Silencing EIF3A ameliorates pulmonary arterial hypertension through HDAC1 and PTEN/PI3K/AKT pathway in vitro and in vivo.

Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation, and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro. EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo. In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.

DPP3 expression promotes cell proliferation and migration in vitro and tumour growth in vivo, which is associated with poor prognosis of oesophageal carcinoma.

Dipeptidyl peptidase III (DPP3), a zinc­dependent metallopeptidase, is upregulated in a variety of malignancies. However, little is known about its roles in the pathogenesis of these malignancies. The present study was designed to investigate the roles of DPP3 in the pathogenesis and progression of oesophageal cancer (EC). The expression level of DPP3 in EC tissues and adjacent normal tissues was detected in 93 cases of tissue biopsies collected from patients diagnosed with oesophageal carcinoma by immunohistochemistry. The effect of DPP3 expression on cell proliferation, migration or apoptosis was determined in DPP3­depleted EC cells created by infection with lentivirus containing short hairpin RNA specific to the human DPP3 mRNA sequence, followed by detection at the cellular level using a Celigo cell count assay, flow cytometry, wound­healing assay and Transwell assay as well as chip screening with a Human Apoptosis Antibody Array kit, which enables the quantitative detection of 43 apoptosis­related genes. A xenograft model was applied to detect the tumour growth and invasion of DPP3­depleted cancer cells in nude mice. The results revealed that DPP3 expression was elevated in EC tissues compared with adjacent non­tumour tissues, and high DPP3 expression was significantly associated with poor prognosis. DPP3 depletion resulted in reduced cell proliferation and migration and enhanced cell cycle arrest and apoptosis of EC cells and led to the inhibition of tumour growth and invasion in a xenograft model. In addition, DPP3 depletion was associated with the upregulation of the proapoptotic proteins SMAC and p53 and the downregulation of the antiapoptotic proteins clAP­2, IGFBP­2 and TRAILR­4. Finally, DPP3 may promote cell proliferation, migration and survival of EC cells in vitro and tumour growth and invasion of oesophageal carcinoma in vivo, and thus may serve as a molecular target for tumour therapy.

Serum Globulin to Albumin Ratio as a Novel Predictor of Adverse Clinical Outcomes in Coronary Artery Disease Patients Who Underwent PCI.

Background: Coronary heart disease is one of the main causes of Mortality. Many biological indicators have been used to predict the prognosis of patients with coronary heart disease. The ratio of serum globulin to albumin (GAR) has been used to predict the prognosis of patients with various cancers. It has been proven that GAR is related to the prognosis of patients with stroke. However, GAR's role in cardiovascular disease remains unclear. Our purpose was to investigate the predictive value of GAR on clinical outcomes in post-percutaneous coronary intervention (PCI) patients with coronary artery disease (CAD). Methods: From Dec. 2016 to Oct. 2021, a total of 14,994 patients undergoing PCI patients admitted to the First Affiliated Hospital of Xinjiang Medical University were divided into high GAR group (GAR ≥ 0.76, n = 4087) and low GAR group (GAR < 0.76, n = 10,907). The incidence of adverse outcomes including all-cause mortality (ACM), cardiovascular mortality (CM), major adverse cardiovascular events (MACE) and major adverse cardiovascular and cerebrovascular events (MACCE) was compared between the two groups. Multivariate Cox regression was used to adjust for the effects of confounding factors, while hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated. Median follow-up time was 24 months. Results: Compared with the low GAR group, the high GAR group had significantly higher incidence of ACM (6.5% vs. 1.7%, p < 0.001); CM (4.9% vs. 1.2%, p < 0.001), MACE (10.5% vs. 6.7%, p < 0.001), and MACCE (11.3% vs. 7.5%, p < 0.001). Cox regression analysis showed the patients in the high GAR group had a 1.62-fold increased risk for ACM (HR = 2.622, 95% CI: 2.130-3.228, p < 0.01), a 1.782-fold increased risk for CM (HR = 2.782, 95% CI: 2.180-3.550, p < 0.01). There was a 37.2% increased risk for MACE (HR = 1.372, 95% CI: 1.204-1.564, p < 0.01), and 32.4% increased risk for MACCE (HR = 1.324, 95% CI: 1.169-1.500, p < 0.01), compared to the patients in the low GAR group. Conclusions: The present study suggested that post-PCI CAD patients with higher GAR presented significantly increased mortality and adverse events GAR level at admission may 296 be considered as part of risk stratification when PCI is possible in patients with coronary heart disease. Clinical Trial Registration: The detailed information of the PRACTICE study has been registered on http://Clinicaltrials.gov (Identifier: NCT05174143).

High Endogenously Synthesized N-3 Polyunsaturated Fatty Acids in Fat-1 Mice Attenuate High-Fat Diet-Induced Insulin Resistance by Inhibiting NLRP3 Inflammasome Activation via Akt/GSK-3ß/TXNIP Pathway.

High-fat (HF) diets and low-grade chronic inflammation contribute to the development of insulin resistance and type 2 diabetes (T2D), whereas n-3 polyunsaturated fatty acids (PUFAs), due to their anti-inflammatory effects, protect against insulin resistance. Interleukin (IL)-1ß is implicated in insulin resistance, yet how n-3 PUFAs modulate IL-1ß secretion and attenuate HF diet-induced insulin resistance remains elusive. In this study, a HF diet activated NLRP3 inflammasome via inducing reactive oxygen species (ROS) generation and promoted IL-1ß production primarily from adipose tissue preadipocytes, but not from adipocytes and induced insulin resistance in wild type (WT) mice. Interestingly, endogenous synthesized n-3 polyunsaturated fatty acids (PUFAs) reversed this process in HF diet-fed fat-1 transgenic mice although the HF diet induced higher weight gain in fat-1 mice, compared with the control diet. Mechanistically, palmitic acid (PA), the main saturated fatty acid in an HF diet inactivated AMPK and led to decreased GSK-3ß phosphorylation, at least partially through reducing Akt activity, which ultimately blocked the Nrf2/Trx1 antioxidant pathway and induced TXNIP cytoplasm translocation and NLRP3 inflammasome activation, whereas docosahexaenoic acid (DHA), the most abundant n-3 PUFA in fat-1 adipose tissue, reversed this process via inducing Akt activation. Our GSK-3ß shRNA knockdown study further revealed that GSK-3ß played a pivot role between the upstream AMPK/Akt pathway and downstream Nrf2/Trx1/TXNIP pathway. Given that NLRP3 inflammasome is implicated in the development of most inflammatory diseases, our results suggest the potential of n-3 PUFAs in the prevention or adjuvant treatment of NLRP3 inflammasome-driven diseases.

Characteristics of the Intestinal Microorganisms in Middle-Aged and Elderly Patients: Effects of Smoking.

Introduction: Smoking affects the occurrence and development of many diseases. We attempt to study the structure of intestinal flora in the middle-aged and elderly population as well as how smoking affects the intestinal flora. Methods: We collected population information, biochemical indicators, and patient feces from 188 middle-aged and elderly male patients, and their feces were tested for the 16S rRNA gene of intestinal flora. Results: We performed a cluster analysis on the intestinal structure of the included population and found that there was a significant difference in the number of smokers between each group (p = 0.011). Subsequently, the microbiological diversity analysis of current smokers and nonsmokers was carried out. The results indicated that there was a significant difference in species composition between the two groups (p = 0.029). Through the analysis on LEfSe differential bacteria, it was found that in current smoking patients, the abundances of the genus Bifidobacterium and the genus Coprobacillus were less, while the abundances of the genera Shigella, Paraprevotella, Burkholderia, Sutterella, Megamonas, and p-75-a5 under the family level of Erysipelotrichaceae were slightly high. We analyzed the correlation between the abundances of these eight different bacteria and clinical indicators. The results revealed the following: the abundance of the genus Bifidobacterium was negatively correlated with fasting blood glucose (r = -0.198, p = 0.006) and positively correlated with uric acid (r = 0.207, p = 0.004) and total bilirubin (r = 0.175, p = 0.017); Shigella bacteria were positively correlated with fasting blood glucose (r = 0.160, p = 0.028) and uric acid (r = 0.153, p = 0.036) levels; the genus Paraprevotella and BMI (r = -0.172, p = 0.018) are negatively correlated; the abundance of the genus Burkholderia was positively correlated with γ-glutamyltransferase (r = 0.146, p = 0.045) levels; Sutterella was correlated with fasting blood glucose (r = 0.143, p = 0.05) and creatinine level (r = -0.16, p = 0.027), which was positively correlated with fasting blood glucose and negatively correlated with creatinine. Conclusions: In middle-aged and elderly patients with cardiovascular disease, smoking can reduce the abundance of Bifidobacterium, while the abundances of some negative bacteria such as Burkholderia, Sutterella, and Megamonas increase.

PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin-II by reducing TGF-ß1/Smads pathway activation.

Fibrosis serves a critical role in driving atrial remodelling-mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang-II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up-regulated in the Ang-II-induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF-ß1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang-II were significantly higher in the Ang-II-induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF-ß1/Smads signalling pathway) diminished these Ang-II-mediated effects, and the si-Smad3-mediated effects were, in turn, antagonized by the addition of a PU.1-overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang-II and attenuated vulnerability to AF, at least in part through the TGF-ß1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang-II-induced atrial fibrosis and vulnerability to AF.

Recent Advances of Salivary Gland Biopsy in Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic, systemic, inflammatory autoimmune disease characterized by lymphocyte proliferation and progressive damage to exocrine glands. The diagnosis of SS is challenging due to its complicated clinical manifestations and non-specific signs. Salivary gland biopsy plays an important role in the diagnosis of SS, especially with anti-Sjögren's syndrome antigen A (SSA) and anti-SSB antibody negativity. Histopathology based on biopsy has clinical significance for disease stratification and prognosis evaluation, such as risk assessment for the development of non-Hodgkin's lymphoma. Furthermore, histopathological changes of salivary gland may be implicated in evaluating the efficacy of biological agents in SS. In this review, we summarize the histopathological features of salivary gland, the mechanism of histopathological changes and their clinical significance, as well as non-invasive imaging techniques of salivary glands as a potential alternative to salivary gland biopsy in SS.

Cardiac Shock Wave Therapy for Coronary Heart Disease: an Updated Meta-analysis.

INTRODUCTION: The aim of this article is to study the efficacy and safety of cardiac shock wave therapy (CSWT) in the treatment of coronary heart disease (CAD). METHODS: A comprehensive search of electronic databases and a manual search of conference papers and abstracts were performed until September 30, 2018. The studies using RevMan 5.3 and STATA 14.0 softwares were reviewed, and meta-analyses were performed on 13 indicators, such as a six-min walking distance test (6MWT), New York Heart Association (NYHA) functional class, Seattle Angina Questionnaire (SAQ) score, angina class (Canadian Cardiology Society [CCS]), etc. RESULTS: A total of 26 articles were included. The total patient population was 855, of which 781 patients were treated with CSWT. Meta-analyses indicated that 6MWT (mean difference [MD] 75.64, 95% confidence interval [CI] 49.03, 102.25, P<0.00001) and NYHA (MD -0.70, 95% CI -0.92) in the CSWT group were comparable to those in the conventional revascularization group (MD -0.70, 95% CI -0.92, -0.49, P<0.00001). SAQ (MD 10.75, 95% CI 6.66, 14.83, P<0.00001), CCS (MD -0.99, 95% CI -1.13, -0.84, P<0.00001), nitrate dosage (MD -1.84, 95% CI -2.77, -1.12, P<0.00001), LVEF (MD 3.77, 95% CI 2.17, 5.37, P<0.00001), and SSS (MD -4.29, 95% CI -5.61, -2.96, P<0.00001), SRS (MD -2.90, 95% CI -4.85, -0.95, P=0.004), and the exercise test (standard mean difference 0.57, 95% CI 0.12, 1.02, P=0.01) all showed significant differences. CONCLUSION: CSWT may offer beneficial effects to patients with CAD, but more large-scale clinical studies are needed to further verify its therapeutic effect.

Cardiac shock wave therapy for coronary heart disease: an updated meta-analysis

Abstract Introduction: The aim of this article is to study the efficacy and safety of cardiac shock wave therapy (CSWT) in the treatment of coronary heart disease (CAD). Methods: A comprehensive search of electronic databases and a manual search of conference papers and abstracts were performed until September 30, 2018. The studies using RevMan 5.3 and STATA 14.0 softwares were reviewed, and meta-analyses were performed on 13 indicators, such as a six-min walking distance test (6MWT), New York Heart Association (NYHA) functional class, Seattle Angina Questionnaire (SAQ) score, angina class (Canadian Cardiology Society [CCS]), etc. Results: A total of 26 articles were included. The total patient population was 855, of which 781 patients were treated with CSWT. Meta-analyses indicated that 6MWT (mean difference [MD] 75.64, 95% confidence interval [CI] 49.03, 102.25, P<0.00001) and NYHA (MD -0.70, 95% CI -0.92) in the CSWT group were comparable to those in the conventional revascularization group (MD -0.70, 95% CI -0.92, -0.49, P<0.00001). SAQ (MD 10.75, 95% CI 6.66, 14.83, P<0.00001), CCS (MD -0.99, 95% CI -1.13, -0.84, P<0.00001), nitrate dosage (MD -1.84, 95% CI -2.77, -1.12, P<0.00001), LVEF (MD 3.77, 95% CI 2.17, 5.37, P<0.00001), and SSS (MD -4.29, 95% CI -5.61, -2.96, P<0.00001), SRS (MD -2.90, 95% CI -4.85, -0.95, P=0.004), and the exercise test (standard mean difference 0.57, 95% CI 0.12, 1.02, P=0.01) all showed significant differences. Conclusion: CSWT may offer beneficial effects to patients with CAD, but more large-scale clinical studies are needed to further verify its therapeutic effect.

Identification of activated pathways in lung adenocarcinoma based on network strategy.

BACKGROUND: Lung adenocarcinoma has increased incidence over the past years and is the cause for almost 50% of deaths attributable to lung cancer. The objective of this paper is to identify activated pathways associated with lung adenocarcinoma based on gene co-expression network analysis. MATERIALS AND METHODS: Kyoto Encyclopedia of Genes and Genomes pathway analysis of dysregulated genes was performed based on Expression Analysis Systematic Explorer test to illuminate the biological pathways. Co-expression networks of lung adenocarcinoma in different tumor Stages (IA, IB, IIA, IIB, IIIA, IIIB, and IV) were constructed by Empirical Bayes approach to reweight gene pair scores. Pathway activity analysis was conducted to compute the distribution of pathways in different stages and to identify "activated" pathways in lung adenocarcinoma. RESULTS: We evaluated 211 dysregulated genes between lung adenocarcinoma patients and normal controls. Pathway activity analysis was performed and P values of pathways, which obtained from co-expression networks (Stage IA, IB, IIA, IIB, IIIA, IIIB, and IV), were calculated. Cell cycle, progesterone-mediated oocyte maturation, and oocyte meiosis were activated during all stages in lung adenocarcinoma. CONCLUSIONS: We successfully identified three activated pathways (cell cycle, progesterone-mediated oocyte maturation, and oocyte meiosis) in different Stages (IA, IB, IIA, IIB, IIIA, IIIB, and IV) of lung adenocarcinoma.

High­fat treatment prevents postoperative cognitive dysfunction in a hyperlipidemia model by protecting the blood­brain barrier via Mfsd2a­related signaling.

Damage to the blood­brain barrier (BBB) resulting from systemic inflammation caused by surgical trauma is associated with cognitive dysfunction, and individuals with hyperlipidemia are more sensitive to such impairment. The present study was designed to ascertain whether dexmedetomidine (Dex) treatment could reduce the incidence of cognitive dysfunction following surgery in a hyperlipidemia model. Hyperlipidemia was induced in Sprague­Dawley rats (male, 6­7 months old) by consuming a high­fat diet, and rats were divided into three groups (n=10 each) and underwent: exploratory laparotomy to introduce surgical trauma (surgery group), laparotomy and Dex treatment (surgery+Dex group), or sham surgery (sham group). Learning, memory and exploration behavior were assessed using the Morris water maze. Concentrations of tumor necrosis factor (TNF)­α and interleukin (IL)­1ß, were determined by enzyme­linked immunosorbent assay. BBB permeability was assessed by Evans blue staining. Relative major facilitator superfamily domain­containing protein 2 (Mfsd2a) mRNA expression was determined by quantitative PCR. In the Morris water maze test, the time and distance ratio for the surgery group was significantly lower than those of the sham and surgery+Dex groups (P<0.05). In addition, the TNF­α concentrations in the sham and surgery+Dex groups were lower than that in the surgery group (P<0.05 on days 1 and 3). Evans Blue staining was increased in the surgery group on day 1 (P<0.01). Mfsd2a mRNA expression was higher in the sham and surgery+Dex groups compared with that noted in the surgery group (P<0.05). In conclusion, Dex treatment decreased the incidence of cognitive dysfunction following surgical trauma in a hyperlipidemia rat model. We demonstrated that Dex stabilized BBB integrity through increased Mfsd2a gene expression.

Cyanidin ameliorates cisplatin-induced cardiotoxicity via inhibition of ROS-mediated apoptosis.

Oxidative stress and apoptosis serve an essential role in cisplatin-induced cardiotoxicity, which limits its clinical use, and increases the risk of cardiovascular disease. As a natural drug, the antioxidant and antitumor effects of cyanidin have been recognized, but its protective effect on cisplatin-induced cardiomyocyte cytotoxicity remains unclear. H9c2 cells were treated with cisplatin (1-40 µM) in the presence or absence of cyanidin (40-80 µM), subsequently; oxidative stress, apoptosis and mitochondrial function were assessed using several techniques. The results demonstrated that cyanidin was able to dose-dependently reverse cisplatin-induced cell damage and apoptosis, attenuate the accumulation of reactive oxygen species (ROS), and mitochondrial membrane potential depolarization, downregulate the expression of Bcl-2 homologous antagonist/killer, upregulate the expression of apoptosis regulator Bcl-2, and reduce the activation of caspase 3, caspase 9, but not caspase 8. Furthermore, the results revealed that the translocation of apoptosis regulator Bax (Bax) from the cytoplasm to the mitochondrial membrane serves an essential role in cisplatin-induced apoptosis. Cyanidin was able to block the translocation of Bax and reduce the release of cytochrome c from cytoplasm. These data indicate that cyanidin attenuates cisplatin-induced cardiotoxicity by inhibiting ROS-mediated apoptosis, while the mitochondrial and extracellular regulated kinase signaling pathways may also serve important roles.

Cordycepin inhibits vascular adhesion molecule expression in TNF-α-stimulated vascular muscle cells.

Atherosclerosis is a chronic inflammatory disease, which is associated with the increased expression of adhesion molecules in vascular smooth muscle cells (VSMCs). Cordycepin is one of the major bioactive components of Ophiocordyceps sinensis that has been demonstrated to exert anti-atherogenic activity; however, its molecular mechanisms are poorly understood. The aim of the present study was to examine the in vitro effects of cordycepin on the tumor necrosis factor (TNF)-α-induced suppression of adhesion molecule expression. The results of the present study demonstrated that cordycepin markedly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in TNF-α-stimulated human aortic vascular smooth muscle cells (HA-VSMCs). Cordycepin significantly inhibited the TNF-α-induced mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) activation (P<0.05), markedly inhibited the TNF-α-induced expression level of nuclear factor (NF)-κB p65 and markedly prevented the TNF-α-associated degradation of IκBα in HA-VSMCs. The results of the present study suggest that cordycepin inhibits the expression of VCAM-1 and ICAM-1 in TNF-α-stimulated HA-VSMCs via downregulating the MAPK/Akt/NF-κB signaling pathway. Therefore, cordycepin may have a potential therapeutic application for preventing the advancement of atherosclerotic lesions.

Myricitrin inhibits vascular adhesion molecule expression in TNF­α­stimulated vascular smooth muscle cells.

Increased expression of adhesion molecules is thought to serve an important role in the pathogenesis of atherosclerosis. Myricitrin, a bioactive compound of Myrica cerifera, has been demonstrated to exhibit anti­atherogenic effects. However, the effect of myricitrin on the expression of adhesion molecules in vascular smooth muscle cells (VSMCs) remains unknown. Therefore, the aim of the present study was to evaluate the inhibitory effects of myricitrin on tumor necrosis factor­α (TNF­α)­induced expression of adhesion molecules in VSMCs in vitro. The results revealed that myricitrin inhibited the adhesion of human THP­1 monocyte cells to TNF­α­stimulated mouse MOVAS­1 VSMC cells, and reduced the expression of adhesion molecules in TNF­α­stimulated MOVAS­1 cells. In addition, myricitrin significantly inhibited the TNF­α­induced expression of nuclear factor (NF)­κB p65, and prevented the TNF­α­induced degradation of nuclear factor of κ light chain enhancer in B­cells inhibitor α. Furthermore, myricitrin inhibited the production of intracellular reactive oxygen species in TNF­α­stimulated MOVAS­1 cells. In conclusion, the results of the present study indicated that myricitrin inhibits the expression of vascular cell adhesion protein­1 and intercellular adhesion molecule­1 in TNF­α­stimulated MOVAS­1 cells potentially via the NF­κB signaling pathway. Therefore, myricitrin may be an effective pharmacological agent for the prevention or treatment of atherosclerosis.

CHADS2 and CHA2DS2-VASc Scores Predict the Risk of Ischemic Stroke Outcome in Patients with Interatrial Block without Atrial Fibrillation.

AIM: To evaluate the role of CHADS2 and CHA2DS2-VASc scores in predicting the risk of ischemic stroke or transient ischemic attack (TIA) outcomes in patients with interatrial block (IAB) without a history of atrial fibrillation (AF). METHODS: A retrospective study was conducted, including 1,046 non-anticoagulated inpatients (612 males, 434 females; mean age: 63±10 years) with IAB and without AF. IAB was defined as P-wave duration ＞120 ms using a 12-lead electrocardiogram. CHADS2 and CHA2DS2-VASc scores were retrospectively calculated. The primary outcomes evaluated were ischemic stroke or TIA. RESULTS: During the mean follow-up period of 4.9±0.7 years, 55 (5.3%) patients had an ischemic stroke or TIA. Receiver operating characteristic (ROC) curve analysis showed that the CHADS2 score [area under the curve (AUC), 0.638; 95% confidence interval (CI), 0.562-0.715; P=0.001] and the CHA2DS2-VASc score (AUC, 0.671; 95% CI, 0.599-0.744; P＜0.001) were predictive of ischemic strokes or TIA. Cut-off point analysis showed that a CHADS2 score ≥3 (sensitivity=0.455 and specificity=0.747) and a CHA2DS2-VASc score ≥4 (sensitivity=0.564 and specificity=0.700) provided the highest predictive value for ischemic stroke or TIA. The multivariate Cox regression analysis showed that CHADS2 [hazard ratio (HR), 1.442; 95% CI, 1.171-1.774; P=0.001] and CHA2DS2-VASc (HR, 1.420; 95% CI, 1.203-1.677; P＜0.001) scores were independently associated with ischemic stroke or TIA following adjustment for smoking, left atrial diameter, antiplatelet agents, angiotensin inhibitors, and statins. CONCLUSIONS: CHADS2 and CHA2DS2-VASc scores may be predictors of risk of ischemic stroke or TIA in patients with IAB without AF.

Usefulness of a Combination of Interatrial Block and a High CHADS2 Score to Predict New Onset Atrial Fibrillation.

Interatrial block (IAB) is associated with an increased risk of atrial fibrillation (AF). The aim of this retrospective study was to investigate the association of a combination of IAB and the CHADS2 score, an AF-related risk score for ischemic stroke, with new onset AF in patients in sinus rhythm. A total of 1,571 patients (803 males, 768 females; mean age: 58 ± 16 years) were included in this study. IAB was defined as a P-wave duration > 120 ms in the 12-lead electrocardiogram, and a high CHADS2 score as ≥ 2 points. During the mean follow-up period of 4.8 ± 0.7 years, new onset AF occurred in 122 patients (16.1 per 1,000 patient-years). The incidence of new onset AF was 4.0 per 1,000 patient-years in patients with no IAB and a low CHADS2 score, and 44.0 per 1,000 patient-years in patients with IAB and a high CHADS2 score. In multivariate Cox regression analysis, the hazard ratio for IAB and a high CHADS2 score compared with no IAB and a low CHADS2 score was 12.18 (95% confidence interval: 6.22-23.87, P < 0.001), after adjustment for age, sex, coronary artery disease, valvular heart disease, smoking, medications, and echocardiographic parameters. In conclusion, IAB and a high CHADS2 score independently and synergistically predict new onset AF in patients in sinus rhythm, indicating an approximately 12-fold higher risk in patients with both IAB and a high CHADS2 score. Patients meeting these criteria should have more aggressive early intervention to prevent AF.

Construction of protein interaction network involved in lung adenocarcinomas using a novel algorithm.

Studies that only assess differentially-expressed (DE) genes do not contain the information required to investigate the mechanisms of diseases. A complete knowledge of all the direct and indirect interactions between proteins may act as a significant benchmark in the process of forming a comprehensive description of cellular mechanisms and functions. The results of protein interaction network studies are often inconsistent and are based on various methods. In the present study, a combined network was constructed using selected gene pairs, following the conversion and combination of the scores of gene pairs that were obtained across multiple approaches by a novel algorithm. Samples from patients with and without lung adenocarcinoma were compared, and the RankProd package was used to identify DE genes. The empirical Bayesian (EB) meta-analysis approach, the search tool for the retrieval of interacting genes/proteins database (STRING), the weighted gene coexpression network analysis (WGCNA) package and the differentially-coexpressed genes and links package (DCGL) were used for network construction. A combined network was also constructed with a novel rank-based algorithm using a combined score. The topological features of the 5 networks were analyzed and compared. A total of 941 DE genes were screened. The topological analysis indicated that the gene interaction network constructed using the WGCNA method was more likely to produce a small-world property, which has a small average shortest path length and a large clustering coefficient, whereas the combined network was confirmed to be a scale-free network. Gene pairs that were identified using the novel combined method were mostly enriched in the cell cycle and p53 signaling pathway. The present study provided a novel perspective to the network-based analysis. Each method has advantages and disadvantages. Compared with single methods, the combined algorithm used in the present study may provide a novel method to analyze gene interactions, with increased credibility.

Synthesis of Ferromagnetic Fe0.6 Mn0.4 O Nanoflowers as a New Class of Magnetic Theranostic Platform for In Vivo T1 -T2 Dual-Mode Magnetic Resonance Imaging and Magnetic Hyperthermia Therapy.

Uniform wüstite Fe0.6 Mn0.4 O nanoflowers have been successfully developed as an innovative theranostic agent with T1 -T2 dual-mode magnetic resonance imaging (MRI), for diagnostic applications and therapeutic interventions via magnetic hyperthermia. Unlike their antiferromagnetic bulk counterpart, the obtained Fe0.6 Mn0.4 O nanoflowers show unique room-temperature ferromagnetic behavior, probably due to the presence of an exchange coupling effect. Combined with the flower-like morphology, ferromagnetic Fe0.6 Mn0.4 O nanoflowers are demonstrated to possess dual-modal MRI sensitivity, with longitudinal relaxivity r1 and transverse relaxivity r2 as high as 4.9 and 61.2 mm(-1) s(-1) [Fe]+[Mn], respectively. Further in vivo MRI carried out on the mouse orthotopic glioma model revealed gliomas are clearly delineated in both T1 - and T2 -weighted MR images, after administration of the Fe0.6 Mn0.4 O nanoflowers. In addition, the Fe0.6 Mn0.4 O nanoflowers also exhibit excellent magnetic induction heating effects. Both in vitro and in vivo magnetic hyperthermia experimentation has demonstrated that magnetic hyperthermia by using the innovative Fe0.6 Mn0.4 O nanoflowers can induce MCF-7 breast cancer cell apoptosis and a complete tumor regression without appreciable side effects. The results have demonstrated that the innovative Fe0.6 Mn0.4 O nanoflowers can be a new magnetic theranostic platform for in vivo T1 -T2 dual-mode MRI and magnetic thermotherapy, thereby achieving a one-stop diagnosis cum effective therapeutic modality in cancer management.

Selection of DNA aptamers against epidermal growth factor receptor with high affinity and specificity.

Epidermal growth factor receptor (EGFR/HER1/c-ErbB1), is overexpressed in many solid cancers, such as epidermoid carcinomas, malignant gliomas, etc. EGFR plays roles in proliferation, invasion, angiogenesis and metastasis of malignant cancer cells and is the ideal antigen for clinical applications in cancer detection, imaging and therapy. Aptamers, the output of the systematic evolution of ligands by exponential enrichment (SELEX), are DNA/RNA oligonucleotides which can bind protein and other substances with specificity. RNA aptamers are undesirable due to their instability and high cost of production. Conversely, DNA aptamers have aroused researcher's attention because they are easily synthesized, stable, selective, have high binding affinity and are cost-effective to produce. In this study, we have successfully identified DNA aptamers with high binding affinity and selectivity to EGFR. The aptamer named TuTu22 with Kd 56±7.3nM was chosen from the identified DNA aptamers for further study. Flow cytometry analysis results indicated that the TuTu22 aptamer was able to specifically recognize a variety of cancer cells expressing EGFR but did not bind to the EGFR-negative cells. With all of the aforementioned advantages, the DNA aptamers reported here against cancer biomarker EGFR will facilitate the development of novel targeted cancer detection, imaging and therapy.

siRNA against KIR3DL1 as a potential gene therapeutic agent in controlling HIV-1 infection.

OBJECTIVES: The aim of this study was to develop a small interfering RNA (siRNA) against the expression of KIR3DL1 receptor on natural killer (NK) cells, in order to promote the ability of NK cells to destroy human immunodeficiency virus (HIV)-infected cells and thus prevent failure of siRNA therapy targeting human immunodeficiency virus type 1 (HIV-1) virus among HIV-1 infected patients in vitro. METHODS: A siRNA targeting KIR3DL1 was synthesized and then modified with cholesterol, methylene, and sulfate. The inhibitory action of the siRNAs on primary cultured NK cells was detected. The amount of IFN-γ and TNF-α secretions in NK cells was measured. The intended functions of NK cells in vitro were analyzed by CFSE and PI methods. RESULTS: There were no significant differences in inhibiting the expression of KIR3DL1 on NK cells between the modified and unmodified siRNAs, while inhibition by each of them differed significantly from controls. The amount of IFN-γ and TNF-α secretions in the NK cells was abundant due to unsuccessful expression of KIR3DL1 on NK cells, which further promoted function of the NK cells. CONCLUSION: The siRNA against KIR3DL1 could enhance the ability of the NK cells to kill the HIV-1 infected cells in vitro and successfully prevented the failure of siRNA therapy targeting the HIV-1 virus. Therefore, it can act as a potential gene therapeutic agent among HIV-1 infected people.