Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization.

Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.

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 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.

Increased expression of IL1-RL1 is associated with type 2 and type 1 immune pathways in asthma.

BACKGROUND: Asthma is a common chronic airway disease in the world. The purpose of this study was to explore the expression of IL1-RL1 in sputum and its correlation with Th1 and Th2 cytokines in asthma. METHODS: We recruited 132 subjects, detected IL1-RL1 protein level in sputum supernatant by ELISA, and analyzed the correlation between the expression level of IL1-RL1 and fraction of exhaled nitric oxide (FeNO), IgE, peripheral blood eosinophil count (EOS#), and Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8). The diagnostic value of IL1-RL1 was evaluated by ROC curve. The expression of IL1-RL1 was further confirmed by BEAS-2B cell in vitro. RESULTS: Compared with the healthy control group, the expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma increased. The AUC of ROC curve of IL1-RL1 in sputum supernatant and serum were 0.6840 (p = 0.0034), and 0.7009 (p = 0.0233), respectively. IL1-RL1 was positively correlated with FeNO, IgE, EOS#, Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8) in induced sputum supernatant. Four weeks after inhaled glucocorticoids (ICS) treatment, the expression of IL1-RL1 in sputum supernatant and serum was increased. In vitro, the expression of IL1-RL1 in BEAS-2B was increased after stimulated by IL-4 or IL-13 for 24 h. CONCLUSION: The expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma was increased, and was positively correlated with some inflammatory markers in patients with asthma. IL1-RL1 may be used as a potential biomarker for the diagnosis and treatment of asthma.

Potential benefit of osismertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer.

BACKGROUND: EGFR-mutant non-small cell lung cancer (NSCLC) is prone to leptomeningeal metastasis (LM) after Tyrosine kinase inhibitors (TKIs) treatment. Our previous study suggested that osimertinib plus bevacizumab was safe and effective in LM from EGFR-mutant NSCLC. This study aimed to compare the efficacy of osimertinib plus bevacizumab with osimertinib in EGFR-mutant NSCLC patients with LM. METHODS: We retrospectively reviewed the data from 27 LM patients with EGFR-mutant NSCLC who received osimertinib with or without bevacizumab at the Second Affiliated Hospital of Nanchang University. Next, we investigated the antitumor efficacy of osimertinib plus bevacizumab in an LM xenograft model using the H1975 (EGFR exon20 T790M and exon21 L858R) cell line. We examined the ability of osimertinib plus bevacizumab compared with osimertinib to penetrate the blood-brain barrier (BBB) and explored the potential mechanism. RESULTS: Our retrospective study observed the improved survival of LM patients in osimertinib plus bevacizumab group. The median overall survival (OS) of the patients who received osimertinib and bevacizumab (n = 16) compared with osimertinib group (n = 11) was 18.0 months versus 13.7 months (log-rank test, p = 0.046, HR = 2.867, 95% CI 1.007-8.162). The median intracranial Progression-free Survival (iPFS) was 10.6 months versus 5.5 months (log-rank test, p = 0.037, HR = 3.401, 95% CI 1.079-10.720). In the LM xenograft model with H1975 cells, the combined treatment significantly increased the effective intracranial concentration of osimertinib, modulated the level of E-cadherin and downregulated the levels of EGFR and downstream signaling pathways including p-AKT and reduced tumor microvessel density (TMD), indicated that combined osimertinib with bevacizumab may exhibit a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin. CONCLUSIONS: Our findings indicate the potential benefit of osimertinib plus bevacizumab in LM with EGFR-mutant NSCLC, and more larger sample size research are still needed.

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.

Elevated CEACAM5 Levels in Patients with Asthma.

INTRODUCTION: Asthma is a common chronic respiratory disease. This study aimed to explore the expression level of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in induced sputum supernatant, induced sputum cells, and serum of asthma patients. METHODS: The protein levels of CEACAM5 in induced sputum supernatant and serum were detected by enzyme-linked immunosorbent assay. The expression of CEACAM5 in induced sputum cells was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We analyzed the correlations between CEACAM5 expression and the clinical characteristics (FeNO and IgE) of asthma. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of CEACAM5 in asthma. The expression level of CEACAM5 in 16HBE and BEAS-2B cells was detected by qRT-PCR. RESULTS: The expression of CEACAM5 in induced sputum supernatant, induced sputum cells, and serum of asthma patients was significantly upregulated. Asthma patients with high CEACAM5 expression in induced sputum supernatant had higher levels of FeNO, IgE, and IL-13. The expression levels of CEACAM5 in induced sputum supernatant and induced sputum cells were positively correlated with FeNO and IgE. The ROC curve showed that CEACAM5 had a good diagnostic value in asthma. CEACAM5 expression was upregulated in BEAS-2B and 16HBE cells after IL-4 or IL-13 stimulation for 48 h. CONCLUSION: The expression levels of CEACAM5 in induced sputum supernatant, induced sputum cells, and serum of asthma patients were significantly increased. CEACAM5 may be involved in eosinophilic inflammation of asthma and may be used as a diagnostic biomarker and therapeutic target of asthma.

Exploration of induced sputum BIRC3 levels and clinical implications in asthma.

BACKGROUND: Baculoviral IAP repeat-containing 3 (BIRC3) which encodes a member of the IAP family of proteins upregulated in the asthma expression profile dataset. However, there was few research on studying the clinical implication of BIRC3 in asthma. OBJECTIVE: To validate BIRC3 expression and its clinical implications in induced sputum of asthma. METHODS: Based on the GSE76262 (118 asthma cases and 21 healthy controls) dataset, differentially expressed genes were screened using R software. Subsequently, BIRC3 mRNA and protein were clinically verified in induced sputum samples through quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Besides, the correlations between BIRC3 expression and asthmatic eosinophilic/allergic inflammation indicators (FeNO, IgE, and EOS%), pulmonary function (FEV1, FEV1% pred, FVC% pred, and FEV1/FVC), and inflammatory cytokines (IL-4, IL-5, IL-13, IL-25, IL-10, IL-33, and TSLP) were analyzed. Finally, BIRC3 mRNA was detected in human primary bronchial epithelial cells stimulated by cytokines (IL-4 or IL-13). RESULTS: BIRC3 was screened as a candidate gene in the GSE76262, which was highly expressed in asthma. Highly expressed BIRC3 was positively correlated with eosinophilic and allergic indicators, including FeNO, blood eosinophil, and serum IgE. Moreover, BIRC3 protein was positively associated with inflammation cytokines, like IL-4, IL-5, IL-13, IL-25, IL-10, IL-33, and TSLP, while negatively correlated with FEV1, FEV1%pred, FVC% pred, and FEV1/FVC. Furthermore, the expression of BIRC3 could be induced in primary bronchial epithelial cells treated by cytokines IL-4 or IL-13. CONCLUSIONS: BIRC3 significantly increased in induced sputum of asthma and positively correlated with airway eosinophilic and peripheral blood allergic inflammation, type 2 cytokines, and airway obstruction. Increased BIRC3 might be involved in the pathogenesis of asthma by affecting the eosinophilic and allergic inflammation.