Involvement of the Constitutive Photomorphogenesis 9 Signalosome Subunit 5 With Programmed Cell Death Protein 1 Ligand in Asthma.

PURPOSE: The constitutive photomorphogenesis 9 signalosome (CSN) is a highly conserved protein complex comprised of eight subunits, each of which play crucial roles in diverse cellular processes, such as signal transduction, gene transcription, angiogenesis, and cell proliferation. In the context of asthma, a potential emerging target is the programmed death-ligand 1 (PD-L1)-mediated pathway, which serves as a significant immune checkpoint inhibitor in this condition. However, the precise involvement of CSN subunit 5 (CSN5) in bronchial asthma and the interplay between CSN5 and PD-L1 in asthma remain poorly understood. METHODS: The potential association between CSN5 and bronchial asthma was explored in a mouse model of ovalbumin (OVA)-induced asthma. Samples were obtained from human lung microvascular endothelial cell (HMVEC-L) treated with Dermatophagoides pteronyssinus (Der p 1) and CSN5 small interfering RNA. The expression of nuclear factor (NF)-κB, IκBα, inhibitor of κB kinase ß (IKKß), PD-L1, and CSN5 was assessed. Additionally, plasma CSN5 levels in asthma patients, both in stable and exacerbated states, were examined. RESULTS: Plasma levels of CSN5 were elevated in patients with exacerbated asthma (n = 19) compared to both healthy controls (n = 10) and patients with stable asthma (n = 19). The CSN5 level demonstrated a correlation with lung function in individuals with asthma. Silencing CSN5 in HMVEC-L led to a reduction in NF-κB protein levels at 4 hours and PD-L1 levels at 4, 8, and 24 hours after Der p 1 treatment. In OVA-sensitized/challenged mice, goblet cell hyperplasia, lung fibrosis, and the levels of CSN5, PD-L1, interleukin-13, interferon-γ, phospho (p)-NF-κB, p-IκBα, and p-IKKß proteins increased at 33 and 80 days compared to control mice. However, these changes were mitigated by treatment with a PD-L1 inhibitor. CONCLUSIONS: These findings suggest that CSN5, along with PD-L1, could serve as a promising target for the treatment of asthma.

CDCP1 Expression Is a Potential Biomarker of Poor Prognosis in Resected Stage I Non-Small-Cell Lung Cancer.

BACKGROUND: Although early-stage lung cancer has increased owing to the introduction of screening programs, high recurrence rate remains a critical concern. We aimed to explore biomarkers related to the prognosis of surgically resected non-small-cell lung cancer (NSCLC). METHODS: In this retrospective study, we collected medical records of patients with NSCLC and matched tissue microarray blocks from surgical specimens. Semiquantitative immunohistochemistry was performed for measuring the expression level of fibroblast activation protein-alpha (FAP-α), Jagged-1 (JAG1), and CUB-domain-containing protein 1 (CDCP1). RESULTS: A total of 453 patients who underwent complete resection between January 2011 and February 2012 were enrolled; 55.2% patients had stage I NSCLC, and 31.1% presented squamous cell carcinoma. Disease stage was a significant risk factor for recurrence and death, and age ≥ 65 years and male sex were associated with poor overall survival. FAP-a and JaG1 were not related to survivals, while CDCP1-expressing patients exhibited poor disease-free and overall survival. Moreover, CDCP1 expression in stage I NSCLC was significantly associated with recurrence. CONCLUSIONS: Old age, male sex, and high pathological stage were poor prognostic factors in patients with NSCLC who underwent surgical resection. Furthermore, CDCP1 expression could serve as a biomarker for poor prognosis in stage I NSCLC.

Clinical impact of rebiopsy among patients with epidermal growth factor receptor-mutant lung adenocarcinoma in a real-world clinical setting.

BACKGROUND: In this study, we investigated the risk factors of acquired T790M mutation among patients with lung adenocarcinoma with epidermal growth factor receptor (EGFR) tyrosine mutation who were treated with EGFR-tyrosine kinase inhibitors (TKIs). The aim was to identify the clinical impact of rebiopsy. METHODS: This multicenter, retrospective cohort study was conducted in South Korea from January 2007 to June 2017. Patients with adenocarcinoma with EGFR mutation who underwent rebiopsy and were treated with EGFR-TKIs were included. RESULTS: Of a total of 352 patients, T790M mutation was identified in 156 (41.9%) at the time of rebiopsy. The median duration from initial biopsy to rebiopsy was 17 months. Univariate logistic regression analysis revealed associations of exon 19 deletion (odds ratio [OR], 1.643; p = 0.026), absence of L858R (OR, 0.627; p = 0.042), and previous EGFR-TKI treatment duration (OR, 1.039; p < 0.001) with T790M mutation. Previous EGFR-TKI treatment duration (OR, 3.580; p < 0.001) was independently associated with T790M mutation. A multivariate Cox proportional hazard model revealed that brain metastasis at initial diagnosis (hazard ratio, 1.390; p = 0.050) tended to be associated with T790M mutation. Among the patients with T790M mutation at rebiopsy, the osimertinib user group (n = 90) had a better one-year survival (68.7 vs. 58.3%, p = 0.048) than the osimertinib nonuser group (n = 66). CONCLUSIONS: Rebiopsy might affect the clinical course of patients with EGFR-mutant adenocarcinoma who receive EGFR-TKIs.