Polygenic risk score predicts all-cause death in East Asian patients with prior coronary artery disease

IntroductionCoronary artery disease (CAD) is a highly heritable and multifactorial disease. Numerous genome-wide association studies (GWAS) facilitated the construction of polygenic risk scores (PRS) for predicting future incidence of CAD, however, exclusively in European populations. Furthermore, identifying CAD patients with elevated risks of all-cause death presents a critical challenge in secondary prevention, which will contribute largely to reducing the burden for public healthcare.MethodsWe recruited a cohort of 1,776 Chinese CAD patients and performed medical follow-up for up to 11 years. A pruning and thresholding method was used to calculate PRS of CAD and its 14 risk factors. Their correlations with all-cause death were computed via Cox regression.Results and discussionWe found that the PRS for CAD and its seven risk factors, namely myocardial infarction, ischemic stroke, angina, heart failure, low-density lipoprotein cholesterol, total cholesterol and C-reaction protein, were significantly associated with death (P ≤ 0.05), whereas the PRS of body mass index displayed moderate association (P < 0.1). Elastic-net Cox regression with 5-fold cross-validation was used to integrate these nine PRS models into a meta score, metaPRS, which performed well in stratifying patients at different risks for death (P < 0.0001). Combining metaPRS with clinical risk factors further increased the discerning power and a 4% increase in sensitivity. The metaPRS generated from the genetic susceptibility to CAD and its risk factors can well stratify CAD patients by their risks of death. Integrating metaPRS and clinical risk factors may contribute to identifying patients at higher risk of poor prognosis

Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects

Objectives: This study aimed to elucidate the contribution of candidate single nucleotide polymorphisms (SNPs) related to pharmacokinetics on the recovery of platelet function after single dose of ticagrelor was orally administered to healthy Chinese subjects.Methods: The pharmacokinetic profiles of ticagrelor and its metabolite AR-C124910XX (M8), and the platelet aggregation (PA), were assessed after 180 mg of single-dose ticagrelor was orally administered to 51 healthy Chinese subjects. Effects of CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT1A1*6, UGT1A1*28, UGT2B7*2, UGT2B7*3, SLCO1B1 388A>G, and SLCO1B1 521T>C, on the pharmacokinetics of ticagrelor and M8, and platelet function recovery were investigated.Results: The time to recover 50% of the maximum drug effect (RT50) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t1/2) of M8 (r = 0.3901, P = 0.0067). The time of peak concentration (Tmax) of ticagrelor for CYP2C19*3 GG homozygotes was significantly higher than that of GA heterozygotes (P = 0.0027, FDR = 0.0243). Decreased peak concentration (Cmax) of M8 was significantly associated with SLCO1B1 388A>G A allele (P = 0.0152, FDR = 0.1368). CYP2C19*2 A was significantly related to decreased Cmax of M8 (P = 0.0455, FDR = 0.2048). While, the influence of these nine SNPs on the recovery of platelet function was not significant.Conclusion: Our study suggests that the elimination of M8 is an important factor in determining the recovery of platelet function. Although CYP2C19 and SLCO1B1 genetic variants were related to the pharmacokinetics of ticagrelor or M8, they did not show a significant effect on the platelet function recovery in this study.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03092076, identifier: NCT0309207

Characteristics of the gut microbiome and metabolic profile in elderly patients with sarcopenia

Introduction: There is growing evidence of research indicating that the gut microbiota is involved in the development of sarcopenia. Nevertheless, there exists a notable deficiency in comprehension concerning the connection between irregularities in the intestinal microbiome and metabolic processes in older individuals suffering from sarcopenia.Methods: To analyze fecal samples obtained from a cohort of 30 older patients diagnosed with sarcopenia as well as 30 older patients without sarcopenia, this study employed 16S rDNA sequencing and liquid chromatography-mass spectrometry (LC-MS)-based non-targeted metabolomics profiling techniques.Results: As a result, we found that 29 genera and 172 metabolites were significantly altered in the sarcopenic patients. Among them, Blautia, Lachnospiraceae_unclassified, and Subdoligranulum were the bacteria with a potential diagnostic value for sarcopenia diagnosis. Correlation analysis between clinical indices and these gut bacteria suggested that the IL-6 level was negatively correlated with Blautia. Function prediction analysis demonstrated that 17 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways differ significantly between sarcopenic and non-sarcopenic patients. The primary classes of metabolites identified in the study included lipids and lipid-like molecules, organic acids and derivatives, and organoheterocyclic compounds. KEGG enrichment analysis showed that purine metabolism, arginine and proline metabolism, alanine, aspartate, and glutamate metabolism, butanoate metabolism, and histidine metabolism may contribute to the development of sarcopenia. The correlation study on gut microbiota and metabolites found that Lachnospiraceae_unclassified was positively associated with seven metabolites that were more abundant in the non-sarcopenia group and negatively correlated with three metabolites that were more abundant in the sarcopenia group. In addition, Subdoligranulum was positively correlated with seven metabolites that were lacking in sarcopenia and negatively correlated with two metabolites that were enriching in sarcopenia. Moreover, Blautia was positively associated with xanthosine.Discussion: We conducted a study on the intestinal microbiota and metabolic profile of elderly individuals with sarcopenia, offering a comprehensive analysis of the overall ecosystem. Through this investigation, we were able to validate existing research on the gut–muscle axis and further investigate potential pathogenic processes and treatment options for sarcopenia

Copper Salt-Catalyzed Formation of a Novel Series of Triazole-Spirodienone Conjugates with Potent Anticancer Activity.

Copper salt-catalyzed oxidative amination resulted in the formation of a novel series of triazole-spirodienone conjugates, 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-3,8-diones and 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-8-ones. A single crystal of compound 1p among them was grown and analyzed by X-ray crystallography. These compounds were evaluated for their antiproliferative activities against MDA-MB-231, HeLa, A549 and MCF-7 cell lines. Most of them showed moderate to high anticancer potency in the four cancer cell lines. The discovery of the triazole-spirodienone conjugates as cytotoxic agents against cancer cells may open up a new field in which these novel small molecules could be further explored as promising anticancer agents

Integrated metabolomics and metagenomics analysis of plasma and urine identified microbial metabolites associated with coronary heart disease

Coronary heart disease (CHD) is top risk factor for health in modern society, causing high mortality rate each year. However, there is no reliable way for early diagnosis and prevention of CHD so far. So study the mechanism of CHD and development of novel biomarkers is urgently needed. In this study, metabolomics and metagenomics technology are applied to discover new biomarkers from plasma and urine of 59 CHD patients and 43 healthy controls and trace their origin. We identify GlcNAc-6-P which has good diagnostic capability and can be used as potential biomarkers for CHD, together with mannitol and 15 plasma cholines. These identified metabolites show significant correlations with clinical biochemical indexes. Meanwhile, GlcNAc-6-P and mannitol are potential metabolites originated from intestinal microbiota. Association analysis on species and function levels between intestinal microbes and metabolites suggest a close correlation between Clostridium sp. HGF2 and GlcNAc-6-P, Clostridium sp. HGF2, Streptococcus sp. M143, Streptococcus sp. M334 and mannitol. These suggest the metabolic abnormality is significant and gut microbiota dysbiosis happens in CHD patients

Synthesis and Antitumor Activity of a Series of Novel 1-Oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione Derivatives

A series of novel 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones were designed and synthesized by using 4-aminophenol and α-glycolic acid or lactic acid as starting materials in three or four steps. The key step is the metal-catalyzed oxidative cyclization of the amide to 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones (10a and 10b), the reaction conditions of which are investigated and optimized. The anticancer activity of 17 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives was evaluated. Preliminary results showed that 15 compounds have moderate to potent activity against human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds 11b and 11h were the most potent against A549 cell line with 0.18 and 0.19 µM of IC50, respectively; compounds 11d, 11h, and 11k showed the most potent cytotoxicity against MDA-MB-231 cell line with 0.08, 0.08, and 0.09 µM of IC50, respectively, while the activities of 11h, 11k, and 12c against HeLa cell line were the most potent with 0.15, 0.14, and 0.14 µM of IC50, respectively. Compound 11h is a promising candidate for further development, which emerged as the most effective compound overall against the three tested cancer cell lines

Boronic Prodrug of 4-hydroxytamoxifen is more Efficacious than Tamoxifen with Enhanced Bioavailability Independent of CYP2D*6 Status

Background: Poor initial response to tamoxifen due to CYP2D*6*4-OHT at therapeutically effective concentrations but at a fraction of the standard tamoxifen dose. Methods: A mouse xenograft tumor model was used to investigate the efficacy of ZB497 in comparison with tamoxifen. Pharmacokinetic studies were conducted to evaluate the metabolism and bioavailability of the drug in mice. Drug and metabolites distribution in xenograft tumor tissues was determined by high performance liquid chromatography-tandem mass spectrometry. Results: The boronic prodrug, ZB497, can not only be efficiently converted to 4-OHT in mice, but also afforded over 30 fold higher plasma concentrations of 4-OHT than in mice given either the same dose of 4-OHT or tamoxifen. Further, ZB497 was more effective than tamoxifen at lowered dosage in inhibiting the growth of xenograft tumors in mice. Consistent with these observations, ZB497 treated mice accumulated over 6 times higher total drug concentrations than tamoxifen treated mice. Conclusions: Our study demonstrates that ZB497 effectively delivers a markedly increased plasma concentration of 4-OHT in mice. The boronic prodrug was shown to have far superior bioavailability of 4-OHT compared to tamoxifen or 4-OHT administration as measured by the area under the plasma concentration time curve (AUC), plasma peak concentrations, and drug accumulation in tumor tissues. Further, ZB497 proves to be a more efficacious hormone therapy than tamoxifen administered at a reduced dose in mice

Fractional Dynamics of Globally Slow Transcription and Its Impact on Deterministic Genetic Oscillation

<div><p>In dynamical systems theory, a system which can be described by differential equations is called a continuous dynamical system. In studies on genetic oscillation, most deterministic models at early stage are usually built on ordinary differential equations (ODE). Therefore, gene transcription which is a vital part in genetic oscillation is presupposed to be a continuous dynamical system by default. However, recent studies argued that discontinuous transcription might be more common than continuous transcription. In this paper, by appending the inserted silent interval lying between two neighboring transcriptional events to the end of the preceding event, we established that the running time for an intact transcriptional event increases and gene transcription thus shows slow dynamics. By globally replacing the original time increment for each state increment by a larger one, we introduced fractional differential equations (FDE) to describe such globally slow transcription. The impact of fractionization on genetic oscillation was then studied in two early stage models – the Goodwin oscillator and the Rössler oscillator. By constructing a “dual memory” oscillator – the fractional delay Goodwin oscillator, we suggested that four general requirements for generating genetic oscillation should be revised to be negative feedback, sufficient nonlinearity, sufficient memory and proper balancing of timescale. The numerical study of the fractional Rössler oscillator implied that the globally slow transcription tends to lower the chance of a coupled or more complex nonlinear genetic oscillatory system behaving chaotically.</p> </div

Metabolism, Pharmacokinetics, and Bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)

ZB716 is a selective estrogen receptor downregulator (SERD) with excellent oral bioavailability and superior efficacy. In this study, we investigate the in vitro and in vivo metabolism and the pharmacokinetics of ZB716 by incubation with liver microsomes, liver cytosol, and by orally dosing rodents. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem +mass spectrometry. The metabolic profile of ZB716 showed fulvestrant and ZB716- sulfone as the two major oxidative metabolites. ZB716 also underwent some degree of sulfation and glucuronidation in vitro. The major oxidative metabolites of ZB716 were found in rat plasma, feces, and urine samples. No sulfation and glucuronidation metabolites from ZB716 were found in plasma. Limited amounts of sulfate conjugates and glucuronides of ZB716 were detected in feces. The glucuronidation on 3-OH position of fulvestrant was the main metabolite found in urine, suggesting that this specific site of phase 2 metabolism is blocked in ZB716 and formation of glucuronide 3-fulvestrant must be preceded by metabolic transformation of ZB716 to fulvestrant. The pharmacokinetic study of ZB716 showed a half-life (t1/2) at 17.03 hour, the area under curve value (AUC) of 1451.82 ng/ml*h, and the maximum plasma concentration (Cmax) at 158.12 ng/mL reached at 2 h after a single dose of 10 mg/kg by oral gavage. Overall this study elucidated important metabolic characteristics of ZB716, an oral SERD that has demonstrated superior bioavailability and efficacy in preclinical studies conducted so far

Different types of one-variable Goodwin model.

<p>A. Goodwin model with regular timescale. B. Goodwin oscillator with explicit time delay. C. The fractional delay Goodwin oscillator described by Eq. (17). The silent interval hinders the product to trigger the reinitiation of gene transcription and hence the time span of the silent interval is equal to the delay time.</p