Inhibition of Inducible Nitric Oxide Synthase Expression by a Novel Small Molecule Activator of the Unfolded Protein Response

The transcription of inducible nitric oxide synthase (iNOS) is activated by a network of proinflammatory signaling pathways. Here we describe the identification of a small molecule that downregulates the expression of iNOS mRNA and protein in cytokine-activated cells and suppresses nitric oxide production in vivo. Mechanistic analysis suggests that this small molecule, erstressin, also activates the unfolded protein response (UPR), a signaling pathway triggered by endoplasmic reticulum stress. Erstressin induces rapid phosphorylation of eIF2α and the alternative splicing of XBP-1, hallmark initiating events of the UPR. Further, erstressin activates the transcription of multiple genes involved in the UPR. These data suggest an inverse relationship between UPR activation and iNOS mRNA and protein expression under proinflammatory conditions

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo

Abstract Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn 2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An A-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC 50 of 0.045 Mmol/L in the screening biochemical assay and an EC 50 of 0.025 Mmol/L in HeLa cell -based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classe

Common Data Element Collection in Underserved School Communities: Challenges and Recommendations

OBJECTIVESTo provide recommendations for future common data element (CDE) development and collection that increases community partnership, harmonizes data interpretation, and continues to reduce barriers of mistrust between researchers and underserved communities. METHODSWe conducted a cross-sectional qualitative and quantitative evaluation of mandatory CDE collection among Rapid Acceleration of Diagnostics-Underserved Populations Return to School project teams with various priority populations and geographic locations in the United States to: (1) compare racial and ethnic representativeness of participants completing CDE questions relative to participants enrolled in project-level testing initiatives and (2) identify the amount of missing CDE data by CDE domain. Additionally, we conducted analyses stratified by aim-level variables characterizing CDE collection strategies. RESULTSThere were 15 study aims reported across the 13 participating Return to School projects, of which 7 (47%) were structured so that CDEs were fully uncoupled from the testing initiative, 4 (27%) were fully coupled, and 4 (27%) were partially coupled. In 9 (60%) study aims, participant incentives were provided in the form of monetary compensation. Most project teams modified CDE questions (8/13; 62%) to fit their population. Across all 13 projects, there was minimal variation in the racial and ethnic distribution of CDE survey participants from those who participated in testing; however, fully uncoupling CDE questions from testing increased the proportion of Black and Hispanic individuals participating in both initiatives. CONCLUSIONSCollaboration with underrepresented populations from the early study design process may improve interest and participation in CDE collection efforts