The compartmentalization and transport of proteins and solutes across the endothelium is a critical biologic function altered during inflammation and disease, leading to pathology in multiple disorders. The impact of tissue damage and subsequent extracellular matrix (ECM) fragmentation in regulating this process is unknown. We demonstrate that the collagen-derived matrikine acetylated proline-glycine-proline (N-α-PGP) serves as a critical regulator of endothelial permeability. N-α-PGP activates human endothelial cells via CXC-chemokine receptor 2 (CXCR2), triggering monolayer permeability through a discrete intracellular signaling pathway. In vivo, N-α-PGP induces local vascular leak after subcutaneous administration and pulmonary vascular permeability after systemic administration. Furthermore, neutralization of N-α-PGP attenuates lipopolysaccharide-induced lung leak. Finally, we demonstrate that plasma from patients with acute respiratory distress syndrome (ARDS) induces VE-cadherin phosphorylation in human endothelial cells, and this activation is attenuated by N-α-PGP blockade with a concomitant improvement in endothelial monolayer impedance. These results identify N-α-PGP as a novel ECM-derived matrikine regulating paracellular permeability during inflammatory disease and demonstrate the potential to target this ligand in various disorders characterized by excessive matrix turnover and vascular leak such as ARDS.
AIM: To investigate the association between thrombocytopenia and relapse after treatment for hepatocellular carcinoma (HCC).
METHODS: We searched the PubMed, EMBASE, and Web of Science databases to obtain eligible studies. The hazard ratios (HRs) values and 95% confidence intervals (CIs) were pooled by random effects model. Subsequently, we estimated the heterogeneity, performed a sensitivity analysis, determined the publication bias, and performed subgroup and meta-regression analyses. Study quality was assessed by using the Oxford Center for Evidence Based Medicine tool.
RESULTS: We identified 18 eligible studies by retrieval (published during 2000-2014). Out of the 4163 patients with HCC who were recruited, 2746 (66.0%) experienced recurrence. In general, our meta-analysis suggested that low platelet count (PLT) before therapy significantly increased the probability of postoperative recurrence (HR = 1.53, 95%CI: 1.29-1.81). PLT was also valuable in the prediction of intrahepatic distant recurrence (HR = 1.49, 95%CI: 1.25-1.77). Subgroup and meta-regression analyses identified various therapeutic modalities as the source of a high degree of heterogeneity. The pooled HR values showed no obvious change when a single study was removed, but otherwise, an opposite-effects model was used. In addition, no significant publication bias was detected.
CONCLUSION: Thrombocytopenia before treatment might be an inexpensive and useful predictor of postoperative recurrence in patients with HCC.
Hepatocellular carcinoma; Blood platelets; Thrombocytopenia; Recurrence; Prognosis
Sirolimus- (SES) and paclitaxel-eluting coronary stents (PES) are used to reduce restenosis, but have different sites of action. The molecular targets of sirolimus (SRL) overlap with those of the PPARγ agonist, rosiglitazone (RSG), but the consequence of this interaction on endothelialization is unknown.
Using the New Zealand White rabbit iliac model of stenting, we examined the effects of RSG on SES, PES and bare metal stent (BMS) endothelialization (ENDO).
Methods and Results
Animals receiving SES, PES, or BMS, and either RSG (3mg/kg/day) or placebo, were sacrificed at 28 days, and arteries evaluated by scanning electron microscopy (SEM). Fourteen-day organ culture (OC) and western blotting (WB) of iliac arteries, and tissue culture experiments were conducted. ENDO was significantly reduced by RSG in SES, but not in PES or BMS. OC revealed reduced VEGF in SES receiving RSG compared to RSG animals receiving BMS or PES. Quantitative PCR in human aortic endothelial cells (HAECs) revealed that SRL (but not paclitaxel) inhibited RSG-induced VEGF transcription. WB demonstrated that inhibition of molecular signaling in SES+RSG treated arteries was similar to findings in HAECs treated with RSG and siRNA to PPARγ, suggesting that SRL inhibits PPARγ. Transfection of HAECs with mTOR shRNA and with Akt2 siRNA significantly inhibited RSG mediated transcriptional upregulation of heme oxygenase-1 (HO-1), a PPARγ target gene. Chromatin immunoprecipitation assay demonstrated SRL interferes with binding of PPARγ to its response elements in HO-1 promoter.
mTOR/Akt2 is required for optimal PPARγ activation. Patients who receive SES during concomitant RSG treatment may be at risk for delayed stent healing.
stents; thrombosis; endothelium; pharmacology
To compare single nucleotide polymorphism (SNP) and comparative genomic hybridization (aCGH) microarray platforms to evaluate embryos for parental translocation imbalances and aneuploidy.
A retrospective review of preimplantation genetic diagnosis and screening (PGD/PGS) results of 498 embryos from 63 couples undergoing 75 in vitro fertilization cycles due to parental carriers of a reciprocal translocation.
There was no significant difference between SNP and aCGH microarrays when comparing the prevalence of embryos that were euploid with no translocation imbalance, euploidy with a parental translocation imbalance or aneuploid with or without the parental chromosome imbalance. The clinical pregnancy rates were also equivalent for SNP (60 %) versus aCGH (65 %) microarrays. Of 498 diagnosed embryos, 45 % (226/498) were chromosomally normal without translocation errors or aneuploidy, 22 % (112/498) were euploid but had a parentally derived unbalanced chromosomal segregant, 8 % (42/498) harbored both a translocation imbalance and aneuploidy and 24 % (118/498) of embryos were genetically balanced for the parental reciprocal translocation but were aneuploid for other chromosomes. The overall clinical pregnancy rate per IVF cycle following SNP or aCGH microarray analysis was 61 % and was higher if the biopsy was done on blastocysts (65 %) versus cleavage stage embryos (59 %), although not statistically significant.
SNP or aCGH microarray technologies demonstrate equivalent clinical findings that maximize the pregnancy potential in patients with known parental reciprocal chromosomal translocations.
Translocation; PGD; PGS; Microarray; IVF; Reciprocal
Src and the mammalian target of rapamycin (mTOR) signaling are commonly activated in non-small cell lung cancer (NSCLC) and hence potential targets for chemotherapy. Although the combined use of Src inhibitor Dasatinib with other chemotherapeutic agents has shown superior efficacy for cancer treatment, the mechanisms that lead to enhanced sensitivity of Dasatinib are not completely understood. In this study, we found that Rapamycin dramatically enhanced Dasatinib-induced cell growth inhibition and cell cycle G1 arrest in human lung adenocarcinoma A549 cells without affecting apoptosis. The synergistic effects were consistently correlated with the up-regulation of cyclin-dependent kinases inhibitor proteins, including p16, p19, p21, and p27, as well as the repression of Cdk4 expression and nuclear translocation. Mechanistic investigations demonstrated that FoxO1/FoxO3a and p70S6K/4E-BP1, the molecules at downstream of Src-PI3K-Akt and mTOR signaling, were significantly suppressed by the combined use of Dasatinib and Rapamycin. Restraining Src and mTOR with small interfering RNA in A549 cells further confirmed that the Src/PI3K/mTOR Pathway played a crucial role in enhancing the anticancer effect of Dasatinib. In addition, this finding was also validated by a series of assays using another two NSCLC cell lines, NCI-H1706 and NCI-H460. Conclusively, our results suggested that the combinatory application of Src and mTOR inhibitors might be a promising therapeutic strategy for NSCLC treatment.
Enamel mineralization is accompanied by the release of protons into the extracellular matrix, which is buffered to regulate the pH value in the local microenvironment. The present study aimed to investigate the role of microRNA 224 (miR-224) as a regulator of SLC4A4 and CFTR, encoding the key buffering ion transporters, in modulating enamel mineralization. miR-224 was significantly downregulated as ameloblasts differentiated, in parallel with upregulation of SLC4A4 and CFTR. Overexpression of miR-224 downregulated SLC4A4 and CFTR expression in cultured human epithelial cells. A microRNA luciferase assay confirmed the specific binding of miR-224 to the 3′ untranslated regions (UTRs) of SLC4A4 and CFTR mRNAs, thereby inhibiting protein translation. miR-224 agomir injection in mouse neonatal incisors resulted in normal enamel length and thickness, but with disturbed organization of the prism structure and deficient crystal growth. Moreover, the enamel Ca/P ratio and microhardness were markedly reduced after miR-224 agomir administration. These results demonstrate that miR-224 plays a pivotal role in fine tuning enamel mineralization by modulating SLC4A4 and CFTR to maintain pH homeostasis and support enamel mineralization.
AIM: To preliminarily investigate the prognostic significance of the platelet to lymphocyte ratio (PLR) in patients with gallbladder carcinoma (GBC).
METHODS: Clinical data of 316 surgical GBC patients were analyzed retrospectively, and preoperative serum platelet and lymphocyte counts were used to calculate the PLR. The optimal cut-off value of the PLR for detecting death was determined by the receiver operating characteristic (ROC) curve. The primary outcome was overall survival, which was estimated by the Kaplan-Meier method. The log-rank test was used to compare the differences in survival. Then, we conducted multivariate Cox analysis to assess the independent effect of the PLR on the survival of GBC patients.
RESULTS: For the PLR, the area under the ROC curve was 0.620 (95%CI: 0.542-0.698, P = 0.040) in detecting death. The cut-off value for the PLR was determined to be 117.7, with 73.6% sensitivity and 53.2% specificity. The PLR was found to be significantly positively correlated with CA125 serum level, tumor-node-metastasis (TNM) stage, and tumor differentiation. Univariate analysis identified carcinoembryonic antigen (CEA), CA125 and CA199 levels, PLR, TNM stage, and the degree of differentiation as significant prognostic factors for GBC when they were expressed as binary data. Multivariate analysis showed that CA125 > 35 U/mL, CA199 > 39 U/mL, PLR ≥ 117.7, and TNM stage IV were independently associated with poor survival in GBC. When expressed as a continuous variable, the PLR was still an independent predictor for survival, with a hazard ratio of 1.018 (95%CI: 1.001-1.037 per 10-unit increase, P = 0.043).
CONCLUSION: The PLR could be used as a simple, inexpensive, and valuable tool for predicting the prognosis of GBC patients.
Platelets; Lymphocyte; Gallbladder carcinoma; Prognosis; Survival
Radiation therapy is the primary treatment in nasopharyngeal carcinoma (NPC), and the effect of radiation therapy is strongly related to the oxygen content of cancer cells. That means, it is imperative to balance the interactions between radiotherapy and anti-angiogenesis therapy when giving combination therapy to improve clinical outcomes. The complicated mechanisms between antiangiogenic agents and radiation involve many interactions between the cancer cells, vasculature, and cancer stroma. The proliferation and metastasis of cancer depends on angiogenesis, while rapid growth of cancers will cause hypoxia, which contributes to radioresistance. Antiangiogenic agents can modulate the cancer blood flow and oxygenation through target cancer vasculature, leading to increased radiosensitivity. This study discusses the mechanisms of the synergistic effect of the antiangiogenic therapy with radiation therapy in metastatic NPC, and reviews the data supporting this strategy as a promising treatment for metastatic NPC.
FTO (Fat mass and obesity-associated) is associated with increased risk of obesity and type 2 diabetes incurrence. Pancreas islet β cells dysfunction and insulin resistance are major causes of type 2 diabetes. However, whether FTO plays an important functional role in pancreatic β cells as well as the related molecular mechanism is still unclear. In the present study, the tissue expression profile of FTO was firstly determined using quantitative PCR and western blot. FTO is widely expressed in various tissues and presented with relative high expression in pancreas tissue, especially in endocrine pancreas. FTO overexpression in MIN6 cells achieved by lentivirus delivery significantly inhibits insulin secretion in the presence of glucose stimulus as well as KCl. FTO silence has no effect on insulin secretion of MIN6 cells. However, FTO overexpression doesn’t affect the transcription of insulin gene. Furthermore, reactive oxygen species (ROS) production and NF-κB activation are significantly promoted by FTO overexpression. Inhibition of intracellular ROS production by N-acetyl-L-cysteine (NAC) can alleviate NF-κB activation and restore the insulin secretion mediated by FTO overexpression. A whole transcript-microarray is employed to analyze the differential gene expression mediated by FTO overexpression. The genes which are modulated by FTO are involved in many important biological pathways such as G-protein coupled receptor signaling and NF-κB signaling. Therefore, our study indicates that FTO may contribute to pancreas islet β cells dysfunction and the inhibition of FTO activity is a potential target for the treatment of diabetes.
AIM: To explore the effects of platelet count (PLT) and 11 platelet-based indices on postoperative recurrence of hepatocellular carcinoma (HCC).
METHODS: We retrospectively analyzed 172 HCC patients who were treated by partial hepatectomy. Preoperative data, including laboratory biochemical results, were used to calculate the 11 indices included in the analysis. We performed receiver operating characteristic curve analysis to determine the optimal cut-off values for predicting recurrence. Cumulative rates of HCC recurrence were calculated using Kaplan-Meier survival curves and differences were analyzed by log-rank tests. Multivariate analyses were performed to identify independent predictors of recurrence, early recurrence (within one year after surgery), and late recurrence in HCC. To obtain better prognostic models, PLT-based indices were analyzed separately after being expressed as binary and continuous variables. Two platelet-unrelated, validated HCC prognostic models were included in the analyses as reference indices. Additional analyses were performed after patients were stratified based on hepatitis B virus infection status, cirrhosis, and tumor size to investigate the significance of platelets in different subgroups.
RESULTS: In the study cohort, 44.2% (76/172) of patients experienced HCC recurrence, and 50.6% (87/172) died during a median follow-up time of 46 mo. PLT and five of the 11 platelet-related models were significant predisposing factors for recurrence (P < 0.05). Multivariate analysis indicated that, among the clinical parameters, presence of ascites, PLT ≥ 148 × 109/L, alkaline phosphatase ≥ 116 U/L, and tumor size ≥ 5 cm were independently associated with a higher risk of HCC recurrence (P < 0.05). Independent and significant models included the aspartate aminotransferase/PLT index, fibrosis index based on the four factors, fibro-quotient, aspartate aminotransferase/PLT/γ-glutamyl transpeptidase/alpha-fetoprotein index, and the PLT/age/alkaline phosphatase/alpha-fetoprotein/aspartate aminotransferase index. There were different risk factors between early and late recurrences, and PLT and these indices were more inclined to influence late recurrence. PLT was only predictive of recurrence in non-cirrhotic HCC patients, and was not influenced by tumor size, which was a critical confounder in our study.
CONCLUSION: PLT and PLT-based noninvasive models are effective tools for predicting postoperative recurrence, especially late recurrence. Larger cohorts are needed to validate our findings.
Alkaline phosphatase; Alpha-fetoprotein; Aspartate aminotransferase; Blood platelets; Hepatocellular carcinoma; Recurrence
AIM: To investigate the prognostic value of preoperative platelet count (PLT) in patients with primary gallbladder cancer (GBC).
METHODS: The clinical data of 223 GBC patients after surgery was retrospectively reviewed. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cutoff point for PLT. Univariate and multivariate survival analyses were performed to identify the factors associated with the prognosis.
RESULTS: The ROC curve showed that the optimum cutoff point for PLT was 178 × 109/L, and the entire cohort was stratified into group A with PLT > 178 × 109/L and group B with PLT ≤ 178 × 109/L. Group A had a better survival than group B (P < 0.001). There was an obvious difference between the two groups in terms of the differentiation degree, advanced tumor stage, lymph node metastasis (P < 0.001) and pathological type (P < 0.05). The univariate analysis demonstrated that tumor location, differentiation degree, TNM stage, Nevin stage, lymph node metastasis and PLT were associated with overall survival (P < 0.001). In the multivariate analysis, PLT (P = 0.032), lymph node metastasis (P = 0.007), tumor location (P < 0.001) and TNM stage (P = 0.005) were independent prognostic factors.
CONCLUSION: PLT is closely correlated with GBC prognosis and could be used to identify the population with a poorer prognosis after surgery.
Prognostic factor; Platelet count; Survival; Gallbladder cancer
In clinic, oral leukoplakia (OLK) may develop into oral cancer. However, the mechanism underlying this transformation is still unclear. In this work, we present a new pipeline to identify oral cancer related genes and microRNAs (miRNAs) by integrating both gene and miRNA expression profiles. In particular, we find some network modules as well as their miRNA regulators that play important roles in the development of OLK to oral cancer. Among these network modules, 91.67% of genes and 37.5% of miRNAs have been previously reported to be related to oral cancer in literature. The promising results demonstrate the effectiveness and efficiency of our proposed approach.
To carry out pectus excavatum (PEx) screening among primary school students in Dongguan, with an attempt to establish a PEx screening program and provide epidemiological evidences for developing guidelines on the diagnosis and treatment of PEx for young children.
A total of 479,402 primary school students who were already in school in 2012 or newly enrolled in 2013 from 422 primary schools in 32 towns in Dongguan, Guangdong Province were screened for PEx. Meanwhile, about 420 medical staff from the infirmaries of 422 primary schools were provided with a serial of training, with an attempt to establish a PEx screening program and network.
Valid screening results were obtained from 477,627 pupils (99.62%) from 406 primary schools in 31 towns. These students aged 4-15 years (mean: 8.78 years), among whom there were 244,545 males (N1; mean age: 8.22 years) and 233,082 females (N2; mean age: 8.89 years). Totally 257 PEx patients were identified, yielding a prevalence of 0.583%, among whom there were 176 males (N3; mean age: 8.79 years) and 81 females (N4; mean age: 8.77 years). With the PEx patients as the PEx group and the healthy children as the control group, chi square test with gender as the dependent variable showed that the incidence of PEx was significantly different between male and female students (P=0.00) (N3:N4 =2.172:1). In addition, 410 medical staff from the school infirmaries were trained, and a PEx screening program and network was established.
The screening for PEx was successfully performed among pupils who were already in school in 2012 or newly enrolled in 2013 from 422 primary schools in Dongguan, Guangdong Province. Statistical analysis showed that the incidence of PEx differed between male and female pupils. A stable effective PEx screening program was established, which will provide personal and technical supports for the early diagnosis and treatment of this condition.
Pectus excavatum (PEx); census; screening network
This study aims to explore the feasibility and safety of video-assisted thoracic surgery (VATS) double sleeve lobectomy in patients with non-small lung cell cancer (NSCLC).
Between June 2012 and August 2014, 13 NSCLC patients underwent thoracoscopic double sleeve lobectomy and mediastinal lymphadenectomy at three institutions. A retrospective analysis of clinical characteristics, operative data, postoperative events and follow-up was performed.
Thirteen NSCLC patients (median age, 60 years; range, 43-67 years) underwent thoracoscopic double sleeve lobectomy. There were no conversions to thoracotomy. Left upper lobectomy was most frequently performed (eleven patients). Median operative time was 263 minutes (range, 218-330 minutes), and median blood loss was 224 mL (range, 60-400 mL). The learning curve revealed reductions in both operative times and blood loss of ten cases from one center. Median data were duration of blocking pulmonary artery (PA) 72 minutes (range, 44-143 minutes), resected lymph nodes 24 (range, 10-46), stations of retrieved lymph nodes 6 (range, 5-9), thoracic drainage 1,042 mL (range, 500-1,700 mL), duration of thoracic drainage 5 days (range, 3-8 days), postoperative hospital stay 10 days (range, 7-20 days), and ICU stay 1 day (range, 1-2 days). One patient (1/13, 7.70%) suffered from pneumonia after surgery. There were no deaths at 30 days. Median duration of follow-up was 6 months (range, 1-26 months). And no local recurrences or distant metastasis were reported.
Thoracoscopic double sleeve lobectomy is a technically challenging, but feasible procedure for NSCLC patients and it should be restricted to skilled VATS surgeons.
Non-small lung cell cancer (NSCLC); video-assisted thoracic surgery (VATS); sleeve lobectomy; learning curve
Oral cancer threats people’s life and health seriously. Traditional treatment (surgery, radiotherapy, chemotherapy and traditional Chinese medicine treatment) is lack of pertinence that affects curative effect and prognosis. Therefore, it is necessary to explore the specific targets for oral cancer treatment. MiRNA-139 was transfected into oral cancer Tca8113 cells. Methyl thiazolyl tetrazolium (MTT) was applied to test cell proliferation. Flow cytometry was used to detect oral cancer Tca8113 cells apoptosis. miR-139 significantly inhibits oral cancer Tca8113 cells proliferation and induces cell apoptosis. SH-5 obviously weakened the cell apoptosis caused by miR-139. miR-139 could induce Tca8113 cell apoptosis through Akt signaling pathway. It may develop a more effective method for oral cancer treatment by this target.
miR-139; Akt signaling pathway; Tca8113; apoptosis
Cytoplasmic male sterility (CMS) is a maternally inherited inability to produce functional pollen found in numerous flowering plant species. CMS is associated with mitochondrial DNA mutation, novel chimeric open reading frames (ORFs), and rearrangement of coding and noncoding regions of the mitochondrial genome.
BLAST (Basic Local Alignment Search Tool) analysis indicated that L-sp1, a new sequence-characterized amplified region, is non-homologous to atp6-orfH79 (or atp6-orf79) and WA352 cloned CMS-associated genes. L-sp1 was found in 11 of 102 wild rice accessions belonging to four AA genome species: Oryza rufipogon, Oryza nivara, Oryza glumaepatula, and Oryza meridionalis. Using L-sp1, two new CMS lines were developed, from either low natural fertility plants or sterile plants, by backcrossing BC1F1 with Yuetai B. Northern blot and RT-PCR revealed that L-sp1 was only expressed in the anthers of w1/YTB, w2/YTB, w1/YTB//YTB, and w2/YTB//YTB when in the same cytoplasm background.
L-sp1 is a single-copy chimeric CMS-associated gene found in the mitochondrial genome. It can be expressed in anthers with the same specific cytoplasm background, and will be a useful molecular marker for the development and marker-assisted selection of new CMS lines.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0205-0) contains supplementary material, which is available to authorized users.
Chimeric DNA L-sp1; Cytoplasmic male sterility; Mitochondrial genome; Rice
To investigate the predictors and treatment of the 6-Fr Perclose Proglide-related complications (PRC) in percutaneous endovascular aortic repair (pEVAR).
We retrospectively analyzed the PRC after pEVAR for the treatment of aortic aneurysm or dissection in our center from December 2012 to November 2013. Procedure success was defined as effective functioning of the two devices and local hemostasis. Access-related adverse events included vascular complications and device failures. Operative data and angiographic and computed tomography images were collected to assess the complications and treatment strategy.
A total of 198 patients with 275 puncture sites underwent pEVAR with the 6-Fr Perclose Proglide. The procedure was successful in 178 patients (89.9%), whereas PRC occurred in 20 cases (10.1%), including 10 device failures and 10 vascular complications. An extra manual ancillary compression was conducted in 7 patients, one more device was used in 8 patients, and surgical repair of the femoral artery was performed in 5 patients. PRC had a tendency to occur in patients with body mass index (BMI)>30 kg/m2 (p = 0.021), thoracic stent grafts (p = 0.038), common femoral artery (CFA) calcification (p = 0.001), CFA depth>4 cm (p = 0.001), and sheath size>20Fr (p = 0.005). Device failure-related mortality was zero. None of the access sites had complications during the midterm follow-up.
The pre-close technique with 6-Fr Perclose Proglide devices for pEVAR appears to be safe and effective with low technical failure and complication rates. Careful patient selection and proficiency in device manipulation might reduce the device related complications.
AIM: To investigate the effects of single nucleotide polymorphisms (SNPs) in glutathione S-transferase (GST) genes on survival of hepatocellular carcinoma (HCC) patients.
METHODS: Twelve tagging SNPs in GST genes (including GSTA1, GSTA4, GSTM2, GSTM3, GSTO1, GSTO2 and GSTP1) were genotyped using Sequenom MassARRAY iPLEX genotyping method in a cohort of 214 Chinese patients with resected HCC. The Cox proportional hazards model and log-rank test were performed to determine the SNPs related to outcome. Additionally, stratified analysis was performed at each level of the demographic and clinical variables. An SNP-gene expression association model was further established to investigate the correlation between SNP and gene expression.
RESULTS: Two SNPs (GSTO2: rs7085725 and GSTP1: rs4147581) were significantly associated with overall survival in HCC patients (P = 0.035 and 0.042, respectively). In stratified analysis, they were more significantly associated with overall survival in patients with younger age, male gender and cirrhosis. We further investigated cumulative effects of these two SNPs on overall survival in HCC patients. Compared with the patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 1.70-fold increased risk of death (P < 0.001). The cumulative effects were more significant in those patients with younger age, male gender and cirrhosis (HR = 2.00, 1.94 and 1.97, respectively; all P < 0.001). Additionally, we found that heavy smoking resulted in a significantly worse overall survival in those patients carrying variant alleles of rs7085725 (HR = 2.07, 95%CI: 1.13-3.76, P = 0.018). The distributions of GSTO2: rs7085725 and GSTP1: rs4147581 genotypes were associated with altered gene expression and contributed to influences on overall survival.
CONCLUSION: Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.
Glutathione S-transferase; Polymorphism; Hepatocellular carcinoma; Clinical outcome; Surgery
Double stranded RNA–dependent protein kinase (PKR) is a eukaryotic initiation factor 2α kinase that inhibits mRNA translation under stress conditions. PKR also mediates inflammatory and apoptotic signaling independent of translational regulation. Congestive heart failure (CHF) is associated with cardiomyocyte hypertrophy, inflammation, and apoptosis, but the role of PKR in left ventricular (LV) hypertrophy and development of CHF has not been examined.
Methods and Results
We observed an increased myocardial PKR expression and translocation of PKR into the nucleus in humans and mice with CHF. To determine the impact of PKR in the development of CHF, PKR knockout and wild-type mice were exposed to pressure overload produced by transverse aortic constriction (TAC). Though heart size increased similarly in wild-type and PKR knockout mice after TAC, PKR knockout mice exhibited very little pulmonary congestion, well preserved LV ejection fraction and contractility, and significantly less myocardial fibrosis as compared to wild-type mice. Bone marrow-derived cells (BMDCs) from wild-type mice did not abolish the cardiac protective effect observed in PKR knockout mice, while BMDCs from PKR knockout mice had no cardiac protective effect in wild-type mice. Mechanistically, PKR knockout attenuated TAC-induced TNF-α expression and leukocyte infiltration, and lowered cardiac expression of pro-apoptotic factors (Bax and Caspase-3) so that PKR knockout hearts were more resistant to TAC-induced cardiomyocyte apoptosis. PKR depletion in isolated cardiomyocytes also conferred protection against TNF-α or LPS-induced apoptosis.
PKR is a maladaptive factor up-regulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis and development of CHF.
heart failure; double stranded RNA–dependent protein kinase; inflammation; apoptosis
Activation of AMP-activated protein kinase (AMPK) α2 protects the heart against pressure overload-induced heart failure in mice. Although metformin is a known activator of AMPK, it is unclear whether its cardio-protection acts independently of an AMPKα2-dependent pathway. Because the role of AMPKα1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPKα1 and AMPKα2 genes on the response to transverse aortic constriction (TAC)-induced left ventricular (LV) hypertrophy and dysfunction in mice. AMPKα2 gene knockout (KO) significantly exacerbated the degree of TAC-induced LV hypertrophy and dysfunction, whereas AMPKα1 gene KO had no effect on the degree of TAC-induced LV hypertrophy and dysfunction. Administration of metformin to both wild type (WT) and AMPKa2 KO mice attenuated the degree of TAC-induced LV remodeling, as evidenced by reduced LV and lung weights, a more favorable body weight to tibia length ratio, preserved LV ejection fraction, and lower levels of p-mTORser2481 and p-p70S6KThr389. These data support the notion that activation of AMPKα1 plays a negligible role in protecting the heart against the adverse effects of chronic pressure overload, and that metformin protects against adverse remodeling through a pathway that appears independent of AMPKα2.
metformin; heart failure
Rheumatoid arthritis (RA) is a common, autoimmune disorder characterized by progressive multiple joint destruction, deformity, disability and premature death in most patients. Fu-Fang-Lu-Jiao-Shuang (FFLJS) is an effective traditional Chinese medicine, which has long been used clinically to treat RA patients.
The objective of this study is aimed to evaluate the anti-rheumatic effects of FFLJS on collagen induced arthritis (CIA) model, as well as the underlying mechanisms, which have not previously been explored.
Materials and Methods:
CIA was induced by immunization with type II collagen (CII) in male Balb/c mice. The mice in the onset of arthritis were treated daily with FFLJS (125 or 500 mg/kg) or 1% carboxymethyl cellulose-Na for 28 days. Paw thickness and arthritic score were evaluated to confirm the anti-arthritic effect of FFLJS on CIA in mice. Levels of anti-CII antibody, proinflammatory cytokines interleukin-1 (IL-1) β, IL-17, and tumor necrosis factor-α (TNF-α) as well as prostaglandin E-2 (PGE-2) in serum and histological changes in the ankle joint were also analyzed. In addition, expressions of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitors of matrix metalloproteases-1 (TIMP-1) in synovial tissue were also detected to further study the molecular mechanism of the anti-arthritic effects of FFLJS.
During therapeutic treatment, FFLJS significantly reduced paw thickness and arthritic score in CIA mice, decreased the amounts of TNF-α, IL-1 β, IL-17, PGE-2 and anti-CII antibody in serum. In addition, FFLJS treatment could prevent the bone destruction by reducing the expression of MMP-1 and MMP-3, increasing the expression of TIMP-1 in synovial tissue of CIA mice.
These findings offer the convincing evidence for the first time that the anti-rheumatic effects of FFLJS might be related to down-regulation of TNF-α, IL-1 β, IL-17 and PGE-2 levels for acute arthritis, and regulation of MMP-1, MMP-3 and TIMP-1 protein expression for chronic arthritis.
Anti-arthritic activity; Fu-Fang-Lu-Jiao-Shuang; matrix metalloproteinases; traditional Chinese medicine
The objective of the current study was to evaluate the feasibility and safety of nonintubated uniportal video-assisted thoracoscopic surgery (VATS) for the management of primary spontaneous pneumothorax (PSP).
From November 2011 to June 2013, 32 consecutive patients with PSP were treated by nonintubated uniportal thoracoscopic bullectomy using epidural anaesthesia and sedation without endotracheal intubation. An incision 2 cm in length was made at the 6th intercostal space in the median axillary line. The pleural space was entered by blunt dissection for placement of a soft incision protector. Instruments were then inserted through the incision protector to perform thoracoscopic bullectomy. Data were collected within a minimum follow-up period of 10 months.
The average time of surgery was 49.0 min (range, 33-65 min). No complications were recorded. The postoperative feeding time was 6 h. The mean postoperative chest tube drainage and hospital stay were 19.3 h and 41.6 h, respectively. The postoperative pain was mild for 30 patients (93.75%) and moderate for two patients (6.25%). No recurrences of pneumothorax were observed at follow-up.
The initial results indicated that nonintubated uniportal video-assisted thoracoscopic operations are not only technically feasible, but may also be a safe and less invasive alternative for select patients in the management of PSP. This is the first report to include the use of a nonintubated uniportal technique in VATS for such a large number of PSP cases. Further work and development of instruments are needed to define the applications and advantages of this technique.
Uniportal; video-assisted thoracoscopic surgery (VATS); spontaneous pneumothorax
The spider suborder Mesothelae, containing a single extant family Liphistiidae, represents a species-poor and ancient lineage. These are conspicuous spiders that primitively retain a segmented abdomen and appendage-like spinnerets. While their classification history is nearly devoid of phylogenetic hypotheses, we here revise liphistiid genus level taxonomy based on original sampling throughout their Asian range, and on the evidence from a novel molecular phylogeny. By combining morphological and natural history evidence with phylogenetic relationships in the companion paper, we provide strong support for the monophyly of Liphistiidae, and the two subfamilies Liphistiinae and Heptathelinae. While the former only contains Liphistius Schiödte, 1849, a genus distributed in Indonesia (Sumatra), Laos, Malaysia, Myanmar, Thailand, we recognize and diagnose seven heptatheline genera, all but three removed from the synonymy of Heptathela: i) Ganthela Xu & Kuntner, gen. n. with the type species Ganthela
yundingensis Xu, sp. n. is known from Fujian and Jiangxi, China; ii) a rediagnosed Heptathela Kishida, 1923 is confined to the Japanese islands (Kyushu and Okinawa); iii) Qiongthela Xu & Kuntner, gen. n. with the type species Qiongthela
baishensis Xu, sp. n. is distributed disjunctly in Hainan, China and Vietnam; iv) Ryuthela Haupt, 1983 is confined to the Ryukyu archipelago (Japan); v) Sinothela Haupt, 2003 inhabits Chinese areas north of Yangtze; vi) Songthela Ono, 2000 inhabits southwest China and northern Vietnam; and vii) Vinathela Ono, 2000 (Abcathela Ono, 2000, syn. n.; Nanthela Haupt, 2003, syn. n.) is known from southeast China and Vietnam.
East Asia; Southeast Asia; biogeography; classification; trapdoor spiders; living fossils