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N 6 -Methyladenosine (m 6 A) is the most prevalent mRNA modification. Its biological function primarily relies on its "Reader" protein, such as YTHDC2. Previous studies have shown that YTHDC2 downregulation is a procarcinogenic phenomenon in lung adenocarcinoma (LUAD). However, further investigation is needed to understand the molecular mechanisms of downstream genes and the associated biological phenomena following YTHDC2 downregulation. Here, we found that YTHDC2 knockout upregulated exosome content in LUAD. Following YTHDC2 knockout, the mRNA levels of OAS family members (OASs) and IFIT family members (IFITs) also decreased; and inhibition of OASs and IFITs could promote exosome content. Several m 6 A modification sites on the NT domain of OASs and the TPR12 domain of IFITs were found to increase the stability of OASs and IFITs in a YTHDC2-dependent manner. OASs and IFITs affected exosome content through target genes including RAB5A, RAB7, and RAB11A, and three arginine (R) amino acids on IFITs were critical for combination IFITs with targeted RAB mRNAs and subsequent degradation. Simultaneously, OASs degraded targeted RABs through RNAseL. Additionally, mutual bindings between OASs and IFITs were critical for their target gene degradation. Collectively, the above findings might provide a theoretical basis for the treatment of LUAD patients with low YTHDC2 expression., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: All known randomized trials of stereotactic radiotherapy (SRT) versus whole brain radiotherapy (WBRT) for brain metastases (BMs) comprise mixed histologies. The phase III HYBRID trial (NCT02882984) attempted to evaluate the non-inferiority of SRT vs. WBRT specifically for EGFR-mutated non-small cell lung cancer (EGFRm NSCLC) BMs., Methods: Inclusion criteria were ≤ 5 BMs (any size) from treatment-naïve EGFRm NSCLC. All patients started a first-generation tyrosine kinase inhibitor on the first day of WBRT (37.5 Gy/15 fractions) or SRT (25-40 Gy/5 fractions per tumor volume). The primary endpoint was 18-month intracranial progression-free survival (iPFS; intention-to-treat)., Results: The trial commenced in June 2015 and was closed in April 2021 after screening 208 patients but enrolling 85 (n = 41 WBRT, n = 44 SRT; median follow-up 31 and 36 months, respectively). Respectively, 9.5 % vs. 10.2 % of patients experienced intracranial progression at 18 months, and the median iPFS was 21.4 vs. 22.3 months (p > 0.05 for all). The SRT arm experienced higher overall survival and cognitive preservation (p < 0.05 for all). The most notable reason for low enrollment was patients not wishing to risk neurocognitive decline from WBRT., Conclusions: Although this phase III trial was underpowered, there was no evidence that SRT yielded outcome detriments compared to WBRT for EGFRm NSCLC BMs. Lessons from prematurely closed trials are valuable, as they often provide important experiential perspectives for investigators designing/executing future trials. In the current era, randomized trials involving WBRT without cognitive sparing measures may be at high risk of underaccrual; trial investigators are encouraged to carefully consider our experience when attempting to design such trials. However, trials of molecular-/biologically-stratified patients are highly recommended as the notion of "individualized medicine/oncology" continues to expand., 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 Elsevier B.V. All rights reserved.)

Background: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive., Purpose: To evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism., Methods: CCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance., Results: PPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC 50 at 2.0 μM). Significantly, treatment with PPI at 1.0 μM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL., Conclusions: We present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that might influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC) treatment, but the response rate remains low. Programmed cell death ligand 1 (PD-L1) in peripheral blood, including soluble form (sPD-L1), expression on circulating tumor cells (CTCs PD-L1) and exosomes (exoPD-L1), are minimally invasive and promising markers for patient selection and management, but their prognostic significance remains inconclusive. Here, we performed a meta-analysis for the prognostic value of PD-L1 blood markers in NSCLC patients treated with ICIs., Methods: Eligible studies were obtained by searching PubMed, EMBAS, Web of Science, and Cochrane Library prior to November 30, 2023. The associations between pre-treatment, post-treatment and dynamic changes of blood PD-L1 levels and progression-free survival (PFS)/over survival (OS) were analyzed by estimating hazard ratio (HR) and 95% confidence interval (CI)., Results: A total of 26 studies comprising 1606 patients were included. High pre- or post-treatment sPD-L1 levels were significantly associated with worse PFS (pre-treatment: HR=1.49, 95%CI 1.13-1.95; post-treatment: HR=2.09, 95%CI 1.40-3.12) and OS (pre-treatment: HR=1.83, 95%CI 1.25-2.67; post-treatment: HR=2.60, 95%CI 1.09-6.20, P=0.032). High pre-treatment exoPD-L1 levels predicted a worse PFS (HR=4.24, 95%CI 2.82-6.38, P<0.001). Pre-treatment PD-L1 + CTCs tended to be correlated with prolonged PFS (HR=0.63, 95%CI 0.39-1.02) and OS (HR=0.58, 95%CI 0.36-0.93). Patients with up-regulated exoPD-L1 levels, but not sPD-L1, after ICIs treatment had significantly favorable PFS (HR=0.36, 95%CI 0.23-0.55) and OS (HR=0.24, 95%CI 0.08-0.68)., Conclusion: PD-L1 blood markers, including sPD-L1, CTCs PD-L1 and exoPD-L1, can effectively predict prognosis, and may be potentially utilized for patient selection and treatment management for NSCLC patients receiving ICIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Chang, Liu, Tian and Yu.)

Background: Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residual disease (MRD) in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer (NSCLC)., Methods: We enrolled 58 NSCLC patients in a real-world setting, and 58 tumor tissues and 325 plasma samples were analyzed. Tumor tissues and plasma samples were subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related and ultra-deep targeted NGS covering 338 genes, respectively., Results: ctDNA was detected in 31.0% of cases at the first postoperative time, which was associated with advanced tumor stage, T stage and KEAP1 or GRIN2A mutations in tissues. ctDNA positivity at landmark and longitudinal indicated the shorter disease-free survival. For patients with ctDNA positivity at the first postoperative time, regardless of adjuvant therapy, all patients who were persistently ctDNA positive during postoperative surveillance had disease recurrence. Among the patients who were ctDNA negative, only two patients (15.4%, 2/13) receiving adjuvant therapy relapsed, while one patient (50.0%, 1/2) without adjuvant therapy relapsed. For the first postoperative ctDNA negative patients, the recurrence rate of patients with adjuvant therapy was and higher than without adjuvant therapy (22.6% [7/31] vs. 11.1% [1/9]). The patients who became ctDNA positive may also benefit from intervention therapy., Conclusion: Postoperative ctDNA is a prognostic marker, and ctDNA-detection may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (K‒M) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1-49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1-49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI., (© 2024. The Author(s).)

Background: Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily and has been implicated in various diseases. However, the specific role of IGSF6 in the anti-tumor immunity within lung adenocarcinoma (LUAD) remains unclear., Methods: We analyzed the IGSF6 expression in LUAD using data from TCGA, and we performed qRT-PCR and western blotting to validate these findings using tissue samples obtained from LUAD patients. Images of IHC staining were obtained from HPA. To assess the clinical relevance of IGSF6 expression, we utilized UALCAN and SPSS to analyze its association with major clinical features of LUAD. Additionally, we employed ROC curves and survival analysis to evaluate the potential diagnostic and prognostic value of IGSF6 in LUAD. To gain insights into the functional implications of IGSF6, we performed enrichment analysis using the R software clusterProfiler package. Moreover, we utilized TIMER2.0 and TISIDB to investigate the relationship between IGSF6 and immune infiltrates in LUAD. The proportion of tumor-infiltrating immune cells in LUAD was assessed using FCM, and their correlation with IGSF6 expression in tumor tissues was analyzed. The localization of IGSF6 protein on macrophages was confirmed using the HPA and FCM. To determine the regulatory role of IGSF6 on macrophage activity in LUAD, we employed ELISA, FCM, and tumor-bearing models., Results: We discovered that both IGSF6 mRNA and protein levels were significantly decreased in LUAD. Additionally, we observed a negative correlation between IGSF6 expression and TNM stages as well as pathologic stages in LUAD. Notably, IGSF6 exhibited high sensitivity and specificity in diagnosing LUAD, and was positively associated with the survival rate of LUAD patients. Furthermore, IGSF6 expression was closely linked to gene sets involved in immune response. IGSF6 expression showed a positive correlation with immune infiltrates exhibiting anti-tumor activity, particularly M1 macrophages. We confirmed the predominant localization of the IGSF6 protein on the membrane of M1 macrophages. Importantly, the knockdown of IGSF6 resulted in a reduction in the anti-tumor activity of M1 macrophages, thereby promoting tumor progression., Conclusion: IGSF6 is a molecule that is essential for the anti-tumor activity of macrophages in LUAD., (© 2023. The Author(s).)

Non-small cell lung cancer (NSCLC) is the main pathological type of lung cancer. In this study, multi-omics analysis revealed a significant increase of pseudouridine synthase 1 (PUS1) in NSCLC and the high expression of PUS1 was associated with shorter OS (Overall Survival), PFS (Progression Free Survival), and PPS (Post Progression Survival) of NSCLC patients. Clinical subgroup analysis showed that PUS1 may be involved in the occurrence and development of NSCLC. Besides, TIMER, ESTIMATE, and IPS analysis suggested that PUS1 expression was associated with immune cell infiltration, and the expression of PUS1 was significantly negatively correlated with DC cell infiltration. GESA analysis also indicated PUS1 may involve in DNA&#95;REPAIR, E2F&#95;TARGETS, MYC&#95;TARGETS&#95;V2, G2M&#95;CHECKPOINT and MYC&#95;TARGETS&#95;V1 pathways and triggered NSCLC malignancy through MCM5 or XPO1. Furthermore, PUS1 may be a potential target for NSCLC therapy.

Aims: Lipid peroxidation occurring in lung adenocarcinoma (LUAD) cells leads to ferroptosis. Lysophosphatidylcholine acyl-transferase 3 (LPCAT3) plays a key role in providing raw materials for lipid peroxidation by promoting esterification of polyunsaturated fatty acids to phospholipids. Whether LPCAT3 determines ferroptosis sensitivity and the mechanism by which its expression is regulated in LUAD has not been reported. Results: LPCAT3 and acyl-coenzyme A (CoA) synthetase long-chain family member (ACSL)4 levels were positively associated with ferroptosis sensitivity in LUAD cell lines. Overexpression of LPCAT3 and ACSL4 sensitized LUAD cells to ferroptosis, while LPCAT3 and ACSL4 knockout showed the opposite effect. Zinc-finger E-box-binding (ZEB) was shown to directly bind the LPCAT3 promoter to stimulate its transcription in a Yes-associated protein (YAP)-dependent manner. An interaction between YAP and ZEB was also observed. E1A-binding protein p300 (EP300) simultaneously bound with YAP and ZEB, and induced H3K27Ac for LPCAT3 transcription. This mechanism was verified in primary LUAD cell and xenograft models. The ACSL4, LPCAT3, and YAP combination can jointly determine LUAD ferroptosis sensitivity. Innovation: The binding site of ZEB exists in the -1600 to -1401 nt region of LPCAT3 promoter, which promotes LPCAT3 transcription after ZEB binding. ZEB and YAP bind, and the ZEB zinc-finger cluster domain and YAP WW domain are crucial for their binding. EP300 may bind with YAP via its Bromo domain and with ZEB via its CBP/p300-HAT domain. In addition, the combination of ACSL4, LPCAT3, and YAP to determine ferroptosis sensitivity of LUAD cells is better than prostaglandin-endoperoxide synthase 2 (PTGS2), transferrin receptor (TFRC), or NADPH oxidase 1 (NOX1). Conclusion: LPCAT3 transcription is regulated by YAP, ZEB, and EP300. LUAD ferroptosis sensitivity can be determined by the combination of ACSL4, LPCAT3, and YAP. Antioxid. Redox Signal. 39, 491-511.

Lung cancer has high morbidity and mortality. This study demonstrated that Bufalin inhibits the proliferation of lung cancer cells in vivo / in vitro by suppressing Hippo-YAP pathway. Here, we found that Bufalin promoted the binding of LATS and YAP to elevate the level of YAP phosphorylation. Phosphorylated YAP could not successfully enter the nucleus to activate the expression of downstream proliferation-related target genes Cyr61 and CTGF, whereas the YAP retained in the cytoplasm further bound to β-TrCP and underwent ubiquitination and degradation. This study verified the key role of YAP in stimulating the proliferation of lung cancer and revealed the anticancer target of Bufalin. Therefore, this study provides a theoretical basis for the anticancer effect of Bufalin, and suggests that Bufalin can be a potential anticancer drug., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to evaluate the efficacy and safety of osimertinib for the treatment of leptomeningeal metastases (LM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC)., Methods: We conducted a systematic review and meta-analysis to aggregate the clinical outcomes of patients with LM from EGFR-mutant NSCLC treated with osimertinib. A comprehensive literature search for published and unpublished studies was implemented in April 2021 of PubMed, EMBASE, the Cochrane Library, and several international conference databases, in accordance with the PRISMA guidelines. Meta-analysis of proportions was conducted to calculate the pooled rate of overall response rate (ORR), disease control rate (DCR), one-year overall survival (OS), and adverse events (AEs)., Results: A total of eleven studies (five prospective and six retrospective) including 353 patients were included. The majority of patients (346/353, 98.0%) received osimertinib as ≥ 2nd-line treatment for LM, either at a dosage of 80 mg (161/353, 45.6%) or 160 mg (191/353, 54.1%). The pooled rates of ORR and DCR were 42% (95% CI 24% to 59%) and 93% (95% CI 88% to 97%), respectively. The pooled one-year OS rate was 59% (95% CI 53% to 65%) in 233 patients from five studies. The highest incidence of AEs of all grades was rash (53%), followed by diarrhea (45%), paronychia (35%), decreased appetite (35%), and dry skin (27%), based on data from four studies., Conclusions: Our study highlighted and confirmed the meaningful efficacy and a manageable safety profile of osimertinib for the treatment of LM from EGFR-mutant advanced NSCLC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To investigate the value of 18 F-fluorodeoxyglucose(FDG) PET/CT multi-time points imaging (MTPI) on the differential diagnosis between lung cancer (LC) and tuberculosis (TB)., Methods: Sixty-four patients underwent 18 F-FDG PET/CT MTPI. The stdSUVmax, stdSUVavg, retention index, metabolic tumor volume, total lesion glycolysis at four-time points and slope of metabolic curve were measured and calculated, and the sex, age, and uniformity of FDG uptake were recorded. The difference in each index between LC and TB was analyzed, and dynamic metabolic curves (DMCs) of LC and TB were fitted by significance indexes. Artificial neural network (ANN) prediction models were established between squamous cell carcinoma (SCC) and TB, as well as between adenocarcinomas and TB., Results: Differences between SCC and TB, stdSUVmax/avg at four-time points, total lesion glycolysis, stdSUVmax/avg slope (1-2 h,1-3 h and 1-4 h), uniformity of FDG uptake and age were significant. stdSUVavg has the largest area under the 4 h curve; age was only significant between adenocarcinomas and TB. DMCs at 1-4 h fitted by stdSUVavg were more helpful in differentiating LC and TB than stdSUVmax. stdSUVavg(1 h and 4 h), stdSUVavg slope 1-4 h, age, and uniformity of FDG uptake were selected to establish an ANN prediction model between SCC and TB; the area under the curve (AUC) was 100.0%. The same indices were used to establish the prediction model between adenocarcinomas and TB; the AUC was up to 83.5, and after adding stdSUVavg (2 and 4 h) to adenocarcinomas and TB models, the AUC was 87.7%., Conclusion: 18 F-FDG PET/CT MTPI fitting DMCs and establishing an ANN prediction model would distinguish SCC from TB relatively accurately and provide certain help in the differentiation between adenocarcinomas and TB., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We analyzed the somatic mutation distributions as well as pathways associated with liver/lung metastasis of CRC using next-generation sequencing panel., Methods: We detected the somatic SNV/indel mutations of 1126 tumor-related genes in CRC, liver/lung metastasis of CRC and liver /lung cancer. We combined the MSK and GEO datasets to identified the genes and pathways related to the metastasis of CRC., Results: We identified 174 genes related to liver metastasis of CRC, 78 genes related to lung metastasis of CRC, and 57 genes related to both liver and lung metastasis in two datasets. The genes related to liver and lung metastasis were collectively enriched in various pathways. Finally we found that IRS1, BRCA2, EphA5, PTPRD, BRAF, and PTEN could be prognosis-related genes in CRC metastasis., Conclusion: Our finding may help clarify the pathogenesis of CRC metastasis more clearly and provide new perspectives for the diagnosis and treatment of CRC metastasis., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKIs remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations; however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures (PARIS) method is used to establish the higher-order RNA structure maps of EGFR-TKIs-resistant and -sensitive cells of NSCLC. Our results show that RNA structural regions are enriched in untranslated regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N 6 -threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs. RNA structure formation in YRDC 3' UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

A previous genome-wide association study (GWAS) revealed an association of the noncoding SNP rs1663689 with susceptibility to lung cancer in the Chinese population. However, the underlying mechanism is unknown. In this study, using allele-specific 4C-seq in heterozygous lung cancer cells combined with epigenetic information from CRISPR/Cas9-edited cell lines, we show that the rs1663689 C/C variant represses the expression of ADGRG6, a gene located on a separate chromosome, through an interchromosomal interaction of the rs1663689 bearing region with the ADGRG6 promoter. This reduces downstream cAMP-PKA signaling and subsequently tumor growth both in vitro and in xenograft models. Using patient-derived organoids, we show that rs1663689 T/T-but not C/C-bearing lung tumors are sensitive to the PKA inhibitor H89, potentially informing therapeutic strategies. Our study identifies a genetic variant-mediated interchromosomal interaction underlying ADGRG6 regulation and suggests that targeting the cAMP-PKA signaling pathway may be beneficial in lung cancer patients bearing the homozygous risk genotype at rs1663689., (© 2023 The Authors.)

Purpose: This study evaluated whether antibiotic treatment before chemoradiotherapy influenced outcomes in patients with locally advanced non-small cell lung cancer (LA-NSCLC)., Methods: The records of LA-NSCLC patients treated with chemoradiotherapy between 2010 and 2017 at West China Hospital of Sichuan University were retrospectively examined together with their antibiotic use (antibiotic type, duration of treatment, and time between discontinuation and chemoradiotherapy). The influence of antibiotics on progression-free survival (PFS) and overall survival (OS) was evaluated with Kaplan-Meier curves and univariate and multivariate Cox regression., Results: Of 522 patients, 176 had received intravenous broad-spectrum antibiotics in the month before chemoradiotherapy. Antibiotic use was linked to both reduced PFS (7.9 vs. 13.4 months, p < 0.001) and OS (20.4 vs. 25.3 months, p = 0.049). Multivariate regression demonstrated that antibiotic treatment was an unfavorable independent prognostic factor for LA-NSCLC patients who received chemoradiotherapy (HR 1.234; 95% CI 1.019-1.494; p = 0.031). Prognosis was also influenced by antibiotic type, length of treatment, and interval between discontinuation and chemoradiotherapy initiation. β‑lactamase inhibitors were found to be the most harmful (median OS for β‑lactamase inhibitors/fluoroquinolones/cephalosporins: 16.5/19.9/25.9 months, p = 0.045). Cutoff values for interval and duration calculated by the X‑tile procedure showed that intervals of 7-16 days or durations ≤ 6 days did not significantly affect OS relative to untreated patients (intervals: p = 0.9; duration: p = 0.93)., Conclusion: Antibiotic treatment for longer than 6 days, especially with β‑lactamase inhibitors, was associated with poor prognosis. Furthermore, delaying chemoradiotherapy for 7-16 days after antibiotic discontinuation may reduce these negative effects., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) can be used in pediatric patients. This study assessed the safety and efficacy of PEG-rhG-CSF as a primary prophylactic drug against neutropenia after chemotherapy in pediatric patients with solid tumors or non-Hodgkin lymphoma (NHL)., Patients and Methods: This phase II study (between October 2020 and March 2022) enrolled pediatric patients with solid tumors or NHL treated with high-intensity chemotherapy and with grade ≥3 myelosuppression for at least 14 days during chemotherapy. Prophylactic PEG-rhG-CSF was given at 100 μg/kg body weight (maximum total dosage of 6 mg) once 24-48 h following chemotherapy for two cycles. The primary endpoint was the incidence of PEG-rhG-CSF-related adverse events (AEs). The key secondary endpoints were the rates of grade 3/4 neutropenia and febrile neutropenia (FN)., Results: This study included 160 pediatric patients with a median age of 6.22 (0.29, 18.00) years. Fifty-eight patients (36.25%) were diagnosed with sarcoma. AEs potentially related to PEG-rhG-CSF included bone pain (n = 32), fatigue (n = 21), pain at the injection site (n = 21), and myalgia (n = 20). The rates of grade 3/4 neutropenia and FN during treatment were 57.28% and 29.45%, respectively., Conclusion: PEG-rhG-CSF is well tolerated and effective in pediatric patients with solid tumors or NHL. These findings should be substantiated with further trials., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04547829., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

WW domain containing E3 ubiquitin protein ligase 2 (WWP2) is a member of the NEDD4 E3 ubiquitin ligase family. WWP2 ligase activity is regulated by the 2, 3-linker auto-inhibition. Tyrosine phosphorylation of the 2, 3-linker was identified as an activating means for releasing the auto-inhibition of WWP2. However, the tyrosine kinase (TK) for the phosphorylation and activation remains unknown. In this report, we have found that non-receptor TK ACK1 binds to the WW3 domain of WWP2 and phosphorylates WWP2. ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity. Unexpectedly, tyrosine phosphorylation of the 2, 3-linker seems not a major mode for activation of WWP2, as ACK1 causes much higher activation of the 2, 3-linker tyrosine phosphorylation defective mutants of WWP2 than that of wild-type WWP2. Furthermore, epidermal growth factor (EGF) stimulates tyrosine phosphorylation of WWP2 and this EGF-stimulated phosphorylation of WWP2 is mediated by ACK1. Finally, knockdown of WWP2 by shWWP2 inhibits the EGF-dependent cell proliferation of lung cancer A549 cells, suggesting that WWP2 may function in the EGFR signaling in lung cancer progression. Taken together, our findings have revealed a novel mechanism underlying activation of WWP2., (© 2023 International Union of Biochemistry and Molecular Biology.)

Background: Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined., Research Question: Which factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis?, Study Design and Methods: The progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV 1 , and generalized linear models were used to identify variables affecting FEV 1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis., Results: VEGF-D levels and sirolimus treatment were associated with FEV 1 changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of ≥ 800 pg/mL lost FEV 1 faster (SE, -38.86 mL/y; 95% CI, -73.90 to -3.82 mL/y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of ≥ 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV 1 by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV 1 of 70% predicted or St. George's Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival., Interpretation: Serum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis., Trial Registry: ClinicalTrials.gov; No.: NCT03193892; URL: www., Clinicaltrials: gov., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether ezrin regulates Yes-associated protein (YAP) and programed cell death ligand-1 (PD-L1), which are involved in the invasion and metastasis of non-small cell lung cancer (NSCLC)., Methods: Immunohistochemistry of 164 NSCLC and 16 para-cancer tissues was performed to detect ezrin, YAP, and PD-L1 expression. Further, H1299 and A549 cells were transfected with lentivirus, and then colony formation, CCK8, transwell, and wound-healing assays were used to assess cell proliferation, migration, and invasion. RT-qPCR and western blotting were used for quantitative analysis of ezrin, PD-L1, and YAP expression. Moreover, the role of ezrin in tumor growth was assessed in vivo, and immunohistochemistry and western blotting were performed to evaluate changes in ezrin expression in mouse samples., Results: The positive protein expression rates of these molecules in NSCLC were as follows: ezrin, 43.9% (72/164); YAP, 54.3% (89/164); and PD-L1, 47.6% (78/164); these were higher than those in normal lung tissues. Moreover, YAP and ezrin expression positively correlated with PD-L1 expression. Ezrin promoted proliferation, migration, invasion, and expression of YAP and PD-L1in NSCLC. Inhibition of ezrin expression reduced the effects of ezrin on cell proliferation, migration, invasion, inhibited the expression of YAP and PD-L1, and obviously reduced experimental tumor volume in vivo., Conclusions: Ezrin is overexpressed in NSCLC patients and correlates with PD-L1 and YAP expression. Ezrin regulates YAP and PD-L1 expression. Inhibition of ezrin delayed NSCLC progression., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.

High tumour programmed cell death-ligand 1 (PD-L1) expression is associated with poor progression-free survival (PFS) after tyrosine kinase inhibitor (TKI) therapy in ALK -rearranged non-small cell lung cancer (NSCLC). However, the characteristics of the tumour microenvironment (TME) and their prognostic values in ALK -rearranged NSCLC are unknown. Here, we collected tumour tissues from pretreated ALK -rearranged NSCLC patients, immunohistochemical staining was used to assess PD-L1 expression, and tumour-infiltrating immune cells were determined via multiplex immunofluorescence staining (mIF). Our data showed that the median values of PFS for the high PD-L1 group and low PD-L1 group who received ALK-TKI treatment were 4.4 and 16.4 months, respectively ( p = 0.008). The median overall survival (OS) of the two groups was 24.0 months and not reached, respectively ( p = 0.021). Via univariate and multivariate analyses, a high PD-L1 expression and a worse ECOG PS were determined to be independent prognostic factors of OS (HR = 3.35, 95% CI: 1.23-9.11, p = 0.018; HR = 6.42, 95% CI: 1.45-28.44, p = 0.014, respectively). In addition, the high PD-L1 group had increased Tregs and exhausted CD8+ T cells in both the tumour and stroma (all p < 0.05). High PD-L1 expression was an adverse predictive and prognostic biomarker for ALK -rearranged NSCLC. The characteristics of the TME in patients with high PD-L1 expression were shown to have an immunosuppressive status.

Background: RNA 5-methylcytosine (m 5 C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m 5 C modification in tumor drug resistance remain unclear., Methods: The correlation between RNA m 5 C methylation, m 5 C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo. RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m 5 C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays., Results: RNA m 5 C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo. Integrated RNA-seq and m 5 C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m 5 C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m 5 C reader Y-box binding protein 1 (YBX1)., Conclusions: Our study reveals a critical function of aberrant RNA m 5 C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC., (© 2023. The Author(s).)

Background and Purpose: The role of postoperative radiotherapy (PORT) in uncertain resection of pN2 non-small cell lung cancer (NSCLC) with highest mediastinal lymph node positive has not been determined. We aim to evaluate the effect of PORT and driver gene mutation status (DGMS) on survival in such patients., Methods: 140 selected patients were grouped according to whether they received PORT and their DGMS. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of each group were evaluated by Kaplan-Meier analyses. COX regression was used to evaluate the effects of various factors on DFS and OS., Results: Of 140 patients, thirty-four patients (24.3%) received PORT, and forty (28.6%) had positive driver gene mutation status (DGp). PORT significantly prolonged LRFS (p = 0.002), DFS (p = 0.019) and OS (p = 0.02), but not DMFS (p = 0.062). By subgroup analysis, in patients with negative driver gene mutation status (DGn), those receiving PORT had notably longer LRFS (p = 0.022) and DFS (p = 0.033), but not DMFS (p = 0.060) or OS (p = 0.215), compared to those not receiving PORT. Cox analysis showed that the number of positive lymph nodes (PLNs) and administration of PORT were independent prognostic factors of DFS, and pathology, PLNs, and DGMS may be prognostic factors of OS (all p < 0.05)., Conclusion: Postoperative radiotherapy may improve locoregional recurrence-free and disease-free survival in patients with pN2 NSCLC with positive highest mediastinal lymph nodes, while driver gene mutation status impacted OS significantly. Only patients with positive driver gene mutations experienced significant overall survival benefits from postoperative radiotherapy., (© 2022. The Author(s) under exclusive licence to Japan Radiological Society.)

Background: This study aims to evaluate the efficacy and therapeutic mechanism of bufalin on lung adenocarcinoma (LUAD) through a comprehensive strategy integrating network pharmacology, metabolomics and molecular biology verification., Methods: The putative targets of bufalin were discerned from PharmMapper and Swiss Target Prediction database. LUAD-related targets were obtained by target filtering of GeneCard database and data mining of GEO database. PPI network was constructed to screen the core targets, and their clinical significance was assessed through several public databases. GO and KEGG pathway analyses were performed to identify possible enrichment of genes with specific biological themes. Molecular docking and molecular dynamics (MD) simulation were employed to determine the correlation and binding pattern between bufalin and core targets. The potential mechanisms of bufalin acting on LUAD, as predicted by network pharmacology analyses, were experimentally validated using in-vitro and in-vivo models. Finally, the effects of bufalin intervention on metabolite profile and metabolic pathway in LUAD nude mice were investigated by non-targeted metabolomics., Results: 209 bufalin targets and 1082 LUAD-associated targets were harvested, of which 51 intersection targets were identified. 10 core targets including Akt1, STAT3, EGFR, CASP3 and SRC were picked out through network topology analysis, and they had a potent binding activity with bufalin as indicated by molecular docking and MD simulation. Hub module of PPI network was closely related to cell proliferation and apoptosis. GO and KEGG enrichment analyses suggested that bufalin exerted therapeutic effects on LUAD possibly by inhibiting proliferation and promoting apoptosis via PI3K/Akt, FoxO1 and MAPK/ERK pathways, which were confirmed by a series of in-vitro studies as well as HE, TUNEL and Ki-67 staining of tumor tissues. Further metabolomics analysis revealed that bufalin mainly regulated ABC transporter and remodeled AA metabolism, thereby contributing to the treatment of LUAD., Conclusion: From molecular and metabolic perspective, the present study not only provided a unique insight into the possible mechanisms of bufalin against LUAD after successfully filtering out associated key target genes, differential endogenous metabolites, and signaling pathways, but also proposed a novel promising therapeutic strategy for LUAD., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Stereotactic radiotherapy (SRT) has been widely used for the treatment of brain metastases and early stage non-small-cell lung cancer (NSCLC). Excellent SRT plans are characterized by steep dose fall-off, making it critical to accurately and comprehensively predict and evaluate dose fall-off., Purpose: A novel dose fall-off index was proposed to ensure high-quality SRT planning., Methods: The novel gradient index (NGI) had two different modes: NGIx V for three-dimensions and NGIx r for one-dimension. NGIx V and NGIx r were defined as the ratios of the decreased percentage dose (x%) to the corresponding isodose volume and equivalent sphere radii, respectively. A total of 243 SRT plans at our institution between April 2020 and March 2022 were enrolled, including 126 brain and 117 lung SRT plans. Measurement-based verifications were performed using SRS MapCHECK. Ten plan complexity indexes were calculated. Dosimetric parameters related to radiation injuries were also extracted, including the normal brain volume exposed to 12 Gy (V 12 ) and 18 Gy (V 18 ) during single-fraction SRT (SF-SRT) and multi-fraction SRT (MF-SRT), respectively, and the normal lung volume exposed to 12 Gy (V 12 ). The performance of NGI and other common dose fall-off indexes, gradient index (GI), R 50% and D 2cm were evaluated using Spearman correlation analysis to explore their correlations with the PTV size, gamma passing rate (GPR), plan complexity indexes, and dosimetric parameters., Results: There were statistically significant correlations between NGI and PTV size (r = -0.98, P < 0.01 for NGI50 V and r = -0.93, P < 0.01 for NGI50 r), which were the strongest correlations compared with GI (r = 0.11, P = 0.13), R 50% (r = -0.08, P = 0.19) and D 2cm (r = 0.84, P < 0.01). The fitted formulas of NGI50 V = 23.86V -1.00 and NGI50 r = 113.5r -1.05 were established. The GPRs of enrolled SRT plans were 98.6 ± 1.7%, 94.2 ± 4.7% and 97.1 ± 3.1% using the criteria of 3%/2 mm, 3%/1 mm, and 2%/2 mm, respectively. NGI50 V achieved the strongest correlations with various plan complexity indexes (|r| ranged from 0.67 to 0.91, P < 0.01). NGI50 V also showed the highest r values with V 12 (r = -0.93, P < 0.01) and V 18 (r = -0.96, P < 0.01) of the normal brain during SF-SRT and MF-SRT, respectively, and V 12 (r = -0.86, P < 0.01) of the normal lung during lung SRT., Conclusions: Compared with GI, R 50% and D 2cm , the proposed dose fall-off index, NGI, had the strongest correlations with the PTV size, plan complexity and V 12 /V 18 of the normal tissues. These correlations established on NGI are more helpful and reliable for SRT planning, quality control, and reducing the risk of radiation injuries., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Circulating tumor DNA (ctDNA) has potential as a promising biomarker for molecular residual disease (MRD) detection in lung cancer. As the next-generation sequencing standardized panel for ctDNA detection emerges, its clinical utility needs to be validated. We prospectively recruited 184 resectable lung cancer patients from four medical centers. Serial postoperative ctDNAs were analyzed by a standardized panel. A total of 427 postoperative plasma samples from 177 eligible patients were enrolled. ctDNA positivity after surgery was an independent predictor for disease recurrence and preceded radiological recurrence by a median of 6.6 months (range, 0.7-27.0 months). ctDNA-positive or -negative patients with tumors of any stage had similar disease-free survival (DFS). Patients who received targeted therapy had significantly improved DFS than those not receiving adjuvant therapy or receiving chemotherapy, regardless of baseline/preadjuvant ctDNA status. According to whether the ctDNA variants were detected in its matched tissue, they were classified into tissue derived and non-tissue derived. Patients with detectable postoperative ctDNA with tissue-derived mutations had comparable DFS with those with non-tissue-derived mutations. Collectively, we demonstrated that postoperative ctDNA has the potential to stratify prognosis and optimize tumor stage in resectable lung cancer. ctDNA variants not identified in tissue samples should be considered in MRD test., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non-small-cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c-MET-specific inhibitor SGX-523 in EBC-1 cells. Next, we discovered increased autocrine production of EGF and TGF-α in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EGF and TGF-α in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-α activated EGFR signaling pathways to survive targeted c-Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. The authors report the case of a young woman diagnosed with PEH. DNA and RNA analysis by next-generation sequencing was performed on the tumor tissue. A novel germline PALB2 mutation and classical  WWTR1-CAMTA1 fusion were identified. She experienced a poor response to sintilimab (a PD-1 inhibitor) plus platinum-based chemotherapy as the first-line treatment. PEH patients harboring a germline PALB2 mutation and WWTR1-CAMTA1 gene fusion may respond poorly to treatment with PD-1 inhibitors plus chemotherapy.

Background: Postoperative pain after video-assisted thoracoscopic surgery (VATS) is common in lung cancer patients, and it is unclear whether cancer itself participates in pain regulation. Programmed cell death ligand-1 (PD-L1) expressed by tumours may be analgesic. Our study aimed to detect the association between PD-L1 and acute postoperative pain., Methods: We reviewed patients who underwent VATS for lung cancer with tumour PD-L1 expression analysed in our centre from Jan 2017 to Jul 2020. They were divided into PD-L1 (-) group and PD-L1 (+) group and were further divided into four subgroups according to opioids for postoperative analgesia: sufentanil PD-L1 (-), sufentanil PD-L1 (+), oxycodone PD-L1 (-), and oxycodone PD-L1 (+). We compared the numeric rating scale (NRS) for the first three postoperative days at rest or cough between groups., Results: A total of 369 patients (167 in PD-L1 (-) vs. 202 in PD-L1 (+)) were included. On the first postoperative day, NRS at cough in the PD-L1 (+) patients were higher than those in the PD-L1 (-) patients (2.91 ± 1.07 vs. 2.66 ± 1.01, p = 0.018). On the third day, NRS at cough in PD-L1 (+) patients was higher (2.50 ± 1.02 vs. 2.26 ± 1.09, p = 0.043). For patients with oxycodone, NRS was higher in PD-L1 (+) than in PD-L1 (-) (p = 0.041) at cough after surgery. In contrast, those with sufentanil did not significantly differ in NRS between groups., Conclusions: Patients with PD-L1 (+) suffered graver pain in the early postoperative period after VATS for lung cancer compared with PD-L1 (-) on tumours. Analgesia with sufentanil seemed to overcome this effect better than oxycodone., Significance: We demonstrated that patients with positive programmed cell death ligand-1 (PD-L1) on tumours suffered graver pain in the early postoperative period after video-assisted thoracoscopic surgery for lung cancer and reacted differently with opioids. It might be beneficial to adjust analgesic protocols according to tumour PD-L1 expression for individualized postoperative pain management., (© 2022 European Pain Federation - EFIC ®.)

Background and Purpose: Currently, there is no standard treatment for patients with lung cancer with deteriorated pulmonary function. In this study, we aimed to assess the efficacy of thoracic radiotherapy for unresectable non-small cell lung cancer (NSCLC) with baseline severe pulmonary dysfunction and severe acute radiation pneumonitis (SARP)., Methods: Patients were categorized into a radiotherapy group and a nonradiotherapy group, followed by analysis of clinical variables. A Cox regression was used to evaluate the impact of various factors on overall survival (OS). Each SARP factor's predictive value was assessed using logistic regression, receiver operating characteristic curve, and Kaplan-Meier analyses., Results: The median OS in the radiotherapy group was 21.6 months vs 8.9 months in the nonradiotherapy group. Cox analysis revealed that chemotherapy (HR, 0.221; 95% CI, 0.149-0.329; P < .001) and radiotherapy (HR, 0.589; 95% CI, 0.399-0.869; P = .008) are independent prognostic factors for the current cohort. The data suggested that the ipsilateral lung V10 (ilV10, the percentage of the lung volume that received more than 10 Gy) was an independent predictor of SARP., Conclusions: Our findings suggested that thoracic radiotherapy might be associated with clinical benefits to inoperable NSCLC in patients with severe pulmonary dysfunction and that ilV10 may be involved in the prediction of risk for SARP in these patients.

Paclitaxel (PTX) remains a cornerstone in the treatment of locally advanced and metastatic lung cancer. To improve its therapeutic indices against lung cancer, novel redox-sensitive pullulan/PTX-based prodrug NPs (PULL-SS-PTX NPs) were accomplished, which were further surface-decorated with transferrin (TF), a cancer cell-targeting ligand, to afford TF-PULL-SS-PTX NPs. These prodrug NPs (drug content, >37% and average size, 134-163 nm) rapidly dismantled their self-assembled architecture upon exposure to simulated reducing conditions, causing a triggered drug release as compared to the control scaffold (PULL-CC-PTX NPs). These scaffolds also evidenced outstanding colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between the cancer and healthy cells. Intravenously delivered redox-sensitive NPs exhibited improved tumor-suppressing properties as compared to the control nanovesicles (PULL-CC-PTX NPs) in a B16-F10 melanoma lung metastasis mice model. The targeting efficiency and associated augmented anticancer potentials of TF-PULL-SS-PTX NPs relative to TF-free redox-responsive NPs and Taxol intravenous injection were also established on the transferrin receptor (TFR) overexpressed Lewis lung carcinoma (LLC-luc) cell-bearing mice model. Moreover, the TF-functionalized scaffold displayed a reduced systemic toxicity compared to that of Taxol intravenous injection. Overall, the proposed TF-decorated prodrug NPs could be a promising nanomedicine for intracellular PTX delivery against metastatic lung cancer.

Background: Carbonic anhydrase 4 (CA4) is a member of a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide and was found to have low expression in non-small cell lung cancer (NSCLC). However, the specific role of CA4 in NSCLC and the underlying mechanisms remain unknown., Methods: The bioinformatic analysis on lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets downloaded from The Cancer Genome Atlas (TCGA) database was performed. We found that CA4 expression was lower in tumors than that in normal tissues, which were verified by Real-time PCR. Lower CA4 levels were significantly associated with higher T stages in LUAD and LUSC cohorts. Multivariate analysis showed that CA4 is an independent prognostic factor for NSCLC. Furthermore, the expression of CA4 also correlated with immune infiltration and drug sensitivity., Results: Ectopic expression of CA4 decreased NSCLC cell proliferation in vitro by CCK-8 assay. CA4 caused G0/G1 cell cycle arrest by cell experiments. Mechanistic studies found that CA affects the cell cycle and inhibits cell proliferation by downregulating the expression of CDK2., Conclusion: The present findings highlight the role of CA4 in NSCLC and identify CA4 as a potential novel diagnostic and prognostic biomarker for the treatment of NSCLC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

YAP is a transcriptional co-activator with critical roles in tumorigenesis. However, its upstream regulatory mechanism, especially how its mRNA stability is regulated, remains to be further studied. Here, we validated that YAP expression was higher in lung adenocarcinoma (LUAD) tissues compared to adjacent normal tissues, and found that YAP m 5 C modification occurred in its 328-331 3' UTR region under the promotion NSUN2 and ALYREF, and increased the stability of YAP mRNA. This m 5 C modification also inhibited miR-582-3p binding and m 6 A modification in the nearby region. In addition, YAP m 5 C modification enhanced the exosome secretion effect, which was caused by two YAP-dependent transcription factors, Mycn and SOX10, and then stimulating the transcription of seven downstream exosome-promoting genes. Furthermore, we found that YAP m 5 C modification and its exosome-secretion-promoting function contributed to the malignant phenotype and AZD9291 (a third-generation EGFR-TKI) resistance of LUAD cells. Collectively, YAP is promoted by its m 5 C modification, and blocking YAP m 5 C modification will be helpful for future LUAD treatment., (© 2022. The Author(s).)

Background: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation., Methods: A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed., Results: The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023)., Conclusions: Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

Hydrogen sulfide releasing agents (or H 2 S donors) have been recognized gasotransmitters with potent cytoprotective and anticancer properties. However, the clinical application of H 2 S donors has been hampered by their fast H 2 S-release, instability, and lack of tumor targeting, despite the unclear molecular mechanism of H 2 S action. Here we rationally designed an amphiphilic pentapeptide (RGDFF) to coassemble with the de novo designed thiol-activated H 2 S donors (CL2/3) into nanocarriers for targeted therapy of non-small-cell lung cancer, which has been proved as a one-stone-three-birds strategy. The coassembly approach simply solved the solubility issue of CL2/3 by the introduction of electron-donating groups (phenyl rings) to slow down the H 2 S release while dramatically improving their biocompatible interface, circulation time, slow release of H 2 S, and tumor targeting. Experimental results confirmed that as-prepared coassembled nanocarriers can significantly induce the intrinsic apoptotic, effectively arrest cell cycle at the G2/M phase, inhibit H 2 S-producing enzymes, and lead to mitochondrial dysfunction by increasing intracellular ROS production in H1299 cells. The mouse tumorigenesis experiments further confirmed the in vivo anticancer effects of the coassembled nanocarriers, and such treatment made tumors more sensitive to radiotherapy then improved the prognosis of tumor-bearing mice, which holds great promise for developing a new combined approach for NSCLC.

Background: To determine whether antibiotic use before chemotherapy is associated with chemotherapy responses and patient outcomes among NSCLC patients and define the optimal interval between chemotherapy initiation and antibiotic treatment., Materials and Methods: One thousand four hundred and four advanced NSCLC patients receiving first-line platinum-based doublets therapy were retrospectively analyzed. Kaplan-Meier curve evaluated the impact of antibiotic use and type of antibiotics on the survival of patients. The factors affect the patient's prognosis were further confirmed by Cox regression. The optimal interval between antibiotic treatment and the initiation of chemotherapy was determined by the X-tile program., Results: NSCLC patients of 33.5% advanced underwent broad-spectrum antibiotic treatment prior to chemotherapy. In the chemotherapy only (Chemo) and chemotherapy plus antiangiogenesis (Chemo-angio) treatment groups, prior antibiotic treatment was associated with worse OS (Chemo: 13.8 vs. 17.6 months, p < 0.001; Chemo-angio:11.9 vs. 18.1 months, p = 0.012) and PFS (Chemo: 3.7 vs. 5.8 months, p < 0.001; Chemo-angio: 3.1 vs. 5.9 months, p < 0.001). Cox regression analysis revealed prior antibiotic administration as an independent predictor of OS and PFS (HR for PFS/OS: 1.925/1.452, both p < 0.001). Antibiotic usage duration (HR for PFS/OS: 1.030/1.036, p = 0.009/0.001) and type (PFS/OS: p < 0.001/p = 0.01) also showed significant association with patient prognosis, with calculated interval time cutoff values of 2, 4, and 2 days for fluoroquinolones, β-lactamase inhibitors, and cephalosporins, respectively., Conclusion: Antibiotic use before first-line chemotherapy was associated with poor results in advanced NSCLC patients; treatment length and type being strongly correlated with patient outcomes. Appropriate prolongation of the time between two treatments may enhance patient survival. Further prospective research is however necessary., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Rationale: Anlotinib is a multi-target tyrosine kinase inhibitor, approved in China for treating several cancer types. Dose individualization based on therapeutic drug monitoring (TDM) is a useful tool to reduce toxicity. However, it is not convenient for patients to go to hospital for routine TDM via venous blood sampling at a certain time., Methods: An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of anlotinib in human plasma and dried blood spot (DBS), characterized by simple sample preparation, high sensitivity, and short analysis time. The assay was validated in the concentration range of 0.2-200 ng/mL in plasma and 5-1000 ng/mL in DBS. This method was applied to monitor anlotinib exposure levels in patients with advanced biliary tract cancer (BTC) and non-small cell lung cancer (NSCLC)., Results: The trough plasma concentration (C trough ) of anlotinib was highly variable among BTC patients with coefficients of variation (CV) of 47.5%. DBS and venous blood samples were also collected from NSCLC patients to determine whether DBS sampling is a viable alternative sampling approach. Pearson correlation coefficient (R) between DBS and plasma concentration was 0.985. Bland-Altman plot demonstrated that the difference between estimated and measured plasma concentration was -2.9%. And 87% of sample pairs had a maximal deviation of ±20%., Conclusions: Anlotinib exhibits a high inter-individual variability in plasma exposure, and DBS sampling could be a promising tool for TDM of anlotinib., (© 2022 John Wiley & Sons Ltd.)

Abnormal nuclear structure caused by dysregulation of skeletal proteins is a common phenomenon in tumour cells. However, how skeletal proteins promote tumorigenesis remains uncovered. Here, we revealed the mechanism by which skeletal protein Emerin (EMD) promoted glucose metabolism to induce lung adenocarcinoma (LUAD). Firstly, we identified that EMD was highly expressed and promoted the malignant phenotypes in LUAD. The high expression of EMD might be due to its low level of ubiquitination. Additionally, the ISGylation at lysine 37 of EMD inhibited lysine 36 ubiquitination and upregulated EMD stability. We further explored that EMD could inhibit aerobic oxidation and stimulate glycolysis. Mechanistically, via its β-catenin interaction domain, EMD bound with PDHA, stimulated serine 293 and 300 phosphorylation and inhibited PDHA expression, facilitated glycolysis of glucose that should enter the aerobic oxidation pathway, and EMD ISGylation was essential for EMD-PDHA interaction. In clinical LUAD specimens, EMD was negatively associated with PDHA, while positively associated with EMD ISGylation, tumour stage and diameter. In LUAD with higher glucose level, EMD expression and ISGylation were higher. Collectively, EMD was a stimulator for LUAD by inhibiting aerobic oxidation via interacting with PDHA. Restricting cancer-promoting role of EMD might be helpful for LUAD treatment., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

This study aimed to explore the spatial and temporal trends of lung cancer burden attributable to residential radon exposure at the global, regional, and national levels. Based on the Global Burden of Disease Study (GBD) 2019, we collected the age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life rate (ASDR) of lung cancer attributable to residential radon exposure from 1990 to 2019. The Joinpoint model was used to calculate the annual average percentage change (AAPC) to evaluate the trend of ASMR and ASDR from 1990 to 2019. The locally weighted regression (LOESS) was used to estimate the relationship of the socio-demographic index (SDI) with ASMR and ASDR. In 2019, the global ASMR and ASDR for lung cancer attributable to residential radon exposure were 1.03 (95% CI: 0.20, 2.00) and 22.66 (95% CI: 4.49, 43.94) per 100 000 population, which were 15.6% and 23.0% lower than in 1990, respectively. According to the estimation, we found the lung cancer burden attributable to residential radon exposure declined significantly in high and high-middle SDI regions, but substantially increased in middle and low-middle SDI regions from 1990 to 2019. Across age and sex, the highest burden of lung cancer attributable to residential radon exposure was found in males and elderly groups. In conclusion, the global burden of lung cancer attributable to residential radon exposure showed a declining trend from 1990 to 2019, but a relatively large increase was found in the middle SDI regions. In 2019, the burden of lung cancer attributable to residential radon exposure remained high, particularly in males, the elderly, and high-middle SDI regions compared with other groups., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Sporadic lymphangioleiomyomatosis (S-LAM) is a rare neoplasm with heterogeneous clinical features that is conventionally considered to be related to TSC2. This study serves to elucidate the mutation landscape and potential correlation between S-LAM genomic profiles and clinical phenotypes., Methods: Genomic profiles of 22 S-LAM patients were obtained by sequencing genomic DNA and cell-free DNA from various specimens using an NGS (next-generation sequencing)-based tumor-driver gene panel. Detected mutations were summarized. Symptoms, serum vascular endothelial growth factor D (VEGF-D) values, pulmonary function, and six-minute walk distance (6MWD) were compared among groups with different TSC2 status and genotypes to analyze genotype-phenotype correlations., Results: 67 Variants in 43 genes were detected, with a TSC2 mutation detection rate of 68.2%. The TSC2 detection rate was similar in specimens obtained either through transbronchial lung biopsy (TBLB) or surgical lung biopsy (70.0% vs. 69.2%, p > 0.05). A novel mutation in VEZF1 (c.A659G) was detected in four participants and may represent a mild disease state. TSC2 mutation was significantly related to a shorter 6MWD (p < 0.05), and a higher percentage of VEGF-D over 800 pg/mL (p < 0.05); stop-gain mutation was significantly related to a higher prevalence of pneumothorax., Conclusions: Tumor-driver mutations in genes other than TSC2 may have a role in S-LAM, and TBLB specimens are practical alternatives for genomic analysis. TSC2 mutation detectability and types are related to the disease severity and phenotypes of S-LAM., (© 2022. The Author(s).)

Genomic fusions of anaplastic lymphoma kinase (ALK) are a well-established therapeutic target in non-small-cell lung cancer (NSCLC). Although various ALK fusion variants have been identified in NSCLC, their responses to ALK tyrosine-kinase inhibitors (TKIs) are heterogeneous. We report the case of a 71-year-old female patient diagnosed with lung adenocarcinoma with liver metastases. A novel CTNND1 (exon 14)-ALK (exon 20) fusion was identified from the biopsy sample by next-generation sequencing (NGS) and validated by immunohistochemistry (IHC) staining. Alectinib was administered, and the patient soon achieved partial response (PR). The progression-free survival (PFS) exceeded 15 months as of January 25, 2022. Our findings expand the spectrum of ALK rearrangements and provide a potential treatment option for lung adenocarcinoma patients with CTNND1-ALK fusions., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Spontaneous pneumothorax has a high incidence and high rate of recurrence in patients with lymphangioleiomyomatosis (LAM). The risk factors for pneumothorax and the effects of sirolimus on pneumothorax in patients with LAM are unknown. In our study, multivariate logistic regression was applied to a cross-sectional cohort to investigate factors associated with pneumothorax in LAM patients. Kaplan-Meier analysis was applied in the historical prospective self-controlled study to determine whether sirolimus reduces the risk of pneumothorax recurrence in patients with LAM., Results: Of the 399 patients registered with LAM-CHINA at our center between May 10, 2017 and August 31, 2020, 142 had a history of pneumothorax at registration. High CT grade and age at presentation ≤ 35 years were associated with a higher risk of pneumothorax in patients with LAM. Postmenopausal status was correlated with a lower risk of pneumothorax. In the historical prospective self-controlled study, the 5-year probability of pneumothorax recurrence was 80% lower in the sirolimus group than in the control group (hazard ratio for pneumothorax recurrence, 0.20; 95% CI, 0.14 to 0.30, P < 0.001 by log-rank test)., Conclusion: Sirolimus reduced the risk of pneumothorax recurrence in LAM patients., (© 2022. The Author(s).)

Circulating microRNAs (miRNAs) can be used as noninvasive biomarkers and are also found circulating in body fluids such as blood. Dysregulated miRNA expression is associated with many diseases, including non-small cell lung cancer (NSCLC), and the miRNA assay is helpful in cancer diagnosis, prognosis, and monitoring. In this work, a versatile electrochemical biosensing system is developed for miRNA detection by DNAzyme-cleavage cycling amplification and hybridization chain reaction (HCR) amplification. With cleavage by Mn 2+ targeted DNAzyme, DNA-walker can move along the predesigned DNA tracks and contribute to the transduction and enhancement of signals. For the electrochemical process, the formation of multiple G-quadruplex-incorporated long double-stranded DNA (dsDNA/G-quadruplex) structures is triggered through HCR amplification. The introduction of G-quadruplex allows sensitive measurement of miRNA down to 5.68 fM with good specificity. Furthermore, by profiling miRNA in the NSCLC cohort, this designed strategy shows high efficiency (area under the curve (AUC) of 0.879 using receiver operating characteristic (ROC) analysis) with the sensitivity of 80.0% for NSCLC early diagnosis (stage I). For the discrimination of NSCLC and benign disease, the assay displays an AUC of 0.907, superior to six clinically-acceptable protein tumor markers. Therefore, this platform holds promise in clinical application toward NSCLC diagnosis and prognosis., (© 2022 Wiley-VCH GmbH.)

Objective: Bioinformatics methods were used to analyze non-small-cell lung cancer gene chip data, screen differentially expressed genes (DEGs), explore biomarkers related to NSCLC prognosis, provide new targets for the treatment of NSCLC, and build immunotyping and line-map model., Methods: NSCLC-related gene chip data were downloaded from the GEO database, and the common DEGs of the two datasets were screened by using the GEO2R tool and FunRich 3.1.3 software. DAVID database was used for GO analysis and KEGG analysis of DEGs, and protein-protein interaction (PPI) network was constructed by STRING database and Cytoscape 3.8.0 software, and the top 20 hub genes were analyzed and screened out. The expression of pivot genes and their relationship with prognosis were verified by multiple external databases., Results: 159 common DEGs were screened from the two datasets. PPI network was constructed and analyzed, and the genes with the top 20 connectivity were selected as the pivotal genes of this study. The results of survival analysis and the patients' survival curve was reflected in the line graph model of NSCLC., Conclusion: Through the screening and identification of the VIM-AS1 gene, as well as the analysis of immune infiltration and immune typing, the successful establishment of the rosette model has a certain guiding value for the molecular targeted therapy of patients with non-small-cell lung cancer., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Sha Tian et al.)

Although fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPM's bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of antitumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN) - an enzyme mediating type IV collagen (Col IV) crosslinking - onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8 + T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourishing of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on the tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks., Competing Interests: ZW, ZZ, CC, XT, ZX, PX, YY, JZ, CW, LD No competing interests declared, (© 2022, Wang et al.)