Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

Background: Lung adenocarcinoma (LUAD) is the most prevalent histotype of non‐small cell lung cancer. Anoikis, an alternative form of programmed cell death, plays a pivotal role in cancer invasion and metastasis, preventing the detached cancer cells from readhering to other substrates for abnormal proliferation. The aim of this study was to conduct a comprehensive analyses of the prognostic implications of anoikis‐related genes (ARGs) in LUAD.Methods: ARGs were selected from The Cancer Genome Atlas (TCGA) database and Genecards dataset using differential expression analysis. The signature incorporating ARGs was identified using univariate Cox regression analysis and LASSO regression analysis. Furthermore, a nomogram containing the signature and clinical information was developed through univariate and multivariate Cox regression analysis. Kaplan–Meier survival analysis and receiver operating characteristic (ROC) curves were applied to evaluate the predictive validity of these risk models. Finally, functional analysis of the selected ARGs in signature and analysis of immune landscape were also conducted.Results: A 16‐gene signature was integrated to stratify LUAD patients into different survival risk groups. The prognostic risk score generated from the signature and TNM stage were identified as independent prognostic factors and utilized to develop a nomogram. Both the signature and the nomogram showed satisfactory prediction performance in predicting overall survival (OS) of LUAD patients. The ARGs were enriched in several biological functions and signaling pathways. Finally, differences of immune landscape were investigated among the high‐ and low‐risk groups stratified by the signature.Conclusions: This study revealed potential relationships between ARGs and prognosis of LUAD. The prognostic predictors identified in present study could be utilized as potential biomarkers for clinical applications.

(1) Background: Several randomized controlled trials (RCTs) have been conducted in combination with Efficacy and Safety of Epidermal Growth Factor Receptor(EGFR)-Tyrosine Kinase Inhibitor (TKI) for the first-line treatment of patients with advanced non-small cell lung cancer; however, head-to-head comparisons of combination therapies are still lacking. Therefore, this study aims to compare the efficacy and safety of various combination treatments. (2) Methods: We conducted a systematic review and Bayesian network meta-analysis by searching MEDLINE, EMBASE, and COCHRANE for relevant RCTs. (3) Results: TKI combined with antiangiogenic therapy, chemotherapy, or radiation achieved a significant benefit compared with TKI alone for progression free survival (PFS). A combination with radiation yielded better benefits in PFS than any other treatment. In terms of overall survival (OS), only the combination with pemetrexed and carboplatin (HR = 0.63, 95% credible interval 0.43–0.86)/radiation (0.44, 0.23–0.83) was superior to TKI alone. All of the combination therapies may increase the incidence of ≥Grade 3 AEs, as the pooled RRs are over 1; different toxicity spectrums were revealed for individual treatments. (4) Conclusions: The TKI combination of radiation/pemetrexed and carboplatin could provide the best antitumor effects among the first generation TKI-based treatments. Considering safety, ramucirumab and bevacizumab may be the ideal additions to TKIs (systematic review registration: PROSPERO CRD42022350474).

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and closely associated with the immune system. Emerging evidence suggests that blood immune cell phenotypes in patients with LUAD may undergo alterations. Nevertheless, the limited amount of relevant research makes it difficult to understand the causal links between LUAD and changes in the immune cells. This study aimed to reveal the potential causal relationships between 731 immune cell phenotypes and LUAD.Methods: A bidirectional two‐sample Mendelian randomization (MR) analysis was used to clarify causal relationships. Four types of immune phenotypes, absolute cell counts, relative cell counts, median fluorescence intensities (MFIs) of surface antigens, and morphological parameters, were investigated in this study. Heterogeneity tests, horizontal pleiotropy tests, and leave‐one‐out analyses were performed to validate the reliability of our study.Results: A total of 26 immune cell characteristics were identified as contributing to the occurrence of LUAD. Memory B cells, IgD⁻CD38^br cells, CD4⁺ regulatory T cells (Tregs), and plasmacytoid dendritic cells (DCs) may play a role in the development of LUAD. Through reverse MR, our study discovered that the presence of LUAD also induced changes in the expression levels of 16 immune cell traits involving specific surface markers and various types of immune cells, some of which pertain to antigen presentation and immune activation processes.Conclusion: Our study demonstrated causal links between several immune cell phenotypes and LUAD, thereby providing indications of the potentially oncogenic physiological state and early screening biomarkers for future research.

Background: Atrial fibrillation (AF) has become the most common postoperative arrhythmia of thoracic surgery. This study aimed to investigate the risk factors and complications of perioperative atrial fibrillation (PoAF) in elderly patients who underwent video-assisted thoracoscopic surgery (VATS). Methods: Data were collected from patients who underwent VATS between January 2013 and December 2022 at Peking Union Medical College Hospital (PUMCH). Univariable analyses and multivariable logistic regression analyses were used to determine the factors correlated with PoAF. Receiver operating characteristic (ROC) curve was used to evaluate the discrimination of the indicators to predict PoAF. Results: The study enrolled 2920 patients, with a PoAF incidence of 5.2% (95% CI 4.4%-6.0%). In the logistic regression analyses, male sex (OR=1.496, 95% CI 1.056– 2.129, P=0.024), left atrial anteroposterior dimension (LAD) ≥ 40 mm (OR=2.154, 95% CI 1.235– 3.578, P=0.004), hypertension (HTN) without regular treatment (OR=2.044, 95% CI 0.961– 3.921, P=0.044), a history of hyperthyroidism (OR=4.443, 95% CI 0.947– 15.306, P=0.030), surgery of the left upper lobe (compared to other lung lobes) (OR=1.625, 95% CI 1.139– 2.297, P=0.007), postoperative high blood glucose (BG) (OR=2.482, 95% CI 0.912– 5.688, P=0.048), and the time of chest tube removal (per day postoperatively) (OR=1.116, 95% CI 1.038– 1.195, P=0.002) were found to be significantly associated with PoAF. The area under the ROC curve was 0.707 (95% CI 0.519– 0.799). 86.9% patients were successfully converted to sinus rhythm. Compared with the non-PoAF group, the PoAF group had significantly greater risks of prolonged air leakage, postoperative acute coronary syndrome, longer ICU stays, and longer hospital stays. Conclusion: Male sex, LAD≥ 40 mm, HTN without regular treatment, a history of hyperthyroidism, surgery of the left upper lobe, postoperative BG, and the time of chest tube removal were associated with PoAF. These findings may help clinicians identify high-risk patients and take preventive measures to minimize the incidence and adverse prognosis of PoAF.

Background Lung squamous cell carcinoma (LUSC), one of the main pathological types of lung cancer, has led to consequential socioeconomic burden. Ferroptosis is an iron-dependent form of cell death process with potentials for therapeutic target in various kinds of tumors. However, whether ferroptosis-related genes (FRGs) are associated with the prognosis of LUSC patients is still unclear. The aim of this study was to establish a FRGs-based signature which could stratify patients with LUSC. Methods The RNA sequencing profiles and corresponding clinical data of LUSC patients were retrieved from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) dataset. A FRG-based signature was developed using the TCGA-LUSC cohort and validated in the GEO cohort. Gene set enrichment analysis (GSEA) and analysis of immune cell characteristics were conducted to assess the relationship between FRGs and biological function or immune status. A nomogram based on selected clinical factors and the risk scores which were generated from the FRG-based signature was developed using the TCGA cohort and validated in the GEO cohort. Results A set of 16 FRGs, significantly associated with overall survival (OS) in the TCGA cohort, was identified and could classify LUSC patients into two risk groups. Kaplan–Meier analysis illustrated that the survival rate of the high-risk group was significantly lower than the low-risk group. Assessment and external validation of the signature showed that the survival predictive performance of this signature was adequate. Additionally, multiple pathways and functions were enriched through GSEA and the analysis of immune cell characteristics showed significantly different abundances of immune cells among the two risk groups. Finally, a nomogram integrating the FRG-based signature and selected clinical factors was also developed and assessed in both the TCGA and GEO cohort. Conclusion This study indicated the association between the FRGs and prognosis of patients with LUSC. Targeting ferroptosis may serve as a novel potential therapeutic alternative for LUSC.