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The chromogranin-secretogranin secretory proteins-granins-are acidic proteins localized in granules of endocrine cells and neurons. The chromogranin family includes chromogranins A (CgA) and B, as well as secretogranin II (once called chromogranin C). Members of this family undergo catalytic proteolysis to produce active peptides. The CgA-derived peptides vasostatin-1 and vasostatin-2, in particular, appear to protect against atherosclerosis, suppressing the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, as well as exerting vasodilatory effects by enhancing nitric oxide bioavailability. Vasostatin-1 also suppresses vasoconstriction and abnormal angiogenesis. Vasostatin-1 and vasostatin-2 may be novel therapeutic targets for atherosclerosis and coronary heart disease, also protecting the myocardium against ischaemic damage., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Vulnerable plaque was associated with recurrent cardiovascular events. This study was designed to explore predictive biomarkers of vulnerable plaque in patients with coronary artery disease., Methods: To reveal the phenotype-associated cell type in the development of vulnerable plaque and to identify hub gene for pathological process, we combined single-cell RNA and bulk RNA sequencing datasets of human atherosclerotic plaques using Single-Cell Identification of Subpopulations with Bulk Sample Phenotype Correlation (Scissor) and Weighted gene co-expression network analysis (WGCNA). We also validated our results in an independent cohort of patients by using intravascular ultrasound during coronary angiography., Results: Macrophages were found to be strongly correlated with plaque vulnerability while vascular smooth muscle cell (VSMC), fibrochondrocyte (FC) and intermediate cell state (ICS) clusters were negatively associated with unstable plaque. Weighted gene co-expression network analysis showed that Secreted Phosphoprotein 1 (SPP1) in the turquoise module was highly correlated with both the gene module and the clinical traits. In a total of 593 patients, serum levels of SPP1 were significantly higher in patients with vulnerable plaques than those with stable plaque (113.21 [73.65 - 147.70] ng/ml versus 71.08 [20.64 - 135.68] ng/ml; P < 0.001). Adjusted multivariate regression analysis revealed that serum SPP1 was an independent determinant of the presence of vulnerable plaque. Receiver operating characteristic curve analysis indicated that the area under the curve was 0.737 (95% CI 0.697 - 0.773; P < 0.001) for adding serum SPP1 in predicting of vulnerable plaques., Conclusion: Elevated serum SPP1 levels confer an increased risk for plaque vulnerability in patients with coronary artery disease., 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 Huang, Chen, Yu, Wu, Chen, Wang, Li, Liu, Wang, Mao, Shen, Zhang, Shen, Lu, Dai and Ding.)

Objective: To investigate the association between circulating secretoneurin (SN) and angiographic coronary collateralization in stable angina patients with chronic coronary total occlusion (CTO)., Methods: SN concentrations in serum were measured in 641 stable angina patients with CTO by radioimmunoassay. The status of coronary collaterals from the contra-lateral vessel was visually estimated using the Rentrop grading system, and was categorized into poor (grade 0 or 1) or good (grade 2 or 3) collateralization., Results: Serum SN levels were significantly higher in patients with good coronary collaterals compared to those with poor collaterals (175.23 ± 52.09 pmol/L vs. 143.29 ± 42.01 pmol/L, P < 0.001). Serum SN increased stepwise across Rentrop score 0 to 3 (P < 0.001), and increasing SN tertiles were associated with higher proportion of good coronary collateralization (OR, 1.907; 95% CI, 1.558 ~ 2.335, P < 0.001). After adjustment for confounding variables, serum SN (per tertile) remained an independent factor for predicting good coronary collaterals (OR, 1.870; 95% CI, 1.515 ~ 2.309; P < 0.001). Moreover, the diagnostic value of serum SN (per tertile) was consistent after stratifying patients based on gender, age, body mass index, hypertension, diabetes, history of smoking, severity of coronary artery disease and kidney function (OR: 1.511 ~ 2.680, P interaction ≥ 0.327)., Conclusion: Elevated circulating SN reflects good angiographic coronary collaterals in stable angina patients with CTO. The findings may provide insight into decision-making for these patients., (© 2024. The Author(s).)

Background: A substantial portion of heart failure (HF) patients adherent to guideline-directed medical therapies have experienced improved ejection fraction (EF), termed HFimpEF. Glycemic variability (GV) has emerged as a critical cardiometabolic factor. However, the relation between long-term GV and the incidence of HFimpEF is still unclear., Methods: A total of 591 hospitalized HF patients with reduced EF (HFrEF, EF≤ 40%) admitted from January 2013 to December 2020 were consecutively enrolled. Repeat echocardiograms were performed at baseline and after around 12 months. The incidence of HFimpEF, defined as (1) an absolute EF improvement ≥10% and (2) a second EF > 40% and its association with long-term fasting plasma glucose (FPG) variability were analyzed., Results: During a mean follow-up of 12.2 ± 0.6 months, 218 (42.0%) patients developed HFimpEF. Multivariate analysis showed FPG variability was independently associated with the incidence of HFimpEF after adjustment for baseline HbA1c, mean FPG during follow-up and other traditional risk factors (odds ratio [OR] for highest vs. lowest quartile of CV of FPG: 0.487 [95% CI 0.257~0.910]). Evaluation of GV by alternative measures yielded similar results. Subgroup analysis revealed that long-term GV was associated with HFimpEF irrespective of glycemic levels and diabetic conditions., Conclusions: This study reveals that greater FPG variability is associated with compromised development of HFimpEF. A more stable control of glycemic levels might provide favorable effects on myocardial functional recovery in HF patients even without diabetes., 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 © 2023 Yang, Chen, Quan, Shu, Feng, Aihemaiti, Ding, Shen, Lu, Zhang and Wang.)

Aims: Members of the chromogranin family play a role in angiogenesis. One such biologically active peptide, generated through the processing of chromogranin A, is vasostatin-2. This study aimed at assessing the association of serum vasostatin-2 levels with coronary collateral vessels (CCV) in diabetic patients with chronic total occlusions (CTO) and the effects of vasostatin-2 on angiogenesis in diabetic mice with hindlimb or myocardial ischemia., Methods and Results: Serum levels of vasostatin-2 in 452 diabetic CTO patients were evaluated. The status of CCV was categorized according to the Rentrop score. Vasostatin-2 recombinant protein or phosphate-buffered saline were then injected intraperitoneally in diabetic mouse models of hindlimb or myocardial ischemia, followed by laser Doppler imaging and molecular biology examinations. The effects of vasostatin-2 were also ascertained in endothelial cells and macrophages, with mechanisms clarified using ribonucleic acid (RNA) sequencing. Serum levels of vasostatin-2 were significantly different and progressively higher across Rentrop score 0, 1, 2, and 3 groups (P < .001), with significantly lower levels in patients with poor CCV (Rentrop score 0 and 1) than in those with good CCV (Rentrop score 2 and 3) (P < .05). Vasostatin-2 significantly promoted angiogenesis in diabetic mice with hindlimb or myocardial ischemia. RNA-seq analyzes verified an angiotensin-converting enzyme 2 (ACE2)-mediated vasostatin-2-induction of angiogenesis in ischemic tissues., Conclusion: Lower serum levels of vasostatin-2 are associated with poor CCV in diabetic CTO patients compared with patients with good CCV. Vasostatin-2 significantly promotes angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Such effects are mediated by ACE2., Competing Interests: Conflict of Interest Statement All authors declare no conflict of interest for this contribution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Video laryngoscope is available for visualizing the motion of vocal cords and aid in the assessment of analyzing the larynx-related lesion preliminarily. Laryngeal Electromyography (EMG) needs to be performed to diagnose the factors of vocal cord paralysis, which may cause patient feeling unwell. Thus, the problem is the lack of credible larynx indicators to evaluate larynx-related diseases in the department of otolaryngology. Therefore, this paper aims to propose a 3D VOSNet model, which has the characteristics of sequence segmentation to extract the time-series features in the video laryngoscope. The 3D VOSNet model can keep the time-series features of three images before and after of the specific image to achieve translation and occlusion invariance, which explicitly signifies that our model can segment and classify each item in the video of laryngoscopy not affected by extrinsic causes such as shaking or occlusion during laryngoscope. Numerical results revealed that the testing accuracy rates of the glottal, right vocal cord, and the left vocal cord are 89.91%, 94.63%, and 93.48%, respectively. Our proposed model can segment glottal and vocal cords from the sequence of laryngoscopy. Finally, using the proposed algorithm computes six larynx indicators, which are the area of the glottal, area of vocal cords, length of vocal cords, deviation of length of vocal cords, and symmetry of the vocal cords. In order to assist otolaryngologists in staying credible and objective when making decisions without any doubt during diagnosis and also explaining the clinical symptoms of the larynx such as vocal cord paralysis to patients after diagnosis, our proposed algorithm provides otolaryngologists with explainable indicators (X-indicators)., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Background: Due to advances in medical treatments, a substantial proportion of heart failure (HF) patients with reduced left ventricular ejection fraction (EF, HFrEF) have experienced partial or complete recovery of EF, termed HFrecEF, and markedly improved clinical outcomes. In the present study, we sought to investigate the relationship between glycemic control and the incidence of HFrecEF in hospitalized HFrEF patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 463 hospitalized T2DM patients with HFrEF were consecutively enrolled. Follow-up echocardiogram was performed after around 12 months. Patients who had an absolute EF improvement ≥10% and a second EF > 40% were classified into HFrecEF, and those who did not meet these criteria were defined as persistent HFrEF., Results: During the 12-month follow-up, 44.5% of T2DM patients developed HFrecEF. Patients with HFrecEF had significantly lower HbA1c level than those with persistent HFrEF (6.5% [IQR 5.8% ∼ 7.2%] vs. 6.7% [IQR 6.1% ∼ 7.8%], P = 0.003), especially in HF of an ischemic etiology. HbA1c levels were inversely correlated with changes in EF during follow-up. After multivariate adjustment, every 1% increase in HbA1c conferred a 17.4% (OR: 0.826 [95% CI 0.701-0.968]) lower likelihood of HFrecEF. Compared to patients with good glycemic control (HbA1c ≤ 6.2%), those with poor glycemic control (HbA1c > 7.1%) had a 52.0% (OR: 0.480 [95% CI 0.281-0.811] decreased likelihood of HFrecEF., Conclusions: This study demonstrates that uncontrolled HbA1c level is associated with compromised development of HFrecEF in T2DM patients with HF, especially in those with an ischemic etiology., Competing Interests: Declaration of Competing Interest 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 © 2022 Elsevier B.V. All rights reserved.)

Ubiquitin-specific-processing protease 7 (USP7) is a promising target protein for cancer therapy, and great attention has been given to the identification of USP7 inhibitors. Traditional virtual screening methods have now been successfully applied to discover USP7 inhibitors aiming at reducing costs and speeding up time in several studies. However, due to their unsatisfactory accuracy, it is still a difficult task to develop USP7 inhibitors. In this study, multiple supervised learning classifiers were built to distinguish active USP7 inhibitors from inactive ligands. Physicochemical descriptors, MACCS keys, ECFP4 fingerprints and SMILES were first calculated to represent the compounds in our in-house dataset. Two deep learning (DL) models and nine classical machine learning (ML) models were then constructed based on different combinations of the above molecular representations under three activity cutoff values, and a total of 15 groups of experiments (75 experiments) were implemented. The performance of the models in these experiments was evaluated, compared and discussed using a variety of metrics. The optimal models are ensemble learning models when the dataset is balanced or severely imbalanced, and SMILES-based DL performs the best when the dataset is slightly imbalanced. Meanwhile, multimodal data fusion in some cases can improve the performance of ML and DL models. In addition, SMOTE, unbiased decoy selection and SMILES enumeration can improve the performance of ML and DL models when the dataset is severely imbalanced, and SMOTE works the best. Our study established highly accurate supervised learning classification models, which would accelerate the development of USP7 inhibitors. Some guidance was also provided for drug researchers in selecting supervised models and molecular representations as well as handling imbalanced datasets., (© 2023. The Author(s).)

Background This study aimed to explore predictive biomarkers of coronary collateralization in patients with chronic total occlusion. Methods and Results By using a microarray expression profiling program downloaded from the Gene Expression Omnibus database, weighted gene coexpression network analysis was constructed to analyze the relationship between potential modules and coronary collateralization and screen out the hub genes. Then, the hub gene was identified and validated in an independent cohort of patients (including 299 patients with good arteriogenic responders and 223 patients with poor arteriogenic responders). Weighted gene coexpression network analysis showed that SERPING1 in the light-cyan module was the only gene that was highly correlated with both the gene module and the clinical traits. Serum levels of serpinG1 were significantly higher in patients with bad arteriogenic responders than in patients with good arteriogenic responders (472.53±197.16 versus 314.80±208.92 μg/mL; P <0.001) and were negatively associated with the Rentrop score (Spearman r =-0.50; P <0.001). Receiver operating characteristic curve analysis indicated that the area under the curve was 0.77 (95% CI, 0.72-0.81; P <0.001) for serum serpinG1 in prediction of bad arteriogenic responders. After adjusting for traditional cardiovascular risk factors, serum serpinG1 levels (per SD) remained an independent risk factor for bad arteriogenic responders (odds ratio, 2.20 [95% CI, 1.76-2.74]; P <0.001). Conclusions Our findings illustrate that SERPING1 screened by weighted gene coexpression network analysis was associated with poor collateralization in patients with chronic total occlusion.

Background: Left ventricular (LV) diastolic dysfunction (LVDD) is the defining feature of heart failure with preserved ejection fraction (HFpEF) and predicts subsequent incident heart failure (HF) and all-cause mortality. Mounting evidence reveals that cardiometabolic risk factors play critical roles in the development of LVDD. In this study, we sought to investigate the relation between serum uric acid (SUA) level and the progression of LVDD in apparently healthy patients., Methods: A total of 1082 apparently healthy subjects without diagnosed cardiovascular disease and LVDD were consecutively enrolled. SUA levels were measured, and repeat echocardiography and tissue Doppler imaging (TDI) were performed at baseline and during 1-year follow-up., Results: By dividing the study population based on quartiles of SUA, we found subjects in higher quartiles had greater increases in TDI-derived early diastolic velocity (e') and E (peak LV filling velocity)/e' ratios during 1-year follow-up. After multivariate adjustment, high SUA persisted to be an independent predictor for the subsequent worsening of LVDD (odds ratio: 1.351 [95% CI 1.125~1.625], per 100  μ mol/L SUA). Subgroup analysis suggested that the association between SUA and LVDD development was more pronounced in subjects without other cardiometabolic risk factors involved. Factor analysis demonstrated that high SUA was the major cardiometabolic attribute in patients with LVDD progression., Conclusion: Our findings suggest that high SUA is an independent cardiometabolic risk factor for the progression of LVDD in apparently healthy subjects., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Chen Die Yang et al.)

Background Because of advances in medical treatments, a substantial proportion of patients with heart failure (HF) have experienced recovery of ejection fraction (EF), termed HF with recovered EF (HFrecEF). Insulin resistance (IR) is prevalent in HF and tightly related with prognosis. This study investigates the relationship between IR and the incidence of HFrecEF in patients who are nondiabetic. Methods and Results A total of 262 patients with HF with reduced EF (HFrEF) who were nondiabetic were consecutively enrolled. Patients were classified into HFrecEF (follow-up EF>40% and ≥10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. IR was estimated by an updated homeostasis model assessment for IR (HOMA2-IR). The median HOMA2-IR level was 1.05 (interquartile range [IQR], 0.67-1.63) in our cohort of patients with HF who were nondiabetic. During follow-up, 121 (odds ratio [OR], 46.2% [95% CI 40.2-52.2]) patients developed HFrecEF. Compared with patients with HFrEF, patients with HFrecEF had significantly lower HOMA2-IR levels (0.92 [IQR, 0.61-1.37] versus 1.14 [IQR, 0.75-1.78], P =0.007), especially in nonischemic HF. Log 2 -transformed HOMA2-IR was inversely correlated to improvements in EF (Pearson's r =-0.25, P <0.001). After multivariable adjustment, a doubling of HOMA2-IR was associated with a 42.8% decreased likelihood of HFrecEF (OR, 0.572 [95% CI, 0.385-0.827]). Conclusions This study reveals that IR is independently associated with compromised development of HFrecEF in patients who are nondiabetic.

Coronary collateralization is substantially impaired in patients with type 2 diabetes and occlusive coronary artery disease, which leads to aggravated myocardial ischemia and a more dismal prognosis. In a diabetic setting, altered serum lipid profiles and profound glycoxidative modification of lipoprotein particles induce endothelial dysfunction, blunt endothelial progenitor cell response, and severely hamper growth and maturation of collateral vessels. The impact of dyslipidemia and lipid-lowering treatments on coronary collateral formation has become a topic of heightened interest. In this review, we summarized the association of triglyceride-based integrative indexes, hypercholesterolemia, increased Lp(a) with its glycoxidative modification, as well as quantity and quality abnormalities of high-density lipoprotein with impaired collateral formation. We also analyzed the influence of innovative lipid-modifying strategies on coronary collateral development. Therefore, clinical management of diabetic dyslipidemia should take into account of its effect on coronary collateralization in patients with occlusive coronary artery disease., 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 © 2022 Shen, Wang, Dai, Wang, Zhang, Lu, Ding and Shen.)

Background: The formation of advanced glycation end-products (AGEs) is a crucial risk factor for the pathogenesis of cardiovascular diseases in diabetes. We investigated whether N-epsilon-carboxymethyllysine (CML), a major form of AGEs in vivo, was associated with poor coronary collateral vessel (CCV) formation in patients with type 2 diabetes mellitus (T2DM) and chronic total occlusion (CTO) of coronary artery., Methods: This study consisted of 242 T2DM patients with coronary angiographically documented CTO. Blood samples were obtained and demographic/clinical characteristics were documented. The coronary collateralization of these patients was defined according to Rentrop or Werner classification. Serum CML levels were evaluated using ELISA assay. Receiver operating characteristic curve and multivariable regression analysis were performed., Results: 242 patients were categorized into poor CCV group or good CCV group (107 vs. 135 by the Rentrop classification or 193 vs. 49 by the Werner classification, respectively). Serum CML levels were significantly higher in poor CCV group than in good CCV group (110.0 ± 83.35 vs. 62.95 ± 58.83 ng/ml by the Rentrop classification and 94.75 ± 78.29 ng/ml vs. 40.37 ± 28.69 ng/ml by Werner classification, both P < 0.001). Moreover, these CML levels were also significantly different across the Rentrop and Werner classification subgroups (P < 0.001). In multivariable logistic regression, CML levels (P < 0.001) remained independent determinants of poor CCV according to the Rentrop or Werner classification after adjustment of traditional risk factors., Conclusions: This study suggests that higher serum CML level is associated with poor collateralization in T2DM patients with CTO., (© 2022. The Author(s).)

Objective To investigate the expression and the potential roles of long non-coding RNA(lncRNA)cancer susceptibility candidate 2(CASC2)and imprinted gene H19 in extrahepatic cholangiocarcinoma(ECC). Methods Four samples from patients with ECC were collected for high-throughput sequencing which was conducted to reveal the transcriptomic profiles of lncRNA CASC2 and H19.Bioinformatics tools were employed to predict the potential roles of the two genes.Another 22 ECC tissue samples and the cholangiocarcinoma cell lines(RBE,QBC939,HuH-28,and HuCCT1)with different degrees of differentiation were selected for validation.The para-carcinoma tissue and normal human intrahepatic biliary epithelial cell(HIBEC)were used as the control groups.The expression levels of lncRNA CASC2 and H19 in carcinoma tissue,para-carcinoma tissue,and cell lines were determined by real-time quantitative polymerase chain reaction(qRT-PCR).The correlation analysis was carried out for the clinical indicators of patients with the expression levels of the target genes. Results The two target genes showed significantly different expression between carcinoma tissue and para-carcinoma tissue(all P <0.05).Specifically,CASC2 had higher expression level in the carcinoma tissue than in the para-carcinoma tissue( t =1.262, P =0.025),whereas the expression of H19 showed an opposite trend( t =1.285, P =0.005).The expression levels of CASC2 in QBC939( t =8.114, P =0.015)and HuH-28( t =9.202, P =0.012)cells were significantly higher than that in the control group.The expression levels of H19 were significantly lower in RBE( t =-10.244, P <0.001),QBC939( t =-10.476, P <0.001),HuH-28( t =-19.798, P <0.001),and HuCCT1( t =-16.193, P =0.004)cells than in the control group.Bioinformatics analysis showed that CASC2 was mainly involved in the metabolic process and H19 in the development of multicellular organisms.Both CASC2 and H19 were related to catalytic activity.The expression level of lncRNA CASC2 was correlated with pathological differentiation( χ 2 =6.222, P =0.022)and lymph node metastasis( χ 2 =5.455, P =0.020),and that of lncRNA H19 with pathological differentiation( χ 2 =1.174, P =0.029)and tumor size( χ 2 =-0.507, P =0.037). Conclusions In the case of ECC,lncRNA CASC2 and H19 have transcription disorders.lncRNA CASC2 is generally up-regulated in the carcinoma tissue,while H19 is down-regulated.Both genes have the potential to become new molecular markers for ECC.

Background: The optimal strategy of percutaneous coronary intervention (PCI) for isolated left anterior descending (LAD) ostial lesions remains debatable. This study aimed to compare clinical outcomes of patients with isolated LAD ostial stenosis treated by single-stent crossover versus accurate ostial stenting., Methods: A total of 216 eligible consecutive patients with isolated de novo LAD ostial stenosis were enrolled, and were stratified according to the stenting techniques. Clinical follow-up was performed by review of medical charts or telephone contact with the patients, and repeat angiography was made at 9-12 months after the procedure. Major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, non-fatal stroke and target vessel revascularization (TVR) were recorded., Results: Single-stent crossover and accurate ostial stenting were applied to 78 (36%) and 138 (64%) patients, respectively. During a mean of 13 ± 4.1 months of follow-up, the rate of composite MACE (19.6 vs. 8.9%; P = 0.040) was higher in LAD ostial stenosis patients treated with accurate ostial stenting than those treated with single-stent crossover technique, mainly driven by more frequent TVR (17.4 vs. 7.7%; P = 0.048). PCI strategy was an independent predictor of MACE (hazard ratio 2.561; 95% CI, 1.041-6.299; P = 0.021) in the multivariable Cox regression analysis., Conclusions: Our retrospective study suggests that the single-stent crossover technique is associated with a better 1-year clinical outcome compared with accurate ostial stenting in patients with isolated LAD ostial stenosis., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chromogranin B (CgB) is increased in heart failure and proportionate to disease severity. We investigated whether circulating CgB level is associated with left ventricular (LV) functional recovery potential after successful recanalization of chronic total occlusion (CTO). Methods: Serum levels of CgB were assayed in 53 patients with stable angina with LV functional recovery [an absolute increase in LV ejection fraction (EF) of ≥5%] and 53 age- and sex-matched non-recovery controls after successful recanalization of CTO during 12-month follow-up. Results: We found that CgB level was significantly lower in the recovery group than in the non-recovery group (593 [IQR 454-934] vs. 1,108 [IQR 696-2020] pg/ml, P < 0.001), and that it was inversely correlated with changes in LVEF (Spearman's r = -0.31, P = 0.001). Receiver operating characteristic (ROC) analysis showed that the area under the curve of CgB for predicting LVEF improvement was 0.76 (95% CI 0.664-0.856), and that the optimal cutoff value was 972.5 pg/ml. In multivariate analyses, after adjusting for confounding factors, high CgB level remained an independent determinant of impaired LV functional recovery after CTO recanalization. LV functional improvement appeared to be more responsive to CgB in patients with poor than with good coronary collaterals. Conclusions: Elevated circulating CgB level confers an increased risk of impaired LV functional recovery after successful recanalization of CTO in patients with stable coronary artery disease., 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 © 2021 Shen, Aihemaiti, Shu, Yang, Chen, Dai, Ding, Yang, Hu, Zhang, Lu, Wang and Shen.)

Background: We investigated whether glycemic control affects the relation between endothelial dysfunction and coronary artery disease in patients with type 2 diabetes mellitus (T2DM)., Methods: In 102 type 2 diabetic patients with stable angina, endothelial function was evaluated using brachial artery flow-mediated dilation (FMD) with high-resolution ultrasound, and significant stenosis of major epicardial coronary arteries (≥ 50% diameter narrowing) and degree of coronary atherosclerosis (Gensini score and SYNTAX score) were determined. The status of glycemic control was assessed by blood concentration of glycated hemoglobin (HbA1c)., Results: The prevalence of significant coronary artery stenosis (67.9% vs. 37.0%, P = 0.002) and degree of coronary atherosclerosis (Gensini score: 48.99 ± 48.88 vs. 15.07 ± 21.03, P < 0.001; SYNTAX score: 15.88 ± 16.36 vs. 7.28 ± 10.54, P = 0.003) were higher and FMD was lower (6.03 ± 2.08% vs. 6.94 ± 2.20%, P = 0.036) in diabetic patients with poor glycemic control (HbA1c ≥ 7.0%; n = 56) compared to those with good glycemic control (HbA1c < 7.0%; n = 46). Multivariate regression analysis revealed that tertile of FMD was an independent determinant of presence of significant coronary artery stenosis (OR = 0.227 95% CI 0.056-0.915, P = 0.037), Gensini score (β =  - 0.470, P < 0.001) and SYNTAX score (β =  - 0.349, P = 0.004) in diabetic patients with poor glycemic control but not for those with good glycemic control (P > 0.05)., Conclusion: Poor glycemic control negatively influences the association of endothelial dysfunction and coronary artery disease in T2DM patients.

Background: Aortic valve sclerosis (AVSc), a common precursor to calcific aortic valve disease, may progress into advanced aortic stenosis with hemodynamic instability. However, plasma biomarkers of such a subclinical condition remain lacking. Since impaired fibrinolysis featuring dysregulated tissue plasminogen activator (t-PA) is involved in several cardiovascular diseases, we investigated whether endogenous t-PA was also associated with AVSc. Methods: Plasma t-PA levels were measured in 295 consecutive patients undergoing standard echocardiography and Doppler flow imaging. Multiple logistic regression analyses were used to assess the association between t-PA and AVSc. Receiver operating characteristic curve analysis was performed for determining the diagnostic value of t-PA for AVSc. The performance of adding t-PA to clinical signatures of AVSc was evaluated. Concentration of t-PA was assessed in human sclerotic and non-sclerotic aortic valves by histology and immunohistochemistry analysis. Results: Plasma t-PA was higher in patients with AVSc than in non-AVSc counterparts (median, 2063.10 vs. 1403.17 pg/mL, p < 0.01). C-statistics of plasma t-PA for discriminating AVSc was 0.698 (95%CI: 0.639-0.758). The performance of t-PA for identifying AVSc was better among male and non-hypertensive patients [C-statistics (95%CI): 0.712 (0.634-0.790) and 0.805 (0.693-0.916), respectively]. Combination of t-PA and clinical factors improved classification of the patients (category-free NRI: 0.452, p < 0.001; IDI: 0.020, p = 0.012). The concentration of t-PA was three times higher in sclerotic compared to non-sclerotic aortic valves. Conclusion: Elevated circulating t-PA level confers an increased risk for AVSc. Further prospective studies with larger sample size are needed to examine if t-PA could serve as a diagnostic clinical marker for AVSc., (Copyright © 2020 Chen, Shen, Xue, Lin, He, Zhang, Yang, Shen, Liu and Yang.)

Background: Patients with type 2 diabetes are under substantially higher risk of in-stent restenosis (ISR) after coronary stent implantation. We sought to investigate whether visit-to-visit HbA 1c variability is a potential predictor of ISR in diabetic patients after stent implantation., Methods: We consecutively enrolled type 2 diabetic patients who underwent successful elective percutaneous coronary intervention and performed follow-up coronary angiography after around 12 months. The incidence of ISR and its relationship with visit-to-visit HbA 1c variability, expressed as coefficient of variation (CV), standard deviation (SD) and variability independent of the mean (VIM), were studied. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of HbA 1c variability for ISR., Results: From September 2014 to July 2018 in Ruijin Hospital, a total of 420 diabetic patients (688 lesions) after stent implantation were included in the final analysis. During a mean follow-up of 12.8 ± 1.3 months, the incidence of ISR was 8.6%, which was significantly increased in patients with higher CV of HbA 1c (P = 0.001). The mean diameter stenosis (DS), net luminal loss and net luminal gain were 22.9 ± 16.8%, 0.42 ± 0.88 mm and 1.66 ± 0.83 mm, respectively. Greater DS was observed in subjects with higher tertiles of CV of HbA 1c (P < 0.001), and this trend was more prominent in patients with optimal glycemic control (HbA 1c  ≤ 7%) in the baseline. In multivariate analysis, HbA 1c variability was independently associated with incidence of ISR after adjustment for traditional risk factors and mean HbA 1c (HR: 3.00 [95% CI 1.14-7.92] for highest vs. lowest tertile). Inclusion of CV of HbA 1c led to a better risk stratification accuracy. Assessing HbA 1c variability by SD or VIM yielded similar findings., Conclusions: This study suggests that visit-to-visit HbA 1c variability is an independent predictor of incidence of ISR in patients with type 2 diabetes after stent implantation. Trial registration NCT02089360: NCT.

Background: Patients with type 2 diabetes mellitus (T2DM) are predisposed to poor cardiovascular outcomes after ST-segment elevation myocardial infarction (STEMI). Left ventricular adverse remodeling (LVAR) triggered upon myocardial infarction is recognized as the predominant pathological process in the development of heart failure. In the present study, we sought to investigate whether visit-to-visit fasting plasma glucose (FPG) variability is a potential predictor of LVAR in T2DM patients after STEMI., Methods: From January 2014 to December 2018 in Ruijin Hospital, T2DM patients with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for ~ 12 months. The changes in left ventricular geometric and functional parameters between baseline and 12-month follow-up were assessed by echocardiography. The incidence of LVAR, defined as 20% increase in indexed left ventricular end-diastolic volume (LVEDV), and its relationship with visit-to-visit FPG variability were analyzed. Multivariate regression models were constructed to test the predictive value of FPG variability for post-infarction LVAR., Results: A total of 437 patients with type 2 diabetes and STEMI were included in the final analysis. During a mean follow-up of 12.4 ± 1.1 months, the incidence of LVAR was 20.6% and mean enlargement of indexed LVEDV was 3.31 ± 14.4 mL/m 2 , which was significantly increased in patients with higher coefficient variance (CV) of FPG (P = 0.002) irrespective of baseline glycemic levels. In multivariate analysis, FPG variability was independently associated with incidence of post-infarction LVAR after adjustment for traditional risk factors, baseline HbA1c as well as mean FPG during follow-up (OR: 3.021 [95% CI 1.081-8.764] for highest vs. lowest tertile of CV of FPG). Assessing FPG variability by other two measures, including standard deviation (SD) and variability independent of the mean (VIM), yielded similar findings., Conclusions: This study suggests that visit-to-visit FPG variability is an independent predictor of incidence of LVAR in T2DM patients with STEMI. Trial registration Trials number, NCT02089360; registered on March 17,2014.

Background: To assess the prognostic role of coronary collaterals in patients with type 2 diabetes mellitus (T2DM) after successful percutaneous coronary intervention (PCI) for chronic total occlusion (CTO)., Methods: Coronary collateralization was graded according to Rentrop scoring system in 198 type 2 diabetic patients and 335 non-diabetics with stable angina undergoing PCI for at least one CTO lesion. Left ventricular ejection fraction (LVEF) was determined and major adverse cardio-cerebral events (MACCE) were recorded during follow-up., Results: Poor collateralization was more common in patients with T2DM than in non-diabetics (40% vs 29%, p = 0.008). At 13.5 ± 4.1 months, the rate of composite MACCE (17.3% vs 27.6%, p = 0.034) and repeat revascularization (15.2% vs 25.5%, p = 0.026) was lower and the increase in LVEF (3.10% vs 1.80%, p = 0.024) was greater in patients with good collaterals than in those with poor collaterals for non-diabetic group. The associations were in the same direction for T2DM group (35% vs 44%; 30% vs 36%; 2.14% vs 1.65%, respectively) with a higher all-cause mortality in diabetic patients with poor collaterals (p = 0.034). Multivariable Cox proportional hazards analysis showed that coronary collateralization was an independent factor for time to MACCE (HR 2.155,95% CI 1.290-3.599, p = 0.003) and repeat revascularization (HR 2.326, 95% CI 1.357-3.986, p = 0.002) in non-diabetic patients, but did not enter the model in those with T2DM., Conclusions: T2DM is associated with reduced coronary collateralization. The effects of the status of coronary collateralization on long-term clinical outcomes and left ventricular function appear to be similar in size in type 2 diabetic patients and non-diabetics after successful recanalization of CTO.

Background: Controversies exist regarding the optimal blood pressure (BP) level that is safe and provides cardiovascular protection in patients with type 2 diabetes mellitus (T2DM) and coexistent coronary artery disease. Several new glucose-lowering agents have been found to lower BP as well, making the interaction between BP and T2DM even more complex., Methods: With the reference to recent literature, this review article describes the potential mechanisms of increased risk of hypertension in T2DM and outlines the possible optimal BP levels based upon recommendations on the management of hypertension by the current guidelines, in combination with our research findings, for type 2 diabetic patients with coronary artery disease., Results: The development of hypertension in T2DM involves multiple processes, including enhanced sympathetic output, inappropriate activation of renin-angiotensin- aldosterone system, endothelial dysfunction induced through insulin resistance, and abnormal sodium handling by the kidney. Both AGE-RAGE axis and adipokine dysregulation activate intracellular signaling pathways, increase oxidative stress, and aggravate vascular inflammation. Pancreatic β-cell specific microRNAs are implicated in gene expression and diabetic complications. Non-pharmacological intervention with lifestyle changes improves BP control, and anti-hypertensive medications with ACEI/ARB, calcium antagonists, β-blockers, diuretics and new hypoglycemic agent SGLT2 inhibitors are effective to decrease mortality and prevent major adverse cardiovascular events. For hypertensive patients with T2DM and stable coronary artery disease, control of BP < 130/80 mmHg but not < 120/70 mmHg is reasonable, whereas for those with chronic total occlusion or acute coronary syndromes, an ideal BP target may be somewhat higher (< 140/90 mmHg). Caution is advised with aggressive lowering of diastolic BP to a critical threshold (< 60 mmHg)., Conclusions: Hypertension and T2DM share certain similar aspects of pathophysiology, and BP control should be individualized to minimize adverse events and maximize benefits especially for patients with T2DM and coronary artery disease.

In the present study, a hypoxia/reoxygenation (H/R) model of cardiomyocytes was established to investigate the effects of long non-coding RNA (LncRNA) Nuclear Enriched Abundant Transcript 1 (NEAT1) and microRNA (miR)-520a on H/R-induced cardiomyocyte apoptosis. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were used to evaluate cell apoptosis. Luciferase activity assay was used to investigate whether miR-520a targets NEAT1. Results revealed that NEAT1 was significantly upregulated and miR-520a was downregulated in the ischemia/reperfusion myocardium and the cardiomyocytes that received H/R treatment. Further study demonstrated that knockdown of NEAT1 and overexpression of miR-520a serves a protective role against H/R-induced cardiomyocyte apoptosis. miR-520a directly targets NEAT1 and its expression level is negatively correlated with that of NEAT1. The findings suggested that NEAT1 and miR-520a may protect cardiomyocytes from apoptosis through regulating apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein, and altering cleaved caspase3 expression levels.

Aberrant changes in endothelial phenotype and morphology are considered to be initial events in the pathogenesis of atherosclerosis. Direct observation of the intact endothelium will provide valuable information for understanding the cellular and molecular events in the dysfunctional endothelial cells. Here, we describe a modified en face immunofluorescence staining technique which enables scientists to obtain clear images of the intact endothelial surface and analyze the molecule expression patterns in situ. The method is simple and reliable for observing the entire endothelial monolayer at different sites of the aorta. This technique may be a promising tool for understanding the pathophysiology of atherosclerosis, especially at an early stage.

Background: Adverse cardiac remodeling after ST-segment elevation myocardial infarction (STEMI) is a major cause for poor cardiovascular outcomes such as heart failure. The predisposing factors and underlying mechanisms remain not fully understood. This study investigates the association of insulin resistance and dysglycemia with left ventricular (LV) remodeling after STEMI in non-diabetic patients., Methods: A total of 485 non-diabetic subjects with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for 12 months. Relation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and glucose levels to changes in echocardiography parameters was studied., Results: Left ventricular dilation was detected in 49.1% of subjects at 12-month follow-up after STEMI, and was more severe in subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and high HOMA-IR levels. HOMA-IR remained correlated to changes in LV dimensions after adjusting for confounding risk factors. Multivariate regression analysis demonstrated that higher HOMA-IR was independently associated with greater LV dilation after STEMI. A significant interaction term was present between HOMA-IR and IGT in the model (P = 0.001)., Conclusions: Our study reveals that insulin resistance and dysglycemia are prevalent in non-diabetic patients with STEMI and are predictors of the post-infarction LV dilation. Trial registration Trials number, NCT02089360; registered on March 17, 2014.

Background: We investigated whether or to what extent the interaction of lipoprotein (a) [Lp(a)] with cholesterol-containing lipids was associated with angiographic coronary collateralization in type 2 diabetic patients with chronic total occlusion., Methods: Serum levels of Lp(a), total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and triglyceride were determined and non-HDL-C was calculated in 706 type 2 diabetic and 578 non-diabetic patients with stable coronary artery disease and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3)., Results: For diabetic and non-diabetic patients, Lp(a), total cholesterol, LDL-C, and non-HDL-C levels were higher in patients with poor coronary collateralization than in those with good collateralization, whereas HDL-C and triglyceride levels were similar. After adjustment for potential confounding factors, tertiles of Lp(a), total cholesterol, LDL-C and non-HDL-C remained independent determinants for poor collateralization. A significant interaction between Lp(a) and total cholesterol, LDL-C or non-HDL-C was observed in diabetic patients (all P interaction < 0.001) but not in non-diabetics. At high tertile of total cholesterol (≥ 5.35 mmol/L), LDL-C (≥ 3.36 mmol/L) and non-HDL-C (≥ 4.38 mmol/L), diabetic patients with high tertile of Lp(a) (≥ 30.23 mg/dL) had an increased risk of poor collateralization compared with those with low tertile of Lp(a) (< 12.66 mg/dL) (adjusted OR = 4.300, 3.970 and 4.386, respectively, all P < 0.001)., Conclusions: Increased Lp(a) confers greater risk for poor coronary collateralization when total cholesterol, LDL-C or non-HDL-C are elevated especially for patients with type 2 diabetes.

Purpose: The present study aimed to investigate the relationship between serum levels of secretory vimentin and coronary artery disease (CAD). The biological effect of secretory vimentin was ascertained by experiments., Methods: We analysed serum levels of secretory vimentin in CAD patients (n = 288) and non-CAD controls (n = 195) by ELISA. To evaluate the pro-inflammatory effects of secreted vimentin, the human aortic endothelial cells (HAECs) and human peripheral blood mononuclear cells (PBMCs) were treated with recombinant vimentin or saline. Intraperitoneal injection of vimentin (1 μg/each) or saline was performed every other day for 12 weeks in ApoE -/- mice for assessment of atherogenic effect., Results: Serum levels of secretory vimentin were significantly increased in CAD patients than in health controls (p < 0.05), and correlated with the number of diseased coronary arteries, Syntax and Gensini score (for all comparison, p < 0.01). Logistic regression analysis showed that vimentin level is an independent determinant of CAD. In experiments, recombinant vimentin protein enhanced the expression of adhesion molecules and inflammatory cytokines in both endothelial cells and macrophages. This protein also promoted macrophage-endothelial cells adhesion in vitro and the recruitment of leukocytes to mesenteric venules in C57BL/6 mice. Compared with saline, intraperitoneal injection of recombinant vimentin (1 μg/each) every other day induced atherogenesis in ApoE -/- mice at 12-weeks, with significant increase of inflammatory cytokine and adhesion molecules expression in aortic tissue (p < 0.05)., Conclusion: Serum vimentin levels are associated with the presence and the severity of CAD. Vimentin protein promotes atherogenesis in ApoE -/- mice., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

High-density lipoprotein (HDL) confers protection against cardiovascular disease partly attributable to its robust anti-oxidant activities, which is largely impaired in diabetic conditions. In this study, we analyzed the anti-oxidant activity of HDL, as represented by the arylesterase activity of paraoxonase 1 (PON1) in HDL particles, in 216 consecutive HF patients with (n = 79) or without (n = 137) type 2 diabetes, and age- and gender-matched 112 diabetic and 189 non-diabetic non-HF controls. We found arylesterase activity was significantly decreased in patients with than without HF, and was further decreased when comorbid with diabetes. After adjusting for conventional risk factors and apolipoprotein A-I levels, arylesterase activity remained correlated positively with left ventricular ejection fraction in diabetic (r = 0.325, P = 0.020) but not non-diabetic patients (r = 0.089, P = 0.415), and negatively with NT-proBNP and NYHA functional class in both subgroups. In regression analyses, a higher risk of HF was observed in diabetic than non-diabetic patients when having low arylesterase activities. In conclusion, our data demonstrate that impaired serum arylesterase activity in patients with HF is further reduced when comorbid with diabetes. The relationship of impaired arylesterase activity to HF is especially enhanced in diabetic patients.

Background: Chronic inflammatory disorders and dyslipidemia in type 2 diabetes mellitus (T2DM) are essential contributors to the development of atherosclerotic cardiovascular disease. Monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) is a novel and simple measure associated positively with the body inflammatory and oxidative stress status. However, little is known regarding the role of MHR in evaluating carotid intima-media thickness (CIMT), a surrogate predictor of subsequent vascular events, especially in diabetic patients. Methods: A total of 494 patients with T2DM and 1,848 non-diabetic subjects were consecutively enrolled in study 1. Correlation between MHR and CIMT was compared between diabetic and non-diabetic subjects. In study 2, a total of 110 T2DM patients from study 1 with normal basal CIMT and a follow-up ultrasonography at 12 months were enrolled. The predictive role of MHR on CIMT progression in diabetic patients was analyzed. Results: In study 1, MHR was higher in patients with T2DM than non-diabetic subjects ( p < 0.001). After adjustment for confounding risk factors, MHR remained correlated significantly with CIMT in diabetic ( r = 0.172, p = 0.001) but not non-diabetic ( r = 0.006, p = 0.813) subjects. Logistic regression analyses demonstrated that MHR is superior to traditional lipid parameters in association with elevated CIMT in diabetic patients. In study 2, MHR at baseline was positively correlated with change in CIMT ( r = 0.313, p = 0.001). Basal MHR was independently associated with change in CIMT [β = 0.059, (95% CI: 0.012-0.105), p = 0.014] in multivariate linear regression analysis. Conclusions: Our study suggests that MHR is a convenient and effective measure in prediction of the presence and progression of subclinical carotid atherosclerosis in patients with T2DM.

Background: Negative coronary artery remodeling is frequent in patients with diabetes, but its mechanism remains unclear. We here evaluated the association of serum levels of glycated albumin (GA) and endogenous secretory receptor for advanced glycation end products (esRAGE) with coronary artery remodeling in type 2 diabetic patients., Methods: Serum levels of GA and esRAGE were measured and intravascular ultrasound was performed in 136 consecutive diabetic patients with 143 coronary intermediate lesions. The remodeling index (RI) was calculated as the ratio between external elastic membrane (EEM) area at the lesion site and EEM area at the reference segment. Negative remodeling (NR) was defined as an RI < 0.95 and intermediate or positive remodeling as an RI ≥ 0.95., Results: Mean plaque burden at the lesion site was 70.96 ± 9.98%, and RI was 0.96 ± 0.18. Negative coronary arterial remodeling existed in 81 (56.6%) lesions. RI correlated closely with serum esRAGE level (r = 0.236, P = 0.005) and was inversely related to serum GA level (r = - 0.240, P = 0.004) and plasma low-density lipoprotein cholesterol (LDL-C) (r = - 0.206, P = 0.014) and total cholesterol levels (r = - 0.183, P = 0.028). Generalized estimating equations logistic regression analysis identified esRAGE (OR 0.037; 95% CI 0.012-0.564, P = 0.021), GA (OR 1.093; 95% CI 1.013-1.179, P = 0.018) and LDL-C (OR 1.479; 95% CI 1.072-2.835, P = 0.023) as independent predictors for negative remodeling., Conclusions: In diabetic patients, negative coronary artery remodeling is associated with increased GA and decreased esRAGE levels in serum.

Background and Aims: Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined., Methods: Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo., Results: We found CTRP5 serum levels were higher in patients with than without CAD (247.26 ± 61.71 vs. 167.81 ± 68.08 ng/mL, p < 0.001), and were positively correlated with the number of diseased vessels (Spearman's r = 0.611, p < 0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis., Conclusions: These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dengue fever is caused by four different serotypes of dengue virus (DENV) which is the leading cause of worldwide arboviral diseases in humans. Virus-like particles (VLPs) containing flavivirus prM/E proteins have been demonstrated to be a potential vaccine candidate; however, the structure of dengue VLP is poorly understood. Herein VLP derived from DENV serotype-2 were engineered becoming highly matured (mD2VLP) and showed variable size distribution with diameter of ~31 nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31 nm diameter possess a T = 1 icosahedral symmetry with a groove located within the E-protein dimers near the 2-fold vertices that exposed highly overlapping, cryptic neutralizing epitopes. Mice vaccinated with mD2VLP generated higher cross-reactive (CR) neutralization antibodies (NtAbs) and were fully protected against all 4 serotypes of DENV. Our results highlight the potential of 'epitope-resurfaced' mature-form D2VLPs in inducing quaternary structure-recognizing broad CR NtAbs to guide future dengue vaccine design., Competing Interests: WS, JG, JL, ML, CH, YW, HW, JL, YL, MW, GC, SC, SW, DC No competing interests declared

Background: We investigated whether and to what extent stenosis of predominant collateral donor artery (PCDA) affects coronary collateral flow in relation to blood pressure (BP) in type 2 diabetic patients with chronic total occlusion (CTO)., Methods: Collateral flow index (CFI) as derived from intracoronary pressure distal to occluded segment and mean aortic pressure in 220 type 2 diabetic patients and 220 propensity score matched non-diabetic controls undergoing percutaneous coronary intervention for CTO. The severity of PCDA stenosis was graded according to lumen diameter narrowing., Results: CFI decreased stepwise from mild to severe stenosis of the PCDA and was lower in diabetic patients with moderate or severe PCDA stenosis than in non-diabetic controls (0.36 ± 0.10 vs. 0.45 ± 0.08, P < 0.001; 0.29 ± 0.09 vs. 0.35 ± 0.08, P = 0.008). When the PCDA was mildly stenotic, CFI increased initially along with a reduction in diastolic BP, and decreased when diastolic BP was below 60 mmHg in diabetic patients (0.38 ± 0.16 vs. 0.57 ± 0.09, P < 0.001). In the presence of moderate PCDA stenosis, diabetic patients had significantly lower CFI compared to non-diabetic controls, with a relative reduction of 19.8% at diastolic BP 70-79 mmHg, 28.2% at 60-69 mmHg and 38.2% below 60 mmHg (all P < 0.05). A severe PCDA stenosis resulted in a more pronounced decrease in CFI, with a relative reduction of 37.3% for diabetics compared to non-diabetics when diastolic BP was below 60 mmHg (P = 0.050)., Conclusions: In the setting of CTO, donor artery stenosis confers greater risk for reduced coronary collateral flow when diastolic BP is decreased. Even a moderate stenosis in the PCDA may be associated with lower collateral flow as diastolic BP decreases below 80 mmHg in type 2 diabetic than in non-diabetic patients.

Background: The extent of coronary collateral formation is a primary determinant of the severity of myocardial damage and mortality after coronary artery occlusion. Type 2 diabetes mellitus (T2DM) represents an important risk factor for impaired collateral vessel growth. However, the mechanism of reduced coronary collateralization in type 2 diabetic patients remains unclear., Methods: With the reference to the recent researches, this review article describes the pathogenic effects of T2DM on collateral development and outlines possible clinical and biochemical markers associated with reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion (CTO)., Results: Diffuse coronary atherosclerosis in T2DM reduces pressure gradient between collateral donor artery and collateral recipient one, limiting collateral vessel growth and function. An interaction between advanced glycation end-products and their receptor activates several intracellular signaling pathways, enhances oxidative stress and aggravates inflammatory process. Diabetic condition decreases pro-angiogenic factors especially vascular endothelial growth factor and other collateral vessel growth related parameters. Numerous clinical and biochemical factors that could possibly attenuate the development of coronary collaterals have been reported. Increased serum levels of glycated albumin, cystatin C, and adipokine C1q tumor necrosis factor related protein 1 were associated with poor coronary collateralization in type 2 diabetic patients with stable coronary artery disease and CTO. Diastolic blood pressure and stenosis severity of the predominant collateral donor artery also play a role in coronary collateral formation., Conclusions: T2DM impairs collateral vessel growth through multiple mechanisms involving arteriogenesis and angiogenesis, and coronary collateral formation in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. This information provides insights into the understanding of coronary pathophysiology and searching for potential new therapeutic targets in T2DM.

The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6-positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6-positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment., Conclusion: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934-1951)., (© 2017 by the American Association for the Study of Liver Diseases.)