Rescue of Familial Lecithin:Cholesterol Acyltranferase Deficiency Mutations with an Allosteric Activator.

Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/ß-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. SIGNIFICANCE STATEMENT: Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.

Early Lessons From Implementation of Holistic Review for Pediatric Surgery Fellowship Applicants.

PURPOSE: Holistic review (HR) considers applicants' unique identities and experiences rather than focusing on academic metrics. Though several residency programs have demonstrated increases in women and those underrepresented in medicine (URiM), this is the first study to examine HR in pediatric surgery (PS). METHODS: Using a retrospective review of applicants, demographic, academic, and non-academic metrics of traditional review (TR) [2015-2017] were compared to HR [2018-2022]. HR initiatives include expansion of faculty reviewers, implementation of a pre-screening rubric, and greater prioritization of non-academic factors. Chi-squared/Fisher's exact tests, Wilcoxon rank-sum tests, and two sample z-test for proportions were used where appropriate. RESULTS: For 635 applicants (TR: 268, HR: 367), the proportion offered interviews in the TR and HR cohorts were similar (31.7 vs 36%, p = 0.30). Candidates selected for interview pre- and post-HR most commonly graduated from residency programs affiliated with PS fellowships (56.5 vs 50%, p = 0.65). After HR implementation, no change in proportion of women interviewees (TR: 52.9 vs HR: 54.5%, p = 0.93) was observed. Though URiM residents applying to PS remained consistently low (TR: 14.6 vs HR: 10.9%, p = 0.21), significantly more received interviews with HR (30.8 vs 42.5%, p = 0.001). The median number of peer-review publications per interviewee increased (17 vs 22, p = 0.02) as did non-academic achievements (leadership, service, athletic awards, etc.) per applicant (1.0 vs 1.5, p = 0.104), though the latter did not reach significance, demonstrating similar qualification of interviewees in HR and TR. CONCLUSION: Holistic review of PS fellowship applications increased the proportion of URiM interviewees, despite a persistently low URiM proportion in the applicant pool. Furthermore, implementing HR did not sacrifice the caliber of interviewees, as publications and non-academic achievements increased by over 25% in the HR cohort. LEVEL OF EVIDENCE: IV.