Prediction value of neutrophil and eosinophil count at risk of COPD exacerbation.

INTRODUCTION: Predicting acute exacerbations (AEs) in chronic obstructive pulmonary disease (COPD) is crucial. This study aimed to identify blood biomarkers for predicting COPD exacerbations by inflammatory phenotypes. MATERIALS AND METHODS: We analyzed blood cell counts and clinical outcomes in 340 COPD patients aged 20-90 years. Patients were categorized into eosinophilic inflammation (EOCOPD) and non-eosinophilic inflammation (N-EOCOPD) groups. Blood cell counts, eosinophil-to-lymphocyte ratio (ELR), neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-eosinophil ratio (NER) were calculated. Linear and logistic regression models assessed relationships between health outcomes and blood cell counts. RESULTS: EOCOPD patients had distinct characteristics compared to N-EOCOPD patients. Increased neutrophil % and decreased lymphocyte % were associated with reduced pulmonary function, worse quality of life and more exacerbations, but they did not show statistical significance after adjusting by age, sex, BMI, smoking status, FEV1% and patient's medication. Subgroup analysis revealed a 1.372-fold increase in the OR of AE for every 1 unit increase in NLR in EOCOPD patients (p < .05). In N-EOCOPD patients, every 1% increase in blood eosinophil decreased the risk of exacerbation by 59.6%. CONCLUSIONS: Our study indicates that distinct white blood cell profiles in COPD patients, with or without eosinophilic inflammation, can help assess the risk of AE in clinical settings.

A mobile-based airway clearance care system using deep learning-based vision technology to support personalized home-based pulmonary rehabilitation for COAD patients: Development and usability testing.

Background: Excessive mucus secretion is a serious issue for patients with chronic obstructive airway disease (COAD), which can be effectively managed through postural drainage and percussion (PD + P) during pulmonary rehabilitation (PR). Home-based (H)-PR can be as effective as center-based PR but lacks professional supervision and timely feedback, leading to low motivation and adherence. Telehealth home-based pulmonary (TH-PR) has emerged to assist H-PR, but video conferencing and telephone calls remain the main approaches for COAD patients. Therefore, research on effectively assisting patients in performing PD + P during TH-PR is limited. Objective: This study developed a mobile-based airway clearance care for chronic obstructive airway disease (COAD-MoAcCare) system to support personalized TH-PR for COAD patients and evaluated its usability through expert validation. Methods: The COAD-MoAcCare system uses a mobile device through deep learning-based vision technology to monitor, guide, and evaluate COAD patients' PD + P operations in real time during TH-PR programs. Medical personnel can manage and monitor their personalized PD + P and operational statuses through the system to improve TH-PR performance. Respiratory therapists from different hospitals evaluated the system usability using system questionnaires based on the technology acceptance model, system usability scale (SUS), and task load index (NASA-TLX). Results: Eleven participant therapists were highly satisfied with the COAD-MoAcCare system, rating it between 4.1 and 4.6 out of 5.0 on all scales. The system demonstrated good usability (SUS score of 74.1 out of 100) and a lower task load (NASA-TLX score of 30.0 out of 100). The overall accuracy of PD + P operations reached a high level of 97.5% by comparing evaluation results of the system by experts. Conclusions: The COAD-MoAcCare system is the first mobile-based method to assist COAD patients in conducting PD + P in TH-PR. It was proven to be usable by respiratory therapists, so it is expected to benefit medical personnel and COAD patients. It will be further evaluated through clinical trials.

Impact of lifetime air pollution exposure patterns on the risk of chronic disease.

Long-term exposure to air pollution can lead to cardiovascular disease, metabolic syndrome, and chronic respiratory disease. However, from a lifetime perspective, the critical period of air pollution exposure in terms of health risk is unknown. This study aimed to evaluate the impact of air pollution exposure at different life stages. The study participants were recruited from community centers in Northern Taiwan between October 2018 and April 2021. Their annual averages for fine particulate matter (PM2.5) exposure were derived from a national visibility database. Lifetime PM2.5 exposures were determined using residential address information and were separated into three stages (<20, 20-40, and >40 years). We employed exponentially weighted moving averages, applying different weights to the aforementioned life stages to simulate various weighting distribution patterns. Regression models were implemented to examine associations between weighting distributions and disease risk. We applied a random forest model to compare the relative importance of the three exposure life stages. We also compared model performance by evaluating the accuracy and F1 scores (the harmonic mean of precision and recall) of late-stage (>40 years) and lifetime exposure models. Models with 89% weighting on late-stage exposure showed significant associations between PM2.5 exposure and metabolic syndrome, hypertension, diabetes, and cardiovascular disease, but not gout or osteoarthritis. Lifetime exposure models showed higher precision, accuracy, and F1 scores for metabolic syndrome, hypertension, diabetes, and cardiovascular disease, whereas late-stage models showed lower performance metrics for these outcomes. We conclude that exposure to high-level PM2.5 after 40 years of age may increase the risk of metabolic syndrome, hypertension, diabetes, and cardiovascular disease. However, models considering lifetime exposure showed higher precision, accuracy, and F1 scores and lower equal error rates than models incorporating only late-stage exposures. Future studies regarding long-term air pollution modelling are required considering lifelong exposure pattern. .1.

Targeting Lung-Gut Axis for Regulating Pollution Particle-Mediated Inflammation and Metabolic Disorders.

Cigarette smoking (CS) or ambient particulate matter (PM) exposure is a risk factor for metabolic disorders, such as insulin resistance (IR), increased plasma triglycerides, hyperglycemia, and diabetes mellitus (DM); it can also cause gut microbiota dysbiosis. In smokers with metabolic disorders, CS cessation decreases the risks of serious pulmonary events, inflammation, and metabolic disorder. This review included recent studies examining the mechanisms underlying the effects of CS and PM on gut microbiota dysbiosis and metabolic disorder development; one of the potential mechanisms is the disruption of the lung-gut axis, leading to gut microbiota dysbiosis, intestinal dysfunction, systemic inflammation, and metabolic disease. Short-chain fatty acids (SCFAs) are the primary metabolites of gut bacteria, which are derived from the fermentation of dietary fibers. They activate G-protein-coupled receptor (GPCR) signaling, suppress histone deacetylase (HDAC) activity, and inhibit inflammation, facilitating the maintenance of gut health and biofunction. The aforementioned gut microbiota dysbiosis reduces SCFA levels. Treatment targeting SCFA/GPCR signaling may alleviate air pollution-associated inflammation and metabolic disorders, which involve lung-gut axis disruption.

Associations between risk of Alzheimer's disease and obstructive sleep apnea, intermittent hypoxia, and arousal responses: A pilot study.

Objectives: Obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD). However, potential associations among sleep-disordered breathing, hypoxia, and OSA-induced arousal responses should be investigated. This study determined differences in sleep parameters and investigated the relationship between such parameters and the risk of AD. Methods: Patients with suspected OSA were recruited and underwent in-lab polysomnography (PSG). Subsequently, blood samples were collected from participants. Patients' plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aß42) were measured using an ultrasensitive immunomagnetic reduction assay. Next, the participants were categorized into low- and high-risk groups on the basis of the computed product (Aß42 × T-Tau, the cutoff for AD risk). PSG parameters were analyzed and compared. Results: We included 36 patients in this study, of whom 18 and 18 were assigned to the low- and high-risk groups, respectively. The average apnea-hypopnea index (AHI), apnea, hypopnea index [during rapid eye movement (REM) and non-REM (NREM) sleep], and oxygen desaturation index (≥3%, ODI-3%) values of the high-risk group were significantly higher than those of the low-risk group. Similarly, the mean arousal index and respiratory arousal index (R-ArI) of the high-risk group were significantly higher than those of the low-risk group. Sleep-disordered breathing indices, oxygen desaturation, and arousal responses were significantly associated with an increased risk of AD. Positive associations were observed among the AHI, ODI-3%, R-ArI, and computed product. Conclusions: Recurrent sleep-disordered breathing, intermittent hypoxia, and arousal responses, including those occurring during the NREM stage, were associated with AD risk. However, a longitudinal study should be conducted to investigate the causal relationships among these factors.

Corrigendum: Heparin binding epidermal growth factor-like growth factor is a prognostic marker correlated with levels of macrophages infiltrated in lung adenocarcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.963896.].

Heparin binding epidermal growth factor-like growth factor is a prognostic marker correlated with levels of macrophages infiltrated in lung adenocarcinoma.

Background: The interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear. Methods: The clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining. Results: The high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD. Conclusions: HB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.

Climate-mediated air pollution associated with COPD severity.

Air pollution has been reported to be associated with chronic obstructive pulmonary disease (COPD). Our study aim was to examine the mediating effects of air pollution on climate-associated health outcomes of COPD patients. A cross-sectional study of 117 COPD patients was conducted in a hospital in Taiwan. We measured the lung function, 6-min walking distance, oxygen desaturation, white blood cell count, and percent emphysema (low attenuation area, LAA) and linked these to 0-1-, 0-3-, and 0-5-year lags of individual-level exposure to relative humidity (RH), temperature, and air pollution. Linear regression models were conducted to examine associations of temperature, RH, and air pollution with severity of health outcomes. A mediation analysis was conducted to examine the mediating effects of air pollution on the associations of RH and temperature with health outcomes. We observed that a 1 % increase in the RH was associated with increases in forced expiratory volume in 1 s (FEV1), eosinophils, and lymphocytes, and a decrease in the total-lobe LAA. A 1 °C increase in temperature was associated with decreases in oxygen desaturation, and right-, left-, and upper-lobe LAA values. Also, a 1 µg/m3 increase in PM2.5 was associated with a decrease in the FEV1 and an increase in oxygen desaturation. A 1 µg/m3 increases in PM10 and PM2.5 was associated with increases in the total-, right-, left, upper-, and lower-lobe (PM2.5 only) LAA. A one part per billion increase in NO2 was associated with a decrease in the FEV1 and an increase in the upper-lobe LAA. Next, we found that NO2 fully mediated the association between RH and FEV1. We found PM2.5 fully mediated associations of temperature with oxygen saturation and total-, right-, left-, and upper-lobe LAA. In conclusion, climate-mediated air pollution increased the risk of decreasing FEV1 and oxygen saturation and increasing emphysema severity among COPD patients. Climate change-related air pollution is an important public health issue, especially with regards to respiratory disease.

Association of air pollution exposure with exercise-induced oxygen desaturation in COPD.

BACKGROUND: There is a link between exposure to air pollution and the increased prevalence of chronic obstructive pulmonary disease (COPD) and declining pulmonary function, but the association with O2 desaturation during exercise in COPD patients with emphysema is unclear. Our aims were to estimate the prevalence of O2 desaturation during exercise in patients with COPD, and determine the association of exposure to air pollution with exercise-induced desaturation (EID), the degree of emphysema, and dynamic hyperinflation (DH). METHODS: We assessed the effects of 10-year prior to the HRCT assessment and 7 days prior to the six-minute walking test exposure to particulate matter with an aerodynamic diameter of < 10 µm (PM10) or of < 2.5 µM (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in patients with emphysema in this retrospective cohort study. EID was defined as a nadir standard pulse oximetry (SpO2) level of < 90% or a delta (△)SpO2 level of ≥ 4%. Ambient air pollutant (PM2.5, PM10, O3, and NO2) data were obtained from Taiwan Environmental Protection Administration (EPA) air-monitoring stations, usually within 10 km to each participant's home address. RESULTS: We recruited 141 subjects with emphysema. 41.1% of patients with emphysema exhibited EID, and patients with EID had more dyspnea, worse lung function, more severe emphysema, more frequent acute exacerbations, managed a shorter walking distance, had DH, and greater long-term exposure to air pollution than those without EID. We observed that levels of 10-year concentrations of PM10, PM2.5, and NO2 were significantly associated with EID, PM10 and PM2.5 were associated with the severity of emphysema, and associated with DH in patients with emphysema. In contrast, short-term exposure did not have any effect on patients. CONCLUSION: Long-term exposure to ambient PM10, PM2.5 and NO2, but not O3, was associated with EID.

lnc-IL7R Expression Reflects Physiological Pulmonary Function and Its Aberration Is a Putative Indicator of COPD.

Despite rapidly evolving pathobiological mechanistic demystification, coupled with advances in diagnostic and therapeutic modalities, chronic obstructive pulmonary disease (COPD) remains a major healthcare and clinical challenge, globally. Further compounded by the dearth of available curative anti-COPD therapy, it is posited that this challenge may not be dissociated from the current lack of actionable COPD pathognomonic molecular biomarkers. There is accruing evidence of the involvement of protracted 'smoldering' inflammation, repeated lung injury, and accelerated lung aging in enhanced predisposition to or progression of COPD. The relatively novel uncharacterized human long noncoding RNA lnc-IL7R (otherwise called LOC100506406) is increasingly designated a negative modulator of inflammation and regulator of cellular stress responses; however, its role in pulmonary physiology and COPD pathogenesis remains largely unclear and underexplored. Our previous work suggested that upregulated lnc-IL7R expression attenuates inflammation following the activation of the toll-like receptor (TLR)-dependent innate immune system, and that the upregulated lnc-IL7R is anti-correlated with concomitant high PM2.5, PM10, and SO2 levels, which is pathognomonic for exacerbated/aggravated COPD in Taiwan. In the present study, our quantitative analysis of lnc-IL7R expression in our COPD cohort (n = 125) showed that the lnc-IL7R level was significantly correlated with physiological pulmonary function and exhibited COPD-based stratification implications (area under the curve, AUC = 0.86, p < 0.001). We found that the lnc-IL7R level correctly identified patients with COPD (sensitivity = 0.83, specificity = 0.83), precisely discriminated those without emphysematous phenotype (sensitivity = 0.48, specificity = 0.89), and its differential expression reflected disease course based on its correlation with the COPD GOLD stage (r = −0.59, p < 0.001), %LAA-950insp (r = −0.30, p = 0.002), total LAA (r = −0.35, p < 0.001), FEV1(%) (r = 0.52, p < 0.001), FVC (%) (r = 0.45, p < 0.001), and post-bronchodilator FEV1/FVC (r = 0.41, p < 0.001). Consistent with other data, our bioinformatics-aided dose−response plot showed that the probability of COPD decreased as lnc-IL7R expression increased, thus, corroborating our posited anti-COPD therapeutic potential of lnc-IL7R. In conclusion, reduced lnc-IL7R expression not only is associated with inflammation in the airway epithelial cells but is indicative of impaired pulmonary function, pathognomonic of COPD, and predictive of an exacerbated/ aggravated COPD phenotype. These data provide new mechanistic insights into the ailing lung and COPD progression, as well as suggest a novel actionable molecular factor that may be exploited as an efficacious therapeutic strategy in patients with COPD.

Lnc-IL7R alleviates PM2.5-mediated cellular senescence and apoptosis through EZH2 recruitment in chronic obstructive pulmonary disease.

BACKGROUND: Long-term exposure to PM2.5 (particulate matter with an aerodynamic diameter of ≤ 2.5 µm) is associated with pulmonary injury and emphysema in patients with chronic obstructive pulmonary disease (COPD). We investigated mechanisms through which the long noncoding RNA lnc-IL7R contributes to cellular damage by inducing oxidative stress in COPD patients exposed to PM2.5. METHODS: Associations of serum lnc-IL7R levels with lung function, emphysema, and previous PM2.5 exposure in COPD patients were analyzed. Reactive oxygen species and lnc-IL7R levels were measured in PM2.5-treated cells. The levels of lnc-IL7R and cellular senescence-associated genes, namely p16INK4a and p21CIP1/WAF1, were determined through lung tissue section staining. The effects of p16INK4a or p21CIP1/WAF1 regulation were examined by performing lnc-IL7R overexpression and knockdown assays. The functions of lnc-IL7R-mediated cell proliferation, cell cycle, senescence, colony formation, and apoptosis were examined in cells treated with PM2.5. Chromatin immunoprecipitation assays were conducted to investigate the epigenetic regulation of p21CIP1/WAF1. RESULTS: Lnc-IL7R levels decreased in COPD patients and were negatively correlated with emphysema or PM2.5 exposure. Lnc-IL7R levels were upregulated in normal lung epithelial cells but not in COPD cells exposed to PM2.5. Lower lnc-IL7R expression in PM2.5-treated cells induced p16INK4a and p21CIP1/WAF1 expression by increasing oxidative stress. Higher lnc-IL7R expression protected against cellular senescence and apoptosis, whereas lower lnc-IL7R expression augmented injury in PM2.5-treated cells. Lnc-IL7R and the enhancer of zeste homolog 2 (EZH2) synergistically suppressed p21CIP1/WAF1 expression through epigenetic modulation. CONCLUSION: Lnc-IL7R attenuates PM2.5-mediated p21CIP1/WAF1 expression through EZH2 recruitment, and its dysfunction may augment cellular injury in COPD.

Associations of the distance-saturation product and low-attenuation area percentage in pulmonary computed tomography with acute exacerbation in patients with chronic obstructive pulmonary disease.

Background: Chronic obstructive pulmonary disease (COPD) has high global health concerns, and previous research proposed various indicators to predict mortality, such as the distance-saturation product (DSP), derived from the 6-min walk test (6MWT), and the low-attenuation area percentage (LAA%) in pulmonary computed tomographic images. However, the feasibility of using these indicators to evaluate the stability of COPD still remains to be investigated. Associations of the DSP and LAA% with other COPD-related clinical parameters are also unknown. This study, thus, aimed to explore these associations. Methods: This retrospective study enrolled 111 patients with COPD from northern Taiwan. Individuals' data we collected included results of a pulmonary function test (PFT), 6MWT, life quality survey [i.e., the modified Medical Research Council (mMRC) scale and COPD assessment test (CAT)], history of acute exacerbation of COPD (AECOPD), and LAA%. Next, the DSP was derived by the distance walked and the lowest oxygen saturation recorded during the 6MWT. In addition, the DSP and clinical phenotype grouping based on clinically significant outcomes by previous study approaches were employed for further investigation (i.e., DSP of 290 m%, LAA% of 20%, and AECOPD frequency of ≥1). Mean comparisons and linear and logistic regression models were utilized to explore associations among the assessed variables. Results: The low-DSP group (<290 m%) had significantly higher values for the mMRC, CAT, AECOPD frequency, and LAA% at different lung volume scales (total, right, and left), whereas it had lower values of the PFT and 6MWT parameters compared to the high-DSP group. Significant associations (with high odds ratios) were observed of the mMRC, CAT, AECOPD frequency, and PFT with low- and high-DSP groupings. Next, the risk of having AECOPD was associated with the mMRC, CAT, DSP, and LAA% (for the total, right, and left lungs). Conclusion: A lower value of the DSP was related to a greater worsening of symptoms, more-frequent exacerbations, poorer pulmonary function, and more-severe emphysema (higher LAA%). These readily determined parameters, including the DSP and LAA%, can serve as indicators for assessing the COPD clinical course and may can serve as a guide to corresponding treatments.

Air pollution-regulated E-cadherin mediates contact inhibition of proliferation via the hippo signaling pathways in emphysema.

Air pollution has been linked to emphysema in chronic obstruction pulmonary disease (COPD). However, the underlying mechanisms in the development of emphysema due to air pollution remain unclear. The objective of this study was to investigate the role of components of the Hippo signaling pathway for E-cadherin-mediated contact inhibition of proliferation in the lungs after air pollution exposure. E-Cadherin-mediated contact inhibition of proliferation via the Hippo signaling pathway was investigated in Sprague-Dawley (SD) rats whole-body exposed to air pollution, and in alveolar epithelial A549 cells exposed to diesel exhaust particles (DEPs), E-cadherin-knockdown, and high-mobility group box 1 (HMGB1) treatment. Underlying epithelial differentiation, apoptosis, and senescence were also examined, and the interaction network among these proteins was examined. COPD lung sections were used to confirm the observations in rats. Expressions of HMGB1 and E-cadherin were negatively regulated in the lungs and A549 cells by air pollution, and this was confirmed by knockdown of E-cadherin and by treating A549 cells with HMGB1. Depletion of phosphorylated (p)-Yap occurred after exposure to air pollution and E-cadherin-knockdown, which resulted in decreases of SPC and T1α. Exposure to air pollution and E-cadherin-knockdown respectively downregulated p-Sirt1 and increased p53 levels in the lungs and in A549 cells. Moreover, the protein interaction network suggested that E-cadherin is a key activator in regulating Sirt1 and p53, as well as alveolar epithelial cell differentiation by SPC and T1α. Consistently, downregulation of E-cadherin, p-Yap, SPC, and T1α was observed in COPD alveolar regions with particulate matter (PM) deposition. In conclusion, our results indicated that E-cadherin-mediated cell-cell contact directly regulates the Hippo signaling pathway to control differentiation, cell proliferation, and senescence due to air pollution. Exposure to air pollution may initiate emphysema in COPD patients.

3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway.

Exposure to environmental and occupational contaminants leads to lung cancer. 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potential carcinogen in ambient air or diesel particulate matter. Studies have revealed that short-term exposure to 3-NBA induces cell death, reactive oxygen species activation, and DNA adduct formation and damage. However, details of the mechanism by which chronic exposure to 3-NBA influences lung carcinogenesis remain largely unknown. In this study, human lung epithelial BEAS-2B cells were continuously exposed to 0-10-µM 3-NBA for 6 months. NanoString analysis was conducted to evaluate gene expression in the cells, revealing that 3-NBA-mediated transformation results in a distinct gene expression signature including carbon cancer metabolism, metastasis, and angiogenesis. Alterations in tumor-promoting genes such as EREG (epiregulin), SOX9, E-cadherin, TWIST, and IL-6 were involved in epithelial cell aggressiveness. Kaplan-Meier plotter analyses indicated that increased EREG and IL-6 expressions in early-stage lung cancer cells are correlated with poor survival. In vivo xenografts on 3-NBA-transformed cells exhibited prominent tumor formation and metastasis. EREG knockout cells exposed to 3-NBA for a short period exhibited high apoptosis and low colony formation. By contrast, overexpression of EREG in 3-NBA-transformed cells markedly activated the PI3K/AKT and MEK/ERK signaling pathways, resulting in tumorigenicity. Furthermore, elevated IL-6 and EREG expressions synergistically led to STAT3 signaling activation, resulting in clonogenic cell survival and migration. Taken together, chronic exposure of human lung epithelial cells to 3-NBA leads to malignant transformation, in which the EREG signaling pathway plays a pivotal mediating role. • Short-term exposure of lung epithelial cells to 3-NBA can lead to ROS production and cell apoptosis. • Long-term chronic exposure to 3-NBA upregulates the levels of tumor-promoting genes such as EREG and IL-6. • Increased EREG expression in 3-NBA-transformed cells markedly contributes to tumorigenesis through PI3K/AKT and MEK/ERK activation and synergistically enhances the IL-6/STAT3 signaling pathway, which promotes tumorigenicity.

The Role of EREG/EGFR Pathway in Tumor Progression.

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.

Determinants of Pulmonary Emphysema Severity in Taiwanese Patients with Chronic Obstructive Pulmonary Disease: An Integrated Epigenomic and Air Pollutant Analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of COPD, with associated advances in diagnostic and therapeutic modalities; however, the identification of pathognomonic biomarkers that determine disease severity, affect disease course, predict clinical outcome, and inform therapeutic strategy remains a work in progress. OBJECTIVES: Hypothesizing that a multi-variable model rather than single variable model may be more pathognomonic of COPD emphysema (COPD-E), the present study explored for disease-associated determinants of disease severity, and treatment success in Taiwanese patients with COPD-E. METHODS: The present single-center, prospective, non-randomized study enrolled 125 patients with COPD and 43 healthy subjects between March 2015 and February 2021. Adopting a multimodal approach, including bioinformatics-aided analyses and geospatial modeling, we performed an integrated analysis of selected epigenetic, clinicopathological, geospatial, and air pollutant variables, coupled with correlative analyses of time-phased changes in pulmonary function indices and COPD-E severity. RESULTS: Our COPD cohort consisted of 10 non-, 57 current-, and 58 ex-smokers (median age = 69 ± 7.76 years). Based on the percentages of low attenuation area below - 950 Hounsfield units (%LAA-950insp), 36 had mild or no emphysema (%LAA-950insp < 6), 22 were moderate emphysema cases (6 ≤ %LAA-950insp < 14), and 9 presented with severe emphysema (%LAA-950insp ≥ 14). We found that BMI, lnc-IL7R, PM2.5, PM10, and SO2 were differentially associated with disease severity, and are highly-specific predictors of COPD progression. Per geospatial levels, areas with high BMI and lnc-IL7R but low PM2.5, PM10, and SO2 were associated with fewer and ameliorated COPD cases, while high PM2.5, PM10, and SO2 but low BMI and lnc-IL7R characterized places with more COPD cases and indicated exacerbation. The prediction pentad effectively differentiates patients with mild/no COPD from moderate/severe COPD cases, (mean AUC = 0.714) and exhibited very high stratification precision (mean AUC = 0.939). CONCLUSION: Combined BMI, lnc-IL7R, PM2.5, PM10, and SO2 levels are optimal classifiers for accurate patient stratification and management triage for COPD in Taiwan. Low BMI, and lnc-IL7R, with concomitant high PM2.5, PM10, and SO2 levels is pathognomonic of exacerbated/aggravated COPD in Taiwan.

Impact of Comorbidities on Beneficial Effect of Lactated Ringers vs. Saline in Sepsis Patients.

Background: Lactated Ringers reduced mortality more than saline in sepsis patients but increased mortality more than saline in traumatic brain injury patients. Method: This prospective cohort study was conducted in a medical intensive care unit (ICU) in central Taiwan. We applied standard sepsis evaluation protocol and identified heart, lung, liver, kidney, and endocrine comorbidities. We also evaluated resuscitation response with central venous pressure, central venous oxygen saturation, and serum lactate level simultaneously. Propensity-score matching and Cox regression were used to estimate mortality. The competing risk model compared the lengths of hospital stays with the subdistribution hazard ratio (SHR). Results: Overall, 938 patients were included in the analysis. The lactated Ringers group had a lower mortality rate (adjusted hazard ratio, 0.59; 95% CI 0.43-0.81) and shorter lengths of hospital stay (SHR, 1.39; 95% C.I. 1.15-1.67) than the saline group; the differences were greater in patients with chronic pulmonary disease and small and non-significant in those with chronic kidney disease, moderate to severe liver disease and cerebral vascular disease. The resuscitation efficacy was the same between fluid types, but serum lactate levels were significantly higher in the lactated Ringers group than in the saline group (0.12 mg/dl/h; 95% C.I.: 0.03, 0.21), especially in chronic liver disease patients. Compared to the saline group, the lactated Ringers group achieved target glucose level earlier in both diabetes and non-diabetes patients. Conclusion: Lactate Ringer's solution provides greater benefits to patients with chronic pulmonary disease than to those with chronic kidney disease, or with moderate to severe liver disease. Comorbidities are important in choosing resuscitation fluid types.

Association Between Air Pollution and Lung Lobar Emphysema in COPD.

The development of emphysema has been linked to air pollution; however, the association of air pollution with the extent of lobar emphysema remains unclear. This study examined the association of particulate matter <2.5 µm in aerodynamic diameters (PM2.5) (≤2.5 µm), nitrogen dioxide (NO2), and ozone (O3) level of exposure with the presence of emphysema in 86 patients with chronic obstructive pulmonary disease (COPD). Exposure to the air pollution estimated using the land-use regression model was associated with lung function, BODE (a body mass index, degree of obstruction, dyspnea severity, and exercise capacity index) quartiles, and emphysema measured as low-attenuation areas on high-resolution CT (HR-CT) lung scans. Using paraseptal emphysema as the reference group, we observed that a 1 ppb increase in O3 was associated with a 1.798-fold increased crude odds ratio of panlobular emphysema (p < 0.05). We observed that PM2.5 was associated with BODE quartiles, modified Medical Research Council (mMRC) dyspnea score, and exercise capacity (all p < 0.05). We found that PM2.5, NO2, and O3 were associated with an increased degree of upper lobe emphysema and lower lobe emphysema (all p < 0.05). Furthermore, we observed that an increase in PM2.5, NO2, and O3 was associated with greater increases in upper lobe emphysema than in lower lobe emphysema. In conclusion, exposure to O3 can be associated with a higher risk of panlobular emphysema than paraseptal emphysema in patients with COPD. Emphysema severity in lung lobes, especially the upper lobes, may be linked to air pollution exposure in COPD.

Suppressor of variegation 3-9 homologue 1 impairment and neutrophil-skewed systemic inflammation are associated with comorbidities in COPD.

BACKGROUND: Systemic manifestations and comorbidities are characteristics of chronic obstructive pulmonary disease (COPD) and are probably due to systemic inflammation. The histone methyltransferase SUV39H1 controls the Th1/Th2 balance. We previously reported that reduced SUV39H1 expression contributed to abnormal inflammation in COPD. Here, we aimed to determine whether impaired SUV39H1 expression in COPD patients associated with neutrophilic/eosinophilic inflammation responses and comorbidities. METHODS: A total of 213 COPD patients and 13 healthy controls were recruited from the Shuang Ho Hospital, Taipei Medical University. SUV39H1 levels in peripheral blood mononuclear cells (PBMCs) from 13 healthy and 30 COPD participants were measured by immunoblotting. We classified the patients into two groups based on low (fold change, FC < 0.5) and high SUV39H1 expression (FC ≥ 0.5) compared to normal controls. Clinical outcomes including neutrophil or eosinophil counts associated with SUV39H1-related inflammation were evaluated by Chi square analyses or Mann-Whitney U test. The correlations between the percentage of neutrophils and number of COPD comorbidities or Charlson Comorbidity Index (CCI) scores were performed by Spearman's rank analysis. RESULTS: Low SUV39H1 expression group had high neutrophil counts relative to high SUV39H1expression group. In the COPD cohort, the high comorbidity group (≥ 2 comorbidities) had higher counts of whole white blood cell (WBC) and neutrophil, and lower proportion of eosinophil and eosinophil/neutrophil, as compared with low comorbidity group (0 and 1 comorbidities). The quantity of neutrophils was associated with COPD comorbidities (Spearman's r = 0.388, p < 0.001), but not with CCI scores. We also found that the high comorbidity group had more exacerbations per year compared with low comorbidity group (1.5 vs. 0.9 average exacerbations, p = 0.005). However, there were no significant differences between groups with these non-frequent (0-1 exacerbation) and frequent exacerbations per year (> 1 exacerbation) in numbers of WBC and proportion of neutrophils, eosinophils or eosinophil/neutrophil. Finally, patients with high comorbidities had lower SUV39H1 levels in their PBMCs than did those with low comorbidities. CONCLUSION: Blood neutrophil counts are associated with comorbidities in COPD patients. Impaired SUV39H1 expression in PBMCs from COPD patients are correlated with neutrophilic inflammation and comorbidities.