Keu Sung Lee

Expression of peroxiredoxin and thioredoxin in human lung cancer and paired normal lung

Background:  Peroxiredoxins (Prxs) have been implicated in regulating many cellular processes including cell proliferation, differentiation and apoptosis. However, the pathophysiological significance of Prx proteins, especially in lung disease, has not been defined. Therefore, the authors investigated the distribution and expression of various Prx isoforms in lung cancer and compared this with normal lung from human and mouse.

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.

Serum angiopoietin-1 as a prognostic marker in resected early stage lung cancer

PURPOSE We evaluated the clinical significance of angiopoietins and vascular endothelial growth factor (VEGF) in patients with resected early stage lung cancer. PATIENTS AND METHODS The study enrolled 101 patients with completely resected non-small cell lung cancer (NSCLC) of stage I or II, along with 70 healthy volunteers. Serum concentrations of angiopoietin-1, angiopoietin-2, and VEGF were measured with an ELISA. Immunohistochemical expression of angiopoietin-1 was compared with the microvessel density on the lung cancer tissues. RESULTS The patients had lower serum angiopoietin-1 (32.1+/-9.9 ng/mL vs. 39.0+/-10.8 ng/mL, p<0.001), higher angiopoietin-2 (1949.2+/-1099.4 pg/mL vs. 1498.6+/-650.0 pg/mL, p<0.01), and higher VEGF (565.1+/-406.3 pg/mL vs. 404.6+/-254.8 pg/mL, p<0.01) levels than the controls. The angiopoietin-2 level was higher in stage II than in stage I patients (p<0.05). The levels of angiopoietin-1 (r=0.28) and angiopoietin-2 (r=0.36) each correlated with the VEGF level. Patients with a higher level of angiopoietin-1 (> or =31.2 ng/mL) had better disease-specific and relapse-free survival than those with a lower angiopoietin-1 level (<31.2 ng/mL). Angiopoietin-1 expression negatively correlated with the microvessel density. CONCLUSION Serum angiopoietin-1 is a potential marker for predicting postoperative survival and recurrence in patients with early stage NSCLC.

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.

The Prognostic Value of Residual Volume/Total Lung Capacity in Patients with Chronic Obstructive Pulmonary Disease.

The prognostic role of resting pulmonary hyperinflation as measured by residual volume (RV)/total lung capacity (TLC) in chronic obstructive pulmonary disease (COPD) remains poorly understood. Therefore, this study aimed to identify the factors related to resting pulmonary hyperinflation in COPD and to determine whether resting pulmonary hyperinflation is a prognostic factor in COPD. In total, 353 patients with COPD in the Korean Obstructive Lung Disease cohort recruited from 16 hospitals were enrolled. Resting pulmonary hyperinflation was defined as RV/TLC ≥ 40%. Multivariate logistic regression analysis demonstrated that older age (P = 0.001), lower forced expiratory volume in 1 second (FEV1) (P < 0.001), higher St. George Respiratory Questionnaire (SGRQ) score (P = 0.019), and higher emphysema index (P = 0.010) were associated independently with resting hyperinflation. Multivariate Cox regression model that included age, gender, dyspnea scale, SGRQ, RV/TLC, and 6-min walking distance revealed that an older age (HR = 1.07, P = 0.027), a higher RV/TLC (HR = 1.04, P = 0.025), and a shorter 6-min walking distance (HR = 0.99, P < 0.001) were independent predictors of all-cause mortality. Our data showed that older age, higher emphysema index, higher SGRQ score, and lower FEV1 were associated independently with resting pulmonary hyperinflation in COPD. RV/TLC is an independent risk factor for all-cause mortality in COPD. Graphical Abstract

Emphysema as a risk factor for the outcome of surgical resection of lung cancer.

It is unclear whether emphysema, regardless of airflow limitation, is a predictive factor associated with survival after lung cancer resection. Therefore, we investigated whether emphysema was a risk factor associated with the outcome after resection for lung cancer. This study enrolled 237 patients with non small cell lung cancer with stage I or II who had surgical removal. Patient outcome was analyzed based on emphysema. Emphysema was found in 43.4% of all patients. Patients with emphysema were predominantly men and smokers, and had a lower body mass index than the patients without emphysema. The patients without emphysema (n=133) survived longer (mean 51.2±3.0 vs. 40.6±3.1 months, P=0.042) than those with emphysema (n=104). The univariate analysis showed a younger age, higher FEV1/FVC, higher body mass index, cancer stage I, and a lower emphysema score were significant predictors of better survival. The multivariate analysis revealed a younger age, higher body mass index, and cancer stage I were independent parameters associated with better survival, however, emphysema was not. This study suggests that unfavorable outcomes after surgical resection of lung cancer should not be attributed to emphysema itself.

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.

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.