Guannan Wu

The plasma mitochondrial DNA is an independent predictor for post-traumatic systemic inflammatory response syndrome.

Background and Purpose Mitochondrial DNA (mtDNA), a newly identified damage-associated molecular pattern, has been observed in trauma patients, however, little is known concerning the relationship between plasma mtDNA levels and concrete post-traumatic complications, particularly systemic inflammatory response syndrome (SIRS). The aim of this study is to determine whether plasma mtDNA levels are associated with injury severity and cloud predict post-traumatic SIRS in patients with acute traumatic injury. Patients and Methods Eighty-six consecutive patients with acute traumatic injury were prospectively enrolled in this study. The plasma mtDNA concentration was measured by a real-time, quantitative PCR assay for the human ND2 gene. The study population’s clinical and laboratory data were analyzed. Results The median plasma mtDNA was higher in trauma patients than in healthy controls (865.196 (251.042-2565.40)pg/ml vs 64.2147 (43.9049-80.6371)pg/ml, P<0.001) and was independently correlated with the ISS score (r=0.287, P<0.001). The plasma mtDNA concentration was also significantly higher in patients who developed post-traumatic SIRS than in patients who did not (1774.03 (564.870-10901.3)pg/ml vs 500.496 (145.415-1285.60)pg/ml, P<0.001). Multiple logistic regression analysis revealed that the plasma mtDNA was an independent predictors for post-traumatic SIRS (OR, 1.183 (95%CI, 1.015-1.379), P=0.032). Further ROC analysis demonstrated that a high plasma mtDNA level predicted post-traumatic SIRS with a sensitivity of 67% and a specificity of 76%, with a cut-off value of 1.3185 µg/ml being established, and the area under the ROC curves (AUC) was 0.725 (95% CI 0.613-0.837). Conclusions Plasma mtDNA was an independent indictor with moderate discriminative power to predict the risk of post-traumatic SIRS.

Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9-p38 MAPK pathway

An increasing number of studies have focused on the phenomenon that mitochondrial DNA (mtDNA) activates innate immunity responses. However, the specific role of mtDNA in inflammatory lung disease remains elusive. This study was designed to examine the proinflammatory effects of mtDNA in lungs and to investigate the putative mechanisms. C57BL/6 mice were challenged intratracheally with mtDNA with or without pretreatment with chloroquine. Changes in pulmonary histopathology, cytokine concentrations, and phosphorylation levels of p38 MAPK were assayed at four time points. In in vitro experiments, THP-1 macrophages were pretreated or not pretreated with chloroquine, TLR9 siRNA, p38 MAPK siRNA, or SB203580 and then incubated with mtDNA. The levels of cytokines and p-p38 MAPK were detected by ELISA and Western blot, respectively. The intratracheal administration of mtDNA induced infiltration of inflammatory cells, production of proinflammatory cytokines (including IL-1β, IL-6, and TNF-α), and activation of p38 MAPK. The chloroquine pretreatment resulted in an abatement of mtDNA-induced local lung inflammation. In vitro experiments showed that the exposure of THP-1 macrophages to mtDNA also led to a significant upregulation of IL-1β, IL-6, and TNF-α and the activation of p38 MAPK. And these responses were inhibited either by chloroquine and TLR9 siRNA or by SB203580 and p38 MAPK siRNA pretreatment. The intratracheal administration of mtDNA induced a local inflammatory response in the mouse lung that depended on the interactions of mtDNA with TLR9 and may be correlated with infiltrating macrophages that could be activated by mtDNA exposure via the TLR9-p38 MAPK signal transduction pathway.

Post-transcriptional regulation of long noncoding RNAs in cancer.

It is a great surprise that the genomes of mammals and other eukaryotes harbor many thousands of long noncoding RNAs (lncRNAs). Although these long noncoding transcripts were once considered to be simply transcriptional noise or cloning artifacts, multiple studies have suggested that lncRNAs are emerging as new players in diverse human diseases, especially in cancer, and that the molecular mechanisms of lncRNAs need to be elucidated. More recently, evidence has begun to accumulate describing the complex post-transcriptional regulation in which lncRNAs are involved. It was reported that lncRNAs can be implicated in degradation, translation, pre-messenger RNA (mRNA) splicing, and protein activities and even as microRNAs (miRNAs) sponges in both a sequence-dependent and sequence-independent manner. In this review, we present an updated vision of lncRNAs and summarize the mechanism of post-transcriptional regulation by lncRNAs, providing new insight into the functional cellular roles that they may play in human diseases, with a particular focus on cancers.

A Serum Vitamin D Level <25nmol/L Pose High Tuberculosis Risk: A Meta-Analysis

Background Low serum Vitamin D is considered to be associated with tuberculosis while the “dangerous” level was not clear. The aim of this study was to identify the association between tuberculosis and serum Vitamin D levels via synthesis of available evidence. Methods A search of EMBASE, Medline, ISI Web of knowledge, and Pubmed was conducted. The number of subjects of tuberculosis and no-tuberculosis groups in four Vitamin D range. Meta-analyses were performed and presented by odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results A total of 15 studies involving 1440 cases and 2558 controls were included. A significantly increased risk of tuberculosis was found in two ranges: ≤ 12.5 nmol/L: pooled OR = 4.556, 95% CI = 2.200-9.435; 13-25 nmol/L: pooled OR = 3.797, 95% CI = 1.935-7.405. No statistically significant risk of tuberculosis was found in the range of 26–50 nmol/L (pooled OR = 1.561, 95% CI =0.997-2.442). In range 51–75 nmol/L, no positive association was found (pooled OR =1.160, 95% CI = 0.708-1.900). Conclusions This study found that a serum Vitamin D level ≤ 25 nmol/L was significantly associated with an increased risk of tuberculosis while the range of 51–75 nmol/L was not. The range 26-50nmol/L posed potential high tuberculosis risk. Future large-scale, well-designed studies are needed to verify these results.

Combination of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio is a useful prognostic factor in advanced non-small cell lung cancer patients.

The neutrophil to lymphocyte ratio (NLR) was recently shown to be a remarkable prognostic factor in tumors. Moreover, some studies have indicated that the combination of NLR and platelet to lymphocyte ratio (PLR) could be a better prognostic factor. As the combined prognostic value of NLR and PLR in non‐small cell lung cancer (NSCLC) is not clear, we conducted this study to explore this further.

Upregulation of long intergenic noncoding RNA 00673 promotes tumor proliferation via LSD1 interaction and repression of NCALD in non-small-cell lung cancer

Despite improvements in diagnostics and treatment of non-small cell lung cancer (NSCLC), it remains the leading causes of cancer-related mortality worldwide. In more recent years, mutiple lines of evidence have highlighted long noncoding RNAs (lncRNAs) serve as novel class of regulators of cancer biological processes, including proliferation, apoptosis and metastasis. LncRNAs serve as a novel class of regulators of cancer biological processes in cancer, but little is known of their expression and potential functions in NSCLC. We identified an oncogene, linc00673, whose expression level was upregulated by bioinformatics analyses and qRT-PCR analyses in NSCLC. The effects of linc00673 on tumor progression were investigated in vitro and in vivo. Linc00673 knockdown significantly inhibited cell proliferation and colony-forming ability, and suppressed S-phase entry in vitro and shRNA linc00673 mediated knockdown significantly inhibit tumor growth in vivo, meanwhile, linc00673 overexpression increased tumor cell growth. Analysis of RNAseq data revealed linc00673 could modulate the transcription of a large amount of genes including oncogene and tumor suppressor gene, so we investigated the role and regulatory mechanism of linc00673 in NSCLC proliferation. Further mechanistic analyses indicated that the oncogenic activity of linc00673 is partially attributable to its repression of NCALD through association with the epigenetic repressor LSD1. Taken together, these findings suggested that linc00673 could play crucial role in NSCLC progression and might be a potential therapeutic target for patients with NSCLC.

The effect of P2X7 receptor 1513 polymorphism on susceptibility to tuberculosis: A meta-analysis

Studies of the association between the purinergic receptor P2X, ligand-gated ion channel 7 (P2X7 receptor) gene 1513A/C polymorphism and susceptibility to tuberculosis have yielded inconsistent results. We performed this meta-analysis to help clarify these inconsistencies. After systematically searching PUBMED, MEDLINE, EMBASE and ISI Web of knowledge, two of the authors independently extracted relevant data and a meta-analysis was performed by using STATA11.0 software. A total number of nine studies involving 2195 cases and 2036 controls were identified. The results indicated that P2X7 receptor gene 1513C allele (OR 1.389, 95% CI 1.161-1.660, p<0.001) and CC genotype (1.582, 95% CI 1.129-2.217, p=0. 012) were significantly associated with increased susceptibility to tuberculosis. Subgroup analysis indicated that this SNP greatly contributed to susceptibility to tuberculosis in Asians. The C allele of P2X7 receptor gene 1513A/C polymorphism was also associated with increased susceptibility to pulmonary tuberculosis in Asians (C vs. A: OR 1.420, 95% CI 1.163-1.733, p=0.001; (CC+AC) vs. AA: OR 1.522, 95% CI 1.186-1.953, p=0.001). Greater association between P2X7 receptor gene 1513A/C polymorphism and susceptibility to extra-pulmonary tuberculosis with bigger ORs were found (C vs. A, OR 2.035, 95% CI 1.236-3.352, p=0.005; CC vs. AA, OR 3.788, 95% CI 1.434-10.009, p=0.007; AC vs. AA, OR 2.148, 95% CI 1.252-3.684, p=0.005; (CC+AC) vs. AA, OR 2.386, 95% CI 1.302-4.374, p=0.005; CC vs. (AC+AA), OR 2.692, 95% CI 1.242-5.836, p=0. 012). This meta-analysis indicates that the C allele of P2X7 receptor gene 1513A/C polymorphism is a risk factor for pulmonary tuberculosis in Asians, while not in Africans or Latinos and a risk for extra-pulmonary tuberculosis. Further well-designed, large scale studies are required to confirm this conclusion.

Prognostic value of Twist in lung cancer: systematic review and meta-analysis

BACKGROUND Twist is identified as an epithelial-mesenchymal transition (EMT) regulator which has been considered to induce metastasis. However, the prognostic value of Twist in patients with lung cancer remains controversial. METHODS A search of database including EMBASE, Medline, ISI Web of knowledge and PubMed was performed. Eligible articles studying on the prognostic significance of Twist were included in this meta-analysis. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were assessed to quantify the prognostic role. RESULTS A total of five studies were included. The pooled HR for Twist was 1.949 (95% CI: 1.408-2.698, I(2)=42.7%, P<0.001), suggesting high Twist expression is associated with poor prognosis in lung cancer patients. Our sensitivity analyses suggested the robustness of the results. Neither Beggs test nor Eggers test found publication bias in any analysis. CONCLUSIONS Overexpressed Twist in lung cancer tissue indicated poor prognosis.

Association of the metformin with the risk of lung cancer: a meta-analysis

OBJECTIVE To assess the correlation between metformin and risk of developing lung cancer by meta-analysis. METHODS Papers on the correlation between metformin and risk of lung cancer were searched from PubMed, MEDLINE, EMBASE, ISI Web of Science, and Cochrane Library. RESULTS Six papers on case-control study were included in this study, involving 39,787 metformin users and 177,752 controls. Meta-analysis showed that the risk of developing lung cancer was lower in metformin users than in those without metformin (OR=0.55, 95% CI: 0.35-0.85, P<0.001). CONCLUSIONS The risk of developing lung cancer is lower in metformin users than in those without metformin.

Long intergenic noncoding RNA 00673 promotes non-small-cell lung cancer metastasis by binding with EZH2 and causing epigenetic silencing of HOXA5

Metastasis of cancer cells is a key impediment to favorable outcomes of cancer treatment. Functional roles of long noncoding RNAs in several biological processes, including metastasis, have recently been discovered. In our previous work, we reported a positive correlation of increased expression of linc00673 in NSCLC tissues with tumor size, lymph node metastasis, TNM stage, and increased proliferation of NSCLC cells, both, in vitro and in vivo. In this study, we demonstrate that ectopic expression of linc00673 promotes migration and invasion of NSCLC cells. Furthermore, our results indicate that linc00673 could silence HOXA5 expression by recruiting epigenetic repressor, EZH2, at its promoter regions. HOXA5 was identified as a tumor suppressor gene, which inhibited NSCLC cell metastasis by regulating cytoskeletal remodeling. To summarize, we for the first time identified the role of lin00673 in promoting invasion and migration of NSCLC cells. Insights from this study may help to identify novel therapeutic targets for NSCLC.