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Acute lung injury (ALI), with high morbidity and mortality, is mainly resulted by infectious or non-infectious inflammatory stimulators, and it will further evolve into acute respiratory distress syndrome if not controlled. Fibroblast growth factors (FGFs) consist of more than 23 kinds of members, which are involved in various pathophysiological processes of body. However, the effect of FGF5, one member of FGFs, is still not certain in lipopolysaccharide (LPS)-induced ALI. In this study, we explored the possible impacts of FGF5 in LPS-induced ALI and primarily focused on endothelial cell, which was one of the most vulnerable cells in septic ALI. In the mouse group of FGF5 overexpression, LPS-induced lung injuries were mitigated, as well as the pyroptosis levels of pulmonary vascular endothelial cells. Additionally, in vitro human umbilical vein endothelial cells (HUVECs), our results showed that the level of cell pyroptosis was ameliorated with FGF5 overexpression, and AKT signal was activated with the overexpression of FGF5, whereas after administration of MK2206, an inhibitor of AKT signal, the protection of FGF5 was inhibited. Therefore, these results suggested that FGF5 exerted protective effects in endothelial cells exposed to LPS, and this protection of FGF5 could be attributed to activated AKT signal.

Sepsis accompanied by myocardial injury is an important cause of multiple organ dysfunction, and its underlying molecular mechanism is not fully clear. Although diverse effects of fibroblast growth factor (FGF) in heart have been discovered till now, the specific role of FGF5 in heart remains unclear. Therefore, our study aims to explore the possible impacts of FGF5 on sepsis-induced cardiac injury. Sepsis-induced cardiac injury was established through administration of lipopolysaccharide (LPS). The expression level of FGF5 in sepsis heart was decreased, and injection of FGF5-overexpressing adenovirus attenuated cardiac injury reflected by echocardiographic and pathological findings. Besides, FGF5 overexpression, not only in vivo heart but also in vitro cardiomyocytes, reduced the levels of oxidative stress and pyroptosis resulted from LPS. In addition, overexpression of FGF5 reduced LPS-activated the levels of phosphorylated CaMKII (p-CaMKII), p-NFκB, NLRP3, caspase-1, IL-1β and IL-18. Furthermore, KN93, the inhibitor of CaMKII, exerted the similarly protective effects on LPS-induced pyroptosis. In summary, our study implied the beneficial effects of FGF5 on LPS-induced cardiac injury, which was at least partially attributed to the inhibition of CaMKII-mediated pyroptotic signaling.

Increasing evidence has shown that vascular aging has a key role in the pathogenesis of vascular diseases. P300/CBP-associated factor (PCAF) is involved in many vascular pathological processes, but the role of PCAF in vascular aging is unknown. This study aims to explore the role and underlying mechanism of PCAF in vascular aging. The results demonstrated that the expression of PCAF was associated with age and aging, and remarkably increased expression of PCAF was present in human atherosclerotic coronary artery. Downregulation of PCAF could reduce angiotensin II (AngII)-induced senescence of rat aortic endothelial cells (ECs) in vitro. In addition, inhibition of PCAF with garcinol alleviated AngII-induced vascular senescence phenotype in mice. Downregulation of PCAF could alleviate AngII-induced oxidative stress injury in ECs and vascular tissue. Moreover, PCAF and nuclear factor erythroid-2-related factor 2 (Nrf2) could interact directly, and downregulation of PCAF alleviated vascular aging by promoting the activation of Nrf2 and enhancing the expression of its downstream anti-aging factors. The silencing of Nrf2 with small interfering RNA attenuated the protective effect of PCAF downregulation from vascular aging. These findings indicate that downregulation of PCAF alleviates oxidative stress by activating the Nrf2 signaling pathway and ultimately inhibits vascular aging. Thus, PCAF may be a promising target for aging-related cardiovascular disease.

Early screening based on computed tomography (CT) pulmonary nodule detection is an important means to reduce lung cancer mortality, and in recent years three dimensional convolutional neural network (3D CNN) has achieved success and continuous development in the field of lung nodule detection. We proposed a pulmonary nodule detection algorithm by using 3D CNN based on a multi-scale attention mechanism. Aiming at the characteristics of different sizes and shapes of lung nodules, we designed a multi-scale feature extraction module to extract the corresponding features of different scales. Through the attention module, the correlation information between the features was mined from both spatial and channel perspectives to strengthen the features. The extracted features entered into a pyramid-similar fusion mechanism, so that the features would contain both deep semantic information and shallow location information, which is more conducive to target positioning and bounding box regression. On representative LUNA16 datasets, compared with other advanced methods, this method significantly improved the detection sensitivity, which can provide theoretical reference for clinical medicine.基于电子计算机断层扫描（CT）的肺结节检测的早期筛查是降低肺癌死亡率的重要手段，而近年来三维卷积神经网络（3D CNN）已经在肺结节检测领域取得了成功并不断深入发展。本文提出了一种基于多尺度注意力机制的3D CNN肺结节检测算法。针对肺结节大小和形状各异的特点，设计了一个多尺度的特征提取模块，提取不同尺度的相应特征。通过注意力模块，从空间和通道两个角度挖掘特征间的关联信息，对特征加强。提取出的特征进入类似金字塔的融合机制，使得特征中同时包含深层的语义信息与浅层的位置信息，更利于目标定位与边界框回归。在具有代表性的LUNA16数据集上，相对于目前先进的其他方法，本文方法能够明显地提高检测灵敏度，可为临床医学提供理论参考。.

Y-chromosome short tandem repeat (Y-STR) and Y-chromosome single nucleotide polymorphism (Y-SNP) are genetic markers on the male Y chromosome for individual identification, forensic applications, and paternal genetic history analysis. In this study we successfully genotyped 38 Y-STR loci and 24 Y-SNP loci of Pudong Han (n = 689) and Chongming Han (n = 530) in Shanghai. The haplotype diversity of the Y filer platinum genotyping system was the highest in the Han population in the Pudong area of Shanghai (0.99996) and Chongming Island (0.99997). The proportion of unique haplotypes was 97.10% (Pudong) and 98.49% (Chongming), respectively. The multidimensional scaling analysis and phylogenetic analysis were performed according to the genetic distance Rst, which was calculated based on the Y-STR gene frequency data. Moreover, we made a comparison on the frequency distribution analysis and principal component analysis of haplogroups in both populations. As a result, Shanghai Pudong Han, Chongming Island Han, and Jiangsu Han were determined to have a strong genetic affinity. The haplogroup distribution characteristics of the Pudong Han and Chongming Han populations were similar to those of the southern Han population. The results of haplotype network analysis showed that Jiangsu Wujiang Han and Jiangsu Changshu Han had more paternal genetic contributions to the formation of Shanghai Pudong Han and Chongming Island Han. Through the joint analysis of SNPs and STRs, this study deeply analyzed the paternal genetic structure of the Pudong Han and Chongming Han populations. The addition of Y-SNP haplogroups to forensic applications can provide information for pedigree investigation.

Motivation With the breakthrough of AlphaFold2, the protein structure prediction problem has made remarkable progress through deep learning end-to-end techniques, in which correct folds could be built for nearly all single-domain proteins. However, the full-chain modelling appears to be lower on average accuracy than that for the constituent domains and requires higher demand on computing hardware, indicating the performance of full-chain modelling still needs to be improved. In this study, we investigate whether the predicted accuracy of the full-chain model can be further improved by domain assembly assisted by deep learning. Results In this article, we developed a structural analogue-based protein structure domain assembly method assisted by deep learning, named SADA. In SADA, a multi-domain protein structure database was constructed for the full-chain analogue detection using individual domain models. Starting from the initial model constructed from the analogue, the domain assembly simulation was performed to generate the full-chain model through a two-stage differential evolution algorithm guided by the energy function with an inter-residue distance potential predicted by deep learning. SADA was compared with the state-of-the-art domain assembly methods on 356 benchmark proteins, and the average TM-score of SADA models is 8.1% and 27.0% higher than that of DEMO and AIDA, respectively. We also assembled 293 human multi-domain proteins, where the average TM-score of the full-chain model after the assembly by SADA is 1.1% higher than that of the model by AlphaFold2. To conclude, we find that the domains often interact in the similar way in the quaternary orientations if the domains have similar tertiary structures. Furthermore, homologous templates and structural analogues are complementary for multi-domain protein full-chain modelling. Availability and implementation http://zhanglab-bioinf.com/SADA Supplementary information Supplementary data are available at Bioinformatics online.

Background. Atrial fibrillation (AF) is the most common arrhythmia in the world. Long noncoding RNA (lncRNA) has been found to play an important role in cardiovascular diseases including heart failure, myocardial infarction, and atherosclerosis. However, the role of lncRNA in AF has rarely been studied. The purpose of this study is to identify the expression profile of lncRNA in AF patients, explore the function of lncRNA in AF, and provide a potential scientific basis for the treatment of AF in the future. Methods. The lncRNA and mRNA expression profiles were obtained from the atrial appendage samples of GSE31821, GSE411774, GSE79768, and GSE115574 in the Gene Expression Omnibus (GEO) database. Functional analysis was performed via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Variation Analysis (GSVA). The “CIBERSORT” R kit was used to analyze 22 immune cell infiltrates in AF and sinus rhythm (SR) patients. The “CORRPLOT” R package was used to analyze the immune correlation between lncRNA and immune cells. Results. A total of 6 differentially expressed lncRNAs and 45 differentially expressed mRNAs were identified in the AF and SR groups. GO, KEGG, and GSVA results showed that abnormally expressed lncRNAs were involved in signaling pathways related to the atrium, including the Toll-like receptor signaling pathway and calcium signaling pathway. Immune cell infiltration analysis revealed that native B cells, follicular helper T cells, and resting dendritic cells may be involved in the AF process. In addition, LINC00844 was negatively correlated with resting dendritic cells. Conclusion. The expression profile of lncRNA in AF patients was different from that in normal controls. The physiological functions of these differentially expressed lncRNAs may be related to the pathogenesis of AF, which provide a scientific basis for the prognosis and treatment of patients with AF.

Patients with myocardial ischemic diseases or who are undergoing one of various heart treatments, such as open heart surgery, coronary artery bypass grafting, percutaneous coronary artery intervention or drug thrombolysis, face myocardial ischemia-reperfusion injury (MIRI). However, no effective treatment is currently available for MIRI. To improve the prognosis of people with cardiovascular disease, it is important to research the mechanism of MIRI. Arachidonic acid (AA) is one of the focuses of current research. The various metabolic pathways of AA are closely related to the development of cardiovascular disease, and the roles of various metabolites in ischemia-reperfusion injury have gradually been confirmed. AA is mainly metabolized in the cyclooxygenase (COX) pathway, lipoxygenase (LOX) pathway, and cytochrome P450 monooxygenase (CYP) pathway. This paper summarizes the progress of research on these three major AA metabolic pathways with respect to MIRI.

Acetylation is one of the most important methods of modification that lead to a change in the function of proteins. In humans, metabolic enzymes commonly undergo acetylation, which regulates the activities of metabolic enzymes and metabolic pathways. Sirtuin 3 (SIRT3) is a prominent deacetylase that participates in mitochondrial metabolism, redox balance, and mitochondrial dynamics by regulating mitochondrial protein acetylation, thereby protecting mitochondria from damage. Normal mitochondrial function is essential for maintaining the metabolism and function of the heart. Therefore, mitochondrial dysfunction caused by SIRT3 consumption and defects leads to the development of a variety of cardiovascular diseases. A comprehensive understanding of the role of SIRT3 in cardiovascular disease is critical for developing new therapeutic strategies. Herein, we summarize the function of SIRT3 in mitochondria, the complex mechanisms mediating cardiovascular diseases, and the potential value of SIRT3 small-molecule agonists in future clinical treatments.

N‐methyl‐D‐aspartate (NMDA) receptors mediate excitatory neurotransmission in the nervous system and are preferentially inhibited by general anesthetics such as sevoflurane. Spontaneous movement is a common complication during sevoflurane anesthesia induction and seriously affects operations. In this study, we investigated the relationship between NMDA polymorphisms and spontaneous movement during sevoflurane induction. This prospective clinical study enrolled 393 patients undergoing sevoflurane anesthesia as part of their surgical routine. In the GRIN1, GRIN2A, and GRIN2B genes, 13 polymorphisms that form a heteromeric complex as part of the NMDA receptor were selected using Haploview and genotyped using matrix‐assisted laser desorption ionization–time of flight mass spectrometry MassARRAY. Both RNAfold and Genotype‐Tissue Expression portals were used to identify gene expression profiles. Our data showed that 35.8% of subjects exhibited spontaneous movement. The GRIN2A rs12918566 polymorphism was associated with spontaneous movement during sevoflurane induction. A logistic regression analysis of additive, dominant, and recessive models indicated a significant association (odds ratio [OR] (95% confidence limit [CI]): 0.58 (0.42–0.80), p = .00086; OR (95% CI): 0.51 (0.31–0.84), p = .0075, and OR (95% CI): 0.47 (0.27–0.81), p = .0060, respectively). After false discovery rate (FDR) correction, the additive model was still significant with a P FDR =0.010. Bioinformatics demonstrated that the rs12918566 genomic variation affected GRIN2A expression in brain tissue. We also revealed that GRIN2A rs12918566 was significantly associated with spontaneous movement during sevoflurane induction. We believe the NMDA receptor plays an important role in regulating the anesthetic effects of sevoflurane., The present study revealed that GRIN2A rs12918566 was significantly correlated with spontaneous movement during sevoflurane anesthesia induction, and this locus can significantly affect the expression of GRIN2A. Suggested NMDA receptor plays an important role in regulating anesthetic effect of sevoflurane.

CD137 (4‐1BB, tumor necrosis factor receptor superfamily 9) is a surface glycoprotein of the tumor necrosis factor receptor family that can be induced on a variety of immunocytes and nonimmune cells, including endothelial cells and smooth muscle cells. The importance of CD137 in immune response has been well recognized; however, the precise biological effects and underlying mechanisms of CD137 in endothelial cells are unclear. A single layer of cells called the endothelium constitutes the innermost layer of blood vessels including larger arteries, veins, the capillaries, and the lymphatic vessels. It not only acts as an important functional interface, but also participates in local inflammatory response. This review covers recent findings to illuminate the role of CD137 in endothelial cells in different pathophysiologic settings.

Background Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS). Objectives This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A. Methods Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure. Results The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%. Conclusions These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.

Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features, which may be deteriorated in patients with cancer. However, cardiac outcomes of cancer patients with COVID-19 have not been closely examined. We retrospectively assessed 1,244 patients with COVID-19 from February 1 to August 31, 2020 (140 cancer and 1,104 noncancer patients). Demographic and clinical data were obtained and compared between cancer and noncancer groups. Including the cardiac biomarkers, we also analyzed laboratory findings between these two groups. Risk factors for in-hospital mortality were identified by multivariable Cox regression models. For cancer group, 56% were in severe and critical status with more diabetes and immune deficiency, whereas the proportion was 10% for noncancer group. Patients with cancer had increased levels of leukocyte, neutrophil count, and blood urea nitrogen (BUN) (all P < 0.01), whereas lymphocyte count was significantly lower (P < 0.001). The most common solid tumor types were gastrointestinal cancer (26%), lung cancer (21%), and breast and reproductive cancer (both 19%). There is a rising for cardiac biomarkers, including pro-B-type natriuretic peptide (Pro-BNP), sensitive troponin I (cTnI), myoglobin (MYO), creatine kinase-MB (CK-MB), as well as D-Dimer in COVID-19 cancer population, especially in deceased subjects with cancer. The 30-day in-hospital mortality in cancer group was dramatically raised than that in noncancer group (12.9% vs. 4.0%, P < 0.01). In multivariable Cox regression models, fever, disease severity status, and underlying diseases were risk factors for mortality. COVID-19 patients with cancer relate to deteriorating conditions and poor cardiac outcomes accompanied by a high in-hospital mortality, which warrants more aggressive treatment. NEW & NOTEWORTHY Our study indicates that the 30-day mortality is higher in COVID-19 patients with cancer; more COVID-19 patients with cancer are in severe and critical status; age, respiratory rate, neutrophil count, AST, BUN, MYO, Pro-BNP, disease severity status, underlying diseases, and fever are risk factors for in-hospital mortality among COVID-19 cancer cases; COVID-19 patients with cancer display severely impaired myocardium, damaged heart function, and imbalanced homeostasis of coagulation; what is more, those with both cancer and CVD have more significantly increased Pro-BNP and D-Dimer level.

What is known and objective Sevoflurane is the most widely used volatile anaesthetic in clinical practice. It exhibits a hypnotic (unconsciousness) effect and causes a loss of reaction to noxious stimuli (immobility). However, to date, the mechanism of action of sevoflurane is poorly understood. In this study, we explored the effects of genetic variations on sevoflurane-induced hypnosis. Methods Sixty-six SNPs in 18 candidate genes were genotyped using MALDI-TOF MassARRAY in a discovery cohort containing 161 patients administered sevoflurane. Significant polymorphisms were assessed in a validation cohort containing 265 patients. Results and discussion Three polymorphisms (GRIN1 rs28681971, rs79901440 and CHRNA7 rs72713539) were significantly associated with the time to loss of consciousness in patients treated with sevoflurane in the discovery cohort; among them, GRIN1 rs28681971 showed a significant association even after false discovery rate (FDR) correction (pFDR = 0.039). Following the validation analysis, GRIN1 rs28681971 and rs79901440 showed statistical efficacy (pFDR = 0.027, 0.034). Combined assessments and meta-analysis of the results of the two cohorts indicated that the C carriers of rs28681971 and T carriers of rs79901440 in GRIN1 require a longer time to achieve unconsciousness. What is new and conclusion These findings suggest that GRIN1 polymorphisms are associated with sevoflurane-induced unconsciousness. Thus, the genotypes of GRIN1 may serve as novel and meaningful biomarkers for sevoflurane-induced unconsciousness.

Background Numerous studies have highlighted the crucial role of microRNA-145 (miR-145) in coronary atherosclerosis and myocardial ischemia reperfusion injury. However, effects of miR-145 on β-adrenergic signaling and cardiac remodeling in heart failure (HF) remains unclarified. Methods and results We established HF model in rats with left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD ligation, rats showed substantial aggravation of cardiac dilation and electrophysiological instability. Up-regulation of miR-145 ameliorated HF-induced myocardial fibrosis and prolonged action potential duration. Echocardiography revealed increased basal contractility and decreased left ventricular inner-diameter in miR-145 over-expressed heart, while cardiac response to β-adrenergic receptor (βAR) stimulation was reduced. Furthermore, miR-145 increased L-type calcium current (ICa) density while decreased ICa response to β-adrenergic stimulation with isoproterenol. The alterations in βAR signaling might be predominant due to miR-145-mediated activation of Akt/CREB cascades. At high frequency pacing, Ca2+ transient, cell shortening and frequency of Ca2+ waves were significantly improved in AD-miR-145 group. Western blotting revealed that increased expression of Cav1.2, Ca2+-ATPase, β2AR, GNAI3 and decreased level of CaMKII might be attributed to the cardioprotective effects of miR-145. Conclusion miR-145 effectively alleviates HF-related cardiac remodeling by improving cardiac dilation, fibrosis, intracellular Ca2+ mishandling and electrophysiological instability.

Diabetic cardiomyopathy (DCM) significantly increased the morbidity of heart failure in diabetic patients. Long-time oxidative stress is an indisputable contributor for DCM development. Apocynin (APO) has been suggested to be a potential drug against oxidative stress. The study aims to find out the effects of APO on DCM and the related mechanisms. Mice were randomly divided into four groups: control (CON), APO, DCM and DCM + APO. Echocardiography analyses, histological analyses, Western blot and RT-PCR were used to explore the roles and mechanisms of APO in DCM. Isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) were used for further confirming the APO treatment effects in vitro. Deteriorated cardiac function, enlarged cardiomyocytes, excess cardiac fibrosis and significant cardiac oxidative stress were observed in DCM group. However, APO treatment successfully improved cardiac function, decreased cardiac hypertrophy and fibrosis, and depressed oxidative stress. Mechanistically, APO treatment markedly suppressed apoptosis signal regulating kinase 1(ASK1)-p38/c-jun N-terminal kinase (JNK) signaling and reduced apoptosis. It also inhibited NRCM apoptosis and CF activation via depressing ASK1-p38/JNK signaling in vitro. Moreover, adenovirus-mediated ASK1 overexpression completely removed the protection of APO in vitro. In conclusion, APO treatment could effectively attenuate DCM-associated injuries in vivo and protect against high glucose-induced NRCM and CF injuries in vitro via suppressing ASK1-p38/JNK signaling. APO might be a potential ASK1 inhibitor for treating DCM.

Background COVID-19 is a respiratory infectious disease caused by SARS-CoV-2, and cardiovascular damage is commonly observed in affected patients. We sought to investigate the effect of SARS-CoV-2 infection on cardiac injury and hypertension during the current coronavirus pandemic. Study design and methods The clinical data of 366 hospitalized COVID-19-confirmed patients were analyzed. The clinical signs and laboratory findings were extracted from electronic medical records. Two independent, experienced clinicians reviewed and analyzed the data. Results Cardiac injury was found in 11.19% (30/268) of enrolled patients. 93.33% (28/30) of cardiac injury cases were in the severe group. The laboratory findings indicated that white blood cells, neutrophils, procalcitonin, C-reactive protein, lactate, and lactic dehydrogenase were positively associated with cardiac injury marker. Compared with healthy controls, the 190 patients without prior hypertension have higher AngⅡ level, of which 16 (8.42%) patients had a rise in blood pressure to the diagnostic criteria of hypertension during hospitalization, with a significantly increased level of the cTnI, procalcitonin, angiotensin-II (AngⅡ) than those normal blood pressure ones. Multivariate analysis indicated that elevated age, cTnI, the history of hypertension, and diabetes were independent predictors for illness severity. The predictive model, based on the four parameters and gender, has a good ability to identify the clinical severity of COVID-19 in hospitalized patients (area under the curve: 0.932, sensitivity: 98.67%, specificity: 75.68%). Conclusion Hypertension, sometimes accompanied by elevated cTnI, may occur in COVID-19 patients and become a sequela. Enhancing Ang II signaling, driven by SARS-CoV-2 infection, might play an important role in the renin-angiotensin system, and consequently lead to the development of hypertension in COVID-19.

Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2.

Background/Amis: Long non-coding RNAs (lncRNAs), a novel class of transcripts, have been shown to play critical roles in diverse cellular biological processes, including tumorigenesis. Small nucleolar RNA host gene 6 (SNHG6) regulates various biological processes in cancer cells. However, the biological role of SNHG6 in gastric cancer still remains to be explored. The aim of this study is to investigate the characteristic of the SNHG6 in gastric cancer. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of SNHG6 in gastric cancer tissues and cell lines. MTT assays, colony formation assays were used to determine the impact of SNHG6 on tumorigenesis . Flow cytometric analysis of cell cycle and apoptosis was performed to measure the effect of SNHG6 on cell cycle and apoptosis rate. Transwell assay was performed to measure the effect of SNHG6 on cell migration. Western blotting and immunofuorescence were utilized to examine the effect of SNHG6 on epithelial-mesenchymal transition (EMT) of GC cells. Chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), RNA-pulldown and luciferase reporter assays were employed to dissect molecular mechanisms. Results: In this study, we revealed that SNHG6 was overexpressed in gastric cancer tissues and cell lines. High expression levels of SNHG6 wereassociated with invasion depth, lymph node metastasis, distant metastasis and tumor/node/metastasis (TNM) stage, and predicted poor prognosis. Loss-of-function assays revealed that silenced SNHG6 obviously inhibited gastric cancer cell growth, weakened cell migration capacity and suppressed the EMT processes of gastric cancer cells. Additionally, ChIP, RIP, RNA-pulldown and luciferase reporter assays evidenced that SNHG6 could epigenetically silenced p27 and could competitively sponging miR-101-3p thereby regulating zinc finger E-box-binding homeobox 1 (ZEB1). Conclusion: In summary, our findings demonstrated that SNHG6 acted as an oncogene in gastric cancer cells through regulating miR-101-3p/ZEB1 at a post-transcriptional level and silencing expression at a transcriptional level by recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p27. SNHG6 might serve as a candidate prognostic biomarker and a target for novel therapies of gastric cancer patients.

Objective There are no generally accepted biomarkers for the optimal selection of radiotherapy-based or surgical-based treatment options for nonbulky early-stage squamous cell carcinoma of the cervix (IA1–IB1 and IIA1). The objective of this study was to assess the value of human squamous cell carcinoma–associated antigen (SCC-Ag) and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in evaluation of patients with nonbulky early-stage squamous cell carcinoma of the cervix to determine if radiotherapy is warranted after radical surgery. Methods Patients with stage IA1–IB1 and IIA1 squamous cell carcinoma of the cervix who were treated at the Department of Gynecological Oncology, Affiliated Tumor Hospital of Guangxi Medical University, from March 2012 to August 2014 (n = 308) were treated with radical hysterectomy and pelvic lymphadenectomy. The levels of SCC-Ag and CYFRA21-1 were detected by enzyme-linked immunosorbent assay before surgery. The relationship between the concentrations of SCC-Ag and CYFRA21-1 and risk factors was estimated through logistic regression and analysis of variance t test. The cutoff values of these 2 markers to evaluate the need for postoperative radiotherapy were identified and validated by receiver operating characteristic curve and κ consistency test, respectively. Results Serum SCC-Ag and CYFRA21-1 levels are significantly increased in patients who require postoperative radiotherapy with a risk factor score of at least 2 (n = 162). Logistic regression analysis revealed that deep stromal invasion and lymph node metastasis are independent risk factors for serum SCC-Ag value, and deep stromal invasion is an independent risk factor for the serum CYFRA21-1 value. Receiver operating characteristic curve revealed that the best predictive cutoff points of SCC-Ag and CYFRA21-1 values were 1.425 and 3.210 ng/mL, respectively. These results were validated by the κ consistency test applied to a validation group of patients. The results suggest that most patients with SCC-Ag and CYFRA21-1 values of at least 1.425 and 3.210 ng/mL, respectively, require postoperative radiotherapy. Conclusions Detection of the levels of SCC-Ag and CYFRA21-1 may help guide an individual primary treatment plan for patients with nonbulky early-stage squamous cell carcinoma of the cervix.

Background Pleckstrin homology‐like domain family A, member 3 ( PHLDA 3), a crucial member of the PHLDA family, is involved in tumor suppression, kidney injury, liver injury, and glucose metabolism. However, the role of PHLDA 3 in pathological cardiac hypertrophy and heart failure remains unclear. Methods and Results In the present study, PHLDA 3 expression was downregulated in hypertrophic murine hearts and angiotensin II ‐treated cardiomyocytes. Next, an in vitro study suggested, by using gain‐ and loss‐of‐function approaches, that PHLDA 3 attenuates Ang II exposure‐induced cardiomyocyte hypertrophy. Consistent with the cell phenotype, disruption of PHLDA 3 aggravated the effects of pressure overload‐induced pathological cardiac hypertrophy, fibrosis, and dysfunction. In contrast, PHLDA 3 overexpression resulted in an attenuated hypertrophic phenotype. Molecular analysis revealed that PHLDA 3 suppressed the activation of AKT ‐ mTOR ‐ GSK 3β‐P70S6K signaling in response to hypertrophic stress, and the blockage of AKT activation rescued these adverse pathological effects of PHLDA 3 deficiency‐induced by AB and Ang II , respectively, in vivo and in vitro. Conclusions Collectively, our data indicated that PHLDA 3 could ameliorate pressure overload‐induced cardiac remodeling mainly by blocking the AKT signaling pathway, suggesting that PHLDA 3 may represent a therapeutic target for the treatment of pathological cardiac hypertrophy and heart failure.

Background Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a member of the TRAF family and is dysregulated in diseases, such as atheroma, lymphoma, and solid tumors, but the role of TRAF1 in gastric cancer remains unknown. This study was aimed to investigate the role of TRAF1 in Helicobacter pylori (H. pylori)-related cell apoptosis and gastric carcinogenesis. Materials and methods The mRNA and protein expression levels of TRAF1 were measured in a panel of gastric cancer cell lines and in H. pylori -infected mice by quantitative real-time PCR (qPCR) and Western blotting. The transcription factor that mainly affects transcription of TRAF1 during H. pylori infection was identified. The roles of H. pylori virulence factors that regulate TRAF1 expression were analyzed using isogenic cagA-, vacA-, and cagE-null mutants. The effects of TRAF1 on gastric cell viability and apoptosis during H. pylori infection were detected using the standard MTS (cell viability) assay and flow cytometry, respectively. Results H. pylori infection induced TRAF1 overexpression in both gastric epithelial cells and mice. The expression of TRAF1 in response to H. pylori infection was majorly regulated by the activation of NF-κB and was strongly related to H. pylori virulence factor CagA. The upregulation of TRAF1 inhibited cell apoptosis and increased the viability of infected cells. Conclusions H. pylori infection induces the overexpression of TRAF1 in gastric epithelial cells. The upregulation of TRAF1 plays an antiapoptotic role in H. pylori -infected gastric cells and may contribute to the gastric carcinogenesis.

Although hyperaldosteronemia exerts detrimental impacts on vascular endothelium in addition to elevating blood pressure, the effects and molecular mechanisms of hyperaldosteronemia on early endothelial progenitor cell (EPC)–mediated endothelial repair after arterial damage are yet to be determined. The aim of this study was to investigate the endothelial repair capacity of early EPCs from hypertensive patients with primary hyperaldosteronemia (PHA). In vivo endothelial repair capacity of early EPCs from PHAs (n=20), age- and blood pressure–matched essential hypertension patients (n=20), and age-matched healthy subjects (n=20) was evaluated by transplantation into a nude mouse carotid endothelial denudation model. Endothelial function was evaluated by flow-mediated dilation of brachial artery in human subjects. In vivo endothelial repair capacity of early EPCs and flow-mediated dilation were impaired both in PHAs and in essential hypertension patients when compared with age-matched healthy subjects; however, the early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs were impaired more severely than essential hypertension patients. Oral spironolactone improved early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs. Increased oxidative stress, oxidative 5,6,7,8-tetrahydrobiopterin degradation, endothelial nitric oxide synthase uncoupling and decreased nitric oxide production were found in early EPCs from PHAs. Nicotinamide adenine dinucleotide phosphate oxidase subunit p47 phox knockdown or 5,6,7,8-tetrahydrobiopterin supplementation attenuated endothelial nitric oxide synthase uncoupling and enhanced in vivo endothelial repair capacity of early EPCs from PHAs. In conclusion, PHAs exhibited more impaired endothelial repair capacity of early EPCs than did essential hypertension patients independent of blood pressure, which was associated with mineralocorticoid receptor–dependent oxidative stress and subsequently 5,6,7,8-tetrahydrobiopterin degradation and endothelial nitric oxide synthase uncoupling.

Objective: The aim of this study was to explore the differences in microRNA (miRNA) profiles in peripheral blood mononuclear cells (PBMCs) between coronary heart disease (CHD) patients with and without heart failure (HF) and to assess the values of differentially expressed miRNAs (DEMs) regarding HF risk in CHD patients. Methods: Six CHD patients with HF and six age- and gender-matched CHD patients without HF were enrolled in the exploration stage, and 44 CHD patients with HF and 42 age- and gender-matched CHD patients without HF were recruited in the validation stage. Peripheral blood samples were collected from all the participants, and PBMCs were separated for miRNA detection. miRNA microarray and quantitative polymerase chain reaction were performed to assess the miRNA expression. Results: In the exploration stage, heat map analysis showed that CHD patients with HF could be distinguished from those without HF using PMBC miRNA expressions; 63 downregulated DEMs and 84 upregulated DEMs in PBMCs were identified in CHD patients with HF using volcano map, and top 8 DEMs were selected based on their p values. In the validation stage, PBMC miR-221, miR-19b-5p, and miR-25-5p were found to be markedly dysregulated in CHD patients with HF. Multiple logistic regression analysis showed PBMC miR-221, miR-19b-5p, miR-25-5p, and hypertension to be the independent predictive factors for HF in CHD patients. A receiver operating characteristic curve demonstrated that area under curve of the combination of miR-221, miR-19b-5p, miR-25-5p, and hypertension was 0.871 (95% CI: 0.794-0.944). Conclusion: CHD patients with and without HF could be differentiated according to PBMC miRNA profiles, and the combination of PBMC miR-19b-5p, miR-221, miR-25-5p, and hypertension correlates with an increased HF risk in CHD patients.

Background Carboxyl‐terminal modulator protein ( CTMP ) has been implicated in cancer, brain injury, and obesity. However, the role of CTMP in pathological cardiac hypertrophy has not been identified. Methods and Results In this study, decreased expression of CTMP was observed in both human failing hearts and murine hypertrophied hearts. To further explore the potential involvement of CTMP in pathological cardiac hypertrophy, cardiac‐specific CTMP knockout and overexpression mice were generated. In vivo experiments revealed that CTMP deficiency exacerbated the cardiac hypertrophy, fibrosis, and function induced by pressure overload, whereas CTMP overexpression alleviated the response to hypertrophic stimuli. Consistent with the in vivo results, adenovirus‐mediated gain‐of‐function or loss‐of‐function experiments showed that CTMP also exerted a protective effect against hypertrophic responses to angiotensin II in vitro. Mechanistically, CTMP ameliorated pathological cardiac hypertrophy through the blockade of the protein kinase B signaling pathway. Moreover, inhibition of protein kinase B activation with LY 294002 rescued the deteriorated effect in aortic banding–treated cardiac‐specific CTMP knockout mice. Conclusions Taken together, these findings imply, for the first time, that increasing the cardiac expression of CTMP may be a novel therapeutic strategy for pathological cardiac hypertrophy.

Background Side-effects have been considered as the limitation of the chemotherapy agents’ administration and life quality in patients with ovarian cancers. In order to explore the influence of the chemotherapy agents commonly used in ovarian cancer patients on the blood glucose metabolism in rat models, we conducted this study which simulated the conditions of clinical protocols. Methods Eighty clean-grade female Wistar rats were randomized into 8 groups: Group 1 (Negative control), Group 1′ (Dexamethasone), Group 2 (Carboplatin), Group 2′ (Carboplatin-plus-dexamethasone), Group 3 (Paclitaxel), Group 3′ (Paclitaxel-plus-dexamethasone), Group 4 (Combined therapy), Group 4′ (Combined-therapy-plus-dexamethasone). On day 0, 4, 7 and 14, after fasted for 12 h, the rats in all groups underwent a glucose load and their blood glucose, glucagon and insulin levels were measured. Results The glucose levels in group 2, 3 and 4 at 1 h after the loading on day 4 significantly increased (P = 0.190, 0.008 and 0.025, respectively). The glucagon levels in group 3 and 4 showed a similar trend and the increase was not suppressed by the glucose loading (P

Background Dickkopf‐3 ( DKK 3) is a negative regulator of the Wnt/β‐catenin signaling pathway, which is involved in inflammation. However, little is known about the relationship between DKK 3 expression and the progression of atherosclerosis. The aim of the present study was to define the role of DKK 3 and its potential mechanism in the development of atherosclerosis. Methods and Results Immunofluorescence analysis showed that DKK 3 was strongly expressed in macrophages of atherosclerotic plaques from patients with coronary heart disease and in hyperlipidemic mice. The expression level was significantly increased in atherogenesis. DKK 3 −/− ApoE −/− mice exhibited a significant decrease in atherosclerotic lesions in the entire aorta, aortic sinus, and brachiocephalic arteries. Transplantation of bone marrow from DKK 3 −/− ApoE −/− mice into lethally irradiated ApoE −/− recipients resulted in a reduction of atherosclerotic lesions, compared with the lesions in recipients transplanted with ApoE −/− donor cells, suggesting that the effect of DKK 3 deficiency was largely mediated by bone marrow–derived cells. A reduction in the necrotic core size, accompanied by increased collagen content and smooth muscle cells and decreased accumulation of macrophages and lipids, contributed to the stability of plaques in DKK 3 −/− ApoE −/− mice. Furthermore, multiple proinflammatory cytokines exhibited marked decreases in DKK 3 −/− ApoE −/− mice. Finally, we observed that DKK 3 ablation increased β‐catenin expression in the nuclei of macrophages both in vivo and in vitro. Conclusions DKK 3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/β‐catenin pathway.

Objective: To observe the efficacy and toxicity of nanoparticle albumin bound paclitaxel (nab-paclitaxel) plus platinum agent (cisplatin or carboplatin) as first line treatment for stage III/IV squamous non-small-cell lung cancer (NSCLC). Methods: Forty chemotherapy naive patients with stage III/IV squamous NSCLC received nab-paclitaxel 125 mg/m 2 on day 1 and day 8, cisplatin 75 mg/m 2 on day 1, carboplatin area under the concentration-time curve of 5 (AUC=5) on day 1. One cycle of treatment was 3 weeks, and at least two were completed in each case. Results: Of the 40 patients who participated in the study, 25 achieved partial responses (PR), 12 reached a stage of stable disease (SD), and 3 suffered progressive disease (PD). The overall response rate (ORR) was 62.5% and the disease control rate (DCR) was 92.5%. Of the 20 patients without surgery or radiotherapy, 10 achieved PR, 7 reached a stage of SD, and 3 PD. The ORR was 50.0% and the DCR was 85.0%. The median progression-free survival time (PFS) of patients without surgery or radiotherapy was 5.0 months. Of the 20 patients receiving surgery or radiotherapy, 15 had PR and 5 p had SD, with an ORR of 75.0% and a DCR of 85.0%. Specifically, the DDP arm demonstrated a significantly higher ORR than the CBP arm (100%vs 54.5%, P

Interferon regulatory factor 1 (IRF1), a critical member of the IRF family, was previously shown to be associated with the immune system and to be involved in apoptosis and tumor suppression. However, the role of IRF1 in pressure overload–induced cardiac remodeling has remained unclear. Using genetic approaches, we established a central role for the IRF1 transcription factor in the regulation of cardiac remodeling both in vivo and in vitro, and we determined the mechanism underlying this process. The expression level of IRF1 was remarkably altered in both failing human hearts and hypertrophic murine hearts. Transgenic mice with cardiac-specific IRF1 overexpression exacerbated aortic banding–induced cardiac hypertrophy, ventricular dilation, fibrosis, and dysfunction, whereas IRF1-deficient (knockout) mice exhibited a significant reduction in the hypertrophic response. Similar results were observed in a global IRF1-knockout rat model. Mechanistically, the prohypertrophic effects elicited by IRF1 in response to pathological stimuli were associated with the direct activation of inducible nitric oxide synthase (iNOS). Furthermore, we identified 1 IRF1-binding site in the promoter region of the iNOS gene, which was essential for its transcription. To examine the IRF1-iNOS axis in vivo, we generated IRF1-transgenic/iNOS-knockout mice. IRF1 exerted profoundly detrimental effects in these mice; however, these effects were nullified by iNOS ablation. These data suggest the IRF1–iNOS axis as a crucial regulator of cardiac remodeling and that IRF1 could be a potent therapeutic target for cardiac remodeling.

Dysfunction of early endothelial progenitor cells (EPCs) is responsible for impaired endothelial repair capacity after arterial injury in patients with hypertension. Here, we hypothesized that diminished signaling of CXC chemokine receptor 7 (CXCR7) contributes to the reduced EPC functions, and enhanced CXCR7 expression restores the capacities of EPCs from hypertensive patients. CXCR7 expression of EPCs from hypertensive patients was significantly reduced when compared with that from healthy subjects. Meanwhile, the phosphorylation of p38 mitogen-activated protein kinase, a downstream signaling of CXCR7, was elevated, which increased cleaved caspase-3 level of EPCs. CXCR7 gene transfer augmented CXCR7 expression and decreased the phosphorylation of p38 mitogen-activated protein kinase, which was paralleled to EPC functional upregulation of in vitro adhesion, antiapoptosis activities, and in vivo re-endothelialization capacity in a nude mouse model of carotid artery injury. The enhanced in vitro and in vivo functions of EPCs were markedly inhibited by neutralizing monoclonal antibody against CXCR7, which was blocked by p38 mitogen-activated protein kinase inhibitor SB203580. Downregulation of cleaved caspase-3 level induced by CXCR7 gene transfer or SB203580 pretreatment improved EPC functions. Furthermore, we found that lercanidipine, a dihydropyridine calcium channel antagonist, enhanced CXCR7 expression and facilitated in vitro and in vivo functions of EPCs. Our study demonstrated for the first time that diminished CXCR7 signal at least partially contributes to the reduced in vitro functions and in vivo re-endothelialization capacity of EPCs from hypertensive patients. Upregulation of CXCR7 expression induced by gene transfer or lercanidipine treatment may be a novel therapeutic target for increased endothelial repair capacity in hypertension.

Oncostatin M (OSM) is a secreted cytokine mainly involved in chronic inflammatory and cardiovascular diseases through binding to OSM receptor β (OSMR-β). Recent studies demonstrated that the presence of OSM contributed to the destabilization of atherosclerotic plaque. To investigate whether OSMR-β deficiency affects atherosclerosis, male OSMR-β−/−ApoE−/− mice were generated and utilized. Here we observed that OSMR-β expression was remarkably upregulated in both human and mouse atherosclerotic lesions, which were mainly located in macrophages. We found that OSMR-β deficiency significantly ameliorated atherosclerotic burden in aorta and aortic root relative to ApoE-deficient littermates and enhanced the stability of atherosclerotic plaques by increasing collagen and smooth muscle cell content, while decreasing macrophage infiltration and lipid accumulation. Moreover, bone marrow transplantation of OSMR-β−/− hematopoietic cells to atherosclerosis-prone mice displayed a consistent phenotype. Additionally, we observed a relatively reduced level of JAK2 and signal transducer and activator of transcription (STAT)3 in vivo and under Ox-LDL stimulation in vitro. Our findings suggest that OSMR-β deficiency in macrophages improved high-fat diet-induced atherogenesis and plaque vulnerability. Mech­anistically, the protective effect of OSMR-β deficiency on atherosclerosis may be partially attributed to the inhibition of the JAK2/STAT3 activation in macrophages, whereas OSM stimulation can activate the signaling pathway.

Background The Bacillus anthracis S-layer protein, BslA, plays a crucial role in mammalian infection. BslA is required to mediate adherence between host cells and vegetative forms of bacteria and this interaction promotes target organs adherence and blood–brain barrier (BBB) penetration in vivo. This study attempts to identify the potential eukaryotic ligand(s) for B. anthracis BslA protein. Results Biochemical approaches have indicated that the putative host cell ligand(s) for BslA is a surface protein, which is independent of the sugar components for binding to Bs1A. A ligand screening using blot overlays, far Western blots and mass spectrometry analyses revealed that BslA binds to mammalian laminin. ELISA based solid-phase binding assays and surface plasmon resonance assays demonstrated that there were high affinity interactions between BslA(260–652) and laminin. The SPR results also revealed the dissociation constants values of 3.172 × 10−9M for the binding of BslA(260–652) to laminin. Conclusions These data demonstrated that laminin is a ligand for BslA. Electronic supplementary material The online version of this article (doi:10.1186/s12866-016-0802-8) contains supplementary material, which is available to authorized users.

Epithelial-mesenchymal transition (EMT) is a critical process providing tumor cells with the ability to migrate and escape from the primary tumor and metastasize to distant sites. Recently, EMT was shown to be associated with the cancer stem cell (CSC) phenotype in breast cancer. Snail is a transcription factor that mediates EMT in a number of tumor types, including colorectal cancer (CRC). Our study was done to determine the role of Snail in mediating EMT and CSC function in CRC. Human CRC specimens were stained for Snail expression, and human CRC cell lines were transduced with a retroviral Snail construct or vector control. Cell proliferation and chemosensitivity to oxaliplatin of the infected cells were determined by the MTT (colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Migration and invasion were determined in vitro using modified Boyden chamber assays. EMT and putative CSC markers were analyzed using Western blotting. Intravenous injection of tumor cells was done to evaluate their metastatic potential in mice. Snail was overexpressed in human CRC surgical specimens. This overexpression induced EMT and a CSC-like phenotype in human CRC cells and enhanced cell migration and invasion (P < 0.002 vs. control). Snail overexpression also led to an increase in metastasis formation in vivo (P < 0.002 vs. control). Furthermore, the Snail-overexpressing CRC cells were more chemoresistant to oxaliplatin than control cells. Increased Snail expression induces EMT and the CSC-like phenotype in CRC cells, which enhance cancer cell invasion and chemoresistance. Thus, Snail is a potential therapeutic target in metastatic CRC.

Aging is associated with dysfunction of endothelial progenitor cells (EPCs), and shear stress has a beneficial impact on EPC function; however, the effects of aging and shear stress on the endothelial repair capacity of EPCs after arterial injury have not been reported. Here we investigated the influence of aging and shear stress on the reendothelialization capacity of human EPCs and the related molecular mechanism. Compared with EPCs isolated from young subjects, EPCs from the elderly displayed an impaired migration and adhesion in vitro and demonstrated a significantly reduced reendothelialization capacity in vivo after transplantation into nude mice with carotid artery denudation injury. Shear stress pretreatment enhances the migration, adhesion, and reendothelialization capacity in both young and elderly EPCs; however, it was to a greater extent in EPCs from the elderly. Although basal CXC chemokine receptor 4 (CXCR4) expression was similar in EPCs from the 2 age groups, the stromal cell derived factor 1-induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs. Shear stress treatment upregulated CXCR4 expression and phosphorylation and, importantly, restored the stromal cell-derived factor 1/CXCR4-dependent Janus kinase 2 phosphorylation in the elderly EPCs. Furthermore, short hairpin RNA-mediated knockdown of CXCR4 expression or pretreatment with Janus kinase 2 inhibitor diminished the enhancement in the migration, adhesion, and reendothelialization capacity of the elderly EPCs from shear stress treatments. Thus, our study demonstrates that upregulation of the CXCR4/Janus kinase 2 pathway by shear stress contributes to the enhanced reendothelialization capacity of EPCs from elderly men.

OBJECTIVE Recent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease. RESEARCH DESIGN AND METHODS Three SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies. RESULTS The association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283-C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002). CONCLUSIONS For the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population.

Endothelial dysfunction is related to reduced arterial elasticity in patients with essential hypertension. Circulating endothelial progenitor cells (EPCs), an important endogenous repair approach for endothelial injury, is altered in hypertensive patients. However, the association between alteration in circulating EPCs and hypertension-related reduced arterial elasticity has not been reported. The purpose of this study is to investigate the association between alteration in circulating EPCs and hypertension-related reduced arterial elasticity. We measured the artery elasticity profiles including brachial-ankle PWV (baPWV) and C1 large and C2 small artery elasticity indices in patients with essential hypertension (n = 20) and age-matched normotensive subjects (n = 21). The number and activity of circulating EPCs isolated from peripheral blood were determined. Compared to normotensive subjects, the patients with hypertension exhibited decreased C1 large and C2 small artery elasticity indices, as well as increased baPWV. The number of circulating EPCs did not differ between the two groups. The migratory and proliferative activities of circulating EPCs in hypertensive patients were lower than those in normotensive subjects. Both proliferatory and migratory activities of circulating EPCs closely correlated with arterial elasticity profiles, including baPWV and C1 large and C2 small artery elasticity indices. Multivariate analysis identified both proliferative and migratory activities of circulating EPCs as independent predictors of the artery elasticity profiles. The present study demonstrates for the first time that impaired activity of circulating EPCs is associated with reduced arterial elasticity in patients with hypertension. The fall in endogenous repair capacity of vascular endothelium may be involved in the pathogenesis of hypertension-related vascular injury.

Dickkopf-3 (DKK3) is a secreted glycoprotein of the Dickkopf family (DKK1-4) that modulates Wnt signalling. DKK3 has been reported to regulate cell development, proliferation, apoptosis, and immune response. However, the functional role of DKK3 in cardiac remodelling after myocardial infarction (MI) has not yet been elucidated. This study aimed to explore the functional significance of DKK3 in the regulation of post-MI remodelling and its underlying mechanisms. MI was induced by surgical left anterior descending coronary artery ligation in transgenic mice expressing cardiac-specific DKK3 and DKK3 knockout (KO) mice as well as their non-transgenic and DKK3(+/+) littermates. Our results demonstrated that after MI, mice with DKK3 deficiency had increased mortality, greater infarct size, and exacerbated left ventricular (LV) dysfunction. Significantly, at 1 week post-MI, the hearts of DKK3-KO mice exhibited increased apoptosis, inflammation, and LV remodelling compared with the hearts of their DKK3(+/+) littermates. Conversely, DKK3 overexpression led to the opposite phenotype after infarction. Similar results were observed in cultured neonatal rat cardiomyocytes exposed to hypoxia in vitro. Mechanistically, DKK3 promotes cardioprotection by interrupting the ASK1-JNK/p38 signalling cascades. In conclusion, our results indicate that DKK3 protects against the development of MI-induced cardiac remodelling via negative regulation of the ASK1-JNK/p38 signalling pathway. Thus, our study suggests that DKK3 may represent a potential therapeutic target for the treatment of heart failure after MI.

The aim of this study was to investigate the value of initial serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations in ST-segment elevation myocardial infarction (STEMI) patients for predicting ST-segment resolution (STR) after primary percutaneous coronary intervention (pPCI). Consecutive STEMI patients (n = 218) who underwent pPCI were assigned to an STR group (≥ 50 % resolution) or a non-STR group (

Growth/differentiation factor 1 (GDF1) is a secreted glycoprotein of the transforming growth factor-β (TGF-β) superfamily that mediates cell differentiation events during embryonic development. GDF1 is expressed in several tissues, including the heart. However, the functional role of GDF1 in myocardial infarction (MI)-induced cardiac remodelling and dysfunction is not known. Here, we performed gain-of-function and loss-of-function studies using cardiac-specific GDF1 transgenic (TG) and knockout (KO) mice to determine the role of GDF1 in the pathogenesis of functional and architectural cardiac remodelling after MI, which was induced by surgical left anterior descending coronary artery ligation. Our results demonstrate that overexpression of GDF1 in the heart causes a significant decrease in MI-derived mortality post-MI and leads to attenuated infarct size expansion, left ventricular (LV) dilatation, and cardiac dysfunction at 1 week and 4 weeks after MI injury. Compared with control animals, cardiomyocyte apoptosis, inflammation, hypertrophy, and interstitial fibrosis were all remarkably reduced in the GDF1-TG mice following MI. In contrast, GDF1 deficiency greatly exacerbated the pathological cardiac remodelling response after infarction. Further analysis of the in vitro and in vivo signalling events indicated that the beneficial role of GDF1 in MI-induced cardiac dysfunction and LV remodelling was associated with the inhibition of non-canonical (MEK-ERK1/2) and canonical (Smad) signalling cascades. Overall, our data reveal that GDF1 in the heart is a novel mediator that protects against the development of post-infarction cardiac remodelling via negative regulation of the MEK-ERK1/2 and Smad signalling pathways. Thus, GDF1 may serve as a valuable therapeutic target for the treatment of MI.

This study aimed to investigate whether interferon regulatory factor 9 (IRF9) is involved in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury and to explore the underlying molecular mechanisms of this process. Cell death plays a major role in myocardial I/R injury. We recently determined the importance of IRF9 in coordinating molecular events in response to hypertrophic stress in cardiomyocytes. However, the roles of IRF9 in lethal myocardial injury remain to be elucidated. The involvement of IRF9 was assessed via functional assays in a mouse myocardial I/R injury model by genetic knockout and cardiomyocyte-specific transgenic overexpression of IRF9, and its effects on cardiomyocyte apoptosis and inflammation were further studied in vivo and in vitro. IRF9 was upregulated in human ischemic heart tissue and mouse hearts after I/R injury. Ablation of IRF9 protected the heart against I/R-induced cardiomyocyte death, development of inflammation, and loss of heart function. In contrast, cardiomyocyte-specific transgenic overexpression of IRF9 aggravated myocardial reperfusion injury and inflammation. IRF9 negatively regulated the Sirt1-p53 axis under I/R conditions in vivo and in vitro. Downregulation of Sirt1 expression and its downstream apoptosis-related signaling cascade, which results from I/R, was ameliorated by loss of IRF9 and exacerbated by overexpression of IRF9. Cardiomyocyte-specific deletion of Sirt1 abolished the protective effect of IRF9 knockout against I/R injury, which further indicated that IRF9 mediated myocardial reperfusion injury by modulating the Sirt1-p53 axis. Thus, IRF9 may be a novel therapeutic target for the prevention of I/R injury resulting from revascularization therapy after acute myocardial infarction (MI).

This study was undertaken to investigate the intraoperative and postoperative complications, efficacy and outcome of two laparoscopic fundoplications for the treatment of esophageal hiatal hernia in children. To find a rational procedure, we performed a retrospective analysis of 136 children with esophageal hiatal hernia who underwent laparoscopic Nissen-Rossetti or Thal fundoplication at two children’s hospitals in Shanghai over 13 years. The median follow-up time of the children was 42 months (range: 1-138 months). Their age varied from 1 month to 11 years (median: 18.6 months). All the children underwent laparoscopic fundoplications (72 cases of Nissen-Rossetti and 60 cases of Thal fundoplication) and 4 children converted to open surgery. The mean age of the children at the time of operation was 1.6±1.9 years, and the mean weight was 9.1±5.6 kg. Gastroesophageal reflux was significantly more severe after a Thal fundoplication (P=0.003) and slight esophageal stenosis was significant after a Nissen-Rossetti fundoplication (P=0.02). The recurrent rate of hiatal hernia was 2.8% (2/72) after Nissen-Rossetti fundoplication in contrast to 5% (3/60) after Thal fundoplication. No death occurred after surgery. There was no statistical difference of recurrence between laparoscopic Nissen-Rossetti and Thal fundoplication in the long-term outcomes. The rate of slight dysphagia was higher in the Nissen-Rossetti group. The Thal group had a significantly higher recurrence rate of gastroesophageal reflux. There still exited learning curve for this procedure. The incidence rate of complications is significantly related to the proficiency of pediatric surgeon.

The aim of this study was to assess the efficacy and safety of ivabradine (Iva) noninferiority to atenolol (Aten) in Chinese patients with chronic stable angina pectoris.In this double-blind, double-dummy trial, patients with symptomatic angina pectoris and positive exercise tolerance test were randomized into the Iva [5 or 7.5 mg bis in die (BID)] or Aten group (12.5 or 25 mg BID) according to computer-generated random numbers for 12 weeks.One hundred and sixty-eight patients were randomized to the Iva group and 166 to the Aten group. In a full analysis set, increases in the total exercise duration (TED) were 54.3 ± 120.1 seconds with Iva 5 mg and 58.8 ± 114.7 seconds with Aten 12.5 mg at the fourth week, and at the 12th week, TED improved by 84.1 ± 130.5 seconds with Iva and 77.8 ± 126.6 seconds with Aten (95%CI: -21.4-34.1 seconds, p = 0.0011 for noninferiority). The analysis of per protocol set yielded similar results (95%CI: -31.4-33.0 seconds, p = 0.0131 for noninferiority). Heart rate was reduced in both groups at rest and during peak exercise. There were small, nonsignificant differences in the number of adverse events between the two groups (66 in Iva and 73 in Aten, p 0.05). Nine patients (5.42%) were reported to develop phosphenes/luminous phenomena and blurred vision in the Iva group (p = 0.0035).Iva is effective in reducing heart rates and improving exercise capacity and noninferior to Aten in Chinese patients with chronic stable angina pectoris. Iva is well tolerated and safe.

To compare the clinical features and prognosis among patients with different chemosensitivity and determine the specific clinical influencing factors of chemotherapeutic resistance.In references to the 2010 NCCN clinical practice guidelines on ovarian cancer and in accordance with the length of disease-free interval, 244 patients were divided into 3 groups: platinum-resistant, partially sensitive and platinum-sensitive. The differences of clinical features, treatment and prognosis were compared among these 3 groups.The resistant, partially sensitive, sensitive rates to platinum-based chemotherapy were 23.4%, 13.5% and 63.1% respectively. Such factors as age, pathological type, primary tumor size. intraperitoneal chemotherapy and venous chemotherapy regimen had no effect on the responses to the combination platinum-based chemotherapy. The platinum-resistant percentage of advanced stage patients without optimal cytoreductive surgery was higher (P0.01). The poorly differentiated rate of partially sensitive patients was higher than that of platinum-sensitive ones (P0.05). The CA125 level and lymph node metastasis rate of platinum-resistant patients were higher than those of platinum-sensitive patients (P0.05, P0.01). The 5-year survival rates of resistant, partially sensitive and sensitive patients were 9.5%, 38.4% and 81.9% respectively. There were statistics differences in overall survival and progression-free survival among the 3 groups (P0.01).Advanced ovarian cancer, poor differentiation, lymph node-positivity, CA125 rising above 1000 × 10(3) U/L and suboptimal cytoreductive surgery would lead to the occurrences of resistance or partially sensitivity. Clinical factors have some reference values for the prediction of resistance. But it is impossible to accurately determine chemoresistance.

Endothelial progenitor cells (EPCs) play an important role in repairing endothelial injury. Aging is associated with EPC dysfunction. Physical exercise has a beneficial impact on EPC activity. However, whether physical exercise can enhance the endothelial repair capacity of EPCs in healthy men with aging is not clear. Here, we investigated the effects of physical exercise on reendothelialization capacity and CXC chemokine receptor four (CXCR4) signaling in human EPCs. Before and after 12-week exercise, EPCs were isolated from elderly and young men. In vitro function and in vivo reendothelialization capacity of EPCs in a mouse model of carotid artery injury were measured. The expression of CXCR4 and its downstream signaling target Janus kinase-2 (JAK-2) were determined. Before exercise, in vitro function and in vivo reendothelialization capacity of EPCs were significantly reduced in elderly men compared with young men. After exercise intervention, in vitro function and in vivo reendothelialization capacity of EPCs from elderly men were markedly enhanced. Physical exercise increased a higher CXCR4 protein expression and higher JAK-2 phosphorylation levels of EPCs. The augmentation in reendothelialization capacity of EPCs was closely correlated with the upregulation of CXCR4/JAK-2 signaling and improvement of endothelial function. This study demonstrates for the first time that physical exercise attenuates age-associated reduction in endothelium-reparative capacity of EPCs by increasing CXCR4/JAK-2 signaling. Our findings provide insight into the novel mechanisms of physical exercise as a lifestyle intervention strategy to promote vascular health in aging population.

Endogenous testosterone has been shown to provide a protective role in the development of cardiovascular diseases in men. This study investigated the changes of testosterone level and its relationship to the severity of coronary artery stenosis in middle-aged men with coronary artery disease (CAD).Serum testosterone concentration was measured in 87 middle-aged men patients with CAD including stable angina pectoris (SAP), unstable angina pectoris (USAP) and acute myocardial infarction (AMI). All patients underwent coronary angiography and the severity of coronary stenosis was estimated by the Gensini coronary score. The patients with the severity of coronary artery stenosis of less than 50% served as control group.The levels of testosterone in SAP group (488.2 ± 96.8ng/dl), USAP group (411.6 ± 128.6ng/dl) and AMI group (365.3 ± 116.6ng/dl) were significantly lower than that in control group (562.8 ± 110.2ng/dl) (all p0.05). When compared with another group among SAP, USAP and AMI groups, the level of testosterone in the AMI group was the lowest, the USAP group was the median while the SAP group was the highest (all p0.05). There was a significant correlation between angiographic Gensini score and testosterone level (n=87, r=-0.513, p0.05). Multiple regression analysis found that testosterone and BMI were independent predictors for CAD (testosterone: odds ratio 0.311, 95% confidence interval 0.174-0.512; BMI: odds ratio 1.905, 95% confidence interval 1.116-2.973).The present study showed that middle-aged male patients with CAD present a lower level of serum testosterone and the testosterone level was negatively correlated with the severity of coronary artery stenosis.

Coronary artery disease (CAD) causes more than 700,000 deaths each year in China. Previous genome-wide association studies (GWAS) in populations of European ancestry identified several genetic loci for CAD, but no such study has yet been reported in the Chinese population. Here we report a three-stage GWAS in the Chinese Han population. We identified a new association between rs6903956 in a putative gene denoted as C6orf105 on chromosome 6p24.1 and CAD (P = 5.00 × 10⁻³, stage 2 validation; P = 3.00 × 10⁻³, P = 1.19 × 10⁻⁸ and P = 4.00 × 10⁻³ in three independent stage 3 replication populations; P = 4.87 × 10⁻¹², odds ratio = 1.51 in the combined population). The minor risk allele A of rs6903956 is associated with decreased C6orf105 mRNA expression. We report the first GWAS for CAD in the Chinese Han population and identify a SNP, rs6903956, in C6orf105 associated with susceptibility to CAD in this population.

Background and Purpose— Genome-wide association studies found that the common allele T of single nucleotide polymorphism rs11206510 on chromosome 1p32 was associated with increased low-density lipoprotein-cholesterol levels (LDL-C) and with risk of coronary artery disease (CAD) in white populations. The goals of this study are to determine whether rs11206510 is associated with LDL-C and CAD in a different ethnic population, namely a Chinese cohort, and to investigate whether rs11206510 is associated with ischemic stroke. Methods— The association of rs11206510 with LDL-C was analyzed in 1415 Chinese Han subjects. The CAD study utilized a GeneID cohort with 1543 CAD patients and 1240 controls. For stroke studies, 2 independent cohorts were used and included the GeneID North cohort, with 1205 cases and 1205 controls, and the GeneID Central cohort, with 692 cases and 882 controls. Results— Different from white populations, the minor allele C of rs11206510 was associated with increased LDL-C levels in the Chinese Han population (adjusted P =0.002) and conferred risk of early-onset CAD (380 cases vs 1240 controls; adjusted P =0.002, odds ratio, 1.89), but not with overall CAD (adjusted P =0.82). The allelic association with ischemic stroke was highly significant in 2 independent cohorts, with adjusted P =1.13×10 −5 (odds ratio,1.71) in the GeneID North cohort and adjusted P =9.32×10 −5 (odds ratio, 1.70) in the GeneID Central cohort. Genotypic association was also significant for both early-onset CAD and ischemic stroke. Conclusions— Our results indicate that single nucleotide polymorphism rs11206510 is associated with LDL-C levels and early-onset CAD in the Chinese Han population. For the first time to our knowledge, this study also demonstrates that rs11206510 confers a significant risk of ischemic stroke.

Aims Endothelial progenitor cells (EPCs) play a pivotal role in endothelial repair after artery injury. The chemokine receptor CXCR4 is a key modulator of the homing of EPCs to impaired artery and reendothelialization. In this study, we addressed the hypothesis that CXCR4 gene transfer could enhance the reendothelialization capacity of EPCs. Methods and results In vitro , human EPCs were expanded and transduced with adenovirus serotype 5 encoding the human CXCR4 gene (Ad5/CXCR4). In vitro , CXCR4 gene transfer augmented EPC migration and enhanced EPC adhesion to endothelial cell monolayers. Adhesion assays under flow conditions showed that CXCR4 gene transfer increased the ability of EPCs to arrest on fibronectin. To determine whether CXCR4 gene transfer facilitated therapeutic reendothelialization, the effect of EPCs on in vivo reendothelialization was examined in nude mice subjected to carotid artery injury. Compared with the vehicle, transplantation of EPCs with or without gene transfer significantly accelerated in vivo reendothelialization; however, transplantation of EPCs transduced with Ad5/CXCR4 had a further enhanced effect compared with control EPCs containing EPCs transduced with an adenovirus encoding enhanced green fluorescent protein gene or non-transduced EPCs. We also found that phosphorylation of Janus kinase-2 (JAK-2), a CXCR4 downstream signalling target, was increased in EPCs transduced with Ad5/CXCR4. The enhanced in vitro function and in vivo reendothelialization capacity of EPCs by CXCR4 gene transfer were abolished by neutralizing antibodies against CXCR4 or/and JAK-2 inhibitor AG490. Conclusion The present study demonstrates that CXCR4 gene transfer contributes to the enhanced in vivo reendothelialization capacity of EPCs. Up-regulation of CXCR4 in human EPCs may become a novel therapeutic target for endothelial repair.