Prognosis Of Non-small Cell Lung Cancer Patients Research Articles

Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous reports suggested an essential role of Sulfiredoxin (Srx) in promoting the development of lung cancer in humans, and was causally related to Peroxiredoxin IV (Prx4), the major downstream substrate and mediator of Srx-enhanced signaling. To further explore the role of the Srx-Prx4 axis in de novo lung tumorigenesis, we established Prx4-/- and Srx-/-/Prx4-/- mice in pure FVB/N background. Together with wild-type litter mates, these mice were exposed to carcinogenic urethane and the development of lung tumorigenesis was evaluated. We found that disruption of the Srx-Prx4 axis, either through knockout of Srx/Prx4 alone or together, led to a reduced number and size of lung tumors in mice. Immunohistological studies found that loss of Srx/Prx4 led to reduced rate of cell proliferation and less intratumoral macrophage infiltration. Mechanistically, we found that exposure to urethane increased the levels of reactive oxygen species, activated the expression of and Prx4 in normal lung epithelial cells, while knockout of Prx4 inhibited urethane-induced cell transformation. Moreover, bioinformatics analysis found that the Srx-Prx4 axis is activated in many human cancers, and their increased expression is tightly correlated with poor prognosis in NSCLC patients.

WDR74 rs11231247 contributes to the susceptibility and prognosis of non-small cell lung cancer.

WD repeat-containing protein 74 (WDR74) has been linked with the development of lung cancer. This study aims to investigate the relationship between WDR74 rs11231247 and non-small cell lung cancer (NSCLC) susceptibility and the prognosis of NSCLC patients. UALCAN, MethPrimer, ensembl and Pancan meQTL databases were used for bioinformatics analysis. The case-control study included 462 NSCLC patients and 462 health controls. WDR74 rs11231247 genotype was determined by PCR-RFLP. Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (95% CI) for analyzing the association of WDR74 SNP with the risk of NSCLC. Log-rank test and Cox regression analysis were used to evaluate the effect of WDR74 genetic variation on the prognosis of NSCLC. Compared with normal tissues, WDR74 expression level was higher and methylation level was lower in LUAD tissues. There were two CpG islands presented in the promoter of WDR74. And rs11231247 was in the second CpG island. We then discovered that rs11231247 CC and CT were more likely modified by methylation. LUAD case-control study demonstrated that rs11231247 CC genotype was associated with NSCLC risk with OR (95%CI) of 5.29 (2.59-10.79). Stratified analysis showed that rs11231247 T>C polymorphism could increase NSCLC risk in younger subjects (age≤58) (OR = 1.64, 95%CI = 1.06-2.54, P=0.027). Survival analysis and Cox regression analysis showed rs11231247 CC genotype contributed to a poor prognosis of NSCLC patients (MST=21, HR=2.09, 95%CI=1.17-3.75). WDR74 rs11231247 polymorphism affected the risk and prognosis of NSCLC.

Dexamethasone activates c-Jun NH2-terminal kinase (JNK) which interacts with GR and protects it from ubiquitin-mediated degradation in NSCLC cells

Dexamethasone-mediated pharmacological activation of the glucocorticoid receptor (GR) is widely used in the treatment regimen of hematological malignancies and solid cancers. However, DEX sensitivity towards patients primarily depends on the endogenous protein levels of GR. We observed that DEX treatment leads to an increase in GR protein levels despite inhibition of neo-protein synthesis in non-small cell lung cancer (NSCLC) cells. Mechanistically, DEX-stimulation concomitantly increased the JNK phosphorylation and GR protein levels, however the JNK stimulation preceds GR upregulation. Moreover, we also observed that DEX-mediated phosphorylation is partially mediated by upregulation in MEKK1 phosphorylation. Further, GR protein levels were significantly decreased in JNK inhibitor (JNKi, SP600125) treated cells whereas MG132 treatment restored GR levels indicating that DEX induced JNK activity regulated the GR protein levels through proteasomal-degradation pathway. Next, we showed that DEX led to JNK activation which physically interacts with GR and protects it from ubiquitination-mediated degradation. Furthermore, at basal level GR interacts with JNK in cytoplasm whereas upon DEX stimulation GR and pJNK both localized to nucleus and interact with each other. Next, we show that JNK-mediated GR stabilization affects its nuclear transcriptional functional activity in NSCLC cells. In line with these in vitro data, patient dataset analysis also shows that increased levels of both JNK and GR contributes towards better prognosis of NSCLC patients. Taken together, our data shows that DEX treatment may lead to positive feedback regulation of GR by activating JNK and thus highlights importance of GR-JNK crosstalk in NSCLC.

Polo-like kinase (PLK) 5, a new member of the PLK family, serves as a biomarker to indicate anabatic tumor burden and poor prognosis for resectable non-small cell lung cancer.

A review argues that polo-like kinase 5 (PLK5) may be linked to unfavorable prognosis in non-small cell lung cancer (NSCLC) patients, which contradicts the discoveries from The Human Protein Atlas database (derived from TCGA analysis). This study intended to comprehensively confirm the association of PLK5 with clinical characteristics and prognosis in NSCLC patients. This two-center, retrospective, cohort study enrolled 210 NSCLC patients receiving surgical resection. PLK5 protein and mRNA were detected by immunohistochemistry and RT-qPCR in tumor and nontumor tissues. Moreover, RNA FPKM data for 994 lung cancer patients were obtained from The Human Protein Atlas database. PLK5 protein was decreased in tumor tissue compared to nontumor tissue (P < 0.001). Additionally, decreased PLK5 protein was linked with increased pathological grade (P = 0.002), lymph node metastasis presence (P = 0.001), elevated tumor-node-metastasis (TNM) stage (P = 0.003), and abnormal cancer antigen 125 (CA125) (P = 0.002). Meanwhile, low PLK5 protein was correlated with shortened disease-free survival (DFS) (P = 0.007) and overall survival (OS) (P = 0.038); further multivariable Cox regression analysis revealed that low PLK5 protein independently predicted unfavorable DFS (hazard ratio = 0.573, P = 0.022). PLK5 mRNA was reduced in tumor tissue compared with nontumor tissue (P < 0.001); its decline was linked with enhanced pathological grade (P = 0.034), climbed TNM stage (P = 0.032), and abnormal CA125 (P = 0.002). Furthermore, low PLK5 mRNA was correlated with unfavorable DFS (P = 0.046). The Human Protein Atlas database also disclosed the link between low PLK5 mRNA and worse OS (P = 0.046). A PLK5 decrement reflects anabatic tumor burden and poor prognosis in NSCLC patients.

Systematic analysis of lncRNA gene characteristics based on PD-1 immune related pathway for the prediction of non-small cell lung cancer prognosis.

Non-small cell lung cancer (NSCLC) is heterogeneous. Molecular subtyping based on the gene expression profiles is an effective technique for diagnosing and determining the prognosis of NSCLC patients. Here, we downloaded the NSCLC expression profiles from The Cancer Genome Atlas and the Gene Expression Omnibus databases. ConsensusClusterPlus was used to derive the molecular subtypes based on long-chain noncoding RNA (lncRNA) associated with the PD-1-related pathway. The LIMMA package and least absolute shrinkage and selection operator (LASSO)-Cox analysis were used to construct the prognostic risk model. The nomogram was constructed to predict the clinical outcomes, followed by decision curve analysis (DCA) to validate the reliability of this nomogram. We discovered that PD-1 was strongly and positively linked to the T-cell receptor signaling pathway. Furthermore, we identified two NSCLC molecular subtypes yielding a significantly distinctive prognosis. Subsequently, we developed and validated the 13-lncRNA-based prognostic risk model in the four datasets with high AUC values. Patients with low-risk showed a better survival rate and were more sensitive to PD-1 treatment. Nomogram construction combined with DCA revealed that the risk score model could accurately predict the prognosis of NSCLC patients. This study demonstrated that lncRNAs engaged in the T-cell receptor signaling pathway played a significant role in the onset and development of NSCLC, and that they could influence the sensitivity to PD-1 treatment. In addition, the 13 lncRNA model was effective in assisting clinical treatment decision-making and prognosis evaluation.

Efficacy and Safety of East Asian Herbal Medicine for Brain Metastases in Non-small Cell Lung Cancer: A Systematic Review and Meta-analysis Protocol to Identify Specific Herbs.

Brain metastasis (BM) is a significant risk factor for survival and prognosis in non-small cell lung cancer (NSCLC). While surgical resection and radiotherapy are the primary treatment modalities, the overall prognosis in NSCLC patients with BM remains poor, and all therapies lead to adverse events. East Asian herbal medicine (EAHM) has broad prospects as an adjuvant treatment, but its efficacy and safety remain controversial. We propose to conduct a systematic review and meta-analysis to summarize the clinical efficacy and safety of EAHM for the treatment of NSCLC with BMs and to identify specific herbs that can improve the prognosis. The PubMed, EMBASE, CENTRAL, Web of Science, CBM, CNKI, Wanfang, VIP, Evidence Reports on Kampo Treatment, ICHUSHI, and Oriental Medicine Advanced Searching Integrated System databases will be searched from their inception to October 2022. Randomized controlled trials will be included. Two authors will evaluate the eligibility and quality of the included trials. The methodological quality will be assessed using the RoB 2 tool, and Stata 16 will be used for data synthesis. Publication bias will be assessed using funnel plots and Egger tests. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system will evaluate the quality of the synthesized evidence. Further sensitivity analyses will be performed to determine the efficacies of specific herbs in EAHM. Given there are currently no systematic reviews and meta-analyses of the efficacy of EAHM as a treatment for NSCLC with BMs, a compilation and analysis of the available high-quality clinical research evidence are essential. The results will help establish guidelines for the application of specific herbs as a complementary alternative therapy for BMs in NSCLC. The findings will be published in a peer-reviewed journal. CRD42022300527.

Glycolytic Genes Predict Immune Status and Prognosis Non‐Small‐Cell Lung Cancer Patients with Radiotherapy and Chemotherapy

Non-small-cell lung cancer (NSCLC) is a major health problem that endangers human health. The prognosis of radiotherapy or chemotherapy is still unsatisfactory. This study is aimed at investigating the predictive value of glycolysis-related genes (GRGs) on the prognosis of NSCLC patients with radiotherapy or chemotherapy. Download the clinical information and RNA data of NSCLC patients receiving radiotherapy or chemotherapy from TCGA and geo databases and obtain GRGs from MsigDB. The two clusters were identified by consistent cluster analysis, the potential mechanism was explored by KEGG and GO enrichment analyses, and the immune status was evaluated by estimate, TIMER, and quanTIseq algorithms. Lasso algorithm is used to build the corresponding prognostic risk model. Two clusters with different GRG expression were identified. The high-expression subgroup had poor overall survival. The results of KEGG and GO enrichment analyses suggest that the differential genes of the two clusters are mainly reflected in metabolic and immune-related pathways. The risk model constructed with GRGs can effectively predict the prognosis. The nomogram combined with the model and clinical characteristics has good clinical application potential. In this study, we found that GRGs are associated with tumor immune status and can assess the prognosis of NSCLC patients receiving radiotherapy or chemotherapy.

Tumor Promoting Function of DUSP10 in Non-Small Cell Lung Cancer Is Associated With Tumor-Promoting Cytokines.

Lung cancer, particularly non-small cell lung cancer (NSCLC) which contributes more than 80% to totally lung cancer cases, remains the leading cause of cancer death and the 5-year survival is less than 20%. Continuous understanding on the mechanisms underlying the pathogenesis of this disease and identification of biomarkers for therapeutic application and response to treatment will help to improve patient survival. Here we found that a molecule known as DUSP10 (also known as MAPK phosphatase 5) is oncogenic in NSCLC. Overexpression of DUSP10 in NSCLC cells resulted in reduced activation of ERK and JNK, but increased activation of p38, which was associated with increased cellular growth and migration. When inoculated in immunodeficient mice, the DUSP10-overexpression NSCLC cells formed larger tumors compared to control cells. The increased growth of DUSP10-overexpression NSCLC cells was associated with increased expression of tumor-promoting cytokines including IL-6 and TGFβ. Importantly, higher DUSP10 expression was associated with poorer prognosis of NSCLC patients. Therefore, DUSP10 could severe as a biomarker for NSCLC prognosis and could be a target for development of therapeutic method for lung cancer treatment.

A study of non small cell lung cancer (NSCLC) patients with brain metastasis: A single centre experience

BackgroundLung cancer is the leading cause of cancer death with the majority of cases being non-small cell lung cancer (NSCLC) [1]. A common complication of NSCLC is brain metastasis (BM) [2, 3], where the prognosis remains poor despite new treatments. Real world data complements data gained from clinical trials, providing information on patients excluded from prospective research [4]. However, information from patient notes may prove incomplete and difficult to extract. We developed an algorithm to identify patients in our clinical database with brain metastasis from the electronic health record (EHR). MethodsWe retrospectively extracted data from the EHR of patients managed at a large teaching hospital between 2007 and 2018. Using the ICD-10 code C34, for lung cancer, our algorithm used phrases associated with BMs to search the unstructured text of radiology reports. Summary statistics and univariant analysis was performed for overall survival. Results818 patients were identified as potentially having BM and 453 patients were confirmed on clinical review of their records. The median age of patients was 69 years, 50% were female and 66% had a performance status of >2. 12.2% had an identifiable mutation and 11.5% were identified as PD-L1 positive. In the first line setting, 65% of patients received symptomatic treatment, 23% received systemic anticancer therapy (SACT), 6.1% surgery and 10% radiotherapy, of which 6.5% had external beam and 3.5% stereotactic radiosurgery. Regarding those treated with SACT, 35% had an intracranial response to treatment (3% had complete response, 32% had a partial response). Median survival was 2 months (1.9 – 2.4 months 95% CI). ConclusionThe real-world prognosis for NSCLC patients with BMs is poor. By using an algorithm, we have reported outcomes on a comprehensive cohort of patients which helps identify those for whom an active treatment approach is appropriate.

CircSCN8A suppresses malignant progression and induces ferroptosis in non-small cell lung cancer by regulating miR-1290/ACSL4 axis

ABSTRACT Circular RNAs (CircRNAs) are reported to exert vital regulatory roles in the occurrence and development of various human malignancies, including non-small cell lung cancer (NSCLC). Bioinformatics methods identified the down-regulation of circSCN8A (circBase ID: hsa_circ_0026337) in NSCLC tissues. However, its biological functions and molecular mechanisms in NSCLC remain unknown. In this study, we found that circSCN8A expression was down-regulated in NSCLC tissues and cells. Low circSCN8A expression was positively associated with aggressive clinicopathological characteristics and poor prognosis in NSCLC patients. CircSCN8A suppressed cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and blocked tumor growth in vivo. Moreover, circSCN8A promoted cell ferroptosis in NSCLC. Mechanistically, circSCN8A acted as a competing endogenous RNA (ceRNA) by sponging miR-1290 to enhance the expression of long-chain acyl-CoA synthetase-4 (ACSL4). Furthermore, the knockdown of ACSL4 or overexpression of miR-1290 reversed the effect of circSCN8A on facilitating ferroptosis and inhibiting cell proliferation and metastasis. In summary, circSCN8A represses cell proliferation and metastasis in NSCLC by regulating the miR-1290/ACSL4 axis to induce ferroptosis. Thus, circSCN8A may represent a promising therapeutic target against NSCLC.

TTI1 promotes non-small-cell lung cancer progression by regulating the mTOR signaling pathway.

The role of TELO2-interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non-small-cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK-8, wound healing, and colony formation assays. In addition, quantitative real-time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan-Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease-free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients.

Concurrent classic driver oncogenes mutation with ROS1 rearrangement predicts superior clinical outcome in NSCLC patients.

There is high mortality rate and poor prognosis in lung cancer, especially non-small-cell lung cancer (NSCLC). Recent study showed that concurrent classic driver oncogene mutation with ROS1 rearrangement was found in NSCLC patients. However, whether this would affect the development and prognosis of NSCLC is still unclear. To explore the clinical characteristics and prognosis of NSCLC patients harboring concurrent classic driver oncogene mutation with ROS1 rearrangement. A retrospective study was conducted on 220 patients diagnosed with NSCLC. All samples were screened for EGFR and KRAS using amplification-refractory mutation system assay, and for ALK, ROS1 using RT-PCR. The clinical characteristics and clinical outcomes of concurrent gene alterations with ROS1 rearrangement were analyzed. In 220 patients, 12 (5.45%) were ROS1 rearrangement, who tend to be younger, non-smokers. The mutation rates of EGFR, KRAS, ALK and ROS1 in NSCLC were 28.64%, 1.82%, 3.64% and 5.45%, respectively. ROS1 rearrangement was identified to co-occur in 5 (2.27%) NSCLC patients. ROS1/EGFR co-alterations were found in 3.17% of NSCLC patients, 16.67% of ROS1-positive NSCLC patients. Concomitant ROS1/ALK rearrangement constituted 37.50% in ALK-positive patients, and 25.00% in ROS1-positive patients. SDC4-ROS1 was the most common fusion partner in concurrent ROS1 rearrangement patients. The median overall survival of NSCLC with concurrent ROS1 rearrangement group and single ROS1 rearrangement group were 25 months and 14 months. Concurrent driver oncogenes mutation with ROS1 rearrangement defines a unique subgroup of NSCLC. Patients with concomitant ROS1 rearrangement might have a better prognosis.

Radiosensitization-Related Cuproptosis LncRNA Signature in Non-Small Cell Lung Cancer.

A new treatment modality targeting cuproptosis is gradually entering the public horizon. Cuproptosis is a new form of regulated cell death distinct from ferroptosis, apoptosis, autophagy, and necrosis. Previous studies have discovered that the copper level varies considerably in various cancers and that an increase in copper content is directly associated with the proliferation and metastasis of cancer cells. In non-small cell lung cancer (NSCLC) after radiation, the potential utility of cuproptosis-related long noncoding RNAs (lncRNAs) is still unclear. This research aimed to develop a prediction signature based on lncRNAs associated with cuproptosis to predict the prognosis of NSCLC patients following radiation. Methods: Expression data of primary tumors and adjacent solid tissues were downloaded from The Cancer Genome Atlas (TCGA) database, along with the corresponding clinical and mutational data. Univariate and multivariate COX analyses and LASSO regression analyses were performed to obtain a predictive signature of lncRNAs associated with cuproptosis. The data were randomly grouped into a training group used for model construction and a test group used for model validation. The model was validated by drawing a survival curve, risk curve, independent prognostic analysis, ROC curve PFS analysis, etc. Results: The lncRNA signature consisting of six cuproptosis-related lncRNAs (AC104088.1, PPP4R3B-DT, AC006042.3, LUCAT1, HHLA3-AS1, and LINC02029) was used to predict the prognosis of patients. Among them, there were three high-risk lncRNAs (LUCAT1, HHLA3-AS1, and LINC02029) with HR > 1 and three protective lncRNAs (AC104088.1, PPP4R3B-DT, and AC006042.3), with an HR < 1. Data analysis demonstrated that the cuproptosis-related lncRNA signatures could well predict the prognosis of NSCLC patients after radiation. Patients in the high-risk category receive a worse prognosis than those in the low-risk group. Cuproptosis-related risk prediction demonstrated better predictive qualities than age, gender, and pathological stage factors. Conclusion: The risk proposed model can independently predict the prognosis of NSCLC patients after radiotherapy, provide a foundation for the role of cuproptosis-related lncRNAs in NSCLC after radiotherapy, and provide a clinical strategy for radiotherapy combined with cuproptosis in NSCLC patients.

CRISPR-based DNA methylation editing of NNT rescues the cisplatin resistance of lung cancer cells by reducing autophagy.

Cisplatin is recommended as a first-line chemotherapeutic agent against advanced non-small cell lung cancer (NSCLC), but acquired resistance substantially limits its clinical efficacy. Recently, DNA methylation has been identified as an essential contributor to chemoresistance. However, the precise DNA methylation regulatory mechanism of cisplatin resistance remains unclear. Here, we found that nicotinamide nucleotide transhydrogenase (NNT) was silenced by DNA hypermethylation in cisplatin resistance A549 (A549/DDP) cells. Also, the DNA hypermethylation of NNT was positively correlated to poor prognosis in NSCLC patients. Overexpression of NNT in A549/DDP cells could reduce their cisplatin resistance, and also suppressed their tumor malignancy such as cell proliferation and clone formation. However, NNT enhanced sensitivity of A549/DDP cells to cisplatin had little to do with its function in mediating NADPH and ROS level, but was mainly because NNT could inhibit protective autophagy in A549/DDP cells. Further investigation revealed that NNT could decrease NAD+ level, thereby inactivate SIRT1 and block the autophagy pathway, while re-activation of SIRT1 through NAD+ precursor supplementation could antagonize this effect. In addition, targeted demethylation of NNT CpG island via CRISPR/dCas9-Tet1 system significantly reduced its DNA methylation level and inhibited the autophagy and cisplatin resistance in A549/DDP cells. Thus, our study found a novel chemoresistance target gene NNT, which played important roles in cisplatin resistance of lung cancer cells. Our findings also suggested that CRISPR-based DNA methylation editing of NNT could be a potential therapeutics method in cisplatin resistance of lung cancer.

Comprehensive analysis of the immunological implication and prognostic value of CXCR4 in non-small cell lung cancer

CXCR4 (C-X-C chemokine receptor type 4) is the most commonly expressed of all chemokine receptors in malignant tumors. However, studies on CXCR4 in non-small cell lung cancer (NSCLC) tumor immune microenvironment, including those determining its immune efficacy and prognostic potential, are still scarce. Therefore, in this study, we determined the ability of CXCR4 to predict immunotherapy response and prognosis in NSCLC using immunohistochemical staining and RT-PCR, respectively, in two independent cohorts from the National Cancer Center of China. We analyzed transcriptome sequencing data and clinical information from multiple public databases to assess immune cell infiltration in NSCLC and constructed immune risk prognostic signatures based on CXCR4-related immunomodulators. We found that immune cell infiltration is significant differences in NSCLC tissues and is moderately correlated with CXCR4 expression. High CXCR4 expression was significantly associated with poor prognosis in NSCLC patients and a higher response rate to immunotherapy. The ROC curve showed that CXCR4 expression exhibited excellent performance in predicting the efficacy of immunotherapy in NSCLC. We identified 30 CXCR4-related immunomodulators in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and constructed immune prognostic signatures based on CXCR4-related immunomodulators and CXCR4-related mutant genes. The signature-based prognostic risk score showed good performance in predicting patient prognosis in both LUAD and LUSC; high risk scores were significantly associated with poor prognosis (P < 0.0001) and was established as an independent prognostic factor by multivariate Cox regression. We postulate that CXCR4 is a potential predictive marker of immunotherapy efficacy in NSCLC and should be used in clinical settings. Moreover, the constructed signatures may be valuable in predicting patient prognosis in NSCLC.

Construction of a B cell-related gene pairs signature for predicting prognosis and immunotherapeutic response in non-small cell lung cancer.

Accumulating evidence indicates that the B cells play important roles in anti-tumor immunity and shaping tumor development. This study aimed to explore the expression profiles of B cell marker genes and construct a B cell-related gene pairs (BRGPs) signature associated with the prognosis and immunotherapeutic efficiency in non-small cell lung cancer (NSCLC) patients. B cell-related marker genes in NSCLC were identified using single-cell RNA sequencing data. TCGA and GEO datasets were utilized to identify the prognostic BRGPs based on a novel algorithm of cyclically single pairing along with a 0-or-1 matrix. BRGPs signature was then constructed using Lasso-Cox regression model. Its prognostic value, associated immunogenomic features, putative molecular mechanism and predictive ability to immunotherapy were investigated in NSCLC patients. The BRGPs signature was composed of 23 BRGPs including 28 distinct B cell-related genes. This predictive signature demonstrated remarkable power in distinguishing good or poor prognosis and can serve as an independent prognostic factor for NSCLC patients in both training and validation cohorts. Furthermore, BRGPs signature was significantly associated with immune scores, tumor purity, clinicopathological characteristics and various tumor-infiltrating immune cells. Besides, we demonstrated that the tumor mutational burden scores and TIDE scores were positively correlated with the risk score of the model implying immune checkpoint blockade therapy may be more effective in NSCLC patients with high-risk scores. This novel BRGPs signature can be used to assess the prognosis of NSCLC patients and may be useful in guiding immune checkpoint inhibitor treatment in our clinical practice.

LINC02389/miR-7-5p Regulated Cisplatin Resistance of Non-Small-Cell Lung Cancer via Promoting Oxidative Stress.

Background Non-small-cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and cisplatin-based chemotherapy is the main treatment for NSCLC. However, cisplatin resistance of NSCLC cells is a major challenge for NSCLC treatment. Materials and Methods qRT-PCR and Western blot were performed to detect the expression of LINC02389 and miR-7-5p in NSCLC tissues and cell lines. Cell counting kit-8 (CCK-8) assay and flow cytometry assay were applied to exam cell proliferation and apoptosis rate of NSCLC cells. The interaction between LINC02389 and miR-7-5p was verified by dual luciferase reporter gene assay, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay. Additionally, cisplatin-resistant NSCLC cells were generated to assess the biological function of LINC02389 and miR-7-5p in cisplatin resistance of NSCLC. Results LINC02389 was highly expressed in NSCLC tissues and was correlated with poor prognosis of NSCLC patients. Knockdown of LINC02389 inhibited cell proliferation and promoted cell apoptosis of NSCLC, whereas miR-7-5p knockdown exerted the opposite effects. Moreover, LINC02389 negatively regulated the expression of miR-7-5p. In addition, LINC02389 was overexpressed, yet miR-7-5p was downregulated in cisplatin-resistant NSCLC cells compared with their parental cells. Moreover, oxidative stress biomarkers were overexpressed in cisplatin-resistant cells and were regulated by LINC02389. Besides, LINC02389 could reverse the inhibitory effect of cisplatin on NSCLC cells, which was partially reversed by attenuating the expression of miR-7-5p. Conclusion Our research firstly demonstrated that lncRNA LINC02389 acted as an oncogene to promote progression, oxidative stress, and cisplatin resistance through sponging miR-7-5p and may provide therapeutic targets for NSCLC.

Prognostic value of plasma D-dimer levels in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: a retrospective study.

Plasma D-dimer is of great significance for the clinical exclusion of tumor-related thrombosis. Previous studies have shown its predictive role in non-small cell lung cancer (NSCLC) treated with chemotherapy. However, whether pretreatment D-dimer could predict the efficacy and prognosis in NSCLC patients treated with immune checkpoint inhibitors (ICIs) remains unclear. Advanced NSCLC patients treated with ICIs at the Chinese PLA General Hospital between January 2015 and March 2019 were enrolled. Patients were divided into a pretreatment normal D-dimer group (≤0.5 µg/mL) and high D-dimer group (>0.5 µg/mL). Optimization-based approach was applied to balance baseline covariates between the 2 groups, including age, sex, histological type, smoking history, stage, Eastern Cooperative Oncology Group Performance Status (ECOG PS), lines of treatment, ICI drugs, brain metastasis, treatment type, and D-dimer levels. Kaplan-Meier analysis and Cox proportional hazards model were used for analyzing survival data, including progression-free survival (PFS, the time from initial ICI treatment to PD or death), overall survival (OS, the time between initial ICI treatment and death), and hazard ratio (HR). Follow-up of all patients was performed by searching electronic medical records and counseling telephone. The follow-up cut-off date was July 6, 2020. This study included 277 advanced NSCLC patients. Among the enrolled patients, 23.1% were female, 64.6% had non-squamous cell lung cancer, and 79.4% were stage IV. Univariate and multivariate analysis showed that pretreatment high D-dimer levels were independently associated with shortened PFS and OS (P<0.01). Subgroup analysis confirmed that pretreatment high D-dimer levels were associated with poor prognosis in most subsets. After balancing baseline covariates between the high D-dimer group and normal D-dimer group, the results indicated that patients with pretreatment high D-dimer levels had significantly shorter PFS [median: 6.4 vs. 11.5 months; HR, 1.70; 95% confidence ratio (CI): 1.25-2.37; P<0.001] and OS (median: 12.7 vs. 30.4 months; HR, 2.29; 95% CI: 1.54-3.41; P<0.001) than those with pretreatment normal D-dimer levels. Pretreatment plasma D-dimer could serve as a convenient prognostic biomarker for advanced NSCLC patients receiving ICI treatment. Patients with pretreatment high D-dimer levels may have poor PFS and OS.

Survival and prognostic factors in patients undergoing the resection of solitary brain metastasis from non-small cell lung cancer: a retrospective cohort study.

Neurosurgery is the standard of care for resectable solitary brain metastasis (BM) from non-small cell lung cancer (NSCLC), but still with a poor outcome. Postoperative whole-brain radiotherapy (WBRT) was reported to reduce local recurrence, whether it could prolong survival was uncertain. In this study, we attempted to evaluate WBRT and other prognostic for overall survival (OS) in these patients. In this retrospective study, NSCLC patients with a solitary BM and controlled primary tumor who underwent neurosurgical resection were selected from the medical records database between January 2014 and December 2018. Clinical data, disease control/progression results and survival outcomes were obtained from the medical records, regular outpatient follow-up and telephone interviews. Univariable and multivariable Cox analyses of potential prognostic factors including patients' characteristics, BM features, tissue-based parameters and postoperative treatments were conducted. OS was illustrated using Kaplan-Meier curves, and group differences were assessed using the log-rank test. The subgroup analysis compared each variable between the WBRT group and the untreated control by the hazard ratio and its 95% confidence interval (CI). A total of 94 patients were included, with a median OS of 812 days. Univariable analysis showed that postoperative WBRT and targeted therapy were associated with OS. Multivariable analysis demonstrated that postoperative WBRT [P<0.001, hazard ratio (HR) 0.357], chemotherapy (P=0.008, HR 0.512), targeted therapy (P<0.001, HR 0.265), and smaller tumor size (P=0.018, HR 0.553) were independent prognostic factors for prolonged OS. However, tissue-based parameters (Ki67 tumor cell proliferation index, epidermal growth factor receptor, and checkpoint levels) were identified as statistically insignificant factors. In the subgroup analysis, the beneficial effect of WBRT was only observed in patients that did not receive systematic treatments. Postoperative WBRT and systematic treatments after solitary BM resection improve the prognosis of NSCLC patients with a controlled primary tumor. Postoperative WBRT could be considered, especially for those who not receive systematic chemotherapy or targeted therapy treatments, as they might be more likely to benefit from it.

A miR-15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum-based chemotherapy.

Platinum-based chemotherapy is regarded as a preferential curative-intent option for non-small cell lung cancer (NSCLC), while the acquired drug resistance has become a major obstacle that limits its clinical application. Since the repair efficiency of tumour cells to platinum-DNA adducts plays a crucial role in chemotherapy resistance, we aimed to explore whether several meaningful polymorphisms of DNA repair genes were associated with the benefits of platinum-based chemotherapy in NSCLC patients. Firstly, six single nucleotide polymorphisms (SNPs) located in the 3'untranslated region (3'UTR) of three DNA repair genes were detected in 246 NSCLC patients receiving platinum-based chemotherapy and analysed the correlation of these candidate SNPs with the overall survival. Cox proportional hazard model showed that NSCLC patients carrying ERCC1 rs3212986 AA genotype had a shorter overall survival compared to those with CC. Mechanistically, we performed tumour chemosensitivity assay to observe the convincing linkage of rs3212986 polymorphism with ERCC1 expression and cisplatin sensitivity. The subsequent in vitro experiments identified that rs3212986 polymorphism altered the post-transcriptional regulation of ERCC1 via affecting the binding of miR-15a, and further changed the sensitivity to platinum analogue. It reminded that patients carrying ERCC1 rs3212986 CC homozygote were expected to respond better to platinum-based chemotherapy due to a lower expression of ERCC1. Compared with previous studies, our current comprehensive study suggested that rs3212986, a 3'UTR polymorphism in ERCC1, might have clinical relevance in predicting the prognosis of NSCLC patients receiving platinum-based chemotherapy.