The Military Career of James Gettys

James Gettys was a Federalist, tried and true. From his role in the American Revolution to his final position as Vice Brigadier General during the War of 1812, James understood the necessity for “we the people” to remain united as one, power in numbers. He lived that way, worked that way, and built his town on that premise. Like most of the frontiersmen of his time, his life was difficult, and his rise to the top was not always met with valor. Much like his father, Samuel, James Gettys fought for everything he had, and his attainments were well earned. Until recently, discussion of James Gettys’ military career began with his 1781 role as a Cornet in a Light Horsemen of York County. While any role in the Revolutionary War was beneficial, his appeared fairly insignificant, as a Cornet was a lower ranked officer, and Gettys’ unit was never activated.1 Seemingly odd given his numerous promotions within the militia, James appeared to witness the fighting safely on the sidelines. New research, however, reveals, that this version of events is not entirely accurate. This article reviews that new evidence and narrates the postwar Revolutionary War life of Gettysburg’s founding father

Use of DNA–Damaging Agents and RNA Pooling to Assess Expression Profiles Associated with BRCA1 and BRCA2 Mutation Status in Familial Breast Cancer Patients

A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes, BRCA1 and BRCA2. Laboratory-based methods that can distinguish between carriers of pathogenic mutations and non-carriers are likely to have utility for the classification of these sequence variants. To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA–damaging agents (irradiation and mitomycin C) on cellular response in relation to BRCA1 and BRCA2 mutation status. A range of regimes was used to treat 27 lymphoblastoid cell-lines (LCLs) derived from affected women in high-risk breast cancer families (nine BRCA1, nine BRCA2, and nine non-BRCA1/2 or BRCAX individuals) and nine LCLs from healthy individuals. Using an RNA–pooling strategy, we found that treating LCLs with 1.2 µM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate BRCA1, BRCA2, and BRCAX mutation status. A classifier was built using the expression profile of nine QRT–PCR validated genes that were associated with BRCA1, BRCA2, and BRCAX status in RNA pools. These nine genes could distinguish BRCA1 from BRCA2 carriers with 83% accuracy in individual samples, but three-way analysis for BRCA1, BRCA2, and BRCAX had a maximum of 59% prediction accuracy. Our results suggest that, compared to BRCA1 and BRCA2 mutation carriers, non-BRCA1/2 (BRCAX) individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from BRCA1, BRCA2, and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

An update on the assessment of culture and environment in the ABCD Study®: Emerging literature and protocol updates over three measurement waves.

Advances in our understanding of risk and resilience factors in adolescent brain health and development increasingly demand a broad set of assessment tools that consider a youth's peer, family, school, neighborhood, and cultural contexts in addition to neurobiological, genetic, and biomedical information. The Culture and Environment (CE) Workgroup (WG) of the Adolescent Brain Cognitive Development (ABCD) Study curates these important components of the protocol throughout ten years of planned data collection. In this report, the CE WG presents an update on the evolution of the ABCD Study® CE protocol since study inception (Zucker et al., 2018), as well as emerging findings that include CE measures. Background and measurement characteristics of instruments present in the study since baseline have already been described in our 2018 report, and therefore are only briefly described here. New measures introduced since baseline are described in more detail. Descriptive statistics on all measures are presented based on a total sample of 11,000+ youth and their caregivers assessed at baseline and the following two years. Psychometric properties of the measures, including longitudinal aspects of the data, are reported, along with considerations for future measurement waves. The CE WG ABCD® components are an essential part of the overall protocol that permits characterization of the unique cultural and social environment within which each developing brain is transactionally embedded

An update on the assessment of culture and environment in the ABCD Study®: emerging literature and protocol updates over three measurement waves.

Advances in our understanding of risk and resilience factors in adolescent brain health and development increasingly demand a broad set of assessment tools that consider a youth's peer, family, school, neighborhood, and cultural contexts in addition to neurobiological, genetic, and biomedical information. The Culture and Environment (CE) Workgroup (WG) of the Adolescent Brain Cognitive Development (ABCD) Study curates these important components of the protocol throughout ten years of planned data collection. In this report, the CE WG presents an update on the evolution of the ABCD Study® CE protocol since study inception (Zucker et al., 2018), as well as emerging findings that include CE measures. Background and measurement characteristics of instruments present in the study since baseline have already been described in our 2018 report, and therefore are only briefly described here. New measures introduced since baseline are described in more detail. Descriptive statistics on all measures are presented based on a total sample of 11,000+ youth and their caregivers assessed at baseline and the following two years. Psychometric properties of the measures, including longitudinal aspects of the data, are reported, along with considerations for future measurement waves. The CE WG ABCD® components are an essential part of the overall protocol that permits characterization of the unique cultural and social environment within which each developing brain is transactionally embedded

CABG improves outcomes in patients with ischemic cardiomyopathy 10-year follow-up of the STICH trial

Objectives: The authors investigated the impact of coronary artery bypass grafting (CABG) on first and recurrent hospitalization in this population. Background: In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, CABG reduced all-cause death and hospitalization in patients with and ischemic cardiomyopathy and left ventricular ejection fraction <35%. Methods: A total of 1,212 patients were randomized (610 to CABG + optimal medical therapy [CABG] and 602 to optimal medical therapy alone [MED] alone) and followed for a median of 9.8 years. All-cause and cause-specific hospitalizations were analyzed as time-to-first-event and as recurrent event analysis. Results: Of the 1,212 patients, 757 died (62.4%) and 732 (60.4%) were hospitalized at least once, for a total of 2,549 total all-cause hospitalizations. Most hospitalizations (66.2%) were for cardiovascular causes, of which approximately one-half (907 or 52.9%) were for heart failure. More than 70% of all hospitalizations (1,817 or 71.3%) were recurrent events. The CABG group experienced fewer all-cause hospitalizations in the time-to-first-event (349 CABG vs. 383 MED, adjusted hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.74 to 0.98; p = 0.03) and in recurrent event analyses (1,199 CABG vs. 1,350 MED, HR: 0.78, 95% CI: 0.65 to 0.94; p < 0.001). This was driven by fewer total cardiovascular (CV) hospitalizations (744 vs. 968; p < 0.001, adjusted HR: 0.66, 95% CI: 0.55 to 0.81; p = 0.001), the majority of which were due to HF (395 vs. 512; p < 0.001, adjusted HR: 0.68, 95% CI: 0.52-0.89; p = 0.005). We did not observe a difference in non-CV events. Conclusions: CABG reduces all-cause, CV, and HF hospitalizations in time-to-first-event and recurrent event analyses. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595

The Serine Hydrolase ABHD6 Is a Critical Regulator of the Metabolic Syndrome

The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6’s role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes