Prognostic role of platelet to lymphocyte ratio in non-small cell lung cancers: A meta-analysis including 3,720 patients.

Platelet to lymphocyte ratio (PLR) was recently reported as a useful index in predicting the prognosis of lung cancer. However, the prognostic role of PLR in lung cancer remains controversial. The aim of this study was to evaluate the association between PLR and clinical outcome of lung cancer patients through a meta-analysis. Relevant literatures were retrieved from PubMed, Ovid, the Cochrane Library and Web of Science databases. Meta-analysis was performed using hazard ratio (HR) and 95% confidence intervals (CIs) as effect measures. A total of 5,314 patients from 13 studies were finally enrolled in the meta-analysis. The summary results showed that elevated PLR predicted poorer overall survival (OS) (HR: 1.526, 95%CI: 1.268-1.836, p < 0.001) in patients with lung cancer and OS (HR: 1.631, 95%CI: 1.447-1.837, p < 0.001) in patients with nonsmall cell lung cancer (NSCLC). Subgroup analysis revealed that increased PLR was also associated with poor OS in NSCLC treated by surgical resection (HR: 1.884, 95%CI: 1.308-2.714, P < 0.001) and non-surgery (HR: 1.570, 95%CI: 1.323-1.863, P < 0.001). In addition, PLR Cut-off value ≤ 160 (HR: 1.506, 95%CI: 1.292-1.756, P < 0.001) and PLR Cut-off value>160 (HR: 1.842, 95%CI: 1.523-2.228, P < 0.001). In contrast, elevated PLR was not associated with OS (HR: 1.117, 95%CI: 0.796-1.569, P > 0.05) in patients with small cell lung cancer (SCLC).This meta-analysis result suggested that elevated PLR might be a predicative factor of poor prognosis for NSCLC patients.

Circulating Tumor Cells as a Screening and Diagnostic Marker for Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: Circulating tumor cells (CTCs) have become potential diagnostic biomarker for several types of cancer, including lung cancer. In this study, we aim to determine whether CTCs detected by CellCollector can be used for early-stage diagnosis of lung cancer. METHODS: In this study, we recruited 64 volunteers, among whom 44 were suspected lung cancer patients requiring surgical treatment and 20 were healthy volunteers. We simultaneously analyzed PD-L1 expression in CTCs isolated using the GILUPI CellCollector and copy number variation by next-generation sequencing (NGS). RESULTS: We enrolled a total of 44 patients with suspected lung cancer who required surgery and 20 healthy volunteers. The patients were classified into 4 groups based on their pathological results: benign disease, in situ cancer, microinvasive, and invasive. The CTCs detection rate for each group was 10.00% (1/10), 45% (5/11), 50% (7/14), and 67% (6/9), respectively. Among the patients with lung cancer, the CTCs detection rate increased with disease progression. The rate of CTCs positivity was 52.94% (18/34) in patients who were diagnosed with lung cancer by pathology and 10% (1/10) in patients with benign disease. CTCs were not detected in the control group. The area under the receiver operating characteristic (ROC) curve, a measure for distinguishing patients with primary lung cancer, was 0.715 (95% CI 0.549-0.880, P=0.041). The sensitivity and specificity of the in vivo CTCs detection strategy for the diagnosis of early-stage lung cancer were 52.94% and 90%, respectively. CTCs were associated with clinical pathology but not with the size and location of the nodules. CONCLUSION: CTCs isolation using the CellCollector in vivo detection method might be effective for distinguishing between benign and malignant nodules and may be used for early-stage diagnosis of lung cancer.

Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis.

Angiogenesis plays a crucial role in tumor development and growth. The present study was carried out to investigate the potential involvement of the cyclooxygenase-2 (Cox-2) pathway in the regulation of angiogenesis in hepatocellular carcinoma (HCC). We inhibited Cox-2 expression in HCC cell line HuH-7 by selective Cox-2 inhibitor (SC-58635) or Cox-2 siRNA. Conditioned media (CMs) from HuH-7 cells were used in angiogenic assays in vitro and in vivo. Compared with CMs from untreated and negative siRNA treated HuH-7 cells, CMs from SC-58635 and Cox-2 siRNA treated HuH-7 dramatically suppressed the proliferation, migration, and differentiation of human umbilical vein endothelial cells (HUVECs) in vitro and neovascularization in vivo. These inhibitory effects could be partially reversed by the addition of exogenous PGE2 to CMs. Furthermore, Cox-2 inhibition by SC-58635 resulted in PGE2 reduction accompanied by the down-regulation of four PGE2 receptor (EP receptor) subtypes. Treatment with SC-58635 led to the down-expression of proangiogenic factors such as VEGF, HGF, FGF2, ANGPT1 and ANGPT2 in HCC. An approximately 78% reduction of VEGF level has been found in the CM from SC-58635 treated HuH-7. Our results suggest an involvement of Cox-2 in the control of HCC-associated angiogenesis. PGE2 as a vital angiogenic factor may act directly on endothelial cells to promote HuH-7-stimulated angiogenic process. Moreover, Cox-2/PGE2/EP/VEGF pathway possibly also contributes to tumor angiogenesis in HCC. This study provides the rationale for clinical studies of Cox-2 inhibitors on the treatment or chemoprevention of HCC.

Prognostic role of platelet to lymphocyte ratio in esophageal cancer: A meta-analysis.

PURPOSE: The prognostic role of inflammation index like platelet to lymphocyte ratio (PLR) in esophageal cancer remains controversial. We evaluated the prognostic significance of PLR in esophageal cancer patients. METHODS: We searched databases to identify relevant literatures. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. A meta-analysis was performed to evaluate the prognostic value of PLR in patients with esophageal cancer. RESULTS: A total of 6,699 patients from 16 studies (17 cohorts) were finally enrolled in the meta-analysis. The results demonstrate that the elevated PLR predicted poorer overall survival (OS) (HR: 1.389, 95% CI: 1.161-1.663) and disease-free survival (DFS) (HR: 1.404, 95% CI: 1.169-1.687) and cancer-specific survival (CSS) (HR: 1.686, 95% CI: 1.146-2.480) in patients with esophageal cancer. Subgroup analysis revealed that the elevated PLR was also associated with poor OS in esophageal cancer treated by surgery (HR: 1.492, 95%CI: 1.149-1.938, P<0.05) and mixed treatment (HR: 1.222, 95%CI: 1.009-1.479, P<0.05). In addition, PLR Cut-off value≤160 (HR: 1.484, 95%CI: 1.088-2.024, P<0.05) and PLR Cut-off value>160 (HR: 1.391, 95%CI: 1.161-1.666, P<0.05). CONCLUSION: This meta-analysis result suggested that PLR might be a significant predicative biomarker of poor prognosis for esophageal cancer patients.

Role of CCL20/CCR6 and the ERK signaling pathway in lung adenocarcinoma.

Previous studies have revealed that carcinoma-associated fibroblasts communicate microenvironment-derived signals through chemokine/chemokine receptor interaction, resulting in carcinogenesis. C-C motif chemokine ligand 20 (CCL20)/C-C motif chemokine receptor 6 (CCR6) interactions are involved in the pathogenesis of colonic malignancies. The present study aimed to characterize the roles of CCL20/CCR6 and the extracellular signal-regulated kinase (ERK) signaling pathway in lung adenocarcinoma growth. Lung adenocarcinoma samples obtained at surgery were assessed for the expression, tissue localization and production of CCL20/CCR6. In addition, colony formation, ERK signaling and chemokine production were measured to assess the responsiveness of the A549 cell line to CCL20 stimulation. CCL20 and CCR6 were found to be highly expressed in the majority of samples in the recurrence group (76 and 66%, respectively). The staining indexes of CCL20 and CCR6 in the recurrence group were 149.3 and 134.4, respectively, which were significantly higher than those in the non-recurrence group (57.2 and 58.0, respectively); the protein and mRNA expression levels determined by western blot and reverse transcription-quantitative polymerase chain reaction were also found to be high in the recurrence group For A549 cells, the colony-forming capacity was increased by CCL20 stimulation, and this effect was dependent in part on ERK phosphorylation. Collectively, the findings suggest that CCR6 and CCL20 may serve a role in lung adenocarcinoma, leading to proliferation and migration via autocrine or paracrine mechanisms. The disruption of CCL20/CCR6 interactions may be a promising strategy for the treatment of cancer.

Diagnostic value of bone-specific alkaline phosphatase in lung carcinoma patients with bone metastases: a meta-analysis.

UNLABELLED: Aim and Backgrounds: The accurate diagnosis of lung carcinoma patients with bone metastases is crucial for therapy and the prevention of complications. We performed a systematic review and meta-analysis to evaluate the diagnostic value of serum bone-specific alkaline phosphatase (BALP) in lung carcinoma patients with bone metastases. METHODS: Such databases as PubMed, Embase, Cochrane Library, Web of Science, Ovid, BioMed Central, Biosis previews and four Chinese databases (Chinese Biomedical Literature Database-disc (CBM), Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP) and Wan Fang DATA) were retrieved on computer, and the relevant journals were also manually searched to collect the trials on BALP in diagnosis of lung carcinoma patients with bone metastases. The meta-analysis was conducted by using Meta-Disc 1.4 software. RESULTS: A total of 8 studies were included, and there were 848 lung carcinoma patients diagnosed by gold standard, patients were divided into two groups: 419 cases with bone metastases and 429 cases without bone metastases. The meta-analysis showed that, the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) was 0.48 [95% CI (0.43 to 0.53)], 0.86 [95% CI (0.82 to 0.89)], 3.14 [95% CI (2.47 to 3.99)], 0.62 [95% CI (0.56 to 0.68)], 6.66 [95% CI (4.62 to 9.60)] respectively. And the AUC of SROC was 0.78, (Q*=0.72). CONCLUSION: BALP has greater diagnostic value in detecting lung carcinoma patients with bone metastases. However, further large scale studies are required to confirm the predictive value.

Prognostic role of neutrophil to lymphocyte ratio in lung cancers: a meta-analysis including 7,054 patients.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) has recently been reported to be a poor prognostic indicator in lung cancer. However, the prognostic value of the NLR in patients with lung cancer still remains controversial. We performed a meta-analysis to evaluate the prognostic value of NLR in patients with lung cancer. METHODS: We performed a comprehensive literature search in PubMed, Ovid, the Cochrane Library, and Web of Science databases in May 2015. Studies were assessed for quality using the Newcastle-Ottawa Scale. RESULTS: Twenty-two studies with a total of 7,054 patients were included in this meta-analysis. The meta-analysis was performed to generate combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). Our analysis results indicated that high NLR predicted poorer OS (HR, 1.51; 95% confidence interval [CI], 1.33-1.71; P<0.001) and PFS (HR, 1.33; 95% CI, 1.07-1.67; P=0.012) in patients with lung cancer. High NLR was also associated with poor OS in lung cancer treated by surgical resection (HR, 1.59; 95% CI, 1.26-1.99; P<0.001) and chemotherapy (HR, 1.15; 95% CI, 1.08-1.22; P<0.001). In addition, NLR cut-off value =5 (HR, 1.57; 95% CI, 1.16-2.12; P=0.003) and NLR cut-off value <5 (HR, 1.47; 95% CI, 1.28-1.69; P<0.001). CONCLUSION: This meta-analysis result suggested that NLR should have significant predictive ability for estimating OS and PFS in patients with lung cancer and may be as a significant biomarker in the prognosis of lung cancer.

Diagnostic value of SHOX2 DNA methylation in lung cancer: a meta-analysis.

The diagnostic value of SHOX2 DNA methylation in patients with lung cancer remains controversial. Thus, we performed a systematic review and meta-analysis to assess diagnostic accuracy of SHOX2 DNA methylation in the lymph node, bronchial aspirates, pleural effusion, plasma, and tumor tissue for lung cancer. We conducted a comprehensive literature search in PubMed, Ovid, the Cochrane library, and Web of Science databases in May 2015. The diagnostic sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve were pooled using STATA 12.0 software. A total of 2,296 subjects included 1,129 lung cancer patients in eight studies were recruited in this meta-analysis. The summary estimates for SHOX2 DNA methylation in the diagnosis of lung cancer in these studies were pooled SEN =0.70 (95% confidence interval [CI]: 0.46-0.87), SPE =0.96 (95% CI: 0.91-0.99), PLR 20.01 (95% CI: 6.96-57.52), NLR 0.31 (95% CI: 0.15-0.64), and DOR 65.11 (95% CI: 13.10-323.61), and the area under the curve (AUC) was 0.96 (95% CI: 0.94-0.97). SHOX2 DNA methylation has greater diagnostic value in detecting lung cancer. In addition, considering the potential publication bias and high heterogeneity, further research studies with more well-designed and large sample sizes are needed in the future.

Overexpression of CYP2E1 enhances sensitivity of hepG2 cells to fas-mediated cytotoxicity.

Hepatocellular carcinoma (HCC) has been reported to be resistant to Fas-mediated apoptosis. In present study, experiments were conducted to investigate the potential effects of CYP2E1 overexpression on susceptibility of HCC to Fas-mediated cytotoxicity. HCC cell line HepG2 was infected with Ad-CYP2E1 to enhance the expression of CYP2E1, followed by treatment with low toxic dose of recombinant human Fas ligand (FasL, 0.5 ng/ml) in the presence of Actinomycin D (Act D, 125 ng/ml). High level of Fas expression was found in HepG2 cells. Its protein level and distribution kept unchanged after different treatments. Compared with control, CYP2E1 expressed HepG2 cells were more sensitive to FasL plus Act D. The sensitivity was elevated in a multiplicity of infection (m.o.i)-dependent manner, which was dramatically suppressed by CYP2E1 inhibitor diallyl disulfide (DAS) (p < 0.01). The percentage of apoptotic cells caused by FasL/Act D was increased from 18.7 to 75% after infection with Ad-CYP2E1 (p < 0.01). DAS treatment resulted in 60% reduction of apoptotic ratio (p < 0.01). Antioxidants GSH ethyl ester, Vitamin C and Vitamin E efficiently protected against cytotoxicity induced by FasL plus Act D in CYP2E1-expressed HepG2 cells. After adding FasL/Act D, increased caspases activities, lipid preoxidation and reduced GSH level, as well as mitochondrial release of cytochrome c were found in Ad-CYP2E1 infected cells (all p < 0.01); these changes were significantly attenuated by DAS (all p < 0.05). These results suggested that CYP2E1 potentiates Fas-mediated HepG2 cells toxicity via the induction of oxidative stress to promote apoptosis. Adenovirus-mediated overexpresson of CYP2E1 may have an important role in the elimination of hepatoma cells mediated by immune effector cells in the liver.

[Expression, purification and activity analysis of human single-chain antibody against hepatocellular cancer].

AIM: To express and characterize an active form of a single-chain antibody (scFv) from the gene of human phage antibodies which is specific for hepatocellular cancer. METHODS: The complementary DNAs encoding the variable regions of the light chain (V(L)) and heavy chain (V(H)) were connected by a (Gly(4)Ser)(3) linker using a splicing by overlap extension polymerase chain reaction. The resultant scFv gene was cloned to the pET28a(+) vector and expressed in E.coli as inclusion bodies. Then the inclusion bodies were solubilized, denatured and renatured. Finally, the affinity constant of scFv was determined by noncompetitive enzyme immunoassay. RESULTS: The target protein amounted 26% of the total protein in the condition of A(600) at 0.8 for 6 hours. After renatured, the purity of target protein was 95% and the affinity constant of the scFv was 3.6x10(7) mol/L. CONCLUSION: An active form of scFv which is specific for hepatocellular cancer can bind selectively with hepatocellular cancer cells, which provides a theoretical basis for immunological detection and clinical use of scFv.

Temporal expression of estrogen receptor alpha in rat bone marrow mesenchymal stem cells.

Estrogen responsiveness of bone formation is mediated by the estrogen receptor alpha (ERalpha) in osteoblastic lineage. As osteoblasts arise from the multipotent bone marrow stromal (mesenchymal) cells, this study was undertaken to observe the ERalpha in primary female adult rat bone marrow mesenchymal stem cells (BMSCs). The ERalpha was localized using immunocytochemical analysis in identified primary BMSCs. Then, using real-time PCR analysis, we measured the expression of ERalpha messenger RNA (mRNA) in BMSCs. ERalpha transcripts showed different trends between untreated cultures (control group) and osteogenic-induced cultures (treated group). In the control group, ERalpha mRNA climbed at peak levels at a confluence stage and decreased until day 20, whereas, in the treated group, the ERalpha mRNA kept climbing from a low level until day 20. Thus, the observed developmental expression of ERalpha mRNA correlates with progressive BMSCs growth and osteogenic differentiation and BMSCs may be a primary target cell for estrogen in maintaining bone formation.