An integrated analysis identifies six molecular subtypes of pancreatic ductal adenocarcinoma revealing cellular and molecular landscape.

Pancreatic ductal adenocarcinoma (PDA) has been found to have a high mortality rate. Despite continuous efforts, current histopathological classification is insufficient to guide individualized therapies of PDA. We first define the molecular subtypes of PDA (MSOP) based on a meta-cohort of 845 samples from 11 PDA datasets. We then performed functional analyses involving immunity, fibrosis and metabolism. We recognized six molecular subtypes with different survival statistics and molecular composition. The squamous basal-like (SBL) subtype had a poor prognosis and high infiltration of ENO1+ (Enolase 1)/ADM+ (Adrenomedullin) cancer-associated fibroblasts (CAFs). The immune mesenchymal-like (IML) subtype and the normal mesenchymal-like (NML) subtype were characterized by genes associated with extracellular matrix (ECM) activities and immune responses, having favorable prognoses. IML was featured by elevated exhausted immune signaling and inflammatory CAFs infiltration, whereas NML was featured with myofibroblastic CAFs infiltration. The exocrine-like (EL) subtype was high in exocrine signals, while the pure classical-like (PCL) subtype lacked immunocytes infiltration. The quiescent-like (QL) subtype had diminished metabolic signaling and high infiltration of NK cells. SBL, IML and NML were enriched in innate anti-PD-1 resistance signatures. In sum, this MSOP depicts a vivid cell-to-molecular atlas of the tumor microenvironment of PDA and might facilitate to design a precise combination of therapies that target immunity, metabolism and stroma.

Cytochrome P450 Enzymes and Drug Metabolism in Humans.

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

Large-scale whole-exome sequencing association study identifies FOXH1 gene and sphingolipid metabolism pathway influencing major depressive disorder.

In the present study, we performed an exome-wide investigation of the burden of rare disease-causing variants for major depressive disorder (MDD) using 16,702 samples from UK biobank. Gene-based association analysis and candidate gene prioritization analysis indicated that FOXH1 have significant association with MDD. In addition, sphingolipid metabolism pathway was found to be less enriched with rare disease-causing variants in the MDD group, suggesting that this gene set may be involved in the pathophysiology of MDD.