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Background: The role of cancer-associated fibroblasts (CAFs) in modulating the anti-tumor immune response in lung adenocarcinoma (LUAD) remains elusive, primarily due to the heterogeneous nature of these cells. This heterogeneity muddles the understanding of their impact on immunotherapy effectiveness., Methods: We utilized the LUAD single-cell dataset to precisely classify tumor cells and CAFs. By employing CSOmap, we predicted cell interactions and reconstructed the three-dimensional spatial organization, highlighting the close association of myofibroblasts with specific tumor cell subsets. A prognostic signature based on myofibroblast-specific genes was developed and validated to predict LUAD patient survival. In vivo, we conducted subcutaneous tumorigenesis assays in mice, treating with PD-L1 and the POSTN inhibitor RGD to assess the combined effects of POSTN pathway blockade and immunotherapy on tumor growth and immune cell dynamics. For analyzing the tumor microenvironment, we used flow cytometry and multiplex immunofluorescence staining. In vitro, with cell lines like A549, H1299, and RAW264.7, we investigated POSTN's role in macrophage recruitment and polarization. Through ELISA, Western blot, and immunofluorescence staining, we explored how POSTN acts via ITGB3, providing a more comprehensive understanding of its mechanism in LUAD., Results: Our analysis discerned six distinct tumor cell subsets, with cluster 1 displaying pronounced cellular communication with myofibroblasts, evidenced by spatial accessibility in three dimensions. The myofibroblast-specific genomic signature was established and confirmed as a robust, independent prognostic indicator. Among the signature genes, CTHRC1, POSTN, and MMP11 emerged as high-variant genes in myofibroblasts, identified via the FindAllMarkers function in Seurat. Of these, only POSTN's differential expression correlated with LUAD prognosis, with high POSTN expression being indicative of poor patient outcomes. In vitro, recombinant POSTN was observed to enhance tumor invasiveness, motility, and proliferation, while attenuating apoptosis and fostering an EMT phenotype. Additionally, Transwell assays showed that rPOSTN could induce macrophage infiltration via ITGB3 and drive M2 polarization via the PI3K-Akt-JNK pathway. Importantly, blocking the POSTN pathway augmented the efficacy of PD-L1 inhibitors. In vivo, in a mouse subcutaneous tumorigenesis model, the combination of POSTN pathway blockade with PD-L1 inhibitor treatment notably inhibited tumor growth and changed the tumor microenvironment's immune cell composition, with an increase in CD8+ T cells and a favorable shift in the M1/M2 macrophage ratio., Conclusion: This study sheds light on the intricate interplay between tumor cells and myofibroblasts in LUAD, pinpointing the pivotal role of the highly mutated gene POSTN. It underscores POSTN's instrumental role in manipulating the tumor microenvironment, primarily by promoting EMT and inhibiting apoptosis in lung cancer cells, alongside enhancing macrophage recruitment and fostering M2 polarization. These insights provide a foundation for enriching immunotherapy strategies, particularly through the inhibition of the POSTN pathway in LUAD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1 WT ) as a potential diagnostic and prognostic biomarker for non-small cell lung cancer (NSCLC), but how IDH1 WT modulates NSCLC progression remains elusive. Here, we report that IDH1 WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1 WT interacts with and stabilizes PHGDH and fragile X-related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1 WT -PHGDH and IDH1 WT -FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine-depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1 WT in serine metabolism, highlighting IDH1 WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

Background: There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations., Methods: In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored., Results: Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression., Conclusions: Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800020262., (© 2022. The Author(s).)

Purpose: In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2 -amplified non-small cell lung cancer (NSCLC)., Patients and Methods: In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety., Results: The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0-69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0-9.6 months), and median OS was 12.5 months (95% CI, 8.2-16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%-40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression., Conclusions: Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2 -amplified patients with NSCLC., (©2021 American Association for Cancer Research.)

High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.

Despite the success of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations, intrinsic or acquired resistance remains the major obstacle to long-term disease remission. Defective autophagy has been reported as an EGFR-TKI resistance mechanism. However, how EGFR regulate autophagic flux are still not fully understood. Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking. SAH-EJ2, a staple optimized EGFR-derived peptide, showed enhanced in vitro and in vivo antitumor activity against NSCLC than the prototype regardless of EGFR mutation status. Mechanistically, SAH-EJ2 disrupts the EGFR-SQSTM1 interaction and protects against EGFR-induced SQSTM1 phosphorylation, which hinders the dimerization of the SQSTM1 UBA domains and restores SQSTM1 cargo function. Moreover, SAH-EJ2 suppresses EGFR activity by blocking its dimerization and reducing its protein stability, which reciprocally activates the core autophagy machinery. Our observations reveal that disturbing the EGFR-SQSTM1 interaction by SAH-EJ2 confers a potential strategy in the treatment of NSCLC through suppressing EGFR signalling and activating autophagy simultaneously., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to evaluate the association between CYP2A13 polymorphisms and lung cancer susceptibility using the HapMap database., Methods: A case-control analysis of 532 subjects with lung cancer and 614 controls with no personal history of the disease was performed. The tag SNPs rs1645690 and rs8192789 for CYP2A13 were selected, and the genetic polymorphisms were confirmed experimentally through real-time PCR, cloning, and sequencing assay., Results: SNP frequency in this study was consistent with the HapMap Project database of Han-Chinese and lung cancer risk was associated with CYP2A13 polymorphisms in non-smokers. CYP2A13 shares a 93.5% identity with CYP2A6 in the amino acid sequence and the homologous sequences may interfere with the study of SNPs of CYP2A13., Conclusions: CYP2A13 may be a potential key metabolic enzyme gene in the carcinogenesis of lung cancer in non-smokers. The common polymorphisms of CYP2A13 may be candidate biomarkers for lung cancer susceptibility in Han-Chinese., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: NSCLC (non-small-cell lung cancer) is the leading cause of cancer-related mortality worldwide. Both epigenetic and genetic changes contribute to the initiation, development and metastasis of NSCLC. Recently, accumulating data have begun to support the notion that long noncoding RNAs (lncRNAs) function as new crucial regulators of diverse biological processes, including proliferation, apoptosis and metastasis, and play crucial roles in tumorigenesis. Nevertheless, further study is warranted to comprehensively determine lncRNAs' functions and potential mechanism., Methods: In this study, we performed a comprehensive analysis of the lncRNA expression profile of NSCLC using data from TCGA and Gene Expression Omnibus (GEO). PCAT6 expression level in a cohort of 60 pairs of NSCLC tissues using quantitative real-time PCR (qRT-PCR). Additionally, Loss-of-function assays and gain-of-function assays were used to assess the role of PCAT6 in promoting NSCLC progression. Tumor formation assay in a nude mouse model was performed to verity the role of PCAT6 in NSCLC in vivo. Meanwhile, RIP, ChIP, resue experiment and western blot assays were used to highlights the potential molecular mechanism of PCAT6 in NSCLC., Findings: We identified that an oncogene, PCAT6, was upregulated in NSCLC, and this upregulation was verified in a cohort of 60 pairs of NSCLC tissues. Additionally, the expression level of PCAT6 was correlated with tumor size (P = .036), lymph node metastasis (P = .029) and TNM stage (P = .038). Loss-of-function and gain-of-function assays were used to assess the role of PCAT6 in promoting NSCLC progression. The results revealed that PCAT6 knockdown mitigated NSCLC cell growth by inducing G1-phase cell cycle arrest and apoptosis in vitro and in vivo. Whereas, PCAT6 overexpression could promoted tumor cell growth. Meanwhile, PCAT6 additionally promoted NSCLC cell migration and invasion. Furthermore, mechanistic investigation demonstrated that the oncogenic activity of PCAT6 is partially attributable to its repression of LATS2 via association with the epigenetic repressor EZH2 (Enhancer of zeste homolog 2). Overall, our study highlights the essential role of PCAT6 in NSCLC, suggesting that PCAT6 might be a potent therapeutic target for patients with NSCLC., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Metastasis-associated gene 1(MTA1) has been identified as an oncogene in many tumors, and aberrant MTA1 expression has been linked to carcinogenesis and metastasis. We aim to investigate the mechanism of MTA1 and metastasis in malignant pleural mesothelioma (MPM)., Methods: Real-time polymerase chain reaction (PCR) and immunohistochemical staining were employed to detect MTA1 and E-cadherin expression in MPM tissues and corresponding adjacent tissues. Stable clone with knock-down of MTA1 was generated with shRNA via lentivirus technology in MPM cell lines. Wound-healing assay, transwell assay and PCR array were carried out for detecting invasion and migration of MPM cells. Luciferase reporter assay was performed to validate the effect of MTA1 on E-cadherin., Results: MTA1 expression is up-regulated in MPM and shown a negative correlation with E-cadherin expression. MTA1 could enhance the invasion and migration of MPM cells via suppressing the expression of E-cadherin. MTA1 overexpression is associated with pathology, metastasis and survival rate of MPM patients., Conclusions: MTA1 plays an important role in Epithelial-to-mesenchymal transition (EMT) to promote metastasis via suppressing E-cadherin expression, resulting in a poor prognosis in MPM. MTA1 is a novel biomarker and indicative of a poor prognosis in MPM patients.

Background: Hypermethylation of CpG islands in tumor suppressor gene plays an important role in carcinogenesis. Many studies have demonstrated that hypermethylation in promoter region of RARβ gene could be found with high prevalence in tumor tissue and autologous controls such as corresponding non-tumor lung tissue, sputum and plasma of the NSCLC patients. But with the small number subjects included in the individual studie, the statistical power is limited. Accordingly, we performed this meta-analysis to further asses the relationship of methylation prevalence between the cancer tissue and atuologous controls (corresponding non-tumor lung tissue, sputum and plasma)., Methods: The published articles about RARβ gene promoter hypermethyltion were identified using a systematic search strategy in PubMed, EMBASE and CNKI databases. The pooled odds ratio (OR) of RARβ promoter methylation in lung cancer tissue versus autologous controls were calculated., Results: Finally, eleven articles, including 1347 tumor tissue samples and 1137 autologous controls were included in this meta-analysis. The pooled odds ratio of RARβ promoter methylation in cancer tissue was 3.60 (95%CI: 2.46-5.27) compared to autologous controls with random-effect model. Strong and significant correlation between tumor tissue and autologous controls of RARβ gene promoter hypermethylation prevalence across studies (Correlation coefficient 0.53) was found., Conclusion: RARβ promoter methylation may play an important role in carcinogenesis of the NSCLC. With significant methylation prevalence correlation between tumor tissue and autologous of this gene, methylation detection may be a potential method for searching biomarker for NSCLC.

Aim: Myeloperoxidase (MPO) and glutathione S-transferase pi 1 (GSTP1) are important carcinogen-metabolizing enzymes. The aim of this study was to investigate the association between the common polymorphisms of MPO and GSTP1 genes and lung cancer risk in Chinese Han population., Methods: A total of 266 subjects with lung cancer and 307 controls without personal history of the disease were recruited in this case control study. The tagSNPs approach was used to assess the common polymorphisms of MOP and GSTP1 genes and lung cancer risk according to the disequilibrium information from the HapMap project. The tagSNP rs7208693 was selected as the polymorphism site for MPO, while the haplotype-tagging SNPs rs1695, rs4891, rs762803 and rs749174 were selected as the polymorphism sites for GSTP1. The gene polymorphisms were confirmed using real-time PCR, cloning and sequencing., Results: The four GSTP1 haplotype-tagging SNPs rs1695, rs4891, rs762803 and rs749174, but not the MPO tagSNP rs7208693, exhibited an association with lung cancer susceptibility in smokers in the overall population and in the studied subgroups. When Phase 2 software was used to reconstruct the haplotype for GSTP1, the haplotype CACA (rs749174+rs1695 + rs762803+rs4891) exhibited an increased risk of lung cancer among smokers (adjust odds ratio 1.53; 95%CI 1.04-2.25, P=0.033). Furthermore, diplotype analyses demonstrated that the significant association between the risk haplotype and lung cancer. The risk haplotypes co-segregated with one or more biologically functional polymorphisms and corresponded to a recessive inheritance model., Conclusion: The common polymorphisms of the GSTP1 gene may be the candidates for SNP markers for lung cancer susceptibility in Chinese Han population.

Aim: To investigate the expression profile of microRNAs in inoperable advanced non-small cell lung cancer (NSCLC) patients receiving chemotherapy and the potential relevance of microRNAs to clinicopathological characteristics and prognosis., Methods: Serum samples were taken from 260 inoperable advanced NSCLC patients and 260 healthy individuals. All the patients received cisplatin-based chemotherapy, including NP/NC regimens, GP/GC regimens, and TP/TC regimens. The serum levels of microRNAs (miR-125b, miR-10b, miR-34a and miR-155) were determined by quantitative real-time PCR., Results: Serum levels of the 4 microRNAs examined in NSCLC patients were significantly increased as compared with healthy individuals. The levels of miR-125b and miR-155 were changed in a similar pattern: the patients with stage IV disease had the highest one, while the patients with stage III A and stage III B disease showed similar increased levels. The levels of miR-10b and miR-34a in the patients with different stages were increased to similar extent. The level of miR-125b in poorly differentiated cancer was significantly higher than those in well and moderately differentiated cancers, while the levels of miR-10b, miR-34a, and miR-155 did not significantly differ with cancer differentiation. Among the 4 microRNAs examined, only miR-125b was significantly associated with therapeutic response, exhibiting higher expression levels in non-responsive patients. Furthermore, the high level of miR-125b was significantly correlated with poor patient survival. A multivariate Cox regression analysis showed that the expression level of miR-125b was an independent prognostic marker in NSCLC patients., Conclusion: Our results suggest that miR-125b is a potential diagnostic or prognostic biomarker for NSCLC. This finding has important implications for development of targeted therapeutics to overcome chemotherapeutic resistance in NSCLC.

Background: Aberrant methylation of CpG islands acquired in tumor cells in promoter regions plays an important role in carcinogenesis. Accumulated evidence demonstrates P(16INK4a) gene promoter hypermethylation is involved in non-small cell lung carcinoma (NSCLC), indicating it may be a potential biomarker for this disease. The aim of this study is to evaluate the frequency of P(16INK4a) gene promoter methylation between cancer tissue and autologous controls by summarizing published studies., Methods: By searching Medline, EMBSE and CNKI databases, the open published studies about P(16INK4a) gene promoter methylation and NSCLC were identified using a systematic search strategy. The pooled odds of P(16INK4A) promoter methylation in lung cancer tissue versus autologous controls were calculated by meta-analysis method., Results: Thirty-four studies, including 2 652 NSCLC patients with 5 175 samples were included in this meta-analysis. Generally, the frequency of P(16INK4A) promoter methylation ranged from 17% to 80% (median 44%) in the lung cancer tissue and 0 to 80% (median 15%) in the autologous controls, which indicated the methylation frequency in cancer tissue was much higher than that in autologous samples. We also find a strong and significant correlation between tumor tissue and autologous controls of P(16INK4A) promoter methylation frequency across studies (Correlation coefficient 0.71, 95% CI:0.51-0.83, P<0.0001). And the pooled odds ratio of P(16INK4A) promoter methylation in cancer tissue was 3.45 (95% CI: 2.63-4.54) compared to controls under random-effect model., Conclusion: Frequency of P(16INK4a) promoter methylation in cancer tissue was much higher than that in autologous controls, indicating promoter methylation plays an important role in carcinogenesis of the NSCLC. Strong and significant correlation between tumor tissue and autologous samples of P(16INK4A) promoter methylation demonstrated a promising biomarker for NSCLC.

Aim: To develop a rational immunotherapy against tumor metastasis by combining a Toll-like-receptor 2 (TLR2)-neutralizing antibody with a TLR9 agonist CpG ODN, and then investigate the mechanism of action for this combinational regimen., Methods: After mouse melanoma B16-F10 cell inoculation, female C57BL/6 mice were treated with either CpG ODN (0.5 mg/kg) or the anti-TLR2 antibody (200 μg/kg), or with a combination of the two agents. Pulmonary metastases were evaluated by counting metastatic nodes on the lung surface using anatomical microscopy. Flow cytometry was used to evaluate the cytotoxicity of the immune cells in tumor-draining lymph nodes, the cell population in the spleen, and the infiltration of immune cells within the lungs. Cytokine and enzyme expression in the lung tissue was evaluated using ELISA or immunostaining., Results: Anti-metastatic effects were detected in mice treated with either CpG ODN or the anti-TLR2 antibody alone. However, treatment with CpG ODN plus the anti-TLR2 antibody synergistically suppressed the metastasis as compared with treatment with either single agent. The combinational treatment resulted in enhanced infiltration of natural killer cells and cytotoxic T cells, reduced recruitment of type 2 macrophages and Tregs, and decreased expression of immunosuppressive factors including TGF-β1, cyclooxygenase-2 and indoleamine 2,3-dioxygenase, thus stimulated tumor cytotoxicity and suppressed metastasis. The anti-metastatic effect of the combinational regimen was further confirmed in spontaneous metastatic mouse model of Lewis lung carcinoma., Conclusion: Our studies suggest that combining a TLR9 agonist with an anti-TLR2 antibody, which eliminates immunosuppressive factors from the tumor environment, is critical for an effective anti-metastatic immunotherapy.

Aim: To explore the association between genetic polymorphisms of the receptor for advanced glycation end-products (RAGE) and susceptibility, chemotherapy response rate and prognosis of non-small cell lung cancer (NSCLC)., Method: This is a prospective study in which 562 patients with NSCLC and 764 healthy controls were enrolled. Three RAGE genetic polymorphisms, namely, -429T/C, -374T/A and 82G/S were genotyped. Platinum-based chemotherapy was given to 432 subjects with advanced inoperable NSCLC and their responses to chemotherapy were evaluated., Results: All the polymorphic genotypes of RAGE polymorphisms were associated with susceptibility for NSCLC. Only the 82G/S polymorphisms denoted a significant difference between responders and non-responders to chemotherapy. The 82SS genotype and 82S allele distribution not only increased the NSCLC risk, but also was associated with a lower chemotherapy response rate and poor prognosis, indicated by overall survival and progression free survival., Conclusion: The 82G/S genetic polymorphism of RAGE gene might be used as a genetic marker to screen for patients sensitive to thermotherapy and to predict the prognosis of NSCLC.

Background and Objective: Although evidence for a significant survival benefit of chest radiotherapy has been proven, no conclusion could be drawn regarding the optimal timing of chest radiation. The aim of this study is to explore whether the timing of chest radiation may influence the survival of the patients with limited-stage small-cell lung cancer (LSSCLC) by performing a literature-based meta-analysis., Methods: By searching Medline, CENTRAL (the Cochrane central register of controlled trials), CBM, and CNKI, et al, we collected both domestic and overseas published documents about randomized trials comparing different timing chest radiotherapy in patients with LS-SCLC. Early chest radiation was regarded as beginning within 30 days after the start of chemotherapy. Random or fixed effect models were applied to conduct meta-analysis on the trials. The combined odds ratio (OR) and the 95% confidence interval (CI) were calculated to estimate the mortality in 2 or 3 years and toxicity of the two treatments. The statistical heterogeneity was determined by cochran's Chi-square test (Q test). The Begg' test was used to determine the publication bias., Results: Six trials that included a total of 1 189 patients were analyzed in the meta-analysis 587 patients were in the early radiation group and 602 patients were in the late radiation group. Considering all 6 eligible trials, the overall survival at 2/3 years was not significantly different between early and late chest radiation (OR=0.78, 95%CI: 0.55-1.05, Z=1.68, P=0.093). For the toxicity, no obvious difference was observed for early chest radiotherapy compared with late irradiation in pneumonitis (OR=1.93, 95%CI: 0.97-3.86, P=0.797), esophagitis (OR=1.43, 95%CI: 0.95-2.13, P=0.572) and thrombocytopenia (OR=1.23, 95%CI: 0.88-1.77, P=0.746), respectively., Conclusions: No statistical difference was observed in 2/3 years survival and toxicity, including pneumonitis, esophagitis and thrombocytopenia, between early radiation and late radiotherapy in LS-SCLC.

Background and Objective: Glutathione S-transferase M1 (GSTM1) is an important phase II metabolic enzyme gene which involves metabolism of various carcinogens in human body. Many studies showed that GSTM1 genetic polymorphism was associated with lung cancer risk. The aim of this study is to investigate the relationship between GSTM1 genetic polymorphism and lung cancer risk among Han nationality population in Tianjin district., Methods: GSTM1 genetic polymorphism was detected by melting curve analysis of SYBR green I real-time PCR assay. Two hundred and sixty-five histological confirmed lung cancer patients and 307 health controls were recruited in this case-control study and the relationship between GSTM1 genetic polymorphism and lung cancer riskwas investigated., Results: (1) The frequency of the GSTMI(-) in lung cancer and control groups was 56.6% and 57.0% respectively, and no significant difference was found between the distribution of the GSTM1 (-) genotype in the two groups (chi2 = 0.831, P = 0.362). (2) When considered the GSTM1(+) genotype as reference, there was no overall statistically increased lung cancer risk for carriers with the GSTM1(-) genotype adjusted by age, gender and smoking status (OR = 0.840, 95% CI: 0.578-1.221, P = 0.362). (3) The frequency of the GSTM1(-) genotype for squamous cell carcinoma, adenocarcinoma, SCLC and other histological types was 65.8%, 48.5%, 47.8% and 52.2% respectively, compared with the control group, no statistically increased lung cancer risk was observed (P > 0.05)., Conclusion: No evidence is found between GSTMI genetic polymorphism and lung cancer risk among Han nationality population in Tianjin district.

Background and Objective: Fourty years ago, Tokuhata and Lilienfeld provided the first epidemiologic evidence of familial aggregation of lung cancer. Familial aggregation and increased familial risk for lung cancer have been reported in several studies, subsequently. But the results are not consistent with each other. The aim of this study is to further explore the relationship between family history of lung cancer and lung cancer risk., Methods: By searching PubMed, CENTRAL, CBM, CNKI and VIP, we collected both domestic and overseas published documents before November, 2009 on family history of lung cancer and lung cancer risk. RevMan version 4.2 was used to perform meta-analysis on the case-control study results, the combined odds ratio (OR) and the 95% confidence interval (CI) were calculated as well., Results: Twenty-eight publications were included into the combined analysis, which indicated that the lung cancer risk of the probands' first-degree relatives was 1.88 times higher than that of their controls' (P < 0.001). In the sub-study, compared with the controls' father mother and siblings, the OR of the probands' father mother and siblings was 1.62 (P < 0.001), 1.96 (P < 0.001) and 1.92 (P < 0.001), respectively. For smoking status, lung cancer risk in first-degree relatives of smoking probands was 1.73 (P < 0.001) times higher than that of their corresponding controls'. And for non-smoking subjects the lung cancer risk was 1.42 (P = 0.02) times higher in proboands' first-degree relatives. For gender categories, lung cancer risk in first-degree relatives of female probands was 1.89 (P < 0.001) times higher than that of their corresponding controls'. And for male subjects, the lung cancer risk was 1.99 (P < 0.001) times higher in proboands' first-degree relatives., Conclusion: Lung cancer risk was increased in probands' first-degree relatives, and obvious familial aggregation of lung cancer was observed in this study.

Background and Objective: It has been proven that telomerase activation correlates with the carcinogenesis, aggressiveness and turnover of lung cancer. Telomerase is one of the improtant molecular biomarkers for diagnosis and targeting therapy in lung cancer. The aim of this study is to investigate the diagnostic value of the combined determination of telomerase activity in induced sputum, pleural effusion and fiberobronchoscopic biopsy in lung cancer patients., Methods: The technique of TRAP (telomeric repeat amplification protocal)-PCR-ELISA was employed to detect telomease levels of induced sputum, pleural effusion and fiberobronchoscopic biopsy in 80 lung cancer patients with pleural effusion and 50 benign pulmonary disease patients with pleural effusion., Results: Telomemse levels of induced sputum, pleural effusion and fiberobronchoscopic biopsy were all significantly higher in patients with lung cancer than those with benign pulmonary disease (P < 0.001). There was no significant difference in the level of telomerase activity between different pathologic types (P > 0.05). The sensitivity of induced sputum, pleural effusion and fiberobronchoscopic biopsy were 62.5% (50/80), 46.3% (37/80) and 60.0% (48/80), respectively. The specificity were 72.0% (36/50), 66.0% (33/50) and 70.0% (35/50), respectively. The overall accuracy were 66.2% (86/130), 53.8% (70/130) and 63.8% (83/130), respectively. The sensitivity, specificity and overall accuracy of combined induced sputum, pleural effusion and fiberobronchoscopic biopsy were 85.0% (68/80), 78.0% (39/50) and 82.3% (107/130), respectively. The sensitivity of telomease level in combined detection for diagnosis of lung cancer was much higher than that in single sample detection (P < 0.01)., Conclusion: The sensitivity of telomease activity in combined three samples was the highest. It can further improve the accuracy for the diagnosis of lung cancer with pleural effusion.

Background and Objective: The relationship between myeloperoxidase G-463A genetic polymorphisms and lung cancer susceptibility has been studied extensively. However, the outcomes are not consistent. The aim of this study is to evaluate the relationship between myeloperoxidase genetic polymorphisms and lung cancer susceptibility by meta analysis., Methods: Documents published were retrieved through databases associated with the study. Taking into account the possibilities of heterogeneity of the studies, a statistical test for heterngeneity was performed. The odds ratio and 95% CI were used to evaluate the risks. The meta analysis was applied with RevMan software 4.2, and the forest plot and funnel plot of meta analysis were worked out., Results: A total of 5 381 cases and 5 827 controls from studies for Caucasian and a total of 1 558 cases and 1 755 controls from studies for East Asians were included. For Caucasian the pooled OR was 0.91 (95% CI: 0.81-1.02); For East Asians, the pooled OR is 0.83 (95% CI: 0.63-1.09). Publication bias exits in the study for Caucasian, but not for East Asians., Conclusion: The results of this study indicated that the polymorphism of myeloperoxidase G-463A was not significantly associated with the lung cancer risk for Caucasian or East Asians. However, further studies for the East Asians is needed for the few subjects.

Background: Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis., Methods and Findings: In this study, we investigated the potential roles and mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8(+) T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice., Conclusions and Significance: Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis.