Chih Cheng Chang

Comparative proteomics of inhaled silver nanoparticles in healthy and allergen provoked mice

Background Silver nanoparticles (AgNPs) have been associated with the exacerbation of asthma; however, the immunological basis for the adjuvant effects of AgNPs is not well understood. Objective The aim of the study reported here was to investigate the allergic effects of AgNP inhalation using proteomic approaches. Methods Allergen provoked mice were exposed to 33 nm AgNPs at 3.3 mg/m3. Following this, bronchoalveolar lavage fluid (BALF) and plasma were collected to determine protein profiles. Results In total, 106 and 79 AgNP-unique proteins were identified in the BALF of control and allergic mice, respectively. Additionally, 40 and 26 AgNP-unique proteins were found in the plasma of control and allergic mice, respectively. The BALF and plasma protein profiles suggested that metabolic, cellular, and immune system processes were associated with pulmonary exposure to AgNPs. In addition, we observed 18 proteins associated with systemic lupus erythematosus that were commonly expressed in both control and allergic mice after AgNP exposure. Significant allergy responses were observed after AgNP exposure in control and allergic mice, as determined by ovalbumin-specific immunoglobulin E. Conclusion Inhaled AgNPs may regulate immune responses in the lungs of both control and allergic mice. Our results suggest that immunology is a vital response to AgNPs.

High incidence of stroke in young women with sleep apnea syndrome

OBJECTIVE Patients with sleep apnea syndrome (SAS) carry a higher stroke risk. The differential stroke risk between sex and among different age groups has not yet been specifically addressed in previous studies. METHODS Using a universal insurance claims database, we identified a large cohort of SAS patients from 1997 to 2010 and assessed the sex- and age-specific stroke risk compared with a control cohort matched for age, sex, and index date. Cox regression analyses were performed to assess the hazard ratio (HR) of stroke and the corresponding 95% confidence interval (CI). Stroke-free probabilities were computed using the Kaplan-Meier method and differences between both cohorts were examined using the log-rank test. RESULTS We identified 29,961 patients with SAS and a control cohort of 119,844 subjects without SAS. The overall incidence of stroke in the SAS cohort was 37% higher compared to the non-SAS cohort (54.6 per 10,000 individual-years vs 39.8 per 10,000 individual-years). After controlling for sex and comorbidities, the SAS cohort exhibited a 19% higher risk for stroke compared to the control cohort (adjusted HR, 1.19 [95% CI, 1.09-1.30]). Women with SAS ages 35 years or younger had the highest stroke risk compared to older age groups of the same sex and their risk for stroke was relatively higher compared to their male counterparts. CONCLUSION Women aged 35 years or younger with SAS have a higher stroke risk.

Allergenicity and toxicology of inhaled silver nanoparticles in allergen-provocation mice models

Silver nanoparticles (AgNP) have been associated with the exacerbation of airway hyperresponsiveness. However, the allergenicity and toxicology of AgNP in healthy and allergic individuals are unclear. We investigated the pathophysiological responses to AgNP inhalation in a murine model of asthma. Continuous and stable levels of 33 nm AgNP were maintained at 3.3 mg/m3 during the experimental period. AgNP exposure concomitant with ovalbumin challenge increased the enhanced pause (Penh) in the control and allergic groups. AgNP evoked neutrophil, lymphocyte and eosinophil infiltration into the airways and elevated the levels of allergic markers (immunoglobulin E [IgE] and leukotriene E4 [LTE4]), the type 2 T helper (Th2) cytokine interleukin-13 (IL-13), and oxidative stress (8-hydroxy-2′-deoxyguanosine [8-OHdG]) in healthy and allergic mice. Bronchocentric interstitial inflammation was observed after AgNP inhalation. After inhalation, the AgNP accumulated predominantly in the lungs, and trivial amounts of AgNP were excreted in the urine and feces. Furthermore, the AgNP induced inflammatory responses in the peritoneum. The inhalation of AgNP may present safety concerns in healthy and susceptible individuals.

Improvement in the Prediction of Ventilator Weaning Outcomes by an Artificial Neural Network in a Medical ICU

BACKGROUND: Twenty-five to 40% of patients pass a spontaneous breathing trial (SBT) but fail to wean from mechanical ventilation. There is no single appropriate and convenient predictor or method that can help clinicians to accurately predict weaning outcomes. This study designed an artificial neural network (ANN) model for predicting successful extubation in mechanically ventilated patients. METHODS: Ready-to-wean subjects (N = 121) hospitalized in medical ICUs were recruited and randomly divided into training (n = 76) and test (n = 45) sets. Eight variables consisting of age, reasons for intubation, duration of mechanical ventilation, Acute Physiology and Chronic Health Evaluation II score, mean inspiratory and expiratory times, mean breathing frequency, and mean expiratory tidal volume in a 30-min SBT (pressure support ventilation of 5 cm H2O and PEEP of 5 cm H2O) were selected as the ANN input variables. The prediction performance of the ANN model was compared with the rapid shallow breathing index (RSBI), maximum inspiratory pressure, RSBI at 1 min (RSBI1) and 30 min (RSBI30) in an SBT, and absolute percentage change in RSBI from 1 to 30 min in an SBT (ΔRSBI30) using a confusion matrix and receiver operating characteristic curves. RESULTS: The area under the receiver operating characteristic curves in the test set of the ANN model was 0.83 (95% CI 0.69–0.92, P < .001), which is better than any one of the following predictors: 0.66 (95% CI 0.50–0.80, P = .04) for RSBI, 0.52 (95% CI 0.37–0.67, P = .86) for maximum inspiratory pressure, 0.53 (95% CI 0.37–0.68, P = .79) for RSBI1, 0.60 (95% CI 0.44–0.74, P = .34) for RSBI30, and 0.51 (95% CI 0.36–0.66, P = .91) for ΔRSBI30. Predicting successful extubation based on the ANN model of the test set had a sensitivity of 82%, a specificity of 73%, and an accuracy rate of 80%, with an optimal threshold of ≥0.5 selected from the training set. CONCLUSIONS: The ANN model improved the accuracy of predicting successful extubation. By applying it clinically, clinicians can select the earliest appropriate weaning time.

Methionine oxidation in albumin by fine haze particulate matter: an in vitro and in vivo study.

The potential effects of inhaled fine particulate matter (PM2.5), found in haze episodes, on the oxidation of the proteins in the lungs are not well understood. We investigated the effects of PM2.5 from haze episodes on protein oxidation. PM2.5 was collected from the air pollution in Beijing (BJ), Xian (XA), Xiamen (XM) and Hong Kong (HK) during a period of intensive haze episodes. The chemical characteristics of these samples and their effects on albumin oxidation were investigated. The levels of PM2.5 in BJ and XA were 4-6 times higher than in XM and HK. The concentrations of the polycyclic aromatic hydrocarbons (PAHs) components of the PM2.5 from BJ and XA were 10 times higher than those found in XM and HK. The haze PM2.5 increased oxidative stress. Addition of PM2.5 samples collected from haze episodes to albumin in vitro resulted in oxidation of methionine moieties; nasal instillation of PM2.5 suspensions in mice resulted in oxidation of methionine in the albumin in the bronchoalveolar lavage fluid. The methionine moieties participate in peptide chain crosslinking, and methionine oxidation in the albumin could be attributed to the PAH compounds. Our findings may be helpful in explaining the potential respiratory effects during haze episodes.

Effects of polycyclic aromatic compounds in fine particulate matter generated from household coal combustion on response to EGFR mutations in vitro

Induction of PM2.5-associated lung cancer in response to EGFR-tyrosine kinase inhibitors (EGFR-TKI) remains unclear. Polycyclic aromatic hydrocarbons (PAHs) and their polar derivatives (oxygenated PAHs: OPAHs and azaarenes: AZAs) were characterized in fine particulates (PM2.5) emitted from indoor coal combustion. Samples were collected in Xuanwei (Yunnan Province), a region in China with a high rate of lung cancer. Human lung adenocarcinoma cells A549 (with wild-type EGFR) and HCC827 (with EGFR mutation) were exposed to the PM2.5, followed by treatment with EGFR-TKI. Two samples showed significant and dose-dependent reduction in the cell viability in A549. EGFR-TKI further demonstrated significantly decreased in cell viability in A549 after exposure to the coal emissions. Chrysene and triphenylene, dibenzo[a,h]anthracene, benzo[ghi]perylene, azaarenes and oxygenated polycyclic aromatic hydrocarbons (carbonyl-OPAHs) were all associated with EGFR-TKI-dependent reduced cell viability after 72-h exposure to the PM2.5. The findings suggest the coal emissions could influence the response of EGFR-TKI in lung cancer cells in Xuanwei.

Novel biomarker analysis of pleural effusion enhances differentiation of tuberculous from malignant pleural effusion.

Lymphocytic pleurisy is commonly observed in tuberculosis and cancer. Noninvasive biomarkers are needed to distinguish tuberculous pleural effusion (TPE) from malignant pleural effusion (MPE) because current clinical diagnostic procedures are often invasive. We identified immune response biomarkers that can discriminate between TPE and MPE. Fourteen pleural effusion biomarkers were compared in 22 MPE patients and five TPE patients. Of the innate immunity biomarkers, the median levels of interleukin (IL)-1β and interferon-induced protein-10 (IP-10) were higher in TPE patients than in MPE patients (P<0.05 and P<0.01, respectively). Of the adaptive immunity biomarkers, the median levels of IL-13 and interferon-γ (IFN-γ) were higher in TPE patients than in MPE patients (P<0.05). In addition, the levels of basic fibroblast growth factor were higher in MPE patients than in TPE patients (P<0.05). Receiver operator characteristic analysis of these biomarkers was performed, resulting in the highest area under the curve (AUC) for IP-10 (AUC =0.95, 95% confidence interval, P<0.01), followed by IL-13 (AUC =0.86, 95% confidence interval, P<0.05). Our study shows that five biomarkers (IL-1β, IP-10, IFN-γ, IL-13, and basic fibroblast growth factor) have a potential diagnostic role in differentiating TPE from MPE, particularly in lung cancer-related MPE.

Associations of autophagy with lung diffusion capacity and oxygen saturation in severe COPD: effects of particulate air pollution.

Although traffic exposure has been associated with the development of COPD, the role of particulate matter <10 μm in aerodynamic diameter (PM10) in the pathogenesis of COPD is not yet fully understood. We assessed the 1-year effect of exposure to PM10 on the pathogenesis of COPD in a retrospective cohort study. We recruited 53 subjects with COPD stages III and IV and 15 healthy controls in a hospital in Taiwan. We estimated the 1-year annual mean levels of PM10 at all residential addresses of the cohort participants. Changes in PM10 for the 1-year averages in quintiles were related to diffusion capacity of the lung for carbon monoxide levels (r=−0.914, P=0.029), changes in the pulse oxygen saturation (ΔSaO2; r=−0.973, P=0.005), receptor for advanced glycation end-products (r=−0.881, P=0.048), interleukin-6 (r=0.986, P=0.002), ubiquitin (r=0.940, P=0.017), and beclin 1 (r=0.923, P=0.025) in COPD. Next, we observed that ubiquitin was correlated with ΔSaO2 (r=−0.374, P=0.019). Beclin 1 was associated with diffusion capacity of the lung for carbon monoxide (r=−0.362, P=0.028), ΔSaO2 (r=−0.354, P=0.032), and receptor for advanced glycation end-products (r=−0.471, P=0.004). Autophagy may be an important regulator of the PM10-related pathogenesis of COPD, which could cause deterioration in the lung diffusion capacity and oxygen saturation.

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB

Background Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient’s MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. Conclusions In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway. Methods Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

Correction: S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: The role of RELB [Oncotarget., 9, (2018), (7631-7643)] DOI: 10.18632/oncotarget.24146

[This corrects the article DOI: 10.18632/oncotarget.24146.].