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Rationale and Objectives: Pulmonary nodules or masses are highly prevalent worldwide, and differential diagnosis of benign and malignant lesions remains difficult. Magnetic resonance imaging (MRI) can provide functional and metabolic information of pulmonary lesions. This study aimed to establish a nomogram model based on clinical features, imaging features, and multi-sequence MRI radiomics to identify benign and malignant solid pulmonary nodules or masses., Materials and Methods: A total of 145 eligible patients (76 male; mean age, 58.4 years ± 13.7 [SD]) with solid pulmonary nodules or masses were retrospectively analyzed. The patients were randomized into two groups (training cohort, n = 102; validation cohort, n = 43). The nomogram was used for predicting malignant pulmonary lesions. The diagnostic performance of different models was evaluated by receiver operating characteristic (ROC) curve analysis., Results: Of these patients, 95 patients were diagnosed with benign lesions and 50 with malignant lesions. Multivariate analysis showed that age, DWI value, LSR value, and ADC value were independent predictors of malignant lesions. Among the radiomics models, the multi-sequence MRI-based model (T1WI+T2WI+ADC) achieved the best diagnosis performance with AUCs of 0.858 (95%CI: 0.775, 0.919) and 0.774 (95%CI: 0.621, 0.887) for the training and validation cohorts, respectively. Combining multi-sequence radiomics, clinical and imaging features, the predictive efficacy of the clinical-imaging-radiomics model was significantly better than the clinical model, imaging model and radiomics model (all P < 0.05)., Conclusion: The MRI-based clinical-imaging-radiomics model is helpful to differentiate benign and malignant solid pulmonary nodules or masses, and may be useful for precision medicine of pulmonary diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Intercellular cell adhesion molecule-1 (ICAM-1) is frequently overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the mechanism underlying the negative effects of neoplastic ICAM-1 remains obscure. Herein, we demonstrate that the survival of NSCLC cells but not normal human bronchial epithelial cells requires an anti-apoptosis signal triggered by fibrinogen γ chain (FGG)-ICAM-1 interaction. ICAM-1-FGG ligation preserves the tyrosine phosphorylation of ICAM-1 cytoplasmic domain and its association with SHP-2, and subsequently promotes Akt and ERK1/2 activation but suppresses JNK and p38 activation. Abolishing ICAM-1-FGG interaction induces NSCLC cell death by activating caspase-9/3 and significantly inhibits tumor development in a mouse xenograft model. Finally, we developed a monoclonal antibody against ICAM-1-FGG binding motif, which blocks ICAM-1‒FGG interaction and effectively suppresses NSCLC cell survival in vitro and tumor growth in vivo. Thus, suppressing ICAM-1-FGG axis provides a potential strategy for NSCLC targeted therapy., (© 2024. The Author(s).)

Background: Chylothorax is a postoperative complication in patients with lung cancer. Diet-control approaches have been the mainstay for managing this condition. However, a surgical intervention is needed for the patients if conservative treatment is ineffective. Because of the lack of accurate indicators to assess the prognosis of the postoperative complication at an early stage, the criteria of surgical treatment were not consistent., Methods: We reviewed 2942 patients who underwent pulmonary resection and lymph node dissection for primary lung cancer at our hospital between March 2021 and December 2022. The prognostic implications of clinical indicators were assessed in patients with postoperative chylothorax who were managed with a low-fat diet. Binary logistic regression was used to explore the predictive value of these indicators for patient prognosis., Results: Postoperative chylothorax occurred in 108 patients and 79 patients were treated with a low-fat diet management while 29 patients were managed with TPN. In contrast to drainage volume, the pleural effusion triglyceride level after 2 days of low-fat diet exhibited enhanced predictive efficacy in predicting patient prognosis. When the pleural fluid triglyceride level of 1.33 mmol/L was used as the diagnostic threshold for prognosis, the sensitivity and specificity reached 100% and 80.6%, respectively., Conclusions: The pleural effusion triglyceride level after 2 days of low-fat diet can serve as a valuable prognostic indicator in patients undergoing lung surgery and experiencing chylothorax. This predictive approach will help thoracic surgeons to identify patients with poor prognosis in a timely manner and make decision to perform necessary surgical interventions., (© 2024. The Author(s).)

Although MRPS16 is involved in cancer development, its mechanisms in developing LAUD remain unclear. Herein, qRT-PCR, WB and IHC were utilized for evaluating MRPS16 expression levels, while functional assays besides animal experiments were performed to measure MRPS16 effect on LAUD progression. Using WB, the MRPS16 effect on PI3K/AKT/Frataxin signalling pathway was tested. According to our study, MRPS16 was upregulated in LAUD and was correlated to the advanced TNM stage as well as poor clinical outcomes, which represent an independent prognostic factor. Based on functional assays, MRPS16 is involved in promoting LAUD growth, migration and invasion, which was validated further in subsequent analyses through PI3K/AKT/Frataxin pathway activation. Moreover, MRPS16-knockdown-mediated Frataxin overexpression was shown to restore the reduction in tumour cells proliferation, migration and invasion. Our results revealed that MRPS16 caused an aggressive phenotype to LAUD and was a poor prognosticator; thus, targeting MRPS16 may be effectual in LAUD treatment., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Genomic diagnostic testing is necessary to guide optimal treatment for non-small cell lung cancer (NSCLC) patients. The proportion of NSCLC patients whose treatment was selected based on genomic testing is still unknown in many countries or needs further improvement. This survey aimed to assess perception of genomic testing and targeted therapy for NSCLC in clinical pathologists and physicians across China., Methods: The web-based survey was conducted with 150 clinical pathologists and 450 physicians from oncology, respiratory and thoracic surgery departments from May to September 2020, across 135 cities in China. The participants had >5 years of clinical experience in genomic testing, diagnosis or treatment of NSCLC., Results: Clinical pathologists reported capability of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS-1) testing as 95.3%, 94.7%, and 84.7%, respectively, but only 81.9%, 75.5%, and 65.6% of physicians believed that the pathology department of the hospital is capable of performing the testing. The proportions of sending out specimens for testing were 21.0% and 49.7% as reported from clinical pathologists and physicians, respectively. Testing for EGFR mutation was recommended by physicians most often, followed by ALK and ROS-1 rearrangement. As first-line treatment, among the newly diagnosed patients with EGFR mutation, 77% received tyrosine kinase inhibitors (TKIs) therapy (49% treated with gefitinib); among patients with ALK rearrangement, 71% received TKI (64% treated with crizotinib); among patients with ROS-1 fusion, 65% received TKI (88% treated with crizotinib)., Conclusions: The improvement of the non-tertiary hospital pathology departments' detection capabilities and the physicians' awareness are needed for enhancing the rate of genomic testing and targeted therapy in NSCLC patients in China.

Background: Lung cancer is a malignant disease with high morbidity and mortality. Lung cancer and diabetes are closely related, and diabetic patients with lung tumors are common in clinical practice. Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is commonly used in the treatment of type 2 diabetes. In this study, we examined the effect of liraglutide on lung cancer and its potential protective effect on high glucose-induced lung aging., Methods: Indirect mmunofluorescence was done to assess the expression levels of p-AKT, ki67, Caspase3, Bax and PI3K. Western blotting was conducted to determine the expression levels of BAX, BCL2, Caspase9, E-cadherin, N-cadherin, PI3K, AKT and vimentin. Cell viability, cell cycle and cell apoptosis were evaluated by colony formation, CCK-8 assay and flow cytometry. Immunohistochemistry was performed to evaluate the expression of Nf-κb, p15, p16, p21 and SMA in vivo. Besides, a high glucose-induced lung cell injury model was established to evaluate the effect of liraglutide on lung aging and oxidative damage. Sa-β-gal staining was used to assess cellular/ tissue senescence. Cell senescence-related markers (p16, p21 and p53 ) were determined by Western-blot analysis., Results: The proliferation, cell cycle, migration of lung cancer cells were significantly inhibited after treatment with liraglutide compared to control group ( p < 0.05). Furthermore, Liraglutide inhibited the epithelial-mesenchymal transition process of lung cancer cell compared to control group ( p < 0.05). Liraglutide also suppressed the proliferation of lung cancer in vivo . Besides, the BEAS-2B cell senescence induced by high glucose was significantly alleviated after treatment with liraglutide compared with control group ( p < 0.05). The lung aging and endoplasmic reticulum stress was significantly suppressed after liraglutide treatment., Conclusions: This work indicates that liraglutide could inhibit lung cancer cell proliferation in vitro and in vivo . In addition, liraglutide exhibited anti-aging effects in vivo and in vivo . The current work has important implications for the treatment of patients with diabetes and lung cancer., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Background: Lung cancer is the most common cancer-related death worldwide. In 2022, the number of daily deaths of lung cancer was estimated to reach around 350 in the United States. Lung adenocarcinoma is the main subtype of lung cancer and patients with malignant pleural effusion (MPE) suffer from poor prognosis. Microbiota and its metabolites are associated with cancer progression. However, the effect of pleural microbiota on pleural metabolic profile of MPE in lung adenocarcinoma patients remains largely unknown., Methods: Pleural effusion samples collected from lung adenocarcinoma patients with MPE (n = 14) and tuberculosis pleurisy patients with benign pleural effusion (BPE group, n = 10) were subjected to microbiome (16S rRNA gene sequencing) and metabolome (liquid chromatography tandem mass spectrometry [LC-MS/MS]) analyses. The datasets were analyzed individually and integrated for combined analysis using various bioinformatic approaches., Results: The metabolic profile of MPE in lung adenocarcinoma patients were clearly distinguished from BPE with 121 differential metabolites across six significantly enriched pathways identified. Glycerophospholipids, fatty and carboxylic acids, and derivatives were the most common differential metabolites. Sequencing of microbial data revealed nine significantly enriched genera (i.e., Staphylococcus, Streptococcus, Lactobacillus) and 26 enriched ASVs (i.e., species Lactobacillus&#95;delbrueckii) in MPE. Integrated analysis correlated MPE-associated microbes with metabolites, such as phosphatidylcholine and metabolites involved in the citrate cycle pathway., Conclusion: Our results provide substantial evidence of a novel interplay between the pleural microbiota and metabolome, which was drastically perturbed in MPE in lung adenocarcinoma patients. Microbe-associated metabolites can be used for further therapeutic explorations., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Somatic alterations in tumors are a frequent occurrence. In small cell lung cancer (SCLC), these include mutations in the tumor suppressors TP53 and retinoblastoma (RB1). We used next generation sequencing (NGS) to study specific genetic variants and compare genetic and clinicopathological features of SCLC with healthy control genome. Ten SCLC patients receiving standard chemotherapy, between 2018 and 2019, from the First Hospital of Jilin University were included in this study. Prior patient treatment, NGS was performed using DNA isolated from blood plasma. New NGS analyses were performed after 2 and 4 treatment cycles. Four patients presented with different metastases at diagnosis. Overall, most genes tested presented missense or frameshift variants. TP53, RB1, CREBBP, FAT1 genes presented gain of stop codons. At the single-gene level, the most frequently altered genes were TP53 (8/10 patients, 80%) and RB1 (4/10 patients, 40%), followed by bromodomain containing 4 (BRD4), CREBBP, FAT1, FMS-like tyrosine kinase 3 (FLT3), KDR, poly ADP-ribose polymerase (PARP1), PIK3R2, ROS1, and splicing factor 3b subunit 1 (SF3B1) (2/10 patients, 20%). We identified 5 genes, which have not been previously reported to bear mutations in the context of SCLC. These genes include BRD4, PARP1, FLT3, KDR, and SF3B1. We observed that among the studied individuals, patients with a high number of genetic events, and in which such mutations were not eradicated after treatment, showed a worse prognosis. There has not yet been given enough attention to the above-mentioned genes in SCLC, which will have great clinical prospects for treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Lung adenocarcinoma (LUAD) is the most common type of lung cancer which accounts for about 40% of all lung cancers. Early detection, risk stratification and treatment are important for improving outcomes for LUAD. Recent studies have found that abnormal accumulation of cystine and other disulfide occurs in the cell under glucose starvation, which induces disulfide stress and increases the content of disulfide bond in actin cytoskeleton, resulting in cell death, which is defined as disulfidptosis. Because the study of disulfidptosis is in its infancy, its role in disease progression is still unclear. In this study, we detected the expression and mutation of disulfidptosis genes in LUAD using a public database. Clustering analysis based on disulfidptosis gene was performed and differential genes of disulfidptosis subtype were analyzed. 7 differential genes of disulfidptosis subtype were used to construct a prognostic risk model, and the causes of prognostic differences were investigated by immune-infiltration analysis, immune checkpoint analysis, and drug sensitivity analysis. qPCR was used to verify the expression of 7 key genes in lung cancer cell line (A549) and normal bronchial epithelial cell line (BEAS-2B). Since G6PD had the highest risk factor of lung cancer, we further verified the protein expression of G6PD in lung cancer cells by western blot, and confirmed through colony formation experiment that interference with G6PD was able to significantly inhibit the proliferation ability of lung cancer cells. Our results provide evidence for the role of disulfidptosis in LUAD and provide new ideas for individualized precision therapy of LUAD.

The aim of this study was to develop dual segmentation models for poorly and well-differentiated hepatocellular carcinoma (HCC), using two-step transfer learning (TSTL) based on dynamic contrast-enhanced (DCE) computed tomography (CT) images. From 2013 to 2019, DCE-CT images of 128 patients with 80 poorly differentiated and 48 well-differentiated HCCs were selected at our hospital. In the first transfer learning (TL) step, a pre-trained segmentation model with 192 CT images of lung cancer patients was retrained as a poorly differentiated HCC model. In the second TL step, a well-differentiated HCC model was built from a poorly differentiated HCC model. The average three-dimensional Dice's similarity coefficient (3D-DSC) and 95th-percentile of the Hausdorff distance (95% HD) were mainly employed to evaluate the segmentation accuracy, based on a nested fourfold cross-validation test. The DSC denotes the degree of regional similarity between the HCC reference regions and the regions estimated using the proposed models. The 95% HD is defined as the 95th-percentile of the maximum measures of how far two subsets of a metric space are from each other. The average 3D-DSC and 95% HD were 0.849 ± 0.078 and 1.98 ± 0.71 mm, respectively, for poorly differentiated HCC regions, and 0.811 ± 0.089 and 2.01 ± 0.84 mm, respectively, for well-differentiated HCC regions. The average 3D-DSC for both regions was 1.2 times superior to that calculated without the TSTL. The proposed model using TSTL from the lung cancer dataset showed the potential to segment poorly and well-differentiated HCC regions on DCE-CT images., (© 2022. Australasian College of Physical Scientists and Engineers in Medicine.)

Previous studies reported the latex from the fruit of Ficus carica L. (fig) has anti-tumor and antioxidant activities in animal models. However, its active constituents, mechanism of action, and safety remain unknown. The alcohol-precipitated fraction of fig fruit latex (AFFL) was purified and prepared for testing against non-small cell lung cancer (NSCLC). UPLC-TOF-MS/MS was used to examined the components of AFFL. We validated efficacy by researching antitumor phenotypes in vitro and constructing subcutaneous grafts of nude mice with NSCLC, as well as showing the underlying mechanism at the protein level. The results showed that 11 components of AFFL were screened. AFFL significantly inhibited the proliferation, migration, invasion, and clonogenesis of NSCLC cells, promoted cell apoptosis, inhibited tumor growth in A549 xenograft mice, but induced no obvious damage to normal mouse tissues (liver or kidney). Molecular mechanism studies revealed that AFFL could increase Caspase-1 expression in cancer cells by activating the cleavage of Caspase-3 and Caspase-9, inhibiting the activity of Bcl-2, and promoting tumor cell apoptosis. These processes cause gasdermin proteins (GSDMD and GSDME) to be cleaved, releasing N-terminal domain proteins to accumulate and perforate the cell membrane, and promoting tumor cell pyroptosis. In conclusion, our findings suggested that AFFL may promote tumor cell apoptosis and pyroptosis via the Caspase/Gasdermin/AKT signaling pathway and inhibit NSCLC growth in vitro and in vivo , demonstrating that fig latex can be developed as a functional food and drug with anti-NSCLC properties.

Background: Dexmedetomidine is a widely used anaesthetic adjuvant for cancer resection surgeries. However, recent reports suggest that it may promote tumour growth or metastasis, so it is essential to clarify its tumour-related effects., Methods: Seven syngeneic murine tumour models were used to assess the impact of dexmedetomidine on primary tumour growth, spontaneous tumour metastasis, and surgical resection-associated metastasis. Cancer cell proliferation and apoptosis experiments, terminal deoxynucleotidyl transferase dUTP nick-end labelling assays, immune cell analysis, specific T-cell depletion experiments, and gene transcription analysis were conducted to identify the underlying mechanisms., Results: Dexmedetomidine did not affect growth of EO771 or 4T1 breast tumours, LAP0297 or LLC lung tumours, MCA205 fibrosarcoma, or their spontaneous lung metastases. It did not promote lung metastasis after breast cancer resection. Dexmedetomidine significantly suppressed MCA38 and CT26 colorectal tumour growth (P<0.01) and promoted apoptosis in MCA38 tumour tissues (P<0.05) without affecting proliferation and apoptosis of MCA38 tumour cells in vitro, suggesting indirect anti-tumour effects. Dexmedetomidine increased the proportions of intratumour CD4 + T (P<0.01), CD8 + T (P<0.001), and natural killer cells (P<0.01), and it upregulated transcription of the cytotoxicity-related genes Infg, Tnfa, and Cxcl9 (P<0.05) in MCA38 tumours. Either CD8 + or CD4 + T-cell depletion reversed the anti-tumour effects of dexmedetomidine on MCA38 tumours (P<0.05)., Conclusions: Dexmedetomidine conferred colorectal tumour-type specific suppression by modulation of tumour CD4 + and CD8 + T cells without tumour-enhancing effects., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Propofol is widely used in clinical anesthesia due to its advantages of rapid onset and less adverse reactions. This study focused on the role of propofol in the balance of Th17/Treg in elderly patients with lung cancer during perioperative period. Patients undergoing lung cancer surgery were anesthetized by propofol or sevoflurane. Veinal blood was collected at different time points to evaluate the changes of Th17/Treg cell. Propofol better maintained the balance of Th17/Treg in vivo. The peripheral blood of patients with lung cancer was collected in vitro before surgery. Cluster of differentiation (CD)4 + T cells were obtained and then treated with propofol at different concentrations and γ-aminobutyric acid A (GABAA) receptor antagonists. Propofol affected Th17/Treg cell balance by increasing Th17 cells, decreasing Treg cells, thus elevating Th17/Treg ratio, and inhibited invasion and migration of lung cancer cells through GABAA receptor, which was counteracted by GABAA receptor inhibitors. Subsequently, tumor in situ model of lung cancer in aged mice was established. Propofol anesthetized mice had lower change of Th17/Treg ratio, higher survival rate and less metastasis. In brief, propofol regulated balance of Th17/Treg in elderly patients undergoing lung cancer surgery through GABAA receptor. Additionally, propofol could inhibit metastasis of lung cancer., (© 2022. The Author(s).)

Ferroptosis is a newly found cell death mechanism, which could bypass apoptosis and reverse multidrug resistance of tumors. However, efficient induction of tumor ferroptosis remains a challenge. In this study, multifunctional "ball-rod" Janus nanoparticles (FTG/L&SMD) were constructed for non-small cell lung cancer (NSCLC) ferroptosis treatment. Protected by tannic acid (TA), FTG/L&SMD maintains long-term function in blood circulation, while modification by 2, 3-dimethylmaleic anhydride (DMMA) confers the FTG/L&SMD with pH-responsive charge reversal. Glucose oxidase (GOD) on FTG/L&SMD catalyzes glucose to produce H 2 O 2 . Then, iron ion converts H 2 O 2 to highly active hydroxyl radicals (OH•) via Fenton reaction, leading to lethal lipid peroxidation (LPO) accumulation. Meanwhile, TA reduces Fe 3+ to Fe 2+ to boost Fenton reaction cycle. Sor down-regulated glutathione peroxidase 4 (GPX4) expression in another pathway to induce ferroptosis synergistically. In vitro studies have shown that compared with sorafenib (Sor), FTG/L&SMD not only has more efficient tumor targeting and higher cytotoxicity, but also inhibits tumor migration. In vivo antitumor therapy experiments demonstrate that FTG/L&SMD inhibits tumor growth efficiently, and its toxicity is negligible. In general, FTG/L&SMD can initiate Fenton reaction cycle and reinforced ferroptosis to kill tumor cells, which is a promising anti-tumor nano-drug for NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: There is no widely employed staging system for mucosal melanoma (MuM) that incorporates all anatomic sites. We hypothesized that MuM patients arising from different anatomical sites could be staged using a common approach., Methods: A prospective database contained 1814 MuM patients with a median follow-up of 5.14 years was employed. Overall survival (OS) was calculated from the time of pathological diagnosis to the date of death from any cause. Multivariate analyses of prognostic variables and OS were performed using the Cox proportional hazard model., Results: For localized MuM, the most significant median OS differences were primary tumors invading submucosa (i.e., T1) versus deeper (i.e., T2/T3/T4): 4.3 versus 3.4, 3.1, and 2.9 years, respectively (p < 0.001). For patients only with regional node metastasis at presentation, the most significant were: 1 versus ≥ 2 regional nodes (N1 vs. N2, 2.5 vs. 2.1 years, p < 0.001). For patients with distant metastasis at presentation, the median OS was 1.5, 1.2, 0.8, and 0.6 years respectively for skin/subcutaneous tissue/distant lymph nodes (M1a), lung metastasis (M1b), all other visceral sites except brain (M1c), and brain (M1d) (p < 0.001). Based on these results, the staging system for MuM is proposed: (1) Stage I: T1N0M0 (median OS, 4.3 years); (2) Stage II: T2-4N0M0 (3.1 years); (3) Stage IIIA: T1-4N1M0 (2.5 years), Stage IIIB: T1-4N2M0 (2.1 years); (4) Stage IV: T any N any M1 (0.9 years) (p < 0.001)., Conclusions: A single, unified, staging system for mucosal melanoma inclusive of all anatomical primary tumor sites can harmonize staging of MuM and the design of clinical trials., (© 2022. Society of Surgical Oncology.)

Current methods for the early diagnosis of cancer can be invasive and costly. In recent years, exosomes have been recognized as potential biomarkers for cancer diagnostics. The common methods for quantitative detection of exosomes, such as nanoparticle tracking analysis (NTA) and flow cytometry, rely on large-scale instruments and complex operation, with results not specific for cancer. Herein, we present a tri-channel electrochemical immunobiosensor for enzyme-free and label-free detecting carcino-embryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragments (Cyfra21-1) from exosomes for specific early diagnosis of lung cancer. The electrochemical immunobiosensor showed good selectivity and stability. Under optimum experimental conditions, the linear ranges were from 10 -3 to 10 ng/mL for CEA, 10 -4 to 10 2 ng/mL for NSE, and 10 -3 to 10 2 ng/mL for Cyfra21-1, and a detection limit down to 10 -4 ng/mL was achieved. Furthermore, we performed exosome analysis in three kinds of lung cancer. The results showed a distinct expression level of exosomal markers in different types. These works provide insight into a promising alternative for the quantification of exosomal markers in specific diseases in the following clinical bioassays.

Background: Current predictive tools assess catheter-related thrombosis (CRT) in patients with lung cancer in a static manner at a single time point of catheterization. The subsequent hazard changes over time are unknown. The conditional catheter-related thrombosis-free probability (CCFP) can provide dynamic information on continual CRT-free expectations. This study aimed to assess the CCFP and hazard rates based on risk categories and various venous access devices (VADs)., Methods: This retrospective study reviewed 939 patients with lung cancer with peripherally inserted central venous catheters (PICCs) or central venous catheters (CVCs) identified at the National Clinical Research Center for Cancer between January 1, 2015 and December 31, 2018. The incidence of CRT has also been reported. Patients were stratified into low- and high-risk groups according to multivariate Cox regression analyses. CCFP is defined as the CRT-free probability given that patients have no CRT for a definite time., Results: A total of 507 patients with PICCs and 432 patients with CVCs were included in this study. The 3-month CCFP increased from 74.2% at catheter insertion to 93.6% at 3 months. The hazards of CRT in the first month were highest (16.4%) and slightly thereafter. The high-risk group initially had a higher (21.4%) but significantly decreased CRT hazard after 2 months (8.3%), whereas the low-risk group maintained a comparable lower risk hazard of less than 5% after 1 month. In the overall cohort, patients with CVCs had lower CRT probability than those with PICCs (HR, 1.76; 95% CI: 1.28-2.41; p < 0.01). Further analysis demonstrated that compared with PICCs, CVCs provided a CRT-free benefit in low-risk patients (p = 0.02) but not in high-risk patients (p = 0.06)., Conclusions: CCFP increased, and the hazards of CRT decreased over time in a risk-dependent manner in patients with lung cancer. These valuable dynamic data may help optimize risk-adjusted choices of VADs and risk-adjusted prophylactic anticoagulation strategies for patients., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Current studies have revealed that the platelet to lymphocyte ratio (PLR) may lead to a poor prognosis in lung cancer patients receiving immunotherapy. We conducted a meta-analysis to explore the prognostic value of PLR in lung cancer patients receiving immunotherapy., Methods: We retrieved potential studies from the PubMed, Web of Science, Embase, and Scopus databases up to June 2021 and merged the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) to evaluate the association between PLR and overall survival (OS) or progression-free survival., Results: Fourteen studies involving 1761 patients were included in our meta-analysis. The results indicated that an elevated level of pretreatment PLR was associated with poorer OS and PFS in lung cancer patients receiving immunotherapy (OS: HR = 1.88, 95% CI: 1.37-2.58; PFS: HR = HR = 1.40, 95% CI: 1.11-1.76). The association remained consistent after subgroup analysis and was robust even after sensitivity analysis., Conclusions: PLR may be a prognostic factor of lung cancer patients receiving immunotherapy, which can lead to worse survival outcomes. However, further studies are necessary for evidence in clinical application., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate sintilimab compared with other PD-L1 inhibitors in combination with platinum-based doublet chemotherapy as the first-line treatment of non-squamous non-small-cell lung cancer. Methods: A frequentist meta-analysis was used to compare outcomes, including progression-free survival, overall survival, objective response rate, time to response and safety profile. Results: The sintilimab combination arm had progression-free survival comparable to that of the pembrolizumab combination arm (hazard ratio [HR] = 1.00; 95% CI: 0.71, 1.41), the atezolizumab combination arm (HR: 0.81; 95% CI: 0.59, 1.10), the tislelizumab combination arm (HR: 0.75; 95% CI: 0.48, 1.16), the camrelizumab combination arm (HR: 0.80; 95% CI: 0.54, 1.20) and the nivolumab combination arm (HR: 0.72; 95% CI: 0.51, 1.02). Any grade or grade ≥3 adverse event was comparable between PD-L1 inhibitors. Conclusion: Sintilimab showed a comparable efficacy and safety profile when compared with other PD-L1 inhibitors combined with platinum-based doublet chemotherapy as the first-line treatment of locally advanced or metastatic non-squamous non-small-cell lung cancer.

Non-small cell lung cancer (NSCLC) poses a serious threat to public health due to its significant morbidity and mortality rates. The processes of NSCLC formation and development are quite complex and involve numerous regulatory biomolecules. Long non-coding RNAs (lncRNAs) have attracted attention since they have been found to play critical roles in the tumorigenesis of various human malignancies. Recently, double homeobox A pseudogene 8 (DUXAP8) was identified as an oncogenic lncRNA that is overexpressed in different tumor types. In NSCLC, high expression of DUXAP8 is associated with poor prognosis in patients. The regulatory mechanism underlying the oncogenic effects of DUXAP8 can be divided into transcriptional level and post-transcriptional level. DUXAP8 promotes proliferation, epithelial-mesenchymal transition, and aerobic glycolysis in NSCLC cells. Moreover, DUXAP8 shows potential for the diagnosis and treatment of NSCLC. Herein, we review the molecular mechanisms underlying the DUXAP8-mediated phenotypes of NSCLC as well as its potential clinical applications., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

DAL-1/4.1B is frequently absent in lung cancer tissues, which is significantly related to the occurrence and development of lung cancer. In this research, we found that DAL-1/4.1B affected the uptake of exosomes by lung cancer cells. When the expression of DAL-1/4.1B increased and decreased, the ability of exosome uptake enhanced and attenuated correspondingly. And we found that when cells were treated with different vesicles uptake inhibitors (chlorpromazine, methyl-β-cyclodextrin (MβCD), cytochalasin D, chloroquine and heparin) and heparinase (HSPE), only heparin and HSPE counteracted the uptake enhancement effect caused by DAL-1/4.1B. Therefore, we speculated that DAL-1/4.1B might promote the uptake of exosomes through the heparan sulfate proteoglycans (HSPGs) pathway. After screening the expression of HSPGs and HSPE in H292 cells, the expression of heparan sulfate proteoglycan 2 (HSPG2) increased with overexpression of DAL-1/4.1B and decreased with knockdown of DAL-1/4.1B. Meanwhile, exosome uptake decreased with HSPG2 knockdown in H292 and DAL-1/4.1B-overexpressing H292 cells. Moreover, knockdown of DAL-1/4.1B and HSPG2 in lung cancer A549 cells resulted in a similar decrease in exosome uptake, and the expression of HSPG2 was also decreased with DAL-1/4.1B knockdown. These results indicated that HSPG2 directly affected the uptake of exosomes, while DAL-1/4.1B positively affected the expression of HSPG2. Therefore, DAL-1/4.1B may promote cellular adhesion and inhibit migration in cancer cells., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

CD4 T follicular helper (TFH) cells support B cells, which are critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found enrichment of TFH cell transcriptional signature correlates with GC B cell signature and with prolonged survival in individuals with lung adenocarcinoma (LUAD). We further developed a murine LUAD model in which tumor cells express B cell- and T cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells requires B cells and B cell-recognized neoantigens. Thus, tumor neoantigens can regulate the fate of tumor-specific CD4 T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Proline metabolic reprogramming is intimately involved in cancer progression. We recently identified a critical role of PINCH-1, a cell-extracellular matrix (ECM) adhesion protein whose expression is elevated in lung adenocarcinoma, in the promotion of proline biosynthesis, fibrosis and lung adenocarcinoma growth. How PINCH-1 promotes proline biosynthesis, however, was incompletely understood. In this study, we show that PINCH-1 promotes the expression of Δ 1 -pyrroline-5-carboxylate synthase (P5CS), a key enzyme that links glutamate metabolism to proline biosynthesis. Depletion of PINCH-1 from lung adenocarcinoma cells reduced the protein but not mRNA level of P5CS, resulting in down-regulation of the cellular level of P5C and cell proliferation. Treatment of the cells with protease inhibitor leupeptin effectively reversed PINCH-1 deficiency-induced reduction of the P5CS level. At the molecular level, PINCH-1, through its LIM2 domain, physically associated with P5CS in lung adenocarcinoma cells. Re-expression of wild type PINCH-1, but not that of the PINCH-1 LIM2 deletion mutant, in PINCH-1 deficient lung adenocarcinoma cells restored P5CS expression, proline biosynthesis and cell proliferation. Finally, P5CS expression, like that of PINCH-1, is elevated in human and mouse lung adenocarcinoma. Using a mouse model of lung adenocarcinoma in which PINCH-1 is conditionally ablated, we show that knockout of PINCH-1 from lung adenocarcinoma effectively reduced the P5CS level in vivo. Our results reveal an important role of PINCH-1 in the promotion of P5CS expression, which likely contributes to proline metabolic reprogramming and consequently lung adenocarcinoma progression., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Lung adenocarcinoma (LUAD) is still one of the primary malignant diseases leading to higher mortality worldwide. It has been previously reported that multiple genes in the CENPA-nucleosome associated complex (NAC) complex in lung cancer can be used as prognostic markers; however, there is lack of comprehensive research on the CENPA-NAC complex., Methods: The hub genes of lung cancer were obtained by analyzing multiple gene expression omnibus (GEO) lung cancer datasets. The key genes of the CENPA-NAC complex in the evolution of LUAD were identified according to lung cancer data obtained from The Cancer Genome Atlas (TCGA) database, and the key genes were constructed as a survival prognostic model. The relationship between the model and immune cell infiltration was studied by the Tumor Immune Estimation Resource (TIMER) and single-sample gene set enrichment analysis (ssGSEA) studies.Droplet Digital polymerase chain reaction (ddPCR) was used to verify the effectiveness of the prognostic model to predict survival using clinical samples., Results: A comprehensive study showed that CENPA, CENPH, CENPM, CENPN and CENPU were key genes in the development and evolution of LUAD. The constructed survival prognosis model was an independent risk factor for LUAD and can be used to assess the survival of LUAD patients. The risk score was closely related to the infiltration of multiple immune cells. The independent cohorts GSE31210 and GSE50081 further confirmed the validity of the prognostic model, and finally, the model was validated with clinical samples., Conclusions: In conclusion, the results of the present study showed that CENPA, CENPH, CENPM, CENPN, and CENPU are a group of potential prognostic markers in LUAD. The constructed model has been confirmed to be applicable in the clinical setting in evaluating the survival of patients with LUAD, and providing more evidence on immunotherapy for LUAD., (Copyright © 2021. Published by Elsevier GmbH.)

“Stem-like” TCF1 + CD8 + T (T SL ) cells are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy, but, as tumors contain signals that should drive T cell terminal differentiation, how these cells are maintained in tumors remains unclear. In this study, we found that a small number of TCF1 + tumor-specific CD8 + T cells were present in lung tumors throughout their development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” (T cell inflamed) to “cold” (non–T cell inflamed). By contrast, most tumor-specific CD8 + T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to T SL from chronic lymphocytic choriomeningitis virus infection, and this population was stable over time despite the changes in the TME. dLN T cells were the developmental precursors of, and were clonally related to, their more differentiated intratumoral counterparts. Our data support the hypothesis that dLN T cells are the developmental precursors of the TCF1 + T cells in tumors that are maintained by continuous migration. Last, CD8 + T cells similar to T SL were also present in LNs from patients with lung adenocarcinoma, suggesting that a similar model may be relevant in human disease. Thus, we propose that the dLN T SL reservoir has a critical function in sustaining antitumor T cells during tumor development and in protecting them from the terminal differentiation that occurs in the TME.

Kras-driven lung adenocarcinoma (LUAD) is the most common lung cancer. A significant fraction of patients with Kras-driven LUAD respond to immunotherapy, but mechanistic studies of immune responses against LUAD have been limited because of a lack of immunotherapy-responsive models. We report the development of the immunogenic KP × NINJA (inversion inducible joined neoantigen) (KP-NINJA) LUAD model. This model allows temporal uncoupling of antigen and tumor induction, which allows one to wait until after infection-induced inflammation has subsided to induce neoantigen expression by tumors. Neoantigen expression is restricted to EPCAM+ cells in the lung and expression of neoantigen was more consistent between tumors than when neoantigens were encoded on lentiviruses. Moreover, tumors were infiltrated by tumor-specific CD8 T cells. Finally, LUAD cell lines derived from KP-NINJA mice were immunogenic and responded to immune checkpoint therapy (anti-PD1 and anti-CTLA4), providing means for future studies into the immunobiology of therapeutic responses in LUAD., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

The lipolysis-stimulated lipoprotein receptor (LSR) displays an important regulatory role in cancer. However, the association between LSR and lung cancer is still elusive. Here, the candidate oncogene LSR on Ch.9q was obtained and assessed by bioinformatics analysis of The Cancer Genome Atlas (TCGA) dataset of lung cancer. We conducted clinical pathology and survival analysis based on the lung cancer database. We assessed the biological effects of LSR in lung cancer cells on cell proliferation. Our data indicated that LSR was upregulated in lung cancer cells. Meanwhile, LSR was identified in this study to be a poor prognostic factor, and its high expression exhibited relations with grades, stages, and nodal metastasis status. Using in vitro analysis, our data revealed that LSR could promote lung cancer progression by regulating cell proliferation, migration, and invasion. In our study, our data demonstrated that LSR was a tumor promoter for lung cancer and was a potential biomarker and target for lung cancer prognosis and treatment., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Min Zhang and Cui Ma.)

Some related reports indicate that the outer retinal membrane protein 1 (ROM1) functions importantly in the regulation of the biological process of tumor. Nevertheless, studies towards the role of ROM1 in lung cancer are few. Here, our data demonstrated that ROM1 displayed a relation with lung cancer tumorigenesis and development. In the Tumor Genome Atlas (TCGA) cohort, reduced ROM1 level was observed in lung cancer tissues, instead of normal tissues. After bioinformatics analysis, the data revealed that ROM1 level was associated with the tumor stage. Additional results indicated that highly expressed ROM1 exhibited a positive correlation with the overall survival rate, and ROM1 was probably a promising prognostic biomarker of lung cancer. Additionally, our results indicated that knocking out ROM1 could promote cell proliferation, migration, and invasion. Our data conclusively demonstrated that ROM1 modulated lung cancer tumorigenesis and development, as a prognosis and treatment biomarker., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Min Zhang et al.)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide underlining the urgent need for new biomarkers and therapeutic targets for this disease. Long noncoding RNAs are critical players in NSCLC but the role of small RNA species is not well understood. In the present study, we investigated the role of H/ACA box small nucleolar RNAs (snoRNAs) and snoRNA-bound ribonucleoproteins (snoRNPs) in the tumorigenesis of NSCLC. H/ACA box snoRNPs including the NOP10 core protein were highly expressed in NSCLC. High levels of either NOP10 mRNA or protein were associated with poor prognosis in NSCLC patients. Loss of NOP10 and subsequent reduction of H/ACA box snoRNAs and rRNA pseudouridylation inhibited lung cancer cell growth, colony formation, migration, and invasion. A focused CRISPR/Cas9 snoRNA knockout screen revealed that genomic deletion of SNORA65, SNORA7A, and SNORA7B reduced proliferation of lung cancer cells. In line, high levels of SNORA65, SNORA7A, and SNORA7B were observed in primary lung cancer specimens with associated changes in rRNA pseudouridylation. Knockdown of either SNORA65 or SNORA7A/B inhibited growth and colony formation of NSCLC cell lines. Our data indicate that specific H/ACA box snoRNAs and snoRNA-associated proteins such as NOP10 have an oncogenic role in NSCLC providing new potential biomarkers and therapeutic targets for the disease.

Background: Lung adenocarcinoma (LUAD) is among the most aggressive malignant tumors in humans. Although AHNAK nucleoprotein 2 (AHNAK2) is considered a new oncogene, the function of the AHNAK2 in LUAD remains unknown., Methods: Oncomine, Tumor Immune Estimation Resource (TIMER), and Human Protein Atlas databases were used to investigate AHNAK2 expression in LUAD. Gene Expression Profiling Interactive Analysis and Kaplan-Meier plotter databases were employed to elucidate the relationship between AHNAK2 and survival time. Data of The Cancer Genome Atlas were downloaded to analyze the correlation between AHNAK2 and clinicopathological parameters. We then immunohistochemically stained tissue chips to further confirm the correlation and conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses to explore the possible functional mechanism of AHNAK2. Finally, we investigated the relationship between AHNAK2 and tumor infiltrating immune cells (TIICs)., Results: AHNAK2 gene was significantly overexpressed in LUAD tumor tissues and an independent prognostic indicator of LUAD patients. The expression of AHNAK2 was related to disease stage, differentiation, tumor size and lymph node metastasis. We found AHNAK2 expression was mainly positively correlated with cell adhesion-related pathways and negatively correlated with oxidative phosphorylation and amino acid metabolism. AHNAK2 expression was also negatively correlated with activated B cell, activated CD8 + T cell, and immature B cell infiltrates and positively correlated with central memory CD4 + T cell, tumor-associated macrophage, M1 macrophage, and M2 macrophage infiltrates., Conclusion: Our findings provide strong evidence of AHNAK2 expression as a prognostic indicator related to TIICs in LUAD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Estrogen receptor (ER)‑negative breast tumors are associated with low survival rates, which is related to their ability to grow and metastasize into distal organs. The aryl hydrocarbon receptor (AhR), a ligand‑activated transcription factor that is involved in several biological processes, is a promising anti‑metastatic target. Luteolin, a non‑toxic naturally occurring plant flavonoid with diverse biological activities, has been demonstrated to be effective against certain types of cancer, and has also been described as a ligand of AhR. In the present study, various cancer cell lines were first investigated following treatment with luteolin, and luteolin exhibited the lowest IC50 in MDA‑MB‑231 cells. Then, the efficiency of luteolin in suppressing the metastasis of ER‑negative breast cancer in vitro was assessed. MDA‑MB‑231 cells were treated with luteolin in vitro. Subsequently, MTT assay and flow cytometry were used to detect cell viability, the cell cycle and apoptosis, and a Transwell assay was used to evaluate cell invasion. In addition, reverse transcription‑semi‑quantitative PCR and western blot were performed to detect the mRNA and protein expression levels of matrix metalloproteinase (MMP)‑2 and MMP‑9. In addition, the number of surface tumor nodules was measured in vivo, in mice bearing B16‑F10 tumors, following treatment with luteolin. Luteolin inhibited the viability and induced the apoptosis of MDA‑MB‑231 cells, which was accompanied by cell cycle arrest. This was associated with a decrease in the expression of the pro‑metastatic markers C‑X‑C chemokine receptor type 4 (CXCR4), MMP‑2 and MMP‑9, which was reversed by AhR inhibition. Furthermore, it was identified that luteolin could inhibit the metastasis in a B16F10 mouse xenograft model, and the levels of MMP‑9, MMP‑2 and CXCR4 were significantly decreased in the lung tissues isolated from tumor‑bearing nude mice following luteolin treatment. In conclusion, luteolin is a potential molecule for inhibiting breast cancer invasion and metastasis, which could have promising clinical applications.

The two broad histological subtypes of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are the leading causes of cancer-related death in the world. Long noncoding RNAs (lncRNAs) have been verified to be critical in the regulation of cancer development. The present study identified and elucidated the regulatory roles of a novel lncRNA MRUL in NSCLC. The results showed that MRUL was overexpressed in NSCLC samples and correlated with the poor prognosis of patients who had NSCLC. Moreover, this research has for the first time demonstrated that MRUL acted as an oncogenetic lncRNA in NSCLC. Knockdown of MRUL considerably repressed NSCLC cell proliferation, invasion, and migration. The bioinformatics analysis showed that MRUL was involved in regulating multiple RNA splicing and proliferation-related biological processes, such as mRNA splicing, RNA splicing, mRNA processing, mRNA 3'-end processing, mRNA splice site selection, and DNA replication. By combining bioinformatics analysis and experimental validation, we found that MRUL regulated NSCLC progression through promoting SRSF2 by sponging miR-17 in NSCLC cells. The discoveries indicated that MRUL could be a therapeutic target and a potential diagnostic for NSCLC., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Ying Chen et al.)

Reprograming of proline metabolism is critical for tumor growth. Here we show that PINCH-1 is highly expressed in lung adenocarcinoma and promotes proline synthesis through regulation of mitochondrial dynamics. Knockout (KO) of PINCH-1 increases dynamin-related protein 1 (DRP1) expression and mitochondrial fragmentation, which suppresses kindlin-2 mitochondrial translocation and interaction with pyrroline-5-carboxylate reductase 1 (PYCR1), resulting in inhibition of proline synthesis and cell proliferation. Depletion of DRP1 reverses PINCH-1 deficiency-induced defects on mitochondrial dynamics, proline synthesis and cell proliferation. Furthermore, overexpression of PYCR1 in PINCH-1 KO cells restores proline synthesis and cell proliferation, and suppresses DRP1 expression and mitochondrial fragmentation. Finally, ablation of PINCH-1 from lung adenocarcinoma in mouse increases DRP1 expression and inhibits PYCR1 expression, proline synthesis, fibrosis and tumor growth. Our results identify a signaling axis consisting of PINCH-1, DRP1 and PYCR1 that regulates mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for alleviation of tumor growth.

Purpose: This study aimed to compare eukaryotic translation initiation factor 3B (EIF3B) expression between tumor tissues and non-cancerous tissues and to investigate the correlation of tumor EIF3B with clinical characteristics and prognosis in non-small cell lung cancer (NSCLC) patients., Methods: The tumor samples and non-cancerous adjacent tissues of 365 operated NSCLC patients were acquired. The EIF3B expression in tumor tissues and non-cancerous tissues was detected by immunohistochemistry and was classified into four groups according to multiple staining intensity and staining density as follows; low EIF3B, high(+)EIF3B, high(++) EIF3B, and high(+++) EIF3B. The clinical characteristics were extracted from the database. The disease-free survival (DFS) and overall survival (OS) was calculated from the survival data., Results: EIF3B was increased in tumor tissues (10.1% in high(+++) EIF3B, 17.5% in high(++) EIF3B, 29.9% in high(+) EIF3B, and 42.5% in low EIF3B group) compared to non-cancer tissues (2.2% in high(+++) EIF3B, 9.6% in high(++) EIF3B, 23.3% in high(+) EIF3B, and 64.9% in low EIF3B group) (p<0.001). Correlation analysis showed that tumor with higher EIF3B expression was correlated with the presence of lymph node metastasis (p=0.001) and more advanced TNM stage (p=0.026). Kaplan-Meier curves revealed that DFS and OS were worst in patients with high (+++) EIF3B expression (p<0.001). Notably, multivariate Cox's regression showed that a higher EIF3B expression was an independent predictive of decreased DFS (p=0.041) and OS (p=0.006)., Conclusion: EIF3B might be a potential biomarker to improve the monitoring and management of NSCLC in clinical practice.

Poly γ-glutamic acid (γ-PGA) is attractive due to its desirable biological properties such as nontoxicity, excellent biocompatibility, and minimal immunogenicity. Additionally, γ-PGA could be recognized by γ-glutamyl transpeptidase, which is regarded as a potential biomarker for many tumors. In this study, we have developed a new biodegradable, reduction sensitive, and tumor-specific gene nano-delivery platform consisting of a cationic carrier (SSBPEI) for siRNA condensation, mPEG shell for nanoparticle stabilization, and γ-PGA for accelerated cellular uptake. Disulfide bonds (-SS-) could be reduced specifically in the tumor environment, which is full of reductants such as glutathione reductase. Conjugating polyethylene glycol (PEG) to the γ-PGA led to the formation of mPEG-g-γ-PGA, with a decreased positive charge on the surface of SSBPEI@siRNA and substantially higher stability in an aqueous medium. As a result, mPEG-g-γ-PGA/SSBPEI@siRNA nanoparticles could protect siRNAs from RNase A degradation and release siRNAs in a reduction sensitive way. The multifunctional delivery system was shown to silence the Survivin gene and further promote chemotherapeutic drug-induced apoptosis in the A549 NSCLC cell line efficiently, thereby representing a novel promising platform for the delivery of siRNAs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The present study aimed to investigate SRY-box transcription factor 30 (SOX30) expression in nonsmall-cell lung cancer (NSCLC) tumor tissues and adjacent noncancerous tissues, and further explore the correlation of tumor SOX30 expression with clinical characteristics and survival profiles in patients with NSCLC.Totally, 365 patients with NSCLC who underwent resection were screened, and SOX30 expression was detected in their tumor tissues and adjacent noncancerous tissues via immunohistochemistry (IHC) assay, which was assessed by a semiquantitative method considering the multiplying staining intensity score and staining density score. According to the tumor SOX30 expression, patients were categorized as tumor SOX30 low (IHC score ≤3) and high (IHC score 4-12) patients, the latter were further divided into tumor SOX30 high+ (IHC score 4-6), high++ (IHC score 7-9), and high+++ (IHC score 10-12) patients.SOX30 was downregulated in NSCLC tumor tissues compared with adjacent noncancerous tissues. Meanwhile, tumor SOX30 high expression associated with well differentiation, absent lymph node metastasis, decreased TNM stage, but did not associated with age, gender, history of smoke and drink, hypertension, hyperlipidemia, diabetes, tumor size, or carcinoembryonic antigen level. Both accumulating disease-free survival and overall survival were the longest in tumor SOX30 high+++ patients, followed by tumor SOX30 high++ patients, and tumor SOX30 high+ patients, and the shortest in tumor SOX30 low patients. Besides, tumor SOX30 high expression was an independent predictor for longer disease-free survival and overall survival.Tumor SOX30 exhibits the potential to be a novel biomarker for survival prediction of patients with NSCLC.

Chemoresistance is still a major obstacle for lung cancer treatment. Increasing studies have demonstrated that microRNAs (miRNAs) are essential meditators of chemoresistance during cancer progression. MiR-451a is reported to be a tumor suppressor during cancer development. However, its effects on lung cancer and drug resistance in lung cancer are still unclear. In the study, the results showed that miR-451a exhibited a significant role in suppressing the drug resistance in lung cancer cells when treated with doxorubicin (DOX) through alleviating epithelialmesenchymal transition (EMT), as evidenced by the markedly reduced expression of N-cadherin and Vimentin, while the enhanced expression of E-cadherin. In addition, miR-451a over-expression markedly promoted the sensitivity of lung cancer cells to DOX treatments, and also disrupted the EMT of lung cancer cells. Mechanistically, miR-451a was found to directly target c-Myc to affect the EMT and drug resistance in lung cancer cells in response to DOX incubation. Furthermore, c-Myc knockdown markedly elevated the sensitivity of lung cancer cells to DOX, whereas over-expressing c-Myc markedly reversed the anti-tumor role of DOX, which was slightly diminished by miR-451a mimic. The in vivo experiments confirmed that miR-451a promoted the sensitivity of lung cancer cells-derived tumors to DOX treatment by reducing c-Myc. Therefore, our results revealed a new insight into DOX resistance of lung cancer cells and miR-451a could be considered as a potential therapeutic target to overcome drug resistance in lung cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier Masson SAS.)

Peptide modification with fatty acids is an effective method to improve peptide performance. We previously investigated the fatty acid modification of R-lycosin-I, a cytotoxic peptide derived from lycosin-I from the venom of the spider Lycosa singoriensis . In this study, we further investigated the position effects of fatty acid modification of lycosin-I. Dodecanoic acid was covalently coupled to the α/ε-amino group of one of the seven Lys residues of lycosin-I, generating eight different lipopeptides. Although all the lipopeptides had significantly improved cytotoxicity compared with lycosin-I, they displayed different cytotoxic potencies and profiles, which might be explained by multifactors including charge, size, helicity, hydrophobicity, and so forth. Of the eight lipopeptides, L-C 12 demonstrated highest cytotoxicity and antimetastasis activity in two-dimensional cells, tumor spheroids, subcutaneous transplantation mouse models, and experimental melanoma metastasis mouse models. Collectively, our finding indicated that fatty acid modification position plays important roles in physiochemical parameters and biological activities of cytotoxic peptides.

Background: Lung cancer has a very high incidence rate and is one of the commonly diagnosed tumors in developed countries., Aims: To investigate the effect of wogonin on A549 and A427 lung cancer cells and explore the mechanism involved., Study Design: Cell study., Methods: The cytotoxicity effect of wogonin on A549 and A427 lung cancer and BEAS-2B cells was assessed by MTT assay. The onset of apoptosis was assessed by flow cytometry using Annexin V FITC/PI staining. Western blotting was used for the determination of changes in apoptotic protein expression., Results: Wogonin treatment exhibited cytotoxicity effect selectively on A549 and A427 cells without affecting BEAS-2B normal lung cells. The viability of A549 and A427 cells was reduced to 31% and 34%, respectively, on treatment with 50 μM of wogonin; however, there was no significant reduction in BEAS-2B cell viability on treatment with the same concentration of it. Moreover, the percentage of apoptotic A427 cells showed a significant (p<0.049) increase on treatment with wogonin. Furthermore, the treatment led to a marked increase in the activation of caspase 3/8/9 and the generation of reactive oxygen species (ROS) at 72 h in A427 cells. Digital tomosynthesis studies showed a marked reduction in tumor development on treatment with wogonin., Conclusion: Wogonin treatment specifically exhibits a cytotoxic effect on lung cancer cells and this effect is associated with activation of apoptosis and generation of reactive oxygen species.

Background: Although the leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) is one of the mitochondrial inner membrane proteins that is involved in cancer prognosis in various tumors, LETM1 as a biomarker for prognostic evaluation of non-small cell lung carcinoma (NSCLC) has not been well studied., Methods: To address this issue, we used 75 cases NSCLC, 20 cases adjacent normal lung tissues and NSCLC cell lines. We performed immunohistochemistry staining and western blot analysis as well as immunofluorescence imaging., Results: Our studies show that expression of LETM1 is significantly correlated with the lymph node metastasis (p = 0.003) and the clinical stage (p = 0.005) of NSCLC. The Kaplan-Meier survival analysis revealed that NSCLC patients with positive expression of LETM1 exhibits a shorter overall survival (OS) rate (p = 0.005). The univariate and multivariate Cox regression analysis indicated that LETM1 is a independent poor prognostic marker of NSCLC. In addition, the LETM1 expression is correlated with cancer stemness-related gene LGR5 (p < 0.001) and HIF1α expression (p < 0.001), but not with others. Moreover, LETM1 expression was associated with the expression of cyclin D1 (p = 0.003), p27 (p = 0.001), pPI3K(p85) (p = 0.025), and pAkt-Thr308 (p = 0.004). Further, our studies show in LETM1-positive NSCLC tissues the microvessel density was significantly higher than in the negative ones (p = 0.024)., Conclusion: These results indicate that LETM1 is a potential prognostic biomarker of NSCLC.

The evolutionarily conserved serine/threonine kinase Nemo‑like kinase (NLK) serves an important role in cell proliferation, migration, invasion and apoptosis by regulating transcription factors among various cancers. In the present study, the function of NLK in human non‑small cell lung cancer (NSCLC) was investigated. Immunohistochemical analysis and western blotting demonstrated that NLK expression was significantly reduced in NSCLC tissues compared with corresponding peritumoral tissues. Statistical analysis revealed that decreased NLK expression was associated with the presence of primary tumors, tumor node metastasis (TNM) staging, differentiation, lymph node metastasis, and E‑cadherin and vimentin expression. Univariate analysis indicated that NLK expression, differentiation, lymph node metastasis, TNM stage, and E‑cadherin and vimentin expression affected the prognosis of NSCLC. Cox regression analyses revealed NLK expression and TNM as independent factors that affected prognosis. Kaplan‑Meier survival analysis revealed that patients with NSCLC and low NLK expression had relatively shorter durations of overall survival. In vitro, NLK overexpression inhibited A549 ncell migration and invasion as determined by wound healing and Transwell migration assays, respectively. Additionally, immunofluorescence staining indicated that downregulation of NLK expression could induce epithelial‑mesenchymal transition in NSCLC. NLK knockdown significantly decreased the expression of the epithelial marker E‑cadherin, and markedly increased that of β‑catenin and the mesenchymal marker vimentin. Furthermore, NLK was reported to directly interact with β‑catenin as determined by a co‑immunoprecipitation assay. Collectively, the results of the present study indicated that decreased NLK expression could promote tumor metastasis in NSCLC.

With the advancement of nanotechnology, various nanocomposites have been applied in the diagnostics and treatment of cancer. We synthetized FePt nanoparticles which were assembled on the surface of graphene oxide (GO). These novel FePt/GO nanosheets simultaneously act as a chemotherapy drug and enhance radiosensitivity. In this study, transmission electron microscope, dynamic light scattering, X-ray photoelectron spectroscope and Fourier transform infrared spectroscopy were used to characterize surface morphology and chemical composition of FePt/GO nanosheets (NSs). Their cytotoxicity in various cancer and normal cells was evaluated by cell counting kit-8 assay, and their effects on radiosensitization were determined by colony formation assay. To explore the underlying mechanisms, we measured the intracellular reactive oxygen species levels and autophagy formation. Monodansylcadaverine-staining, Western Blotting and ultrastructure analysis were utilized to assess autophagy. The results demonstrated that FePt/GO NSs not only selectively suppressed the proliferation of cancer cells, but also increased their radiosensitization. Moreover, FePt/GO NSs induced autophagy, which might result in promoted sensibilization of radiotherapy. In conclusion, with good safety and efficacy, FePt/GO NSs are safe and effective to suppress proliferation, enhance radiosensitization and induce autophagy of human non-small cell lung cancer cells. They are potential for the treatment of lung cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Several factors within the perioperative period may influence postoperative metastatic spread. Dexmedetomidine and midazolam are widely used general anesthetics during surgery. The authors assessed their effects on human lung carcinoma (A549) and neuroglioma (H4) cell lines in vitro and in vivo., Methods: Cell proliferation and migration were measured after dexmedetomidine (0.001 to 10 nM) or midazolam (0.01 to 400 μM) treatment. Expression of cell cycle and apoptosis markers were assessed by immunofluorescence. Mitochondrial membrane potential and reactive oxygen species were measured by JC-1 staining and flow cytometry. Antagonists atipamezole and flumazenil were used to study anesthetic mechanisms of action. Tumor burden after anesthetic treatment was investigated with a mouse xenograft model of lung carcinoma., Results: Dexmedetomidine (1 nM) promoted cell proliferation (2.9-fold in A549 and 2-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), migration (2.2-fold in A549 and 1.9-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), and upregulated antiapoptotic proteins in vitro. In contrast, midazolam (400 μM) suppressed cancer cell migration (2.6-fold in A549 cells, P < 0.0001; n = 4), induced apoptosis via the intrinsic mitochondrial pathway, decreased mitochondrial membrane potential, and increased reactive oxygen species expression in vitro-effects partly attributable to peripheral benzodiazepine receptor activation. Furthermore, midazolam significantly reduced tumor burden in mice (1.7-fold vs. control; P < 0.05; n = 6 per group)., Conclusions: Midazolam possesses antitumorigenic properties partly mediated by the peripheral benzodiazepine receptor, whereas dexmedetomidine promotes cancer cell survival through signaling via the α2-adrenoceptor in lung carcinoma and neuroglioma cells.

Purpose: Lentinan is a polysaccharide extracted from Shiitake mushrooms that have been used to improve general health for thousands of years in Asia. Lentinan injection is a clinically approved drug in several countries in Asia. The purpose of this study is to review the structure, preclinical and clinical studies, and molecular mechanisms of lentinan. Most importantly, the clinical effectiveness of lentinan as an adjuvant therapeutic drug in treating patients with lung cancer in China during the past 12 years is analyzed statistically., Methods: We carried out literature search of randomized controlled trials (RCTs) published from 2004 to 2016 based on CNKI (China National Knowledge Infrastructure), VIP (Chongqing VIP Chinese Scientific Journals Database) and Wanfang database, and 38 eligible RCTs of lentinan-associated lung cancer treatment were identified, containing 3,117 patients., Results: The structure and function relationship and underlying molecular mechanism of lentinan as an immunostimulant has been summarized. The mean value of overall response rate in treating lung cancer was increased from 43.3% of chemotherapy alone to 56.9% of lentinan plus chemotherapy [p < 0.001, 95% confidence interval (CI) 0.102-0.170]. Compared with chemotherapy alone, lentinan plus chemotherapy showed more efficacy in treating lung cancer (pooled RR 0.79, 95% CI 0.74-0.85) and no statistical heterogeneity was found among studies (I 2  = 11%)., Conclusion: Clinical data presented in the past 12 years shows that lentinan is effective not only in improving quality of life, but also in promoting the efficacy of chemotherapy during lung cancer treatment.

15-Lipoxygenase-2 (15-LOX-2) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) have been considered as latent mediators of diverse biological processes including cancer. However, their functions in lung adenocarcinoma (LAC) are unclear. In this study, we aimed to determine whether 15-LOX-2/15(S)-HETE is involved in the proliferation and migration of A549 cells and to identify the signaling pathways that participate in this process. We used immunohistochemistry to identify the expression levels of 15-LOX-2 in lung cancer tissue samples. The effects of 15(S)-HETE on the proliferation and migration of A549 cells under hypoxic conditions were assessed by cell viability assays, immunofluorescence, western blotting, scratch wound assays and transwell assays. We found that the expression of 15-LOX-2 was significantly up-regulated in LAC tissue samples compared with adjacent normal tissue samples. The content of 15(S)-HETE in A549 cells was increased under hypoxic conditions. Moreover, 15(S)-HETE could stimulate the expression of PCNA, cyclin A and cyclin D. In addition, siRNA of 15-LOX-2 inhibited the proliferation and migration of A549 cells in vitro. Our data also provide novel evidence demonstrating that the STAT3 pathway participates in the 15(S)-HETE-induced proliferation and migration of A549 cells. This study may provide a greater understanding of LAC metastasis and shed new light on the mechanisms by which the 15(S)-HETE/STAT3 pathway is related to this disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Radiomics has shown potential in disease diagnosis, but its feasibility for non-small cell lung carcinoma (NSCLC) subtype classification is unclear. This study aims to explore the diagnosis value of texture and colour features from positron emission tomography computed tomography (PET-CT) images in differentiation of NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). Two patient cohorts were retrospectively collected into a dataset of 341 18 F-labeled 2-deoxy-2fluoro-d-glucose ([ 18 F] FDG) PET-CT images of NSCLC tumours (125 ADC, 174 SqCC, and 42 cases with unknown subtype). Quantification of texture and colour features was performed using freehand regions of interest. The relation between extracted features and commonly used parameters such as age, gender, tumour size, and standard uptake value (SUVmax) was explored. To classify NSCLC subtypes, support vector machine algorithm was applied on these features and the classification performance was evaluated by receiver operating characteristic curve analysis. There was a significant difference between ADC and SqCC subtypes in texture and colour features (P  <  0.05); this showed that imaging features were significantly correlated to both SUVmax and tumour diameter (P  <  0.05). When evaluating classification performance, features combining texture and colour showed an AUC of 0.89 (95% CI, 0.78-1.00), colour features showed an AUC of 0.85 (95% CI, 0.71-0.99), and texture features showed an AUC of 0.68 (95% CI, 0.48-0.88). DeLong's test showed that AUC was higher for features combining texture and colour than that for texture features only (P  =  0.010), but not significantly different from that for colour features only (P  =  0.328). HSV colour features showed a similar performance to RGB colour features (P  =  0.473). The colour features are promising in the refinement of NSCLC subtype differentiation, and features combining texture and colour of PET-CT images could result in better classification performance.