👤 Manal Kordahi

Many adults fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals on statin monotherapy, requiring additional nonstatin lipid-lowering medication. Enlicitide, an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, lowered LDL-C by 60% compared with placebo; its efficacy compared with other oral nonstatin therapies has yet to be examined. This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies. In this phase 3, randomized, double-blind, active-comparator trial, statin-treated adults aged ≥18 years with LDL-C ≥55 mg/dL and a previous major atherosclerotic cardiovascular disease (ASCVD) event, or LDL-C ≥70 mg/dL if at intermediate to high risk for a first event, were randomized in 2:1:1:2 fashion to 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) once daily for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C). Safety endpoints included overall adverse events (AEs) and discontinuations due to AEs. Among 301 randomized participants (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin), 298 (99.0%) completed the trial. The mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe; enlicitide was superior to each comparator (all P < 0.001). Reductions in ApoB and nonHDL-C were also greater with enlicitide (all P < 0.001). Proportions of participants with AEs and discontinuations due to AEs were similar across treatment arms. In statin-treated adults with a history of a major ASCVD event or at increased risk for a first event, enlicitide achieved greater reductions in LDL-C, ApoB, and nonHDL-C than other oral nonstatin therapies, demonstrating its potential role as an important add-on option when LDL-C goals are not met with the use of statins alone. (A Study to Evaluate the Efficacy and Safety of Enlicitide Decanoate [MK-0616, Oral PCSK9 Inhibitor] Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia [MK-0616-018] [CORALreef AddOn; NCT06450366). Show less

Zinc-finger protein 768 (ZNF768) is an emerging transcription factor regulating cell proliferation and senescence. Although the role of ZNF768 in regulating cell fate decision has been demonstrated in vitro, its importance in controlling physiological and pathophysiological processes in vivo is still unclear. Here, we report the generation of a transgenic mouse model allowing the conditional overexpression of ZNF768. This was achieved by inserting an inverted Znf768 coding sequence surrounded by heterologous Cre recognition sites in the Gt(ROSA)26Sor mouse locus (FLExZnf768). To study the impact linked to systemic overexpression of ZNF768, mice carrying the FLExZnf768 allele were crossed with CMV-Cre mice to produce a whole-body ZNF768 transgenic mouse (WB-ZNF768-Tg). As expected, WB-ZNF768-Tg mice showed higher ZNF768 levels in various tissues. These mice were born at the expected Mendelian ratio and did not display apparent phenotypes. Because ZNF768 levels are often overexpressed in cancer, we assessed tumor development in WB-ZNF768-Tg mice. However, ZNF768 overexpression was not sufficient to promote 3-methylcholantrene-induced fibrosarcoma and KRAS Show less

Cell proliferation is a fundamental process required for organismal development, growth, and maintenance. Failure to control this process leads to several diseases, including cancer. Zinc finger protein 768 (ZNF768) is an emerging transcription factor that plays key roles in driving proliferation. In addition to controlling a gene network supporting cell division, ZNF768 physically interacts and inhibits the activity of the tumor suppressor p53. Although the importance of ZNF768 in promoting cell proliferation has been well demonstrated in vitro, the physiological and pathological roles of ZNF768 in vivo are still unknown. Here, we report the generation and characterization of a ZNF768 null mouse model. ZNF768 null mice are viable but show a growth defect early in life. Mouse embryonic fibroblasts (MEFs) isolated from ZNF768 null embryos exhibit higher p53 levels, premature senescence, and higher sensitivity to genotoxic stress. In line with these findings, ZNF768 null mice showed increased radiosensitivity. This effect was associated not only with higher expression of a subset of p53 target genes, but also with alterations in genes regulating transmembrane receptor signaling, cell adhesion, and growth. Because ZNF768 levels are elevated in tumors, we tested the impact of ZNF768 loss on cancer development in mice. Here, we show that ZNF768 deletion was sufficient to repress lung tumor development in a KRAS Show less