Myung Jae Park

Alterations in the INK4a/ARF locus and their effects on the growth of human osteosarcoma cell lines

Two different proteins, p16(INK4a) and p14(ARF), encoded by the INK4a/ARF locus play important roles in the RB and p53 pathways, respectively. This study was performed to determine genetic and epigenetic alterations in the INK4a/ARF locus and their effects on the growth of osteosarcoma. Among six cell lines examined, both p16(INK4a) and p14(ARF) exons were homozygously deleted in two cell lines, MG63 and HOS, and both p16(INK4a) and p14(ARF) promoters were methylated in one cell line, U2OS. Wild-type mRNA and proteins for p16(INK4a) and p14(ARF) were expressed in three other cell lines, SaOS2, HuO9, and G292. Transfection studies were performed using two cell lines, U2OS and MG63. Both the RB and p53 genes were wild types in U2OS, whereas p53 but not RB was mutated in MG63. Both p16(INK4a) and p14(ARF) suppressed the growth of U2OS, whereas p16(INK4a) but not p14(ARF) suppressed the growth of MG63. p53 only did not suppress the growth of MG63 either; however, coexpression of p14(ARF) with p53 increased the fraction of the G0/G1 phase in MG63 cells. The data presented here demonstrate the importance of genetic and epigenetic alterations in the INK4a/ARF locus for the growth of osteosarcoma and thus will be useful to further understand the biologic behavior of osteosarcoma in association with the defects in the p53 and RB pathways.

The COPD assessment test (CAT) assists prediction of COPD exacerbations in high-risk patients

UNLABELLED We evaluated the predictive value of the COPD assessment test (CAT™) for exacerbation in the following six months or time to first exacerbation among COPD patients with previous exacerbations. COPD outpatients with a history of exacerbation from 19 hospitals completed the CAT questionnaire and spirometry over six months. Exacerbation events were prospectively collected using a structured questionnaire. The baseline CAT score categorised into four groups (0-9, 10-19, 20-29, and 30-40) showed strong prediction for time to first exacerbation and modest prediction for any exacerbation or moderate-severe exacerbation (AUC 0.83, 0.64, and 0.63 respectively). In multivariate analyses, the categorised CAT score independently predicted all three outcomes (p = 0.001 or p < 0.001). Compared with the lowest CAT score category, the higher categories were associated with significantly shorter time to first exacerbation and higher exacerbation risks. The corresponding adjusted median time was >24, 14, 9, and 5 weeks and the adjusted RR was 1.00, 1.30, 1.37, and 1.50 in the category of 0-9, 10-19, 20-29, and 30-40 respectively. Exacerbation history (≥2 vs. 1 event in the past year) was related to time to first exacerbation (adjusted HR 1.35; p = 0.023) and any exacerbation during the study period (adjusted RR 1.15; p = 0.016). The results of this study support the use of the CAT as a simple tool to assist in the identification of patients at increased risk of exacerbations. This could facilitate timely and cost-effective implementation of preventive interventions, and improve health resource allocation. TRIAL REGISTRATION Clinicaltrials.gov: NCT01254032.

Association of lung function genes with chronic obstructive pulmonary disease.

AbstractBackgroundSpirometric measurements of pulmonary function are important in diagnosing and determining the severity of chronic obstructive pulmonary disease (COPD). We performed this study to determine whether candidate genes identified in genome-wide association studies of spirometric measurements were associated with COPD and if they interacted with smoking intensity. MethodsThe current analysis included 1,000 COPD subjects and 1,000 controls recruited from 24 hospital-based pulmonary clinics. Thirteen SNPs, chosen based on genome-wide association studies of spirometric measurements in the Korean population cohorts, were genotyped. Genetic association tests were performed, adjusting for age, sex, and smoking intensity, using models including a SNP-by-smoking interaction term. ResultsPID1 and FAM13A were significantly associated with COPD susceptibility. There were also significant interactions between SNPs in ACN9 and FAM13A and smoking pack-years, and an association of ACN9 with COPD in the lowest smoking tertile. The risk allele of FAM13A was associated with increased expression of FAM13A in the lung.ConclusionsWe have validated associations of FAM13A and PID1 with COPD. ACN9 showed significant interaction with smoking and is a potential candidate gene for COPD. Significant associations of genetic variants of FAM13A with gene expression levels suggest that the associated loci may act as genetic regulatory elements for FAM13A gene expression.

Clinical characteristics of patients with tuberculosis-destroyed lung.

SETTING Multicentre study. OBJECTIVE To define the clinical characteristics of patients with tuberculosis (TB) destroyed lung due to past TB. DESIGN We reviewed patients with TB-destroyed lung between May 2005 and June 2011. RESULTS A total of 595 patients from 21 hospitals were enrolled. The mean age was 65.63 ± 0.47 (mean ± standard error); 60.5% were male. The mean number of lobes involved was 2.59 ± 0.05. Pleural thickening was observed in 54.1% of the patients. Mean forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)), FEV(1)/FVC, bronchodilator response and number of exacerbations per year were respectively 2.06 ± 0.03 l (61.26% ± 0.79), 1.16 ± 0.02 l (49.05% ± 0.84), 58.03% ± 0.70, 5.70% ± 0.34, and 0.40 ± 0.04. The number of lobes involved was significantly correlated with FVC and FEV(1), and with the number of exacerbations per year. Use of long-acting muscarinic antagonists or long-acting beta-2 agonists plus inhaled corticosteroids resulted in bronchodilatory effects. Multivariable regression analysis showed that age, initial FEV(1) (%) and number of exacerbations during follow-up were independent factors affecting change in FEV(1). CONCLUSION Decreased lung function with exacerbation, and progressive decline of FEV(1) were observed in patients with TB-destroyed lung.

Expression of placental growth factor gene in lung cancer.

Differences in the gene expression profiles in small cell lung cancers (SCLC) and non-small cell lung cancers (NSCLC) may explain their different clinical characteristics. The aims of this study were (1) to identify genes differentially expressed in SCLC and NSCLC using mRNA differential display, and (2) to determine the clinical relevance of such genes in lung cancer. RNA differential display using three SCLC and six non-SCLC cell lines was used to identify a differentially expressed gene. Differential expression of the gene was confirmed in additional lung cancer cell lines using RT-PCR. Immunohistochemical staining for the gene product was performed on paraffin-embedded tissue from lung cancer patients. We examined the relationship between the expression of the gene and clinical parameters, including disease stage, response to treatment and survival time. The placental growth factor (PGF) gene was identified as preferentially expressed in SCLC compared with NSCLC cell lines using mRNA differential display. Further analysis of 45 lung cancer cell lines using RT-PCR showed that the placental growth factor (PGF) gene was expressed in nine of 13 SCLC cell lines (69%) and five of 32 NSCLC cell lines (15.6%) (p < 0.001, Fisher’s exact test). Immunohistochemistry using anti-PGF antibody on the paraffin blocks from lung cancer patients showed that PGF expression was significantly higher in SCLC than NSCLC tissue sections (32 vs. 5.6%, p = 0.041, Fisher’s exact test). Expression of PGF protein did not correlate with disease stage, response to treatment or survival time in SCLC patients. The present study suggests there is higher expression of PGF in SCLC compared to NSCLC. It may be that higher expression of the angiogenic factor PGF contributes to differences between the progression of SCLC and NSCLC, especially in regard to the nature of SCLC metastasis.

Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis

Rationale: Neutrophils are key effectors in the hosts immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. Objectives: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community‐acquired pneumonia. Methods: Neutrophils were isolated from patients with sepsis and stimulated with phorbol 12‐myristate 13‐acetate (PMA). The levels of reactive oxygen species generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. Measurements and Main Results: Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET‐dependent mechanism. Conclusions: These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis.

Zabofloxacin versus moxifloxacin in patients with COPD exacerbation: a multicenter, double-blind, double-dummy, randomized, controlled, Phase III, non-inferiority trial.

A new quinolone, zabofloxacin, has now been developed; hence, a non-inferiority trial is needed to compare this new compound with another widely used quinolone to examine its efficacy and safety for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations. This was a prospective, multicenter, double-blind, double-dummy, randomized, controlled, parallel-group, Phase III, non-inferiority clinical trial designed to compare oral zabofloxacin (367 mg once daily for 5 days) with moxifloxacin (400 mg once daily for 7 days) for the treatment of patients with COPD exacerbation. In all, 345 COPD patients with a moderate COPD exacerbation were enrolled in the study via the outpatient clinics at 31 university hospitals. Clinical per protocol analysis revealed that the clinical cure rate for zabofloxacin was 86.7% and that for moxifloxacin was 86.3% (the rate difference, 0.4%; 95% confidence interval, −7.7%–8.6%). Intention-to-treat analysis revealed clinical cure rates of 77.1% and 77.3% (difference, −0.2%; 95% confidence interval, −9.0%–8.8%), respectively. These results confirm that zabofloxacin is not inferior to moxifloxacin. The favorable microbiological response rate for zabofloxacin was 67.4% and that for moxifloxacin was 79.5% (P=0.22). Patients in the zabofloxacin group showed better patient-oriented outcomes, as measured by EXAcerbations of Chronic Pulmonary Disease Tool-Patient-Reported Outcome and the COPD assessment test scores, than patients in the moxifloxacin group. Adverse drug reactions related to zabofloxacin occurred in 9.7% of cases and those related to moxifloxacin occurred in 9.6% of cases (P=0.97). The dropout rate due to adverse events was 0% (0/175) in the zabofloxacin group and 1.8% (3/167) in the moxifloxacin group (P=0.12). Oral zabofloxacin (367 mg once daily for 5 days) was not inferior to oral moxifloxacin (400 mg once daily for 7 days) for the treatment of patients with COPD exacerbation.

Incidence of toxic optic neuropathy with low-dose ethambutol.

OBJECTIVE To investigate the incidence of ethambutol (EMB) induced optic neuropathy prescribed at a relatively low dose of ≤ 15 mg/kg/day for the treatment of tuberculosis (TB) or Mycobacterium avium complex (MAC) lung disease. DESIGN Patients diagnosed with TB or MAC lung disease received multidrug regimens including EMB at a single institution from August 2003 to July 2009. Visual monitoring was performed at baseline and at regular follow-up. The incidence of EMB-induced visual disturbances was evaluated. RESULTS Of the 415 patients included in the study, three (0.7%) developed toxic optic neuropathy over the 6-year period. Of the 289 patients prescribed a dose of ≤ 15 mg/kg/day EMB, only one (0.3%) developed toxic optic neuropathy. CONCLUSIONS The incidence of EMB-induced optic neuropathy among Koreans is estimated to be 0.7%, and can be reduced with lower doses of EMB.

History of pneumonia is a strong risk factor for chronic obstructive pulmonary disease (COPD) exacerbation in South Korea: the Epidemiologic review and Prospective Observation of COPD and Health in Korea (EPOCH) study

BACKGROUND In South Korea, chronic obstructive pulmonary disease (COPD) is one of the ten leading causes of death. COPD exacerbations are significantly associated with mortality in COPD patients. This study was conducted to investigate the epidemiology of COPD in South Korea, specifically the clinical characteristics of South Korean COPD patients, the COPD exacerbation rate and the risk factors associated with COPD exacerbations. METHODS This study covers a 2-year interval. One year was data collected retrospectively and the second year was prospectively obtained data. RESULTS A total of 1,114 subjects were enrolled in the study. These subjects were observed for a period of 1 year from the enrollment, and a total of 920 subjects completed the study. A total of 1,357 COPD exacerbations occurred in 711 subjects (63.8%) out of the total of 1,114 subjects during the study period of 2 years. Multivariate logistic regression results showed that if patients had had a pneumonia before the retrospective year of analysis, they had a 18 times greater chance of having an exacerbation during the prospective year when other variables were controlled. Also, the subjects who had a history of two or more exacerbations during the retrospective year were approximately 6 times more likely to experience the COPD exacerbation compared to those who did not. CONCLUSIONS This study examined the demographic and clinical characteristics of South Korean COPD patients and found that a history of pneumonia and two or more occurrences of exacerbation within 1 year was significantly associated with a higher rate of COPD exacerbation.

Efficacy and safety of aclidinium bromide in patients with COPD: A phase 3 randomized clinical trial in a Korean population

Aclidinium bromide (‘aclidinium’) is a novel, inhaled long‐acting muscarinic antagonist. Therapeutic effects of aclidinium on chronic obstructive pulmonary disease (COPD) have been demonstrated in Caucasian populations in several clinical trials. This was a randomized, double‐blind, multi‐centre phase‐3 clinical trial to evaluate the efficacy and safety of aclidinium in a Korean population.