Gefitinib Increases the Incidence of QT Prolongation in Patients with Non-Small Cell Lung Cancer.

Gefitinib (GEF) may increase the risk of corrected QT prolongation (QTc). We aimed to evaluate whether gefitinib increases the risk of corrected QT interval (QTc) prolongation and analyze the associated risk factors.A total of 122 cases of advanced EGFR-mutated non-small cell lung cancer (NSCLC) who received gefitinib therapy from January 2015 to December 2020 were evaluated. The results of at least two resting 12-lead electrocardiogram before and after gefitinib treatment were obtained. The Bazett and Fridericia formulas were used to calculate the QTc interval, and the changes of QTc interval values before and after treatment were evaluated. The correlation between gefitinib and QTc interval prolongation and related risk factors were analyzed.After gefitinib-targeted therapy, 23 patients (18.9%) had a prolonged QTc interval, which increased from a mean of 446 ± 25 ms at baseline to 478 ± 18 ms (P < 0.001). Three of the patients met criteria for Grade 3 QTc prolongation in the common term V5.0 for clinical adverse events. Univariate analysis showed that age (ORR, 1.054; 95% confidence interval [CI], 1.003-1.107; P = 0.038), history of hypertension (ORR, 3.409; 95% CI, 1.334-8.713; P = 0.01), CCB medication history (ORR, 0.259; 95% CI, 0.094-0.712; P = 0.009), history of lung cancer surgery (ORR, 0.231; 95% CI, 0.064-0.829; P = 0.025), and baseline QT interval (ORR, 0.978; 95% CI, 0.964-0.993; P = 0.004) were important predictors of QTc interval prolongation in patients treated with gefitinib. The results of multivariate analysis showed that the history of lung cancer surgery and the baseline QT interval were important factors affecting QTc interval prolongation in patients treated with gefitinib.Gefitinib increases the risk of QTc prolongation in NSCLC patients, which may be more pronounced in patients with advanced age, hypertension, CCB therapy, lung cancer surgery, and a long QT interval at baseline.

Efficacy and Safety of Evinacumab for the Treatment of Hypercholesterolemia: A Meta-Analysis.

ABSTRACT: Angiopoietin-like protein 3 is essential in lipid metabolism regulation. However, the efficacy and safety of evinacumab (angiopoietin-like protein 3 inhibition drug) for hypercholesterolemia treatment is unknown. In this study, a meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of evinacumab. RCTs published between January 1, 2000, and November 1, 2020, were obtained from PubMed, Embase, and Cochrane Library. All RCTs evaluating the efficacy and safety of evinacumab were included without language restrictions. Our primary end points included the percent change of low-density lipoprotein cholesterol (LDL-C) from baseline and the incidence of at least one treatment emergent adverse events including nasopharyngitis, influenza-like illness, headache, dizziness, injection-site reaction, increased aspartate aminotransferase, increased alanine aminotransferase, and any other discomfort during treatments. Percentage changes of triglycerides and high-density lipoprotein cholesterol (HDL-C) from baseline indicated secondary end points. A random-effects model was used to assess pooled data if there was moderate to high heterogeneity between studies. Four studies with 5 RCTs (568 participants) were identified. Evinacumab significantly reduced LDL-C [mean difference (MD) -33.123%, 95% confidence interval (CI), -48.639% to -17.606%, P < 0.0001], triglycerides (MD -50.959%, 95% CI, -56.555% to -45.362%, P < 0.0001), and HDL-C (MD -12.773%, 95% CI, -16.359% to -9.186%, P < 0.0001) compared with placebo. The incidence of at least 1 treatment emergent adverse events was not significantly different between evinacumab and placebo groups (relative risk 1.080, 95% CI, 0.901-1.296, P = 0.405). Evinacumab decreased triglycerides, LDL-C, and HDL-C without significant adverse effects, indicating that it can be a therapeutic strategy for hypercholesterolemia.

DualFluidNet: An attention-based dual-pipeline network for fluid simulation.

Fluid motion can be considered as a point cloud transformation when using the SPH method. Compared to traditional numerical analysis methods, using machine learning techniques to learn physics simulations can achieve near-accurate results, while significantly increasing efficiency. In this paper, we propose an innovative approach for 3D fluid simulations utilizing an Attention-based Dual-pipeline Network, which employs a dual-pipeline architecture, seamlessly integrated with an Attention-based Feature Fusion Module. Unlike previous methods, which often make difficult trade-offs between global fluid control and physical law constraints, we find a way to achieve a better balance between these two crucial aspects with a well-designed dual-pipeline approach. Additionally, we design a Type-aware Input Module to adaptively recognize particles of different types and perform feature fusion afterward, such that fluid-solid coupling issues can be better dealt with. Furthermore, we propose a new dataset, Tank3D, to further explore the network's ability to handle more complicated scenes. The experiments demonstrate that our approach not only attains a quantitative enhancement in various metrics, surpassing the state-of-the-art methods, but also signifies a qualitative leap in neural network-based simulation by faithfully adhering to the physical laws. Code and video demonstrations are available at https://github.com/chenyu-xjtu/DualFluidNet.

Association of HMGCR rs17671591 and rs3761740 with lipidemia and statin response in Uyghurs and Han Chinese.

Background: Dyslipidemia plays a very important role in the occurrence and development of cardiovascular disease (CVD). Genetic factors, including single nucleotide polymorphisms (SNPs), are one of the main risks of dyslipidemia. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is not only the rate-limiting enzyme step of endogenous cholesterol production, but also the therapeutic target of statins. Methods: We investigated 405 Han Chinese and 373 Uyghur people who took statins for a period of time, recorded their blood lipid levels and baseline data before and after oral statin administration, and extracted DNA from each subject for SNP typing of HMGCR rs17671591 and rs3761740. The effects of HMGCR rs17671591 and rs3761740 on lipid levels and the effect of statins on lipid lowering in Han Chinese and Uyghur ethnic groups were studied. Results: In this study, for rs17671591, the CC vs. TT+CT model was significantly correlated with the level of LDL-C before oral statin in the Uyghur population, but there were no correlations between rs17671591 and the level of blood lipid before oral statin in the Han population. The CC vs. TT+CT and CT vs. CC+TT models were significantly correlated with the level of LDL-C after oral statin in the Uyghur population. There was no significant correlation between rs3761740 with blood lipids before and after oral statin in the Han population. For rs3761740, before oral statin, the CC vs. AA+CA model was significantly correlated with the level of LDL-C, and the CA vs. CC+AA model was significantly correlated with the level of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and non-high density lipoprotein cholesterol (HDL-C) in the Uyghur population. After oral statin, the CC vs. AA+CA and CA vs. CC+AA models were significantly correlated with the level of TC, LDL-C, and apolipoprotein (APOB), and the C vs. A model was significantly correlated with the level of TC, triglyceride (TG), LDL-C, and APOB in the Uyghur population. Particularly, the CT vs. CC+TT model of rs17671591 was significantly correlated with the changes of LDL-C after oral statin in the Uyghur population. In this study, we also explored the association of rs17671591 and rs3761740 with the rate of dyslipidemia as a reference. Conclusion: We found that HMGCR rs3761740 was correlated with the levels of TC, LDL-C, and non-HDL-C before and after oral statin in Uyghurs, but not with blood lipid levels in the Han population. In the Uyghur population, HMGCR rs17671591 was associated with the level of LDL-C before and after oral statin, and also affected the changes of LDL-C after oral statin.

Mechanisms Underlying Brain Aging Under Normal and Pathological Conditions.

Aging is a major risk factor for many human diseases, including cognitive impairment, which affects a large population of the elderly. In the past few decades, our understanding of the molecular and cellular mechanisms underlying the changes associated with aging and age-related diseases has expanded greatly, shedding light on the potential role of these changes in cognitive impairment. In this article, we review recent advances in understanding of the mechanisms underlying brain aging under normal and pathological conditions, compare their similarities and differences, discuss the causative and adaptive mechanisms of brain aging, and finally attempt to find some rules to guide us on how to promote healthy aging and prevent age-related diseases.

Effect of PCSK9 antibodies on coronary plaque regression and stabilization derived from intravascular imaging in patients with coronary artery disease: A meta-analysis.

BACKGROUND: Despite extensive evidence demonstrating the beneficial effects of the additional PCSK9 antibodies with high-density statins treatment on cardiovascular clinical outcomes, the potent causes underlying these effects remain elusive. This meta-analysis aimed at exploring the underlying causes to assess the effect of PCSK9 antibodies on the regression and stabilization of coronary plaque derived from intravascular imaging in statin-treated patients with coronary artery disease (CAD). METHODS: PubMed, Embase, and Cochrane Library were searched from inception to February 1, 2023, for randomized controlled trials (RCTs), nonrandomized studies without language restrictions if they described the association between PCSK9 antibodies with coronary plaque regression and stabilization evaluated by intravascular imaging in statin-treated patients with CAD. Meta-analyses were performed for mean difference (MD) and odds ratio (OR) using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. RESULTS: A total of 9 studies (7 RCTs and 2 non-RCTs) with 2290 CAD patients were identified and included. Among statin-treated CAD patients, the addition use of PCSK9 antibodies was associated with IVUS-derived percent atheroma volume (PAV) (4 studies with 1875 participants; MD, -1.26; 95% CI, -1.51 to -1.00; P < 0.01), total atheroma volume (TAV) (4 studies with 1875 participants; MD, -7.23; 95% CI, -11.28 to -3.18; P < 0.01), incidence of PAV regression (4 studies with 1875 participants; OR, 2.24; 95% CI, 1.81 to 2.77; P < 0.01) and incidence of TAV regression (3 studies with 1256 participants; OR, 1.66; 95% CI, 1.33 to 2.09; P < 0.01) in Caucasians instead of Asians from multiple countries; OCT-derived minimum fibrous cap thickness (FCT) (6 studies with 841 participants; MD, 25.16; 95% CI, 14.06 to 36.27; P < 0.01), incidence of thin-capped fibroatheroma (TCFA) regression (2 studies with 222 participants; OR, 2.56; 95% CI, 1.42 to 4.61; P < 0.01) and maximum lipid arc (4 studies with 280 participants; MD, -14.96; 95% CI, -22.10 to -7.83; P < 0.01) in Asians and Caucasians without races restrictions. CONCLUSIONS: PCSK9 antibodies resulted in significantly greater coronary plaque regression and stabilization in statin-treated CAD patients, mostly Caucasians from multiple countries. Further studies are needed to assess the effect for Asian patients.

Development of a high-throughput micropatterned agarose scaffold for consistent and reproducible hPSC-derived liver organoids.

Liver organoids represent emerging human-relevantin vitroliver models that have a wide range of biomedical applications in basic medical studies and preclinical drug discovery. However, the generation of liver organoids currently relies on the conventional Matrigel dome method, which lacks precise microenvironmental control over organoid growth and results in significant heterogeneity of the formed liver organoids. Here, we demonstrate a novel high-throughput culture method to generate uniform liver organoids from human pluripotent stem cell-derived foregut stem cells in micropatterned agarose scaffold. By using this approach, more than 8000 uniformly-sized liver organoids containing liver parenchyma cells, non-parenchymal cells, and a unique stem cell niche could be efficiently and reproducibly generated in a 48-well plate with a size coefficient of variation significance smaller than that in the Matrigel dome. Additionally, the liver organoids highly expressed liver-specific markers, including albumin (ALB), hepatocyte nuclear factor 4 alpha (HNF4α), and alpha-fetoprotein (AFP), and displayed liver functions, such as lipid accumulation, glycogen synthesis, ALB secretion, and urea synthesis. As a proof of concept, we evaluated the acute hepatotoxicity of acetaminophen (APAP) in these organoids and observed APAP-induced liver fibrosis. Overall, we expect that the liver organoids will facilitate wide biomedical applications in hepatotoxicity analysis and liver disease modeling.