👤 Dean H Betts

The Helix Research Network program is a large population genomics initiative that screens an all-comers population of patients for Centers for Disease Control and Prevention Tier 1 genetic conditions, including familial hypercholesterolemia (FH). We evaluated changes in clinical management and low-density lipoprotein cholesterol (LDL-C) levels among patients we identified to have FH. Participants across 9 US health systems provided samples that underwent clinical-grade exome sequencing. Individuals with a positive screening result for a Tier 1 condition were offered no-cost genetic counseling through their health system. Using medication and laboratory testing records, we evaluated changes in patients' lipid-lowering therapies and LDL-C levels. Among 228 602 adults enrolled between 2017 to 2025, 1155 (≈1/198) had a pathogenic FH variant in Following genetic screening, many patients with a pathogenic FH variant experienced improvements in clinical management and LDL-C levels. Electronic health record documentation of the diagnosis code was associated with a greater likelihood of therapeutic modifications, which, in turn, were associated with larger LDL-C reductions. Findings underscore the powerful potential of population genomic screening for supporting optimal lipid management in individuals with FH. Show less

Salivary gland cancers (SGCs) are rare and comprise multiple histologic entities. In the recurrent or metastatic (R/M) setting, there is limited evidence for effective systemic anticancer treatment for most subtypes, affecting prognosis and quality of life. Molecular analysis of SGCs holds promise to more accurately classify SGC subtypes and to determine novel therapeutic targets. Fifteen patients with R/M SGC underwent tumor biopsy and blood sampling to perform whole-genome sequencing (WGS) of tumor and germline as part of their standard-of-care management. Small somatic mutations, structural alterations, copy number variation, and mutational signatures were processed using WGS pipelines alongside germline testing. Alterations were correlated to clinical features and fed back to clinical team to inform treatment decisions. WGS quality control was acceptable in 14 of 15 patients (adenoid cystic carcinoma [AdCC, n = 10], salivary duct carcinoma ex pleomorphic adenoma [n = 1]; clear cell myoepithelial carcinoma [n = 1]; epithelial-myoepithelial carcinoma [n = 1]; and acinic cell carcinoma [n = 1]). Genomic rearrangements/fusions were present in 12 of 14. Rearrangements involving MYB and or NFIB were identified in 8 of 10 patients with AdCC. One patient harbored a clinically actionable WGS in SGC is achievable in clinically relevant timeframes, providing genomic information for deeper understanding of disease pathophysiology, to clarify histologic subtype and can identify actionable genomic targets which may not be found through routine sequencing technologies. Further use of WGS has the potential to improve care for patients with SGC. Show less

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83 Show less

Recent evidence has emerged that cancer cells can use various metabolites as fuel sources. Restricting cultured cancer cells to sole metabolite fuel sources can promote metabolic changes leading to enhanced glycolysis or mitochondrial OXPHOS. However, the effect of metabolite-restriction on non-transformed cells remains largely unexplored. Here we examined the effect of restricting media fuel sources, including glucose, pyruvate or lactate, on the metabolic state of cultured human dermal fibroblasts. Fibroblasts cultured in lactate-only medium exhibited reduced PDH phosphorylation, indicative of OXPHOS, and a concurrent elevation of ROS. Lactate exposure primed fibroblasts to switch to glycolysis by increasing transcript abundance of genes encoding glycolytic enzymes and, upon exposure to glucose, increasing glycolytic enzyme levels. Furthermore, lactate treatment stabilized HIF-1α, a master regulator of glycolysis, in a manner attenuated by antioxidant exposure. Our findings indicate that lactate preconditioning primes fibroblasts to switch from OXPHOS to glycolysis metabolism, in part, through ROS-mediated HIF-1α stabilization. Interestingly, we found that lactate preconditioning results in increased transcript abundance of MYC and SNAI1, key facilitators of early somatic cell reprogramming. Defined metabolite treatment may represent a novel approach to increasing somatic cell reprogramming efficiency by amplifying a critical metabolic switch that occurs during iPSC generation. Show less