Objective: Reverse cholesterol transport, removing excess cholesterol from peripheral tissues, is an important therapeutic target for atherosclerosis treatment. In this study, we propose a new small molecule, E17241, that may be used to treat atherosclerosis by promoting reverse cholesterol transport via ABCA1 (ATP-binding cassette transporter A1) upregulation. Approach and Results: E17241 (4-(1,3-dithiolan-2-yl)-N-(3-hydroxypyridin-2-yl)benzamide) was first identified as an ABCA1 upregulator using a cell-based reporter assay. E17241 significantly increases the mRNA and protein expression levels of ABCA1 in both hepatic cells and macrophages. It promotes cholesterol efflux to apo AI in macrophage cells, and this effect depends on ABCA1. It also decreases total cholesterol content in Ox-LDL (oxidized low-density lipoprotein) loading macrophage cells. E17241 treatment increases the content of 3 H-labeled cholesterol in the feces of male C57BL/6J mice intraperitoneally injected with 3H-cholesterol-labeled macrophage J774 cells, indicating that it could promote in vivo macrophage reverse cholesterol transport. Compared with the western diet group (western diet–fed male ApoE −/− mice), the E17241 group (western diet+E17241 treatment) shows decreased plasma cholesterol, liver cholesterol, and triglyceride levels, with increased fecal cholesterol content. Importantly, E17241 reduces atherosclerotic lesion areas in the en face aorta and aortic sinus while increasing ABCA1 protein levels in both liver and macrophages. Human proteome microarray, coimmunoprecipitation, and other assays demonstrate that PKCζ (protein kinase C zeta) is a binding target of E17241, and this small molecule increases ABCA1 expression in macrophages via the PKCζ-NR (nuclear receptor) pathway. Conclusions: E17241 may be developed as a new lead or drug candidate for the treatment of atherosclerosis by upregulating ABCA1.
PurposeAccording to sociotechnical systems theory, this study examines the configurational effects of modularity (product and process modularity), supply chain integration (information, operational and relational integration) and the characteristics of customer need (customer need tacitness and diversity) on MCC and the impact of high MCC generated by different configurations on economic performance.Design/methodology/approachThis study tests the model by combining fuzzy set qualitative comparative analysis (fsQCA) with propensity score matching methods based on data from 277 Chinese manufacturers.FindingsThe authors identify four equifinal configurations sufficient for high MCC and categorize them into three types: modularity + integration oriented, integration + customer need oriented, modularity + integration + customer need balance. The results further indicate that the high MCC triggered by three types of configuration affects economic performance in different ways.Practical implicationsThe results deliver an important message to manufacturing enterprises that high MCC can be achieved through multiple equally-effective combinations. Moreover, managers should focus on the fit between multiple conditions and choose the appropriate pathway to enhance economic performance.Originality/valueFrom a configurational perspective, these findings enrich the literature on enablers and performance outcomes of MCC by introducing an integrated model.
Background: Fine needle aspiration (FNA) has been widely applied for the preoperative diagnosis of thyroid nodules. However, it is limited mainly to testing for a single gene--BRAFV600E, whereas multi-gene testing data are extremely scarce, especially in the Asian population. This study aimed to explore the clinical value of multi-gene testing in the differential diagnosis of benign and malignant thyroid nodules based on The Bethesda System for Reporting Thyroid Cytopathology (BSRTC). Methods: A total of 615 thyroid nodules underwent ultrasound-guided fine-needle aspiration cytology (FNAC) were collected from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. The next-generation sequencing (NGS) platform was applied for multi-gene testing. A panel of well recognized commonly mutated genes in thyroid cancer were analyzed, including BRAFV600E, KRAS, NRAS, HRAS, TERT, TP53, PAX8/PPARγ, RET/PTC1 and RET/PTC3. Results: Gene mutations were identified in 324 nodules (52.7%), BRAFV600Ewas the driver gene with the highest alteration frequency (233/324, 79.1%), followed by RAS (77/324, 23.8%). The overall malignancy rate of gene mutations was 89.7% in our cohort, of which the lymph node metastasis rate was 45.3%. The combination of multi-gene testing and cytology resulted in 89.3% sensitivity, 95.2% specificity, 98.9% positive predictive value, 64.5% negative predictive value and 83.1% accuracy, which were significantly higher than those from mere cytology (sensitivity 68.6%, specificity 87.5%, positive predictive value 95.9%, negative predictive value 39.8%, accuracy 72.7%). Conclusions: Multi-gene testing could greatly increase the detection rate of malignant thyroid nodules and protect patients with benign nodules from unnecessary surgeries. Multi-gene testing provides a valuable reference for individualized preoperative decision-making, which may serve as a crucial method for postoperative treatment and prognosis assessment.
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