No abstract

Pyruvate dehydrogenase kinase (PDK) can regulate the catalytic activity of pyruvate decarboxylation oxidation via the mitochondrial pyruvate dehydrogenase complex, and it further links glycolysis with the tricarboxylic acid cycle and ATP generation. This review seeks to elucidate the regulation of PDK activity in different species, mainly mammals, and the role of PDK inhibitors in preventing increased blood glucose, reducing injury caused by myocardial ischemia, and inducing apoptosis of tumor cells. Regulations of PDKs expression or activity represent a very promising approach for treatment of metabolic diseases including diabetes, heart failure, and cancer. The future research and development could be more focused on the biochemical understanding of the diseases, which would help understand the cellular energy metabolism and its regulation by pharmacological effectors of PDKs.

Mediation analysis with high-dimensional DNA methylation markers is important in identifying epigenetic pathways between environmental exposures and health outcomes. There have been some methodology developments of mediation analysis with high-dimensional mediators. However, high-dimensional mediation analysis methods for time-to-event outcome data are still yet to be developed. To address these challenges, we propose a new high-dimensional mediation analysis procedure for survival models by incorporating sure independent screening and minimax concave penalty techniques for variable selection, with the Sobel and the joint method for significance test of indirect effect. The simulation studies show good performance in identifying correct biomarkers, false discovery rate control, and minimum estimation bias of the proposed procedure. We also apply this approach to study the causal pathway from smoking to overall survival among lung cancer patients potentially mediated by 365,307 DNA methylations in the TCGA lung cancer cohort. Mediation analysis using a Cox proportional hazards model estimates that patients who have serious smoking history increase the risk of lung cancer through methylation markers including cg21926276,

Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical behavior are not fully understood. Here we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA sequencing data from 48 samples. We classified MCL into four robust clusters (C). C1 featured mutated IGHV, CCND1 mutation, amp(11q13) and active BCR signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-B and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1 and NSD2 with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q) and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these four clusters had distinct outcomes (5-year OS rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively, p<0.001). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.