure. Women were more likely to choose private practice careers because of part-time options (P = .025). Equal numbers of men and women in practice reported difficulty balancing work and family life. CONCLUSIONS: Significantly more female than male gastroenterologists perceive that gender has affected their career advancement. Female academic gastroenterologists reported less overall career satisfaction and promotion than male academic gastroenterologists.

Factors predictive of malignancy and endoscopic resectability in ampullary neoplasia.

OBJECTIVE: Endoscopic treatment of ampullary lesions has been well described, though it remains uncertain if specific features predict malignancy, and whether identifiable factors are associated with successful endoscopic resection of benign lesions. METHODS: Fifty-six consecutive patients undergoing endoscopic evaluation of ampullary neoplasia between March 2000 and May 2004 were included in the study. Clinical presentation, underlying medical conditions, endoscopic treatment, endoscopic ultrasound (EUS) to define extent of local involvement, pathology results, and outcome were documented. Data elements for analysis included EUS findings, lesion lifting with submucosal injection, age, gender, tumor size, and endoscopic intervention. Analyses were performed to determine the ability to predict malignancy and the ability to extirpate benign lesions. RESULTS: Thirty-one males and 25 females were included; mean age was 62 yr. Final diagnoses included 29 adenomas, 20 adenocarcinomas, 4 adenomyomas, 2 paragangliomas, and 1 neuroendocrine tumor. Thirty of 35 patients with benign lesions had extirpation with a mean of two endoscopic procedures. Complications of endoscopic resection included cholangitis (1), bleeding (2), and pancreatitis (4). The presence of malignancy was associated by multivariate analysis with the inability to obtain a cleavage plane with saline injection. Univariate analysis also identified EUS T stage as a predictor of malignancy. In benign lesions, none of the analyzed variables predicted successful endoscopic resection. CONCLUSION: In ampullary lesions, failure to achieve a cleavage plane with submucosal injection is the strongest predictor of malignancy followed by EUS T stage. Endoscopic treatment of benign ampullary neoplasia is effective; no factor was predictive of successful extirpation.

Interventional EUS cholangiography: A report of five cases.

BACKGROUND: ERCP may be unsuccessful because of the presence of a complex peripapillary diverticulum, prior surgery, obstructing tumor, papillary stenosis, or impacted stones. Percutaneous transhepatic cholangiography is a classic technique for accessing the bile duct and remains the primary alternative when biliary ERCP is unsuccessful. With the evolution of interventional EUS, additional options are available for management of biliary obstruction. METHODS: EUS cholangiography was performed, after which the puncture was enlarged to form an enterocholedochal fistula that was used for interventions that resulted in biliary decompression in 5 patients with obstructive jaundice. OBSERVATIONS: Cholangiography was readily performed in all 5 patients. In one patient, a guidewire could not be manipulated across the papilla via the enterocholedochal fistula, necessitating percutaneous intervention. Biliary decompression was achieved in the other 4 patients, in the last two, as a single procedure. CONCLUSIONS: Interventional EUS cholangiography is a new technique that allows drainage of a dilated biliary system when the bile duct is inaccessible by conventional ERCP.

EUS antegrade pancreatography with gastropancreatic duct stent placement: Review of two cases.

BACKGROUND: Endoscopic retrograde pancreatography is an established procedure for palliation of patients with pain caused by chronic pancreatitis associated with pancreatic ductal stricture. Some patients may not be candidates for endoscopic retrograde pancreatography because of surgically altered anatomy. Two cases are presented in which endoscopic retrograde pancreatography was unsuccessful and EUS-guided antegrade pancreatography with gastropancreatic stent placement was performed. METHODS: EUS-guided antegrade pancreatography was performed in both patients by creating a gastropancreatic fistula through which dilation and stent placement were performed over a guidewire. RESULTS: Stent insertion was successful in both cases. Both patients experienced rapid improvement in symptoms. CONCLUSIONS: EUS-guided antegrade pancreatography with stent placement may be an alternative to endoscopic retrograde pancreatography when surgical reconstruction precludes access to the major and minor papillae.

Gastric cancers overexpress S100A calcium-binding proteins.

Serial analysis of gene expression provides quantitative and comprehensive expression profiling in a given cell population. In our efforts to define the genes overexpressed in carcinoma of the stomach, we performed serial analysis of gene expression analyses on dissected neoplastic and normal gastric epithelia. We identified 91,334 expressed tags, including 26,633 that were unique. The 20 most up-regulated genes (P < 0.01) in gastric cancer (GC) compared with normal gastric epithelia included several keratins that are specific for epithelial cells such as keratin 6A, 13, and 17. Interestingly, five calcium-binding proteins (S100A2, S100A7, S100A8, S100A9, and S100A10) were overexpressed. Quantitative real-time PCR on primary GC samples demonstrated overexpression of S100A2 in 18 of 20 tumors (90%). The other calcium-binding proteins were overexpressed in 25-45% of the GC samples that we studied. Our results indicate that S100A proteins may be important for gastric tumorigenesis. Additional investigations are required to elucidate the biological role of calcium-binding proteins in cancer.