👤 Richard E Gregg

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( Show less

This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor β (LXRβ) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRβ and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRβ with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis. Show less

Atherogenic dyslipidemia associated with elevated plasma triacylglycerol concentrations and reduced HDL is improved by both caloric restriction and reduced carbohydrate consumption. We aimed to identify the molecular pathways responsive to both caloric restriction and dietary composition within adipose tissue by monitoring transcriptional expression. Subcutaneous adipose tissue biopsy specimens were obtained from 131 moderately overweight men [body mass index (in kg/m2): 29.2 +/- 2.0] after 1 wk of a basal diet [54%, 16%, and 30% carbohydrate, protein, and fat, respectively; 7% saturated fat), after 3 wk with 1 of 4 randomized diets [basal diet; moderate-carbohydrate (39%) diet; low-carbohydrate (26%) and low-saturated-fat (9%) diet; low-carbohydrate (26%) and high-saturated-fat (15%) diet], after 5 wk of acute weight loss with a randomized diet (-1103.0 +/- 216.5 kcal/d, which resulted in a loss of 10.0 +/- 3.3 lb, or 4.5 +/- 1.5 kg), and after 4 wk of being stabilized at a reduced weight. Transcriptional response was identified by using expression array analysis and was confirmed by using real-time polymerase chain reaction analysis. Of the 1473 transcripts significantly decreased in expression in response to acute weight loss, 30 were responsive to isocaloric alterations in dietary composition, including stearoyl-coenzyme A desaturase (SCD), fatty acid desaturases 1 and 2 (FADS1 and FADS2), and diacylglycerol transferase 2 (DGAT2). Response was confirmed by real-time polymerase chain reaction analysis for these genes (P < 0.003). SCD expression in response to isocaloric dietary change was most strongly correlated with carbohydrate intake (P = 0.019) and, with the low-carbohydrate diet, SCD expression was inversely correlated with saturated fat intake (P = 0.05). Triacylglycerol responses to changes in dietary composition were independently correlated with SCD (P = 0.003) and DGAT2 (P = 0.05) responses. SCD expression in adipose tissue is independently regulated by weight loss and by carbohydrate and saturated fat intakes. Moreover, SCD and DGAT2 expression may be involved in dietary regulation of systemic triacylglycerol metabolism. Show less