Purine metabolism in lung adenocarcinoma: A single-cell analysis revealing prognostic and immunotherapeutic insights.

Lung adenocarcinoma (LUAD) is a prevalent subtype of lung cancer, yet the contribution of purine metabolism (PM) to its pathogenesis remains poorly elucidated. PM, a critical component of intracellular nucleotide synthesis and energy metabolism, is hypothesized to exert a significant influence on LUAD development. Herein, we employed single-cell analysis to investigate the role of PM within the tumour microenvironment (TME) of LUAD. PM scoring (PMS) across distinct cell types was determined using AUCell, UCell, singscore and AddModuleScore algorithms. Subsequently, we explored communication networks among cells within high- and low-PMS groups, establishing a robust PM-associated signature (PAS) utilizing a comprehensive dataset comprising LUAD samples from TCGA and five GEO datasets. Our findings revealed that the high-PMS group exhibited intensified cell interactions, while the PAS, constructed using PM-related genes, demonstrated precise prognostic predictive capability. Notably, analysis across the TCGA dataset and five GEO datasets indicated that low-PAS patients exhibited a superior prognosis. Furthermore, the low-PAS group displayed increased immune cell infiltration and elevated CD8A expression, coupled with reduced PD-L1 expression. Moreover, data from eight publicly available immunotherapy cohorts suggested enhanced immunotherapy outcomes in the low-PAS group. These results underscore a close association between PAS and tumour immunity, offering predictive insights into genomic alterations, chemotherapy drug sensitivity and immunotherapy responses in LUAD. The newly established PAS holds promise as a valuable tool for selecting LUAD populations likely to benefit from future clinical stratification efforts.

Clinical prognostication and immunotherapy response prediction in esophageal squamous cell carcinoma using the DNA damage repair-associated signature.

BACKGROUND: The relationship between DNA damage repair (DDR) and cancer is intricately intertwined; however, its specific role in esophageal squamous cell carcinoma (ESCC) remains enigmatic. METHODS: Employing single-cell analysis, we delineated the functionality of DDR-related genes within the tumor microenvironment (TME). A diverse array of scoring mechanisms, including AUCell, UCell, singscore, ssgsea, and AddModuleScore, were harnessed to scrutinize the activity of DDR-related genes across different cell types. Differential pathway alterations between high-and low-DDR activity cell clusters were compared. Furthermore, leveraging multiple RNA-seq datasets, we constructed a robust DDR-associated signature (DAS), and through integrative multiomics analysis, we explored differences in prognosis, pathways, mutational landscapes, and immunotherapy predictions among distinct DAS groups. RESULTS: Notably, high-DDR activity cell subpopulations exhibited markedly enhanced cellular communication. The DAS demonstrated uniformity across multiple datasets. The low-DAS group exhibited improved prognoses, accompanied by heightened immune infiltration and elevated immune checkpoint expression. SubMap analysis of multiple immunotherapy datasets suggested that low-DAS group may experience enhanced immunotherapy responses. The "oncopredict" R package analyzed and screened sensitive drugs for different DAS groups. CONCLUSION: Through the integration of single-cell and bulk RNA-seq data, we have developed a DAS associated with prognosis and immunotherapy response. This signature holds promise for the future stratification and personalized treatment of ESCC patients in clinical settings.

A cuproptosis-related lncRNA signature-based prognostic model featuring on metastasis and drug selection strategy for patients with lung adenocarcinoma.

Introduction: Lung adenocarcinoma is a common cause of mortality in patients with cancer. Recent studies have indicated that copper-related cell death may not occur in the same way as previously described. Long non-coding RNAs (lncRNAs) play a key role in the occurrence and development of tumors; however, the relationship between cuproptosis and lncRNAs in tumorigenesis and lung adenocarcinoma (LUAD) treatment has not been well established. Our study aimed to construct a model to analyze the prognosis of lung adenocarcinoma in patients using a carcinogenesis-related lncRNA (CR) signature. Methods: The transcriptional profiles of 507 samples from The Cancer Genome Atlas were assessed. Cox regression and co-expression analyses, and the least absolute shrinkage and selection operator (LASSO) were used to filter the CR and develop the model. The expression status of the six prognostic CRs was used to classify all samples into high- and low-risk groups. The overall disease-free survival rate was compared between the two groups. The Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes were used to identify the pathways and mechanisms involved in this model. Subsequently, immunotherapy response, sensitivity, and correlation analyses for several anti-tumor medications were performed. In vitro experiments, including qPCR, were conducted in nine lung adenocarcinoma cell lines and 16 pairs of lung adenocarcinoma and para-carcinoma tissues. Results: After confirmation using the ROC curve, patients in the low-risk category benefited from both overall and disease-free survival. Gene Ontology analysis highlighted cell movement in the model. In the in vitro experiments, qPCR results showed the expression levels of six CRs in 16 pairs of carcinoma and para-carcinoma tissues, which were in accordance with the results of the model. AL138778.1 is a protective factor that can weaken the invasion and migration of A549 cells, and AL360270.1 is a hazardous factor that promotes the invasion and migration of A549 cells. According to this model, targeted treatments such as axitinib, gefitinib, linsitinib, pazopanib, and sorafenib may be more appropriate for low-risk patients. Conclusion: Six CR profiles (AL360270.1, AL138778.1, CDKN2A-DT, AP003778.1, LINC02718, and AC034102.8) with predictive values may be used to evaluate the prognosis of patients with lung adenocarcinoma undergoing therapy.

CT-based radiomics model to predict spread through air space in resectable lung cancer.

BACKGROUND: Spread through air space (STAS) has been identified as a pathological pattern associated with lung cancer progression. Patients with STAS were related to a worse prognosis compared with patients without STAS. The objective of this study was to establish a radiomics model capable of forecasting STAS before surgery, which can assist surgeons in selecting the most appropriate operation type for patients with STAS. METHOD: There were 537 eligible patients retrospectively included in this study. ROI segmentation was performed manually on all CT images to identify the region of interest. From each segmented lesion, a total of 1688 features were extracted. The tumor size, maximum tumor diameters, and tumor type were also recorded. Using Spearman's correlation coefficient to calculate the correlation and redundancy of elements, and redundant features less than 0.80 were removed. In order to reduce the level of overfitting and avoid statistical biases, a dimension reduction process of the dataset was conducted to decrease the number of features. Finally, a radiomics model included 44 features was established to predict STAS. To evaluate the performance of the model, the receiver operating characteristic (ROC) curve was used, and the area under the curve (AUC) was calculated, and the accuracy of the model was verified by 10-fold cross-validation. RESULTS: The incidence of STAS was 38.2% (205/537). The tumor type, maximum tumor diameters, and consolidation tumor ratio were significantly different between STAS group and non-STAS group. The training group included 430 patients, while the test group was consisted with 107. The training group achieved an AUC of 0.825 (sensitivity, 0.875; specificity, 0.621; and accuracy, 0.749) and the test group had an AUC of 0.802 (sensitivity, 0.797; specificity,0.688; and accuracy, 0.748). The 10-fold cross-validation had an AUC of 0.834. CONCLUSION: CT-based radiomic model can predict STAS effectively, which is of great importance to guide the selection of operation types before surgery.

Effects of cavitation erosion-induced surface damage on the corrosion behaviour of TA31 Ti alloy.

This study used electrochemical noise technology to analyse the effects of surface damage induced by cavitation erosion (CE) on the pitting and passivation behaviours of TA31 Ti alloy. According to the results, TA31 Ti alloy exhibited high corrosion resistance in NaCl solutions. However, the residual tensile stress layer generated during grinding and polishing reduced its passivation ability. Subsequently, the residual tensile stress layer was eliminated after CE for 1 h, improving the passivation ability of the material. Thereafter, pitting corrosion was initiated on the material surface. Increasing the CE time from 1 h to 2 h gradually decreased the passivation ability of the alloy. A large number of CE holes promoted the transition from pitting initiation to metastable pitting growth. which gradually dominated the surface of TA31 Ti alloy. The damage mechanism of uniform thinning increased the passivation ability and stability of the alloy with the increase in CE time from 2 h to 6 h. Therefore, the surface of TA31 Ti alloy was dominated by the initiation of pitting corrosion.

Ion channel gene GJB2 influences the intercellular communication by Up-regulating the SPP1 signaling pathway identified by the single-cell RNA sequencing in lung adenocarcinoma.

Objective: Firstly, observe the prognostic significance and the biological functional effects of gap junction protein beta 2 (GJB2 or Cx26) in lung adenocarcinoma (LUAD). Subsequently, explore the role played by GJB2 in intercellular communication by single-cell RNA sequencing. Method: We made a differential analysis of GJB2 expression through public databases and investigated the clinical characteristics and prognostic significance. ESTIMATE analysis and Tumor Immune Estimation Resource (TIMER) database were utilized to illustrate the association of GJB2 with immune infiltration and components of the tumor microenvironment. Gene Ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and Gene set enrichment analysis (GSEA) were performed to study the biological function of GJB2. Cell-cell communication was analyzed using the CellChat R package through sc-RNA data. Results: GJB2 has an outstanding prognosis value in LUAD and a close relationship was found between GJB2 and immune infiltration in LUAD. GJB2 could participate in several tumor biological processes, including extracellular matrix remodeling and upregulation of multiple cancer-related active pathways. GJB2 related hub-genes influence intercellular communication through the SPP1 signaling pathway. Conclusion: Our study illustrates one mechanism by which GJB2 exerts its cancer-specific relevant effects, that is, causing changes in intercellular communication through the SPP1 signaling pathway. Blockade of this pathway may limit the functional role of GJB2 and provide us with promising new perceptions for LUAD treatment.

Understanding the Corrosion Behavior of Nickel-Aluminum Bronze Induced by Cavitation Corrosion Using Electrochemical Noise: Selective Phase Corrosion and Uniform Corrosion.

Nickel-aluminum bronze (NAB) is widely used to fabricate flow-handling components because of its good cavitation corrosion (CE) resistance and superior casting property. The existence of different phases, e.g., the α phase, ß phase and κ phase, can cause significant selective phase corrosion on NAB. However, under the action of CE with different times, the influence of these phases on the corrosion behavior of NAB, including selective phase corrosion and uniform corrosion, needs to be further studied, which can contribute to a deep understanding of the CE mechanism of NAB in corrosive media. In this work, the corrosion behavior of NAB in 3.5 wt.% NaCl solution after different CE times was evaluated by electrochemical noise (EN), combined with scanning Kelvin probe force microscopy (SKPFM) and morphology analysis. The results showed that the corrosion behavior of NAB was closely associated with the variation in its complex microstructure after different CE times. Selective phase corrosion played a crucial role in the surface damage before 0.5 h of CE. With the prolongation of CE time, the stripping of κ phases decreased the degree of selective phase corrosion of NAB. As a result, both selective phase corrosion and uniform corrosion presented equal performances after 1 h of CE. However, after CE for 2-5 h, uniform corrosion had a dominant impact on the surface damage of NAB. Eventually, the corrosion mechanism of NAB after different CE times was clarified based on the relevant experimental results.

Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) usually contains heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. However, the genomic features of the MIP subtype responsible for its malignant behaviors are substantially unknown. In this study, eight FFPE samples from LUAD patients were micro-dissected to isolate MIP and LEP components, then sequenced by whole-exome sequencing. More comprehensive analyses involving our samples and public validation cohorts on the two subtypes were performed to better decipher the key biological and evolutionary mechanisms. As expected, the LEP and MIP subtypes exhibited the largest disease-free survival (DFS) differences in our patients. EGFR was found with the highest mutation frequency. Additionally, shared mutations were observed between paired LEP and MIP components from single patients, and recurrent mutations were verified in the Lung-Broad, Lung-OncoSG, and TCGA-LUAD cohorts. Distinct biological processes or pathways were involved in the evolution of the two components. Besides, analyses of copy number variation (CNV) and intratumor heterogeneity (ITH) further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level, ITH, and the pervasive DNA damage response and WNT pathway gene alternations in the MIP component. Phylogenetic analysis of five pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analyses combining our samples and public cohorts, PTP4A3, NAPRT, and RECQL4 were identified to be co-amplified. Multi-omics data also demonstrated the immunosuppression prevalence in the MIP component. Our results uncovered the evolutionary pattern of the concomitant LEP and MIP components from the same patient that they were derived from the same initiation cells and the pathway-specific mutations acquired after EGFR clonal mutation could shape the subtype-specificity. We also confirmed the immunosuppression prevalence in the MIP subtype by multi-omics data analyses, which may have resulted in its unfavorable prognosis.

Integrated Multiomics Analyses Revealing Different Molecular Profiles Between Early- and Late-Stage Lung Adenocarcinoma.

The molecular differences in genetic and epigenetic profiling between early-stage (ES) and late-stage (LS) lung adenocarcinoma (LUAD), which might help to understand cancer progression and biomarker guided precision treatment, need further be investigated. In this study, we performed comprehensive analysis using multi-omics next-generation sequencing (NGS) on tissue samples from 7 ES (stage I) and 10 LS (stage III/IV) LUAD patients to study molecular characteristics between the two groups. Characterization of the genomic and transcriptomic profiles showed stage-specific somatic mutations, copy number variations (CNVs) and differentially expressed genes (DEGs). LS samples tend to have more TP53, ERBB2 and CHD4 mutations. Gene copy number loss occurs in immune-related gene pathways in the late stage of LUAD. ATAC-seq analysis showed that LS samples harbored more open chromatin peaks around promoter regions and transcription start sites (TSS) than ES samples. We then identified the known transcription factor (TF) binding motifs for the differentially abundant ATAC-seq peaks between the ES and LS samples and found distinct regulatory mechanisms related to each stage. Furthermore, integrative analysis of ATAC-seq with WGS and RNA-seq data showed that the degree of chromatin accessibility is related to copy number changes, and the open chromatin regions could directly regulate the expression of some DEGs. In conclusion, we performed a comprehensive multi-omics analysis of the early and late stages of LUAD and highlighted some important molecular differences in regulatory mechanisms during cancer progression. Those findings help to further understand mechanism and biomarker related targeted therapy.

miR-423-3p activates FAK signaling pathway to drive EMT process and tumor growth in lung adenocarcinoma through targeting CYBRD1.

BACKGROUND: Lung adenocarcinoma (LUAD) is a malignant tumor with a high fatality rate and poor overall survival, while molecular targets diagnosing and alleviating lung cancer remain inadequate. METHODS: In this article, we highlighted the upregulation of microRNA-423-3p (miR-423-3p) in LUAD, especially in smokers aged over 40, and revealed that the high expression of miR-423-3p was significantly associated with smoker, age, and pathologic stage of LUAD patients. RESULTS: Moreover, overexpressing miR-423-3p could facilitate LUAD cell proliferation, invasion, adhesion, and epithelial-mesenchymal transition (EMT) process, while depleted miR-423-3p caused repressive influence upon it. Mechanically, we identified that miR-423-3p could activate FAK signaling pathway through binding to the 3'-UTR of cytochrome B reductase 1 (CYBRD1). Furthermore, we demonstrated that CYBRD1 was lowly expressed in LUAD, and miR-423-3p overexpression could rescue the impairment of LUAD cell proliferation, invasion, adhesion, and EMT caused by CYBRD1 depletion. Noticeably, miR-423-3p depletion efficiently hindered LUAD tumor growth in vivo. CONCLUSION: Collectively, our findings demonstrated that miR-423-3p/CYBRD1 axis could be regarded as a promising biomarker to alleviate the poor LUAD prognosis.

CITED4 enhances the metastatic potential of lung adenocarcinoma.

BACKGROUND: CITED4 belongs to the CBP/p300-interacting transactivator with glutamic acid and aspartic acid-rich tail (CITED) family which is induced by various cytokines and participates in cytokine-induced proliferation and differentiation. CITED4 is induced by HB-EGF in lung cancer cells. However, it is unclear whether and how CITED4 contributes to the invasion and metastasis of lung adenocarcinoma (ADC). METHODS: CITED4 expression in lung adenocarcinoma and its association with disease-free survival (DFS) and overall survival were analyzed based on a cohort of 261 patients. The roles of CITED4 were validated via loss-of-function and gain-of-function experiments. The relationship between CITED4 and CLDN3 was validated by immunohistochemistry, Western blotting, and luciferase reporter assays. The function of the CITED4-CTNNB1-CLDN3 complex was fully validated and described. RESULTS: CITED4 expression was significantly upregulated in ADC tissues and cells and a predictor for DFS. Downregulation of CITED4 attenuated the proliferation and invasion, whereas CITED4 overexpression enhanced these effects. Overexpression and knockdown of CITED4 resulted in the upregulation and downregulation of CLDN3, respectively. Moreover, CITED4 downregulation suppressed CLDN3-mediated ADC cell metastasis in vivo. CITED4 was highly expressed and positively correlated with CLDN3. Mechanistically, CITED4 interacted with CTNNB1 and functioned synergistically to enhance CLDN3 transcription. Importantly, CITED4 induced ADC invasion via a CLDN3-dependent pathway. CITED4 determined the level of CLDN3, which in turn affected the sensitivity of tumors to Clostridium perfringens enterotoxin treatment. CONCLUSIONS: The CITED4-CTNNB1-CLDN3 axis plays a key role in the invasion and metastasis of ADC and provides a novel therapeutic target for lung cancer treatment.

Genomic characteristics in Chinese non-small cell lung cancer patients and its value in prediction of postoperative prognosis.

BACKGROUND: The genomic profile of non-small cell lung cancer (NSCLC) in Asians is distinct from that of Caucasians, but comprehensive genetic profiling reports have been limited for Asian patients. We aimed to elucidate genomic characteristics of Chinese NSCLC patients and develop potential model including genomic characteristics to predict postoperative prognosis. METHODS: Resected tumor samples from 511 patients with stage I-IV lung cancer were subjected to targeted sequencing using a panel of 295 cancer-related genes. Based on the molecular profiles and clinical features, we established nomogram models with predictors consisting of integrated clinical and genomic characteristics to provide post-operative risk stratification. RESULTS: Compared to the TCGA population (mainly Caucasians), there was a significantly higher frequency of EGFR (53.7% vs. 14.4%) and NOTCH3 (8.4% vs. 1.3%) mutations and less mutated KRAS (11.0% vs. 32.6%), KEAP1 (4.4% vs. 17.4%) and LRP1B (16.3% vs. 29.6%) in Chinese lung adenocarcinomas (LUAD). Distinct patterns of mutually exclusive and co-occurring mutations were identified between LUAD and lung squamous cell carcinoma (LUSC), indicating the unique histology-specific tumorigenesis mechanism of each subtype. We observed alterations in pathways correlated with clinical characteristics. Additionally, we constructed nomogram model with predictors consisting of clinical and genomic characteristics, which were more accurate than models with clinical characteristics or TNM staging only both in stage I-IIIA patients and T1-2N0M0 sub-cohort. CONCLUSIONS: This study revealed Chinese NSCLC patients have unique genomic profile. Furthermore, the nomogram model combining clinical features with genomic characteristics could improve risk stratification in early-stage NSCLC.

Feasibility of sleeve lobectomy after neo-adjuvant chemo-immunotherapy in non-small cell lung cancer.

Immunotherapy is one of the most effective treatments for patients with advanced lung cancer. In many advanced non-small cell lung cancer (NSCLC) cases, the tumor is centrally located. For such patients, sleeve lobectomy has been considered as a more effective therapeutic option compared with pneumonectomy, achieving better long-term survival and quality of life with no increase in morbidity or mortality. Until now, there have been no studies regarding the efficacy and safety of neo-adjuvant chemo-immunotherapy prior to sleeve lobectomy for lung cancer. From January 2019 through October 2019, nine patients were diagnosed as NSCLC and evaluated to undergo sleeve lobectomy surgery (SLS). Of these patients, four received two cycles of pembrolizumab plus paclitaxel and cisplatin (PPC) followed by sleeve lobectomy, while five patients underwent SLS alone. The patients' clinical characteristics, perioperative parameters, and postoperative outcomes were analyzed. Multiplex fluorescent immunohistochemistry was performed to determine the number of macrophages, CD4+ and CD8 T cells, and Treg cells in the bronchial mucosa. Three of the four patients achieved a complete pathological response [0% viable tumor, pathologic complete response (pCR)]. All of the patients in the PPC group achieved major pathological response (≤10% viable tumor, MPR). No grade 3 or 4 treatment-related adverse events occurred in the PPC group, nor did any of the patients in the group experience treatment-related surgical delays. The mean surgical time and the number of lymph nodes dissected were the same in the two groups. The PPC group had a higher number of CD8 + T cells compared to the SLS group (P<0.01). No postoperative chylothorax, pneumonia, or other postoperative complications occurred in either group. The surgical difficulty and post-surgical complication rate of sleeve lobectomy with neo-adjuvant chemo-immunotherapy were similar to those of SLS alone. Neo-adjuvant chemo-immunotherapy is effective and safe with sleeve lobectomy for NSCLC patients. Additional prospective multi-center randomized studies using larger patient cohorts are necessary to validate our findings.

LncRNA H19 downregulation confers erlotinib resistance through upregulation of PKM2 and phosphorylation of AKT in EGFR-mutant lung cancers.

First-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib have significant activity in NSCLC patients with activating EGFR mutations. However, EGFR-TKI resistance inevitably occurs after approximately 12 months of treatment. Acquired mechanisms of resistance, other than secondary mutations in EGFR (T790 M) which account for 50-60%, are less well understood. Here, we identified lncRNA H19 as a significantly downregulated lncRNA in vitro models and clinical specimens with acquired EGFR-TKI resistance, H19 knockdown or overexpression conferred resistance or sensitivity, respectively, both in vitro and in vivo models. H19 downregulation contributed to erlotinib resistance through interaction and upregulation of PKM2, which enhanced the phosphorylation of AKT. AKT inhibitors restored the sensitivity of erlotinib-resistant cells to erlotinib. In EGFR-mutant patients treated with EGFR-TKIs, low H19 levels were associated with a shorter progression-free survival (PFS) (P = 0.021). These findings revealed a novel mechanism of low-level H19 in the regulation of erlotinib resistance in EGFR-mutant lung cancers. Combination of AKT inhibitors and EGFR-TKIs could be a rational therapeutic approach for some subgroups of EGFR-mutant lung cancer patients.

[Robot-assisted Lobectomy under Port-only Mode with Artificial Pneumothorax].

BACKGROUND: Da Vinci robotic system is currently widely used in thoracic surgery. The ports employment and procedures vary in different medical center in China. Usually, a small incision was used for assistant. METHODS: Based on clinical practice, we summarized domestic and foreign experience, combined with the characteristics of the Chinese body anatomy, employ portal technique and artificial pneumothorax, summarized a set of simplified and easier surgical method. RESULTS: Port-only artificial pneumothorax robot-assisted lobectomy has further improvement in anatomical safety, hemostatic effect and aesthetic appearance of the wound. CONCLUSIONS: This study optimizes the procedure of port-only artificial pneumothorax robot-assisted lobectomy in order to serve lung cancer patients better.

Survival benefit and toxicity profile of adjuvant icotinib for patients with EGFR mutation-positive non-small cell lung carcinoma: a retrospective study.

BACKGROUND: Adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasing considered for the tailored management of resectable non-small cell lung cancer (NSCLC). This study aimed to analyze the survival and toxicity profile of patients with EGFR mutation-positive NSCLC treated with adjuvant icotinib. METHODS: This was a single-center retrospective study of patients with EGFR mutation-positive NSCLC who underwent R0 (microscopically margin-negative) resection and received adjuvant icotinib between November 2011 and December 2017. The outcomes included 2-year disease-free survival (DFS) rate, 3-year overall survival (OS) rates, DFS, OS, and adverse events (AEs). RESULTS: A total of 86 patients receiving adjuvant icotinib were included. Their mean age was 59.7±10.0 years, and 26 (30.2%) patients were male. The 2-year DFS rate was 86.7%, and the 3-year OS rate was 95.3% with adjuvant icotinib. DFS (P=0.044) and OS (P=0.003) are better in stage I/II disease than in stage III disease. There seems no differences in DFS and OS between patients with low or high preoperative CEA levels (cutoff of 5 ng/mL), patients with exon 19 or 21 EGFR mutation or patients with or without smoking history. The most common AEs with adjuvant icotinib were rash (83.7%) and diarrhea (19.8%). One (1.2%) patient-reported grade ≥3 AEs. No treatment-related death occurred. CONCLUSIONS: For patients with EGFR mutation-positive NSCLC, adjuvant icotinib might be associated with a promising survival benefit, with an acceptable toxicity profile.

Fluzoparib increases radiation sensitivity of non-small cell lung cancer (NSCLC) cells without BRCA1/2 mutation, a novel PARP1 inhibitor undergoing clinical trials.

PROPOSE: Poly (ADP-ribose) polymerase 1 inhibitors were originally investigated as anti-cancer therapeutics with BRCA1/2 genes mutation. Here, we investigate the effectiveness of a novel PARP1 inhibitor fluzoparib, for enhancing the radiation sensitivity of NSCLC cells lacking BRCA1/2 mutation. METHODS: We used MTS assays, western blotting, colony formation assays, immunofluorescence staining, and flow cytometry to evaluate the radiosensitization of NSCLC cells to fluzoparib and explore the underlying mechanisms in vitro. Through BRCA1 and RAD50 genes knockdown, we established dysfunctional homologous recombination (HR) DNA repair pathway models in NSCLC cells. We next investigated the radiosensitization effect of fluzoparib in vivo using human NSCLC xenograft models in mice. The expression of PARP1 and BRCA1 in human NSCLC tumor samples was measured by immunohistochemistry. Furthermore, we sequenced HR-related gene mutations and analyzed their frequencies in advanced NSCLC. RESULTS: In vitro experiments in NSCLC cell lines along with in vivo experiments using an NSCLC xenograft mouse model demonstrated the radiosensitization effect of fluzoparib. The underlying mechanisms involved increased apoptosis, cell-cycle arrest, enhanced irradiation-induced DNA damage, and delayed DNA-damage repair. Immunohistochemical staining showed no correlation between the expression of PARP1 and BRCA1. Moreover, our sequencing results revealed high mutation frequencies for the BRCA1/2, CHEK2, ATR, and RAD50 genes. CONCLUSION: The potential therapeutic value of fluzoparib for increasing the radiation sensitivity of NSCLC is well confirmed. Moreover, our findings of high mutation frequencies among HR genes suggest that PARP1 inhibition may be an effective treatment strategy for advanced non-small cell lung cancer patients.

lncRNA­u50535 promotes the progression of lung cancer by activating CCL20/ERK signaling.

The ligand/receptor pair C­C motif chemokine ligand 20 (CCL20)/C­C motif chemokine receptor 6 (CCR6) is considered to be highly activated in lung cancer and significantly accelerates lung cancer progression through activation of ERK signaling. In addition, it has been shown that long non­coding RNA­u50535 (lncRNA­u50535) upregulates CCL20 expression and facilitates cancer progression in colorectal cancer (CRC). However, the effects of lncRNA­u50535 in lung cancer progression and whether lncRNA­u50535 regulates CCL20/CCR6/ERK signaling in lung cancer remain ill­defined. Therefore, the aim of the present study was to investigate the effects of lncRNA­u50535 on CCL20/CCR6/ERK signaling in lung cancer progression. The results demonstrated that lncRNA­u50535 expression was upregulated in lung cancer tissues and cell lines compared with normal tissues and cells. Knockdown of lncRNA­u50535 decreased lung cancer cell proliferation and migration, induced G0/G1 phase arrest and promoted cell apoptosis. Western blot and luciferase reporter gene assays demonstrated that lncRNA­u50535 overexpression increased the translation and transcription of CCL20. In addition, knockdown of lncRNA­u50535 decreased CCL20, CCR6 and p­ERK levels. The effects of lncRNA­u50535 on cell proliferation and cell apoptosis were weakened when CCL20 was silenced. Overall, the present study demonstrated that lncRNA­u50535 may function as an oncogene in lung cancer progression by regulating CCL20/ERK signaling.

The prognostic value of the preoperative albumin to alkaline phosphatase ratio in patients with non-small cell lung cancer after surgery.

BACKGROUND: To assess the potential prognostic value of the albumin to alkaline phosphatase ratio (AAPR) in patients with non-small cell lung cancer (NSCLC) after surgery. METHODS: The log-rank and Kaplan-Meier analyses were performed to detect differences in survival levels between different groups. A model of Cox proportional hazards was used to perform univariate and multivariate survival analyses. Comparisons of receiver operating characteristic (ROC) curves and the likelihood ratio test (LRT) were also utilized to compare the prognostic abilities of different systems for overall survival (OS) prediction. RESULTS: The optimal cut-off value of the preoperative AAPR was 0.64. A decreased AAPR was associated with several clinicopathological and clinicolaboratory variables related to cancer progression. The preoperative AAPR of patients was positively correlated with the poor prognosis of NSCLC. In multivariate analyses, the preoperative AAPR was identified as an independent prognostic factor for disease-free survival (DFS; P = 0.001) and overall survival (OS; P = 0.003). The LRT showed that the AAPR tumor-node-metastasis (TNM) system presented a significantly larger χ2 value (112.4 vs. 89.2, respectively, P < 0.01) and a relatively smaller Akaike information criterion (AIC) value (2955 vs. 2977, respectively, P < 0.01) than the TNM staging system. CONCLUSION: Preoperative AAPR was a potentially valuable prognostic factor in NSCLC patients who underwent surgery. Our results further showed that the AAPR-TNM system was superior to the current TNM staging system.

TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells.

PURPOSE: Maintaining telomeres by recruiting telomerase-to-chromosome ends is essential for cancer cell survival. Inhibiting telomerase recruitment to telomeres represents a novel strategy for telomere-based lung cancer therapy. However, approaches for interrupting telomerase recruitment for cancer therapy still need to be explored. METHODS: The telomere-binding protein TPP1 is responsible for recruiting telomerase to telomeres and synthesizing telomeres through the association between the oligosaccharide/oligonucleotide-binding (OB)-fold domain of TPP1 and telomerase reverse transcriptase. We overexpressed the TPP1 OB domain (TPP1-OB) by lentivirus infection in lung cancer cells. Telomere length was examined by Southern blot analysis of terminal restriction fragments. The effects of TPP1-OB on cell proliferation, the cell cycle, apoptosis, chemosensitivity, and tumor growth were evaluated in vitro and in vivo. RESULT: TPP1-OB inhibited the recruitment of telomerase to telomeres and shortened telomere length by acting as a dominant-negative mutant of TPP1. TPP1-OB resulted in reduced cell proliferation, G1 cell cycle arrest, and increased cell apoptosis in lung cancer cells. Cell apoptosis occurred mainly through the caspase-3-dependent signaling pathway. TPP1-OB also suppressed anchorage-independent growth and tumor growth in vivo. Moreover, we demonstrated that TPP1-OB enhances the sensitivity of lung cancer cells to the chemotherapeutic drug paclitaxel. CONCLUSION: Our results suggest that inhibiting TPP1-mediated telomerase recruitment by expressing the TPP1-OB domain is a potential novel strategy for telomere-targeted lung cancer therapy.