Tzu Tao Chen

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.

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.

Inter-alpha-trypsin inhibitor heavy chain 4: A novel biomarker for environmental exposure to particulate air pollution in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that is correlated with environmental stress. Particulate matter ≤10 μm (PM10) is considered to be a risk factor for COPD development; however, the effects of PM10 on the protein levels in COPD remain unclear. Fifty subjects with COPD and 15 healthy controls were recruited. Gene ontology analysis of differentially expressed proteins identified immune system process and binding as the most important biological process and molecular function, respectively, in the responses of PM10-exposed patients with COPD. Biomarkers for PM10 in COPD were identified and compared with the same in healthy controls and included proteoglycan 4 (PRG4), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), and apolipoprotein F (APOF). PRG4 and ITIH4 were associated with a past 3-year PM10 exposure level. The receiver operating characteristic curve analysis showed that ITIH4 is a sensitive and specific biomarker for PM10 exposure (area under the curve [AUC] =0.690, P=0.015) compared with PRG4 (AUC =0.636, P=0.083), APOF (AUC =0.523, P=0.766), 8-isoprostane (AUC =0.563, P=0.405), and C-reactive protein (CRP; AUC =0.634, P=0.086). ITIH4 levels were correlated with CRP (r=0.353, P=0.005), suggesting that ITIH4 may be involved in an inflammatory mechanism. In summary, serum ITIH4 may be a PM10-specific biomarker in COPD and may be related to inflammation.

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.

Proteoglycan 4 is a diagnostic biomarker for COPD.

Introduction The measurement of C-reactive protein (CRP) to confirm the stability of COPD has been reported. However, CRP is a systemic inflammatory biomarker that is related to many other diseases. Objective The objective of this study is to discover a diagnostic biomarker for COPD. Methods Sixty-one subjects with COPD and 15 healthy controls (10 healthy non-smokers and 5 smokers) were recruited for a 1-year follow-up study. Data regarding the 1-year acute exacerbation frequency and changes in lung function were collected. CRP and the identified biomarkers were assessed in the validation COPD cohort patients and healthy subjects. Receiver operating characteristic values of CRP and the identified biomarkers were determined. A validation COPD cohort was used to reexamine the identified biomarker. Correlation of the biomarker with 1-year lung function decline was determined. Results Proteoglycan 4 (PRG4) was identified as a biomarker in COPD. The serum concentrations of PRG4 in COPD Global initiative for chronic Obstructive Lung Disease (GOLD) stages 1+2 and 3+4 were 10.29 ng/mL and 13.20 ng/mL, respectively; 4.99 ng/mL for healthy controls (P<0.05); and 4.49 ng/mL for healthy smokers (P<0.05). PRG4 was more sensitive and specific than CRP for confirming COPD severity and acute exacerbation frequency. There was no correlation between CRP and PRG4 levels, and PRG4 was negatively correlated with the 1-year change in predicted forced vital capacity percent (R2=0.91, P=0.013). Conclusion PRG4 may be a biomarker for identification of severity in COPD. It was related to the 1-year forced vital capacity decline in COPD patients.

Mid-arm and calf circumferences are stronger mortality predictors than body mass index for patients with chronic obstructive pulmonary disease

Background Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of death in the world. Patients with COPD experience airflow obstruction, weight loss, skeletal muscle dysfunction, and comorbidities. Anthropometric indicators are risk factors for mortality in geriatric assessment. Purpose This study examined and compared the associations of anthropometric indicators, such as low body mass index (BMI), low mid-arm circumference (MAC), and low calf circumference (CC), with the prediction of a 3-year follow-up mortality risk in patients with COPD. Methods We recruited nonhospitalized patients with COPD without acute conditions from a general hospital in Taiwan. The BMI, MAC, and CC of all patients were measured, and they were followed for 3 years through telephone interviews and chart reviews. The Kaplan–Meier survival curves stratified by BMI, MAC, and CC were analyzed. Variables univariately associated with survival were entered into a multivariate Cox regression model. The Bayesian information criterion was used to compare the predictive ability of the three anthropometric indicators to predict mortality rate. Results In total, 104 patients were included (mean ± standard deviation age, 74.2±6.9 years; forced expiratory volume in 1 second [%], 58.4±20.4 predicted; males, 94.2%); 22 patients (21.2%) died during the 36-month follow-up. During this long-term follow-up, the three anthropometric indicators could predict mortality risk in patients with COPD (low BMI [<21 kg/m2], hazard ratio [HR] =2.78, 95% confidence interval [CI] =1.10–7.10; low MAC [<23.5 cm], HR =3.09, 95% CI =1.30–7.38; low CC [<30 cm], HR =4.40, 95% CI =1.82–10.63). CC showed the strongest potential in predicting the mortality risk, followed by MAC and BMI. Conclusion Among the three anthropometric variables examined, CC can be considered a strong predictor of mortality risk in patients with COPD.

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.

Proteasome activity related with the daily physical activity of COPD patients

Background COPD is a debilitating disease that affects patients’ daily lives. One’s daily physical activity (DPA) decreases due to multifactorial causes, and this decrease is correlated with a poor prognosis in COPD patients. Muscle wasting may at least be partly due to increased activity of the ubiquitin proteasome pathway and apoptosis. Methods This study investigated the relationships among DPA, circulating proteasome activity, and protein carbonyl in COPD patients and healthy subjects (HSs). This study included 57 participants (42 patients and 15 healthy subjects). Ambulatory DPA was measured using actigraphy, and oxygen saturation was measured with a pulse oximeter. Results COPD patients had lower DPA, lower 6 min walking distance (6MWD), lower delta saturation pulse oxygenation (SpO2) during the 6MWT, and lower delta SpO2 during DPA than HSs. COPD patients had higher proteasome activity and protein carbonyl than HSs. Circulating proteasome activity was significantly negatively correlated with DPA (r=−0.568, P<0.05) in COPD patients, whereas delta SpO2 during the 6MWT was significantly positively correlated with proteasome activity (r=0.685, P<0.05) in HSs. Protein carbonyl was significantly negatively correlated with the body mass index (r=−0.318, P<0.05), mid-arm circumference (r=0.350, P<0.05), calf circumference (r=0.322, P<0.05), forced expiratory volume in the first second (r=-0.441, P<0.01), and 6MWD (r=−0.313, P<0.05) in COPD patients. Our results showed no significant difference in inflammatory markers (interleukin-6 and tumor necrosis factor-α) or ubiquitin between the two groups. Conclusion COPD patients had lower DPA levels and higher circulating proteasome activity than HSs, and a negative correlation of DPA with circulating proteasome activity.

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.].