Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO.

Phenol-soluble modulins (PSMs) and Staphylococcal protein A (SpA) are key virulence determinants for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), an important human pathogen that causes a wide range of diseases. Here, using chemical and genetic approaches, we show that inhibition of TarO, the first enzyme in the wall teichoic acid (WTA) biosynthetic pathway, decreases the expression of genes encoding PSMs and SpA in the prototypical CA-MRSA strain USA300 LAC. Mechanistically, these effects are linked to the activation of VraRS two-component system that directly represses the expression of accessory gene regulator (agr) locus and spa. The activation of VraRS was due in part to the loss of the functional integrity of penicillin-binding protein 2 (PBP2) in a PBP2a-dependent manner. TarO inhibition can also activate VraRS in a manner independent of PBP2a. We provide multiple lines of evidence that accumulation of lipid-linked peptidoglycan precursors is a trigger for the activation of VraRS. In sum, our results reveal that WTA biosynthesis plays an important role in the regulation of virulence gene expression in CA-MRSA, underlining TarO as an attractive target for anti-virulence therapy. Our data also suggest that acquisition of PBP2a-encoding mecA gene can impart an additional regulatory layer for the modulation of key signaling pathways in S. aureus.

Association of LAMA1 Single-Nucleotide Polymorphisms with Risk of Esophageal Squamous Cell Carcinoma among the Eastern Chinese Population.

Introduction: LAMA1, also known as laminin subunit α1, is a member of the laminin family, which is widely reported to be a key basement membrane molecule that affects various biological activities and is associated with many kinds of diseases. We aimed to investigate the association between LAMA1single-nucleotide polymorphisms and the occurrence and progression of esophageal squamous cell carcinoma in the Chinese population. Method: 2,186 participants were collected retrospectively between October 2008 and January 2017, including 1,043 ESCC patients and 1,143 noncancer patients. A 2 mL blood sample was obtained intravenously for the LDR for SNP analysis. The 6 SNP loci of LAMA1 were selected and examined. We analyzed the association of several genetic models of 6 LAMA1 SNP loci, sex, age, smoking and drinking status, and the occurrence of esophageal squamous cell carcinoma. Results: In the rs62081531 G > A locus, genotype GA was a protective factor for ESCC compared with GG (OR: 0.830, P=0.046), especially among the younger and nondrinkers. At rs607230 T > C, genotype TC was linked with a lower risk of ESCC compared with TT. (OR: 0.613, P=0.034). Haplotype Frequencies revealed that Ars62081531Grs621993Ars539713Trs566655Ars73938538Crs607230 (OR: 0.803, P=0.028) and Grs62081531Grs621993Ars539713Trs566655Crs73938538Crs607230 (OR: 0.679, P=0.010) were strongly associated with lower susceptibility of ESCC. Conclusion: The LAMA1 rs62081531, rs539713, rs566655, and rs607230 polymorphisms were demonstrated to be related to susceptibility to ESCC in the Chinese population. LAMA1 SNPs may have a significant impact on the occurrence of esophageal cancer and may serve as potential diagnostic biomarkers.

The enzyme activity of sortase A is regulated by phosphorylation in Staphylococcus aureus.

In many Gram-positive bacteria, the transpeptidase enzyme sortase A (SrtA) anchors surface proteins to cell wall and plays a critical role in the bacterial pathogenesis. Here, we show that in Staphylococcus aureus, an important human pathogen, the SrtA is phosphorylated by serine/threonine protein kinase Stk1. S. aureus SrtA can also be phosphorylated by small-molecule phosphodonor acetyl phosphate (AcP) in vitro. We determined that various amino acid residues of S. aureus SrtA are subject to phosphorylation, primarily on its catalytic site residue cysteine-184 in the context of a bacterial cell lysate. Both Stk1 and AcP-mediated phosphorylation inhibited the enzyme activity of SrtA in vitro. Consequently, deletion of gene (i.e. stp1) encoding serine/threonine phosphatase Stp1, the corresponding phosphatase of Stk1, caused an increase in the phosphorylation level of SrtA. The stp1 deletion mutant mimicked the phenotypic traits of srtA deletion mutant (i.e. attenuated growth where either haemoglobin or haem as a sole iron source and reduced liver infections in a mouse model of systemic infection). Importantly, the phenotypic defects of the stp1 deletion mutant can be alleviated by overexpressing srtA. Taken together, our finding suggests that phosphorylation plays an important role in modulating the activity of SrtA in S. aureus.

Identification and Validation of Common Reference Genes for Normalization of Esophageal Squamous Cell Carcinoma Gene Expression Profiles.

Esophageal squamous cell carcinoma (ESCC) is one of the subtypes of esophageal cancer with Chinese characteristics, and its five-year survival rate is less than 20%. Early diagnosis is beneficial to improving the survival rate of ESCC significantly. Quantitative Real-Time Polymerase Chain Reaction is a high-throughput technique that can quantify tumor-related genes for early diagnosis. Its accuracy largely depends on the stability of the reference gene. There is no systematic scientific basis to demonstrate which reference gene expression is stable in ESCC and no consensus on the selection of internal reference. Therefore, this research used four software programs (The comparative delta-Ct method, GeNorm, NormFinder, and BestKeeper) to evaluate the expression stability of eight candidate reference genes commonly used in other tumor tissues and generated a comprehensive analysis by RefFinder. Randomly selected transcriptome sequencing analysis confirmed the SPP1 gene is closely related to ESCC. It was found that the expression trend of SPP1 obtained by RPS18 and PPIA as internal reference genes were the same as that of sequencing. The results show that RPS18 and PPIA are stable reference genes, and PPIA + RPS18 are a suitable reference gene combination. This is a reference gene report that combines transcriptome sequencing analysis and only focuses on ESCC, which makes the quantification more precise, systematic, and standardized, and promotes gene regulation research and the early diagnosis of ESCC in the future.

Metabolomics of Esophageal Squamous Cell Carcinoma Tissues: Potential Biomarkers for Diagnosis and Promising Targets for Therapy.

Background: The incidence of esophageal squamous cell carcinoma in China ranks first in the world. The early diagnosis technology is underdeveloped, and the prognosis is poor, which seriously threatens the quality of life of the Chinese people. Epidemiological findings are related to factors such as diet, living habits, and age. The specific mechanism is not clear yet. Metabolomics is a kind of omics that simultaneously and quantitatively analyzes the comprehensive profile of metabolites in living systems. It has unique advantages in the study of the diagnosis and pathogenesis of tumor-related diseases, especially in the search for biomarkers. Therefore, it is desirable to perform metabolic profiling analysis of cancer tissues through metabolomics to find potential biomarkers for the diagnosis and treatment of esophageal squamous cell carcinoma. Methods: HPLC-TOF-MS/MS technology and Illumina Hiseq Xten Sequencing was used for the analysis of 210 pairs of matched esophageal squamous cell carcinoma tissues and normal tissues in Zhenjiang City, Jiangsu Province, a high-incidence area of esophageal cancer in China. Bioinformatics analysis was also performed. Results: Through metabolomic and transcriptomic analysis, this study found that a total of 269 differential metabolites were obtained in esophageal squamous cell carcinoma and normal tissues, and 48 differential metabolic pathways were obtained through KEGG enrichment analysis. After further screening and identification, 12 metabolites with potential biomarkers to differentiate esophageal squamous cell carcinoma from normal tissues were obtained. Conclusions: From the metabolomic data, 4 unknown compounds were found to be abnormally expressed in esophageal squamous cell carcinoma for the first time, such as 9,10-epoxy-12,15-octadecadienoate; 3 metabolites were found in multiple abnormal expression in another tumor, but upregulation or downregulation was found for the first time in esophageal cancer, such as oleoyl glycine; at the same time, it was further confirmed that five metabolites were abnormally expressed in esophageal squamous cell carcinoma, which was similar to the results of other studies, such as PE.

The Single Nucleotide Polymorphisms of AP1S1 are Associated with Risk of Esophageal Squamous Cell Carcinoma in Chinese Population.

Background: The σ1A subunit of the adaptor protein 1 (AP1S1) participates in various intracellular transport pathways, especially the maintenance of copper homeostasis, which is pivotal in carcinogenesis. It is therefore rational to presume that AP1S1 might also be involved in carcinogenesis. In this hospital-based case-control study, we investigated the genetic susceptibility to ESCC in relation to SNPs of AP1S1 among Chinese population. Methods: A database containing a total of 1303 controls and 1043 ESCC patients were retrospectively studied. The AP1S1 SNPs were analyzed based on ligation detection reaction (LDR) method. Then, the relationship between ESCC and SNPs of AP1S1 was determined with a significant crude P<0.05. Then the logistic regression analysis was used for the calculation for adjusted P in the demographic stratification comparison if a significant difference was observed in the previous step. Results: AP1S1 rs77387752 C>T genotype TT was an independent risk factor for ESCC, while rs4729666 C>T genotype TC and rs35208462 C>T genotype TC were associated with a lower risk for ESCC, especially in co-dominant model and allelic test for younger, male subjects who are not alcohol-drinkers nor cigarette smokers. Conclusion: AP1S1 rs77387752, rs4729666 and rs35208462 polymorphisms are associated with susceptibility to ESCC in Chinese individuals. AP1S1 SNPs may exert an important role in esophageal carcinogenesis and could serve as potential diagnostic biomarkers.

Human Umbilical Cord-Derived Mesenchymal Stem Cells Repair SU5416-Injured Emphysema by Inhibiting Apoptosis via Rescuing VEGF-VEGFR2-AKT Pathway in Rats.

Background and Objectives: Chronic obstructive pulmonary disease (COPD) is a common, frequently-occurring disease and poses a major health concern. Unfortunately, there is current no effective treatment for COPD, particularly emphysema. Recently, experimental treatment of COPD using mesenchymal stem cells (MSCs) mainly focused on bone marrow-derived MSCs (BM-MSCs). Human umbilical cord-derived MSCs (hUC-MSCs) have more advantages compared to BM-MSCs. However, studies on the role of hUC-MSCs in management of COPD are limited. This study sought to explore the role of hUC-MSCs and its action mechanisms in a rat model of VEGF receptor blocker SU5416-injured emphysema. Methods and Results: hUC-MSCs were characterized by immunophenotype and differentiation analysis. Rats were divided into four groups: Control, Control＋MSC, SU5416 and SU5416＋MSC. Rats in model group were administered with SU5416 for three weeks. At the end of the second week after SU5416 administration, model group were infused with 3×106 hUC-MSCs through tail vein. After 14 days from hUC-MSCs transplantation, rats were euthanized and data were analyzed. HE staining and mean linear intercepts showed that SU5416-treated rats exhibited typical emphysema while emphysematous changes in model rats after hUC-MSCs transplantation disappeared completely and were restored to normal phenotype. Furthermore, hUC-MSCs inhibited apoptosis as shown by TUNEL and Western blotting. ELISA and Western blotting showed hUC-MSCs rescued VEGF-VEGFR2-AKT pathway in emphysematous lungs. Conclusions: The findings show that hUC-MSCs effectively repair the emphysema injury. This study provides the first evidence that hUC-MSCs inhibit apoptosis via rescuing VEGF- VEGFR2-AKT pathway in a rat model of emphysema.

Case-control study on TP73 rs1801173 C > T gene polymorphism and susceptibility to gastric cancer in a Chinese Han population.

BACKGROUND: This study investigated the role of TP73 gene polymorphism, rs1801173on risk of gastric cancer. METHODS: We conducted a case-controlled study including 577 primary gastric cancer and 678 normal control cases. The target gene fragment was amplified using PCR using blood samples collected from patients. Allele analysis and genotyping were performed using snapshot method. RESULTS: The findings showed that the control group had consistent genotype frequency distribution and presented Hardy-Weinberg equilibrium. The results showed no significant differences in sex, drinking history and age distributions between subjects with the polymorphism and subjects in the control group. Smoking status was correlated with incidence of gastric cancer (P = 0.006). The rs1801173 locus of TP73 gene contained 3 genotypes including: TT, CT, and CT. Logistic regression analysis showed that distribution of recessive model and dominant model was comparable between the two groups before (P = 0.688; 0.937) or after (P = 0.703; 0.990) adjusting for confounders. The distribution frequency in case group was not significantly different relative to that of the control group (P = 0.763). CONCLUSION: Smoking can independently influence the risk of gastric cancer. TP73 gene rs1801173 polymorphism was not significantly correlated with risk of gastric cancer.

Genomics and proteomics combined analysis revealed the toxicity response of silkworm Bombyx mori to the environmental pathogen Bacillus cereus ZJ-4.

Bacterial contamination has caused a major public health problem worldwide. Bacillus cereus is a conditional environmental pathogenic bacteria that can cause food poisoning. Whether environmental pathogens can cause widespread transmission in the insect kingdom is unclear. In this study, a Bacillus cereus ZJ-4 was isolated from the hospital environment of Zhenjiang City, Jiangsu Province, China. It was fatal by injection into the silkworm hemolymph. To investigated the potential toxic factors of ZJ-4 and clarified the toxicity response mechanism of silkworm by the ZJ-4 infection. Then, the whole genome of ZJ-4 was sequenced, and the immune mechanism of silkworm fat body to ZJ-4 pathogen was studied by HE pathological section and proteomics. Bacterial genome sequencing indicated that ZJ-4 had 352 drug resistance genes and 6 virulence genes. After 36 h of subcutaneous puncture with ZJ-4 suspension, the pathological changes were obviously found in HE pathological sections of fat body tissue. Comparative proteomic results indicated that differentially expressed proteins are mainly involved in stress reactions, biological regulation, and innate immunity. The qRT-PCR analysis showed that the expressions of ß-GRP, Spaetzle, MyD88, Tube and Dorsal genes in Toll pathway were up-regulated, while Pell and Cactus genes were down-regulated; in the antimicrobial peptide pathway, Glv2, Lzm, Mor, and Leb3 genes were up-regulated, while attacin1 and defensin genes were down-regulated; Sod gene was up-regulated, while Cat gene was down-regulated in the antioxidant pathway; Ldh, Sdh, and Mdh genes were down-regulated in glucose metabolism pathway. These results indicated that ZJ-4 can damage the innate immune pathway of silkworm, and also affect the normal immune function of fat body cells.

Status of diagnosis and treatment of esophageal cancer and non-coding RNA correlation research: a narrative review.

OBJECTIVE: To describe and discuss the progression of the non-coding RNA as biomarkers in early esophageal cancer. BACKGROUND: Esophageal cancer without obvious symptoms during early stages is one of the most common cancers, the current clinical treatments offer possibilities of a cure, but the survival rates and the prognoses remain poor, it is a serious threat to human life and health. Most patients are usually diagnosed during terminal stages due to low sensitivity of esophageal cancer's early detection techniques. With the development of molecular biology, an increasing number of non-coding RNAs are found to be associated with the occurrence, development, and prognosis of esophageal cancer. Some of these have begun to be used in clinics and laboratories for diagnosis, treatment, and prognosis, with the goal of reducing mortality. METHODS: The information for this paper was collected from a variety of sources, including a search of the keynote's references, a search for texts in college libraries, and discussions with experts in the field of esophageal cancer clinical treatment. CONCLUSIONS: Non-coding RNA does play a regulatory role in the development of esophageal cancer, which can predict the occurrence or prognosis of tumors, and become a new class of tumor markers and therapeutic targets in clinical applications. In this review, we survey the recent developments in the incidence, diagnosis, and treatment of esophageal cancer, especially with new research progresses on non-coding RNA biomarkers in detail, and discuss its potential clinical applications.

Case-Control Study on TNFRSF6B Gene Polymorphism and Susceptibility to Gastric Cancer in a Chinese Han Population.

PURPOSE: To explore the relationship between rs2297440 and rs2297441 polymorphisms of TNFRSF6B gene and susceptibility to gastric cancer. METHODS: A hospital-based case-control study was conducted. A total of 577 gastric cancer cases and 678 normal controls were recruited. Their genotypes were determined using the SnapShot method. RESULTS: The smoking rate in the case group (34.49%) was higher than that in the control group (27.29%). For TNFRSF6B rs2297440, among people <62 years old, the risk of gastric cancer in TC people was 1.84 times that in TT people. Among the non-drinking people, the risk of gastric cancer in the CC type was 0.66 times that in the TT+TC type. Among the drinking population, the risk of gastric cancer in the TC type was 1.67 times that in the TT type, and the risk in the TC+CC type was 1.70 times that in the TT type. As for TNFRSF6B rs2297441, in males and non-drinkers, the risk of gastric cancer in the AG type was less than that in the GG type. No matter how old the patient is, the risk of gastric cancer in the AA type was less than that in the AG+GG type. CONCLUSION: A correlation exists between smoking and gastric cancer. For TNFRSF6B rs2297440, the TC genotype may be a risk factor for gastric cancer in people <62 years old. In the non-drinking population, the homozygous mutant of CC may be a protective factor for gastric cancer. In the drinking population, TC type may be a risk factor, whereas the TC+CC type dominated by C may be a protective factor. For TNFRSF6B rs2297441, the AG genotype may be a risk factor for gastric cancer in males and non-drinkers. The AA homozygous mutant may be a protective factor for gastric cancer.

Clinical Prediction of Surgical Revascularization Outcome in Moyamoya Disease Via Transcranial Color Sonography.

OBJECTIVE: Transcranial color-duplex sonography (TCCS) is a promising method in evaluating the hemodynamics in patients with moyamoya disease (MMD). This study aimed to explore the feasibility of preoperative TCCS in predicting the outcome of revascularization surgery in MMD patients. METHODS: We retrospectively analysed 64 cases of MMD patients receiving revascularization surgery from January 2012 to January 2014. We utilized TCCS to perform comprehensive hemodynamic examination on the hemodynamics of bilateral intracranial and extracranial cerebrovascular flow and assessed the surgical outcomes and prognosis through the longitudinal comparison of the preoperative and postoperative cerebrovascular hemodynamics. Occurrence of bypass blockage was regarded as surgical failure. RESULTS: We established a prediction model for bypass blockage among MMD patients with an AUC of 0.858 (95% CI: 0.666-1). The parameters, EDV of ECA and PSV of MA obtained by the model are the main preoperative predictors for bypass blockage. CONCLUSIONS: TCCS could preoperatively determine the degree of MMD and evaluate the outcome of revascularization surgery. It also is a feasible tool to predict the curative effect by providing preoperative hemodynamic information.

The Relationship Between Single Nucleotide Polymorphisms of SMAD3/SMAD6 and Risk of Esophageal Squamous Cell Carcinoma in Chinese Population.

BACKGROUND: The TGF-ß signal pathways play a key role in the development and promotion of squamous cell carcinoma (SCC). The pathway is mediated by the SMAD family proteins that include SMAD3 and SMAD6. Our study aimed to evaluate the relationship between single nucleotide polymorphism (SNP) of SMAD3/SMAD6 and susceptibility to esophageal squamous cell carcinoma (ESCC) in the Chinese population. PATIENTS AND METHODS: This was a hospital-based case-control study compromised of 1043 ESCC patients and 1315 non-cancer patients. Seven SMAD3/SMAD6 (rs8028147, rs3743343, rs3743342, rs8025774, rs8031440, rs803167, and rs34643453) SNPs were selected and used to evaluate their correlation with ESCC susceptibility. Genetic model tests, stratified analyses, linkage disequilibrium analyses, and haplotype analyses were performed in our study. RESULTS: Participants with SMAD3 rs3743342 C>T, rs8025774 C>T, rs8031440 G>A or rs8031627 G>A had a significantly higher risk of ESCC. This was more evident in males, older patients (>63 years), smokers, and non-alcohol drinking participants. Linkage disequilibrium analyses further revealed that there were strong correlations between SMAD3 rs3743342 C>T, rs8025774 C>T, rs8031440 G>A, and rs8031627 G>A. In the same line, haplotype analyses revealed that SMAD3 ACCCGGSMAD6A and SMAD3AGCCGGSMAD6A were associated with less susceptibility to ESCC while SMAD3ATTTAASMAD6A was associated with a higher risk of ESCC. CONCLUSION: SNPs of SMAD3 were related to higher susceptibility to ESCC. As such, they may contribute to the development of viable strategies for early diagnosis and treatment of ESCC. However, more detailed association mechanisms between SMAD3/SMAD6 SNPs and ESCC need further experiments to prove.

Association Study of MAP3K1 SNPs and Risk Factors with Susceptibility to Esophageal Squamous Cell Carcinoma in a Chinese Population: A Case-Control Study.

PURPOSE: The aim of this study was to screen the predisposed population and explore possible interactions between genetic polymorphisms and risk factors involved in the tumorigenesis and progression of ESCC (esophageal squamous cell carcinoma), in hope of identifying possible therapeutic targets along the way. PATIENTS AND METHODS: Cases (1043) and controls (1315) were enrolled to evaluate the possible association between MAP3K1 SNPs and ESCC risk. Subgroup analyses include MAP3K1 variants, gender, age, smoking and drinking status. RESULTS: Among all three single locus polymorphisms of MAP3K1, only the heterozygote genotype of rs702689 AG is shown to be associated with increased risk for developing ESCC (OR=1.272, 95% confidence interval=1.061-1.525, p=0.009). Moreover, stratified analysis results observed altered susceptibility among patients with exposure to risk factors combined with certain genetic variant to ESCC. CONCLUSION: This study reveals that MAP3K1 rs702689 AG genotype might facilitate the tumorigenesis in ESCC, particularly among women, patients who were over 63y and those who never drink nor smoke.

Association of Genetic Polymorphisms in TNFRSF11 with the Progression of Genetic Susceptibility to Gastric Cancer.

OBJECTIVE: To investigate the relationship between polymorphism of TNFRSF11 gene rs9533156 and rs2277438 and susceptibility to gastric cancer. METHODS: A case-control study was conducted to select 577 cases of primary gastric cancer and 678 cases of normal control. We extracted whole blood genomic DNA and amplified the target gene fragment by PCR. The genotyping and allele were tested through the snapshot method. RESULTS: In this case-control study, we observed that there was a difference in the genotype distribution of TNFRSF11 gene rs9533156 between the case group and the control group. The frequency distribution of TC heterozygous mutation in the case group was higher than that in the control group. The smoking rate in the case group (34.49%) was higher than that in the control group (27.29%), and the difference in frequency distribution between the two groups was statistically significant (P=0.006). Our findings suggest that TNFRSF11 rs9533156 is associated with susceptibility to GC, which is more evident among elderly patients (>62 years), nonsmokers, and patients who do not consume alcohol. The analysis of the relationship between the TNFSF11 gene rs9533156 site variant and clinical factors of gastric cancer showed that, compared with the tumor size <2 cm group, patients with tumor size ≥2 cm and whom carrying rs9533156 site mutations had a higher frequency distribution, and the difference was statistically significant (P=0.022). Compared with the nonhyperglycemic group, the frequency distribution of patients with rs9533156 site mutations in the diabetes group was higher, and the difference was statistically significant (P < 0.001). CONCLUSION: This study shows that there is a correlation between smoking and the occurrence of gastric cancer. Based on our research, the functional SNP TNFRSF11 TC genotype may be an indicator of individual susceptibility to GC. The mutation at rs9533156 may be related to the size of gastric cancer. The mutation rate of rs9533156 of TNFSF11 gene is higher in diabetic gastric cancer patients.

Association of Genetic Polymorphisms in FOXA1 with the Progression of Genetic Susceptibility to Gastric Cancer.

OBJECTIVE: To investigate the relationship between polymorphism of FOXA1 gene rs12894364 and rs7144658 and susceptibility to gastric cancer. METHODS: A case-control study was conducted to select 577 cases of primary gastric cancer and 678 cases of normal control. We extracted whole blood genomic DNA and amplified the target gene fragment by PCR. The genotyping and allele was tested through a snapshot method. RESULTS: There was no significant difference in the frequency distribution of genotype between the case group and control group (P > 0.05). Stratified analyses showed the SNPs were not correlated with the susceptibility of GC according to different age, gender, cigarette smoking, and alcohol drinking status. CONCLUSION: There is no significant correlation between the polymorphisms of FOXA1 gene rs12894364 and rs7144658 and the risk of gastric cancer.

Association between apurinic/apyrimidinic endonuclease 1 rs1760944 T>G polymorphism and susceptibility of cancer: a meta-analysis involving 21764 subjects.

BACKGROUND: Previous case-control studies have suggested that apurinic/apyrimidinic endonuclease 1 (APE1) rs1760944 T>G polymorphism may be associated with cancer risk. Here, we carried out an updated meta-analysis to focus on the correlation between APE1 rs1760944 T>G locus and the risk of cancer. METHODS: We used the crude odds ratios (ORs) with their 95% confidence intervals (CIs) to evaluate the possible relationship between the APE1 rs1760944 T>G polymorphism and cancer risk. Heterogeneity, publication bias and sensitivity analysis were also harnessed to check the potential bias of the present study. RESULTS: Twenty-three independent studies involving 10166 cancer cases and 11598 controls were eligible for this pooled analysis. We found that APE1 rs1760944 T>G polymorphism decreased the risk of cancer in four genetic models (G vs. T: OR, 0.87; 95% CI, 0.83-0.92; P<0.001; GG vs. TT: OR, 0.77; 95% CI, 0.69-0.86; P<0.001; GG/TG vs. TT: OR, 0.83; 95% CI, 0.77-0.89, P<0.001 and GG vs. TT/TG: OR, 0.85; 95% CI, 0.80-0.92, P<0.001). Results of subgroup analyses also demonstrated that this single-nucleotide polymorphism (SNP) modified the risk among lung cancer, breast cancer, osteosarcoma, and Asians. Evidence of publication bias was found in the present study. When we treated the publication bias with 'trim-and-fill' method, the adjusted ORs and CIs were not significantly changed. CONCLUSION: In conclusion, current evidence highlights that the APE1 rs1760944 T>G polymorphism is a protective factor for cancer susceptibility. In the future, case-control studies with detailed risk factors are needed to confirm or refute our findings.

Association of miRNA-499 rs3746444 A>G variants with adenocarcinoma of esophagogastric junction (AEG) risk and lymph node status.

BACKGROUND: MicroRNAs (miRNAs) miRNA-499 rs3746444 A>G polymorphism may be complicated in the susceptibility to cancer. However, the correlation of this polymorphism with adenocarcinoma of esophagogastric junction (AEG) was unknown. PATIENTS AND METHODS: A total of 1063 AEG patients and 1677 controls were included in this study to assess the association of miR-499 rs3746444 A>G with AEG risk. SNPscanTM genotyping assay was harnessed to obtain the genotypes of miRNA-499 rs3746444 A>G polymorphism. RESULTS: We identified that SNP miR-499 rs3746444 A>G increased the susceptibility of AEG (AG vs AA: adjusted OR=1.25, 95% CI=1.05-1.49, P=0.012 and AG/GG vs AA: adjusted OR=1.30, 95% CI=1.10-1.54, P=0.002). In a stratified analysis, we found that miR-499 rs3746444 A>G polymorphism had an increased susceptibility of AEG in several subgroups (male subgroup: AG vs AA: adjusted P=0.004 and AG/GG vs AA: adjusted P=0.002; female subgroup: GG vs AG/AA: adjusted P=0.046; <64 years subgroup: AG vs AA: adjusted P=0.006 and AG/GG vs AA: adjusted P=0.003; never smoking subgroup: AG vs AA: adjusted P=0.003 and AG/GG vs AA: adjusted P=0.001; and never drinking subgroup: AG vs AA: adjusted P=0.008 and AG/GG vs AA: adjusted P=0.002). The results of power calculation indicated that miR-499 rs3746444 A>G polymorphism increased the risk of AEG in overall comparison, male, <64 years, never smoking, and never drinking subgroups. Among the AEG cases, 625 patients accompanied by positive lymph node. However, the distribution of miRNA-499 rs3746444 A>G variants was no significant difference between different lymph node status. CONCLUSION: Our findings indicate that miR-499 rs3746444 A>G polymorphism is significantly associated with AEG susceptibility. In the future, further exploration of this genetic factor in relation to AEG susceptibility with an adequate methodological quality is needed.

Connexin 40 regulates lung endothelial permeability in acute lung injury via the ROCK1-MYPT1- MLC20 pathway.

Increased pulmonary vascular permeability is a hallmark of acute lung injury (ALI). Connexin 40 (Cx40) is a gap junctional protein abundantly present in the lung microvascular endothelium. Yet, the role of Cx40 in the regulation of lung vascular permeability and its underlying mechanisms are unclear. Here, we tested the hypothesis that Cx40 participates in regulation of lung endothelial permeability via a mechanism involving a Rho-associated protein kinase (ROCK) dependent regulation of myosin light chain (MLC). In murine models of intratracheal acid- or LPS-induced lung injury, genetic deficiency of Cx40 attenuated key features of ALI including vascular barrier failure. In human pulmonary microvascular endothelial cells (PMVECs), thrombin-induced loss of transendothelial electrical resistance was attenuated by a Cx40-inhibiting mimetic peptide (40GAP27), Cx40-specific shRNA, or ROCK inhibitor Y27632. In isolated perfused mouse lungs, platelet-activating factor-induced lung weight gain was abrogated by gap junction blocker carbenoxolone, 40GAP27, Y27632, or genetic deficiency of Cx40. Phosphorylation of MLC20 increased drastically in both LPS-treated PMVECs and HCl-treated mouse lungs. Expression of ROCK1 was increased in both LPS-treated PMVECs and HCl-treated mouse lungs, and paralleled by phosphorylation of MLC20. Coimmunoprecipitation experiments revealed protein-protein interaction between ROCK1 and Cx40. LPS-induced upregulation of ROCK1 and phosphorylation of MLC20 were blocked by knockdown of Cx40. LPS caused phosphorylation of myosin phosphatase targeting subunit 1, which could be abrogated by Y27632 or Cx40-shRNA. Our findings reveal a role of Cx40 in regulation of ROCK1 and MLC20 that contributes critically to lung vascular barrier failure in ALI.

Preoperative evaluation of moyamoya spontaneous anastomosis of combined revascularization donor vessels in adults by duplex ultrasonography.

OBJECTIVE: To evaluate the preoperative diagnostic value of duplex ultrasonography in moyamoya spontaneous anastomosis of combined revascularization donor vessels in adults. METHODS: A total of 99 preoperative adult patients who underwent superficial temporal artery-to-middle cerebral artery (STA-MCA) anastomosis were retrospectively analyzed. Each side of the cerebral hemisphere was examined as a separate procedure. A total of 198 cerebral hemispheres were divided into three groups: a collateral, non-collateral, and control group based on digital subtraction angiography (DSA). Hemodynamic parameters, including peak systolic velocity (PSV), end diastolic velocity (EDV), and resistance index (RI) were analyzed. RESULTS: There were only four of cases (5%, 4/198) of STA spontaneous anastomosis, whereas those of maxillary artery (MA) anastomosis were 44 (23.7%, 44/186). Compared with the control group, MA PSV and EDV of the collateral group increased significantly, while RI decreased significantly (p < .05). The area under the curve (AUC) of MA RI was 0.654. As a predictor of MA spontaneous anastomosis, duplex ultrasonography had high specificity but poor sensitivity. In collateral group, PSV and EDV detected two weeks post-surgery were significantly higher than those detected pre-operatively (PSV: p = .018, EDV: p = .025). By contrast, there were no significant difference of the PSV and EDV detected six months post-surgery compared with pre-operation (PSV: p = .450, EDV: p = .099). Additionally, MA RI in two weeks after the surgery was comparable with preoperative values. CONCLUSIONS: Duplex ultrasonography could be applied to evaluate the adult moyamoya spontaneous anastomoses of MA preoperatively. Despite its poor sensitivity, this diagnostic modality is still reliable and specific. STA-MCA anastomosis combined with EDMS did not affect MA pre-operative spontaneous anastomosis.