Wou Young Chung

Nuclear factor E2-related factor 2 Dependent Overexpression of Sulfiredoxin and Peroxiredoxin III in Human Lung Cancer

Background/Aims Oxidative stress results in protein oxidation and is implicated in carcinogenesis. Sulfiredoxin (Srx) is responsible for the enzymatic reversal of inactivated peroxiredoxin (Prx). Nuclear factor E2-related factor 2 (Nrf2) binds to antioxidant responsive elements and upregulates the expression of Srx and Prx during oxidative stress. We aimed to elucidate the biological functions and potential roles of Srx in lung cancer. Methods To study the roles of Srx and Prx III in lung cancer, we compared the protein levels of Nrf2, Prxs, thioredoxin, and Srx in 40 surgically resected human lung cancer tissues using immunoblot and immunohistochemical analyses. Transforming growth factor-β1, tumor necrosis factor-α, and camptothecin treatment were used to examine Prx III inactivation in Mv1Lu mink lung epithelial cells and A549 lung cancer cells. Results Prx I and Prx III proteins were markedly overexpressed in lung cancer tissues. A significant increase in the oxidized form of a cysteine sulfhydryl at the catalytic site of Prxs was found in carcinogenic lung tissue compared to normal lung tissue. Densitometric analyses of immunoblot data revealed significant Srx expression, which was higher in squamous cell carcinoma tissue (60%, 12/20) than in adenocarcinoma (20%, 4/20). Also, Nrf2 was present in the nuclear compartment of cancer cells. Conclusions Srx and Prx III proteins were markedly overexpressed in human squamous cell carcinoma, suggesting that these proteins may play a protective role against oxidative injury and compensate for the high rate of mitochondrial metabolism in lung cancer.

An updated review of case-control studies of lung cancer and indoor radon-Is indoor radon the risk factor for lung cancer?

Lung cancer is a leading cause of cancer-related death in the world. Smoking is definitely the most important risk factor for lung cancer. Radon (222Rn) is a natural gas produced from radium (226Ra) in the decay series of uranium (238U). Radon exposure is the second most common cause of lung cancer and the first risk factor for lung cancer in never-smokers.Case–control studies have provided epidemiological evidence of the causative relationship between indoor radon exposure and lung cancer. Twenty-four case–control study papers were found by our search strategy from the PubMed database. Among them, seven studies showed that indoor radon has a statistically significant association with lung cancer. The studies performed in radon-prone areas showed a more positive association between radon and lung cancer. Reviewed papers had inconsistent results on the dose–response relationship between indoor radon and lung cancer risk.Further refined case–control studies will be required to evaluate the relationship between radon and lung cancer. Sufficient study sample size, proper interview methods, valid and precise indoor radon measurement, wide range of indoor radon, and appropriate control of confounders such as smoking status should be considered in further case–control studies.

CXCR3 ligands as clinical markers for pulmonary tuberculosis.

SETTING A tertiary care academic medical centre. OBJECTIVE To evaluate the clinical usefulness of CXC chemokine receptor 3 (CXCR3) ligands in active pulmonary tuberculosis (TB). DESIGN Patients with various pulmonary diseases and healthy controls were recruited into this cross-sectional study. Plasma levels of interferon-gamma (IFN-γ) and the CXCR3 ligands (CXCL9 [monokine induced by IFN-γ, MIG], CXCL10 [IFN-γ-inducible 10-kDa protein, IP-10] and CXCL11 [IFN-inducible T-cell α chemoattractant, I-TAC] were measured using enzyme immunoassays. RESULTS The study included 846 subjects: 201 patients with active pulmonary TB, 389 with other pulmonary diseases, and 256 controls. CXCR3 ligand levels were higher in TB patients than in controls and all other disease groups, whereas the IFN-γ levels did not differ. The area under the curve (AUC) for differentiating active TB from all other groups was 0.797 for CXCL9, 0.726 for CXCL10, 0.846 for CXCL11 and 0.534 for IFN-γ. The AUC for differentiating active TB from controls was 0.926 for CXCL9, 0.818 for CXCL10, 0.865 for CXCL11 and 0.575 for IFN-γ. CXCR3 levels correlated with sputum acid-fast bacilli smear grades and the radiographic extent of pulmonary TB. CONCLUSION CXCR3 ligands may be useful surrogate markers for diagnosing active TB and for assessing TB patients clinically.

Independent risk factors for mortality in patients with chronic obstructive pulmonary disease who undergo comprehensive cardiac evaluations.

Background: Cardiovascular disease is the most common cause of death in chronic obstructive pulmonary disease (COPD). However, the impact of cardiovascular comorbidities on the prognosis of COPD is not well known. Objectives: This study was performed to investigate the effects of cardiovascular comorbidities on the prognosis of COPD. Methods: We enlisted 229 patients with COPD who underwent comprehensive cardiac evaluations including coronary angiography and echocardiography at Ajou University Hospital between January 2000 and December 2012. Survival analyses were performed in this retrospective cohort. Results: Kaplan-Meier analyses showed that COPD patients without left heart failure (mean survival = 12.5 ± 0.7 years) survived longer than COPD patients with left heart failure (mean survival = 6.7 ± 1.4 years; p = 0.003), and the survival period of nonanemic COPD patients (mean survival = 13.8 ± 0.8 years) was longer than that of anemic COPD patients (mean survival = 8.3 ± 0.8 years; p < 0.001). The survival period in COPD with coronary artery disease (CAD; mean survival = 11.37 ± 0.64 years) was not different from that in COPD without CAD (mean survival = 11.98 ± 0.98 years; p = 0.703). According to a multivariate Cox regression model, a lower hemoglobin level, a lower left ventricular ejection fraction, and the forced expiratory volume in 1 s (FEV1) were independently associated with higher mortality in the total COPD group (p < 0.05). Conclusions: Hemoglobin levels and left ventricular ejection fraction along with a lower FEV1 were identified as independent risk factors for mortality in COPD patients who underwent comprehensive cardiac evaluations, suggesting that multidisciplinary approaches are required in the care of COPD.

A TB Antigen-Stimulated CXCR3 Ligand Assay for the Diagnosis of Active Pulmonary TB

BACKGROUND The ligands for CXC chemokine receptor 3 (CXCR3) recruit T-helper type 1 cells, which play a major role in cell-mediated immunity in TB. METHODS A total of 409 subjects were enrolled. The study population comprised 186 patients with active TB, 58 patients with non-TB pulmonary diseases, 50 control subjects with a positive interferon (IFN)-γ release assay (IGRA) result, and 115 control subjects with a negative IGRA result. Whole-blood samples were collected using IGRA methodology. After incubation, plasma IFN-γ levels and two CXCR3 ligands, IFN-inducible T-cell α-chemoattractant (I-TAC, CXCL11) and monokine induced by IFN-γ (MIG, CXCL9), were measured by enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) analysis was performed. Sensitivity and specificity were based on cutoff values selected to maximize the Youden index. RESULTS The TB antigen-stimulated levels of IFN-γ, I-TAC, and MIG were significantly increased in the active pulmonary TB group compared with all other groups. From ROC analysis, for the diagnosis of active TB, I-TAC and MIG outperformed IFN-γ in all comparisons with the IGRA-positive and -negative control groups and the non-TB pulmonary disease group. The areas under the curve (95% CI) for differentiating active pulmonary TB from all other groups were 0.893 (0.864-0.924) for IFN-γ, 0.962 (0.946-0.978) for I-TAC, and 0.944 (0.922-0.965) for MIG. Sensitivity and specificity were 90.3% and 90.7%, respectively, for I-TAC; 92.5% and 85.2% for MIG; and 84.9% and 79.8% for IFN-γ. CONCLUSIONS TB antigen-stimulated assays of I-TAC and MIG may be useful surrogate markers in the diagnosis of active pulmonary TB.

Epithelial apoptosis as a clinical marker in idiopathic interstitial pneumonia

BACKGROUNDS Epithelial cell apoptosis plays an important role in the pathogenesis of idiopathic interstitial pneumonia (IIP). METHODS Serum levels of caspase-cleaved cytokeratin-18 (M30) were measured in 55 patients with IIP and 34 healthy controls using enzyme-linked immunosorbent assays. The IIP cases included usual interstitial pneumonia (UIP; n = 30), nonspecific interstitial pneumonia (NSIP; n = 15), and cryptogenic organizing pneumonia (COP; n = 10). The radiological scoring was performed based on high-resolution computed tomography (HRCT) findings. RESULTS Patients with IIP had higher serum M30 levels than did the control group (178.6 ± 91.5 vs. 113.7 ± 46.8 U/L, p < 0.05). Among IIP patients, COP patients had higher serum M30 levels than did UIP or NSIP patients (264.9 ± 132.7, 139.2 ± 49.7, and 201.2 ± 81.1 U/L, respectively; COP vs. UIP, p < 0.01). Serum M30 levels were negatively correlated with forced vital capacity (FVC; r(s) = -0.31), percent-predicted FVC (FVC%; r(s) = -0.38), and percent-predicted forced expiratory volume in 1 s (FEV(1)%; r(s) = -0.36). Serum M30 levels were correlated with radiological ground-glass opacity scores (r(s) = 0.61). CONCLUSION The epithelial apoptosis marker serum level was correlated with IIP clinical status and is a potential marker to assess IIP.

Selectively Decreased Expression of Peroxiredoxins Induced by Silica in Pulmonary Epithelial Cells

Background/Aims Peroxiredoxin (Prx) belongs to a ubiquitous family of antioxidant enzymes that regulates many cellular processes through intracellular oxidative signal transduction pathways. Silica-induced lung damage involves reactive oxygen species (ROS) that trigger subsequent toxic effects and inflammatory responses in alveolar epithelial cells resulting in fibrosis. Therefore, we investigated the role of Prx in the development of lung oxidant injury caused by silicosis, and determined the implication of ROS in that process. Methods Lung epithelial cell lines A549 and WI26 were treated with 1% silica for 0, 24, or 48 hours, following pretreatment of the A549 cells with N-acetyl-L-cysteine and diphenylene iodonium and no pretreatment of the WI26 cells. We transfected an HA-ubiquitin construct into the A549 cell line and then analyzed the cells via Western blotting and co-immunoprecipitation. Results Silica treatment induced cell death in the A549 lung epithelial cell line and selectively degraded Prx I without impairing protein synthesis in the A549 cells, even when the ROS effect was blocked chemically by N-acetyl-L-cysteine. A co-immunoprecipitation study revealed that Prx I did not undergo ubiquitination. Conclusions Silica treatment induces a decrease of Prx I expression in lung epithelial cell lines regardless of the presence of ROS. The silica-induced degradation of Prx does not involve the ubiquitin-proteasomal pathway.

Serum CXCR3 ligands as biomarkers for the diagnosis and treatment monitoring of tuberculosis.

SETTING Tertiary care academic medical centre. OBJECTIVE To evaluate the clinical utility of CXC chemokine receptor 3 (CXCR3) ligands in the diagnosis and monitoring of tuberculosis (TB). DESIGN Presumptive TB patients (active TB, 256; non-TB disease, 52) and 201 healthy controls were enrolled. The serum levels of interferon-gamma (IFN-γ) and CXCR3 ligands (CXCL9, a monokine induced by IFN-γ [MIG] and CXCL11, an IFN-inducible T-cell α chemoattractant [I-TAC]) were measured using enzyme-linked immunosorbent assay. An IFN-γ release assay (IGRA) was also performed. Serial samplings were performed in 19 TB patients at baseline and at 1, 2, 3, 6 and 12 months after treatment initiation. RESULTS All marker levels were higher in TB patients than in controls and non-TB patients. The area under the curve (AUC) for differentiating between all TB patients and controls was 0.96 (95%CI 0.94-0.98) for CXCL9, 0.84 (95%CI 0.80-0.87) for CXCL11 and 0.61 (95%CI 0.57-0.66) for IFN-γ. CXCL9 levels afforded particularly high discriminatory power between TB patients and IGRA-positive controls (AUC = 0.95, 95%CI 0.92-0.97). The levels of CXCR3 ligands decreased significantly during follow-up, and these changes were correlated with treatment response. CONCLUSION CXCR3 ligands CXCL9 and CXCL11 may be useful surrogate markers for the diagnosis and follow-up of TB.

Consideration of additional factors in Sequential Organ Failure Assessment score

PURPOSE The Sequential Organ Failure Assessment (SOFA) score, originally developed to assess organ failure status, is widely used as a prognostic indicator in intensive care unit patients. Additional prognostic factors, such as age and comorbidities, may complement the predictive performance of the SOFA. METHODS In total, 1049 consecutive patients were enrolled prospectively. SOFA and other admission-based intensive care unit scores were recorded during the first 24 hours. A complemented SOFA (cSOFA) score model was constructed by adding age and comorbidity scores to the original SOFA score, based on logistic regression analysis. The predictive performance was evaluated with regard to hospital mortality by receiver operating characteristics analysis. The Hosmer-Lemeshow goodness-of-fit test was used to assess calibration of the model, and leave-one-out cross-validation was performed. RESULTS The cSOFA score (maximum 30 points) was calculated as the SOFA score (24 points) + age score (2 points) + comorbidity score (4 points). The cSOFA score model showed satisfactory calibration and cross-validation performance. The AUC (95% CI) of the cSOFA score (0.812 [0.787-0.835]) was higher than the SOFA score (0.743 [0.715-0.769], P < .0001). CONCLUSION The performance of the SOFA score to predict hospital mortality can be improved by considering age and comorbidity factors.

The Usefulness of Serum CXCR3 Ligands for Evaluating the Early Treatment Response in Tuberculosis: A Longitudinal Cohort Study.

AbstractCell-mediated immunity plays an important role in the pathobiology of tuberculosis (TB). The ligands for CXC chemokine receptor 3 (CXCR3) activate the T-helper type 1 lymphocyte pathway. The CXCR3 ligands are reportedly useful clinical markers for the diagnosis and follow-up of TB. The objective of this study was to assess the utility of CXCR3 ligands for evaluating early treatment responses in TB.We recruited 88 patients who underwent antituberculous chemotherapy. The serum levels of interferon (IFN)-&ggr; and the CXCR3 ligands CXCL9 (monokine induced by IFN-&ggr; [MIG]), CXCL10 (IFN-&ggr;-inducible 10-kDa protein [IP-10]), and CXCL11 (IFN-inducible T-cell &agr; chemoattractant [I-TAC]) were measured before and 2 months after the start of treatment. Treatment responses were divided into “fast” and “slow” based on the clinical, radiological, and bacteriological improvement at 2 months. A change in level of 20% or more at 2 months was defined as “significant.”In patients with treatment success, 58 patients exhibited a fast response and 20 patients exhibited a slow response. Treatment failure occurred in 5 patients, and the diagnoses were changed to non-TB diseases in 5 patients. The levels of all CXCR3 ligands significantly decreased in the fast-response group (P < 0.01) but did not decrease in the other groups. IFN-&ggr; levels showed no significant changes. The ability of significant decreases in marker levels to predict a fast response was evaluated. CXCL9 showed a sensitivity of 83%, and CXCL10 showed a specificity of 100%. Use of various combinations of CXCR3 ligands resulted in improvements in sensitivity (88%–93%), while specificity (92%–96%) was similar to that using single CXCR3 ligands. The decreases in CXCR3 ligand levels were less marked in the 2-month Mycobacterium tuberculosis culture-positive group than in the culture-negative group. There were significant differences in treatment outcomes in terms of 2-month culture positivity (P < 0.001), the significance of CXCL9 decreases (P < 0.01), and the significance of CXCL11 decreases (P < 0.05).In conclusion, CXCR3 ligands may be useful surrogate markers for the evaluation of early treatment response and showed utility as indicators of possible treatment failure in TB.