👤 Donald A Bergstrom

A 3-year-old patient presented with severe hypertriglyceridemia and suspected familial chylomicronemia syndrome. Genetic analysis of the patient's DNA revealed the presence of 2 different heterozygous nonsense variants in the APOA5 gene encoding apolipoprotein (apo) A-V, namely p.Q275X and p.L242C fs X54. Our objective was to characterize the structural and functional consequences of the patient's co-occuring compound heterozygous variants in APOA5. Biozentrum's SWISS-MODEL was employed to predict the structure of apo A-V variants. Plasma from the patient and their family was used to determine lipid profiles, quantify apo C-II and apo C-III protein levels, and measure lipoprotein lipase (LPL) activity. High-density lipoprotein (HDL) was isolated from plasma and was used to assess sterol efflux capacity and proteome. Structural characterization of the patient's APOA5 variants indicated premature truncation of the C-terminus of apo A-V that comprises the lipid binding domain. The patient's apo A-V was completely absent from the very-low density lipoprotein (VLDL) plasma fraction, associating almost exclusively with the low-density lipoprotein (LDL) and lipoprotein-free fractions. The patient's plasma also demonstrated reduced LPL activity and elevated apo C-II and C-III compared to other family members. The patient's HDL had the lowest sterol efflux capacity of all family members and a distinct proteome with reduced phospholipid transfer protein. Dietary intervention alone was effective in preventing recurring hypertriglyceridemia. These findings add to the current knowledge of apo A-V's role in plasma lipid homeostasis, pointing to a critical role for apo A-V binding to the lipoprotein particle in normal hydrolysis of triglyceride-rich lipoproteins. Show less

Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting. Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1-4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949. Show less

Prospective cohort studies question the value of HDL-C (high-density lipoprotein cholesterol) for stroke risk prediction. Investigate the relationship between long-term functional recovery and HDL proteome and function. Changes in HDL protein composition and function (cholesterol efflux capacity) in patients after acute ischemic stroke at 2 time points (24 hours, 35 patients; 96 hours, 20 patients) and in 35 control subjects were measured. The recovery from stroke was assessed by 3 months, the National Institutes of Health Stroke Scale and modified Rankin scale scores. When compared with control subject after adjustments for sex and HDL-C levels, 12 proteins some of which participate in acute phase response and platelet activation (APMAP [adipocyte plasma membrane-associated protein], GPLD1 [phosphate inositol-glycan specific phospholipase D], APOE [apolipoprotein E], IHH [Indian hedgehog protein], ITIH4 [inter-alpha-trypsin inhibitor chain H4], SAA2 [serum amyloid A2], APOA4 [apolipoprotein A-IV], CLU [clusterin], ANTRX2 [anthrax toxin receptor 2], PON1 [serum paraoxonase/arylesterase], SERPINA1 [alpha-1-antitrypsin], and APOF [apolipoprotein F]) were significantly (adjusted Changes in HDL proteins during early acute phase of stroke associate with recovery. Monitoring HDL proteins may provide clinical biomarkers that inform on stroke recuperation. Show less