ABO blood group influences risk of venous thromboembolism and myocardial infarction.

ABO blood group has been associated with various disease phenotypes. However, ABO blood group to influence patients in risk of venous thromboembolic events (VTEs) and arterial thromboembolic events (ATEs) remains controversial after evaluation in several reports. To fully assess effects of ABO blood group on VTEs and ATEs, we conducted a cross-sectional study and investigated the interaction between blood group and age, and between blood group and sex on the prevalence of VTEs and ATEs. In addition, the effect of blood group on ATEs in patients with atrial fibrillation (AF) was observed. Detailed information of 7830 patients was collected. Multivariate logistic regression analyses were used to evaluate the association between blood group and VTEs, pulmonary embolism (PE) and myocardial infarction (MI). In those 7830 patients, the respective risk of VTEs and PE was higher for patients with blood group A compared with blood group O individually. In those 6713 patients with rheumatic heart disease, cardiomyopathy, myocarditis, constrictive pericarditis, or valvular heart disease excluded, blood group A was associated with the risk of MI. For VTEs, PE, and MI, blood group also exhibited significant interactions with sex and age, although there was no evidence of interaction between blood group and age for VTEs. In addition, interactions among blood group, age, and AF for the ATEs were observed. Similar to prior population studies an association of ABO blood group with susceptibility to VTEs and MI was found. Age and sex may modulate the association between ABO blood group and these thromboembolic diseases.

Sex differences in risk factors for stroke in patients with hypertension and hyperhomocysteinemia.

Data on the sex-specific differences in risk of stroke among patients with H-type hypertension are limited. We aimed to analyze interactions between sex and other risk factors on stroke, including the sex-methylenetetrahydrofolate reductase (MTHFR) interaction. A retrospective analysis of baseline data from 2040 patients with hypertension and hyperhomocysteinemia (HHcy) included demographic characteristics, biomarkers, history of chronic diseases and lifestyle factors. Polymerase chain reaction-restriction fragment length polymorphism method was used to investigate the C677T polymorphism of MTHFR gene. We examined independent effects and interactions between sex and stratified factors on the risk of stroke by logistic regression model. A total of 1412 patients suffered stroke, and the prevalence of stroke was 70.65% in men and 66.53% in women. Both men and women had independent risk factors for stroke, including diabetes mellitus, atrial fibrillation, smoking, increased level of systolic blood pressure (SBP) and plasma total homocysteine (tHcy), as well as the decreased level of high-density lipoprotein cholesterol. Diastolic blood pressure (DBP) -specific risk of stroke was unique to men. Interactions between sex and other risk factors on stroke risk were statistically significant: age, fasting plasma glucose (FPG), SBP, DBP, triglycerides (TG) and tHcy. Furthermore, tHcy interacted with age, SBP and DBP in men, and age, SBP, DBP, FPG, and TG in women to modulate the risk of stroke. Although TT genotype did not have an independent effect on stroke, it could interact with sex and FPG, TG and SBP to increase stroke. In conclusion, sex-specific differences are useful to stratify the risk of stroke and assist clinicians in the decision to select a reasonable therapeutic option for high-risk patients.

Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth.

PURPOSE: Glioma is a highly aggressive and lethal brain tumor. Signal transducers and activators of transcription (STAT) pathway are widely implicated in glioma carcinogenesis. Our previous study found that the Fynrelated kinase (FRK) gene, plays as a tumor suppressor in the development and progression of glioma. This study aimed to investigate the role of FRK in the activation pathway of STATs and its effect on the growth of glioma. METHODS: The U251 and U87 cells with stable FRK overexpression were generated by lentivirus technique. The effects of FRK on the related proteins of STAT signaling pathway were detected by western blotting. Coimmunoprecipitation was used to detect the association of FRK and STAT1. The effects of STAT1 on the proliferation of glioma cells were detected by CCK8 or Edu cell proliferation assays. The expressions and correlation of FRK and p-STAT1 in glioma tissues were detectd by western blotting or immunohistochemistry. The effect of FRK on the growth of glioma was investigated in vivo mouse model. RESULTS: The level of p-JAK2 and p-STAT1 increased after FRK overexpression, while they decreased after FRK downregulation both in U251 and U87 cells. However, FRK had no effect on STAT3 phosphorylation. FRK-induced STAT1 activation was not dependent on JAK2. FRK associated with STAT1, induced STAT1 nuclear translocation and regulated the expressions of STAT1-related target genes. STAT1 overexpression suppressed the proliferation of glioma cells. In contrast, STAT1 knockdown by siRNA promoted glioma cell growth. Importantly, down-regulation of STAT1 partially attenuated FRK-induced growth suppression. The clinical sample-based study indicated that the expression of FRK was significantly correlated with the expression of p-STAT1. FRK significantly inhibited glioma tumor growth in vivo. CONCLUSIONS: Our findings highlighted a critical role of FRK in tumor suppression ability through promoting STAT1 activation, and provided a potential therapeutic target for glioma.

Self-assembled angiopep-2 modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles delivery TMZ for glioma synergistic TMZ and RT therapy.

The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH2s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.

Association between homocysteine and conventional predisposing factors on risk of stroke in patients with hypertension.

Previous studies have focused mostly on independent effects of the stroke risk factors, whereas little attention has been paid to interactions between individual factors which may be important for stroke prevention. We collected data related to the patients' demographic characteristics, history of chronic diseases and lifestyle factors in 2258 patients with primary hypertension. Logistic regression models based on odds ratio (OR) with their associated 95% confidence interval (CI) were used to estimate an independent effect of homocysteine (Hcy) on the risk of stroke but also include the interactions between Hcy and other risk factors. Hcy was associated with an increased OR of the risk of stroke in both hypertension patients (OR, 1.027; 95% CI, 1.016-1.038; P < 0.001) and H-type hypertension patients (OR, 1.026; 95% CI, 1.014-1.037; P < 0.001), after adjustment for potential confounding factors. Among the hypertension participants, three tests of interactions between Hcy and other risk factors were statistically significant: sex, systolic blood pressure and diastolic blood pressure. In conclusion, complexities of the interactions of Hcy stratified by sex and blood pressure need to be considered in predicting overall risk and selecting certain treatments for stroke prevention.

PCDH8 inhibits glioma cell proliferation by negatively regulating the AKT/GSK3ß/ß-catenin signaling pathway.

Protocadherin-8 (PCDH8), a member of the protocadherin superfamily of proteins, is frequently lost in numerous types of cancer. However, the role that PCDH8 serves in human glioma, and the molecular mechanisms underlying this, remain unclear. Data from the present study demonstrated that the expression levels of PCDH8 mRNA and protein were significantly decreased in human glioma tissue compared with normal brain tissue. This suggested that PCDH8 is associated with the development of glioma. Thus, the role of PCDH8 in glioma cell proliferation was investigated by silencing and overexpressing PCDH8 in U251 glioma cells. Overexpression of PCDH8 significantly inhibited glioma cell proliferation, while silencing of PCDH8 using small interfering RNA promoted glioma cell proliferation. Restoration of PCDH8 decreased phosphorylated (p)-Rac-α serine/threonine-protein kinase (AKT) [Threonine (T)308/Serine (S)473] and p-glycogen synthase kinase-3ß (p-GSK3ß) (S9) protein expression, thereby reducing the level of ß-catenin when compared with the control. By contrast, silencing of PCDH8 increased levels of p-AKT (T308/S473) and p-GSK3ß (S9), thereby increasing the level of ß-catenin. In conclusion, the results of the present study suggested that PCDH8 suppressed glioma cell proliferation, and that the loss of PCDH8 may stimulate the proto-oncogene Wnt/ß-catenin signaling pathway and therefore promote glioma cell proliferation.

Predictive value of CHADS2 and CHA2DS2-VASc scores for acute myocardial infarction in patients with atrial fibrillation.

The presence of acute myocardial infarction (AMI) confers a poor prognosis in atrial fibrillation (AF), associated with increased mortality dramatically. This study aimed to evaluate the predictive value of CHADS2 and CHA2DS2-VASc scores for AMI in patients with AF. This retrospective study enrolled 5140 consecutive nonvalvular AF patients, 300 patients with AMI and 4840 patients without AMI. We identified the optimal cut-off values of the CHADS2 and CHA2DS2-VASc scores each based on receiver operating characteristic curves to predict the risk of AMI. Both CHADS2 score and CHA2DS2-VASc score were associated with an increased odds ratio of the prevalence of AMI in patients with AF, after adjustment for hyperlipidaemia, hyperuricemia, hyperthyroidism, hypothyroidism and obstructive sleep apnea. The present results showed that the area under the curve (AUC) for CHADS2 score was 0.787 with a similar accuracy of the CHA2DS2-VASc score (AUC 0.750) in predicting "high-risk" AF patients who developed AMI. However, the predictive accuracy of the two clinical-based risk scores was fair. The CHA2DS2-VASc score has fair predictive value for identifying high-risk patients with AF and is not significantly superior to CHADS2 in predicting patients who develop AMI.

Association of High Homocysteine Levels With the Risk Stratification in Hypertensive Patients at Risk of Stroke.

PURPOSE: We aimed to investigate the association between stroke morbidity and different stratifications of classic risk factors, such as increasing age, body mass index (BMI), blood lipids, and blood glucose, in hypertensive patients with high homocysteine levels. METHODS: A cross-sectional study of 2258 patients with primary hypertension were enrolled in this study, including 871 stroke cases (62.89%) in 1385 hypertensive patients without hyperhomocysteinemia (HHcy) and 647 (74.11%) stroke cases in 873 hypertensive patients with HHcy. Basic information of patients were collected, including age, sex, height, weight, smoking, alcohol consumption, and disease history. Blood chemical assays were performed to determine the levels of glucose, triglycerides, high-density lipoprotein cholesterol (HDL-C), total cholesterol, and homocysteine. Subsequently, comparison of stroke morbidity between the 2 groups was performed after the stratification of risk factors. Moreover, the correlation between the stroke morbidity and the risk factors was analyzed using a trend test in patients with H-type hypertension. Univariate and multivariate logistic regression analyses were used to evaluate the association between baseline factors and prevalence of stroke in H-type hypertensive patients. FINDINGS: After the stratification of risk factors, a statistical difference was noted in age (range, 45-74 yrs), glucose ranges (<6.1 and ≥7.0 mmol/L), BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), non-HDL-C, and triglyceride level of <200 mg/dL (P<0.05) in the H-type hypertension group compared with those in non-H-type hypertension group. Gradual elevation of stroke morbidity was identified with the increase of fasting glucose, SBP, and DBP. In multivariate logistic regression analysis, only higher SBP, DBP, fasting glucose level, homocysteine, and history of diabetes mellitus were the independent predictors for the stroke morbidity. IMPLICATIONS: Comprehensive evaluation and strict management of multiple risk factors have become increasingly important in the alleviation of stroke morbidity for H-type hypertensive patients because these patients were more sensitive to the classic risk factors.

Effect of apelin on the cardiac hemodynamics in hypertensive rats with heart failure.

It is known that apelin has definite protective effects on various cardiovascular diseases; however, the mechanism through which hypertension with heart failure (H-HF) is affected by pyroglutamylated apelin-13 (Pyr-AP13) remain unclear. Thus, in the present study, we investigated the effects of apelin on the cardiac hemodynamics in rats with hypertension and heart failure. In our study, cardiac function, dimensions and histological determination of the fibrosis of rats with two-kidney, one-clip induced hypertension and sham-operated rats were assessed using an echocardiography system and Masson's trichrome. The infusion of either 5% glucose injection (GS) alone or 5% GS containing Pyr-AP13 as a dose, time-matched design on the cardiac hemodynamics in H-HF rats and sham-operated rats was recorded. For the determination of the effects of potential related proteins on cardiac hemodynamics in the H-HF rats, the animals were divided into 5 groups: i) the sham-operated group (n=8); ii) H-HF (n=8); iii) H-HF with infusion of 0.1 µg dose of Pyr-AP13 (n=8) or 5% glucose (GS) (n=8); iv) H-HF with infusion of 1 µg dose of Pyr-AP13 (n=8) or 5% GS (n=8); and v) H-HF with infusion of 10 µg dose of Pyr-AP13 (n=8) or 5% GS (n=8). The concentration of cyclic adenosine 3',5'-monophosphate (cAMP) was determined by ELISA. The expression of membrane and cytosolic proteins was evaluated by western blot analysis. Significant cardiac and perivascular fibrosis was observed in the H-HF rats. Following the infusion of Pyr-AP13, the systolic and diastolic function was significantly improved in the cardiac hemodynamic parameters in the H-HF rats treated with Pyr-AP13. The apelin receptor (APJ), which was activated by the exogenous infusion of Pyr-AP13, was partially recycled from the cytoplasm back to the plasma membrane; however, membrane APJ was eventually downregulated in the H-HF rats treated with Pyr-AP13 compared with the sham-operated group rats. Our findings suggested that a complex was formed after Pyr-AP13 combined with cellular membrane APJ receptor. However, the endogenous downregulation of the APJ receptor results in benefits from the exogenous administration of apelin.