Lung Squamous Cell Carcinoma Research Articles

Plasma extracellular vesicle long RNA profiling identifies a predictive signature for immunochemotherapy efficacy in lung squamous cell carcinoma.

The introduction of Immune Checkpoint Inhibitors (ICIs) has marked a paradigm shift in treating Lung Squamous Cell Carcinoma (LUSC), emphasizing the urgent need for precise molecular biomarkers to reliably forecast therapeutic efficacy. This study aims to identify potential biomarkers for immunochemotherapy efficacy by focusing on plasma extracellular vesicle (EV)-derived long RNAs (exLRs). We enrolled 78 advanced LUSC patients undergoing first-line immunochemotherapy. Plasma samples were collected, and exLR sequencing was conducted to establish baseline profiles. A retrospective analysis was performed on 42 patients to identify differentially expressed exLRs. Further validation of the top differentially expressed exLRs was conducted using quantitative reverse transcription PCR (qRT-PCR). Univariate Cox analysis was applied to determine the prognostic significance of these exLRs. Based on these findings, we developed a predictive signature (p-Signature). In the retrospective analysis of 42 patients, we identified 460 differentially expressed exLRs, with pathways related to leukocyte migration notably enriched among non-responders. Univariate Cox analysis revealed 45 exLRs with prognostic significance. The top 6 protein-coding exLRs were validated using qRT-PCR, identifying CXCL8, SSH3, and SDHAF1 as differentially expressed between responders and non-responders. The p-Signature, comprising these three exLRs, demonstrated high accuracy in distinguishing responders from non-responders, with an Area Under the Curve (AUC) of 0.904 in the retrospective cohort and 0.812 in the prospective cohort. This study highlighted the potential of plasma exLR profiles in predicting LUSC treatment efficacy. Intriguingly, lower p-Signature scores were associated with increased abundance of activated CD4+ and CD8+ T cells, indicating a more robust immune environment. These findings suggest that the p-Signature could serve as a valuable tool in guiding personalized and effective therapeutic strategies for LUSC.

ASO Visual Abstract: Clinical Significance of SIRPα Expression on Tumor-Associated Macrophages in Patients with Lung Squamous Cell Carcinoma.

ASO Visual Abstract: Clinical Significance of SIRPα Expression on Tumor-Associated Macrophages in Patients with Lung Squamous Cell Carcinoma.

Volatile organic compounds in exhaled breath: a promising approach for accurate differentiation of lung adenocarcinoma and squamous cell carcinoma

Lung cancer subtyping, particularly differentiating adenocarcinoma (ADC) from squamous cell carcinoma (SCC), is paramount for clinicians to develop effective treatment strategies. In this study, we aimed: (i) to discover volatile organic compound (VOC) biomarkers for precise diagnosis of ADC and SCC, (ii) to investigated the impact of risk factors on ADC and SCC prediction, and (iii) to explore the metabolic pathways of VOC biomarkers. Exhaled breath samples from patients with ADC (n= 149) and SCC (n= 94) were analyzed by gas chromatography-mass spectrometry. Both multivariate and univariate statistical analysis method were employed to identify VOC biomarkers. Support vector machine (SVM) prediction models were developed and validated based on these VOC biomarkers. The impact of risk factors on ADC and SCC prediction was investigated. A panel of 13 VOCs was found to differ significantly between ADC and SCC. Utilizing the SVM algorithm, the VOC biomarkers achieved a specificity of 90.48%, a sensitivity of 83.50%, and an area under the curve (AUC) value of 0.958 on the training set. On the validation set, these VOC biomarkers attained a predictive power of 85.71% for sensitivity and 73.08% for specificity, along with an AUC value of 0.875. Clinical risk factors exhibit certain predictive power on ADC and SCC prediction. Integrating these risk factors into the prediction model based on VOC biomarkers can enhance its predictive accuracy. This work indicates that exhaled breath holds the potential to precisely detect ADCs and SCCs. Considering clinical risk factors is essential when differentiating between these two subtypes.

From Tumor Macroenvironment to Tumor Microenvironment: The Prognostic Role of the Immune System in Oral and Lung Squamous Cell Carcinoma.

The interplay between cancer cells and the immune system is crucial in cancer progression and treatment. In this regard, the tumor immune microenvironment and macroenvironment, marked by systemic inflammation markers and TILs, could be considered key prognostic factors in tumors, including oral and lung squamous cell carcinoma. We conducted a retrospective clinical study on patients with Oral Squamous Cell Carcinoma (OSCC) and Lung Squamous Cell Carcinoma (LUSCC), examining stages, comorbidities, treatments, and outcomes. We evaluated the prognostic significance of pre-surgical systemic inflammation markers and tumor microenvironment composition. Associations were found between systemic inflammation markers-NLR, MLR, and PLR-and tumor microenvironment factors, such as TILs and CD8+ cell prevalence-elevated inflammation markers correlated with advanced stages. Specifically, NLR was prognostic in OSCC, whereas PLR was prognostic in LUSCC. Using a cutoff value, we divided our tumor samples into two prognostic groups. Moreover, TILs levels >15% of tumor stroma correlated with prolonged overall survival in both OSCC and LUSCC, while increased CD8+ expression was linked to extended disease-free survival in LUSCC. Systemic inflammation markers and TILs can be valuable prognostic factors of survival, highlighting the immune response's role in OSCC and LUSCC. Despite limited clinical integration of the presented cohorts due to a lack of standardization, we concluded that analyzing tumor immune profiles may offer novel prognostic insights. Future integration into cancer classification could improve risk stratification and treatment guidance.

Identifying the keyhub genes linked with lung squamous cell carcinoma by examining the differentially expressed and survival genes.

Lung Squamous Cell Carcinoma is characterised by significant alterations in RNA expression patterns, and a lack of early symptoms and diagnosis results in poor survival rates. Our study aimed to identify the hub genes involved in LUSC by differential expression analysis and their influence on overall survival rates in patients. Thus, identifying genes with the potential to serve as biomarkers and therapeutic targets. RNA sequence data for LUSC was obtained from TCGA and analysed using R Studio. Survival analysis was performed on DE genes. PPI network and hub gene analysis was performed on survival-relevant genes. Enrichment analysis was conducted on the PPI network to elucidate the functional roles of hub genes. Our analysis identified 2774 DEGs in LUSC patient datasets. Survival analysis revealed 511 genes with a significant impact on patient survival. Among these, 20 hub genes-FN1, ACTB, HGF, PDGFRB, PTEN, SNAI1, TGFBR1, ESR1, SERPINE1, THBS1, PDGFRA, VWF, BMP2, LEP, VTN, PXN, ABL1, ITGA3 and ANXA5-were found to have lower expression levels associated with better patient survival, whereas high expression of SOX2 correlated with longer survival. Enrichment analysis indicated that these hub genes are involved in critical cellular and cancer-related pathways. Our study has identified six key hub genes that are differentially expressed and exhibit significant influence over LUSC patient survival outcomes. Further, in vitro and in vivo studies must be conducted on the key genes for their utilisation as therapeutic targets and biomarkers in LUSC.

FAM65A promotes the progression and growth of lung squamous cell carcinoma in vivo and vitro

BackgroundsCurrently, family with sequence similarity 65 member A (FAM65A) is reported as a pivotal regulator in various cancers. However, the effect of FAM65A in lung squamous cell carcinoma (LSCC) is still unclear, the prime objective of this research is to explore the role of FAM65A in LSCC.MethodsGene expression data and correlated clinical information were downloaded from the public database and the expression of FAM65A was detected. The expression of FAM65A was also detected in our collected clinical samples and LSCC cell lines. Survival package of R language was used to determine the survival significance of FAM65A. Proteins expression level was determined via western blot assay. Cell function experiments and in vivo experiments were performed to explore the effect of FAM65A on LSCC cell biological behaviors.ResultsFAM65A expression was significantly increased in LSCC clinical samples and cell lines. High FAM65A expression predicted poor prognosis in LSCC patients. After silencing FAM65A, the ability of LSCC cell proliferation, invasion and migration was decreased, and LSCC cell cycle was blocked. Moreover, in vivo experiments revealed that silencing FAM65A could inhibit LSCC cell proliferation.ConclusionsHigh FAM65A expression could enhance proliferative, invasive and migratory abilities of LSCC. FAM65A might be a novel biomarker of LSCC.

Toll-like Receptors: Key Players in Squamous Cell Carcinoma Progression.

Background/Objectives Lung squamous cell carcinoma (SCC) is one of the major subtypes of lung cancer, characterized by diverse molecular pathways and variable clinical outcomes. This study focused on assessing the levels of TLR-2, TLR-3, TLR-4, TLR-7, TLR-8, and TLR-9 on peripheral blood lymphocytes in patients with newly diagnosed SCC compared to a group of healthy controls, in the context of disease development and patient survival, conducted over three years. The study aimed to investigate the differences in TLR expression between SCC patients and healthy people and to understand their role in the development of the disease and patient survival over three years. Methods: The study included the assessment of TLR-2, TLR-3, TLR-4, TLR-7, TLR-8, and TLR-9 levels on peripheral blood lymphocytes in patients with newly diagnosed SCC and in the control group. The expression of TLRs was measured using flow cytometry, and the soluble forms of the tested TLRs were measured using enzyme-linked immunosorbent assays. All the analyses were conducted over a three-year period from the time patients were recruited to the study. The obtained test results were statistically analyzed. Results: Results showed statistically significant differences in TLR expression between the groups, with higher TLR levels correlating with an advanced stage of disease and poorer survival rates. This suggests that the deregulation of TLR levels may be involved in promoting tumor development and influencing its microenvironment. Conclusions: The research, conducted over three years, indicates the need for further research on the role of TLRs in SCC, including their potential use as therapeutic targets and biomarkers. This may help to increase the effectiveness of standard treatments and improve clinical outcomes in patients with SCC.

Spatial profiling of non-small cell lung cancer provides insights into tumorigenesis and immunotherapy response

Lung cancer is the second most common cancer worldwide and a leading cause of cancer-related deaths. Despite advances in targeted therapy and immunotherapy, the prognosis remains unfavorable, especially in metastatic cases. This study aims to identify molecular changes in non-small cell lung cancer (NSCLC) patients based on their response to treatment. Using tumor and matched immune cell rich peritumoral tissues, we perform a retrospective, comprehensive spatial transcriptomic analysis of a proven malignant NSCLC sample treated with immune checkpoint inhibitor (ICI). In addition to T cells, other immune cell types, such as B cells and macrophages, were also activated in responders to ICI treatment. In particular, B cells and B cell-mediated immunity pathways are consistently found to be activated. Analysis of the histologic subgroup (lung squamous cell carcinoma, LUSC; lung adenocarcinoma, LUAD) of NSCLC also confirms activation of B cell mediated immunity. Analysis of B cell subtypes shows that B cell subtypes were more activated in immune cell-rich tissues near tumor tissue. Furthermore, increased expression of B cell immunity-related genes is associated with better prognosis. These findings provide insight into predicting ICI treatment responses and identifying appropriate candidates for immunotherapy in NSCLC patients.

Single-cell transcriptome analysis deciphers the CD74-mediated immune evasion and tumour growth in lung squamous cell carcinoma with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) contributes to the incidence and prognosis of lung cancer. The presence of COPD significantly increases the risk of lung squamous cell carcinoma (LSCC). COPD may promote an immunosuppressive microenvironment in LSCC by regulating the expression of immune-inhibitory factors in T cells, although the mechanisms remain unclear. In this study, we aimed to decipher the tumour microenvironment signature for LSCC with COPD at a single-cell level. We performed single-cell RNA sequencing on tumour tissues from LSCC with or without COPD, then investigated the features of the immune and tumour cells. We employed multiple techniques, including multispectral imaging, flow cytometry, tissue microarray analysis, survival analysis, co-culture systems and in vitro and in vivo treatment experiments, to validate the findings obtained from single-cell analyses. LSCC with COPD showed increased proportions of tumour-associated macrophages (TAMs) and higher levels of CD8+ T cell exhaustion molecules, which contributed to an immunosuppressive microenvironment. Further analysis revealed a critical cluster of CD74+ tumour cells that expressed both epithelial and immune cell signatures, exhibited a stronger capacity for tumorigenesis and predicted worse overall survival. Notably, migration inhibitory factor (MIF) secreted by TAMs from LSCC with COPD may promote the activation of CD74. MIF-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-programmed cell death-1 ligand 1 signalling pathway, facilitating tumour proliferation and immune evasion. Our comprehensive picture of the tumour ecosystem in LSCC with COPD provides deeper insights into relevant immune evasion mechanisms and potential targets for immunotherapy. Our results demonstrated higher proportions of tumour-associated macrophages (TAMs) and higher levels of exhaustion molecules in CD8+ T cells in the microenvironment of LSCC with COPD. CD74+tumour cells were associated with poor disease prognosis. Migration inhibitory factor (MIF)-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-PD-L1 signalling pathway, facilitating immune evasion.

Bioinformatic Analysis Reveals Bone Marrow Kinase as a Potential Diagnostic and Prognostic Biomarker for Multiple Cancer Types.

Bone marrow kinase, or BMX, is alternatively referred to as endothelial tyrosine kinase (Etk). It plays a vital role in the processes of cell proliferation, survival, immune activation, and the modulation of diverse signaling pathways. Since there are few direct comprehensive studies linkingBMX role with multiple cancers, this study aimed to utilize bioinformatic tools to conduct a comprehensive analysis of BMX across multiple cancers, assessing its potential role. Multiple databases including the Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), and University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), have been used to explore BMX expression across different cancers, which has been further validated by using Gene Expression Omnibus (GEO) public datasets. In addition, we used the Kaplan-Meier plotter to estimate overall survival and cBioPortal for genetic alterations analysis. This study accommodates several other analyses like clinical parameters, immune cell infiltration, and DNA promoter methylation profiles to evaluate the general role of BMXin several cancers. Results: The present investigation revealed that the BMX gene expression was significantly downregulated and could serve as an effective diagnostic biomarker in five types of cancers, namely breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and rectum adenocarcinoma (READ) (all p < 0.05). Detailed analyses revealed notable downregulation of BMX in various clinical parameters such as age, gender, race, and cancer stage (all p < 0.05). To better understand the immunotherapeutic role of BMX, this investigation further examined the immune infiltration which exhibited positive correlations between BMX expression and the infiltration of immunological cells such as B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells, especially in COAD, LUAD, and LUSC(all p < 0.05).In addition, the present study has demonstrated that diminished BMX gene expression is correlated with an unfavorable prognosis in kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), sarcoma (SARC), and uterine corpus endometrial carcinoma (UCEC); thus BMX gene expression can be used as a prognostic target for these specific cancers. Also, the results showed that the promoter methylation level of BMX was significantly elevated in LUAD and LUSC, whereas it was significantly decreased in BRCA (all p < 0.001). Importantly, our findings of significantly low BMX expression inLUAD and LUSC, along with their methylation profiles suggest that the low expression of BMX across these cancers is due to epigenetic factors. However, genetic alteration analysis revealed that mutations existed in only approximately 2% of the TCGA samples. Our study revealed BMX as a diagnostic biomarker in BRCA, COAD, LUAD, LUSC, and READ and a prognostic biomarker in KIRC, LIHC, SARC, and UCEC. Furthermore, epigenetic variables may have a greater impact on BMX expression levels especially in LUAD and LUSC. This study also emphasized the role of BMX in the infiltration of immune cells, such as B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells, in certain cancers. The BMX expression level highlights the prognostic value and potential therapeutic potential of BMX.

FOXA2 Activates RND1 to Regulate Arachidonic Acid Metabolism Pathway and Suppress Cisplatin Resistance in Lung Squamous Cell Carcinoma.

The primary cause of cancer-related fatalities globally is lung cancer. Although the chemotherapy drug cisplatin (DDP) has brought certain benefits to patients, the rapid development of drug resistance has greatly hindered treatment success. We used the lung squamous cell carcinoma (LUSC) mRNA data set to explore the differentially expressed gene (RND1) in LUSC and detected RND1 expression in LUSC cells and DDP-resistant cells by qRT-PCR. Meanwhile, we performed abnormal expression treatment on RND1 and conducted CCK8, colony formation, and flow cytometry to evaluate the impact of RND1 expression on cell proliferation, apoptosis, and DDP resistance. In addition, we analyzed metabolism pathways involving RND1 using GSEA. We also used online tools such as hTFtarget and JASPAR to screen for the upstream transcription factor FOXA2 of RND1 and verified their relationship through CHIP and dual luciferase experiments. Finally, we validated the role of FOXA2-RND1 in DDP resistance in LUSC through the above experiments. RND1 was downregulated in LUSC, and overexpression of RND1 repressed proliferation and DDP resistance of LUSC cells and facilitated cell apoptosis. RND1 modulated the arachidonic acid (AA) metabolism pathway, and FOXA2 positively manipulated RND1 expression. By activating FOXA2, stabilizing RND1, and regulating AA levels, the sensitivity of LUSC cells to DDP could be enhanced. Our study suggested that FOXA2 positively modulated the RND1-AA pathway, which repressed the resistance of LUSC cells to DDP.

Development of a disulfidptosis-related lncRNA prognostic signature for enhanced prognostic assessment and therapeutic strategies in lung squamous cell carcinoma

Limited treatment options and poor prognosis present significant challenges in the treatment of lung squamous cell carcinoma (LUSC). Disulfidptosis impacts cancer progression and prognosis. We developed a prognostic signature using disulfidptosis-related long non-coding RNAs (lncRNAs) to predict the prognosis of LUSC patients. Gene expression matrices and clinical information for LUSC were downloaded from the TCGA database. Co-expression analysis identified 209 disulfidptosis-related lncRNAs. LASSO-Cox regression analysis identified nine key lncRNAs, forming the basis for establishing a prognostic model. The model’s validity was confirmed by Kaplan–Meier and ROC curves. Cox regression analysis identified the risk score (RS) as an independent prognostic factor inversely correlated with overall survival. A nomogram based on the RS demonstrated good predictive performance for LUSC patient prognosis. The relationship between RS and immune function was explored using ESTIMATE, CIBERSORT, and ssGSEA algorithms. According to the TIDE database, a negative correlation was found between RS and immune therapy responsiveness. The GDSC database revealed that 49 drugs were beneficial for the low-risk group and 25 drugs for the high-risk group. Silencing C10orf55 expression in SW900 cells reduced invasiveness and migration potential. In summary, this lncRNA model based on TCGA-LUSC data effectively predicts prognosis and assists clinical decision-making.

Specific association of MTHFD1 expressions with small cell lung cancer development and chemoradiotherapy outcome.

To identify biomarkers that can discriminated small cell lung cancer (SCLC) from non-SCLC (NSCLC), and explore their association with the prognosis of SCLC under chemoradiotherapy. The GSE40275 dataset was used to identify potential targets in SCLC. There were 196 patients of lung cancer (LC) in cohort 1 of this study. MTHFD1 levels in tissues were determined by immunohistochemistry assay in cohort 1. Lung cancer patients who were all underwent local chemoradiotherapy (CRT) were included in cohort 2, and the association of MTHFD1 levels with CRT treatment outcome were determined in cohort 2. Cell experiments were used to determine the function of MTHFD1 on the radio-sensitivity of SCLC and NSCLC cells. The MTHFD1 levels in LC tissues were increased, and could discriminate SCLC from both lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). Small cell lung cancer patients with MTHFD1 high phenotype had a poorer prognosis after CRT treatment, whereas no significant correlation was found between MTHFD1 levels and prognosis in LUSC and LUAD group. Cell experiments demonstrated that overexpression of MTHFD1 increases radio-resistance in both SCLC and NSCLC in vitro. MTHFD1 expressions might be a novel specifically prognostic biomarker for SCLC and the CRT treatment outcome.

A gene set enrichment analysis for the cancer hallmarks

The "hallmarks of cancer" concept provides a valuable framework for understanding fundamental organizing principles common to various cancers. However, without a consensus gene set for cancer hallmarks, data comparison and integration result in diverse biological interpretations across studies. Therefore, we aimed to form a consensus cancer hallmark gene set by merging data from available mapping resources and establishing a framework for mining these gene sets. By consolidating data from seven projects, 6,763 genes associated with ten cancer hallmarks were identified. A cancer hallmarks enrichment analysis was performed for prognostic genes associated with overall survival across twelve types of solid tumors. "Tissue invasion and metastasis" was most prominent in cancers of the stomach (P = 2.2×10−11), pancreas (P = 4.2×10−9), bladder (P = 3.3×10−8), and ovaries (P = 0.0007), aligning with their heightened potential to spread. "Sustained angiogenesis" was most prominent in squamous cell carcinomas of the lung (P = 2.5×10−7), while "genome instability" showed strong enrichment in lung adenocarcinomas (P = 1.5×10−8) and cancers of the liver (P = 5.5×10−10), pancreas (P = 2.1×10−5), and kidney (P = 0.018). Pancreatic cancers displayed the highest enrichment of hallmarks, emphasizing the disease's complexity, while in melanomas, and cancers of the liver, prostate, and kidney, a single hallmark was enriched among the prognostic markers of survival. Additionally, an online tool (www.cancerhallmarks.com) that allows the identification of cancer-associated hallmarks from new gene sets was established. In summary, our aim of establishing a consensus list of cancer hallmark genes was achieved. Furthermore, the analysis of survival-associated genes revealed a unique pattern of hallmark enrichment with potential pharmacological implications in different tumor types.

RETRACTION: Elevated GAPDH expression is associated with the proliferation and invasion of lung and esophageal squamous cell carcinomas.

Hao, L., Zhou, X., Liu, S., Sun, M., Song, Y., Du, S., Sun, B., Guo, C., Gong, L., Hu, J., Guan, H., Shao, S. (2015). Elevated GAPDH expression is associated with the proliferation and invasion of lung and esophageal squamous cell carcinomas, Proteomics, 15(17), 3087-3100. https://doi.org/10.1002/pmic.201400577 The above article, published online on May 6, 2015 in Wiley Online Library (wileyonlinelibrary.com), and a corresponding correction (https://doi.org/10.1002/pmic.202070084; published May 25, 2020) have been retracted by agreement between the journal Editor-in-Chief, Lucie Kalvodova; and Wiley-VCH GmbH, Weinheim. The retraction has been agreed following concerns raised by the authors; the same shVector panel was used in two of the figures, suggesting the same control data was used for different experiments.

Application of computed tomography-based radiomics analysis combined with lung cancer serum tumor markers in the identification of lung squamous cell carcinoma and lung adenocarcinoma.

To establish a prediction model of lung cancer classification by computed tomography (CT) radiomics with the serum tumor markers (STM) of lung cancer. Two-hundred NSCLC patients were enrolled in our study. Clinical data including age, sex, and STM (squamous cell carcinoma [SCC], neuron-specific enolase [NSE], carcinoembryonic antigen [CEA], pro-gastrin-releasing peptide [PRO-GRP], and cytokeratin 19 fragment [cYFRA21-1]) were collected. A radiomics signature was generated from the training set using the least absolute shrinkage and selection operator (LASSO) algorithm. The risk factors were identified using multivariate logistic regression analysis, and a radiomics nomogram based on the radiomics signature and clinical features was constructed. The capability of the nomogram was evaluated using the training set and validated using the validation set. A correction curve and the Hosmer-Lemeshow test were used to evaluate the predictive performance of the radiomics model for the training and test sets. Twenty-nine of 1234 radiomics parameters were screened as important factors for establishing the radiomics model. The training (area under the curve [AUC] = 0.925; 95% confidence interval [CI]: 0.885-0.966) and validation sets (AUC = 0.921; 95% CI: 0.854-0.989) showed that the CT radiomics signature, combined with STM, accurately predicted lung squamous cell carcinoma and lung adenocarcinoma. Moreover, the logistic regression model showed good performance based on the Hosmer-Lemeshow test in the training (P = 0.954) and test sets (P = 0.340). Good calibration curve consistency also indicated the good performance of the nomogram. The combination of the CT radiomics signature and lung cancer STM performed well for the pathological classification of NSCLC. Compared with the radiomics signature method, the nomogram based on the radiomics signature and clinical factors had better performance for the differential diagnosis of NSCLC.

Identification of a prognostic gene signature in patients with cisplatin resistant squamous cell lung cancer.

In the absence of targeted mutations and immune checkpoints, platinum-based chemotherapy remains a gold standard agent in the treatment of patients with lung squamous cell carcinoma (LUSC). However, cisplatin resistance greatly limits its therapeutic efficacy and presents challenges in the treatment of lung cancer patients. Therefore, the potential clinical needs for this research focus on identifying novel molecular signatures to further elucidate the underlying mechanisms of cisplatin resistance in LUSC. A growing body of evidence indicates that alternative splicing (AS) events significantly influence the tumor progression and survival of patients with LUSC. However, there are few systematic analyses of AS reported in LUSC. This study aims to explore the role of messenger RNA (mRNA), microRNA (miRNA), and AS in predicting prognosis in patients with cisplatin-resistant LUSC and provide potential therapeutic targets and drugs. Gene expression and miRNA expression, using RNA sequencing (RNA-seq), and SpliceSeq data were downloaded from The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis were used to construct predictive models. Kaplan-Meier survival analyses were used to evaluate patients' prognosis. Single-sample gene set enrichment analysis (ssGSEA) conducted via the R package "GSEAbase" was used to evaluate the immune-related characteristics. Immunohistochemistry was used to examine protein expression. The Connectivity Map (CMap) database was used to screen for potential drugs. The 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was used to determine and calculate the half-maximal inhibitory concentration (IC50) of the drugs, sulforaphane and parthenolide. In this study, bioinformatics were used to identify mRNAs, miRNAs, and AS events related to response to cisplatin and to establish an integrated prognostic signature for 70 patients with LUSC and cisplatin resistance. The prognostic signature served as an independent prognostic factor with high accuracy [hazard ratio (HR) =2.346, 95% confidence interval (CI): 1.568-3.510; P<0.001], yielding an area under the curve (AUC) of 0.825, 0.829, and 0.877 for 1-, 3-, and 5-year survival, respectively. It also demonstrated high predictive performance in this cohort of patients with LUSC, with an AUC of 0.734, 0.767, and 0.776 for 1-, 3-, and 5-year survival, respectively. This integrated signature was also found to be an independent indicator among conventional clinical features (HR =2.288, 95% CI: 1.547-3.383; P<0.001). In addition, we analyzed the correlation of the signature with immune infiltration and identified several small-molecule drugs that had the potential to improve the survival of patients with LUSC. This study provides a framework for the mRNA-, miRNA-, and AS-based evaluation of cisplatin response and several potential therapeutic drugs for targeting cisplatin resistance in LUSC. These findings may serve as a theoretical basis for the clinical alleviation of cisplatin resistance and thus help to improve treatment responses to chemotherapy in patients with LUSC.

Efficacy analysis of ALK inhibitors for treating lung squamous carcinoma patients harboring ALK rearrangement.

Anaplastic lymphoma kinase (ALK)-rearranged pulmonary squamous cell carcinoma (SCC) is a rare subtype of non-small cell lung cancer and the treatment options are limited. We aimed to evaluate the efficacy of ALK tyrosine kinase inhibitors (TKIs) in advanced lung SCC patients with ALK rearrangement. We collected 11 primary lung SCC samples at the Zhejiang Cancer Hospital between March 2015 and October 2022. In addition, we conducted a literature search of previous studies, and a pooled analysis of 34 patients was performed. The Kaplan-Meier method was applied to generate progression-free survival (PFS) and overall survival (OS) curves, and a log-rank test was used to compare PFS and OS curves for different subgroups. A pooled analysis of 36 patients was performed. Nineteen patients (52.8%) achieved partial response and 9 (25.0%) had stable disease. The objective response rate was 52.8%, and the disease control rate was 77.8%. The median PFS was 7.10 months. Further, alectinib was not superior to crizotinib in prolonging PFS (9.00 vs. 6.00 months, P=0.60). The median PFS of patients receiving initial ALK TKIs as the first-line therapy and second- or further-line therapy was 9.00 and 6.00 months (P=0.26), respectively. Patients with ALK-rearranged lung SCC obtained moderate benefit from ALK-inhibitor therapy. Compared with crizotinib, alectinib did not show superior efficacy in the treatment of ALK-positive lung SCC. Further high-quality trials are warranted.

Age at first sexual intercourse, age at menarche, and age at menopause: a mendelian randomization study on lung cancer risk.

There is increasing evidence that sex hormones are involved in the development of lung cancer, but the correlation between the reproductive behavior that changes sex hormone levels and lung cancer is not yet clear. Many previous studies have investigated the association between reproductive factors and lung cancer risk, but the results have been inconsistent. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to explore the potential relationship between age at first sexual intercourse (AFS), age at menarche, and age at menopause, and lung cancer. We performed a MR analysis of the data from the genome-wide association study (GWAS) of European ancestry to evaluate the independent effects of three reproductive behaviors on lung cancer overall (LUCA), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small cell lung cancer (SCLC). We mainly used the inverse-variance weighting method for the MR analysis. Sensitivity was determined by a MR-pleiotropy residual sum and outlier analysis, a weighted median analysis, a MR-Egger analysis, and a leave-one-out analysis. The MR analysis results revealed that older AFS had a causal relationship with LUCA [odds ratio (OR) =0.6283, 95% confidence interval (CI): 0.4959-0.7961, P=0.0001), LUAD (OR =0.7042, 95% CI: 0.4967-0.9984, P=0.049), and LUSC (OR =0.6231, 95% CI: 0.4386-0.8853, P=0.0083). Our results revealed a causal relationship between older AFS and a lower risk of lung cancer. Our findings emphasize the importance of providing sex education, as early sexual intercourse may have undesirable effects. In addition, early psychological treatment is also essential.

RILPL2 as a potential biomarker for predicting enhanced Tcell infiltration in non-small cell lung cancer.

Our previous bioinformatics analysis has revealed that Rab-interacting lysosomal protein-like 2 (RILPL2) is associated with tumor immune microenvironment in non-small cell lung cancer (NSCLC). In our study, we collected 140 patients with primary NSCLC to verify the RILPL2 expression and its prognostic value, the relationship between RILPL2 expression and CD4+, CD8+T cell infiltration. A total of 140 patients who had been diagnosed with primary NSCLC (including 66 lung adenocarcinomas and 74 lung squamous cell carcinomas) were enrolled in our study. Immunohistochemical (IHC) staining was performed to analyze the expression of RILPL2, CD4, and CD8 in these patients. Compared with peri-cancer tissues, the RILPL2 expression in NSCLC tissues was significantly lower (P < 0.0001). RILPL2 expression was significantly related to clinical stage (P = 0.019), and low RILPL2 expression indicated higher stage. Low RILPL2 expression predicted worse overall survival (OS) in NSCLC patients (P = 0.017). Correlational analyses revealed that RILPL2 expression was significantly positively correlated with CD4+T cell infiltration in NSCLC (R = 0.294, P < 0.001), LUAD subgroup (R = 0.256, P = 0.038), and LUSC subgroup (R = 0.333, P = 0.004); RILPL2 expression was also significantly positively correlated with CD8+ T cell infiltration in NSCLC (R = 0.263, P = 0.002), LUAD subgroup (R = 0.280, P = 0.023), and LUSC subgroup (R = 0.250, P = 0.031).In conclusion, RILPL2 expression was downregulated in NSCLC; low RILPL2 expression was significantly related to higher stage and worse prognosis; RILPL2 expression was significantly positively correlated with CD4+, CD8+T cell infiltration.