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Aims: Based on the quantitative and qualitative fusion data of traditional Chinese medicine (TCM) and Western medicine, a diabetic foot (DF) prediction model was established through combining the objectified parameters of TCM and Western medicine., Methods: The ResNet-50 deep neural network (DNN) was used to extract depth features of tongue demonstration, and then a fully connected layer (FCL) was used for feature extraction to obtain aggregate features. Finally, a non-invasive DF prediction model based on tongue features was realized., Results: Among the 391 patients included, there were 267 DF patients, with their BMI (25.2 vs. 24.2) and waist-to-hip ratio (0.953 vs. 0.941) higher than those of type 2 diabetes mellitus (T2DM) group. The diabetes (15 years vs. 8 years) and hypertension durations (10 years vs. 7.5 years) in DF patients were significantly higher than those in T2DM group. Moreover, the plantar hardness in DF patients was higher than that in T2DM patients. The accuracy and sensitivity of the multi-mode DF prediction model reached 0.95 and 0.9286, respectively., Conclusion: We established a DF prediction model based on clinical features and objectified tongue color, which showed the unique advantages and important role of objectified tongue demonstration in the DF risk prediction, thus further proving the scientific nature of TCM tongue diagnosis. Based on the qualitative and quantitative fusion data, we combined tongue images with DF indicators to establish a multi-mode DF prediction model, in which tongue demonstration and objectified foot data can correct the subjectivity of prior knowledge. The successful establishment of the feature fusion diagnosis model can demonstrate the clinical practical value of objectified tongue demonstration. According to the results, the model had better performance to distinguish between T2DM and DF, and by comparing the performance of the model with and without tongue images, it was found that the model with tongue images performed better., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tian, Wang, Sun, Cui and Wang.)

The CsPbI3 perovskite is a promising candidate for photovoltaic applications, for which several critical phase transitions govern both its efficiency and stability. Large-scale molecular dynamics simulations are valuable in understanding the microscopic mechanisms of these transitions, in which the accuracy of the simulation heavily depends on the empirical potential. This study parameterizes two efficient and stable empirical potentials for the CsPbI3 perovskite. In these two empirical potentials, the short-ranged repulsive interaction is described by the Lennard-Jones model or the Buckingham model, while the long-ranged Coulomb interaction is summed by the damped shifted force method. Our molecular dynamics simulations show that these two empirical potentials accurately capture the γ ↔ β ↔ α and δ → α phase transitions for the CsPbI3 perovskite. Furthermore, they are up to two orders of magnitude more efficient than previous empirical models, owing to the high efficiency of the damped shifted force truncation treatment for the Coulomb interaction., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The gas permeation through nanoscale membranes like graphene has been extensively studied by experiments and empirical models. In contrast to planar membranes, the single-walled carbon nanotube has a natural confined hollow structure, which shall affect the gas permeation process. We perform molecular dynamics simulations to investigate the effect of the nanotube diameter on the gas permeation process. It is found that the permeance constant increases with the increase of the nanotube diameter, which can not be explained by existing empirical models. We generalize the three-state model to describe the diameter dependence for the permeance constant, which discloses a distinctive confinement-induced adsorption phenomenon for the gas molecule on the nanotube's inner surface. This adsorption phenomenon effectively reduces the pressure of the bulk gas, leading to the decrease of the permeance constant. These results illustrate the importance of the adsorption within the confined space on the gas permeation process., (© 2022 IOP Publishing Ltd.)

A challenging but critical question is that new foot-and-mouth disease (FMD) vaccines should be to induce B cell memory to provide antibodies for long-term protection. The maintenance of B cell memory is dependent on long-lived plasma cells (LLPCs) and memory B cells. We developed a chimeric FMDV virus-like particles (FMDV-VLPs), fusing VP1-VP4 into HBcAg. In our study, we investigated if or how long B cell memory was induced by FMDV-VLPs in mice. The data showed that FMDV-VLPs can induce memory humoral responses with a high level of total IgG1, IgG2a, IgA, and FMDV-specific IgG antibodies in serum. The persistence of antibody levels in serum could depend on LLPCs. The proportion of LLPCs in CD19 + cells in bone marrow exhibited a dynamic trend with two peaks at 28 days post-immunization (dpi) and 72 dpi, respectively. Additionally, the proportion of memory B cells in CD19 + cells in the spleen increased significantly both at 7 days post primary immunization and at 7 days post -boost immunization. Of note, LLPCs together with memory B cells contribute to the production of FMDV-specific IgG and IgG1. The changes of LLPCs and memory B cells may be related to TNF-α, IL-6 and, CXCL12. Taken together, FMDV-VLPs could induce B cells memory responses. A further understanding of the mechanisms that FMDV-VLPs how we can manipulate the induction and maintenance of memory B cells and LLPCs will promote vaccine design and likely address several challenges to develop FMDV new vaccines in the future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Familial hypercholesterolemia (FH) is a metabolic disease in which patients are prone to develop premature atherosclerosis (AS). Sorbin and SH3 Domain Containing 2 (SORBS2) is known to play a role in coronary heart disease (CHD). However, the mechanism underlying SORBS2 involvement in the development of hypercholesterolemia remains unknown. Here, we investigated the effects of SORBS2 on inflammation and foam cell formation and its underlying mechanisms., Methods: Using Bioinformatics analysis, we established that SORBS2 is upregulated in patients with FH. Circulating concentrations of SORBS2 were measured using ELISA kit (n = 30). The association between circulating SORBS2 levels and inflammatory factors or lipid indexes were conducted using Spearman correlation analysis. We further conducted in vitro experiments that the expression of SORBS2 were analyzed, and SORBS2 siRNA were transfected into oxidized LDL (OxLDL)-induced macrophages, followed by western blot and immunofluorescence., Results: Circulating SORBS2 levels were positively associated with inflammatory factors and lipid indexes. We also observed that high in vitro expression of SORBS2 in OxLDL-induced macrophages. After SORBS2 silencing, Nod like receptor family pyrin domain-containing 3 protein(NLRP3)-Caspase1 activation and NF-κB activation were attenuated, and secretion of pro-inflammatory cytokines (IL-1β and IL-18) was decreased. Moreover, SORBS2 silencing blocked reactive oxygen species (ROS) production and lipid accumulation, and promoted cholesterol efflux through ABCG1-PPARγ pathway., Conclusions: SORBS2 regulates lipid-induced inflammation and foam cell formation, and is a potential therapeutic target for hypercholesterolemia., (© 2022. The Author(s).)

Few-layer graphene has been widely regarded as an efficient filter for gas separation, but the effect of the layer number on the gas permeation process is still unclear. To explore the layer number effect, we perform molecular dynamics simulations to investigate the gas permeation through a nanopore within the few-layer graphene. Our numerical simulations show that the permeation constant decreases with increasing layer number, which is analyzed based on the macroscopic Kennard empirical model. The macroscopic model is in good agreement with the numerical result in the limit of large layer number, but there are obvious deviations for the medium layer number. We generalize the macroscopic model by considering the nanoscale effect from the surface morphology of the nanoscale pore, which can well describe the layer number dependence for the gas permeation constant in the full range. These results provide valuable information for the application of few-layer graphene in the gas permeation field., (© 2022 IOP Publishing Ltd.)

Background: Lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular diseases, while its role in vascular calcification has not been well-established. Here, we investigated an association of Lp(a) with vascular calcification using population-based and in vitro study designs., Methods: A total of 2806 patients who received coronary computed tomography were enrolled to assess the correlation of Lp(a) with the severity of coronary artery calcification (CAC). Human aortic smooth muscle cells (HASMCs) were used to explore mechanisms of Lp(a)-induced vascular calcification., Results: In the population study, Lp(a) was independently correlated with the presence and severity of CAC (all p < 0.05). In vitro study showed that cell calcific depositions and alkaline phosphatase (ALP) activity were increased and the expression of pro-calcific proteins, including bone morphogenetic protein-2 (BMP2) and osteopontin (OPN), were up-regulated by Lp(a) stimulation. Interestingly, Lp(a) activated Notch1 signaling, resulting in cell calcification, which was inhibited by the Notch1 signaling inhibitor, DAPT. Lp(a)-induced Notch1 activation up-regulated BMP2-Smad1/5/9 pathway. In contrast, Noggin, an inhibitor of BMP2-Smad1/5/9 pathway, significantly blocked Lp(a)-induced HASMC calcification. Notch1 activation also induced translocation of nuclear factor-κB (NF-κB) accompanied by OPN overexpression and elevated inflammatory cytokines production, while NF-κB silencing alleviated Lp(a)-induced vascular calcification., Conclusions: Elevated Lp(a) concentrations are independently associated with the presence and severity of CAC and the impact of Lp(a) on vascular calcification is involved in the activation of Notch1-NF-κB and Notch1-BMP2-Smad1/5/9 pathways, thus implicating Lp(a) as a potential novel therapeutic target for vascular calcification., Competing Interests: Declaration of competing interest No conflict of interest with this manuscript was reported., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Camrelizumab, a programmed cell death 1 (PD-1) inhibitor, has been approved for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma, nasopharyngeal cancer and non-small cell lung cancer. The aim of this study was to perform a population pharmacokinetic (PK) analysis of camrelizumab to quantify the impact of patient characteristics and to investigate the appropriateness of a flat dose in the dosing regimen. A total of 3092 camrelizumab concentrations from 133 patients in four clinical trials with advanced melanoma, relapsed or refractory classical Hodgkin lymphoma and other solid tumor types were analyzed using nonlinear mixed effects modeling. The PKs of camrelizumab were properly described using a two-compartment model with parallel linear and nonlinear clearance. Then, covariate model building was conducted using stepwise forward addition and backward elimination. The results showed that baseline albumin had significant effects on linear clearance, while actual body weight affected intercompartmental clearance. However, their impacts were limited, and no dose adjustments were required. The final model was further evaluated by goodness-of-fit plots, bootstrap procedures, and visual predictive checks and showed satisfactory model performance. Moreover, dosing regimens of 200 mg every 2 weeks and 3 mg/kg every 2 weeks provided similar exposure distributions by model-based Monte Carlo simulation. The population analyses demonstrated that patient characteristics have no clinically meaningful impact on the PKs of camrelizumab and present evidence for no advantage of either the flat dose or weight-based dose regimen for most patients with advanced solid tumors., (© 2020. CPS and SIMM.)

Background: Melanoma brain metastasis is a common cause of death in melanoma patients and is associated with a poor prognosis. There are relatively few reports on intracranial infections after brain metastasis resection., Case Summary: Here we report a case of melanoma brain metastases in a patient harboring a BRAF V600E mutation, who experienced intracranial tumor progression despite previous combined treatment with a programmed death (PD)-1 inhibitor, axitinib, and vemurafenib. She repeatedly underwent local therapy, including stereotactic radiosurgery and intracranial surgery, and developed central nervous system infection. Treatment with vemurafenib combined with cobimetinib resulted in an intracranial progression-free survival of 10 mo. During the coronavirus disease 2019 (COVID-19) pandemic, the patient did not visit the hospital for regular vemurafenib treatment, and experienced intracranial progression after involuntary drug reduction for 1 mo. The patient subsequently received various systemic treatments including vemurafenib, PD-1 inhibitor, and chemotherapy, with an overall survival of 29 mo as of September 2020., Conclusion: We report the first case of melanoma brain metastases with co-occurring intracranial infection and unintended drug reduction during the COVID-19 outbreak. Long-term control of the intracranial lesions was achieved with systemic and local therapies., Competing Interests: Conflict-of-interest statement: No conflicts of interest are declared., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Although non-invasive liver fibrosis scores (LFSs) have already been considered as effective tools for estimating cardiovascular risk, their roles in predicting disease severity and cardiovascular event (CVEs) in patients with stable coronary artery disease (CAD) are not comprehensively evaluated. The aim of the present study was to investigate whether non-alcoholic fatty liver disease fibrosis score (NAFLD-FS) and fibrosis-4 (FIB-4) are associated with CVEs in a large cohort with long-term follow-up., Methods: A cohort of 5143 patients with angiography-proven stable CAD were consecutively enrolled and followed up for CVEs. The degree of coronary severity was assessed using the number of diseased vessels, Gensini, Syntax, and Jeopardy scores. The predictive values of NAFLD-FS and FIB-4 scores to coronary severity, coronary calcification (CAC), and CVEs were assessed, respectively., Results: During a median follow-up of 7 years, 435 CVEs were recorded. Both NAFLD-FS and FIB-4 were predictors for the presence of CAC. The degree of coronary stenosis was significantly higher in high NAFLD-FS categories while FIB-4 was only positively associated with the number of diseased vessels and Gensini score. In Kaplan-Meier analysis, the patients with intermediate and high NAFLD-FS and FIB-4 had higher risk of CVEs and cardiovascular mortality. In multivariate Cox regression analysis, NAFLD-FS and FIB-4 were independently associated with CVEs [hazard ratio (95% confidence interval): 1.150 (1.063-1.244), p < 0.001 and 1.128 (1.026-1.240), p = 0.012]., Conclusion: The current data first indicated that both NAFLD-FS and FIB-4 scores were not only significantly related to coronary severity but also associated with CAC and CVEs., Clinical Trials Registration: None.

Background: The platelet to lymphocyte ratio (PLR) is a novel biomarker to predict the prognosis of acute myocardial infarction (AMI) patients., Aim: The study aimed to evaluate the in-hospital outcomes of elderly patients with AMI and assessed the prognostic value of PLR on in-hospital adverse events., Methods: A total of 1,001 patients were divided into an older group (n = 560) and a younger group (n = 441) based on age ≥ 60 years and successfully underwent primary percutaneous coronary intervention (PCI) within 12 h after presentation. Total white blood cells (WBCs), neutrophils, lymphocytes, and platelets counts were measured at admission., Results: The incidence of heart rupture, acute heart failure, total adverse events, and death resulting from all events were significantly higher in patients ≥ 60 years than in younger patients, whereas the incidence of postoperative angina and reinfarction were similar between groups. Regarding blood counts, total white blood cells, neutrophils, lymphocytes, and platelets were lower in the older group than in the younger group. The platelet-to-lymphocyte ratio (PLR) was significantly higher in the older group. In receiver operating characteristic curve analysis, high PLR > 147 predicted adverse events (specificity 72% and sensitivity 63%). In multiple logistic regression analysis, age, hypertension, and PLR were identified as independent predictors of adverse events., Conclusions: The in-hospital outcomes of elderly patients with acute myocardial infarction were poor. PLR was an independent risk factor for in-hospital adverse events, which suggested that strong inflammation and prothrombotic status may contribute to the poor prognoses of elderly patients.

Objective: Previous studies have demonstrated that small dense LDL-cholesterol (sdLDL-C) is related to the pathogenesis of coronary artery disease (CAD). However, its prognostic role in hypertensive patients with CAD has been undetermined. The aim of the study was to investigate the association between sdLDL-C with disease severity, hypertensive status and clinical outcome in patients with CAD., Methods: A total of 4594 patients with angiography-proven CAD were consecutively enrolled and categorized into subgroups according to blood pressure status. Serum sdLDL-C levels were measured by direct quantitative measurement using automated chemistry analyzers. The severity of coronary artery lesions were determined by Gensini score, Syntax score and the number of lesion vessels. The associations of sdLDL-C with disease severity, hypertensive status and cardiovascular events (CVEs) were evaluated., Results: Patients with hypertension had higher sdLDL-C levels than ones without (P = 0.010). In hypertensive patients, sdLDL-C was positively associated with the severity of CAD (P < 0.05). In addition, hypertensive patients with poorly controlled hypertension had higher sdLDL-C levels than those with well controlled (P < 0.05). Moreover, 149 CVEs occurred in patients with poorly controlled hypertension and Cox regression analysis indicated that elevated sdLDL-C levels were independently associated with CVEs in hypertensive patients with poorly controlled hypertension (adjusted hazard ratio: 1.673, 95% confidence interval: 1.105-2.535, P = 0.015)., Conclusion: The current data, for the first time, showed that serum sdLDL-C levels were correlated with hypertension control, disease severity and worse outcomes in hypertensive patients with CAD, suggesting that paying more attention on sdLDL-C in these patients were warranted., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Heart-type fatty acid binding protein (H-FABP) has been reported to be a prognostic predictor for cardiovascular outcome in acute coronary syndrome (ACS). However, its prognostic utility in patients with stable coronary artery disease (CAD) has not been well established. The aim of this study was to assess the association between H-FABP with the severity of coronary disease and cardiovascular events (CVEs) in patients with stable CAD., Methods: A total of 4,370 angiography-proven CAD patients were consecutively enrolled. The severity of CAD was assessed by Gensini Score (GS) and the numbers of diseased vessels. The CVEs included cardiovascular death, myocardial infarction, stroke and coronary revascularization. Cox regression analysis with adjusted hazard ratios (HRs) and Kaplan-Meier analysis were used to evaluate the relation of H-FABP to CVEs in this cohort., Results: During a median follow-up of 51 months, 353 CVEs occurred. Overall, patients in the highest levels of H-FABP group had increased rate of multi-vessel stenosis and higher GS compared with those in the lowest group (P<0.05, respectively). Moreover, H-FABP levels were significantly higher in patients with events compared to those without (P<0.001). In Cox regression analysis, elevated H-FABP levels were found to be independently associated with a high risk of CVEs [adjusted HRs: 1.453; 95% confidence intervals (CIs): 1.040-2.029, P=0.028], especially with cardiovascular death (adjusted HRs: 2.865; 95% CI: 1.315-6.243, P=0.008)., Conclusions: Our results demonstrated that H-FABP was also a useful predictor for CVEs in patients with stable CAD, which needed to be verified by further studies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-2493). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: Elevated lipoprotein(a) [Lp(a)] and fibrinogen (Fib) are both associated with coronary artery disease (CAD). The atherogenicity of Lp(a) can be partly due to the potentially antifibrinolytic categories. We hypothesize that patients with higher Lp(a) and Fib may have worse outcomes., Methods: In this prospective study, we consecutively enrolled 8,417 Chinese patients with stable CAD from March 2011 to March 2017. All subjects were divided into 9 groups according to Lp(a) (Lp(a)-Low, Lp(a)-Medium, Lp(a)-High) and Fib levels (Fib-Low, Fib-Medium, Fib-High) and followed up for CVEs, including nonfatal acute myocardial infarction, stroke, and cardiovascular mortality. Kaplan-Meier, Cox regression and C-statistic analyses were performed., Results: During a median of 37.1 months' follow-up, 395 (4.7%) CVEs occurred. The occurrence of CVEs increased by Lp(a) (3.5 vs. 5.3 vs. 5.6%, p = 0.001) and Fib (4.0 vs. 4.4 vs. 6.1%, p < 0.001) categories. When further classified into 9 groups by Lp(a) and Fib levels, the CVEs were highest in the 9th (Lp(a)-High and Fib-High) compared with the 1st (Lp(a)-Low and Fib-Low) group (7.2 vs. 3.3%, p < 0.001). The highest risk of subsequent CVEs was found in the 9 th group (HR adjusted 2.656, 95% CI 1.628-4.333, p < 0.001), which was more significant than Lp(a)-High (HR adjusted 1.786, 95% CI 1.315-2.426, p < 0.001) or Fib-High (HR adjusted 1.558, 95% CI 1.162-2.089, p = 0.003) group. Moreover, adding the combined Lp(a) and Fib increased the C-statistic by 0.013., Conclusion: Combining Fib and Lp(a) enhance the prognostic value for incident CVEs beyond Lp(a) or Fib alone.

Background: Recent guidelines highlighted the association between atherosclerosis and triglyceride-enriched lipoproteins in patients with impaired glucose metabolism. However, evidence from prospective studies for long-term prognostic utility of low-density lipoprotein triglyceride (LDL-TG) in real-world patients with prediabetes (Pre-DM) or diabetes mellitus (DM) and coronary artery disease (CAD) is currently not available. The aim of the present study was to evaluate the impact of LDL-TG on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism status., Methods: A total of 4381 patients with CAD were consecutively enrolled and plasma LDL-TG level was measured by an automated homogeneous assay. They were categorized according to both status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] and tertiles of LDL-TG. All subjects were followed up for the occurrence of MACEs., Results: During a median of 5.1 (interquartile range 3.9 to 5.9) years' follow-up, 507 (11.6%) MACEs occurred. Cubic spline models showed a significant association between LDL-TG and MACEs in DM and Pre-DM but not in NGR. When the combined effect of elevated LDL-TG and glucose disorders was considered for risk stratification, the medium tertile of LDL-TG plus DM, and the highest tertile of LDL-TG plus Pre-DM or plus DM subgroups were associated with significantly higher risk of MACEs after adjustment of confounders including triglyceride [hazard ratios (95% confidence intervals): 1.843 (1.149-2.955), 1.828 (1.165-2.867), 2.212 (1.396-3.507), all p < 0.05]. Moreover, adding LDL-TG into the original model increased the C-statistic from 0.687 to 0.704 (∆C-statistic = 0.016, p = 0.028) and from 0.734 to 0.749 (∆C-statistic = 0.014, p = 0.002) in Pre-DM and DM, respectively., Conclusions: In this longitudinal cohort study on real-world practice, higher LDL-TG was associated with worse outcomes among Pre-DM and DM patients with stable CAD.

Background: The atherogenicity of remnant cholesterol (RC) has been underlined by recent guidelines, which was linked to coronary artery disease (CAD), especially for patients with diabetes mellitus (DM). This study aimed to examine the prognostic value of plasma RC in the patients with CAD under different glucose metabolism status., Methods: Fasting plasma RC were directly calculated or measured in 4331 patients with CAD. Patients were followed for the occurrence of major adverse cardiovascular events (MACEs) and categorized according to both glucose metabolism status [DM, pre-DM, normoglycemia (NG)] and RC levels. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals., Results: During a mean follow-up of 5.1 years, 541 (12.5%) MACEs occurred. The risk for MACEs was significantly higher in patients with elevated RC levels after adjustment for potential confounders. No significant difference in MACEs was observed between pre-DM and NG groups (p > 0.05). When stratified by combined status of glucose metabolism and RC, highest levels of calculated and measured RC were significant and independent predictors of developing MACEs in pre-DM (HR: 1.64 and 1.98; both p < 0.05) and DM (HR: 1.62 and 2.05; both p < 0.05). High RC levels were also positively associated with MACEs in patients with uncontrolled DM. ., Conclusions: In this large-scale and long-term follow-up cohort study, data firstly demonstrated that higher RC levels were significantly associated with the worse prognosis in DM and pre-DM patients with CAD, suggesting that RC may be a target for patients with impaired glucose metabolism.

Background: Green tea drinking has been proven to lower lipid and exert cardiovascular protection, while the potential mechanism has not been fully determined. This study was to investigate whether the beneficial impact of epigallocatechingallate (EGCG), a type of catechin in green tea on lipids is associated with proprotein convertase subtilisin/kexin type 9 (PCSK9) pathways., Methods: We studied the effects and underlying molecular mechanism of EGCG or green tea on regulating cholesterol from human, animal and in vitro., Results: In the age- and gender-matched case control observation, we found that individuals with frequent tea consumption (n = 224) had the lower plasma PCSK9 and low density lipoprotein cholesterol (LDL-C) levels compared with ones without tea consumption (n = 224, p < 0.05). In the high fat diet (HFD) fed rats, EGCG administration significantly lowered circulating PCSK9 concentration and liver PCSK9 expression, along with up-regulated LDL receptor (LDLR) expression but decreased level of LDL-C. In hepatic cell study, similar results were obtained regarding the impact of EGCG on LDLR and PCSK9 expression. The assay transposase-accessible chromatic with high-throughput sequencing (ATAC-seq) and subsequent results suggested that two transcription factors, hepatocyte nuclear factor-1α (HNF-1α) and forkhead box class O (FoxO) 3a involved in inhibitory action of EGCG on PCSK9 expression., Conclusions: The present study demonstrates that EGCG suppresses PCSK9 production by promoting nuclear FoxO3a, and reducing nuclear HNF1α, resulting in up-regulated LDLR expression and LDL uptake in hepatocytes. Thereby inhibiting liver and circulating PCSK9 levels, and ultimately lowering LDL-C levels.

Background: Elevation in small dense low-density lipoprotein (sdLDL) is common in patients with diabetes mellitus (DM), which has already been reported to be associated with incidence of coronary artery disease (CAD). The aim of the present study was to investigate the prognostic value of plasma sdLDL level in patients with stable CAD and DM., Methods: A total of 4148 consecutive patients with stable CAD were prospectively enrolled into the study and followed up for major cardiovascular events (MACEs) up to 8.5 years. Plasma sdLDL level was measured in each patient by a direct method using automated chemistry analyzer. The patients were subsequently divided into four groups by the quartiles of sdLDL and the association of sdLDL level with MACEs in different status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] was evaluated., Results: A total of 464 MACEs were documented. Both Kaplan-Meier analysis and Cox regression analysis indicated that the patients in quartile 4 but not quartile 2 or 3 of sdLDL level had significantly higher rate of MACEs than that in lowest quartile. When the prognostic value of high sdLDL was assessed in different glucose metabolism status, the results showed that the high sdLDL plus DM was associated with worse outcome after adjustment of confounding risk factors (hazard ratio: 1.83, 95% confident interval: 1.24-2.70, p < 0.05). However, no significant association was observed for high sdLDL plus Pre-DM or NGR., Conclusions: The present study firstly indicated that elevated levels of plasma sdLDL were associated with increased risk of MACEs among DM patients with proven CAD, suggesting that sdLDL may be useful for CAD risk stratification in DM.

Background: Heart-type fatty acid-binding protein (H-FABP) is a novel marker of myocardial injury and has been reported to be associated with cardiovascular diseases (CVD) including patients with diabetes mellitus (DM). Unfortunately, its prognostic value in patients with CVD and impaired glucose metabolism (IGM) is unclear. The objective of this study was to investigate the prognostic value of H-FABP in CVD patients with IGM., Methods: A total of 4594 patients with angiography-proven coronary artery disease (CAD) were enrolled and divided into subgroup according to glucose metabolism status (normal glucose regulation [NGR], pre-DM, and DM). Baseline levels of H-FABP were measured using latex immunoturbidimetric method. The cardiovascular events (CVE) were defined as cardiovascular death, myocardial infarction, stroke and coronary revascularization. Cox regression and Kaplan-Meier analysis were used to evaluate the relations of H-FABP and glucose metabolism status to CVEs., Results: During the follow-up period with up to 7.1 years, 380 CVEs occurred. Patients with CVE had higher levels of H-FABP compared to those without CVE (p < 0.001). Interestingly, H-FABP levels were also elevated in DM and pre-DM groups compared with NGR group (p < 0.001), when combined glucose metabolism status with H-FABP stratification, patients in the highest tertile of H-FABP appeared to have higher risk of CVEs with pre-DM (adjusted hazard ratio [HR]: 1.855, 95% confidential intervals [CIs] 1.076-3.214; p = 0.033) and DM (adjusted HR: 2.560, 95% CIs 1.409-4.650; p = 0.002). The Kaplan-Meier curve indicated that DM patients with the highest H-FABP levels were associated with the greatest risk of CVEs (p < 0.05)., Conclusions: Our data firstly showed that elevated H-FABP levels were associated with worse outcomes in CAD patients with pre-DM and DM, which provided the novel information that H-FABP might be a prognostic marker for clinical outcomes among patients with CAD and IGM.

The proliferation and migration of vascular smooth muscle cells (VSMCs) are major cellular events in hypertension‑induced vascular remodeling, which is closely involved in the progression of atherosclerosis (AS). Although long non‑coding RNAs (lncRNAs) are gaining recognition as novel regulators of VSMCs, their functioning and role in AS remain to be elucidated. In the present study, the role of lncRNA ENST00000430945 (lncRNA 430945) in AS was investigated. VSMCs transfected with a small interfering RNA (siRNA; si‑430945) and a negative control (si‑NC) were used. Cell Counting Kit‑8, wound‑healing and Transwell migration arrays were performed to determine whether lncRNA 430945 influenced VSMC proliferation and migration. Furthermore, the study examined whether a correlation exists between lncRNA 430945 and the receptor tyrosine kinase‑like orphan receptor 2 (ROR2) signaling pathway. It was found that the expression of lncRNA 430945 was high in human AS tissues, which in turn promoted angiotensin II (AngII)‑induced VSMC proliferation. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses showed that lncRNA 430945 mediated the AngII‑induced upregulation of ROR2. In addition, the microarray and RT‑qPCR results showed that the expression of lncRNA 430945 was increased considerably in AS tissues. The downregulation of lncRNA 430945 significantly suppressed AngII‑induced VSMC proliferation and migration. In addition, ROR2 levels in VSMCs transfected with si‑430945 were markedly lower than those cells transfected with si‑NC. Additionally, western blotting showed that lncRNA 430945 activated the signaling pathways associated with ROR2 and Ras homolog gene family member A (RhoA). The upregulation of lncRNA 430945 in AS promoted the proliferation and migration of VSMCs via activation of the ROR2/RhoA signaling pathway. Therefore, targeting ROR2 or RhoA may be a promising technique in developing therapeutic strategies for treating AS.

Purpose: Apoptin can specifically kill cancer cells but has no toxicity to normal cells. Human telomerase reverse transcriptase (hTERT) acts as a tumor-specific promoter, triggering certain genes to replicate or express only in tumor cells, conferring specific replication and killing abilities. This study aimed to investigate the anticancer potential of the recombinant adenovirus Ad-apoptin-hTERTp-E1a (Ad-VT) in prostate cancer., Methods: The pGL4.51 plasmid was used to transfect PC-3 cells to construct tumor cells stably expressing luciferase (PC-3-luc). Crystal violet staining and MTS assays determined the ability of Ad-VT to inhibit cell proliferation. Ad-VT-induced apoptosis of PC-3-luc cells was detected using Hoechst, Annexin V, JC-1 staining, and caspases activity analysis. PC-3-luc cells invasion and migration were detected using cell-scratch and Transwell assays. In vivo tumor inhibition was detected using imaging techniques., Results: Crystal violet staining and MTS results showed that the proliferation ability of PC-3-luc cells decreased significantly. Hoechst, JC-1, and Annexin V experiments demonstrated that Ad-VT mainly induced apoptosis to inhibit PC-3-luc cell proliferation. Ad-VT could significantly inhibit the migration and invasion of PC-3-luc cells over a short period of time. In vivo, Ad-VT could effectively inhibit tumor growth and prolong survival of the mice., Conclusions: The recombinant adenovirus, comprising the apoptin protein and the hTERTp promoter, was able to inhibit the growth of prostate cancer PC-3 cells and promote their apoptosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Although there have been many reports in the genetics of familial hypercholesterolemia (FH) worldwide, studies in regard of Chinese population are lacking. In this multi-center study, we aim to characterize the genetic spectrum of FH in Chinese population, and examine the genotype-phenotype correlations in detail., Methods: A total of 285 unrelated index cases from China with clinical FH were consecutively recruited. Next-generation sequencing and bioinformatics tools were used for mutation detection of LDLR, APOB and PCSK9 genes and genetic analysis., Results: Overall, the detection rate is 51.9% (148/285) in the unrelated index cases with a total of 119 risk variants identified including 84 in the LDLR gene, 31 in APOB and 4 in PCSK9 gene. Twenty-eight variants were found in more than one individual and LDLR c.1448G > A (p. W483X) was most frequent one detected in 9 patients. Besides, we found 8 (7 LDLR and 1 APOB) novel variants referred as "pathogenic (or likely pathogenic) variants" according to in silico analysis. In the phenotype analysis, patients with LDLR null mutation had significantly higher LDL cholesterol level than LDLR defective and APOB/PCSK9 mutation carriers and those with no mutations (p < 0.001). Furthermore, 13 double heterozygotes, 16 compound heterozygotes and 5 true LDLR homozygotes were identified and the true LDLR homozygotes had the most severe phenotypes., Conclusions: The present study confirmed the heterogeneity of FH genetics in the largest Chinese cohort, which could replenish the knowledge of mutation spectrum and contribute to early screening and disease management.

Background: The current study aims at using the whole genome expression profile chips for systematically investigating the diagnostic and prognostic values of excision repair cross-complementation (ERCC) genes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)., Materials and Methods: Whole genome expression profile chips were obtained from the GSE14520. The receiver-operating characteristic (ROC) curve, survival analysis, and nomogram were used to investigate the diagnostic and prognostic values of ERCC genes. Investigation of the potential function of ERCC8 was carried out by gene set enrichment analysis (GSEA) and genome-wide coexpression analysis., Results: ROC analysis suggests that six ERCC genes ( ERCC1 , ERCC2 , ERCC3 , ERCC4 , ERCC5 , and ERCC8 ) were dysregulated and may have potential to distinguish between HBV-related HCC tumor and paracancerous tissues (area under the curve of ROC ranged from 0.623 to 0.744). Survival analysis demonstrated that high ERCC8 expression was associated with a significantly decreased risk of recurrence (adjusted P =0.021; HR=0.643; 95% CI=0.442-0.937) and death (adjusted P =0.049; HR=0.631; 95% CI=0.399-0.998) in HBV-related HCC. Then, we also developed two nomograms for the HBV-related HCC individualized prognosis predictions. GSEA suggests that the high expression of ERCC8 may have involvement in the energy metabolism biological processes. As the genome-wide coexpression analysis and functional assessment of ERCC8 suggest, those coexpressed genes were significantly enriched in multiple biological processes of DNA damage and repair., Conclusion: The present study indicates that six ERCC genes ( ERCC1 , ERCC2 , ERCC3 , ERCC4 , ERCC5 , and ERCC8 ) were dysregulated between HBV-related HCC tumor and paracancerous tissues and that the mRNA expression of ERCC8 may serve as a potential biomarker for the HBV-related HCC prognosis., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Familial hypercholesterolemia (FH) is one of the most common causes of premature myocardial infarction (MI). However, The patterns of FH remained unrecognized in clinical care, especially in very young patients (VYPs, ≤35 years) with MI. The present study enrolled a total of 1,093 VYPs (≤35 years) presenting a first MI. Clinical diagnosis of FH was made using Dutch Lipid Clinic Network criteria. Coronary severity was assessed by Gensini score (GS). Patients were followed for a median of 40-months with cardiac death, stroke, MI, post-discharge revascularization or unstable angina as primary endpoints. The detected rates of definite/probable FH were 6.5%. The prevalence reached up to 10.3% in patients ≤25 years. The FH had similar levels of comorbidities but was younger, more likely to be very high risk (VHR) and had higher GS (p < 0.05) than unlikely FH. Notably, the FH on prior lipid-lowering medication presented a lower GS compared to those untreated. Differences in event rates were similar in FH as unlikely FH (11.8% vs. 8.1%, adjusted hazard ratio 1.35 [0.64-2.86], p = 0.434) but patients on treatment improved outcome (6.5% vs. 10.5%, adjusted hazard ratio 0.35[0.13-0.95], p = 0.039). The early identification and treatment might be critical to reduce cardiovascular risk in VYPs with MI.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol homeostasis, is associated with glucose metabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist, can increase insulin secretion in a glucose-dependent manner and lower blood glucose. We aimed to investigate the relationship between liraglutide and PCSK9., Methods: At the cellular level, the expressions of PCSK9 and hepatocyte nuclear factor 1 alpha (HNF1α) protein in HepG2 cells stimulated by liraglutide was examined using Western blot. Seven-week old db/db mice and wild type (WT) mice were administered either liraglutide (200 μg/kg) or equivoluminal saline subcutaneously, twice daily for 7 weeks. Fasting glucose level, food intake and body weight were measured every week. After the 7-week treatment, the blood was collected for lipid and PCSK9 levels detection and the liver was removed from the mice for oil red O staining, immunohistochemical analysis, immunofluorescence test and Western bolt., Results: Firstly, liraglutide suppressed both PCSK9 and HNF1α expression in HepG2 cells in a time and concentration dependent manner. Secondly, liraglutide induced weight loss in WT and db/db mice, decreased serum PCSK9, glucose and lipid levels and improved hepatic accumulation in db/db but not WT mice. Thirdly, liraglutide reduced both hepatic PCSK9 and low-density lipoprotein receptor (LDLR) expression with a decrease in HNF1α in db/db mice but not in WT mice., Conclusions: Liraglutide suppressed PCSK9 expression through HNF1α-dependent mechanism in HepG2 cells and db/db mice, and decreased LDLR possibly via PCSK9-independent pathways in db/db mice.

Excessive radiation exposure may lead to edema of the spinal cord and deterioration of the nervous system. Magnetic resonance imaging can be used to judge and assess the extent of edema and to evaluate pathological changes and thus may be used for the evaluation of spinal cord injuries caused by radiation therapy. Radioactive 125 I seeds to irradiate 90% of the spinal cord tissue at doses of 40-100 Gy (D90) were implanted in rabbits at T 10 to induce radiation injury, and we evaluated their safety for use in the spinal cord. Diffusion tensor imaging showed that with increased D90, the apparent diffusion coefficient and fractional anisotropy values were increased. Moreover, pathological damage of neurons and microvessels in the gray matter and white matter was aggravated. At 2 months after implantation, obvious pathological injury was visible in the spinal cords of each group. Magnetic resonance diffusion tensor imaging revealed the radiation injury to the spinal cord, and we quantified the degree of spinal cord injury through apparent diffusion coefficient and fractional anisotropy., Competing Interests: None declared

Background: Recent data have suggested an important role of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) in the development of atherosclerotic cardiovascular disease (ASCVD) in both general population and family hypercholesterolemia (FH), while the relation of Lp(a) to PCSK9 has not been examined., Objective: The aim of the present study was to investigate the association between plasma PCSK9 and Lp(a)in patients with heterozygous FH (HeFH)., Methods: Two hundred and fifty-five molecularly confirmed patients with HeFH were compared to 255 age- and gender-matched non-FH controls. Plasma PCSK9 and Lp(a) concentrations were measured using ELISA and immunoturbidimetric method respectively, and finally their association was assessed., Results: Both plasma PCSK9 and Lp(a) levels were significantly higher in patients with HeFH compared to control group (p<0.001). Besides, the Lp(a) concentration and percentage of Lp(a)≥300mg/L were increased by PCSK9 tertiles in HeFH group (both p<0.05) while not in control group. In partial correlation analysis, Lp(a) was associated with PCSK9 (r=0.254, p<0.001) in HeFH group but not in control, which were further confirmed by multivariable linear regression analysis. Furthermore, significant associations between Lp(a) and PCSK9 were also found in subgroups of HeFH group irrespective of definite or probable FH, with and without coronary artery disease (CAD), and with statin or not., Conclusions: Plasma Lp(a) level was associated with PCSK9 in patients with HeFH alone, suggesting that much about the interaction of PCSK9 with Lp(a) in FH need further explorations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Elevated levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been reported to be related to dyslipidemia, including patients with kidney dysfunction. However, its association with estimated glomerular filtration rate (eGFR) in individuals with normal serum creatinine (SCr) has not been determined., Methods: A total of 2,089 subjects with normal SCr and without lipid-lowering treatment were consecutively enrolled in this study. Plasma PCSK9 levels were measured by ELISA kit and eGFR was evaluated by the Chronic Kidney Disease Epidemiology Collaboration equation. Subjects were divided into a normal eGFR group (n = 1,205, ≥90 mL/min/1.73 m2) and a decreased eGFR group (n = 884, < 90 mL/min/1.73 m2). Baseline characteristics and laboratory findings were compared between the two groups. Spearman's correlation and linear regression were performed to determine the association between PCSK9 and eGFR., Results: No significant difference in PCSK9 levels was found between the normal eGFR group and the decreased eGFR group (236.84 ± 67.87 vs. 239.98 ± 68.72 ng/mL, p = 0.303). In Spearman's correlation and multivariable linear regression analysis, no association of PCSK9 levels with eGFR was detected in the total cohort (r = -0.039, p = 0.079; adjusted β = -0.013, p = 0.630). This result remained the same in the subgroups of normal eGFR (r = -0.038, p = 0.190; adjusted β = -0.031, p = 0.367) and decreased eGFR (r = -0.054, p = 0.109; adjusted β = -0.034, p = 0.319)., Conclusion: In this single-center study with moderate sample size, the data showed no relationship of PCSK9 levels with normal or decreased eGFR in untreated patients with normal SCr, suggesting that further studies may be needed to understand the relationship between PCSK9 and lipid disorder in different stage of kidney dysfunction., (© 2018 S. Karger AG, Basel.)

Objective: To assess the association between resting heart rate (RHR) and lipoprotein subfractions to provide potential evidence for the relationship between RHR and severity of CAD., Methods: A total of 1119 consecutive non-treated subjects scheduled for coronary angiography were enrolled. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) separation were performed by Lipoprint System. The link of RHR with lipoprotein subfractions was assessed., Results: Increased RHR was significantly associated with higher triglyceride, total cholesterol, non-HDL-cholesterol, and apolipoprotein B (all p < .01). Furthermore, data indicated that higher RHR was related to more severe CAD (all p < .05). In the following linear regression models, we observed that higher RHR (HRh bpm) was significantly associated with lower large HDL (β = -0.073, p = .024) and higher small LDL subfraction (β = 0.103, p = .005) after adjusting for potential confounders., Conclusions: Increased RHR was associated with more severe CAD, which may be partly due to the significant relation to atherogenic lipoprotein subfractions.

Background: It has been demonstrated that an elevated ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) is a risk factor of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM) and is also found to be associated with cardiovascular events (CVEs) in the general population. However, its prognostic value in patients with T2DM along with CAD remains to be determined., Materials and Methods: A total of 1,447 consecutive patients with T2DM with angiographic-proven stable CAD were enrolled in the present study and followed-up for an average of 20.3 months. The characteristics of all patients including fasting lipid profile were obtained at baseline and multivariate Cox proportional hazards models were constructed using log TG/HDL-C as a predictor variable. The relationships between CVEs and total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, TC/HDL-C, LDL-C/HDL-C and apolipoprotein B/ apolipoprotein AI (apoB/apoAI) were also explored., Results: Compared with patients without CVEs, the ones who experienced CVEs had a higher TG/HDL-C ratio. Univariable regression revealed a significant association of log TG/HDL-C with CVEs (hazard ratio = 2.5, P = 0.015). After adjusting for multiple traditional risk factors of cardiovascular disease, the association was still found (hazard ratio = 2.47, P = 0.047). Moreover, results suggested that the ratios of non-HDL-C, TC/HDL-C, LDL-C/HDL-C and apoB/apoAI were not predictors for CVEs in T2DM., Conclusions: In our primary study, data suggested that elevated TG/HDL-C value might be a useful predictor for future CVEs in Chinese patients with T2DM with stable CAD. Further study is needed to confirm our findings., (Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the association of serum fibrinogen with cardiovascular events (CVE) in Chinese patients with type 2 diabetes mellitus (T2DM) and stable coronary artery disease (CAD)., Design: An observational study., Setting: FuWai Hospital in Beijing, China., Participants: A cohort of 1466 patients with T2DM and angiographic-proven stable CAD was evaluated., Outcome Measures: Baseline serum fibrinogen levels were measured and trisected into 'low', 'middle' and 'high'. Their association with CVE was explored using Cox proportional hazard models., Results: With 20.2 months (average) follow-up, 44 (3%) were lost to follow-up and 96 patients developed CVE. Compared with the patients without CVE, the ones who developed CVE had higher levels of fibrinogen. Univariable regression revealed a significant relation of fibrinogen to CVE (HR (HR) 1.25, 95% CI 1.06 to 1.47, p=0.010) per SD increase of fibrinogen at baseline. After adjusting for multiple established cardiovascular disease (CVD) risk factors, the association persisted (HR 1.30, 95% CI 1.02 to 1.66, p=0.037). Moreover, after adjusting for CVD risk factors, the HRs for middle-serum and high-serum fibrinogen concentration, using 'low' group as reference, were 1.23 (95% CI 0.69 to 2.20) and 2.20 (95% CI 1.11 to 3.36, p=0.049)., Conclusions: We first indicated that elevated fibrinogen level was independently associated with increased CVE in Chinese patients with T2DMand stable CAD., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Aims: Patients with familial hypercholesterolemia (FH) are often characterized by premature coronary artery disease (CAD) with heterogeneity at onset. The aim of the present study was to investigate the associations of lipoprotein (a) [Lp(a)] with the FH phenotype, genotype and roles of Lp(a) in determining CAD risk among patients with and without FH., Methods: We enrolled 8050 patients undergoing coronary angiography, from our Lipid clinic. Clinical FH was diagnosed using the Dutch Lipid Clinic Network criteria. Mutational analysis (LDLR, APOB, PCSK9) in definite/probable FH was performed by target exome sequencing., Results: Lp(a) levels were increased, with a clinical FH diagnosis (unlikely, possible, definite/probable FH) independent of the patients status, with Lp(a)-hyperlipoproteinemia [Lp(a)-HLP] (median 517.70 vs. 570.98 vs. 604.65 mg/L, p < 0.001) or without (median 89.20 vs. 99.20 vs. 133.67 mg/L, p < 0.001). Patients with Lp(a)-HLP had a higher prevalence of definite/probable FH than those without (6.1% vs. 2.4%, p < 0.05). However, no significant difference in Lp(a) was observed in patients with definite/probable FH phenotype carrying LDLR or LDLR-independent (APOB, PCSK9) or neither mutations (p > 0.05). Multivariate analysis showed that Lp(a) and FH phenotype were both significant determinants in predicting the early onset and severity of CAD. Subsequently, patients with Lp(a)-HLP in definite/probable FH increased significantly the CAD risk (all p < 0.05)., Conclusions: Lp(a) levels were higher in patients with FH phenotype than in those without, but no difference were found in FH patients of different mutated backgrounds. Moreover, Lp(a) and FH played a synergistic role in predicting the early onset and severity of CAD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Big endothelin-1 (ET-1) has been proposed as a novel prognostic indicator of acute coronary syndrome, while its predicting role of cardiovascular outcomes in patients with stable coronary artery disease (CAD) is unclear., Methods and Results: A total of 3154 consecutive patients with stable CAD were enrolled and followed up for 24months. The outcomes included all-cause death, non-fatal myocardial infarction, stroke and unplanned revascularization (percutaneous coronary intervention and coronary artery bypass grafting). Baseline big ET-1 was measured using sandwich enzyme immunoassay method. Cox proportional hazard regression analysis and Kaplan-Meier analysis were used to evaluate the prognostic value of big ET-1 on cardiovascular outcomes. One hundred and eighty-nine (5.99%) events occurred during follow-up. Patients were divided into two groups: events group (n=189) and non-events group (n=2965). The results indicated that the events group had higher levels of big ET-1 compared to non-events group. Multivariable Cox proportional hazard regression analysis showed that big ET-1 was positively and statistically correlated with clinical outcomes (Hazard Ratio: 1.656, 95% confidence interval: 1.099-2.496, p=0.016). Additionally, the Kaplan-Meier analysis revealed that patients with higher big ET-1 presented lower event-free survival (p=0.016)., Conclusions: The present study firstly suggests that big ET-1 is an independent risk marker of cardiovascular outcomes in patients with stable CAD. And more studies are needed to confirm our findings., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Familial hypercholesterolemia (FH) is characterized by an elevated low-density lipoprotein cholesterol and increased risk of premature coronary artery disease. However, the general picture and mutational spectrum of FH in China are far from recognized, representing a missed opportunity for the investigation., Approach and Results: A total of 8050 patients undergoing coronary angiography were enrolled. The diagnosis of clinical FH was made using Dutch Lipid Clinic Network criteria, and the information of relatives was obtained by inquiring for the probands or from their own medical records of certain clinics/hospitals. Molecular analysis of FH was performed using target exome sequencing in LDLR (low-density lipoprotein cholesterol receptor gene), APOB (apolipoprotein B gene), and PCSK9 (proprotein convertase subtilisin/kexin type 9 gene). As a result, 3.5% of the patients with definite/probable FH phenotype (definite 1.0% and probable 2.5%) were identified. Women FH had fewer premature coronary artery disease (women <60, or men <55 years of age) when compared with men FH (70.6% versus 82.7%; P <0.001), whereas angiographic extension of coronary artery disease was significantly increased with FH diagnosis in both men and women ( P <0.001). Patterns of medication use in definite/probable FH were as follows: nontreated, 20.6%; low intensity, 6.0%; moderate intensity, 68.3%; and high intensity, 5.0%. However, none of them had achieved the low-density lipoprotein cholesterol <100 mg/dL. Additionally, mutational analysis was performed in 245 definite/probable FH cases, and risk variants were identified in 115 patients, giving a detection rate of 46.9%., Conclusions: We showed firsthand a common identification but poor treatment of patients with FH phenotype in Chinese coronary angiography patients. Genetic data in our FH cases might contribute to update the frequency and spectrum of Chinese FH scenarios., (© 2016 American Heart Association, Inc.)

Plasma C-reactive protein (CRP) concentration is associated positively with cardiovascular risk, including dyslipidemia. We suggested a regulating role of CRP on pro-protein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein (LDL) metabolism, and demonstrated the PCSK9 as a pathway linking CRP and LDL regulation. Firstly, experiments were carried out in the presence of human CRP on the protein and mRNA expression of PCSK9 and LDL receptor (LDLR) in human hepatoma cell line HepG2 cells. Treatment with CRP (10 μg/ml) enhanced significantly the mRNA and protein expression of PCSK9 and suppressed the expression of LDLR. Of note, a late return of LDLR mRNA levels occurred at 12 hrs, while the LDLR protein continued to decrease at 24 hrs, suggesting that the late decrease in LDLR protein levels was unlikely to be accounted for the decrease in LDL mRNA. Secondly, the role of PCSK9 in CRP-induced LDLR decrease and the underlying pathways were investigated. As a result, the inhibition of PCSK9 expression by small interfering RNA (siRNA) returned partly the level of LDLR protein and LDL uptake during CRP treatment; CRP-induced PCSK9 increase was inhibited by the p38MAPK inhibitor, SB203580, resulting in a significant rescue of LDLR protein expression and LDL uptake; the pathway was involved in hepatocyte nuclear factor 1α (HNF1α) but not sterol responsive element-binding proteins (SREBPs) preceded by the phosphorylation of p38MAPK. These findings indicated that CRP increased PCSK9 expression by activating p38MAPK-HNF1α pathway, with a certain downstream impairment in LDL metabolism in HepG2 cells., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Familial hypercholesterolemia (FH) is marked by an elevated plasma cholesterol and risk of premature cardiovascular disease. An increased burden of FH is being realized., Objective: To provide data on FH in Chinese patients with myocardial infarction (MI) and its potential contribution to early MI., Methods: A total of 1843 consecutive patients undergoing coronary angiography with their first MI were recruited. The clinical FH was diagnosed using the Dutch Lipid Clinic Network criteria. The prevalence and clinical features of FH and the relationship of FH to risk of early MI were investigated., Results: Of the 1843 patients, 48.2% were detected as premature MI (pMI, the onset age ≤55 years for men, ≤60 years for women). The prevalence of definite/probable FH reached 3.9% (7.1% in pMI and 0.9% in non-pMI). Furthermore, we found that the risk of pMI was significantly elevated in both definite/probable FH (vs. unlikely FH, odds ratio, 5.05 [1.10-23.23]) and possible FH (vs unlikely FH, odds ratio, 2.65 [1.22-5.77]), independently from classical risk factors and medications. Additionally, patients with definite/probable FH occurred 10 years younger than those with unlikely FH in the onset age of MI (48.63 ± 1.20 vs 58.35 ± 0.30 years, P < .001). When considered in subgroup of pMI or non-pMI, an early onset of MI was also observed in definite/probable FH (pMI, 45.83 ± 0.89 vs 47.87 ± 0.34 years; non-pMI, 60.75 ± 1.96 vs 65.07 ± 0.22 years; both P < .05)., Conclusion: The prevalence of FH among Chinese patients with MI appeared common, particularly among those with pMI. The phenotypic FH might significantly promote the early onset of MI., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies have suggested that people with obesity showed elevated serum levels of leptin as well as lipid dysfunction and proprotein convertase subtilisin/kexin type 9 (PCSK9) played an important role in the regulation of lipid metabolism recently. The aim of this study was to determine if leptin participated in regulating the uptake of low-density lipoproteins (LDL) in hepatocytes via PCSK9., Methods: HepG2 cells were treated with human recombinant leptin. The impact of leptin on cellular low density lipoprotein receptor (LDLR) and PCSK9 protein levels was determined by Western blot. Dil-LDL uptake assay was performed to examine the LDLR function. Specific small interfering RNAs (siRNAs) were used to interfere the expressions of target proteins., Results: The expression of LDLR and LDL uptake could be significantly down-regulated by leptin treatment while the expressions of PCSK9 and hepatocyte nuclear factor 1α (HNF1α) were enhanced in HepG2 cells. Furthermore, inhibition of PCSK9 or HNF1α expression by siRNAs rescued the reduction of LDLR expression and LDL uptake by leptin. We found that leptin activated the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. Moreover, the changes of the expressions of HNF1α, PCSK9, LDLR, and LDL uptake induced by leptin could be blocked by p38MAPK inhibitor (SB203580). Additionally, leptin attenuated the up-regulation of LDLR caused by atorvastatin in HepG2 cells., Conclusions: These findings indicated firstly that leptin reduced LDLR levels in hepatocyte via PCSK9 pathway, suggesting that PCSK9 might be a alternative target for dyslipidemia in the obesity.

Coronary artery disease (CAD) in very young individuals is a rare disease associated with poor prognosis. However, the role of specific lipoprotein subfractions in very young CAD patients (≤45 years) is not established yet. A total of 734 consecutive CAD subjects were enrolled and were classified as very early (n = 81, ≤45), early (n = 304, male: 45-55; female: 45-65), and late (n = 349, male: >55; female: >65) groups. Meanwhile, a group of non-CAD subjects were also enrolled as controls (n = 56, ≤45). The lipoprotein separation was performed using Lipoprint System. As a result, the very early CAD patients have lower large high-density lipoprotein (HDL) subfraction and higher small low-density lipoprotein (LDL) subfraction (p < 0.05). Although body mass index was inversely related to large HDL subfraction, overweight did not influence its association with very early CAD. In the logistic regression analysis, large HDL was inversely [OR 95% CI: 0.872 (0.825-0.922)] while small LDL was positively [1.038 (1.008-1.069)] related to very early CAD. However, after adjusting potential confounders, the association was only significant for large HDL [0.899 (0.848-0.954)]. This study firstly demonstrated that large HDL subfraction was negatively related to very early CAD suggestive of its important role in very early CAD incidence.

Objective: Very early-onset coronary artery disease (CAD) is a great challenge in cardiovascular medicine throughout the world, especially regarding its early diagnosis. This study explored whether circulating microRNAs (miRNAs) could be used as potential biomarkers for patients with very early-onset CAD., Methods: We performed an initial screening of miRNA expression using RNA isolated from 20 patients with angiographically documented very early-onset CAD and 20 age- and sex-matched normal controls. For further confirmation, we prospectively examined the miRNAs selected from 40 patients with very early-onset CAD and 40 angiography-normal controls., Results: A total of 22 overexpressed miRNAs and 22 underexpressed miRNAs were detected in the initial screening. RT-qPCR analysis of the miRNAs obtained from the initial screening revealed that four miRNAs including miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p exhibited significantly decreased expression in patients compared with that in controls (P<0.05). The areas under the receiver operating characteristic curve for these miRNAs were 0.824 (95% CI, 0.731-0.917; P<0.001), 0.758 (95% CI, 0.651-0.864; P<0.001), 0.753 (95% CI, 0.643-0.863; P<0.001), and 0.782 (95% CI, 0.680-0.884; P<0.001), respectively, in the validation set., Conclusion: To our knowledge, this is an advanced study to report about four serum miRNAs (miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p) that could be used as novel biomarkers for the diagnosis of very early-onset CAD., (Copyright © 2016 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been demonstrated to be involved in not only lipid metabolism but also glucose homeostasis. Glycated haemoglobin (HbA1c ) is a 'gold standard' for monitoring long-term glycaemic control. However, the correlation of plasma PCSK9 levels with HbA1c remains undetermined., Methods: We consecutively enrolled 805 subjects undergoing coronary angiography, including 176 patients with type 2 diabetes mellitus (T2DM) and 629 non-diabetic patients. The baseline characteristics were collected, and serum PCSK9 level was assessed by ELISA. Univariable regression analysis and multiple-variable regression analysis were used to examine the associations of PCSK9 with HbA1c . Furthermore, the HbA1c was compared across the tertiles of PCSK9 levels. And also, PCSK9 levels were compared in poorly controlled (HbA1c  ≥ 7.0%) and well-controlled (HbA1c  < 7.0%) patients with T2DM., Results: PCSK9 levels were positively correlated with low-density lipoprotein cholesterol in both T2DM and non-T2DM. Univariable regression analysis revealed a positive association between PCSK9 and HbA1c in patients with T2DM (β = 0.255, p = 0.001) but not in patients without diabetes (β = 0.061, p = 0.128). Multiple-variable regression analysis exhibited that PCSK9 was independently correlated with HbA1c in T2DM after adjustment for traditional atherosclerotic risk factors (β = 0.197, p = 0.020). Moreover, HbA1c level was higher in patients with the highest tertile of PCSK9 than that in the lowest tertile (p = 0.042). Additionally, higher levels of PCSK9 were found in poorly controlled group compared with the well-controlled group (p = 0.029)., Conclusions: Data suggest a positive correlation of PCSK9 levels with HbA1c in patients with T2DM but not in patients without T2DM, indicating a potential role of PCSK9 in T2DM. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

High-density lipoprotein (HDL) is highly heterogeneous in its size and composition. Till now, the link of HDL subfractions to coronary risk is less clear. We aimed to investigate the associations of HDL subfractions with traditional risk factors (RFs), coronary severity, and outcomes in a cohort of nontreated patients with stable coronary artery disease (CAD). We prospectively enrolled 591 eligible patients. Baseline HDL subfractions were separated by Lipoprint system. HDL subfractions (large, medium, and small) and HDL-cholesterol (HDL-C) levels were dichotomized into low and high group according to the 50 percentile. Coronary severity was evaluated by SYNTAX, Gensini, and Jeopardy scoring systems. Patients were followed up annually for major adverse cardiovascular events (MACEs). Cox proportional hazards' models were used to evaluate the risk of HDL subfractions on MACEs. Patients with high large HDL-C levels had a decreased number of RFs. Significantly, large HDL-C levels were negatively associated with coronary severity assessed by SYNTAX and Gensini score (both P < 0.05). New MACEs occurred in 67 (11.6%) patients during a median 17.0 months follow-up. Moreover, the log-rank test revealed that there was a significant difference between high and low large HDL-C groups in event-free survival analysis (P = 0.013), but no differences were observed in total HDL-C groups and medium or small HDL-C groups (both P > 0.05). In particular, the multivariate Cox-proportional hazards model revealed that high large HDL-C was associated with lower MACEs risk (hazard ratio [95% confidence interval] 0.531 [0.295-0.959]) independent of potential confounders. Higher large HDL-C but not medium, small, or total HDL-C is associated with lower cardiovascular risk, highlighting the potential beneficial of HDL subfractionation., Competing Interests: The authors have no conflicts of interest to disclose.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly-recognized protein, plays a key role in regulating cholesterol homeostasis. PCSK9 reduces hepatic low-density lipoprotein receptors (LDLRs) thereby increasing LDL-cholesterol (LDL-C). Recently, biologic and genetic research proposed several approaches to inhibit or reduce PCSK9 to improve lipid profile and cardiovascular performance in patients with dyslipidemia, particularly hypercholesterolemia. Of note, PCSK9 is a secreted protein under tight control by multiple modulators. Therefore, elucidating the factors that influence PCSK9 would enhance our understanding of PCSK9 and potentially day-to-day management of these patients at high cardiovascular risk. This review will focus on genetic variants, physiologic processes, pharmacologic agents and pathologic conditions related to PCSK9 in order to assess current and future therapeutic strategies targeting this molecule., (Copyright © 2014. Published by Elsevier B.V.)

Three new cyclohexadepsipeptides of the isaridin class including isaridin G (1), desmethylisaridin G (2), and desmethylisaridin C1 (3), along with three related known metabolites (4-6), were isolated and identified from the marine bryozoan-derived fungus Beauveria felina EN-135. The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis, and the structures and absolute configurations of compounds 1-3 were confirmed by single-crystal X-ray diffraction analysis. The crystal structures showed the presence of β-turns for the Tyr(3)/N-Me-Val(4) and Phe(3)/N-Me-Val(4) amide bonds in compounds 2 and 3, respectively, in the cis conformations, which were opposite other reported isaridins. The conformations of the HMPA(1)-Pro(2) amide bond in compound 2 are different in the solution and in the crystal structures, which showed trans and cis geometries, respectively, while compounds 1 and 3 do not exhibit this phenomenon. Each of the isolated compounds was evaluated for antimicrobial activity and brine shrimp lethality. Compound 3 exhibited antibacterial activity against E. coli with an MIC value of 8 μg/mL.

Objective: To study the expression and prognostic significance of galectin-1 and galectin-3 in different melanocytic lesions., Methods: The expression of galectin-1 and galectin-3 in 39 cases of benign nevus, 58 cases of primary cutaneous melanoma, 24 cases of primary mucosal melanoma, 69 cases of melanoma with lymph node metastasis and 8 cases of melanoma with distant metastasis were studied by immunohistochemistry and tissue microarray., Results: The expression of galectin-1 and galectin-3 was higher in benign nevi than in melanomas (P < 0.01). The nuclear expression of galectin-3 was higher in primary cutaneous melanomas than in primary mucosal melanomas or melanomas with metastases (P < 0.01, respectively). The expression correlated with age of patients (P < 0.05), necrosis (P < 0.05) and survival time (P < 0.01). Clark's level also correlated with survival time in patients with cutaneous melanomas (P = 0.037). TNM staging was the only independent prognostic factor for melanomas (P < 0.01)., Conclusions: The expression of galectin-1 and galectin-3 is decreased in melanomas. The decrease in nuclear expression of galectin-3 may represent a poor prognostic factor for melanomas. TNM staging is an independent prognostic factor which influences the survival time.

Objective: To investigate the correlations among Ki-67 expression, mitosis and other clinicopathological parameters of primary cutaneous malignant melanoma, and search for prognostic factors of malignant melanoma., Methods: Totally 127 cases of primary cutaneous malignant melanoma were collected from Beijing Cancer Hospital. Immunohistochemical study for Ki-67 was performed, and the mitosis was calculated referring to "hot spot" method recommended by the seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system. The correlations of Ki-67 expression, mitosis and other clinicopathological parameters were analyzed, and the survival analysis of all these risk factors including TNM and Clark level was conducted based on follow up data., Results: The expression level of Ki-67 was associated with necrosis and Breslow thickness (P < 0.05). Mitosis was correlated with Clark level and Ki-67 expression (P < 0.05). Univariate analysis indicated Ki-67 expression level (P = 0.043), mitosis (P = 0.030) and TNM stage (P < 0.001) might influence the survival of patients. However, multivariate analysis showed that the TNM staging was the only independent prognostic factor affecting survival., Conclusions: The prognosis of patients with primary cutaneous malignant melanoma was closely related to the TNM staging at the fist examination. Ki-67 expression and mitosis are two important clinicopathological parameters of primary cutaneous malignant melanoma.

In addition to 13 known compounds, four new bisabolane sesquiterpenes, okamurenes A-D (1-4), a new chamigrane derivative, okamurene E (5), and a new C₁₂-acetogenin, okamuragenin (6), were isolated from the marine red alga Laurencia okamurai. The structures of these compounds were determined through detailed spectroscopic analyses. Of these, okamurenes A and B (1 and 2) are the first examples of bromobisabolane sesquiterpenes possessing a phenyl moiety among Laurencia-derived sesquiterpenes, while okamuragenin (6) was the first acetogenin aldehyde possessing a C₁₂-carbon skeleton. Each of the isolated compounds was evaluated for the brine shrimp (Artemia salina) lethal assay and 7-hydroxylaurene displayed potent lethality with LD₅₀ 1.8 μM.

Objective: To evaluate the safety and efficacy of sorafenib plus cisplatin in the treatment of metastatic renal cell carcinoma (mRCC) with pleural effusion., Methods: A total of 30 patients with mRCC (clear cell carcinoma) with pleural effusion from April 2009 to January 2011 were recruited. All received sorafenib 400 mg twice daily. And 11 patients in chemotherapy group received sorafenib plus local chemotherapeutic perfusion of cisplatin 40 mg weekly for 2 weeks while another 19 patients in control group received sorafenib alone., Results: The response rate of pleural effusion was 10/11 for chemotherapy group versus 3/19 for control group (χ(2) = 13.097, P < 0.01). Followed up to April 30(th), 2011, 5 of 11 patients in chemotherapy group and 10 of 19 patients in control group died. Among those on sorafenib, the median overall survival time was 22 months (95%CI: 2.12 - 41.88) for local chemotherapy versus 9 months (95%CI: 8.20 - 9.80) without local therapy (P = 0.04). The most common events in local chemotherapy group were I-II thoracic pain, nausea and vomiting. And the incidence rates were 8/11 and 9/11 versus 4/19 and 3/19 respectively (P < 0.01). The main laboratory abnormalities were similar in two groups., Conclusion: The regimen of sorafenib plus pleural cavity perfusion of cisplatin is both effective and safe in the treatment of mRCC with pleural effusion. It may control local symptoms and achieve a better overall survival.

Objective: To study effective active constituents of Cayratia japonica,a genuine herbal medicine from Fujian., Method: Such chromatographic methods as Macroporous, Sephadex LH-20, ODS and normal phase silica gel column chromatography were adopted to separate the chemical components of C. japonica., Result: Thirteen compounds were obtained, and their structures were identified by analyzing multiple spectral data as luteolin(1), apigenin(2), triethyl citrate-(3), 3-formylindole(4), esculetin(5), bis(2-ethylhexyl)-phthalate(6), calendin(7), ethyl-trans-3,4-dihydr-oxycinnamate(8), luteolin7-O-D-glucoside(9),5-hydroxy-3,4-dimethyl-5-pentyl-2(5H-furanone(10),ethyl-3,4-dihydroxybenzoate(11), eriodictyol(12) and daucosterol(13)., Conclusion: Among them, compounds 3-8 and 10-12 were separated from the plant for the first time.

Bioassay-guided fractionation of the culture extract of Aspergillus wentii EN-48, an endophytic fungus isolated from an unidentified marine brown algal species of the genus Sargassum, led to the isolation of three new tetranorlabdane diterpenoids, asperolides A-C (1-3), and five related derivatives (4-8). The structures of these compounds were established on the basis of spectroscopic interpretation, and compound 1 was confirmed by X-ray crystallographic analysis. The absolute configuration of 1 was determined by application of the modified Mosher's method. An X-ray structure for wentilactone B (6) is also reported. Compounds 1-8 were evaluated for cytotoxic and antibacterial activities.

The marine sediment-derived fungus Penicillium commune QSD-17 was re-investigated and cultured on rice solid medium. Two new compounds, isophomenone (1) and 3-deacetylcitreohybridonol (2), together with seven known derivatives (3-9), were identified. Their structures were determined by spectroscopic analysis.