Daniel J Rader

A synthetic or recombinant human lecithin cholesterol acyltransferase (LCAT) variant is provided which comprises an LCAT enzyme having a substitution at position 114 based on the residue numbering of wild-type (WT) human LCAT [SEQ ID NO: 1], wherein said variant is characterized by one or more of:(i) an esterification rate higher than the esterification rate of WT human LCAT; and/or (ii) an association with higher density lipoprotein levels as compared to subjects having WT LCAT. Also provided are vectors encoding the variant, compositions containing same, and methods of using the variant proteins and vectors for treatment of a variety of disorders associated with defective wt LCAT.

In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Reexpression of Ppp1r3b in livers lacking …

MethodsA two-step method was used to contact biobank participants with an actionable genetic research result. In Step 1, we invited participants with an actionable result (cases) and procedural controls (no actionable result) to engage in digital pre-disclosure education and provided options for opting out of return of results. In Step 2, invited cases who had not opted out of ROR were randomized to ROR via a patient-centered digital disclosure intervention or with a genetic counselor (GC). Participants could opt-out of ROR or speak to a GC, regardless of arm. Clinical confirmation testing was offered after ROR. Participants completed surveys evaluating cognitive and affective patient-reported outcomes (PROs). Descriptive statistics with rank sum and Fisher’s exact tests were used for analyses.ResultsOne hundred and thirty cases and 130 procedural controls were contacted. Participants were a mean age of 62.4 YO …

Despite recent advancements in machine learning (ML) applications in health care, there have been few benefits and improvements to clinical medicine in the hospital setting. To facilitate clinical adaptation of methods in ML, this review proposes a standardized framework for the step-by-step implementation of artificial intelligence into the clinical practice of radiology that focuses on three key components: problem identification, stakeholder alignment, and pipeline integration. A review of the recent literature and empirical evidence in radiologic imaging applications justifies this approach and offers a discussion on structuring implementation efforts to help other hospital practices leverage ML to improve patient care. Clinical trial registration no. 04242667 © RSNA, 2024

BackgroundTesticular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk.ObjectiveTo identify coding genomic variants associated with predisposition to TGCT.Design, setting, and participantsThe study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls.Outcome measurements and statistical analysisWe carried out exome sequencing and gene burden analysis to identify associations with TGCT risk.Results and limitationsGene burden association identified several genes, including loss-of-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for …

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered PLIN2 coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of PLIN2-Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism in vivo and research the metabolic phenotypes associated with this variant in humans.MethodsFor our animal model, we used Plin2 knockout mice in which we expressed either human PLIN2-Pro251 (Pro251 mice) or wild-type human PLIN2-Ser251 (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks.ResultsPro251 …

Kagami–Ogata syndrome is a rare imprinting disorder and its phenotypic overlap with multiple different etiologies hampers diagnosis. Genetic etiologies include paternal uniparental isodisomy (upd(14)pat), maternal allele deletions of differentially methylated regions (DMR) in 14q32.2 or pure primary epimutations. We report a patient with Kagami–Ogata syndrome and an atypical diagnostic odyssey with several negative standard-of-care genetic tests followed by epigenetic testing using methylation microarray and a targeted analysis of whole-genome sequencing to reveal a 203 bp deletion involving the MEG3 transcript and MEG3:TSS-DMR. Long-read sequencing enabled the simultaneous detection of the deletion, phasing, and biallelic hypermethylation of the MEG3:TSS-DMR region in a single assay. This case highlights the challenges in the sequential genetic testing paradigm, the utility of long-read …

PurposeNatural selection (Mendelian randomization) studies support a causal relationship between elevated triglyceride-rich lipoproteins (TRLs) and atherosclerotic cardiovascular disease (ASCVD). This post-hoc analysis assessed the efficacy of evinacumab in reducing TRLs in patient cohorts from three separate clinical trials with evinacumab.MethodsPatients with homozygous familial hypercholesterolemia (HoFH) and low-density lipoprotein cholesterol (LDL-C)≥ 70 mg/dL were enrolled in a phase III trial (R1500-CL-1629; NCT03399786). Patients diagnosed with refractory hypercholesterolemia, with LDL-C≥ 70 mg/dL or≥ 100 mg/dL for those with or without ASCVD, respectively, were enrolled in a phase II trial (R1500-CL-1643; NCT03175367). Patients with severe hypertriglyceridemia (fasting TGs≥ 500 mg/dL) were enrolled in a phase II trial (R1500-HTG-1522; NCT03452228). Patients received …