CircRNA Larp4b/miR-298-5p/Mef2c Regulates Cardiac Hypertrophy Induced by Angiotensin II.

Cardiac hypertrophy (CH) is an early marker in the clinical course of heart failure. Circular RNAs (circRNAs) play important roles in human disease. However, the role of circ_Larp4b in myocardial hypertrophy has not been studied. Angiotensin II (Ang II) treated HL-1 cells to induce a CH cell model. Quantitative real-time polymerase chain reaction was used to detect the expression of circ_Larp4b, microRNA-298-5p, and myocyte enhancer factor 2 (Mef2c). Western blot detected the protein level of alpha-actinin-2 (ACTN2), beta-myosin heavy chain (ß-MHC), atrial natriuretic peptide (ANP), and Mef2c. The relationship between miR-298-5p and circ_Larp4b or Mef2c was verified by dual-luciferase reporter assay and RNA pull-down assay. Circ_Larp4b and Mef2c were upregulated in HL-1 cells treated with Ang II. Moreover, circ_Larp4b down-regulation regulated the progress of CH induced by Ang II. MiR-298-5p was a target of circ_Larp4b, and Mef2c was a target of miR-298-5p. Overexpressed Mef2c reversed the cell size inhibited by miR-298-5p in Ang II-induced HL-1 cells. Circ_Larp4b regulated CH progress by regulating miR-298-5p/Mef2c axis.

Insights into circular RNAs: Biogenesis, function and their regulatory roles in cardiovascular disease.

As a distinctive member of the noncoding RNA family, circular RNAs (circRNAs) are generated from single-stranded, covalently closed structures and are ubiquitous in mammalian cells and tissues. Due to its atypical circular architecture, it was conventionally deemed insignificant dark matter for a prolonged duration. Nevertheless, studies conducted over the last decade have demonstrated that this abundant, structurally stable and tissue-specific RNA has been increasingly relevant in diverse diseases, including cancer, neurological disorders, diabetes mellitus and cardiovascular diseases (CVDs). Therefore, regulatory pathways controlled by circRNAs are widely involved in the occurrence and pathological processes of CVDs through their function as miRNA sponges, protein sponges and protein scaffolds. To better understand the role of circRNAs and their complex regulatory networks in CVDs, we summarize current knowledge of their biogenesis and function and the latest research on circRNAs in CVDs, with the hope of paving the way for the identification of promising biomarkers and therapeutic strategies for CVDs.

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a heterogeneous disorder characterized by the replacement of cardiac myocytes with fibro-fatty tissues, leading to abnormal excitation-contraction (EC) coupling and a range of malignant events, such as ventricular tachycardia (VT), sudden cardiac death/arrest (SCD/A) and heart failure (HF). The concept of ACM has recently been ex-tended to include right ventricular cardiomyopathy (ARVC), left ventricular cardiomyopathy (ALVC) and biventricular cardiomyopathy. ARVC is generally seen as the most common type of ACM. The pathogenesis of ACM involves mutation variants in desmosomal or non-desmosomal gene loci, as well as various external factors, such as intense exercise, stress and infections. Ion channel alterations, autophagy and non-desmosomal variants are also important components in the development of ACM. As clinical practice enters the era of precision therapy, it is important to review recent studies on these topics to better diagnose and treat the molecular phase of ACM.

Impacts of Non-alcoholic Fatty Liver Disease on Acute Coronary Syndrome: Evidence and Controversies.

PURPOSE OF REVIEW: Acute coronary syndrome (ACS) and non-alcoholic fatty liver disease (NAFLD) are two clinically common disease entities that share numerous risk factors. This review aimed to discuss the impacts of NAFLD on ACS. RECENT FINDINGS: In an era of improved control of traditional risk factors, the substantial burden of cardiometabolic abnormalities has caused widespread concern. NAFLD is considered the hepatic component of metabolic syndrome, which can exert an impact on human health beyond the liver. Accumulating studies have demonstrated that NAFLD is closely related to cardiovascular disease, especially coronary artery disease. Interestingly, although recent data have suggested an association between NAFLD and the incidence and outcomes of ACS, the results are not consistent. In this review, we comprehensively summarized evidence and controversies regarding whether NAFLD is a contributor to either the development of ACS or worse outcomes in patients with ACS. The potential pathophysiological and molecular mechanisms involved in the impacts of NAFLD on ACS were also elucidated.

Impact of Hypocalcemia on the Prognosis of Patients with Acute Myocarditis.

Acute viral myocarditis is a serious complication of viral infectious diseases, including coronavirus disease 2019 (COVID-19). To better understand the pathogenesis of acute viral myocarditis, we retrospectively analyzed the incidence and prognostic significance of hypocalcemia among patients with acute myocarditis, most of whom were considered to have acute viral myocarditis. We retrospectively reviewed the demographic and clinical data of patients with clinically confirmed acute myocarditis treated in our hospital over a 13-year period from 2006 to 2019, including laboratory results, cardiac imaging findings, and clinical outcomes. These data were compared between lower, middle, and higher calcium groups depending on the minimum calcium level measured during hospitalization. Among the 288 patients with acute myocarditis included, the hypocalcemia group (lower calcium group) had poorer clinical and laboratory results, received more medications and device support, and experienced poorer outcomes, including heart failure, arrhythmias, and death. Specifically, the left ventricular ejection fraction was significantly lower, and the length of hospital stay was significantly longer in the hypocalcemia group than in the other two groups. Furthermore, the incidence rates of atrioventricular block, ventricular tachycardia/ventricular fibrillation, cardiogenic shock, and mortality were significantly higher in the hypocalcemia group. Multivariate Cox regression analysis identified hypocalcemia as an independent risk factor for 30-day mortality in patients with acute myocarditis. In conclusion, the clinical evidence provided by the present study indicates that hypocalcemia is a risk factor for poorer outcomes in patients with acute myocarditis that should be considered carefully in the diagnosis and treatment of these patients.

Mediators of SARS-CoV-2 entry are preferentially enriched in cardiomyocytes.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has spread rapidly around the world. In addition to common respiratory symptoms such as cough and fever, some patients also have cardiac injury, however, the mechanism of cardiac injury is not clear. In this study, we analyzed the RNA expression atlases of angiotensin-converting enzyme 2(ACE2), cathepsin B (CTSB) and cathepsin L (CTSL) in the human embryonic heart at single-cell resolution. RESULTS: The results showed that ACE2 was preferentially enriched in cardiomyocytes. Interestingly, serine protease transmembrane serine protease 2 (TMPRSS2) had less expression in cardiomyocytes, but CTSB and CTSL, which belonged to cell protease, could be found to be enriched in cardiomyocytes. The results of enrichment analysis showed that differentially expressed genes (DEGs) in ACE2-positive cardiomyocytes were mainly enriched in the processes of cardiac muscle contraction, regulation of cardiac conduction, mitochondrial respiratory chain, ion channel binding, adrenergic signaling in cardiomyocytes and viral transcription. CONCLUSIONS: Our study suggests that both atrial and ventricular cardiomyocytes are potentially susceptible to severe acute respiratory syndrome coronavirus-2(SARS-CoV-2), and SARS-CoV-2 may enter ventricular cardiomyocytes using CTSB/CTSL for S protein priming. This may be the partial cellular mechanism of cardiac injury in patients with COVID-19.

MiR-135a Protects against Myocardial Injury by Targeting TLR4.

Emerging evidence highlights the importance of microRNAs (miRNAs) as functional regulators in cardiovascular disease. This study aimed to investigate the functional significance of miR-135a in the regulation of cardiac injury after isoprenaline (ISO) stimulation and the underlying mechanisms of its effects. Murine models with cardiac-specific overexpression of miR-135a were constructed with an adeno-associated virus expression system. The cardiac injury model was induced by ISO injection (60 mg/kg per day for 14 d). In vitro, we used H9c2 cells to establish a cell injury model by ISO stimulation (10 µM). The results indicated that miR-135a was increased during days 0-6 of ISO injection and was then downregulated during days 8-14 of ISO injection. The expression of miR-135a was consistent with the in vivo findings. Moreover, mice with cardiac overexpression of miR-135a exhibited reduced cardiac fibrosis, lactate dehydrogenase levels, Troponin I, inflammatory response and apoptosis. Overexpression of miR-135a also ameliorated cardiac dysfunction induced by ISO. MiR-135 overexpression in H9c2 cells increased cell viability and decreased cell apoptosis and inflammation in response to ISO. Conversely, miR-135 silencing in H9c2 cells decreased cell viability and increased cell apoptosis and inflammation in response to ISO. Mechanistically, we found that miR-135a negatively regulated toll-like receptor 4 (TLR4), which was confirmed by luciferase assay. Furthermore, the TLR4 inhibitor eritoran abolished the adverse effect of miR-135 silencing. Overall, miR-135a promotes ISO-induced cardiac injury by inhibiting the TLR4 pathway. MiR-135a may be a therapeutic agent for cardiac injury.

Mycobacterium tuberculosis type III-A CRISPR/Cas system crRNA and its maturation have atypical features.

Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems are prokaryotic adaptive immune systems against invading nucleic acids. CRISPR locus variability has been exploited in evolutionary and epidemiological studies of Mycobacterium tuberculosis, the causative agent of tuberculosis, for over 20 yr, yet the biological function of this type III-A system is largely unexplored. Here, using cell biology and biochemical, mutagenic, and RNA-seq approaches, we show it is active in invader defense and has features atypical of type III-A systems: mature CRISPR RNA (crRNA) in its crRNA-CRISPR/Cas protein complex are of uniform length (∼71 nt) and appear not to be subject to 3'-end processing after Cas6 cleavage of repeat RNA 8 nt from its 3' end. crRNAs generated resemble mature crRNA in type I systems, having both 5' (8 nt) and 3' (28 nt) repeat tags. Cas6 cleavage of repeat RNA is ion dependent, and accurate cleavage depends on the presence of a 3' hairpin in the repeat RNA and the sequence of its stem base nucleotides. This study unveils further diversity among CRISPR/Cas systems and provides insight into the crRNA recognition mechanism in M. tuberculosis, providing a foundation for investigating the potential of a type III-A-based genome editing system.-Wei, W., Zhang, S., Fleming, J., Chen, Y., Li, Z., Fan, S., Liu, Y., Wang, W., Wang, T., Liu, Y., Ren, B., Wang, M., Jiao, J., Chen, Y., Zhou, Y., Zhou, Y., Gu, S., Zhang, X., Wan, L., Chen, T., Zhou, L., Chen, Y., Zhang, X.-E., Li, C., Zhang, H., Bi, L. Mycobacterium tuberculosis type III-A CRISPR/Cas system crRNA and its maturation have atypical features.

Efficacy and safety of iron therapy in patients with chronic heart failure and iron deficiency: a systematic review and meta-analysis based on 15 randomised controlled trials.

Trials studying iron administration in patients with chronic heart failure (CHF) and iron deficiency (ID) have sprung up these years but the results remain inconsistent. The aim of this meta-analysis was to comprehensively evaluate the efficacy and safety of iron therapy in patients with CHF and ID. A literature search was conducted across PubMed, Embase, Cochrane Library, OVID and Web of Science up to 31 July 2019 to search for randomised controlled trials (RCT) comparing iron therapy with placebo in CHF with ID, regardless of presence of anaemia. Published studies reporting data of any of the following outcomes were included: all-cause death, cardiovascular hospitalisation, adverse events, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), N-terminal pro b-type natriuretic peptide, peak oxygen consumption, 6 min walking test (6MWT) distance and quality of life (QoL) parameters. 15 RCTs with a total of 1627 patients (911 in iron therapy and 716 in control) were included. Iron therapy was demonstrated to reduce the risk of cardiovascular hospitalisation (OR 0.35, 95% CI 0.12 to 0.99, p=0.049), but was ineffective in reducing all-cause death (OR 0.59, 95% CI 0.33 to 1.06, p=0.078) or cardiovascular death (OR 0.80, 95% CI 0.39 to 1.63, p=0.540). Iron therapy resulted in a reduction in NYHA class (mean difference (MD) -0.73, 95% CI -0.99 to -0.47, p<0.001), an increase in LVEF (MD +4.35, 95% CI 0.69 to 8.00, p=0.020), 6MWT distance (MD +35.44, 95% CI 11.55 to 59.33, p=0.004) and an improvement in QoL: EQ-5D score (MD +4.07, 95% CI 0.84 to 7.31, p=0.014); Minnesota Living With Heart Failure Questionnaire score (MD -19.47, 95% CI -23.36 to -15.59, p<0.001) and Patients Global Assessment (PGA) scale (MD 0.71, 95% CI 0.32 to 1.10, p<0.001). There was no significant difference in adverse events or serious adverse events between iron treatment group and control group. Iron therapy reduces cardiovascular hospitalisation in patients with CHF with ID, and additionally improves cardiac function, exercise capacity and QoL in patients with CHF with ID and anaemia, without an increase of adverse events.

Association Between R353Q (rs6046) Polymorphism in Factor VII with Coronary Heart Disease.

A number of studies have showed the relationship between R353Q (rs6046) polymorphism in factor VII gene and coronary heart disease (CHD). However, the results remain controversial due to the limitations of the research objects and small sample size of individual study. We conducted this meta-analysis to validate the association between R353Q (rs6046) polymorphism and the risk of CHD.The relevant data was collected up to March 25, 2019 from PubMed, Web of Science, CNKI, and Wanfang databases. We examined all eligible studies using the Newcastle-Ottawa Quality Assessment Scale (NOS). The odds ratio (OR) and its corresponding 95% confidence interval (CI) were adopted to evaluate the relationship between the R353Q (rs6046) polymorphism and CHD. Stata version 14.0 (Stata Corporation, USA) was used in all statistical tests.There were at least 28 eligible studies, including 14626 cases and 17994 controls, included in our meta-analysis. R353Q (rs6046) polymorphism was associated with the reduced risk of CHD in four genetic models: allele model (Q versus R: OR = 0.79, 95% CI: 0.69 to 0.90, P < 0.001, I2 = 56.4%), homozygote (co-dominant) model (QQ versus RR: OR = 0.72, 95% CI = 0.58 to 0.92, P = 0.004, I2 = 5.8%), heterozygote (co-dominant) model (RQ versus RR: OR = 0.71, 95% CI = 0.58 to 0.86, P = 0.001, I2 = 75.4%), and dominant model (RQ+QQ versus RR: OR = 0.74, 95% CI = 0.63 to 0.865, P < 0.001, I2 = 64.1%) excluding recessive model (QQ versus RR+RQ: OR = 0.86, 95% CI = 0.57 to 1.28, P = 0.447, I2 = 51.6%).The results of the current meta-analysis suggested that R353Q (rs6046) polymorphism was associated with the reduced risk of CHD, especially in Asians.

ALDH2 Gene rs671 Polymorphism May Decrease the Risk of Essential Hypertension.

Aldehyde dehydrogenase-2 (ALDH2) rs671 G>A polymorphism can influence the activity of ALDH2 and may be associated with the risk of essential hypertension (EH). Although many previous studies have explored such a relationship, the conclusion is still controversial.The PubMed, Embase, and China National Knowledge Infrastructure databases were searched on the ALDH2 gene and EH. We used the Newcastle-Ottawa Scale to evaluate the quality of the study. Then we calculated the strength of relationship between ALDH2 rs671 mutation and EH by utilizing odds ratios and 95% confidence intervals. Besides, subgroup analysis and sensitivity analysis were performed and the publication bias was assessed.There were 12 studies containing 8153 cases and 10,162 controls. Our meta-analysis showed significant association between ALDH2 rs671 polymorphism and EH in four genetic models (the allele model, the homozygote model, the heterozygote model, and the dominant model), whereas it did not indicate this connection in the recessive model. However, a trend of decreased risk still could be seen. Furthermore, we also found an obvious association between rs671 mutation and the risk of EH in the male group than in the female group in all five genetic models.We concluded that ALDH2 rs671 G>A polymorphism may decrease the risk of EH. Furthermore, susceptibility to EH reduced in males but not in females. As a variant in ALDH2, rs671 G>A could be an attractive candidate for genetic therapy of EH. In addition, more case-control studies should be conducted to strengthen our conclusion and evaluate the gene-gene and gene-environment interactions between the ALDH2 gene and EH.

Association Between MTHFR C677T Polymorphism and Congenital Heart Disease.

Many published studies have evaluated the association between the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) polymorphism and the risk of congenital heart disease (CHD); however, the specific conclusion is still controversial.To get a more accurate conclusion, we used a meta-analysis to evaluate the association between the MTHFR gene C677T polymorphism and the risk of CHD.Based on the design-based search strategy, a comprehensive literature search was conducted on PubMed, OVID, Cochrane Library, Embase, Wanfang, CNKI, and Web of Science. We selected the Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies. We performed a heterogeneity test on the results of the study and calculated the combined odds ratios (ORs) and its corresponding 95% confidence intervals (95% CIs) under a random- or fixed-effect model. Subgroup analyses were conducted by ethnicity, source of controls, sample size, and genotyping method. Sensitivity analysis was used to insure authenticity of this meta-analysis result. Egger's test and Begg's funnel plot were performed to detect publication bias.Eventually, our meta-analysis included 15 eligible studies. We observed a significant correlation between the MTHFR C677T polymorphism and the development of CHD in the recessive model (OR: 1.35, 95% CI: 1.06-1.71, P = 0.006) for the overall population. In subgroups stratified by ethnicity and source of controls, subgroup analyses indicated similar associations in Asians and hospital-based groups, but not for Caucasians and population-based groups. Egger's test and Begg's funnel plot demonstrated no significant publication bias in our study.Our analysis identified that MTHFR C677T allele is a risk genetic for CHD development, especially in Asians compared with Caucasians.

Identifying occult maternal malignancies from 1.93 million pregnant women undergoing noninvasive prenatal screening tests.

PURPOSE: Multiple chromosomal aneuploidies may be associated with maternal malignancies and can cause failure of noninvasive prenatal screening (NIPS) tests. However, multiple chromosomal aneuploidies show poor specificity and selectivity for diagnosing maternal malignancies. METHODS: This multicenter retrospective analysis evaluated 639 pregnant women who tested positive for multiple chromosomal aneuploidies on initial NIPS test between January 2016 and December 2017. Women were assessed using genome profiling of copy-number variations, which was translated to cancer risk using a novel bioinformatics algorithm called the cancer detection pipeline (CDP). Sensitivity, specificity, and positive predictive value (PPV) of diagnosing maternal malignancies were compared for multiple chromosomal aneuploidies, the CDP model, and the combination of CDP and plasma tumor markers. RESULTS: Of the 639 subjects, 41 maternal malignant cancer cases were diagnosed. Multiple chromosomal aneuploidies predicted maternal malignancies with a PPV of 7.6%. Application of the CDP algorithm to women with multiple chromosomal aneuploidies allowed 34 of the 41 (83%) cancer cases to be identified, while excluding 422 of 501 (84.2%) of the false positive cases. Combining the CDP with plasma tumor marker testing gave PPV of 75.0%. CONCLUSION: The CDP algorithm can diagnose occult maternal malignancies with a reasonable PPV in multiple chromosomal aneuploidies-positive pregnant women in NIPS tests. This performance can be further improved by incorporating findings for plasma tumor markers.

Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model. METHODS: HFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined. RESULTS: Blood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment. CONCLUSION: 9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.

Role of Endothelial Nitric Oxide Synthase Polymorphisms in Atrial Fibrillation: A PRISMA-Compliant Meta-Analysis.

BACKGROUND Research interest in endothelial nitric oxide synthase(eNOS) polymorphisms and atrial fibrillation (AF) has grown in last recent years, but the results of individual studies are inconsistent due to their small sample sizes. MATERIAL AND METHODS We searched databases for eligible studies on eNOS and AF, extracted the relevant data, and rigorously screened them according to inclusion and exclusion criteria. Then, we evaluated the study quality according to the Newcastle-Ottawa scale score, and we pooled the odds ratios (ORs) and 95% confidence intervals (CIs) by using a random-effects model or fixed-effects model based on inter-study heterogeneity. In addition, we performed subgroup analysis and sensitivity analysis and assessed publication bias. RESULTS According to the inclusion and exclusion criteria, we finally found 8 studies in this search. The recessive (OR=0.81; 95% CI=0.67 to 0.97; p=0.988; I²=0.0%) model showed that the eNOS 786T/C polymorphism was relevant to AF. We also found that the eNOS 786T/C polymorphism decreases the risk of AF, especially in white people (OR=0.81; 95% CI=0.67 to 0.97; P=0.023 for recessive model) and in the control population (OR=0.79; 95% CI=0.65 to 0.97; P=0.022 for recessive model). We found no obvious publication bias. CONCLUSIONS The eNOS gene loci 786T/C polymorphism is relevant to the risk of AF. Our results suggest that the 786T/C polymorphism significantly decreases AF risks in white people and control populations. Larger studies are required for further evaluation.

Evaluation of acute myocardial infarction patients with mid-range ejection fraction after emergency percutaneous coronary intervention.

BACKGROUND: There is currently no classification for acute myocardial infarction (AMI) according to left ventricular ejection fraction (LVEF). We aimed to perform a retrospective analysis of patients undergoing emergency percutaneous coronary intervention (PCI), comparing the clinical characteristics, in-hospital acute heart failure and all-cause death events of AMI patients with mid-range ejection fraction (mrEF), preserved ejection fraction (pEF) and reduced ejection fraction (rEF). MATERIAL AND METHODS: Totally 1270 patients were stratified according to their LVEF immediately after emergency PCI into pEF group (LVEF 50% or higher), mrEF group (LVEF 40%-49%) and rEF group (LVEF <40%). Kaplan-Meier curves and log rank tests were used to assess the effects of mrEF, rEF and pEF on the occurrence of acute heart failure and all-cause death during hospitalisation. The Cox proportional hazards model was used for multivariate correction. RESULTS: Compared with mrEF, rEF was an independent risk factor for acute heart failure events during hospitalisation (HR 5.01, 95% CI 3.53 to 7.11, p<0.001), and it was also an independent risk factor for all-cause mortality during hospitalisation (HR 7.05, 95% CI 4.12 to 12.1, p<0.001); Compared with mrEF, pEF was an independent protective factor for acute heart failure during hospitalisation (HR 0.49, 95% CI 0.30 to 0.82, p=0.01), and it was also an independent protective factor for all-cause death during hospitalisation (HR 0.33, 95% CI 0.11 to 0.96, p=0.04). CONCLUSIONS: mrEF patients with AMI undergoing emergency PCI share many similarities with pEF patients in terms of clinical features, but the prognosis is significantly worse than that of pEF patients, suggesting that we need to pay attention to the management of mrEF patients with AMI.

Growth of Rhodes grass and leaching of ions from seawater neutralized bauxite residues after amendment with gypsum and organic wastes.

A 32-week leaching column study was carried out in the greenhouse to investigate the effects of incorporation of gypsum, cattle manure, biosolids, gypsum plus cattle manure and gypsum plus biosolids into the topsoil layer (0-10 cm) on growth of Rhodes grass, and on root distribution and chemical and microbial properties in the topsoil and subsoil (10-30 cm) layers of seawater neutralized bauxite residues. The columns were leached for a period of 8 weeks prior to sowing Rhodes grass and during that time the bulk of the salts accumulated during seawater neutralization were leached out. The main cation leached was Na+ and the main balancing anions were Cl- and SO42-. During this period the pH of leachates rose from 7 to 8 up to 9-10. At the end of the study, exchangeable Na and pH were lowered in the surface horizon by all treatments with a combination of gypsum plus organic amendments having the greatest effect. The latter treatments also caused a significant decrease in pH, extractable Al and exchangeable Na in the subsoil. Rhodes grass dry matter production followed the order Control < gypsum < cattle manure = gypsum plus cattle manure < biosolids = gypsum plus biosolids. Growth of roots into the subsoil layer was inhibited in the Control and gypsum treatments but when organic amendments were applied, 50% or more of root dry matter was recovered in the subsoil layer. It was concluded that incorporating a combination of gypsum and organic matter into the surface soil is an effective strategy for revegetation of bauxite residue.

Tumor Necrosis Factor-α Gene Polymorphism (G-308A) and Dilated Cardiomyopathy.

The issue that genetic polymorphism of tumor necrosis factor-α (TNF-α) is associated with dilated cardiomyopathy (DCM) is debatable. We sought to investigate the potential role of TNF-α gene polymorphism (G-308A) in the susceptibility to dilated cardiomyopathy.We retrieved PubMed, EMBASE, and CNKI to collect all articles which reported on the association between TNF-α G-308A polymorphism and dilated cardiomyopathy. Two authors used the Newcastle-Ottawa Scale (NOS) checklist to assess the quality of the included studies. The odds ratio (OR) with 95% confidence intervals (CI) were pooled in a specific genetic model to assess the association and Stata version 14.0 software was used.A total of 9 studies with 1338 patients and 1677 controls were included in this study. The results from this meta-analysis indicated that TNF-α G-308A polymorphism significantly increased the risk of dilated cardiomyopathy in heterozygous comparison (GA versus GG: OR = 1.87; 95%CI = 1.03-3.40; P < 0.05). The increased risk of DCM was also found in Asian populations using a dominant model and heterozygous comparison (GA+AA versus GG: OR = 2.00, 95%CI = 1.02-3.92, P < 0.05; GA versus GG: OR = 1.94, 95%CI = 1.23-3.06, P < 0.05).The current meta-analysis revealed that TNF-α gene polymorphism (G-308A) may be associated with the susceptibility to DCM.

Biotransformation of a crizotinib intermediate using a mutant alcohol dehydrogenase of Lactobacillus kefir coupled with glucose dehydrogenase.

(S)-1-(2, 6-dichloro-3-fluorophenyl) ethanol, the key chiral intermediate of crizotinib, was prepared from 1-(2, 6-dichloro-3-fluorophenyl) ethanone using the alcohol dehydrogenases from Lactobacillus kefir (ADH-LK) with a tetrad mutant (ADH-LKM, F147L/Y190P/V196L/A202W), coupled with glucose dehydrogenase (GDH). In the present study, ADH-LKM and GDH were successfully heterologous expressed in recombinant Escherichia coli. During the regeneration of NADPH with GDH, 150 g/L substrate was totally transformed into target chiral alcohol with an enantiomeric excess value of 99.9% after 12 h at 30 °C (pH 7.0). Our study demonstrates the potential for industrial green production of the key chiral intermediate of crizotinib.

BET Bromodomain inhibition promotes De-repression of TXNIP and activation of ASK1-MAPK pathway in acute myeloid leukemia.

BACKGROUND: Targeted therapy has always been the focus in developing therapeutic approaches in cancer, especially in the treatment of acute myeloid leukemia (AML). A new small molecular inhibitor, JQ1, targeting BRD4, which recognizes the acetylated lysine residues, has been shown to induce cell cycle arrest in different cancers by inhibiting MYC oncogene. However, the downstream signaling of MYC inhibition induced by BET inhibitor is not well understood. METHODS: In this study, we explored the more mechanisms of JQ1-induced cell death in acute myeloid lukemia and downstream signaling of JQ1. RESULTS: We found that JQ1 is able to reactivate the tumor suppressor gene, TXNIP, and induces apoptosis through the ASK1-MAPK pathway. Further studies confirmed that MYC could repress the expression of TXNIP through the miR-17-92 cluster. CONCLUSIONS: These findings provide novel insight on how BET inhibitor can induce apoptosis in AML, and further support the development of BET inhibitors as a promising therapeutic strategy against AML.