HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.

Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants.

A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.

Association of clonal haematopoiesis with severe postoperative complications in patients undergoing radical oesophagectomy.

BACKGROUND: Clonal haematopoiesis (CH) is an age-associated clonal expansion of blood cells driven by leukaemia-associated somatic mutations. Although CH has been reported to be a risk factor for leukaemia and a number of non-haematopoietic diseases, its role in perioperative medicine remains unexplored. METHODS: This was a single-centre, prospective, observational study. Patients undergoing radical oesophagectomy were enrolled, and peripheral blood samples were collected for DNA sequencing. Patients with haematopoietic somatic mutations (variant allele frequencies ≥1%) in the DNMT3A gene, TET2 gene, or both were defined as CH carriers. The primary outcome was the incidence of severe postoperative complications (Clavien-Dindo classification ≥3). The secondary outcomes included the major types of postoperative complications, mortality, and other common perioperative variables. RESULTS: Clonal haematopoiesis was found in 21.2% (33/156) of the patients (mean age: 66 yr [range: 26-79 yr]; 83% males). Some 14/33 (42.4%) patients with CH had severe postoperative complications, compared with patients without CH carriers (28/123 [22.8%]; P=0.024). Multivariable logistic regression analysis showed that CH was associated with an increased risk of developing severe postoperative complications (odds ratio, 3.63; 95% confidence interval, 1.37-9.66; P=0.010). Among the major postoperative complications, the incidence of pulmonary complications was significantly higher in the patients with CH than in those without CH (15 in 33 [45.5%] vs 30 in 123 [24.4%], P=0.018). CONCLUSIONS: Clonal haematopoiesis was associated with a higher incidence of severe postoperative complications in patients undergoing radical oesophagectomy, suggesting that clonal haematopoiesis can play an important role in perioperative medicine. CLINICAL TRIAL REGISTRATION: ChiCTR2100044175 (Chinese Clinical Trial Registry, http://www.chictr.org.cn/showproj.aspx?proj=123193).

Pharmacokinetics, withdrawal period and risk assessment of enrofloxacin in the northern snakehead (Channa argus) following bath administration.

Enrofloxacin (ENR) is widely used in aquaculture practice, but little is known about its pharmacokinetic, withdrawal period and dietary risk in fish via bath administration. The purpose of this study was to provide data support for the use of ENR bath therapy in the northern snakehead (Channa argus). The pilot study was carried out to evaluate the therapy concentrations of ENR in northern snakehead with immersion concentrations ranged from 5 to 40 mg/L for 6 h. Based on results of the pilot study, an ENR immersion concentration of 20 mg/L was used for the formal experiment. At this dose, the peak concentrations of ENR in plasma, muscle plus skin, liver and kidney were 4.85, 4.55, 3.87 and 7.42 µg/mL (or g), respectively. According to the AUC0-∞ values, the distribution of ENR in northern snakehead followed the order of kidney > plasma > liver > muscle + skin. The elimination of ENR in northern snakehead was very slow, the half-lives (T1/2λz ) were up to 90.31, 85.5, 104.56 and 120.9 h in plasma, muscle plus skin, liver and kidney, respectively. Ciprofloxacin (CIP) was not detected in any samples in the pilot study and was only occasionally detected in muscle plus skin and liver samples in formal experiment. Based on the calculated PK/PD index AUC/MIC and Cmax /MIC, the current bath treatment regimen will have a good therapeutic effect on infections caused by bacteria with MIC below 0.6 µg/mL. The dietary risk assessment suggested that there was a dietary risk (Hazard Quotients > 10%) until day 6 after bath treatment. It is mandatory for ENR to maintain a withdrawal period of at least 450°C-day in northern snakehead after bath treatment ceased.

The evaluation of an online nurse-assisted eye-screening tool in older adults receiving home healthcare.

PURPOSE: To investigate the agreement between an online nurse-assisted eye-screening tool and reference tests in older adults receiving home healthcare and to collect user experiences. METHODS: Older adults (65+) receiving home healthcare were included. Home healthcare nurses assisted in administering the eye-screening tool at participants' homes. Approximately 2 weeks later, a researcher administered reference tests at participants' homes. Experiences from participants and home healthcare nurses were collected. Agreement in outcomes (distance and near visual acuity, with the latter being measured using two different optotypes, and macular problems) between the eye-screening tool and reference clinical testing was compared. A difference of less than ±0.15 logMAR was considered acceptable. RESULTS: A total of 40 participants were included. Here, we describe the results for the right eye; results for the left eye were similar. The mean difference between the eye-screening tool and reference tests for distance visual acuity was 0.02 logMAR. The mean difference between the eye-screening tool and reference tests using two different optotypes for near visual acuity was 0.06 and 0.03 logMAR, respectively. The majority of the individual data points were within the ±0.15 logMAR threshold (75%, 51% and 58%, respectively). The agreement between tests for macular problems was 75%. Participants and home healthcare nurses were generally satisfied with the eye-screening tool, although remarks for further improvements were made. CONCLUSIONS: The eye-screening tool is promising for nurse-assisted eye screening in older adults receiving home healthcare, with the mostly satisfactory agreement. After implementing the eye-screening tool in practice, cost-effectiveness needs to be investigated.

Genome-Wide Identification and Comprehensive Analysis of the FtsH Gene Family in Soybean (Glycine max).

The filamentation temperature-sensitive H (FtsH) gene family is critical in regulating plant chloroplast development and photosynthesis. It plays a vital role in plant growth, development, and stress response. Although FtsH genes have been identified in a wide range of plants, there is no detailed study of the FtsH gene family in soybean (Glycine max). Here, we identified 34 GmFtsH genes, which could be categorized into eight groups, and GmFtsH genes in the same group had similar structures and conserved protein motifs. We also performed intraspecific and interspecific collinearity analysis and found that the GmFtsH family has large-scale gene duplication and is more closely related to Arabidopsis thaliana. Cis-acting elements analysis in the promoter region of the GmFtsH genes revealed that most genes contain developmental and stress response elements. Expression patterns based on transcriptome data and real-time reverse transcription quantitative PCR (qRT-PCR) showed that most of the GmFtsH genes were expressed at the highest levels in leaves. Then, GO enrichment analysis indicated that GmFtsH genes might function as a protein hydrolase. In addition, the GmFtsH13 protein was confirmed to be localized in chloroplasts by a transient expression experiment in tobacco. Taken together, the results of this study lay the foundation for the functional determination of GmFtsH genes and help researchers further understand the regulatory network in soybean leaf development.

Renal denervation ameliorates cardiac metabolic remodeling in diabetic cardiomyopathy rats by suppressing renal SGLT2 expression.

This study aimed to investigate the effects of renal denervation (RDN) on diabetic cardiomyopathy (DCM) and explore the related mechanisms. Male Sprague-Dawley rats were fed high-fat chow and injected with low-dose streptozotocin to establish a DCM model. Six rats served as controls. The surviving rats were divided into three groups: control group, DCM group and DCM + RDN group. RDN surgery was performed in the fifth week. At the end of the experiment, all rats were subjected to 18F-FDG PET/CT and metabolic cage studies. Cardiac function and structure were evaluated by echocardiography and histology. Myocardial substrate metabolism and mitochondrial function were assessed by multiple methods. In the 13th week, the DCM rats exhibited cardiac hypertrophy and interstitial fibrosis accompanied by diastolic dysfunction. RDN ameliorated DCM-induced cardiac dysfunction (E/A ratio: RDN 1.07 ± 0.18 vs. DCM 0.93 ± 0.12, P < 0.05; E/E' ratio: RDN 10.74 ± 2.48 vs. DCM 13.25 ± 1.99, P < 0.05) and pathological remodeling (collagen volume fraction: RDN 5.05 ± 2.05% vs. DCM 10.62 ± 2.68%, P < 0.05). Abnormal myocardial metabolism in DCM rats was characterized by suppressed glucose metabolism and elevated lipid metabolism. RDN increased myocardial glucose uptake and oxidation while reducing the absorption and utilization of fatty acids. Meanwhile, DCM decreased mitochondrial ATP content, depolarized the membrane potential and inhibited the activity of respiratory chain complexes, but RDN attenuated this mitochondrial damage (ATP: RDN 30.98 ± 7.33 µmol/gprot vs. DCM 22.89 ± 5.90 µmol/gprot, P < 0.05; complexes I, III and IV activity: RDN vs. DCM, P < 0.05). Furthermore, both SGLT2 inhibitor and the combination treatment produced similar effects as RDN alone. Thus, RDN prevented DCM-induced cardiac dysfunction and pathological remodeling, which is related to the improvement of metabolic disorders and mitochondrial dysfunction.

A kind of HIV-1 protease inhibitors containing phenols with antiviral activity against DRV-resistant variants.

Based upon the preliminary design of enhancing genetic barrier to drug-resistant viral mutants by maximizing hydrogen-bonding or other van der Waals contacts, we have designed, synthesized and biologically evaluated a new class of HIV-1 protease inhibitors with phenol derived P2 ligands and nitro or halogens in P2' ligands. Results indicate that a majority of inhibitors exhibit robust enzyme inhibitory with IC50 values in picomolar or single digit nanomolar ranges. Among which, compound 17d displays potency with IC50 value of 21 pM and high protease selectivity. Of note, 17d exhibits greater antiviral activity against the DRV-resistant variant than the efficacy against the wild type virus. Furthermore, the molecular modeling studies demonstrate important interactions between 17d and the active sites of both the wild-type and DRV-resistant HIV-1 protease, as well as furnish insights for further optimization of new inhibitors.

The toxicokinetics and risk assessment of pyrethroids pesticide in tilapia (Oreochromis mossambicus) upon short-term water exposure.

Pyrethroids pesticides (PPs) are the widely adopted synthetic pesticides for agriculture and fishery. The frequent use of these pesticides leads to the accumulation of residues in the freshwater environments in China, subsequently affecting aquatic organisms and ecosystems. However, there are few reports on the toxicological and risk assessment of aquaculture aquatic products. In this study, the uptake, depuration kinetics and potential risk to human health and ecology of fenpropathrin, cypermethrin, fenvalerate, and deltamethrin were assessed using tilapia. The results indicated that four PPs were readily accumulated by tilapia. The bioconcentration factors (BCF) of the PPs in plasma and muscle were between 71.3 and 2112.1 L/kg and 23.9-295.3 L/kg, respectively. The half-lives (t1/2) of muscle and plasma were 2.90-9.20 d and 2.57-8.15 d. The risks of PPs residues in the muscle of tilapia and exposed water were evaluated by hazard quotient (HQ) and risk quotient (RQ). Although PPs residues in tilapia had a low dietary risk to human health, the residues in the exposed water had a high ecological risk to fish, daphnia, and green algae. Therefore, assessing the PPs content in freshwater aquaculture and monitoring their dosages and frequencies are highly necessitated to avoid their adverse effect on the aquaculture environment.

Betacellulin regulates peripheral nerve regeneration by affecting Schwann cell migration and axon elongation.

BACKGROUND: Growth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve repair and regeneration. Our previous sequencing data showed that the mRNA coding for betacellulin (Btc), an epidermal growth factor protein family member, was up-regulated in rat sciatic nerve segment after nerve injury, implying the potential involvement of Btc during peripheral nerve regeneration. METHODS: Expression of Btc was examined in Schwann cells by immunostaining. The function of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or treating cells with Btc recombinant protein. The influence of Schwann cell-secreted Btc on neurons was determined using a co-culture assay. The in vivo effects of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated. RESULTS: Immunostaining images and ELISA outcomes indicated that Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that transfection with siRNA against Btc impeded Schwann cell migration while application of exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells influenced neuron behavior and increased neurite length. In vivo evidence supported the promoting role of Btc in nerve regeneration after both rat sciatic nerve crush injury and transection injury. CONCLUSION: Our findings demonstrate the essential roles of Btc on Schwann cell migration and axon elongation and imply the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.

Discovery of 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents via repressing PI3K/AKT/Smad and JAK2/STAT3 pathways.

Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor ß1 (TGFß1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.

Combination treatment of perifosine and valsartan showed more efficiency in protecting against pressure overload induced mouse heart failure.

The optimum strategy for heart failure (HF) treatment has yet to be elucidated. This study intended to test the benefit of a combination of valsartan (VAL) and perifosine (PER), a specific AKT inhibitor, in protecting against pressure overload induced mouse HF. Mouse were subjected to aortic banding (AB) surgery to establish HF models and then were given vehicle (HF), VAL (50 mg/kg/d), PER (30 mg/kg/d) or combination of VAL and PER for 4 weeks. Mouse with sham surgery treated with VEH were used for control (VEH). VAL or PER treatment could significantly alleviate mouse heart weight, attenuate cardiac fibrosis and improve cardiac function. The combination treatment of VAL and PER presented much better benefit compared with VAL or PER group respectively. PER treatment significantly inhibited AKT/GSK3ß/mTORC1 signaling. Besides the classic AT1 inhibition, VAL treatment significantly inhibited MAPK (ERK1/2) signaling. Furthermore, VAL and PER treatment could markedly prevent neonatal rat cardiomyocyte hypertrophy and the activation of neonatal rat cardiac fibroblast. Combination of VAL and PER also presented superior beneficial effects than single treatment of VAL or PER in vitro experiments respectively. This study presented that the combination of valsartan and PER may be a potential treatment for HF prevention.

Pharmacokinetics and tissue residues of enrofloxacin in the largemouth bass (Micropterus salmoides) after oral administration.

The study was carried out to evaluate the pharmacokinetic disposition of enrofloxacin (ENF) with a single dose of 20 mg/kg after oral administration in largemouth bass (Micropterus salmoides) at 28°C. The concentrations of ENF and of its metabolite ciprofloxacin (CIP) in plasma, liver, and muscle plus skin in natural proportions were determined using HPLC. The concentration-time data for ENF in plasma were best described by a two-compartment open model. After oral administration, the maximum ENF concentration (Cmax ) of 10.99 µg/ml was obtained at 0.60 hr. The absorption half-life (T1/2Ka ) of ENF was calculated to be 0.07 hr whereas the elimination half-life (T1/2ß ) of the drug was 90.79 hr. The estimates of area under the plasma concentration-time curve (AUC) and apparent volume of distribution (Vd/F) were 1,185.73 µg hr/ml and 2.21 L/kg, respectively. ENF residues were slowly depleted from the liver and muscle plus skin of largemouth bass with the T1/2ß of 124.73 and 115.14 hr, respectively. Very low levels of ciprofloxacin were detected in the plasma and tissues. A withdrawal time of 24 days was necessary to ensure that the residues of ENF + CIP in muscle plus skin were less than the maximal residue limit (MRL) of 100 µg/kg established by the European Union.

Effects of Angiotensin Receptor Neprilysin Inhibitors on Inducibility of Ventricular Arrhythmias in Rats with Ischemic Cardiomyopathy.

The aims of the present study were to investigate the effects of angiotensin receptor neprilysin inhibitors (ARNi) on the susceptibility of ventricular arrhythmias (VAs) in rats with myocardial infarction (MI) and to explore the related mechanisms.A total of 32 adult male Sprague-Dawley rats were divided into 3 groups: a control group, MI group, and MI+ARNi group. MI was generated by ligation of the left anterior descending coronary artery. ARNi was given at 68 mg/kg/day for 4 weeks after MI surgery. At 4 weeks after MI, electrical programmed stimulation (EPS) was performed in all groups for the evaluation of VAs, and echocardiography was used to evaluate cardiac function. Indicators of sympathetic neural remodeling and cardiac remodeling were detected to further explore the related mechanisms.Four weeks after MI, rats in the ARNi group exhibited low susceptibility of VAs in comparison with that in the MI group, which was coincident with the attenuation of sympathetic nerve remodeling, amelioration of cardiac fibrosis, and regulation of Cx43 expression.ARNi is effective in reducing VAs in rats with ischemic cardiomyopathy, which is associated with attenuating sympathetic nerve remodeling and myocardial fibrosis.

The Social Effects of Exergames on Older Adults: Systematic Review and Metric Analysis.

BACKGROUND: Recently, many studies have been conducted to investigate the effects of exergames on the social well-being of older adults. OBJECTIVE: The aim of this paper is to synthesize existing studies and provide an overall picture on the social effects of exergames on older adults. METHODS: A comprehensive literature search with inclusive criteria was conducted in major social science bibliographic databases. The characteristics of exergames, participants, methodology, as well as outcome measurements were extracted from the relevant studies included in the review. The bibliometric and altmetric outreach of the included studies were also investigated. RESULTS: A total of 10 studies were included in the review, with 8 studies having used the Nintendo Wii platform. Most of the studies recruited healthy older adults from local communities or senior activity centers. Three groups of social-related outcomes have been identified, including emotion-related, behavior-related, and attitude-related outcomes. A metric analysis has shown that the emotion-related and behavior-related outcomes received high attention from both the academic community and social media platforms. CONCLUSIONS: Overall, the majority of exergame studies demonstrated promising results for enhanced social well-being, such as reduction of loneliness, increased social connection, and positive attitudes towards others. The paper also provided implications for health care researchers and exergame designers.

Pharmacokinetic/pharmacodynamic relationship of enrofloxacin against Aeromonas hydrophila in crucian carp (Carassius auratus gibelio).

The pharmacokinetic (PK) properties of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated in crucian carp following oral administration at different dose levels (5, 10, 20, 40 mg/kg body weight). The disposition kinetics of ENR was found to be linear over the dose range studied. Serum half-lives ranged from 64.56 to 72.68 hr. The in vitro and ex vivo activities of ENR in serum against a pathogenic strain of Aeromonas hydrophila were determined. In vitro and ex vivo bactericidal activity of ENR was concentration dependent. Dosing of 10 mg/kg resulted in an AUC/minimum inhibitory concentration (MIC) ratio of 368.92 hr and a Cmax /MIC ratio of 7.23, respectively, against A. hydrophila 147 (MIC = 0.48 µg/ml), indicating a likely high level of effectiveness in clinical infections caused by A. hydrophila with MIC value ≤ 0.48 µg/ml. Modeling of ex vivo growth inhibition data to the sigmoid Emax equation provided the values of AUC24 hr /MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria, these values were 21.70, 53.01, and 125.21 hr, respectively. These findings in conjunction with MIC90 data suggested that ENR at the dose of 7.81 mg/kg predicted a positive clinical outcome and minimize the risk of emergence of resistance.

6-Hydroxydopamine induces brain vascular endothelial inflammation.

Disruption of the blood-brain barrier associated with endothelial dysfunction is an important hallmark of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a synthetic dopamine derivate often used to model PD as it results in retrograde degeneration of striatal dopaminergic (DA) terminals. Presently, the effects of 6-OHDA on endothelial dysfunction remain unknown. Using a 6-OHDA rodent model of PD, we found that administration of 6-OHDA could increase the expression of endothelial adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin. An in vitro study displayed that treatment with 6-OHDA increased the release of these molecules in human brain microvascular endothelial cells in a dose-dependent manner. Correspondingly, 6-OHDA significantly increased attachment of THP-1 monocytes to brain endothelial cells. In addition, real-time polymerase chain reaction and enzyme-linked immunosorbent assay results indicated that 6-OHDA elevated the production of proinflammatory cytokines, such as interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Furthermore, 6-OHDA treatment increased the expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as the production of prostaglandin E2 and nitric oxide. Importantly, 6-OHDA elevated the transcriptional activity of NF-кB by increasing the phosphorylation, degradation, and subsequent nuclear translocation of p65. Mechanistically, the angiotensin II type 1 receptor was found to mediate 6-OHDA-induced endothelial dysfunction. Our findings suggest that 6-OHDA-induced endothelial inflammation may play an important role in the pathogenesis of PD. © 2017 IUBMB Life, 69(11):887-895, 2017.

Meta-Analysis of Efficacy and Safety of Apixaban in Patients Undergoing Catheter Ablation for Atrial Fibrillation.

BACKGROUND: The efficacy and safety of apixaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF) are little investigated. METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE were searched up to September 2015. Four literatures comparing apixaban with vitamin K antagonists (VKAs) were included. Data were pooled in Review Manager Software, using Mantel-Haenszel methods with a fixed-effects model. The funnel plots and Egger's test were used to examine publication bias. Heterogeneity was assessed using the I(2) test. Risk ratios (RR) and 95% confidence intervals (CI) of each study were calculated and pooled. RESULTS: No significant differences were observed in rates of total bleeding (RR = 0.91, 95% CI [0.57, 1.46], I(2) = 0.0%), thromboembolic complications (RR = 0.75, 95% CI [0.03, 18.22], I(2) = 0.0%), or total events (RR = 0.90, 95% CI [0.56, 1.44], I(2) = 0.0%) between apixaban and VKAs group. The frequency of major bleeding was similar between apixaban and VKAs group (RR = 1.34, 95% CI [0.34, 5.30], I(2) = 0.0%). CONCLUSION: Apixaban was as effective and safe as VKAs in the periprocedural period of CA.

The prognostic value of serum C-reactive protein-bound serum amyloid A in early-stage lung cancer.

BACKGROUND: Elevated levels of serum C-reactive protein (CRP) have been reported to have prognostic significance in lung cancer patients. This study aimed to further identify CRP-bound components as prognostic markers for lung cancer and validate their prognostic value. METHODS: CRP-bound components obtained from the serum samples from lung cancer patients or healthy controls were analyzed by differential proteomics analysis. CRP-bound serum amyloid A (CRP-SAA) was evaluated by co-immunoprecipitation (IP). Serum samples from two independent cohorts with lung cancer (retrospective cohort, 242 patients; prospective cohort, 222 patients) and healthy controls (159 subjects) were used to evaluate the prognostic value of CRP-SAA by enzyme-linked immunosorbent assay. RESULTS: CRP-SAA was identified specifically in serum samples from lung cancer patients by proteomic analysis. CRP binding to SAA was confirmed by co-IP in serum samples from lung cancer patients and cell culture media. The level of CRP-SAA was significantly higher in patients than in healthy controls (0.37 ± 0.58 vs. 0.03 ± 0.04, P < 0.001). Elevated CRP-SAA levels were significantly associated with severe clinical features of lung cancer. The elevation of CRP-SAA was associated with lower survival rates for both the retrospective (hazard ration [HR] = 2.181, 95% confidence interval [CI] = 1.641-2.897, P < 0.001) and the prospective cohorts (HR = 2.744, 95% CI = 1.810-4.161, P < 0.001). Multivariate Cox analysis showed that CRP-SAA was an independent prognostic marker for lung cancer. Remarkably, in stages I-II patients, only CRP-SAA, not total SAA or CRP, showed significant association with overall survival in two cohorts. Moreover, univariate and multivariate Cox analyses also showed that only CRP-SAA could be used as an independent prognostic marker for early-stage lung cancer patients. CONCLUSION: CRP-SAA could be a better prognostic marker for lung cancer than total SAA or CRP, especially in early-stage patients.

Research progress of genome editing and derivative technologies in plants.

Genome editing technologies using engineered nucleases have been widely used in many model organisms. Genome editing with sequence-specific nuclease (SSN) creates DNA double-strand breaks (DSBs) in the genomic target sites that are primarily repaired by the non-homologous end joining (NHEJ) or homologous recombination (HR) pathways, which can be employed to achieve targeted genome modifications such as gene mutations, insertions, replacements or chromosome rearrangements. There are three major SSNs─zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) system. In contrast to ZFN and TALEN, which require substantial protein engineering to each DNA target, the CRISPR/Cas9 system requires only a change in the guide RNA. For this reason, the CRISPR/Cas9 system is a simple, inexpensive and versatile tool for genome engineering. Furthermore, a modified version of the CRISPR/Cas9 system has been developed to recruit heterologous domains that can regulate endogenous gene expression, such as activation, depression and epigenetic regulation. In this review, we summarize the development and applications of genome editing technologies for basic research and biotechnology, as well as highlight challenges and future directions, with particular emphasis on plants.