Combined BRM270 and endostatin inhibit relapse of NSCLC while suppressing lung cancer stem cell proliferation induced by endostatin.

Endostatin (ES, ENDO) has been reported to suppress the growth of tumors while inducing the proliferation of lung cancer stem cells (LCSCs), causing a poor prognosis for lung cancer. In this study, we aimed to clarify whether BRM270 can inhibit the proliferation of cancer stem cells (CSCs). Endostatin + BRM270 showed anti-tumor effects by reducing tumor volume and increasing survival. Administration of BRM270 reduced the number of aldehyde dehydrogenase-positive (ALDH+) cells and the level of ALDH1A1 expression in tumors by increasing the level of miR-128 while decreasing the levels of BMI-1, ABCC-5, E2F3, and c-MET. The luciferase activity of miR-128 promoter was increased by an increasing concentration of BRM270. In addition, BMI-1, ABCC-5, E2F3, and c-MET were identified as candidate targets of miR-128, and the overexpression of miR-128 significantly reduced mRNA/protein levels of BMI-1, ABCC-5, E2F3, and c-MET in A549 and H460 cells. Administration of BRM270 inhibited the expression of BMI-1, ABCC-5, E2F3, and c-MET in a dose-dependent manner. In this study, we showed for the first time that the combined administration of endostatin and BRM270 achieved anti-tumor effects while suppressing the proliferation of stem cells.

Mitochondrial-Targeting Antioxidant SS-31 Suppresses Airway Inflammation and Oxidative Stress Induced by Cigarette Smoke.

This study investigated whether the mitochondrial-targeted peptide SS-31 can protect against cigarette smoke- (CS-) induced airway inflammation and oxidative stress in vitro and in vivo. Mice were exposed to CS for 4 weeks to establish a CS-induced airway inflammation model, and those in the experimental group were pretreated with SS-31 1 h before CS exposure. Pathologic changes and oxidative stress in lung tissue, inflammatory cell counts, and proinflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. The mechanistic basis for the effects of SS-31 on CS extract- (CSE-) induced airway inflammation and oxidative stress was investigated using BEAS-2B bronchial epithelial cells and by RNA sequencing and western blot analysis of lung tissues. SS-31 attenuated CS-induced inflammatory injury of the airway and reduced total cell, neutrophil, and macrophage counts and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, and matrix metalloproteinase (MMP) 9 levels in BALF. SS-31 also attenuated CS-induced oxidative stress by decreasing malondialdehyde (MDA) and myeloperoxidase (MPO) activities and increasing that of superoxide dismutase (SOD). It also reversed CS-induced changes in the expression of mitochondrial fission protein (MFF) and optic atrophy (OPA) 1 and reduced the amount of cytochrome c released into the cytosol. Pretreatment with SS-31 normalized TNF-α, IL-6, and MMP9 expression, MDA and SOD activities, and ROS generation in CSE-treated BEAS-2B cells and reversed the changes in MFF and OPA1 expression. RNA sequencing and western blot analysis showed that SS-31 inhibited CS-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway in vitro and in vivo. Thus, SS-31 alleviates CS-induced airway inflammation and oxidative stress via modulation of mitochondrial function and regulation of MAPK signaling and thus has therapeutic potential for the treatment of airway disorders caused by smoking.

Mitochondrial Damage-Associated Molecular Patterns Exacerbate Lung Fluid Imbalance Via the Formyl Peptide Receptor-1 Signaling Pathway in Acute Lung Injury.

OBJECTIVES: To investigate the effect of mitochondrial damage-associated molecular patterns on the lung fluid homeostasis in experimental acute lung injury. DESIGN: Experimental study. SETTING: Research laboratory. SUBJECTS: Patients with acute respiratory distress syndrome and control subjects, wild-type C57BL/6 and formyl peptide receptor-1 gene knockout mice, and primary rat alveolar epithelial type II cells. INTERVENTIONS: Samples of bronchoalveolar lavage fluid and serum were obtained from patients and control subjects. Mice were intratracheally instilled with lipopolysaccharide and mitochondrial damage-associated molecular patterns. The primary rat alveolar epithelial type II cells were isolated and incubated with mitochondrial damage-associated molecular patterns. MEASUREMENTS AND MAIN RESULTS: Patients were divided into direct (pulmonary) and indirect (extrapulmonary) injury groups based on etiology. The release of mitochondrial peptide nicotinamide adenine dinucleotide dehydrogenase 1 in both bronchoalveolar lavage fluid and serum was induced in patients and was associated with etiology. In the lipopolysaccharide-induced lung injury, administration of mitochondrial damage-associated molecular patterns exacerbated the lung fluid imbalance, which was mitigated in formyl peptide receptor-1 knockout mice. Proteomic analysis of mouse lung tissues revealed the involvement of ion channels and tight junction proteins in this process. Treatment with mitochondrial damage-associated molecular patterns decreased the expression of epithelial sodium channel α, zonula occludens-1, and occludin via the formyl peptide receptor-1/p38 pathway in the primary rat alveolar epithelial type II cells. CONCLUSIONS: Mitochondrial damage-associated molecular patterns exacerbate lung fluid imbalance in the experimental acute lung injury model through formyl peptide receptor-1 signaling, the inhibition of which may prevent exacerbation of lung fluid imbalance induced by mitochondrial damage-associated molecular patterns. Thus, formyl peptide receptor-1 is a potential therapeutic target for acute respiratory distress syndrome.

Microarray profiling of lung long non-coding RNAs and mRNAs in lipopolysaccharide-induced acute lung injury mouse model.

Long non-coding RNAs (lncRNAs) are involved in various biological processes as well as many respiratory diseases, while the role of lncRNAs in acute lung injury (ALI) remains unclear. The present study aimed to profile the expression of lung lncRNAs and mRNAs in lipopolysaccharide (LPS)-induced ALI mouse model. C57BL/6 mice were exposed to LPS or phosphate-buffered saline for 24 h, and lncRNAs and mRNAs were profiled by Arraystar mouse LncRNA Array V3.0. Bioinformatics analysis gene ontology including (GO) and pathway analysis and cell study in vitro was used to investigate potential mechanisms. Based on the microarray results, 2632 lncRNAs and 2352 mRNAs were differentially expressed between ALI and control mice. The microarray results were confirmed by the quantitative real-time PCR (qRT-PCR) results of ten randomized selected lncRNAs. GO analysis showed that the altered mRNAs were mainly related to the processes of immune system, immune response and defense response. Pathway analysis suggests that tumor necrosis factor (TNF) signaling pathway, NOD-like receptor pathway, and cytokine-cytokine receptor interaction may be involved in ALI. LncRNA-mRNA co-expression network analysis indicated that one individual lncRNA may interact with several mRNAs, and one individual mRNA may also interact with several lncRNAs. Small interfering RNA (siRNA) for ENSMUST00000170214.1, - ENSMUST00000016031.13 significantly inhibited LPS-induced TNF-α and interleukin (IL)-1ß production in murine RAW264.7 macrophages. Our results found significant changes of lncRNAs and mRNAs in the lungs of LPS-induced ALI mouse model, and intervention targeting lncRNAs may attenuate LPS-induced inflammation, which may help to elucidate the role of lncRNAs in the pathogenesis and treatment of ALI.

Accuracy of the interferon-gamma release assay for the diagnosis of tuberculous pleurisy: an updated meta-analysis.

Background and Objectives. The best method for diagnosing tuberculous pleurisy (TP) remains controversial. Since a growing number of publications focus on the interferon-gamma release assay (IGRA), we meta-analyzed the available evidence on the overall diagnostic performance of IGRA applied to pleural fluid and peripheral blood. Materials and Methods. PubMed and Embase were searched for relevant English papers up to October 31, 2014. Statistical analyses were performed using Stata and Meta-DiSc. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), negative predictive value (NPV) and diagnostic odds ratio (DOR) were count. Summary receiver operating characteristic curves and area under the curve (AUC) were used to summarize the overall diagnostic performance. Results. Fifteen publications met our inclusion criteria and were included in the meta analysis. The following pooled estimates for diagnostic parameters of pleural IGRA were obtained: sensitivity, 0.82 (95% CI [0.79-0.85]); specificity, 0.87 (95% CI [0.84-0.90]); PLR, 4.94 (95% CI [2.60-9.39]); NLR, 0.22 (95% CI [0.13-0.38]); PPV, 0.91 (95% CI [0.85-0.96]); NPV, 0.79 (95% CI [0.71-0.85]); DOR, 28.37 (95% CI [10.53-76.40]); and AUC, 0.91. The corresponding estimates for blood IGRA were as follows: sensitivity, 0.80 (95% CI [0.76-0.83]); specificity, 0.70 (95% CI [0.65-0.75]); PLR, 2.48 (95% CI [1.95-3.17]); NLR, 0.30 (95% CI [0.24-0.37]); PPV, 0.79 (95% CI [0.60-0.87]); NPV, 0.75 (95% CI [0.62-0.83]); DOR, 9.96 (95% CI [6.02-16.48]); and AUC, 0.89. Conclusions. This meta analysis suggested that pleural IGRA has potential for serving as a complementary method for diagnosing TP; however, its cost, high turn around time, and sub-optimal performance make it unsuitable as a stand-alone diagnostic tool. Better tests for the diagnosis of TP are required.

Emodin ameliorates LPS-induced acute lung injury, involving the inactivation of NF-κB in mice.

Acute lung injury (ALI) and its severe manifestation of acute respiratory distress syndrome (ARDS) are well-known illnesses. Uncontrolled and self-amplified pulmonary inflammation lies at the center of the pathology of this disease. Emodin, the bio-active coxund of herb Radix rhizoma Rhei, shows potent anti-inflammatory properties through inactivation of nuclear factor-κB (NF-κB). The aim of this study was to evaluate the effect of emodin on lipopolysaccharide (LPS)-induced ALI in mice, and its potential bio-mechanism. In our study, BALB/c mice were stimulated with LPS to induce ALI. After 72 h of LPS stimulation, pulmonary pathological changes, lung injury scores, pulmonary edema, myeloperoxidase (MPO) activity, total cells, neutrophils, macrophages, TNF-α, IL-6 and IL-1ß in bronchoalveolar lavage fluid (BALF), and MCP-1 and E-selectin expression were notably attenuated by emodin in mice. Meanwhile, our data also revealed that emodin significantly inhibited the LPS-enhanced the phosphorylation of NF-κB p65 and NF-κB p65 DNA binding activity in lung. Our data indicates that emodin potently inhibits LPS-induced pulmonary inflammation, pulmonary edema and MCP-1 and E-selectin expression, and that these effects were very likely mediated by inactivation of NF-κB in mice. These results suggest a therapeutic potential of emodin as an anti-inflammatory agent for ALI/ARDS treatment.

Performance of osteopontin in the diagnosis of malignant pleural mesothelioma: a meta-analysis.

It is reported that osteopontin has shown promising diagnostic value for malignant pleural mesothelioma (MPM), this meta-analysis aimed to establish the overall diagnostic accuracy of the osteopontin measurement for diagnosing MPM. Based on a systematic review of English language studies, the sensitivity, specificity and other measures of accuracy of osteopontin in the diagnosis of MPM were pooled using random-effects model. Summary receiver operating characteristic curves were used to summarize overall test performance. Seven publications met our inclusion criteria, the pooled sensitivity was 0.57 (95%CI: 0.52-0.61), specificity was 0.81, 95%CI: 0.79-0.84). The PLR was 3.78 (95%CI: 2.23-6.41), the NLR was 0.51 (95%CI: 0.38-0.67) and the DOR was 9.04 (95%CI: 5.28-15.48), the area under the summary receiver operating characteristic curve was 0.80. Our data suggest that osteopontin is likely to be a useful diagnostic marker for MPM, considering for the limited studies and patients included, larger studies are needed to confirm these findings.

Diagnostic performance of lung ultrasound in the diagnosis of pneumonia: a bivariate meta-analysis.

BACKGROUND AND OBJECTIVE: Pneumonia is a common disease with both high morbidity and mortality, the diagnosis of pneumonia remains a clinical challenge. Many studies have been conducted to identify the usefulness of lung ultrasound for the diagnosis of pneumonia, but with inconsistent and inconclusive results. The present study aimed to establish the overall diagnostic accuracy of lung ultrasound in diagnosing pneumonia. METHODS: Based on a comprehensive search of the Pubmed, Embase, and the Cochrane database, we identified out-come data from all articles estimating diagnostic accuracy with lung ultrasound for pneumonia. Quality was assessed with the Quality Assessment for Diagnostic Accuracy Studies. Results from different studies were pooled using a bivariate meta-analysis. Summary receiver operating characteristic curve was used to assess the overall performance of lung ultrasound-based assays. RESULTS: Nine studies containing 1080 subjects were included in this meta-analysis. The summary estimates for lung ultrasound in the diagnosis of pneumonia in the studies included were as follows: sensitivity, 0.97 (95% CI: 0.93-0.99); specificity, 0.94 (95% CI: 0.85-0.98); DOR, 507.99 (95% CI: 128.11-2014.34); positive likelihood ratio, 15.62 (95% CI: 6.31-38.68); negative likelihood ratio, 0.03 (95% CI: 0.01-0.08); The area under the summary receiver operating characteristic curve was 0.99 (95% CI: 0.98-1.00). CONCLUSION: Lung ultrasound is a capable of diagnosing pneumonia with high accuracy and is a promising attractive alternative to chest radiography and thoracic CT scan.

Diagnostic accuracy of adenosine deaminase for tuberculous peritonitis: a meta-analysis.

INTRODUCTION: Tuberculous peritonitis remains a diagnostic challenge for clinicians. Many studies have investigated the usefulness of adenosine deaminase (ADA) in ascites for the diagnosis of tuberculous peritonitis; however, the overall diagnostic accuracy of ADA for tuberculous peritonitis remains unclear. The aim of the present meta-analysis was to determine the overall accuracy of ADA measurements in the diagnosis of tuberculous peritonitis. MATERIAL AND METHODS: We performed a systematic search in PubMed and Embase to identify published studies that evaluated the diagnostic role of ADA for tuberculous peritonitis. Quality was assessed according to standardized Quality Assessment of Diagnostic Accuracy Studies criteria. Sensitivity, specificity and other measures of accuracy of ADA assay in order to diagnose tuberculous peritonitis were pooled using random effects models. Summary receiver operating characteristic curve (SROC) was used to summarize overall test performance. RESULTS: Sixteen studies met inclusion criteria for the present meta-analysis. The pooled sensitivity and specificity for diagnosing tuberculous peritonitis were 0.93 (95% CI: 0.89-0.95) and 0.96 (95% CI: 0.94-0.97), respectively. The positive likelihood ratio was 15.80 (95% CI: 10.87-22.95), negative likelihood ratio was 0.09 (95% CI: 0.05-0.16) and diagnostic odds ratio was 249.28 (95% CI: 113.11-549.39). The area under the SROC was 0.98. CONCLUSIONS: Ascitic ADA determination is a relatively sensitive and specific test for the diagnosis of tuberculous peritonitis. Measurement of ADA in ascites is thus likely to be a useful diagnostic method for tuberculous peritonitis.

Interleukin-18 promoter gene -607C/A polymorphism and tuberculosis risk: a meta-analysis.

BACKGROUND: Numerous studies have evaluated the association between interleukin-18 (IL-18) promoter gene -607C/ A (rs1946518) polymorphism and tuberculosis (TB) risk. However, the results remain apparently conflicting. The aim of this study was to investigate whether IL-18-607C/A polymorphism is associated with susceptibility to TB. METHODS: Publications addressing the association between the IL-18-607C/A polymorphism and TB risk were selected from the Pubmed, Cochrane Library, Embase, CNKI and Wanfang databases. Data were extracted from the studies by two independent reviewers. Statistical analysis was performed using RevMan 5.0.25 and STATA 11.0 software. RESULTS: Eight case-control studies with a total of 1166 TB patients and 1734 controls were retrieved. Meta-analysis results showed significant association between IL-18-607C/A polymorphism and TB risk in all comparisons of the A allele versus C allele (OR=1.17, 95% CI 1.05-1.30, P=0.004), AA versus CC (OR=1.43, 95% CI 1.14-1.81, P=0.002), CA+AA versus CC (OR=1.20, 95% CI 1.01-1.42, P=0.04) and AA versus CA+CC (OR=1.30, 95% CI 1.07-1.58, P=0.007). In subgroup analysis by nationality, a significant association between IL-18-607C/A polymorphism and TB risk in the comparisons of A versus C, CA+AA versus CC and AA versus CA+CC (OR=1.22, 95% CI 1.07-1.38, P=0.002; OR=1.31, 95% CI 1.06-1.61, P=0.01; OR=1.32, 95% CI 1.07-1.63, P=0.01, respectively) were found in Chinese population but not in Indian and Iranian populations. CONCLUSION: This study suggests that the -607C/A polymorphism of IL-18 gene would be a risk factor for TB, especially in Chinese population. To further evaluate gene-to-gene and gene-to-environment interactions on -607C/A polymorphism and tuberculosis risk, more studies with thousands of patients are required.

Diagnostic accuracy of neutrophil CD64 expression in neonatal infection: a meta-analysis.

OBJECTIVE: The aim of the present study was to establish the predictive values of neutrophil CD64 expression in diagnosing neonatal infection. METHODS: A comprehensive search of the PubMed and Embase® literature databases identified outcome data from published studies estimating the diagnostic accuracy of neutrophil CD64 expression for neonatal infection. Summary estimates for sensitivity, specificity, diagnostic odds ratios (DOR) and the area under the summary receiver operating characteristic curve (AUC) were calculated using a bivariate random-effects approach. RESULTS: Twelve studies including 1915 neonates were analysed. Summary estimates (95% confidence intervals) for CD64 expression in the diagnosis of neonatal infection were: sensitivity, 0.78 (0.75, 0.81); specificity, 0.81 (0.78, 0.83); DOR, 21.27 (11.71, 38.65); positive-likelihood ratio, 4.53 (3.22, 6.36); negative-likelihood ratio, 0.23 (0.14, 0.37); AUC, 0.89. CONCLUSIONS: Neutrophil CD64 expression can be used as an additional test in the diagnosis of neonatal infection. Results of a CD64 assay should not be used alone to diagnose such infections, but should be interpreted in combination with other test results and clinical findings.

The 2518 A/G polymorphism in the MCP-1 gene and cancer risk: a meta-analysis.

BACKGROUND: The 2518 A/G polymorphism in the MCP-1 gene has been extensively studied for associations with cancer; however, results from replication studies have been inconsistent. The aim of this investigation was to determine links with risk of cancer by meta-analysis. METHODS: We searched Pubmed, Embase, CNKI, Weipu and Wanfang databases, covering all case-control studies until March, 2013. Statistical analyses were performed using the Revman 5.0 software. RESULTS: A total of 11 case-control studies met our inclusion criteria, including 1,422 cases and 2,237 controls. The results indicated that the MCP-1 2518 gene polymorphism had no association with cancer risk overall (GG vs.GA+ AA: OR = 0.89, 95%CI = 0.61-1.28, P = 0.52). However, in the subgroup analysis by ethnicity, a decrease of cancer risk was found in Asian populations (GG vs.GA+ AA: OR = 0.79, 95%CI = 0.63-0.99, P = 0.04). CONCLUSION: This meta-analysis suggested that the 2518A/G polymorphism of MCP-1 gene is associated with risk of cancer among Asian, but not in Caucasian populations.

Receptor for advanced glycation end products: a new theraputic target for chronic obstructive pulmonary disease?

Receptor for advanced glycation end products (RAGE), a multiligand receptor, has been suggested to be implicated in inflammatory response. However, its role in chronic obstructive pulmonary disease (COPD) has not been well elucidated. Recently, several studies reported RAGE and its common ligands were upregulated in airways and lung tissues from COPD smokers. Moreover, inhibition of RAGE activation significantly attenuated cigarette smoke extract or bacteria-induced pulmonary inflammation. Based on these findings, a conclusion could be made that ligand-activated RAGE may play a key role in COPD and thus RAGE could be a new therapeutic target for COPD.

Telomerase activity assay for the diagnosis of malignant pleural effusion: A meta-analysis.

The telomerase activity assay has been established for the detection of malignant pleural effusion (MPE), however, the overall diagnostic accuracy of the telomerase activity assay for MPE remains unclear. We performed a systematic search in the Pubmed, Embase and Cochrane databases to identify published studies that have evaluated the diagnostic role of the telomerase activity assay for MPE. Sensitivity, specificity and other measures of accuracy of the telomerase activity assay in the diagnosis of MPE were pooled using the random effects models. A summary receiver operating characteristic (SROC) curve was used to summarize overall test performance. A total of eight studies met the inclusion criteria for the meta-analysis. The pooled sensitivity and specificity for diagnosing MPE were 0.76 [95% confidence intervals (CI), 0.72-0.80] and 0.87 (95% CI, 0.83-0.91), respectively. The positive likelihood ratio was 5.19 (95% CI, 2.36-11.42), the negative likelihood ratio was 0.25 (95% CI, 0.11-0.53) and the diagnostic odds ratio was 23.18 (95% CI, 6.11-87.83). The area under the SROC curve was 0.92. The telomerase activity assay plays a role in the diagnosis of MPE with a relatively high specificity. The results of a telomerase activity assay should be interpreted together with the combination of other test results and clinical findings.

Diagnostic value of fluorescence in situ hybridization assay in malignant mesothelioma: a meta-analysis.

The diagnosis of malignant mesothelioma (MM) remains a clinical challenge and the fluorescence in situ hybridization (FISH) assay has been reported to be one promising tool. The present meta-analysis aimed to establish the overall diagnostic accuracy of FISH for diagnosing MM. After a systematic review of English language studies, the sensitivity, specificity and other measures of accuracy of FISH in the diagnosis of MM were pooled using random-effects models. Summary receiver operating characteristic curves were applied to summarize overall test performance. Nine studies met our inclusion criteria, the pooled sensitivity and specificity for FISH for diagnosing MM being 0.72 (95% CI 0.67-0.76) and 1.00 (95% CI 0.98-1.00), respectively. The positive likelihood ratio was 34.5 (95% CI 14.5-82.10), the negative likelihood ratio was 0.24 (95% CI 0.16-0.36), and the diagnostic odds ratio was 204.9 (95% CI 76.8-546.6), the area under the curve being 0.99. Our data suggest that the FISH assay is likely to be a useful diagnostic tool for confirming MM. However, considering the limited studies and patients included, further large scale studies are needed to confirm these findings.