Novel small molecule compounds based on various scaffolds including chalcone, flavonoid, and resorcinol dibenzyl ether were designed and tested for their inhibitory activity against the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) pathway. Among them, compound NP19 inhibited the human PD-1/PD-L1 interaction with IC50 values of 12.5 nM in homogeneous time-resolved fluorescence (HTRF) binding assays. In addition, NP19 dose-dependently elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, NP19 displayed significant in vivo antitumor efficacy in two different mouse models of cancer (a melanoma B16-F10 tumor model and an H22 hepatoma tumor model). Moreover, H&E staining and flow cytometry data suggested that NP19 activated the immune microenvironment in the tumor, which may contribute to its antitumor effects. This work shows NP19 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the PD-1/PD-L1 pathway.
Aims To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. Methods and results Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43–3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20–80%) PRS. Conclusion The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility. Key question Key finding Take-home message The incorporation of polygenic risk into clinical care setting may provide a valuable risk stratification guidance to identify high-risk individuals for targeted intervention in primary prevention of CAD.
A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, P18 showed the highest inhibitory activity against PD-1/PD-L1 with an IC50 value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (e.g., t 1/2 of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.
Objective:To construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke.Methods:Using meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals.Results:During a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age of 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (HR: 1.99, 95% CI: 1.66-2.38), with the lifetime risk of stroke being 25.2% (95% CI: 22.5%-27.7%) and 13.6% (95% CI: 11.6%-15.5%), respectively. Individuals with both high polygenic risk and family history displayed the lifetime risk as high as 41.1% (95% CI: 31.4%-49.5%). Moreover, individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of the low polygenic risk (from 34.6 % to 13.2%).Conclusions:Our metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH.Classification of Evidence:This study provides Class I evidence that a meta-polygenic risk score is predictive of stroke risk.
SARS‐CoV‐2 caused the emerging epidemic of coronavirus disease in 2019 (COVID‐19). To date, there are more than 82.9 million confirmed cases worldwide, there is no clinically effective drug against SARS‐CoV‐2 infection. The conserved properties of the membrane fusion domain of the spike (S) protein across SARS‐CoV‐2 make it a promising target to develop pan‐CoV therapeutics. Herein, two clinically approved drugs, Itraconazole (ITZ) and Estradiol benzoate (EB), are found to inhibit viral entry by targeting the six‐helix (6‐HB) fusion core of SARS‐CoV‐2 S protein. Further studies shed light on the mechanism that ITZ and EB can interact with the heptad repeat 1 (HR1) region of the spike protein, to present anti‐SARS‐CoV‐2 infections in vitro, indicating they are novel potential therapeutic remedies for COVID‐19 treatment. Furthermore, ITZ shows broad‐spectrum activity targeting 6‐HB in the S2 subunit of SARS‐CoV and MERS‐CoV S protein, inspiring that ITZ have the potential for development as a pan‐coronavirus fusion inhibitor.
Background: Circular RNAs (circRNAs) play a pivotal regulatory role in a variety of tumors. Nevertheless, the detailed function of circ_0000003 in non-small cell lung cancer (NSCLC) and its regulatory mechanism remain elusive. Methods: RT-PCR was carried out to detect the expressions of circ_0000003, miR-338-3p and insulin receptor substrate 2 (IRS2)in NSCLC tissues. Besides, western blot was done to monitor IRS2 expression in NSCLC cells. The correlation between circ_0000003 and clinicopathologic characteristics of NSCLC patients was analyzed as well.CCK8 and BrdUassays were used to monitor cell proliferation; flow cytometry was used to detect apoptosis; and transwell assay was conducted to detect its migration and invasion.Moreover, dual luciferase reporter gene assay was done to verify the targeting relationship between circ_0000003 and miR-338-3p.Additionally, the effect of circ_0000003 on the growth of NSCLC cells in vivo was evaluated by tumorigenesis assay in nude mice. Results: The expression of circ_0000003 was significantly high in NSCLC tissues and cell lines, and its high expression level was notably correlated with lymph node metastasis andTNM staging.In vitro experiments showed that overexpression of circ_0000003 facilitated the proliferation, migration, invasion and inhibited the apoptosis of NSCLC cells, while the knockdown of circ_0000003 had the opposite effect.In vivo experiments revealed that knockdown of circ_0000003 impeded tumor growth and metastasis. Further, the underlying mechanism showed that circ_0000003 functioned as endogenous competitive RNA and directly targeted miR-338-3p to positively regulated IRS2 expression. Conclusion: Circ_0000003 promotes the proliferation and metastasis of NSCLC cells via modulating miR-338-3p/IRS2 axis.
Abstract:Purpose: In information economy era, innovation is the key to improve the competitiveness of enterprises. The traditional way of enterprise innovation is outdated and supply chain collaborative innovation has becoming popular. This paper aims to analyze the mechanism of knowledge sharing between enterprises in supply chain collaborative innovation.Design/methodology/approach: This paper analyzes the supply chain members' willingness to share knowledge by using the game theory. The result of knowledge sharing between two companies is analyzed by using the evolutionary game. Findings:We broke the knowledge sharing process in supply chain collaborative innovation into knowledge mining and knowledge transferring. We got the best knowledge sharing strategy of each supply chain member. We gave the influencing factors of knowledge sharing between members for the knowledge sharing mechanisms in supply chain collaborative innovation. Research limitations/implications:We didn't study the willingness of more than two supply chain members to share knowledge and the result of knowledge sharing between them. And this situation is more realistic. Practical implications:Our findings can help to improve the effect of knowledge sharing in supply chain collaborative innovation.-152-Journal of Industrial Engineering and Management -http://dx.doi.org/10.3926/jiem.1368 Originality/value: The paper introduces the game theory to knowledge sharing between members in supply chain collaborative innovation, deepens the understanding of knowledge sharing in supply chain collaborative innovation, and gives some interesting findings.
ApoG2, a novel anti-apoptotic Bcl-2 agent, inhibits proliferation of breast cancer cell line MCF-7 by inducing cell apoptosis and autophagy.
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