Effect of overweight/obesity on relationship between fractional exhaled nitric oxide and airway hyperresponsiveness in Chinese elderly patients with asthma.

Purpose: This retrospective study investigates the influence of overweight and obesity status on pulmonary function, airway inflammatory markers, and airway responsiveness in elderly asthma patients. Methods: Patients with asthma older than 65 years old who completed a bronchial provocation test (BPT) or bronchial dilation test (BDT) and a fractional exhaled nitric oxide (FeNO) test between December 2015 and June 2020 were identified retrospectively for this study. All of the patients were categorized into overweight/obesity and non-obesity groups based on their BMI. Pulmonary function test (PFT) and FeNO measurements were accomplished according to the 2014 recommendations of the Chinese National Guidelines of Pulmonary Function Test and American Thoracic Society/European Respiratory Society recommendations, respectively. Results: A total of 136 patients with an average age of 71.2 ± 5.40 years were identified. The average BMI was 23.8 ± 3.63, while the value of FeNO was 42.3 ± 38.4 parts per billion (ppb). In contrast to the non-obesity group, which had a value of 48.8 ± 43.1 ppb for FeNO, the overweight/obesity group had a significant lower value of 35.4 ± 31.4 ppb. There was no significant difference in the proportion of individuals with high airway hyperresponsiveness between the overweight/obesity and non-obesity groups (96 patients in total). Multiple linear regression analysis established an inverse correlation between FeNO and Provocation concentration causing a 20% fall in FEV1(PC20) but excluded significant relationships with age and BMI. The model's R is 0.289, and its p value is 0.045. Conclusion: The elderly Chinese Han asthmatics with overweight/obesity had lower FeNO levels than those with non-obese according to our findings. In addition, the FeNO level was inversely correlated between FeNO levels and PC20 in elderly asthmatics.

Neopterin in patients with COPD, asthma, and ACO: association with endothelial and lung functions.

BACKGROUND AND OBJECTIVE: Endothelial dysfunction has been widely recognized in chronic airway diseases, including chronic obstructive pulmonary disease (COPD) and asthma; however, it remains unclear in asthma-COPD overlap (ACO). Neopterin (NP), a metabolite of guanosine triphosphate, is a novel biomarker for identifying the increased risk of adverse cardiovascular events. This study aims to investigate the association of NP with endothelial dysfunction and impaired lung function in COPD, asthma, and ACO patients. METHODS: A total of 77 subjects were prospectively recruited. All the participants underwent lung function test, endothelial function evaluation, including pulse wave velocity (PWV) and flow-mediated dilation (FMD), and blood sample detection. Moreover, the effect of NP on endothelial cells (ECs) in anoxic environments was assessed in vitro. RESULTS: Endothelial function was significantly decreased in the COPD and ACO patients compared with that in the healthy controls (P < 0.05). Forced expiratory volume in 1 s (FEV1) was negatively correlated with PWV and positively correlated with FMD (P < 0.05). NP was significantly increased in patients with chronic respiratory diseases compared with that in the control group, with COPD being the highest, followed by asthma, and ACO as the last (P < 0.05). The plasma level of NP exhibited negative correlations with FEV1 and positive correlations with PWV (P < 0.05). In vitro, a high level of NP increased the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential (ΔΨm) of ECs dose-dependently in a hypoxic environment (P < 0.05). CONCLUSION: NP was related to disease severity of chronic airway diseases and involved in the pathogenesis of endothelial dysfunction. A high NP level may contribute to endothelial dysfunction by increasing the oxidative stress of ECs dose-dependently in a hypoxic environment. Our findings may provide a novel evaluation and therapeutic target for endothelial dysfunction related to chronic airway diseases.

Eosinophilic bronchiectasis increases length and cost of hospitalization: a retrospective analysis in a hospital of southern China from 2012 to 2020.

BACKGROUND: The concept of eosinophilic bronchiectasis has received clinical attention recently, but the association between blood eosinophil count (BEC) and hospital characteristics has rarely been reported yet. We aim to investigate the clinical impact of BEC on patients with acute bronchiectasis exacerbation. METHODS: A total of 1332 adult patients diagnosed with acute exacerbation of bronchiectasis from January 2012 to December 2020 were included in this retrospective study. A propensity-matched analysis was performed by matching age, sex and comorbidities in patients with high eosinophil count (≥ 300 cell/µL) and low eosinophil count (< 300 cell/µL). Clinical characteristics, length of hospital stay (LOS), hospitalization cost and inflammatory markers were compared between the two groups. RESULTS: Eosinophilic bronchiectasis occurred in approximately 11.7% of all patients. 156 propensity score-matched pairs were identified with and without high eosinophil count. Eosinophilic bronchiectasis presented with a longer LOS [9.0 (6.0-12.5) vs. 5.0 (4.0-6.0) days, p < 0.0001] and more hospitalization cost [15,011(9,753-27,404) vs. 9,109(6,402-12,287) RMB, p < 0.0001] compared to those in non-eosinophilic bronchiectasis. The median white blood cell (WBC), lymphocyte, platelet (PLT) and C-reactive protein (CRP) levels in eosinophilic bronchiectasis were significantly increased. Multivariate logistic regression analysis confirmed that the high levels of eosinophil count (OR = 13.95, p < 0.0001), worse FEV1% predicted (OR = 7.80, p = 0.0003) and PLT (OR = 1.01, p = 0.035) were independent prognostic factors for length of hospital (LOS) greater than 7 days. CONCLUSION: Eosinophilic bronchiectasis patients had longer length of hospital stay and more hospitalization cost compared to those in non-eosinophilic bronchiectasis group, which might be associated with the stronger inflammatory reaction.

Association between serum C-reactive protein (CRP) and Omicron variant COVID-19 pneumonia in cancer patients: A multicenter cross-sectional study at the end of 2022 in China.

Cancer patients with COVID-19 have a higher infection rate and mortality rate than non-cancer patients. However, there are few studies on the correlation between the serum C-reactive protein (CRP) and cancer patients with COVID-19. This study aims to investigate the association between serum CRP and the incidence of COVID-19 pneumonia in cancer patients at the end of 2022 in China. This cross-sectional study with a retrospective cohort between December 2022 and February 2023 assessed cancer patients complicated with COVID-19 infection in 2 Chinese institutions. Logistic regression analyses were used to compute Odds ratio (OR) and 95%CIs for the association between serum CRP and the incidence of COVID-19 pneumonia in cancer patients. A total of 213 cancer patients with COVID-19 were enrolled. Eighty-six patients (40.4%) developed COVID-19 pneumonia, among which 23 patients (10.8%) progressed to severe cases. Univariate Logistic regression showed that high CRP levels were found to be an unfavorable predictor of COVID-19 outcomes (OR = 17.9, 95%CI: 7.3, 43.6; P < .001). In the multivariate analysis, high CRP levels were associated with a higher incidence rate of COVID-19 pneumonia (OR = 9.8, 95%CI: 2.2, 43.8; P = .003). In the multivariate logistic regression model and smooth curve fitting, we found a correlation between CRP and COVID-19 pneumonia. The serum CRP was associated with the incidence of Omicron variant COVID- 19 pneumonia in cancer patients. Hence, cancer patients with high CRP level maybe need for timely computer tomography examination and more aggressive treatment.

Non-small cell lung cancer cells with uncommon EGFR exon 19delins variants respond poorly to third-generation EGFR inhibitors.

BACKGROUND: This study compared the clinical efficacy of first-, second-, and third-generation tyrosine kinase inhibitors (TKIs) in previously untreated non-small cell lung cancer (NSCLC) patients harboring uncommon epidermal growth factor receptor (EGFR) exon 19delins variants. METHODS: We retrospectively analyzed the clinical outcomes of NSCLC patients with EGFR exon 19delins mutations who were treated with third- and first-generation EGFR TKIs. In vitro and in vivo studies were conducted to verify the sensitivity of these mutations to distinct generations of TKIs. Molecular simulation was used to investigate the structural characteristics of the EGFR mutant molecules. RESULTS: In a multicenter cohort of 1,526 patients, 37 (2.4 %) had uncommon EGFR 19delins mutations. Twenty-four patients were treated with first-generation EGFR TKIs, and third-generation TKIs were administered to ten patients as frontline therapy. Patients carrying EGFR exon 19delins mutations who were given third-generation TKIs exhibited comparatively shorter progression-free survival (PFS) and overall survival (OS) in relation to those who received first-generation EGFR inhibitors; median PFS: 6.9 months vs. 19.1 months (p < 0.001), Median OS: 19.1 months vs. 32.6 months (p < 0.001). In vivo and in vitro studies revealed that uncommon EGFR 19delins variants exhibit limited sensitivity to third-generation EGFR inhibitors in contrast to first- and second-generation EGFR inhibitors. The molecular binding affinity of third-generation EGFR TKIs toward uncommon EGFR 19delins mutations was less than that of first- and second-generation EGFR inhibitors. CONCLUSIONS: Uncommon EGFR 19delins variants respond poorly to third-generation EGFR inhibitors in NSCLC. Uncommon EGFR 19delins mutations may serve as an unfavorable predictive factor for the efficacy of third-generation EGFR TKI therapy, offering potential guidance for future clinical decision-making.

Oncostatin M/Oncostatin M Receptor Signal Induces Radiation-Induced Heart Fibrosis by Regulating SMAD4 in Fibroblast.

PURPOSE: Radiation-induced heart fibrosis (RIHF) is a severe consequence of radiation-induced heart damage (RIHD) leading to impaired cardiac function. The involvement of oncostatin M (OSM) and its receptor (OSMR) in RIHD remains unclear. This study aimed to investigate the specific mechanism of OSM/OSMR in RIHF/RIHD. METHODS AND MATERIALS: RNA sequencing was performed on heart tissues from a RIHD mouse model. OSM levels were assessed in serum samples obtained from patients receiving thoracic radiation therapy (RT), as well as in RIHF mouse heart tissues and serum using enzyme-linked immunosorbent assay. Fiber activation was evaluated through costimulation of primary cardiac fibroblasts and NIH3T3 cells with RT and OSM, using Western blotting, immunofluorescence, and quantitative Polymerase Chain Reaction (qPCR). Adeno-associated virus serotype 9-mediated overexpression or silencing of OSM specifically in the heart was performed in vivo to assess cardiac fibrosis levels by transthoracic echocardiography and pathologic examination. The regulatory mechanism of OSM on the transcription level of SMAD4 was further explored in vitro using mass spectrometric analysis, chromatin immunoprecipitation-qPCR, and DNA pull-down. RESULTS: OSM levels were elevated in the serum of patients after thoracic RT as well as in RIHF mouse cardiac endothelial cells and mouse serum. The OSM rate (post-RT/pre-RT) and the heart exposure dose in RT patients showed a positive correlation. Silencing OSMR in RIHF mice reduced fibrosis, while OSMR overexpression increased fibrotic responses. Furthermore, increased OSM promoted histone acetylation (H3K27ac) in the SMAD4 promoter region, influencing SMAD4 transcription and subsequently enhancing fibrotic response. CONCLUSIONS: The findings demonstrated that OSM/OSMR signaling promotes SMAD4 transcription in cardiac fibroblasts through H3K27 hyperacetylation, thereby promoting radiation-induced cardiac fibrosis and manifestations of RIHD.

Reflecting on the cardiac toxicity in non-small cell lung cancer in the era of immune checkpoint inhibitors therapy combined with thoracic radiotherapy.

In recent years, immune checkpoint inhibitors (ICIs) have become a widely used treatment for non-small cell lung cancer (NSCLC), and the combination with traditional radiotherapy (RT) has shown significant potential in prolonging patient survival. However, both thoracic RT and ICIs can lead to cardiac toxicity, including radiation-induced heart damage (RIHD) and immunotherapy-related heart damage (IRHD). It still remains uncertain whether the combination of thoracic RT and immunotherapy will exacerbate acute or late cardiovascular (CV) toxicity and incidence. In this review, we summarize safety data from relevant clinical studies regarding CV toxicity for the combination therapy in NSCLC patients, explore the underlying synergetic mechanisms and common risk factors, and proposed treatment and management strategies. We hope to increase emphasis on the long-term assessment of CV toxicity risks associated with the combination therapy, and reduce the incidence of CV deaths resulting from such regimens.

Association of immune-related adverse events with COVID-19 pneumonia in lung cancer patients receiving immune checkpoint inhibitors: a cross-sectional study in China.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are commonly used to treat lung cancer patients, but their use can lead to immune-related adverse events (irAEs), which pose a challenge for treatment strategies. The impact of irAEs on the incidence of COVID-19 pneumonia in lung cancer patients during the ongoing COVID-19 pandemic is unclear. This study aims to investigate the association between irAEs and COVID-19 pneumonia in lung cancer patients receiving ICIs. METHODS: We conducted a cross-sectional study of lung cancer patients who received ICIs and were infected with COVID-19 due to the Omicron variant between December 2022 and February 2023 in China. We collected data on irAEs and COVID-19 outcomes. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between irAEs and the incidence of COVID-19 pneumonia. RESULTS: A total of 193 patients were enrolled, with 72 patients (37.30%) in the irAEs group and 121 patients (62.70%) in the non-irAEs group. Twenty-six patients (13.47%) developed COVID-19 pneumonia and 6 patients (3.11%) progressed to severe cases after COVID-19 infection. Multivariate logistic regression showed that the lung cancer patients who experienced irAEs was significantly associated with a higher incidence rate of COVID-19 pneumonia (OR = 9.56, 95%CI: 2.21-41.33; P = 0.0025). CONCLUSION: Our study suggests that lung cancer patients receiving ICIs and experiencing irAEs may have a higher risk of developing COVID-19 pneumonia due to the Omicron variant. Therefore, close monitoring of these patients during the COVID-19 pandemic is necessary to mitigate this risk.

Simultaneous evaluation of the fractional exhaled nitric oxide and blood eosinophil count of T2-high endotype in patients with non-cystic fibrosis bronchiectasis.

OBJECTIVE: Recently, a type 2 inflammation (T2) high endotype in bronchiectasis was identified. The fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (BEC) are recognized as representative biomarkers of T2 inflammation. Herein, we investigate the clinical characteristics of T2-high endotype in non-cystic fibrosis bronchiectasis patients classified by FeNO and BEC. METHODS: This retrospective study included 164 bronchiectasis patients treated in the First Affiliated Hospital of Sun Yat-sen University from December 2017 to July 2022. Clinical characteristics were analyzed after classifying patients into four groups according to T2 inflammation biomarkers (FeNO ≥25 ppb; BEC ≥200/µL). RESULTS: Among the 164 bronchiectasis patients, 35.3% (58/164) presented with high FeNO, 30.5% (50/164) presented with high BEC, and 10.4% (17/164) had high FeNO and BEC. Patients with high FeNO and low BEC presented with better lung function, fewer affected lobes, and lower dyspnea prevalence compared with the three other groups. Moreover, decreased FeNO, instead of decreased BEC, is revealed to be an independent predictor for disease severity and airflow obstruction in bronchiectasis. CONCLUSIONS: Simultaneous evaluation of FeNO and BEC proposed different endotypes of bronchiectasis established that patients with low BEC and high FeNO had better lung function, fewer affected lobes, lower dyspnea prevalence, and less disease severity. This result will contribute to a more comprehensive assessment of the disease severity and lead to more precise treatment of T2 inflammation in bronchiectasis patients.

Corrigendum: The efficacy and safety analysis of first-line immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma.

[This corrects the article DOI: 10.3389/fimmu.2022.956982.].

Efficacy of PD-1 Inhibitors Combined with Anti-Angiogenic Therapy in Driver Gene Mutation Negative Non-Small-Cell Lung Cancer with Brain Metastases.

OBJECTIVE: Anti-angiogenic therapy has proven effective in non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the efficacy of programmed cell death protein 1 (PD-1) inhibitors combined with anti-angiogenic therapy in patients with driver gene mutation negative NSCLC and brain metastases (BMs). METHODS: A retrospective analysis was performed on NSCLC BMs in patients without driver gene mutations who received PD-1 inhibitors. Two groups, receiving either PD-1 inhibitor monotherapy or PD-1 inhibitor plus anti-angiogenesis therapy, were identified. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). The secondary endpoints were safety, intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). RESULTS: 113 NSCLC patients were included, 51 (45.1%) in the PD-1 inhibitor monotherapy group and 62 (54.9%) in the PD-1 inhibitor plus anti-angiogenesis therapy group. The median follow-up time was 26.2 months. OS was higher in the combination therapy cohort than in the monotherapy cohort (OS: 21.4 vs. 11.8 months; p = 0.004), with no significant difference in iPFS (p = 0.088). Moreover, the PD-1 inhibitor + anti-angiogenic therapeutic regimen exhibited the preferred iDCR (p = 0.005) but not the iORR (p = 0.121). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups. In multivariate Cox regression analysis, PD-1 inhibitor therapy combined with anti-angiogenic treatment (p = 0.003) was an independent prognostic indicator of OS. CONCLUSIONS: Combining PD-1 inhibitor therapy with anti-angiogenic treatment significantly improves the OS of driver gene mutation negative NSCLC patients with BMs.

Increased expression of CSF1 in patients with eosinophilic asthma.

BACKGROUND: The link between colony-stimulating factor 1 (CSF1) and asthma was reported recently. However, the role and mechanism of CSF1 in asthma remain poorly understood. In this study, we aimed to explore the expression and its potential mechanism of CSF1 in asthma. METHODS: CSF1 expression in the airway samples from asthmatics and healthy controls were examined, then the correlations between CSF1 and eosinophilic indicators were analyzed. Subsequently, bronchial epithelial cells (BEAS-2B) with CSF1 overexpression and knockdown were constructed to investigate the potential molecular mechanism of CSF1. Finally, the effect of CSF1R inhibitor on STAT1 was investigated. RESULTS: The expression of CSF1 was significantly increased in patients with asthma compared to healthy controls, especially in patients with severe and eosinophilic asthma. Upregulated CSF1 positively correlated with airway-increased eosinophil inflammation. In vitro, cytokines interleukin 13 (IL-13) and IL-33 can stimulate the upregulation of CSF1 expression. CSF1 overexpression enhanced p-CSF1R/CSF1R and p-STAT1/STAT1 expression, while knockdown CSF1 using anti-CSF1 siRNAs decreased p-CSF1R/CSF1R and p-STAT1/STAT1 expression. Furthermore, the inhibitor of CSF1R significantly decreased p-STAT1/STAT1 expression. CONCLUSIONS: Sputum CSF1 may be involved in asthmatic airway eosinophil inflammation by interacting with CSF1R and further activating the STAT1 signaling. Interfering this potential pathway could serve as an anti-inflammatory therapy for asthma.

Immune Checkpoint Inhibitors and Tuberculosis Infection in Lung Cancer: A Case Series and Systematic Review With Pooled Analysis.

The association between immune checkpoint inhibitors (ICIs) and tuberculosis (TB) infection in patients with lung cancer remains largely elusive. We performed a systematic review and conducted a retrospective analysis of TB infection in patients with lung cancer and ICI exposure to assess the clinical characteristics and outcomes using PubMed, EMBASE, and the Cochrane Library. The time interval from ICI administration to diagnosis of TB between patients with and without a history of TB was compared using Kaplan-Meier analysis. A multivariate Cox regression model was used to identify potential risk factors associated with the time interval of TB development. Twenty-four studies including 53 patients with lung cancer were included. The median age of the patients was 64 years. Eight patients had a history of TB. The median time interval from ICI administration to TB diagnosis was 3 months. In retrospective analysis, 5 (1.16%, 95%CI 0.38% to 2.68%) patients with lung cancer developed TB during ICI treatment. The median time interval was 10.4 months. In a pooled analysis, the median time interval in the without-TB and with-TB groups was 7.00 and 2.35 months, respectively (P = .034). Multivariate Cox regression analyses revealed a history of TB to be an independent factor affecting the time interval of TB activation in patients with lung cancer and ICI exposure (HR 3.59; 95%CI 1.17 to 11.02; P = .026). Therefore, TB infection should be considered in patients with lung cancer during or after ICI treatment. Moreover, we found TB history to be a positive risk factor for a shorter median time interval from ICI to TB diagnosis in patients with lung cancer receiving ICI.

Novel DNA Promoter Hypermethylation in Nasal Epithelium of Asthma.

BACKGROUND: Abnormal epigenetic alterations influenced by external factors and affecting DNA expression contribute to the development of asthma. However, the role of the nasal epithelium in airway inflammation remains unknown. OBJECTIVE: The objective of this study is to identify novel DNA promoter hypermethylation, which suppresses mRNA expression in nasal epithelial of asthma. METHODS: Microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Gene expression and DNA promoter methylation sites in key correlated modules between asthma and normal were identified by weighted gene co-expression network analysis. Gene Oncology and Kyoto Encyclopedia of Genes and Genomes were conducted to analyse the function of genes. Further validation was performed in human BEAS-2B cells challenged by IL-4 or IL-13. RESULTS: Lightcyan, lightgreen, midnightblue, cyan and tan modules in the mRNA expression dataset showed a close relationship with asthma, in which genes were enriched in TNF, IL-17, ErbB, MAPK and Estrogen signalling pathways. Blue and turquoise modules in the methylation profiling dataset were associated with asthma. Forty nine lowly expressed genes were identified to be correlated with aberrant DNA hypermethylation of promoters. Among these genes, the mRNA levels of BCL10, GADD45B, LSR and SQSTM1 were downregulated in BEAS-2B cells challenged with IL-4 or IL-13. CONCLUSION: Four potential genes in the nasal epithelium, by hypermethylating their own DNA promoter, might mediate the inflammatory response in the pathogenesis of asthma. Analyzing epigenomic data by integrated bioinformatics helps to understand the role of DNA methylation in asthma, with the goal of providing new perspectives for diagnosis and therapy.

Arrhythmic events associated with immune checkpoint inhibitors therapy: A real-world study based on the Food and Drug Administration Adverse Event Reporting System database.

BACKGROUND: Although arrhythmias have been reported in patients treated with immune checkpoint inhibitors (ICIs), the association between arrhythmias and ICIs has not been thoroughly evaluated in real-world studies. We aimed to describe the major features of ICI-related arrhythmic events and identify the factors that contributed to death. METHODS: A disproportionality analysis was performed using data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 2011 to December 2021. Reporting odds ratios (RORs), proportional reporting ratio and information component were used to assess whether adverse arrhythmic events were associated with ICIs. The clinical characteristics of patients with ICI-associated arrhythmias were compared with fatal and non-fatal arrhythmias. The time to onset (TTO), fatality rates of arrhythmic events were also investigated. RESULTS: We identified a total of 1945 cases of ICI-related arrhythmic events. Men (64.78%) were identified significantly more frequently than women (28.84%). The median age was 68 years ([interquartile range, IQR] 60-75 years). Anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) were associated with adverse arrhythmic events, corresponding to ROR 1.11 (95% confidence interval [CI] 1.05-1.17) and ROR 1.34 (95% CI 1.20-1.49), respectively. However, anti-cytotoxic T-lymphocyte associated protein 4 or combination immunotherapy did not appear to be associated with arrhythmic events. Atrial fibrillation (N  = 576, 0.62%), cardiac arrest (N  = 284, 0.31%), tachycardia (N  = 175, 0.19%) were the most common adverse arrhythmic events. Sudden death and complete atrioventricular block are adverse events that are significantly associated with ICI-related arrhythmic events and have strong signal intensity. The TTO of cases that resulted in death (30 days [IQR] 11-73.75) was significantly earlier than that of cases that did not result in death (33 days [IQR 10.5-88.5], p  = 0.003). ICI-related arrhythmic events were severe with death occurring in 507 (26.07%) of 1945 arrhythmias cases. CONCLUSIONS: Treatment with PD-1/PD-L1 may cause arrhythmic events, which are severe and tend to occur early on during treatment. It is important to identify ICI-related arrhythmias as early as possible, and to manage them appropriately.

Effect of EGFR amplification on the prognosis of EGFR-mutated advanced non-small-cell lung cancer patients: a prospective observational study.

BACKGROUND: Epidermal growth factor receptor (EGFR) amplification refers to the copy number increase of EGFR gene, and is often identified as a "bypass" way of Epidermal growth factor receptor Tyrosine kinase inhibitors (EGFR-TKI) resistance. We aimed to explore the effect of EGFR amplification on EGFR mutation treatment-naive advanced non-squamous non-small cell lung cancer (NSCLC) patients. METHODS: We conducted a prospective observational study in single center, enrolling advanced non-squamous NSCLC patients receiving Tyrosine kinase inhibitors (TKIs) between March 3, 2019, and February 1, 2022. Next-generation sequencing (NGS) was used to detect genetic alterations in tumor tissue samples. Progression-free survival (PFS) curves were performed using the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate factors affecting the efficacy of TKIs. RESULTS: A total of 117 treatment-naive advanced NSCLC patients were identified in this study. EGFR amplification was found in 22 of 117 (18.8%) patients with EGFR mutations. Of 22 patients with EGFR amplification, 10 patients harbored EGFR 19 del, 11 patients with 21-L858R. The median follow-up time was 22.47 months. The median PFS of the patients with or without EGFR amplification was 8.25 months and 10.67 months, respectively (log-rank test, P = 0.63). In multivariate analysis, EGFR amplification was not an independent prognosis factor for the patients receiving first-line TKIs [HR = 1.38, 95%CI (0.73-2.58), P = 0.321]. Subgroup analysis revealed that EGFR amplification is a risk factor for progression in the brain metastasis population. [HR = 2.28, 95%CI (1.01, 5.14), P = 0.047]. CONCLUSION: EGFR amplification is not an independent prognosis factor for PFS in advanced non-squamous NSCLC patients receiving first-line TKIs. However, it is an independent risk factor for PFS in the brain metastasis population.

Identification and Application of a Novel Immune-Related lncRNA Signature on the Prognosis and Immunotherapy for Lung Adenocarcinoma.

Background: Long non-coding RNA (lncRNA) participates in the immune regulation of lung cancer. However, limited studies showed the potential roles of immune-related lncRNAs (IRLs) in predicting survival and immunotherapy response of lung adenocarcinoma (LUAD). Methods: Based on The Cancer Genome Atlas (TCGA) and ImmLnc databases, IRLs were identified through weighted gene coexpression network analysis (WGCNA), Cox regression, and Lasso regression analyses. The predictive ability was validated by Kaplan−Meier (KM) and receiver operating characteristic (ROC) curves in the internal dataset, external dataset, and clinical study. The immunophenoscore (IPS)-PD1/PD-L1 blocker and IPS-CTLA4 blocker data of LUAD were obtained in TCIA to predict the response to immune checkpoint inhibitors (ICIs). The expression levels of immune checkpoint molecules and markers for hyperprogressive disease were analyzed. Results: A six-IRL signature was identified, and patients were stratified into high- and low-risk groups. The low-risk had improved survival outcome (p = 0.006 in the training dataset, p = 0.010 in the testing dataset, p < 0.001 in the entire dataset), a stronger response to ICI (p < 0.001 in response to anti-PD-1/PD-L1, p < 0.001 in response to anti-CTLA4), and higher expression levels of immune checkpoint molecules (p < 0.001 in PD-1, p < 0.001 in PD-L1, p < 0.001 in CTLA4) but expressed more biomarkers of hyperprogression in immunotherapy (p = 0.002 in MDM2, p < 0.001 in MDM4). Conclusion: The six-IRL signature exhibits a promising prediction value of clinical prognosis and ICI efficacy in LUAD. Patients with low risk might gain benefits from ICI, although some have a risk of hyperprogressive disease.

Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer.

Chronic exposure to airborne carbon black ultrafine (nCB) particles generated from incomplete combustion of organic matter drives IL-17A-dependent emphysema. However, whether and how they alter the immune responses to lung cancer remains unknown. Here, we show that exposure to nCB particles increased PD-L1+ PD-L2+ CD206+ antigen-presenting cells (APCs), exhausted T cells, and Treg cells. Lung macrophages that harbored nCB particles showed selective mitochondrial structure damage and decreased oxidative respiration. Lung macrophages sustained the HIF1α axis that increased glycolysis and lactate production, culminating in an immunosuppressive microenvironment in multiple mouse models of non-small cell lung cancers. Adoptive transfer of lung APCs from nCB-exposed wild type to susceptible mice increased tumor incidence and caused early metastasis. Our findings show that nCB exposure metabolically rewires lung macrophages to promote immunosuppression and accelerates the development of lung cancer.

Mid-Term Outcomes of Cemented Stem and Subtrochanteric Shortening Derotational Osteotomy in Total Hip Arthroplasty for Crowe IV Developmental Dysplasia.

OBJECTIVE: Performing subtrochanteric osteotomy with cemented components in patients with Crowe IV developmental dysplasia of the hip (DDH) is technically challenging and not widely reported. This study aimed to evaluate the mid-term outcomes of cemented stem total hip arthroplasty (THA) with subtrochanteric femoral shortening and transverse derotational osteotomy in patients with Crowe IV DDH. METHODS: Data collected from patients with Crowe IV DDH who underwent cemented stem THA with subtrochanteric femoral shortening and transverse derotational osteotomy between 2010 and 2018 were retrospectively evaluated. The cemented Lubinus SP II femoral component and the cementless CombiCup acetabular component were used together in all cases. These data, including Harris hip scores, limb length discrepancy (LLD), severity of limp, Trendelenburg test, bone union, length of the resected femur, limb lengthening, level of the osteotomy site, and length bridging the osteotomy site, as well as complications, were analyzed. A paired Student t-test was used to analyze continuous variables, categorical data were compared using Fisher's exact probability test, and correlation analysis was performed using Spearman's rank correlation coefficient. RESULTS: Among 14 included patients (10 females and four males), the mean age was 60.4 years (range, 47-73). The mean follow-up period was 49.1 months, and no patient was lost to follow-up. The mean Harris hip score improved from 40.7 to 87.7. The mean LLD decreased from 52 to 12.7 mm. The mean length of the excised femoral segment was 38.4 mm, and the mean length of limb lengthening was 27.1 mm. The mean distance between the osteotomy site and the lesser trochanter was 21.1 mm after surgery. The mean length of the femoral stem bridging the osteotomy site was 97.6 mm. Finally, the mean osteotomy union time was 10.6 months. No statistically significant correlation was found between the osteotomy union time and these factors. No neurological deficits were noted. Delayed union was observed in one patient, and postoperative dislocation was observed in two patients. Cement leakage into the osteotomy gap was observed in one patient, however, no revisions were required, and no signs of loosening or migration were observed. CONCLUSIONS: Cemented stem THA combined with subtrochanteric femoral shortening and transverse derotational osteotomy is safe and effective in treating patients with Crowe IV DDH. Rather than leading to nonunion, cement leakage may negatively affect bone healing.

Acetylation of Atp5f1c Mediates Cardiomyocyte Senescence via Metabolic Dysfunction in Radiation-Induced Heart Damage.

Objective: Ionizing radiation (IR) causes cardiac senescence, which eventually manifests as radiation-induced heart damage (RIHD). This study is aimed at exploring the mechanisms underlying IR-induced senescence using acetylation proteomics. Methods: Irradiated mouse hearts and H9C2 cells were harvested for senescence detection. Acetylation proteomics was used to investigate alterations in lysine acetylation. Atp5f1c acetylation after IR was verified using coimmunoprecipitation (Co-IP). Atp5f1c lysine 55 site acetylation (Atp5f1c K55-Ac) point mutation plasmids were used to evaluate the influence of Atp5f1c K55-Ac on energy metabolism and cellular senescence. Deacetylation inhibitors, plasmids, and siRNA transfection were used to determine the mechanism of Atp5f1c K55-Ac regulation. Results: The mice showed cardiomyocyte and cardiac aging phenotypes after IR. We identified 90 lysine acetylation sites from 70 protein alterations in the heart in response to IR. Hyperacetylated proteins are primarily involved in energy metabolism. Among them, Atp5f1c was hyperacetylated, as confirmed by Co-IP. Atp5f1c K55-Ac decreased ATP enzyme activity and synthesis. Atp5f1c K55 acetylation induced cardiomyocyte senescence, and Sirt4 and Sirt5 regulated Atp5f1c K55 deacetylation. Conclusion: Our findings reveal a mechanism of RIHD through which Atp5f1c K55-Ac leads to cardiac aging and Sirt4 or Sirt5 modulates Atp5f1c acetylation. Therefore, the regulation of Atp5f1c K55-Ac might be a potential target for the treatment of RIHD.