👤 Ghada M Anwar

Hypertriglyceridemia (HTG) increases cardiovascular and pancreatitis risk. Antisense oligonucleotide (ASO) therapies like volanesorsen and olezarsen target ApoC-III mRNA to reduce ApoC-III, enhancing lipoprotein lipase activity and lowering triglycerides (TGs). This meta-analysis evaluates the efficacy and safety of these ASOs in severe HTG. A systematic review (PROSPERO: CRD42024577110) was conducted following PRISMA, sourcing studies from PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov until July 2024. Randomized controlled trials (RCTs) involving severe HTG (≥200 mg/dL) treated with volanesorsen or olezarsen vs. placebo were included. Data were synthesized using a random effects model in RevMan 5.4, and bias was assessed with the Cochrane tool. Of 31 identified articles, 9 RCTs (341 patients treated with ASOs, 209 controls) were included. ASOs significantly reduced TG levels [mean difference (MD): -53.72; 95% confidence interval (CI): -77.04 to -30.40; p<0.00001]. Reductions were also seen in very low-density lipoprotein cholesterol (MD: -55.76; p<0.00001), ApoC-III (MD: -74.78; p<0.00001), and APOB48 (MD: -69.45; p<0.00001). Olezarsen uniquely reduced APOB (MD: -15.60; p<0.00001). Non-high-density lipoprotein cholesterol (HDL-C) decreased (MD: -23.25; p<0.00001), while HDL-C increased (MD: +42.14; p<0.00001). Volanesorsen was linked to higher low-density lipoprotein-cholesterol (MD: +62.74; p=0.004). For safety, local injection reactions, thrombocytopenia, and nausea were more common with volanesorsen. Acute pancreatitis occurred only in the placebo group (relative risk: 0.15; p=0.0004), indicating ASO protection. This meta-analysis confirms that ASOs effectively lower TGs and improve lipid profiles in severe HTG. Show less

Mendelian randomization studies suggest a causal effect of lipoprotein(a) (Lp(a)) on atherosclerotic cardiovascular disease. Noncardiovascular effects (eg, diabetes risk) are inadequately investigated. In this noninterventional phenome-wide association study designed to better understand the potential causal role of Lp(a), direct causal phenotypic effects of exposure to Lp(a) were estimated. Also, the association between LPA null allele rs41272114 with type 2 diabetes was assessed, and ancestry-specific Lp(a) thresholds were determined. In the UK Biobank (n = 425,677 adults, 55% female), we studied 1,456 phenotypes spanning 18 classes using 4 ancestry-specific polygenic risk scores and false discovery rate multiple testing correction. Network deconvolution Mendelian randomization was leveraged to separate direct from indirect (ie, associations via mediating variables) causal phenotypic effects and account for confounding, reverse causation, and bidirectionality. Lp(a) was significantly associated with 80 phenotypes across 7 classes. Higher Lp(a) exposure had significant direct causal effects, independent of low-density lipoprotein cholesterol, on coronary artery disease (OR: 1.36; 95% CI: 1.21-1.54) and glycated hemoglobin (HbA1c; β = 0.099; 95% CI: 0.051-0.15) only. Very low Lp(a) exposure was not associated with type 2 diabetes (OR: 0.92; 95% CI: 0.64-1.31) or HbA1c (β = -0.016; 95% CI: -0.062 to 0.030). Among European and African ancestries, 86 (77th percentile) and 93 (59th percentile) nmol/L optimally discriminated myocardial infarction risk, respectively. Increasing Lp(a) exposure had direct, independent causal effects on coronary artery disease and HbA1c only; very low Lp(a) exposure is suggested to not be causally associated with type 2 diabetes. The optimal European and African ancestry threshold to stratify cardiovascular risk is comparable, and below 125/105 nmol/L in current U.S./European medical professional society guidelines. Show less

Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8⁺ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less

In a previous report, we demonstrated that Cbx1, PurB and Sp3 inhibited cardiac muscle differentiation by increasing nucleosome density around cardiac muscle gene promoters. Since cardiac and skeletal muscle express many of the same proteins, we asked if Cbx1, PurB and Sp3 similarly regulated skeletal muscle differentiation. In a C2C12 model of skeletal muscle differentiation, Cbx1 and PurB knockdown increased myotube formation. In contrast, Sp3 knockdown inhibited myotube formation, suggesting that Sp3 played opposing roles in cardiac muscle and skeletal muscle differentiation. Consistent with this finding, Sp3 knockdown also inhibited various muscle-specific genes. The Cbx1, PurB and Sp3 proteins are believed to influence gene-expression in part by altering nucleosome position. Importantly, we developed a statistical approach to determine if changes in nucleosome positioning were significant and applied it to understanding the architecture of muscle-specific genes. Through this novel statistical approach, we found that during myogenic differentiation, skeletal muscle-specific genes undergo a set of unique nucleosome changes which differ significantly from those shown in commonly expressed muscle genes. While Sp3 binding was associated with nucleosome loss, there appeared no correlation with the aforementioned nucleosome changes. In summary, we have identified a novel role for Sp3 in skeletal muscle differentiation and through the application of quantifiable MNase-seq have discovered unique fingerprints of nucleosome changes for various classes of muscle genes during myogenic differentiation. Show less

Developing highly potent covalent inhibitors of Fibroblast growth factor receptors 1 (FGFR1) has always been a challenging task. In the current study, various computational techniques, such as 3D-QSAR, covalent docking, fingerprinting analysis, MD simulation followed by MMGB/PBSA, and per-residue energy decomposition analysis were used to explore the binding mechanism of pyrazolo[3,4-d]pyridazinone derivatives to FGFR1. The high q2 and r2 values for the CoMFA and CoMSIA models, suggest that the constructed 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The structural requirements revealed by the model's contour maps were strategically used to computationally create an in-house library of more than 100 new FGFR1 inhibitors using the R-group exploration technique implemented in the Spark Show less

Early childhood obesity is a real public health problem worldwide. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Measurement of serum leptin levels is helpful in the diagnosis of congenital leptin and leptin receptor deficiencies which are considered important rare causes of early childhood obesity. The main aim of this study was to investigate the frequency of LEP, LEPR, and MC4R gene variants among a cohort of Egyptian patients with severe early onset obesity. The current cross-sectional study included 30 children who developed obesity during the first year of life with BMI > 2SD (for age and sex). The studied patients were subjected to full medical history taking, anthropometric measurements, serum leptin and insulin assays, and genetic testing of LEP, LEPR and MC4R. Disease causing variants in LEP and LEPR were identified in 10/30 patients with a detection rate of 30%. Eight different homozygous variants (two pathogenic, three likely pathogenic, and three variants of uncertain significant) were identified in the two genes, including six previously unreported LEPR variants. Of them, a new frameshift variant in LEPR gene (c.1045delT, p.S349Lfs*22) was recurrent in two unrelated families and seems to have a founder effect in our population. In conclusion, we reported ten new patients with leptin and leptin receptor deficiencies and identified six novel LEPR variants expanding the mutational spectrum of this rare disorder. Furthermore, the diagnosis of these patients helped us in genetic counseling and patients' managements specially with the availability of drugs for LEP and LEPR deficiencies. Show less

In this association study on chromosome 11, the data from 12,537 Korean individuals within the Health Examinee (HEXA) and the Korea Association Resource (KARE) projects were analysed to identify genetic loci correlating with increased and decreased plasma triglyceride (TG) levels. We identified a locus in chromosomal region 11q23.3 that harbours genes BUD13, ZNF259, APOA5, APOA1, and SIK3, which may be associated with plasma TG levels. In this locus, 13 relevant single-nucleotide polymorphisms (SNPs) were found: rs184616707, rs118175510, rs60954647, rs79408961, and rs180373 (near BUD13); rs11604424 (in ZNF259); rs2075291, rs651821, and rs7123666 (in or near APOA5); rs525028 (near APOA1), and rs645258, rs10160754, and rs142395187 (in or near SIK3). All 13 SNPs satisfied the genome-wide significance level (P < 5.0 × 10 Show less

Tumor necrosis factor- (TNF-) α is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-α monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-α and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) α, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-α alone or TNF-α with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-α significantly reduced both ABCA1 and LXR-α mRNA (to 68.5 ± 1.59%, P < 0.05, and 41.2 ± 0.25%, P < 0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-α effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-α. TNF-α treatment significantly reduces ABCA1 and LXR-α expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes. Show less