22 research outputs found
MBOAT7 rs641738 Variant Is Not Associated with an Increased Risk of Hepatocellular Carcinoma in a Latin American Cohort
Background: The rs641738 C > T single-nucleotide polymorphism of MBOAT7 has been associated with hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Latin Americans have high rates of HCC and NAFLD, but no assessment between MBOAT7 and HCC has been performed in this population. Aims: We provide the first assessment of the impact of MBOAT7 on HCC risk in Latin Americans. Methods: Patients were prospectively recruited into the ESCALON network, designed to collect samples from Latin American patients with HCC in 6 South American countries (Argentina, Ecuador, Brazil, Chile, Peru, and Colombia). A European cohort and the general Hispanic population of gnomAD database were included for comparison. Associations between HCC and MBOAT7 were evaluated using logistic regression. Results:In total, 310 cases of HCC and 493 cases of cirrhosis without HCC were assessed. The MBOAT7 TT genotype was not predictive of HCC in Latin Americans (TT vs CC OR adjusted = 1.15, 95% CI 0.66–2.01, p = 0.610) or Europeans (TT vs CC OR adjusted = 1.20, 95% CI 0.59–2.43, p = 0.621). No significant association was noted on subgroup analysis for NAFLD, viral hepatitis, or alcohol-related liver disease. The TT genotype was increased in the NAFLD-cirrhosis cohort of Latin Americans compared to a non-cirrhotic NAFLD cohort (TT vs CC + CT OR = 2.75, 95% CI 1.10–6.87, p = 0.031). Conclusion: The rs631738 C > T allele of MBOAT7 was not associated with increased risk of HCC in Latin Americans or Europeans. An increase in the risk of cirrhosis was noted with the TT genotype in Latin Americans with NAFLD. Graphical Abstract: [Figure not available: see fulltext.]</p
Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl‑1<i>H</i>‑benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors
Miniaturization and parallel processing
play an important role
in the evolution of many technologies. We demonstrate the application
of miniaturized high-throughput experimentation methods to resolve
synthetic chemistry challenges on the frontlines of a lead optimization
effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors.
Reactions were performed on ∼1 mg scale using glass microvials
providing a miniaturized high-throughput experimentation capability
that was used to study a challenging S<sub><i>N</i></sub>Ar reaction. The availability of robust synthetic chemistry conditions
discovered in these miniaturized investigations enabled the development
of structure–activity relationships that ultimately led to
the discovery of soluble, selective, and potent inhibitors of DGAT1