Narrative Review of Anomalous Origin of Coronary Arteries: Pathophysiology, Management, and Treatment.

Coronary artery anomalies (CAA) are a diverse group of congenital anomalies and are the second most common cause of sudden cardiac death in the young population after Hypertrophic Cardiomyopathy (HCM). Symptoms range from chest pain, syncope, or sudden cardiac arrest to completely asymptomatic. The prevalence of congenital coronary artery anomalies in the general population is estimated to be between 1% and 2%. CAA often gets underdiagnosed due to the lack of knowledge of the disease process. Approximately 5% of patients with acute myocardial infarction do not have atherosclerotic coronary artery disease or luminal narrowing due to other causes. Congenital coronary artery anomalies account for 50-60% of this 5% of patients. Most patients are asymptomatic for most of their lives, and chest pain is the most common symptom in symptomatic patients when referred for coronary angiography, typically when the diagnosis is typically made. The malignant coronary artery is a rare presentation of a coronary anomaly when associated with atherosclerotic coronary artery disease or valvular heart disease. Patients with symptoms of an abnormal coronary artery origin will receive medical treatment/observation, exercise restriction, coronary angioplasty with stent deployment, or surgical repair.

Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.

Feeding Rates in the Swordtail Fish Xiphophorus multilineatus: A Model System for Genetic Variation in Nutritional Programming.

A better understanding of the role of appetite regulation in obesity and metabolic disorders requires consideration of both genetic and developmental influences on appetite. Previously we detected genetic differences in responses to nutritional programming (e.g., the permanent influence that nutrition in early life has on the physiological and metabolic states in adults) on a presumed measure of appetite (feeding rate) in the swordtail fish Xiphophorus multilineatus. In this study we validate that feeding rate is a good measure of appetite, by first demonstrating that it is repeatable and correlated with food consumed when controlling for body size. Second, we detected a significant positive correlation between juvenile growth rates and feeding rates measured in adult males, when growth has ceased. In addition, feeding rates explained significant variation in the size of the nuchal hump, a fat deposit that develops after sexual maturity. Finally, we show that the feeding rates of "courter" males were significantly greater than "sneaker" males, alternative reproductive tactics that are influenced by variation in the Mc4r gene on the Y-chromosome. Our results suggest that examining feeding rate in X. multilineatus could provide valuable insights into how nutritional programming influences appetite independently from food intake, as well as insights into the mechanisms that produce the correlation between delayed maturation and faster growth rates of the courter males as compared with the sneaker males that mature early and grow slower in this species.