👤 Dmitrij Frishman

The obesity pandemic continues to increase in prevalence in children and adolescents, with its increase outpacing the rate of adult obesity; the human developmental index, body mass index, and family income all display associations to childhood obesity. There are numerous adverse complications of childhood obesity, including cardiovascular, endocrine, and gastrointestinal manifestations. Obesity is thought to be an interaction of several different factors, such as leptin, proopiomelanocortin, glucose uptake in adipocytes, melanocortin receptor 4, protein convertase 1/3, brain-derived neurotrophic factor, fat-mass and obesity-associated gene, melanocortin receptor 4, tumor necrosis factor, interleukin-6, and long noncoding RNA. Epigenetic regulation, the unique gut microbiome role in contributing to obesity, environmental factors, and the social context of a child can precipitation of childhood obesity. In this review, we hope to explore the different medications for obesity, orlistat, glucagon-like peptide-1 agonists, liraglutide, semaglutide, exenatide, setmelanotide, metreleptin, naltrexone, lorcaserin, phentermine, metformin, fluoxetine, lisdexamfetamine, and zonisamide, while also reviewing surgeries such as the Roux-en-Y gastric bypass, laparoscopic or vertical sleeve gastrectomy, and adjustable gastric banding. Show less

Despite widespread use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, substantial atherosclerotic cardiovascular disease risk persists, especially in people with heterozygous familial hypercholesterolemia or elevated lipoprotein(a) [Lp(a)] levels. Cholesteryl ester transfer protein (CETP) inhibitors block the transfer of hydrophobic cholesteryl esters from high-density lipoprotein to apolipoprotein B (apoB)-containing particles. This process raises high-density lipoprotein-C and lowers low-density lipoprotein-C, apoB, and Lp(a) levels. The first-generation of CETP inhibitors was limited by toxicity, neutral outcomes, or unfavorable pharmacokinetics. Obicetrapib is a next-generation amphipathic CETP inhibitor that selectively targets both CETP's hydrophobic and hydrophilic tunnels. It reduces low-density lipoprotein-C by about 30-51%, apoB by 20-33%, and Lp(a) by 30-57% without causing tissue accumulation or toxicity. Phase 3 trials (BROOKLYN, BROADWAY, TANDEM) show that obicetrapib is effective when added to maximized therapy, with a safety profile similar to placebo. Its consistent reduction of Lp(a) addresses an important unmet need. In addition to lowering atherogenic lipoproteins, early data suggest potential for neuroprotection, such as reductions in p-tau217 seen among APOE4 carriers. A 2025 pooled analysis offers initial evidence that major adverse cardiovascular events are reduced, as studied in the ongoing PREVAIL outcomes trial. This review covers CETP biology and tunnel mechanics, outcomes from earlier CETP inhibitor studies, obicetrapib's pharmacology, and current efficacy and safety data, and will clarify its potential place in lipid management today. Show less

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has expanded from experimental biology to early clinical application, raising the possibility of durable therapies for cardiovascular disease. Because many cardiac conditions are monogenic, they provide clear targets for allele-specific correction or modulation. In hypertrophic cardiomyopathy, preclinical research has shown that base editing of pathogenic MYH7 and MYBPC3 mutations can restore sarcomere function; concurrently, RNA-targeting approaches selectively suppress mutant transcripts. Dilated cardiomyopathy is more heterogeneous: TTN truncations cause haploinsufficiency that can be offset by CRISPR activation, while RBM20 and LMNA mutations require precise correction or interference to restore splicing and nuclear stability. Genome editing is also being tested in familial hypercholesterolemia, where inactivation of PCSK9 using lipid nanoparticle-delivered base editors has now advanced to first-in-human trials, achieving sustained LDL-C lowering. Concurrently, efforts targeting ANGPTL3 and APOB highlight the prospect of multigene modulation of lipid metabolism. In arrhythmic syndromes, patient-derived cardiomyocytes edited at SCN5A and KCNQ1 genes have enabled high-fidelity disease models, while in vivo correction of RYR2 in catecholaminergic polymorphic ventricular tachycardia confirms the viability of editing an arrhythmia substrate. In cardiac regeneration, CRISPR activation of developmental transcription factors has enabled direct reprogramming of fibroblasts into cardiomyocyte-like cells within scar tissue. Even with these advances, delivery remains a bottleneck due to immune responses to viral vectors, limitations in the efficiency of lipid nanoparticles in the heart, and the precision required to target cardiomyocytes or conduction cells, all of which slow progress. Future work will depend as much on technical refinement as on navigating ethical, regulatory, and societal concerns. Show less

This systematic review and meta-analysis evaluated the lipid-lowering efficacy and safety of evolocumab in statin-treated patients at high cardiovascular risk, focusing on changes in LDL-C, TG, ApoB, HDL-C, and Lp(a) after 12 weeks. A comprehensive search identified randomized controlled trials comparing evolocumab to placebo in adults on statin therapy. Studies reporting baseline and 12-week lipid and safety data were included. Risk of bias was assessed using the Cochrane tool. Random-effects models were used to calculate mean differences (MD) or odds ratios (OR) with 95% confidence intervals (CI). Five trials with 4,009 participants were analyzed. Evolocumab significantly reduced LDL-C (MD: -64.67; 95% CI: -66.72 to -62.61), TG, ApoB, and Lp(a), and increased HDL-C. No significant difference was observed in total TEAEs (OR: 0.97; 95% CI: 0.84 to 1.14) or serious TEAEs (OR: 1.23; 95% CI: 0.80 to 1.89) versus placebo. Evolocumab offers robust lipid-lowering benefits with a safety profile comparable to placebo in statin-treated patients. Limitations include short follow-up and variable statin regimens. Further long-term studies are needed to confirm cardiovascular outcome benefits. www.crd.york.ac.uk/prospero identifier is CRD42024543525. Show less

High-density lipoprotein cholesterol (HDL-C) has long been inversely associated with atherosclerotic cardiovascular disease risk, but pharmacologic efforts to raise HDL-C have consistently failed to reduce cardiovascular events. This has shifted focus from HDL quantity to quality, emphasizing functional properties such as cholesterol efflux, antioxidative capacity, and anti-inflammatory activity. Dysfunctional HDL, often modified by oxidative and inflammatory processes mediated by myeloperoxidase, loses its ability to promote reverse cholesterol transport, support endothelial function, and suppress vascular inflammation. Advanced proteomic and lipidomic studies have revealed compositional remodeling that underlies HDL's functional heterogeneity and disease-specific signatures. Functional measures like cholesterol efflux capacity and cell-free HDL assays correlate more strongly with cardiovascular outcomes than static HDL-C levels, providing a more accurate index of vascular protection. Despite the promising therapies such as cholesterol ester transfer protein (CETP) inhibitors, niacin, and apolipoprotein A-I infusions (reconstituted high-density lipoprotein (CSL112)), none have yet demonstrated definitive event reduction. Future directions include standardizing HDL functional assays, prioritizing quality over concentration, and integrating HDL-targeted and metabolic therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose transport 2 (SGLT2) inhibitors, to restore HDL's protective phenotype and redefine preventive cardiology. Show less

Cholesterol metabolism and transport has been a major focus in cardiovascular disease risk modification over the past several decades. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been the most commonly used agents, with the greatest benefit in reducing both the primary and secondary risks of cardiovascular disease. However, heart disease remains the leading cause of death in both men and women in the United States. Further investigation and intervention are required to further reduce the risk for cardiovascular disease and cardiovascular-related deaths. This review will focus on high-density lipoprotein metabolism and transport, looking particularly at cholesteryl ester transfer protein (CETP) inhibitors. While studies of the other CETP inhibitors in its class have not shown a significant improvement in the prevention of primary or secondary cardiovascular risk, anacetrapib, the fourth and latest of the CETP inhibitors to be investigated, may be more promising. Show less

Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has been recently studied as a cholesterol modifying agent to reduce cardiovascular risk and mortality in high risk cardiovascular disease patients. Evacetrapib acts to decrease lipid exchange through CETP inhibition. CETP acts to transfer cholesteryl esters from high-density lipoprotein-cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoprotein (VLDL-C). HDL-C is involved in reverse cholesterol transport and its blood levels have been shown to be inversely correlated with cardiovascular risk. Thus, a pharmacologic agent that can elevate HDL-C has been seen as an exciting area of research. In recent studies, evacetrapib was shown to be safe and efficacious. It produced an increase in HDL-C up to 128% and a 35% decrease in LDL-C, in comparison to placebo. In addition, evacetrapib was also shown to be more potent than previous CETP inhibitors. HDL-C particles treated with evacetrapib remained functional and had improved cholesterol efflux. A previously studied CETP inhibitor, torcetrapib, exhibited side effects of hyperaldosteronism, manifesting in electrolyte disturbances, and hypertension. These detrimental effects were not seen with evacetrapib. Recently, the results of evacetrapib's phase III ACCELERATE trial showed no significant reduction in major adverse cardiovascular events or mortality, and the drug will not be marketed. Although beneficial cholesterol effects were seen with this drug, more needs to be known to understand what role, if any, evacetrapib has in the reduction of cardiovascular risk. Show less

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS-specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole-genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA). Genes or regions frequently targeted by SCNAs were identified. Breakage analysis revealed OS specific unstable regions in which well-known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2 and LSAMP are located. Certain genomic features, such as transposable elements and non-B DNA-forming motifs were found to be significantly enriched in the vicinity of chromosomal breakage sites. A complex breakage pattern-chromothripsis-has been suggested as a widespread phenomenon in OS. It was further demonstrated that hyperploidy and in particular chromothripsis were strongly correlated with OS patient clinical outcome. The revealed OS-specific fragility pattern provides novel clues for understanding the biology of OS. Show less

The specification of the seven retinal cell types from a common pool of retina progenitor cells (RPCs) involves complex interactions between the intrinsic program and the environment. The proneural basic helix-loop-helix (bHLH) transcriptional regulators are key components for the intrinsic programming of RPCs and are essential for the formation of the diverse retinal cell types. However, the extent to which an RPC can re-adjust its inherent program and the mechanisms through which the expression of a particular bHLH factor influences RPC fate is unclear. Previously, we have shown that Neurod1 inserted into the Atoh7 locus activates the retinal ganglion cell (RGC) program in Atoh7-expressing RPCs but not in Neurod1-expressing RPCs, suggesting that Atoh7-expressing RPCs are not able to adopt the cell fate determined by Neurod1, but rather are pre-programmed to produce RGCs. Here, we show that Neurod1-expressing RPCs, which are destined to produce amacrine and photoreceptor cells, can be re-programmed into RGCs when Atoh7 is inserted into the Neurod1 locus. These results suggest that Atoh7 acts dominantly to convert a RPC subpopulation not destined for an RGC fate to adopt that fate. Thus, Atoh7-expressing and Neurod1-expressing RPCs are intrinsically different in their behavior. Additionally, ChIP-Seq analysis identified an Atoh7-dependent enhancer within the intronic region of Nrxn3. The enhancer recognized and used Atoh7 in the developing retina to regulate expression of Nrxn3, but could be forced to use Neurod1 when placed in a different regulatory context. The results indicate that Atoh7 and Neurod1 activate distinct sets of genes in vivo, despite their common DNA-binding element. Show less