Intratumoral Delivery of Interleukin 9 via Oncolytic Vaccinia Virus Elicits Potent Antitumor Effects in Tumor Models.

The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4+ and CD8+ T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy.

Declined plasma microfibrillar-associated protein 4 levels in acute coronary syndrome.

BACKGROUND: Microfibrillar-associated protein (MFAP4), initially identified as an extracellular matrix protein, has been demonstrated in multiple human disorders, but it is yet to be discovered following acute coronary syndrome (ACS) in clinical practice. Therefore, this study aimed to investigate the relationship between circulating MFAP4 levels and coronary stenosis in ACS. METHODS: We performed the study in 148 ACS subjects, including 75 ST-segment elevation myocardial infarction (STEMI), 27 non-ST-segment elevation myocardial infarction (non-STEMI) and 46 unstable angina (UA). Clinical variables were collected and Gensini and Syntax stenosis scoring systems were applied to assess the severity of coronary stenosis. Kaplan-Meier and logistic regression analysis were used to analyze the relationship between MFAP4 and the severity of coronary stenosis or ACS outcomes. Spearman analysis was used to describe the correlation between MFAP4 and clinical parameters. RESULTS: Circulating MFAP4 levels were significantly decreased in the STEMI group (0.008 ng/ml) compared with the non-STEMI group (0.014 ng/ml) and UA group (0.019 ng/ml) (p < 0.001). After adjusting for confounding factors, we found that MFAP4 was an independent risk factor for STEMI (odds ratio = 0.395, 95% CI 0.174-0.895, p = 0.026). MFAP4 level was negatively correlated with Gensini score and Syntax score (r = - 0.311 and - 0.211, p < 0.001 and 0.01, respectively). Based on the MFAP4 level of 0.117 ng/ml, ACS patients were divided into two groups: the low-MFAP4 group (< 0.117 ng/ml, n = 60) and the high-MFAP4 group (≥ 0.117 ng/ml, n = 88). After the median follow-up of 165 days, Kaplan-Meier survival analysis revealed that the MACE-free rate was significantly lower in ACS patients with lower MFAP4 levels (p = 0.009). CONCLUSIONS: MFAP4 has a potential as a biomarker for the degree of coronary stenosis in ACS. Confirmation of observations in larger cohorts and longer follow-up periods is warranted.

A Novel Reperfusion Strategy for Primary Percutaneous Coronary Intervention in Patients with Acute ST-Segment Elevation Myocardial Infarction: A Prospective Case Series.

BACKGROUND: Ischemia reperfusion injury (IRI) remains a major problem in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). We have developed a novel reperfusion strategy for PCI and named it "volume-controlled reperfusion (VCR)". The aim of the current study was to assess the safety and feasibility of VCR in patients with STEMI. METHODS: Consecutive patients admitted to Beijing Chaoyang Hospital with STEMI were prospectively enrolled. The feasibility endpoint was procedural success. The safety endpoints included death from all causes, major vascular complications, and major adverse cardiac event (MACE), i.e., a composite of cardiac death, myocardial reinfarction, target vessel revascularization (TVR), and heart failure. RESULTS: A total of 30 patients were finally included. Procedural success was achieved in 28 (93.3%) patients. No patients died during the study and no major vascular complications or MACE occurred during hospitalization. With the exception of one patient (3.3%) who underwent TVR three months after discharge, no patient encountered death (0.0%), major vascular complications (0.0%), or and other MACEs (0.0%) during the median follow-up of 16 months. CONCLUSION: The findings of the pilot study suggest that VCR has favorable feasibility and safety in patients with STEMI. Further larger randomized trials are required to evaluate the effectiveness of VCR in STEMI patients.

Ferroptosis Inducer Improves the Efficacy of Oncolytic Virus-Mediated Cancer Immunotherapy.

Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. In this study, we explore the combination of a ferroptosis activator with an oncolytic vaccinia virus in tumor models. Erastin induced cell death in hepatoma, colon, and ovarian cancer cells, but not in melanoma cancer cells. Erastin, not the oncolytic vaccinia virus (OVV), induced the expression of key marker genes for ferroptosis in cancer cells. In hepatocellular carcinoma and colon cancer models, either erastin or OVV inhibited tumor growth, but a combination of the two yielded the best therapeutic effects, as indicated by inhibited tumor growth or regression and longer host survival. Immunological analyses indicate that erastin alone had little or no effect on systemic immunity or local immunity in the tumor. However, when combined with OV, erastin enhanced the number of activated dendritic cells and the activity of tumor-infiltrating T lymphocytes as indicated by an increase in IFN-γ+CD8+ and PD-1+CD8+ T cells. These results demonstrate that erastin can exert cytotoxicity on cancer cells via ferroptosis, but has little effect on immune activity by itself. However, when combined with an OVV, erastin promoted antitumoral immunity and efficacy by increasing the number of activated dendritic cells and promoting the activities of tumor specific CD8+ T cells in the tumor.

Elevated Plasma Thymic Stromal Lymphopoietin After Acute Myocardial Infarction.

Background: Thymic stromal lymphopoietin (TSLP), a distant paralog of the cytokine IL-7, has been shown to be associated with atherosclerosis. However, the effect of plasma TSLP level after acute myocardial infarction (AMI) remains largely unclear. Thus, we aimed to assess the relationship between the concentration of TSLP at admission and the risk of major adverse cardiovascular events (MACE) in AMI patients. Methods: A total of 175 patients with AMI and 145 unstable angina (UA) controls were recruited in the present study. The clinical characteristics were collected, and MACE was recorded during hospitalization and the follow-up period after discharge. Results: The median value (25, 75 percentiles) of TSLP concentrations in the AMI group was higher than that in the UA group [11.18 (8.14-15.22) vs. 8.56 (5.26-11.94) pg/ml, p < 0.001, respectively]. Multivariate linear regression analysis revealed that Troponin-I (standardized ß = 0.183, p = 0.004) was an independent factor for TSLP. According to the median of TSLP concentrations, all the AMI patients were divided into the high-level group (TSLP level ≥ 11.18 pg/ml, N = 91) and the low-level group (TSLP <11.18 pg/ml, N = 84). In a receiver operating characteristic curve analysis, the area under the curve for TSLP as a predictor of AMI was 0.674 with a cut-off value of 9.235 pg/ml. After a median follow-up of 14 months, Kaplan-Meier survival analysis showed no significant difference in MACE-free survival between the two groups (p = 0.648). Finally, the multivariate logistic regression analyses demonstrated that TSLP was a negative predictor of MACE in AMI patients (OR:0.778,95% CI:0.733-0.876, p = 0.032). Conclusions: Plasma TSLP levels were elevated in patients with AMI than those in UA. The lower TSLP concentration was associated with MACE after AMI.

Patients with end-stage renal disease requiring hemodialysis benefit from percutaneous coronary intervention after non-ST-segment elevation myocardial infarction.

Percutaneous coronary intervention (PCI) treatment significantly improves outcomes after acute myocardial infarction (AMI). It remains unclear whether the benefits of PCI exist in patients with end-stage renal disease (ESRD) and non-ST-segment elevation myocardial infarction (NSTEMI). The present study was designed to investigate the effects of PCI on the short- and long-term prognosis of patients with ESRD and NSTEMI. We conducted a retrospective study from 1 January 2015 to 1 January 2020, which includes 148 consecutive patients with ESRD and NSTEMI. All patients were estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 and had received regular hemodialysis treatment before hospitalization. Logistic regression analyses were used to identify the risk factors for in-hospital mortality. Cox proportional hazard model was used to identify independent predictors of 1-year major adverse cardiac events (MACE). In this study, 62 patients received PCI treatment. Univariable logistic regression analysis showed that PCI treatment was associated with the trend of reduction in the risk of in-hospital mortality (11.3% vs 43%, P = 0.022), but was not independently related to lower in-hospital mortality risk after multivariable logistic regression analysis (P = 0.131). After a 1-year follow-up, Kaplan-Meier survival analysis demonstrated that MACE rate was significantly lower in patients with ESRD and NSTEMI who had received PCI treatment during hospitalization (P < 0.001). After multivariate Cox proportional hazard analysis, no PCI treatment was independently associated with 1-year MACE (hazard ratios 3.217, 95% CI 2.03-8.489, P = 0.003). PCI treatment during hospitalization is associated with reduced 1-year MACE in patients with ESRD and NSTEMI, which suggests that more aggressive therapies may be beneficial for this special higher risk population.

Oncolytic Virus Immunotherapy: Showcasing Impressive Progress in Special Issue II.

Cancer immunotherapy has recently become the most promising strategy for hard-to-treat, advanced-stage malignancies [...].

Impact of Prior Digestive System Disease on In-Hospital Gastrointestinal Bleeding in Patients with Acute Myocardial Infarction.

OBJECTIVE: Patients presenting with acute myocardial infarction (AMI) with prior digestive system disease are more likely to suffer from gastrointestinal (GI) bleeding than those without these diseases. However, few articles reported how the different conditions of the digestive tract produced different risks of GI bleeding. METHODS: A single-center study on 7464 patients admitted for AMI from December 2010 to June 2019 in the Beijing Chaoyang Heart Center was retrospectively examined. Patients with major GI bleeding (n = 165) were compared with patients without (n = 7299). Univariate and multivariate logistic regression models were constructed to test the association between GI bleeding and prior diseases of the digestive tract, including gastroesophageal reflux disease, chronic gastritis, peptic ulcer, hepatic function damage, diseases of the colon and rectum, and gastroenterological tract tumors. RESULTS: Of the 7464 patients (mean age, 63.4; women, 25.6%; STEMI, 58.6%), 165 (2.2%) experienced major GI bleeding, and 1816 (24.3%) had a history of digestive system disease. The risk of GI bleeding was significantly associated with peptic ulcer (OR = 4.19, 95% CI: 1.86-9.45) and gastroenterological tumor (OR = 2.74, 95% CI: 1.07-7.04), indicated by multivariate logistic regression analysis. CONCLUSION: Preexisting peptic ulcers and gastroenterological tract tumors rather than other digestive system diseases were indicators of gastrointestinal bleeding in patients with AMI who undergo standard antithrombotic treatment during hospitalization.

The long-term impact of a chronic total occlusion in a non-infarct-related artery on acute ST-segment elevation myocardial infarction after primary coronary intervention.

OBJECTIVES: To investigate the long-term outcome of patients with acute ST-segment elevation myocardial infarction (STEMI) and a chronic total occlusion (CTO) in a non-infarct-related artery (IRA) and the risk factors for mortality. METHODS: The enrolled cohort comprised 323 patients with STEMI and multivessel diseases (MVD) that received a primary percutaneous coronary intervention between January 2008 and November 2013. The patients were divided into two groups: the CTO group (n = 97) and the non-CTO group (n = 236). The long-term major adverse cardiovascular and cerebrovascular events (MACCE) experienced by each group were compared. RESULTS: The rates of all-cause mortality and MACCE were significantly higher in the CTO group than they were in the non-CTO group. Cox regression analysis showed that an age ≥ 65 years (OR = 3.94, 95% CI: 1.47-10.56, P = 0.01), a CTO in a non-IRA(OR = 5.09, 95% CI: 1.79 ~ 14.54, P < 0.01), an in-hospital Killip class ≥ 3 (OR = 4.32, 95% CI: 1.71 ~ 10.95, P < 0.01), and the presence of renal insufficiency (OR = 5.32, 95% CI: 1.49 ~ 19.01, P = 0.01), stress ulcer with gastraintestinal bleeding (SUB) (OR = 6.36, 95% CI: (1.45 ~ 28.01, P = 0.01) were significantly related the 10-year mortality of patients with STEMI and MVD; an in-hospital Killip class ≥ 3 (OR = 2.97,95% CI:1.46 ~ 6.03, P < 0.01) and the presence of renal insufficiency (OR = 5.61, 95% CI: 1.19 ~ 26.39, P = 0.03) were significantly related to the 10-year mortality of patients with STEMI and a CTO. CONCLUSIONS: The presence of a CTO in a non-IRA, an age ≥ 65 years, an in-hospital Killip class ≥ 3, and the presence of renal insufficiency, and SUB were independent risk predictors for the long-term mortality of patients with STEMI and MVD; an in-hospital Killip class ≥ 3 and renal insufficiency were independent risk predictors for the long-term mortality of patients with STEMI and a CTO.

A risk score model to predict in-hospital mortality of patients with end-stage renal disease and acute myocardial infarction.

Chronic kidney disease (CKD) significantly increases the rate of adverse cardiovascular events in patients with coronary artery disease. In this study, we aimed to establish a risk score (RS) model to predict in-hospital mortality risk in patients with end-stage renal disease (ESRD) and acute myocardial infarction (AMI). A total of 113 consecutive patients with ESRD and AMI were retrospectively enrolled between January 1, 2015 and December 31, 2019. All patients received regular hemodialysis and were divided into two groups according to the prognosis during hospitalization. Univariable and multivariable logistic regression analyses were used to identify the risk factors of in-hospital mortality. A RS model was developed based on multiple regression analysis and was internally validated using 1000 bootstrap analysis. The receiver operating characteristic (ROC) curve was performed, and the area under curve (AUC) was analyzed to evaluate the performance of the RS model. AUCs were compared using the Z test. Thirty-three patients died during hospitalization, resulting in in-hospital mortality rate of 29.2%. After multivariate logistic regression, an RS model (0-8) was established based on five independent factors that were assigned with different points according to relative coefficients (coefficient of the index risk factor divided by the lowest coefficient among these five risk factors; rounded to closest integer): 1 for C-reactive protein (CRP) ≥ 14.2 mg/L and left ventricular ejection fraction (LVEF) ≤ V3%; 2 for age ≥ 65 years old, heart rate (HR) at admission ≥ 86 beats per minute (bpm) and D-dimer ≥ 2.4 mg/L FEU. The present RS model had a sensitivity of 85.7%, the specificity of 84%, and an accuracy of 78.1%. In ROC curve analysis, the model demonstrated a good discriminate power in predicting in-hospital mortality (AUC = 0.895, 95% CI 0.814-0.96; P < 0.001), which was significantly better than the predictive power of the Global Registry of Acute Coronary Events risk score (GRACE RS) (AUC = 0.754, 95% CI 0.641-0.868; P < 0.001 after Z test). A novel RS model, which was established to help predict in-hospital mortality of patients with ESRD and AMI, was easy to use and had higher accuracy than the GRACE RS.

Blood group A: a risk factor for heart rupture after acute myocardial infarction.

INTRODUCTION: Studies have been performed to identify the association between ABO blood groups and coronary artery disease. However, data is scarce about the impact of ABO blood groups on heart rupture (HR) after acute myocardial infarction (AMI). METHODS: We conducted a retrospective case-control study that included 61 consecutive patients with HR after AMI during a period from 1 January 2012 to 1 December 2019. The controls included 600 patients who were selected randomly from 8143 AMI patients without HR in a ratio of 1:10. Univariate and multivariate logistic regression analysis were used to identify the association between ABO blood groups and HR. RESULTS: Patients with blood group A had a greater risk of HR after AMI than those with non-A blood groups (12.35% vs 7.42%, P < 0.001). After adjusting for age, gender, heart rate at admission, body mass index (BMI), and systolic blood pressure (SBP), blood group A was independently related to the increased risk of HR after AMI (OR = 2.781, 95% CI 1.174-7.198, P = 0.035), and remained as an independent risk factor of HR after AMI in different multivariate regression models. CONCLUSION: Blood group A is significantly associated with increased HR risk after AMI.

Circulating Serpina3 levels predict the major adverse cardiac events in patients with myocardial infarction.

BACKGROUND: Serine proteinase inhibitor A3 (Serpina3), initially discovered as an acute phase plasma protease inhibitor, has been demonstrated in the pathology of complex human disorders, but it is yet to be discovered following acute myocardial infarction (AMI) in clinical practice. Therefore, we aimed to evaluate the relationship between Serpina3 concentrations at admission and the risk of major adverse cardiovascular events (MACE) in patients with AMI. METHODS: A total of 120 AMI patients and 60 healthy participants were consecutively enrolled in our study. Clinical parameters variables were collected, and MACE was followed since hospitalization. RESULTS: Plasma concentrations of Serpina3 were elevated after AMI [159.11 (121.81, 237.07) vs. 300.18 (187.90, 478.59) µg/mL, P < 0.001]. Multivariate linear regression analysis indicated that total cholesterol (standardized ß = -0.204, P = 0.024) and ESR (standardized ß = 0.513, P < 0.001) were independent factors for Serpina3. Based on the median value of Serpina3 in the AMI population, patients were divided into the high-Serpina3 group (≥300.18 µg/mL, n = 65) and the low-Serpina3 group (<300.18 µg/mL, n = 60). After a median follow-up of 9 months, Kaplan-Meier survival analysis revealed that the MACE-free survival rate was significantly lower in AMI patients with higher Serpina3 levels (P = 0.002). Multivariate Cox proportional hazards analyses demonstrated that Serpina3 was a positive predictor of MACE (hazard ratios 4.03, 95% CI 1.25-12.98, P = 0.019). CONCLUSIONS: Increased circulating Serpina3 levels following AMI is significantly associated with MACE, which suggest that Serpina3 may be a potential predictive marker of clinical outcomes in AMI.

Proteomics of epicardial adipose tissue in patients with heart failure.

Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot closely linked to the pathogenesis of heart failure (HF). But the molecular signatures related to the mechanism of HF have not been systematically explored. Here, we present comprehensive proteomic analysis of EAT in HF patients and non-HF patients as controls. A total of 771 proteins were identified in liquid chromatography-tandem mass spectrometry experiments. Amongst them, 17 increased in abundance in HF and seven decreased. They were involved in HF-related processes including inflammation and oxidative stress response and lipid metabolism. Of these proteins, serine proteinase inhibitor A3 (Serpina3) levels in EAT were highly up-regulated in HF, with HF/non-HF ratio of 4.63 (P = .0047). Gene expression of Serpina3 via quantitative polymerase chain reaction was significantly increased in the HF group. ELISA analysis confirmed a significant increase in circulating plasma Serpina3 levels in the HF group (P = .004). In summary, for the first time, we describe that parts of EAT proteome may be reactive and work as modulators of HF. Our profiling provides a comprehensive basis for linking EAT with pathogenesis of HF. Understanding the role of EAT may offer new insights into the treatment of HF.

Analysis of long non-coding RNA and mRNA profiles in epicardial adipose tissue of patients with atrial fibrillation.

Accumulating studies have suggested that epicardial adipose tissue (EAT) play an important role in the pathogenesis of atrial fibrillation (AF), but few have characterized the underlying mechanism between their interactions. Recent evidence suggested that bioactive molecules secreted from EAT, including exosomes carrying long non-coding RNAs (lncRNAs), may modulate atrial remodeling. LncRNAs are associated with cardiovascular disorders, including AF, but their roles in EAT remain elusive. The aim of the present study was to investigate the expression profile of lncRNAs in EAT with AF. Differentially expressed lncRNAs and nearby mRNAs interaction networks were constructed. Epicardial adipose samples were collected from patients with persistent non-valvular AF (n = 6) and sinus rhythm (SR) (n = 6), and the expression of lncRNAs and mRNAs were profiled using RNA-sequencing method. A total of 46,577 transcripts, including 35,552 protein-coding pattern, corresponding to 15,404 genes in EAT, among which, 655 mRNAs (265 upregulated and 390 downregulated) and 57 lncRNAs (17 upregulated and 40 downregulated) were differentially expressed between AF and SR (P < 0.05; fold change>1.5). GO enrichment, KEGG pathway analysis and interaction network construction showed that these differentially expressed lncRNAs were enriched in functional categories, including metabolism and stress response, which might contribute to the pathogenesis of AF. Our study demonstrated a differentially expressed lncRNA profile in EAT with AF, and provide a novel insight into the interactions between EAT and AF.

Does pre-angiography Total ST-segment resolution reliably predict spontaneous reperfusion of the infarct-related artery in patients with acute myocardial infarction?

BACKGROUND: ST resolution (STR) after AMI is a non-invasive indicator of IRA reperfusion. We investigated whether pre-angiography STR predicted spontaneous IRA reperfusion in STEMI patients. METHOD: Patients with STEMI undergoing primary PCI were recruited. Standard 12-lead ECG tracings were recorded at first medical contact, immediately prior to arterial puncture and 60 min after PCI. STR was classified as total (≥70%; group I), partial (≥30 and < 70%; group II) or none (< 30%; group III). Patients were followed up for 1-year. RESULTS: The final analysis included 349 patients (n = 77, 160 and 112 for groups I, II and III, respectively). Compared with groups I/II, pre-procedural TIMI flow in group III was less frequently grades 2 or 3 (P < 0.001). Pre-PCI STR ≥70% was an independent predictor of pre-PCI TIMI-3 flow (OR: 2.8; P < 0.001). Pre-PCI STR < 30% was independently associated with pre-PCI TIMI flow 0-2 (OR: 3.1; P < 0.001). STR = 35.55% seems to be an optimal cut off for pre-procedural TIMI-3 flow prediction with sensitivity 0.943, specificity 0.456, Youden index 0.399, P = 0.027. STR prior to PCI was inversely correlated with 1-year combined CV events rate. STR > 70% may predict a better clinical outcome. CONCLUSIONS: Assessment of STR could potentially be used to stratify risk in patients with STEMI before PCI.

Impact of Cardiogenic Vomiting in Patients with STEMI: A Study From China.

BACKGROUND Different patients with ST-elevation myocardial infarction (STEMI) have different symptoms. A third of them may have medical emergencies caused by symptoms such as vomiting and syncope. These concomitant symptoms may influence subsequent therapy and final outcomes. The aim of this study was to determine whether cardiogenic vomiting is a predictor of clinical outcomes in patients with STEMI. MATERIAL AND METHODS We classified 152 STEMI patients from different areas into 2 groups on the basis of vomiting: group A and group B. Their demographics and conditions of hospitalization were recorded. After follow-up, major adverse cardiac events (MACE) were regarded as study endpoints for the effect of cardiogenic vomiting in STEMI patients. RESULTS We found no significant difference in demographic and clinical characteristics of the 2 groups (P>0.05). The hospitalized conditions of group A were more serious than in group B. During a follow-up of 6 months, MACE rate was higher in vomiting patients (42; 67.7%) compared with group B (25; 27.8%). Multivariate Cox regression analysis revealed that cardiogenic vomiting was an independent predictor of clinical outcomes. CONCLUSIONS Cardiogenic vomiting is a useful predictor of major adverse cardiac events in STEMI patients for the hospitalization and after discharge.

miR-574-5p negatively regulates Qki6/7 to impact ß-catenin/Wnt signalling and the development of colorectal cancer.

OBJECTIVE: Deficiency or reduced expression of signal transduction and activation of RNA family protein Quaking (Qki) is associated with developmental defects in neural and vascular tissues and the development of debilitating human diseases including colorectal cancer (CRC). However, the mechanisms underlying the aberrant downregulation or deficiency of Qki were uncertain. DESIGN: Expression of miR-574-5p, Qki5/6/7/7b splicing variants, ß-catenin and p27(Kip1) was determined in mouse and human CRC cells and tissues to investigate the post-transcriptional regulation of Qki isoforms by miR-574-5p and its impact on ß-catenin/p27(Kip1) signalling, cell cycle progression, proliferation, migration, invasion and tumour growth. RESULTS: In the CRC tissues of C57BL/6-Apc(min/+) mice, miR-574-5p was found to be significantly upregulated and negatively correlated with the expression of Qki but positively correlated with the expression of ß-catenin. In mouse and human CRC cells, miR-574-5p was shown to regulate Qki isoforms (Qki6/7 in particular) post-transcriptionally and caused altered expression in ß-catenin and p27(Kip1) , increased proliferation, migration and invasion and decreased differentiation and cell cycle exit. Furthermore, in clinical CRC tissues, miR-574-5p was shown to be greatly upregulated and inversely correlated with the expression of Qkis. Finally, inhibition of miR-574-5p was shown to suppress the growth of tumours in the nude mice. CONCLUSIONS: Together, these novel findings suggest that miR-574-5p is a potent ribo-regulator for Qkis and that aberrant miR-574-5p upregulation can be oncogenic.

Aldo-keto reductase-7A protects liver cells and tissues from acetaminophen-induced oxidative stress and hepatotoxicity.

UNLABELLED: Aldo-keto reductase-7A (AKR7A) is an enzyme important for bioactivation and biodetoxification. Previous studies suggested that Akr7a might be transcriptionally regulated by oxidative stress-responsive transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a protein highly responsive to acetaminophen (APAP) or its intermediate metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). This study was, therefore, carried out to investigate whether Akr7a is involved in the protection against APAP-induced oxidative stress and hepatotoxicity. We found that in response to APAP or NAPQI exposure, Akr7a3 mRNA and protein were significantly up-regulated in vitro in human HepG2 and LO2 cells. Similarly, strong induction was observed for Akr7a5 in mouse AML12 hepatocytes exposed to APAP. In vivo in wild-type rats, significant up-regulation of hepatic AKR7A1 protein was observed after administration of APAP. On the other hand, depletion of Nrf2 reduced the expression of Akr7a3, suggesting that Nrf2, indeed, contributes significantly to the induction of Akr7a. Moreover, loss of cell viability in Nrf2-depleted cells was significantly rescued by coexpression of AKR7A3. Furthermore, increased AKR7A3 in HepG2 cells was associated with the up-regulation of oxidative stress-related enzymes to enhance cellular antioxidant defense, which appeared to contribute significantly to protection against APAP-induced toxicity. In a line of transgenic rats overexpressing AKR7A1, increased AKR7A1 stimulated the expression of Nrf2 and other Nrf2-regulated genes, but did not better protect rats from APAP insults. In contrast, depletion of Akr7a5 in vitro in cultured AML12 cells or depletion of Akr7a1 in vivo in rat liver greatly increased APAP-induced hepatotoxicity. CONCLUSION: AKR7A proteins are significantly up-regulated in response to APAP/NAPQI exposure to contribute significantly to protection against APAP-induced hepatotoxicity. AKR7A mediates this protection, in part, through enhancing hepatocellular antioxidant defense.

Gender differences in efficacy of primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction.

BACKGROUND: The clinical outcome of percutaneous coronary intervention (PCI) is poorer in women than that in men. This study aimed at comparing the impact of gender difference on the strategy of primary PCI in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: Two hundred and fifty-nine patients with STEMI who underwent primary PCI within 12 hours of symptom onset were enrolled. The male group consisted of 143 men aged > 55 years, and a female group included 116 women without age limitation. Procedural success was defined as residual stenosis < 20% with thrombolysis in myocardial infarction flow grade > 2 and without death, emergency bypass surgery or disabling cerebral events during the hospitalization. The rate of major adverse cardiac events (MACE), including death, nonfatal myocardial infarction and target vessel revascularization during follow-up, was recorded. RESULTS: Female patients were more hypertensive and diabetic and with fewer cigarette smokers than male counterparts. The prevalence of angiographic 3-vessel disease was higher in the female group, but the procedural success rate was comparable between the two groups (94.4% vs 92.2%). The occurrence rate of MACE did not differ during the hospitalization (4.2% vs 6.0%, P = 0.50), but was significantly higher in the female group during follow-up (mean (16.0 +/- 11.2) months) than that in the male group (5.4% vs 0.7%, P = 0.02). CONCLUSION: Despite a similar success rate of primary PCI and in-hospital outcomes in both genders, female patients with acute STEMI still have a worse prognosis during the long-term follow-up.