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.

Identification of a novel RMST-ALK rearrangement in advanced lung adenocarcinoma and durable response to ceritinib: A case report.

Next-generation sequencing technology has enabled the identification of fusion partners of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer, and various ALK fusion partners have been confirmed. Here, a novel rhabdomyosarcoma 2-associated transcript (RMST)-ALK rearrangement was identified in an 80-year-old Chinese man with advanced lung adenocarcinoma. The patient was prescribed ceritinib and achieved a partial response, which has been sustained for more than 18 months. This is the first report of the RMST-ALK rearrangement, and we showed that a patient with lung adenocarcinoma carrying this rearrangement can benefit from ceritinib treatment; therefore, this is a significant finding in clinical practice.

Corrigendum: The Identification of Two RNA Modification Patterns and Tumor Microenvironment Infiltration Characterization of Lung Adenocarcinoma.

[This corrects the article DOI: 10.3389/fgene.2022.761681.].

The Identification of Two RNA Modification Patterns and Tumor Microenvironment Infiltration Characterization of Lung Adenocarcinoma.

Background: RNA modification plays an important role in many diseases. A comprehensive study of tumor microenvironment (TME) characteristics mediated by RNA modification regulators will improve the understanding of TME immune regulation. Methods: We selected 26 RNA modification "writers" of lung adenocarcinoma (LUAD) samples and performed unsupervised clustering analysis to explore RNA modification patterns in LUAD. Differentially expressed genes (DEGs) with RNA modification patterns were screened to develop a "writers" of RNA modification score (WM score) system. The infiltration ratio of TME cell subsets was analyzed by CIBERSORT. Results: We identified two RNA modification modes showing different characteristics of overall survival (OS) and TME cell infiltration. According to WM score, LUAD patients were divided into a high-WM score group and a low-WM score group. High-scored patients had a poor prognosis and higher tumor mutation burden (TMB), they were more sensitive to four LUAD therapies (erlotinib, XA V939, gefitinib, and KU-55933) and more clinically responsive to PD-L1 treatment. Those with a low WM score showed higher stromal scores, ESTIMATE scores, and survival chance. Conclusion: Our work revealed the potential role of RNA modification patterns in TME, genetic variation, targeted inhibitor therapy, and immunotherapy. Identifying RNA modification pattern of LUAD patients help understand the characteristics of TME and may promote the development of immunotherapy strategies.

Inhibition of macrophage migration inhibitory factor (MIF) as a therapeutic target in bleomycin-induced pulmonary fibrosis rats.

Macrophage migration inhibitory factor (MIF) inhibition can attenuate pulmonary fibrosis, but the antifibrotic mechanism is unclear. Here we investigated the antifibrotic effect of MIF knockdown in rats with bleomycin (BLM)-induced pulmonary fibrosis. The results showed that MIF inhibition attenuated lung injury and extracellular matrix deposition; significantly reduced the levels of cytokines including transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), hydroxyproline (hyp), fibroblast growth factor 23 (FGF23), and secreted phosphoprotein 1 (Spp1); and inhibited the expression of CD68, F4/80, and α-smooth muscle actin (α-SMA) protein. MIF inhibition is associated with reduction of proinflammatory mediators and macrophage infiltration in lungs. In addition, MIF knockdown in the day 14 group was significantly better than MIF knockdown in day 1 group in terms of the above mentioned cytokines TGF-ß1, IL-17, TNF-α. MIF knockdown in day 14 group showed a better trend than MIF knockdown in day 1 group in inhibition of hyp and α-SMA formation. Furthermore, MIF inhibition downregulated the FGF23, Spp1, anti-integrin alpha 10 (Itga10), laminin subunit alpha 1 (Lama1), thrombospondin 2 (THBS2), and Serpin family B member 5 (SERPINB5) mRNA levels and the p-Smad2/3 protein level. MIF knockdown may inhibit fibrosis through the TGF-ß1/Smads signaling pathway. In addition, MIF inhibition protects against vascular remodeling via Thbs2 and Serpinb5 signaling. In summary, our study showed that knockdown of MIF can significantly inhibit lung inflammation and fibrosis in rats with BLM-induced pulmonary fibrosis. The future development of inhibitors targeting MIF may contribute to the treatment of pulmonary fibrosis.

Low prognostic nutrition index predicts poorer quality of life in late-stage lung cancer.

BACKGROUND: Quality of life (QOL) is one of the most important endpoints in lung cancer care. Both nutritional and immune status reportedly correlate with QOL, so we investigated whether the prognostic nutritional index (PNI), a reliable marker of nutritional and immune status, can predict QOL in late-stage lung cancer. METHODS: We enrolled 80 lung cancer patients and their clinical data including PNI were obtained. The FACT-L questionnaire in Chinese version 4 was administered to every patient. RESULTS: Of the 80 lung cancer patients, 16 were stage III and 64 were stage IV. The average PNI value was 44.24±5.53. The average FACT-L score was 99.58±21.84, indicating impaired QOL. The FACT-L score in the stage IV group was significantly lower than that in the stage III group (P=0.001), especially for the four subscales of physical, social/family, emotional, and functioning well-being. In the stage IV group, the FACT-L score in the high PNI group was significantly higher than that in the low PNI group (P=0.042), with especially higher score for the physical well-being subscale. PNI was significantly related to both the FACT-L score (r=0.3265, P=0.0085) and physical well-being subscale (r=0.4746, P<0.0001). CONCLUSIONS: PNI is a simple but valuable biomarker of QOL in stage IV lung cancer patients. A lower PNI may indicate the need for detailed QOL evaluation and intervention.

Evaluation of the Characteristics of Asthma in Severe and Extremely Severe COPD.

Background: Biotherapy for asthma may be useful in patients suffering from chronic obstructive pulmonary disease (COPD) with asthma characteristics. Therefore, the evaluation and close monitoring of asthma characteristics in severe and extremely severe COPD can guide treatment decisions to improve prognosis. Methods: Stable patients suffering from COPD and having a forced expiratory volume in 1 s (FEV1%) of ≤50% (GOLD 3-4) in the First Affiliated Hospital of Sun Yat-Sen University from December 2014 to June 2018 were retrospectively enrolled in this study and evaluated in terms of their asthma characteristics (blood eosinophil counts, fractional exhaled NO [FeNO] values, and reversibility). Results: A total of 178 patients with an average age of 65.62±9.28 years were enrolled in this study. A total of 85 patients had an improvement of ≥12% in FEV1%, and 61 of these patients had an absolute increase of >200 mL. Of 122 patients, 68 had blood eosinophil counts of ≥150 cells/µl, whereas 27 showed blood eosinophil counts ≥300 cells/µl. The blood eosinophil of ≥2% was found in 66/122 (54.10%) patients, whereas ≥3% was found in 51/122 (41.80%) patients. A total of 46 of 58 patients had an increased serum IgE level of ≥30 IU/mL, and 32 patients had an IgE of ≥100 IU/mL. The FeNO value of ≥25 ACO (ppb) was found in 51/155 (32.90%) patients. Furthermore, 43 patients had asthma-COPD overlap (ACO), and the FeNO values in the ACO group was 26.13±14.91 ppb, which was significantly higher than that in the COPD alone group (20.99±9.16 ppb; P=0.016). A total of 12 patients with ACO had a negative response after bronchodilation. In the COPD alone group, 34 patients had an absolute increase of >200 mL, whereas 55 of the 95 patients had blood eosinophil counts of ≥150 cells/µl. The blood eosinophilia of ≥2% was found in 54/95 (56.84%) patients. A total of 36 of 45 patients had an increased serum IgE level of ≥30 IU/mL. The FeNO value of 34/123 (27.64%) patients was ≥25 ppb. Conclusion: The characteristics of asthma are common findings in patients with severe and extremely severe COPD. Biomarkers should be actively used to evaluate the characteristics of asthma in these patients. If the characteristics of asthma exist, then anti-IgE or anti-IL-5 therapy should be considered to reduce exacerbation.

Acinar-Predominant Pattern Correlates With Poorer Prognosis in Invasive Mucinous Adenocarcinoma of the Lung.

OBJECTIVES: Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma with several growth patterns, such as lepidic acinar and papillary. However, to our knowledge, no study regarding prognostic and clinicopathologic aspects of IMAs with different growth patterns has been reported. METHODS: Of 2,236 patients with primary lung adenocarcinoma, 16 were identified as having lepidic-predominant IMA and 10 as having acinar-predominant IMA. Data regarding the clinicopathologic characteristics, computed tomography (CT) features, and prognosis were collected. RESULTS: No statistically significant difference was noted in sex, age, smoker proportion, and T classification between both groups. The proportion of lymph node metastasis was significantly higher in acinar-predominant IMA (P = .046). Both groups shared many signs in CT findings. Air bronchogram was a relatively specific sign for lepidic-predominant IMA. Survival analysis showed that acinar-predominant IMA had a poorer prognosis (P = .0294). CONCLUSIONS: Lepidic-predominant and acinar-predominant IMA are two different subtypes of IMA. Acinar-predominant IMA is associated with lymph node metastasis and a poorer prognosis.

Endothelial progenitor cell dysfunction in acute exacerbation of chronic obstructive pulmonary disease.

Endothelial progenitor cells (EPCs) are decreased in cardiac dysfunction morbidity associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Therefore, the present study aimed to assess the role of EPCs in AECOPD. Patients with AECOPD (n=27) or stable COPD (n=26) were enrolled. Systemic inflammatory markers (high­sensitivity C­reactive protein) were measured. In addition, EPCs were counted, isolated and cultured, and their proliferative, migratory, adhesive and tube­forming capabilities were determined, in cells from patients with AECOPD and stable COPD. EPC number was lower in patients with AECOPD (5.1±2.6x103/ml) compared with patients with stable COPD (6.0±3.2x103/ml). Migration assay indicated that the early­EPCs isolated from patients with AECOPD were significantly less mobile than EPCs derived from stable COPD subjects, at a stromal­cell derived factor­1α concentration of 100 ng/ml (3,550/30,000 vs. 7,853/30,000, P<0.05). C­X­C chemokine receptor­4 positivity was significantly reduced in AECOPD patients (16.1±9.9 vs. 56.33±6.3%, P<0.05). Furthermore, fewer early­EPC clusters were formed by EPCs derived from AECOPD, compared with those derived from stable COPD (8.2±0.86 vs. 14.4±1.36, P=0.027). Stable COPD late­EPCs were markedly deficient in intact tubule formation, however AECOPD late­EPCs formed no tubules. The number of AECOPD­ and stable COPD­derived late­EPCs adhering to Matrigel­induced tubules was 36.8±1.85 and 20.6±1.36 (P<0.05) respectively, and the cluster of differentiation 31 positivity in late­EPCs was 79.69±1.3 and 29.1±2.47%, in AECOPD and stable COPD patients, respectively (P<0.001). The findings demonstrated that early­EPCs are decreased and dysfunctional in AECOPD patients, which may contribute to the altered vascular endothelium in this patient population.

Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway.

Sirtuin6 (SIRT6), a member of the sirtuins protein family, plays multiple complex roles in cancer. Here, we report that elevated SIRT6 expression was correlated with clinicopathological parameters such as T and N classification in non-small cell lung cancer (NSCLC) patient tumors. SIRT6 overexpression in NSCLC cell lines increased extracellular signal-regulated kinase (p-ERK)1/2 phosphorylation, activated matrix metalloproteinase 9 (MMP9) and promoted tumor cell migration and invasion. Upon treatment with a specific mitogen-activated protein kinase (MEK) 1/2 inhibitor, these effects were abolished. Our results demonstrate SIRT6 upregulation in NSCLC for the first time and suggest a functional role for SIRT6 in promoting migration and invasion through ERK1/2/MMP9 signaling. SIRT6 may serve as a potential therapeutic target in NSCLC and its utility as a prognostic indicator warrants further study.

Importance of fractional exhaled nitric oxide in the differentiation of asthma-COPD overlap syndrome, asthma, and COPD.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is an easy, sensitive, reproducible, and noninvasive marker of eosinophilic airway inflammation. Accordingly, FeNO is extensively used to diagnose and manage asthma. Patients with COPD who share some of the features of asthma have a condition called asthma-COPD overlap syndrome (ACOS). The feasibility of using FeNO to differentiate ACOS patients from asthma and COPD patients remains unclear. METHODS: From February 2013 to May 2016, patients suspected with asthma and COPD through physician's opinion were subjected to FeNO measurement, pulmonary function test (PFT), and bronchial hyperresponsiveness or bronchodilator test. Patients were divided into asthma alone group, COPD alone group, and ACOS group according to a clinical history, PFT values, and bronchial hyperresponsiveness or bronchodilator test. Receiver operating characteristic (ROC) curves were obtained to elucidate the clinical functions of FeNO in diagnosing ACOS. The optimal operating point was also determined. RESULTS: A total of 689 patients were enrolled in this study: 500 had asthma, 132 had COPD, and 57 had ACOS. The FeNO value in patients with ACOS was 27 (21.5) parts per billion (ppb; median [interquartile range]), which was significantly higher than that in the COPD group (18 [11] ppb). The area under the ROC curve was estimated to be 0.783 for FeNO. Results also revealed an optimal cutoff value of >22.5 ppb FeNO for differentiating ACOS from COPD patients (sensitivity 70%, specificity 75%). CONCLUSION: FeNO measurement is an easy, noninvasive, and sensitive method for differentiating ACOS from COPD. This technique is a new perspective for the management of COPD patients.

CUEDC2 down-regulation is associated with tumor growth and poor prognosis in lung adenocarcinoma.

CUE domain-containing 2 (CUEDC2) is a multi-functional protein, which regulates cell cycle, growth factor signaling and inflammation. We found that CUEDC2 was low in lung adenocarcinoma cell lines and lung adenocarcinoma tissues at both mRNA and protein levels. Low levels of CUEDC2 were correlated with a shorter survival time in patients with lung adenocarcinoma (p = 0.004). CUEDC2 expression was correlated with tumor T classification (P = 0.001) at clinical stage (P = 0.001) and tumor size (P = 0.033). Multivariate analysis suggested that CUEDC2 expression is an independent prognostic indicator for patients with lung adenocarcinoma. Ectopic expression of CUEDC2 decreased cell proliferation in vitro and inhibited tumor growth in nude mice in vivo. Knockdown of endogenous CUEDC2 by short hairpin RNAs (shRNAs) increased tumor growth. Inhibition of proliferation by CUEDC2 was associated with inactivation of the PI3K/Akt pathway, induction of p21 and down-regulation of cyclin D1. Our results suggest that decreased expression of CUEDC2 contributes to tumor growth in lung adenocarcinoma, leading to a poor clinical outcome.

Decreased CD34+ cell number is correlated with cardiac dysfunction in patients with acute exacerbation of COPD.

BACKGROUND AND PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with a higher risk of cardiovascular disease (CVD). Previous studies have indicated that the reduction of bone marrow-derived multipotent progenitors (CD34+ cells) may lead to reduced vascular repair capacity and may help to identify patients that pose an increased cardiovascular risk. However, the relationship between CD34+cells and CVD risk in AECOPD remains unclear. The aim of the present study was to assess CD34+ cell counts and their relationship with classical adverse cardiac outcome predictors in AECOPD. METHODS: For our study, 27 patients with AECOPD (GOLD stage III, IV), 26 with stable COPD (GOLD stage III, IV), and 24 healthy controls were enrolled. CD34+ cells were enumerated, and plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a systemic inflammation marker (high-sensitivity C-reactive protein, hsCRP) and mobilisation marker (matrix metalloproteinase-9, MMP-9), were measured. Echocardiography was performed to evaluate cardiac dysfunction and pulmonary hypertension. RESULTS: Compared with healthy controls, AECOPD patients had a significantly decreased CD34+ cell count (5.1 ± 2.6 versus 9.4 ± 3.6 × 10³/ml), especially in patients with a prior history of acute exacerbation. For patients with AECOPD, the CD34+ cell count was inversely correlated with NT-proBNP levels, pulmonary artery systolic pressure (PASP) and resting heart rate, and positively correlated with left ventricular ejection fraction (LVEF). In all three groups, CD34+ cell count was negatively correlated with hsCRP. CONCLUSIONS: The circulating CD34+ cell count was decreased and correlated with cardiac dysfunction in AECOPD patients, and thus may account for the increased cardiovascular risk in this population.

Overexpression of muscarinic receptor 3 promotes metastasis and predicts poor prognosis in non-small-cell lung cancer.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer development, but the mechanism is not fully understood. Muscarinic receptor 3 (M3R) has been found to be involved in the progression of small-cell lung cancer and the pathological process of COPD. We hypothesized that M3R may contribute to lung cancer development, especially in patients with COPD. METHODS: The correlation between M3R expression and clinical features of non-small-cell lung cancer (NSCLC) was evaluated in 148 paraffin-embedded archived NSCLC specimens with the use of immunohistochemistry. M3R agonist and siRNA treatments were used to study the role of M3R in NSCLC cell lines. Western blotting and zymography were used to examine the impact of M3R on the PI3K/Akt/matrix metalloproteinase 9 signaling pathway. RESULTS: The expression of M3R in NSCLC was significantly increased and correlated with tumor metastasis and poor survival of NSCLC patients. NSCLC patients with COPD showed higher expression of M3R than those without COPD (p = 0.0014). Moreover, M3R expression was inversely related to percent forced expiratory volume in 1 second (r = 0.7017, p < 0.0001) and forced expiratory volume in 1 second /forced vital capacity (r = 0.5057, p < 0.0001), but positively related to smoking history. Down-regulation of M3R resulted in the inhibition of migration and invasion ability of NSCLC cell lines A549 and L78. Furthermore, M3R enhanced the expression and activity of matrix metalloproteinase 9 through PI3K/Akt, which promoted the migration and invasion of NSCLC cell lines. CONCLUSION: Our results suggest that overexpression of M3R in NSCLC promotes the progression of NSCLC, which could contribute to lung cancer development in COPD patients. M3R could be another pharmacological target in lung cancer, especially in COPD patients.

The role of the ß2 adrenergic receptor on endothelial progenitor cells dysfunction of proliferation and migration in chronic obstructive pulmonary disease patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), with > 44% of these patients presenting with generalized atherosclerosis at autopsy. It is accepted that endothelial progenitor cells (EPCs) participate in the repair of dysfunctional endothelium, thereby, protecting against atherosclerosis. The ß2 adrenergic receptor (ß2AR) expressed on mononuclear cells in peripheral blood and CD34(+) cells in bone has been shown to regulate T-cell traffic and proliferation. At present, there have been few systematic studies evaluating ß2AR expression on EPCs in the peripheral blood of COPD patients and its role in EPCs migration and proliferation. Therefore, the objective of this study was to determine the role of ß2ARs in EPCs function and, if this role is altered, in the COPD population. METHODS: EPCs from 25 COPD and 16 control patients were isolated by Ficoll density-gradient centrifugation and identified using fluorescence-activated cell sorting. ß2AR expression on EPCs was determined by western blotting and real-time PCR. The transwell migration assay was performed to determine the migration capacity of EPCs treated with a ß2AR agonist, antagonist and ß2AR monoclonal antibody. EPCs proliferation was assayed throughout the cell cycle. Following arterial damage in NOD/SCID mice, the number of EPCs treated with siRNA-ß2AR incorporated at the injured vascular site was determined by fluorescence microscopy. RESULTS: Data showed a significant increase in the total number of ß2ARs in addition to an increased expression on early EPCs in COPD patients. COPD EPCs treated with ß2AR antagonist (ICI 118551) increased migration to SDF-1α when compared to treatment with the ß2AR agonist, norepinephrine. These changes were directly correlated to increase CXCR4 on EPCs. The proliferation of early EPCs treated with ß2AR antagonist was improved and was correlated to an intercellular decrease in reactive oxygen species. CONCLUSION: Changes in ß2AR in COPD patients alter EPCs migration and proliferation, contributing to altered EPC repair capacity in this patient population.