Publications by authors named "Young Kyoon Kim"

138 Publications

Associations of clinical, psychological, and socioeconomic characteristics with nicotine dependence in smokers.

Sci Rep 2021 Sep 17;11(1):18544. Epub 2021 Sep 17.

Respiratory Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Cigarette smoking is a risk factor of mortality and morbidity from various cancerous, respiratory, and myocardial diseases. Nicotine dependence is assessed based on the degree of physical dependence. We aimed to determine the clinical, socioeconomic and psychological factors associated with the smoking status and degree of nicotine dependence of smokers. From April 2009 to September 2010, we retrospectively collected data from 17,577 subjects aged ≥ 18 years who had undergone a general health examination at a health promotion center. The instruments used included the Fagerström Tolerance Questionnaire (FTQ), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Stress Response Inventory (SRI), and Alcohol Use Disorder Identification Test (AUDIT). Of the current smokers (N = 3946), 2345 (59%), 1154 (29%), and 447 (12%) had low, moderate, and high nicotine dependence, respectively. In multiple logistic analysis, predictors of high nicotine dependence were male sex (odds ratio [OR] 3.705, 95% confidence interval [CI] 1.997-6.945), older age (≥ 65 years) (OR 1.016, 95% CI 1.004-1.029), higher body mass index (BMI) (OR 1.048, 95% CI 1.018-1.078), diabetes (OR 1.870, 95% CI 1.251-2.794), single marital status (OR 1.575, 95% CI 1.186-2.092), lower education level (OR 1.887, 95% CI 1.463-2.433), and a higher stress level (OR 1.018, 95% CI 1.997-6.945). Thus, clinical, psychological, socioeconomic status including male, older age, higher BMI, diabetes, single marital status, lower education, and higher stress should be taken into consideration by promoting smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-97387-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448893PMC
September 2021

Evaluation of copper alloys for reducing infection by methicillin resistant Staphylococcus aureus and vancomycin resistant Enterococcus faecium in intensive care unit and in vitro.

Korean J Intern Med 2021 Sep 18;36(5):1204-1210. Epub 2021 Aug 18.

Department of Infectious Diseases, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu, Korea.

Background/aims: Multi-drug resistant pathogens are increasing among healthcare-associated infections. It is well known that copper and copper alloys have antimicrobial activity. We evaluated the activity of copper against bacteria in a hospital setting in Korea.

Methods: This study was conducted in a laboratory and medical intensive care unit (ICU). Methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecium (VRE) were inoculated onto copper, copper alloy and stainless steel plates. After 24 hours of incubation, colony-forming units (CFU) were counted in the laboratory. Two similar rooms were chosen in the ICU; one room had copper-containing surface, and the other room contained items with a stainless steel surfaces. Items were sampled weekly for 8 weeks when the rooms were not crowded and when the rooms were busier with healthcare workers or visitors.

Results: In vitro time-kill curves showed copper or, a copper alloy yielded a significant reduction in MRSA and VRE CFUs over 15 minutes. Upon exposure to stainless steel plates, CFUs were slowly reduced for 24 hours. In vivo, MRSA CFUs were lower in rooms with copper-containing surfaces compared with controls, both after cleaning and after patients had received visitors (p < 0.05). Analysis of VRE revealed similar results, but VRE CFUs from copper-containing surfaces of drug carts in the ICU did not decrease significantly.

Conclusion: Copper has antimicrobial activity and appears to reduce the number of multi-drug resistant microorganisms in a hospital environment. This finding suggests the potential of the use of copper fittings, instruments and surfaces in hospital.
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http://dx.doi.org/10.3904/kjim.2020.643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435501PMC
September 2021

MicroRNA-21 inhibition attenuates airway inflammation and remodelling by modulating the transforming growth factor β-Smad7 pathway.

Korean J Intern Med 2021 05 18;36(3):706-720. Epub 2021 Feb 18.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background/aims: Current asthma therapies remain unsatisfactory for controlling airway remodelling in asthma. MicroRNA-21 is a key player in asthma pathogenesis, but the molecular mechanisms underlying its effects on airway remodelling are not completely understood. We investigated the effects of inhibition of microRNA-21 on allergic airway inflammation and remodelling.

Methods: Female BALB/c mice were divided into four groups: control, ovalbumin-sensitized and -challenged for 3 months, microRNA-negative control-treated ovalbumin-treated, and microRNA-21 inhibitor-treated ovalbumin-treated groups. Parameters related to airway remodelling, cytokine production, airway inflammation, and airway hyperresponsiveness were compared between groups. Human bronchial smooth muscle cells were used in a mechanism study.

Results: In this asthma model, ovalbumin-sensitized and -challenged mice exhibited allergic airway inf lammation and airway remodelling. MicroRNA-21 inhibitor-treated mice had fewer inflammatory cells, lower TH2 cytokine production, and suppressed parameters related to remodelling such as goblet cell hyperplasia, collagen deposition, hydroxyproline content, and expression of smooth muscle actin. Inhibition of microRNA-21 decreased transforming growth factor β1 expression and induced Smad7 expression in lung tissue. In human bronchial smooth muscle cells stimulated with transforming growth factor β1, microRNA-21 inhibition upregulated Smad7 expression and decreased markers of airway remodelling.

Conclusion: Inhibition of microRNA-21 had both anti-inflammatory and anti-remodelling effects in this model of ovalbumin-induced chronic asthma. Our data suggest that the microRNA-21-transforming growth factor β1-Smad7 axis modulates the pathogenesis of ovalbumin-induced chronic asthma and in human bronchial smooth muscle cells. MicroRNA-21 inhibitors may be a novel therapeutic target in patients with allergic asthma, especially those with airway remodelling.
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http://dx.doi.org/10.3904/kjim.2020.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137415PMC
May 2021

Glucagon-like peptide 1 receptor (GLP-1R) agonist relieved asthmatic airway inflammation via suppression of NLRP3 inflammasome activation in obese asthma mice model.

Pulm Pharmacol Ther 2021 04 12;67:102003. Epub 2021 Feb 12.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Background: Obesity is a correctable factor for uncontrolled bronchial asthma. However, the effects of glucagon-like peptide-1 receptor (GLP-1R) agonist, a recently approved antiobestic drug, on airway hyperresponsiveness (AHR) and immune responses are not known.

Methods: Mice were fed with high-fat diet (HFD, 60% fat) for 8 weeks to induce obesity. Ovalbumin (OVA) sensitization and challenges were performed for 7 weeks. The mice were injected intraperitoneally with GLP-1R agonist 5 times a week for 4 weeks after OVA sensitization. After AHR measurement, expression of Th2, Th17 cytokines, and interleukin (IL)-33 were measured in BALF and lung tissues. Moreover, IL-1β and activity level of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) were analyzed to investigate the mechanism of GLP-1R agonist on asthmatic airway inflammation.

Results: HFD induced significant weight gain, OVA sensitization and challenge in obese mice made eosinophilic airway inflammation, and increased AHR. Treatment with GLP-1R agonist-induced weight loss suppressed eosinophilic airway inflammation and decreased AHR. Expression of IL-4, 5, and 33 was increased in BALF of obese asthma mice followed by a decrease in response to GLP-1R agonist treatment. Moreover, lung tissue H&E stain revealed that peribronchial inflammation induced by obesity and OVA was effectively suppressed by GLP-1R agonist. Expressions of NLRP3, activated caspase-1, and IL-1β were increased in lung tissues of obese asthma mice and demonstrated a decrease in response to GLP-1R agonist treatment.

Conclusions: GLP-1R agonist effectively induced weight loss, suppressed eosinophilic bronchial airway inflammation, and AHR in obese asthma mice. These effects were mediated by suppression of NLRP3 inflammasome activity and IL-1β. GLP-1R agonist is proposed as a novel anti-asthmatic agent targeting the obese asthmatics.
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http://dx.doi.org/10.1016/j.pupt.2021.102003DOI Listing
April 2021

TGF-β induced EMT and stemness characteristics are associated with epigenetic regulation in lung cancer.

Sci Rep 2020 06 30;10(1):10597. Epub 2020 Jun 30.

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Transforming growth factor-β (TGF-β) promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT). EMT is often related with acquisition of stemness characteristics. The objective of this study was to determine whether EMT and stemness characteristics induced by TGF-β might be associated with epigenetic regulation in lung cancer. A human normal lung epithelial cell line and four lung cancer cell lines were treated with TGF-β. Transcriptome analysis of BEAS-2B and A549 cells incubated with TGF-β were analyzed through next-generation sequencing (NGS). Western blotting was carried out to investigate expression levels of epithelial and mesenchymal markers. Wound healing and Matrigel invasion assay, sphere formation assay, and in vivo mice tumor model were performed to evaluate functional characteristics of EMT and stemness acquisition. To investigate whether activation of EMT and stem cell markers might be involved in epigenetic regulation of lung cancer, experiment using a DNA methyltransferase inhibitor (5-azacytidine, AZA), methylation-specific PCR (MSP) and bisulfite sequencing were performed. NGS revealed changes in expression levels of EMT markers (E-cadherin, N-cadherin, fibronectin, vimentin, slug and snail) and stem cell markers (CD44 and CD87) in both BEAS-2B and A549 cells. Functional analysis revealed increased migration, invasion, sphere formation, and tumor development in mice after TGF-β treatment. Expression of slug and CD87 genes was activated following treatment with AZA and TGF-β. MSP and bisulfite sequencing indicated DNA demethylation of slug and CD87 genes. These results suggest that TGF-β induced EMT and cancer stemness acquisition could be associated with activation of slug and CD87 gene by their promoter demethylation.
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http://dx.doi.org/10.1038/s41598-020-67325-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326979PMC
June 2020

Evaluation of Human MSCs Treatment Frequency on Airway Inflammation in a Mouse Model of Acute Asthma.

J Korean Med Sci 2020 Jun 15;35(23):e188. Epub 2020 Jun 15.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Studies in experimental models of allergic asthma have shown that mesenchymal stem cells (MSCs) have therapeutic potential for T-helper 2 (T2) cell-mediated inflammation. However, the mechanisms underlying these therapeutic effects are not fully understood and their safety has not been confirmed.

Methods: Using a mouse model of experimental allergic asthma, we investigated the efficacy of human adipose-derived mesenchymal stem cells (hADSCs) or human bone marrow-derived mesenchymal stem cells (hBMSCs) according to treatment frequency and timing.

Results: Ovalbumin (OVA)-sensitized and -challenged mice exhibited airway hyperresponsiveness (AHR), airway inflammation, and significant increases in T2 cytokine levels. Both double and single human mesenchymal stem cell (hMSC) treatments significantly decreased AHR and bronchoalveolar lavage fluid counts. In addition, single treatment with hMSCs showed significant attenuation of allergic airway inflammation. However, double treatment with hMSCs during OVA -sensitization and -challenge further increased inflammatory cell infiltration, and T2 cytokine levels.

Conclusion: The results of treatment with hADSCs or hBMSCs suppresses AHR and airway inflammation. However, double hMSC treatment significantly induces eosinophilic airway inflammation and lung histological changes. Therefore, double hMSC treatment is ineffective against asthma and single injection frequency appears to be more important for the treatment of asthma. These results suggest that hMSC therapy can be used for treatment of asthma patients but that it should be used carefully.
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http://dx.doi.org/10.3346/jkms.2020.35.e188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295606PMC
June 2020

Use of intrapulmonary administration of thrombin in hematological malignancy patients with alveolar haemorrhage: A case series.

Medicine (Baltimore) 2020 May;99(20):e20284

Division of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Introduction: Alveolar hemorrhage (AH) is characterized by the acute onset of alveolar bleeding and hypoxemia and can be fatal. Thrombin has been widely used to achieve coagulation and hemostasis. However, the efficacy of thrombin in patients with AH is unclear. Thus, this study aimed to evaluate the efficacy of thrombin administration in patients with hematological malignancy and AH.

Patient Concerns And Diagnoses: This retrospective study included 15 hematological malignancy patients (8 men and 7 women; mean age 47.7 ± 17.3 years) with AH who were administered intrapulmonary thrombin between March 2013 and July 2018.

Interventions And Outcomes: All patients received bovine-origin thrombin (1000 IU/ml, Reyon Pharmaceutical Co., Ltd., Seoul, Korea) via a fiberoptic bronchoscope. A maximum of 15 ml of thrombin was injected via the working channel to control bleeding. The ability of thrombin to control bleeding was assessed. Additionally, the change in the PaO2/FiO2 (PF) ratio after intrapulmonary thrombin administration was evaluated. Intrapulmonary thrombin was administered a minimum of 3 days after starting mechanical ventilation in all patients, and it immediately controlled the active bleeding in 13 of 15 patients (86.7%). However, AH relapse was noted in 3 of the 13 patients (23.1%). The PF ratio improved in 10 of 15 patients (66.6%), and the mean PF ratio was significantly higher after thrombin administration than before administration (P = .03). No adverse thromboembolic complications or systemic adverse events were observed.

Conclusion: Thrombin administration was effective in controlling bleeding in hematological malignancy patients with AH. Intrapulmonary thrombin administration might be a good therapeutic option for treating AH.
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http://dx.doi.org/10.1097/MD.0000000000020284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253869PMC
May 2020

Blockade of thymic stromal lymphopoietin and CRTH2 attenuates airway inflammation in a murine model of allergic asthma.

Korean J Intern Med 2020 05 19;35(3):619-629. Epub 2020 Mar 19.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background/aims: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a key role in Th2-mediated inflammation, both directly by promoting the proliferation of naïve CD4 Th2 cells, and indirectly by activating dendritic cells (DCs). TSLP-activated DCs induce the expansion of chemoattractant receptor homologous molecule expressed on Th2 (CRTH2)+ CD4+ Th2 memory cells, which undergo a Th2 response and express prostaglandin D2 (PGD2) synthase. CRTH2, a PGD2 receptor, is a selective Th2-cell surface marker. We investigated the effects of an anti-TSLP antibody (Ab) and a CRTH2 antagonist, as well as their mechanisms of action, in a mouse model of acute asthma.

Methods: BALB/c mice were sensitized and challenged with ovalbumin. We then evaluated the effects of the administration of an anti-TSLP Ab either alone or together with a CRTH2 antagonist on cell counts, Th2 cytokine levels in bronchoalveolar fluid, and the levels of epithelium-derived cytokines such as TSLP, interleukin (IL) 33, and IL-25 in lung homogenates, as well as airway hyper-responsiveness (AHR).

Results: Anti-TSLP Ab and the CRTH2 antagonist significantly attenuated eosinophilic airway inflammation, AHR, and the expression of Th2 cytokines. The expression of GATA-3 and the levels of IL-33 and IL-25 in lung tissues were affected by the combined anti-TSLP and CRTH2 antagonist treatment.

Conclusion: These results suggest that the dual blockade of TSLP and CRTH2 may serve as an effective treatment target for eosinophilic asthma.
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http://dx.doi.org/10.3904/kjim.2018.248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214371PMC
May 2020

Pravastatin alleviates allergic airway inflammation in obesity-related asthma mouse model.

Exp Lung Res 2019 Nov - Dec;45(9-10):275-287. Epub 2019 Oct 12.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated. C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization and challenge. Pravastatin was administered intraperitoneally during the OVA treatment. Airway inflammation and airway hyper-responsiveness (AHR) were analyzed and lung tissues were examined. The changes in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were measured in the lung tissues. HFD with OVA sensitization and challenge exacerbated eosinophilic and neutrophilic airway inflammation and increased AHR compared to lean asthma mice. The levels of cytokines examined in bronchoalveolar lavage fluid (BALF) revealed that the expressions of IL-4, 5, and 17 were elevated in the obese asthmatic group and decreased after pravastatin treatment, indicating that both the Th2 and Th17 pathways were stimulated by HFD-induced obesity and OVA challenge and suppressed by pravastatin treatment. Moreover, the serum leptin and adiponectin ratio was elevated only in obese asthmatic mice and decreased with pravastatin administration. Pravastatin successfully alleviated the airway inflammation of lung tissues and AHR in both obese and lean asthmatic mice, however, treatment with pravastatin had no effects on BALF cell counts and cytokines in lean asthma mice. In lung tissues, the phosphorylation of p38 MAPK was significantly decreased in lean as well as obese asthmatic mice. Pravastatin treatment in obese asthmatic mice suppressed allergic airway infiltration and AHR by inhibition of Th2 and Th17-associated signaling pathways, decreasing the leptin expression and downstream p38 MAPK signaling pathways. The effect on lean asthmatic mice was different, independent of airway cell counts and cytokines.
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http://dx.doi.org/10.1080/01902148.2019.1675807DOI Listing
May 2020

Impact of Different Extraction Solvents on Phenolic Content and Antioxidant Potential of Bark Extract.

Biomed Res Int 2019 29;2019:3520675. Epub 2019 Jul 29.

Department of Forest Products and Biotechnology, College of Science and Technology, Kookmin University, 861-1 Chongnung-dong, Songbuk-gu, Seoul, 136-702, Republic of Korea.

It is well established that various extraction factors, including the method, temperature, time, and solvent system, significantly influence the antioxidant quality of plant-derived products. Previously, we observed that extraction of bark (PDB) by the most common traditional Soxhlet method using water at two different temperature conditions 60°C and 100°C for 6-15 h noticeably altered their antioxidant quality. In this study, we examined the impact of different extraction solvents such as ethanol, methanol, isopropanol, acetonitrile, and acetone at a different percentage with water (vol/vol) on antioxidant efficiency as well as the total phenolic content (TPC) of PDB extracts. Among the fourteen different PDB extracts, the extracts obtained from 20% ethanol (E20), 40% ethanol (E40), and 20% acetonitrile (ACN20) showed more significant antioxidant potential, as well as high total phenol content (TPC). Extracts from other aqueous mixtures of organic solvents such as isopropanol, acetone, and methanol, as well as water, showed lesser antioxidant capacity and also had less TPC compared to these three most active extracts, E20, E40, and ACN20. Moreover, using ethanol at 100% for extraction significantly decreased the TPC and antioxidant capacity of PDB extracts. Data are implicating that an increased phenolic content in PDB extracts proportionally increases their antioxidant efficiency.
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http://dx.doi.org/10.1155/2019/3520675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699328PMC
January 2020

The clinical value of F-18 FDG PET/CT in differentiating malignant from benign lesions in pneumoconiosis patients.

Eur Radiol 2020 Jan 23;30(1):442-451. Epub 2019 Jul 23.

Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

Objectives: We reviewed PET/CT findings of pneumoconiosis and determined the ability of PET/CT to differentiate lung cancer from progressive massive fibrosis (PMF), and metastatic lymph nodes (LNs) from underlying reactive LN hyperplasia.

Methods: This was a retrospective study of patients with pneumoconiosis and suspected lung cancer. Maximum standardized uptake value (SUVmax), long- and short-axis diameters (D and D), ratio of D to D (D), and Hounsfield unit (HU) from the lung mass and mediastinal LNs were measured. The cutoff values of each parameter were obtained by ROC analysis, and we evaluated the diagnostic sensitivity.

Results: Forty-nine pneumoconiosis patients were included. Eighty-three lung masses were detected, of which 42 were confirmed as lung cancer (23 squamous cell carcinomas, 12 adenocarcinomas, and 7 small cell carcinomas) and 41 were PMF. There were significant differences between lung cancer and PMF in terms of SUVmax, D, D, and HU (all p < 0.05). The sensitivity, specificity, and accuracy for diagnosis of lung cancer were 81.0%, 73.2%, and 77.1%, respectively, with an SUVmax cutoff value of 7.4; and 92.8%, 87.8%, and 90.4%, respectively, with a HU cutoff value of 45.5. Among the 40 LNs with available pathological results, 7 were metastatic. Metastatic LNs showed higher SUVmax, larger D, and lower HU than benign lesions (all p < 0.05). The sensitivity, specificity, and accuracy for predicting metastatic LNs by PET/CT were 85.7%, 93.9%, and 92.5%, respectively.

Conclusion: By applying PET and CT parameters in combination, the accuracy for differentiating malignant from benign lesions could be increased. PET/CT can play a central role in the discrimination of lung cancer and PMF.

Key Points: • Lung cancer showed significantly higher SUVmax than PMF. • Lung cancer showed similar D but longer D , resulting in a smaller D than PMF. • SUVmax demonstrated additive value in differentiating lung cancer from PMF, compared with HU alone.
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http://dx.doi.org/10.1007/s00330-019-06342-1DOI Listing
January 2020

Effect of an extraction solvent on the antioxidant quality of needle extract.

J Pharm Anal 2019 Jun 15;9(3):193-200. Epub 2019 Mar 15.

Department of Forest Products and Biotechnology, College of Science and Technology, Kookmin University, 861-1 Chongnung-dong, Songbuk-gu, Seoul, 136-702, South Korea.

needle extract (PDNE) is widely reported to have many pharmacological activities including antioxidant potential. However, the solvent system used for extraction greatly affects its antioxidant quality. Hence, in the present study, we investigated the effect of a different ratio (vol/vol) of ethanol to water (0-100%) in the extraction of PDNE with potent antioxidant capacity. The chemical assays, 2,2-diphenyl-1 picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), were conducted to assess the antioxidant potential of PDNE. Subsequently, the cytoprotective effect of PDNE was determined using -butyl hydroperoxide (TBHP)-challenged HepG2 cellular model. The needle extracts from 40% ethanol (PDNE-40) showed greater radical scavenging activity followed by 60%, 20%, 80%, 0% and 100% ethanol extracts. EC value of the most active extract, PDNE-40, was 8.56 ± 0.51 μg/mL, relative to 1.34 ± 0.28 μg/mL of the standard trolox (for ABTS radical), and 75.96 ± 11.60 μg/mL, relative to 4.83 ± 0.26 μg/mL of the standard trolox (for DPPH radical). Either PDNE-20 or PDNE-40 pretreatment remarkably decreased the levels of reactive oxygen species (ROS), lipid peroxides and protein carbonyls in TBHP-challenged HepG2 cells. In addition, both PDNE-20 and PDNE-40 significantly reversed the decreased ratio of reduced (GSH) to oxidized (GSSG) glutathione. Moreover, these two extracts showed a significant inhibitory effect on TBHP-induced nuclear damage and loss of cell viability. In summary, the inclusion of 40% ethanol in water for extraction of needle greatly increases the antioxidant quality of the extract.
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http://dx.doi.org/10.1016/j.jpha.2019.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598446PMC
June 2019

Comparison of PANAMutyper and PNAClamp for Detecting KRAS Mutations from Patients With Malignant Pleural Effusion.

In Vivo 2019 May-Jun;33(3):945-954

Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Background/aim: KRAS is one of the frequently mutated genes in human cancers and often relates with drug resistance and poor prognosis. PANAMutyper™ is a novel technology that integrates PNAClamp™ and PANA S-Melting™. In the present study, PANAMutyper™ and PNAClamp™ were compared for the detection of KRAS mutations using different samples of patients with malignant pleural effusion.

Patients And Methods: A total of 103 patients (including 56 lung adenocarcinoma, 10 lung squamous carcinoma, 17 small cell lung cancer, 3 large cell lung cancer, 3 stomach cancer, 2 ovarian cancer, and others) with malignant pleural effusion were investigated using matched tumor tissue, cell block, and pleural effusion samples. The diagnostic performance of these two methods was compared.

Results: KRAS mutations were detected in 18 (17.5%) of 103 patients using tissue, cell block, and pleural effusion samples. All 18 patients with KRAS mutations were detected by PANAMutyper™ using any sample type, however, only 7 cases were detected by PNAClamp™. Among the subtypes of KRAS mutations, substitution in codon 12, 35G>T was the most frequent, followed by substitution in codon 12, 35G>A and codon 12, 34G>A. In pleural effusion specimens, PANAMutyper™ showed a better diagnostic performance compared to PNAClamp™.

Conclusion: PANAMutyper™ had a diagnostic superiority for the detection of KRAS mutations in patients with malignant pleural effusion compared to PNAClamp™, although there was a concordance between PANAMutyper™ and PNAClamp™ results. Therefore, PANAMutyper™ can be used for a more sensitive and accurate detection of KRAS mutations.
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http://dx.doi.org/10.21873/invivo.11563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559923PMC
August 2019

CT-guided coaxial biopsy of malignant lung lesions: are cores from 20-gauge needle adequate for histologic diagnosis and molecular analysis?

J Thorac Dis 2019 Mar;11(3):753-765

Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: To determine the number of cores adequate for histopathologic diagnosis as well as evaluate the success rate of molecular analyses in CT-guided percutaneous core needle biopsy (PCNB) for malignant pulmonary lesions using a 20-guage coaxial needle.

Methods: Biopsy records of 196 malignant lung lesions were reviewed. Core obtained from each needle pass was put in a separate container for individual pathological analysis. Types of molecular analysis attempted and their success rates were recorded for each patient. We categorized each patient into one of six groups according to the number of cores (n=1, n=2, n=3, n=4, n=5, n≥6) acquired, and diagnostic sensitivity for histopathologic diagnosis was calculated for each core in each group. In order to assess the increase in cumulative sensitivity up to 4th core, the data from 1st to 4th needle passes in 4-, 5-, and ≥6-core groups were pooled and cumulative diagnostic sensitivities up to 4th core were calculated.

Results: Of 196 cases of lung malignancies, five different types of molecular studies (EGFR mutation, ALK translocation, KRAS mutation, RET and ROS1 rearrangements) were attempted with PCNB specimens in 100 cases and successfully done in 96 cases (96.0%). In ≥4-core group (4-, 5-, and ≥6-core groups combined; n=148), cumulative sensitivity increased from 83.8% to 89.9% between 1st and 2nd cores, 89.9% to 93.2% between 2nd and 3rd cores, and 93.2% to 94.6% between 3rd and 4th cores.

Conclusions: The cumulative diagnostic sensitivity for the histopathologic diagnosis increases significantly between the second and fourth sampling. Multiple samples obtained with a 20-guage coaxial needle are adequate and have a high success rate for various molecular studies for lung malignancy.
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http://dx.doi.org/10.21037/jtd.2019.02.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462692PMC
March 2019

Clinical implications of discrepant results between genotypic MTBDR and phenotypic Löwenstein-Jensen method for isoniazid or rifampicin drug susceptibility tests in tuberculosis patients.

J Thorac Dis 2019 Feb;11(2):400-409

Department of Internal Medicine, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: The widespread use of molecular, genotypic drug susceptibility tests (DSTs) for antituberculosis (anti-TB) drugs has led to the dilemma of interpreting discordant results between genotypic and conventional, phenotypic DSTs. We investigated the clinical characteristics, including treatment patterns and outcomes, of TB patients with a genotype-phenotype discrepancy in susceptibility to isoniazid (INH) or rifampicin (RIF).

Methods: We retrospectively reviewed the medical records of TB patients who had results for 2 DSTs (genotypic method, MTBDR test for INH and RIF, and phenotypic method) treated between August 2010 and October 2016 in a tertiary university hospital.

Results: Among 1,069 TB patients, 63 (5.9%) had discrepant results for the 2 DSTs. Of the 57 multidrug-resistant (MDR) TB cases diagnosed by either DST, 18 (31.6%) showed discordant results for INH or RIF. The most frequent pattern of discordance was genotypic susceptibility with phenotypic resistance to INH. RIF-discordant subjects with genotypic resistance were more likely to have been exposed previously to anti-TB drugs and to have an MDR TB diagnosis and concurrent INH resistance. Forty-five of the 54 patients managed in our hospital (83.3%) had a favorable outcome with a mean treatment duration of 14.0 months. Ten of the 16 INH-discrepant patients with a genotypic mutation continued taking INH, but more than half patients in the RIF-discrepant group (8/14) with a genotypic mutation discontinued taking RIF.

Conclusions: Despite the low frequency, discordant results were obtained between the genotypic and phenotypic DSTs for INH or RIF, especially for patients with MDR TB or INH resistance. Furthermore, it seemed that RIF discrepancy with a genotypic mutation might have a greater impact on the clinical outcome than INH discrepancy.
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http://dx.doi.org/10.21037/jtd.2019.01.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409268PMC
February 2019

Comparison of PNA Clamping-assisted Fluorescence Melting Curve Analysis and PNA Clamping in Detecting Mutations in Matched Tumor Tissue, Cell Block, Pleural Effusion and Blood of Lung Cancer Patients With Malignant Pleural Effusion.

In Vivo 2019 Mar-Apr;33(2):595-603

Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Background/aim: This study compared the efficacy of PANAMutyper™, a novel technology that integrates PNAClamp™ and PANA S-Melting™, and PNAClamp™ alone for the detection of EGFR mutations in lung cancer patients.

Materials And Methods: PANAMutyper™ and PNAClamp™ were used to assess the EGFR mutation status in tissue, cell block, pleural effusion, and blood samples of 90 lung cancer patients with malignant pleural effusion.

Results: PANAMutyper™ detected more EGFR mutations than PNAClamp™, especially in body fluids (pleural effusion and serum). Patients with additional EGFR mutations detected using PANAMutyper™ had a favorable response to EGFR-tyrosine kinase inhibitor (TKI) treatment.

Conclusion: The diagnostic performance of PANAMutyper™ was superior to that of PNAClamp™ for the detection of EGFR mutations. It was also better at identifying lung cancer patients with malignant pleural effusion who were likely to benefit from EGFR-TKI treatment.
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http://dx.doi.org/10.21873/invivo.11516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506303PMC
June 2019

Hypoxia-induced cancer stemness acquisition is associated with CXCR4 activation by its aberrant promoter demethylation.

BMC Cancer 2019 Feb 13;19(1):148. Epub 2019 Feb 13.

Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.

Background: A hypoxic microenvironment leads to an increase in the invasiveness and the metastatic potential of cancer cells within tumors via the epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. However, hypoxia-induced changes in the expression and function of candidate stem cell markers and their possible molecular mechanism is still not understood.

Methods: Lung cell lines were analyzed in normoxic or hypoxic conditions. For screening among the stem cell markers, a transcriptome analysis using next-generation sequencing was performed. For validation, the EMT and stem cell characteristics were analyzed. To determine whether an epigenetic mechanism was involved, the cell lines were treated with a DNA methyltransferase inhibitor (AZA), and methylation-specific PCR and bisulfite sequencing were performed.

Results: Next-generation sequencing revealed that the CXCR4 expression was significantly higher after the hypoxic condition, which functionally resulted in the EMT and cancer stemness acquisition. The acquisition of the EMT and stemness properties was inhibited by treatment with CXCR4 siRNA. The CXCR4 was activated by either the hypoxic condition or treatment with AZA. The methylation-specific PCR and bisulfite sequencing displayed a decreased CXCR4 promoter methylation in the hypoxic condition.

Conclusions: These results suggest that hypoxia-induced acquisition of cancer stem cell characteristics was associated with CXCR4 activation by its aberrant promoter demethylation.
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http://dx.doi.org/10.1186/s12885-019-5360-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375212PMC
February 2019

Metabolic health is more closely associated with decrease in lung function than obesity.

PLoS One 2019 23;14(1):e0209575. Epub 2019 Jan 23.

Division of Pulmonary Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Objective: Previous studies have evaluated the link between metabolic syndrome and obesity with impaired lung function, however findings have been controversial. We aimed to compare lung function among subjects with different metabolic health and obesity status.

Methods: Total 10,071 participants were evaluated at the Health Promotion Center in Seoul St. Mary's Hospital between January 2012 and December 2014. Being metabolically healthy was defined as having fewer than three of the following risk factors: high blood pressure, high fasting blood glucose, high triglyceride, low high-density lipoprotein cholesterol and abdominal obesity. Obesity status was defined as body mass index (BMI) higher than 25 kg/m2. Analyses of pulmonary function were performed in four groups divided according to metabolic health and obesity: metabolically healthy non-obese (MHNO), metabolically health obese (MHO), metabolically unhealthy non-obese (MUHNO), and metabolically unhealthy obese (MUHO).

Results: Metabolically unhealthy subjects were more prone to decreased lung function compared with their metabolically healthy counterparts, regardless of obesity status. When multinomial logistic regression analysis was performed according to quartiles of forced vital capacity (FVC) or forced expiratory volume in 1 second (FEV1) (% pred), after adjusting for age, sex, and smoking status, odds ratio (OR) for the lowest FVC and FEV1 (% pred) quartiles were significantly higher in MUHO subjects (1.788 [95% CI, 1.531-2.089] and 1.603 [95% CI, 1.367-1.881]) and lower in MHO subjects (0.768 [95% CI, 0.654-0.902] and 0.826 [95% CI, 0.700-0.976]) with MHNO group as the reference, when OR for highest FVC and FEV1 quartiles were considered as 1.0.

Conclusion: Metabolic health is more closely associated with impaired lung function than obesity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343891PMC
November 2019

Effect of nintedanib on airway inflammation in a mouse model of acute asthma.

J Asthma 2020 01 11;57(1):11-20. Epub 2019 Jan 11.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

New treatments are needed for cases of asthma that are refractory to traditional therapies. In this study, we examined the effect of oral nintedanib, an intracellular inhibitor of tyrosine kinases, on airway hyper-responsiveness (AHR) and airway smooth muscle cells, using a mouse model of experimental asthma. Asthma was experimentally induced in mice via subcutaneous injection of ovalbumin (OVA). A group of saline-injected mice served as a control group. The OVA mice were then divided into four treatment groups according to the dose of nintedanib. AHR was examined via exposure to vaporized methacholine. Airway inflammation was assessed via bronchoalveolar lavage fluid (BALF) cell counts and Th2 cytokine concentrations. Baseline levels of AHR and airway inflammation were higher in OVA mice than in the control group. Treatment with nintedanib lowered AHR, BALF cell counts and BALF cytokine levels in a dose-dependent fashion. The effect of nintedanib was comparable to that of dexamethasone. In particular, treatment with nintedanib lowered the expression of transforming growth factor-β1 and inhibited the expression and phosphorylation of platelet-derived growth factor receptor-β, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, fibroblast growth factor receptor 2 (FGFR2), FGFR3, and extracellular signal-regulated kinase. Nintedanib lowered AHR and the expression of factors associated with airway inflammation and remodeling in a mouse model of experimental asthma. Our results suggest that nintedanib may be useful in the treatment of asthma.
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http://dx.doi.org/10.1080/02770903.2018.1544641DOI Listing
January 2020

Clinical significance of Glasgow Prognostic Score in patients with tuberculous pleurisy.

J Thorac Dis 2018 Nov;10(11):6077-6087

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: The Glasgow Prognostic Score (GPS) reflects the host systemic inflammatory response and is a validated, independent prognostic factor for various malignancies. We investigated the clinical significance of the GPS in patients with tuberculosis (TB) pleurisy, focusing on treatment outcomes including paradoxical response (PR).

Methods: This was a retrospective study performed between January 2010 and December 2015 in two referral and university hospitals in South Korea, with intermediate incidences of TB. In all, 462 patients with TB pleurisy were registered in the study. The patients were classified into three groups based on GPS score, as follows: (I) GPS of 2, elevated CRP level (>1.0 mg/dL) and hypoalbuminemia (<3.5 g/dL); (II) GPS of 1, elevated CRP level or hypoalbuminemia; and (III) GPS of 0, neither elevated CRP level nor hypoalbuminemia.

Results: A total of 367 patients with TB pleurisy were finally included. PR occurred in 102 (27.8%) patients after a mean of 75 days following initiation of anti-TB treatment. The proportion of PR occurrence was significantly lower in the GPS 2 group (P=0.007). Successful treatment outcomes including cure and completion were also significantly lower in the GPS 2 group (P=0.001), while all-cause mortality and TB-specific mortality were higher in the GPS 2 group (P=0.001 and <0.001, respectively). Old age over than 65 years old was an independent predicting factor for high mortality and lower PR occurrence. However, the TB relapse rate was not different among the three GPS groups.

Conclusions: Higher GPS value and elderly age were identified as prognostic factors for poor outcomes in TB pleurisy and as predicting factors for lower PR occurrence. More prospective studies are needed to clarify the utility of GPS in patients with TB pleurisy.
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http://dx.doi.org/10.21037/jtd.2018.10.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297411PMC
November 2018

Expression of Muscarinic Receptors and the Effect of Tiotropium Bromide in Aged Mouse Model of Chronic Asthma.

Tuberc Respir Dis (Seoul) 2019 Jan;82(1):71-80

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Efficacy and safety of tiotropium bromide, a muscarinic receptor antagonist, in treatment of asthma have been reported. However, its effect on airway remodeling in chronic asthma of the elderly has not been clearly verified. The objective of this study was to investigate the effect of tiotropium and expression of muscarinic receptors as its related mechanism in an aged mouse model of chronic asthma with airway remodeling.

Methods: BALB/c female mice age 6 weeks, 9 and 15 months were sensitized and challenged with ovalbumin (OVA) for three months. Tiotropium bromide was administered during the challenge period. Airway hyperresponsiveness (AHR) and pulmonary inflammation were measured. Parameters of airway remodeling, and expression levels of M₂ and M₃ receptors were examined.

Results: Total cell with eosinophils, increased in the OVA groups by age, was decreased significantly after treatment with tiotropium bromide, particularly in the age group of 15 months. AHR and levels of interleukin (IL)-4, IL-5, and IL-13 were decreased, after tiotropium administration. In old aged group of 9- and 15-months-treated groups, hydroxyproline contents and levels of α-smooth muscle actin were attenuated. Tiotropium enhanced the expression of M₂ but decreased expression of M₃ in all aged groups of OVA.

Conclusion: Tiotropium bromide had anti-inflammatory and anti-remodeling effects in an aged mouse model of chronic asthma. Its effects seemed to be partly mediated by modulating expression M₃ and M₂ muscarinic receptors. Tiotropium may be a beneficial treatment option for the elderly with airway remodeling of chronic asthma.
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http://dx.doi.org/10.4046/trd.2018.0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304325PMC
January 2019

Nationwide use of inhaled corticosteroids by South Korean asthma patients: an examination of the Health Insurance Review and Service database.

J Thorac Dis 2018 Sep;10(9):5405-5413

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

Background: Previous studies have found that the prescription rates of inhaled corticosteroid (ICS) were considerably low although it is recommended as the optimal asthma treatment. The aim of this study was to analyze the current status of ICS prescription for asthma patients in the South Korea.

Methods: We evaluated quality assessment data based on nationwide Health Insurance Review and Service (HIRA) database from July 2013 to June 2014. ICS prescription rates in asthma patients were analyzed by types and specialty of medical institutions. Also, we graded medical institutions by their ICS prescription rate. In addition, ICS prescription rates were calculated by patient gender, age, and insurance type.

Results: This study included 831,613 patients and 16,804 institutions in the analysis. The overall mean ICS prescription rate was 22.58%. Tertiary hospitals had the highest mean prescription rate (84.16%) whereas primary healthcare clinics had the lowest (20.71%). By specialty, internal medicine physicians prescribed ICS more frequently compared to other specialists. Of all, 47.17% of medical institutions prescribed ICS to <10% of asthma patients, while less than 6% of institutions prescribed ICS to >80% of asthma patients. Also, we found that female and patients with age >90 or <20 years exhibited lower ICS prescription rate.

Conclusions: The ICS prescription rate was found to be inadequate, given the importance of ICS as an asthma treatment. The prescription rates were especially low in primary healthcare clinics, and by specialists in fields other than internal medicine.
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http://dx.doi.org/10.21037/jtd.2018.08.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196168PMC
September 2018

Nationwide pulmonary function test rates in South Korean asthma patients.

J Thorac Dis 2018 Jul;10(7):4360-4367

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Previous studies have shown that pulmonary function tests (PFTs) are performed at considerably lower rates than would be expected if standard guidelines were followed. The goal of this study was to evaluate the current status of PFT performance in the Republic of Korea.

Methods: We analysed quality assessment data from a nationwide Health Insurance Review and Assessment Service database collected from July 2013 to June 2014. PFT performance rates were compared among types and specialties of medical institutions. PFT performance rates were also measured by patient gender, age, and insurance type. Possession rates of PFT equipment and performance rates of each type of PFT were also evaluated.

Results: A total of 16,804 institutions and 831,613 patients were included in this study. The mean overall PFT performance rate was 22.67%. The performance rate in tertiary hospitals was 78.00%, while PFTs were performed in only 20.87% of asthma patients at primary health clinics. Male and elderly patients received PFTs more frequently than did female and younger patients. Also, patients who were covered by the Korean Veterans Health Service received a PFT more frequently than those covered by other insurance services. The possession rate of PFT equipment was significantly higher in tertiary hospitals than in primary health clinics. Of all PFT types, spirometry with flow-volume curve was performed for most patients.

Conclusions: The PFT performance rate was significantly lower than would be expected if guidelines were followed. Average performance rates were higher in tertiary hospitals and for male and elderly patients.
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http://dx.doi.org/10.21037/jtd.2018.06.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106001PMC
July 2018

Clinical Characteristics of False-Positive Lymph Node on Chest CT or PET-CT Confirmed by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Lung Cancer.

Tuberc Respir Dis (Seoul) 2018 Oct 19;81(4):339-346. Epub 2018 Jun 19.

Division of Pulmonary, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a standard procedure to evaluate suspicious lymph node involvement of lung cancer because computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography-CT (PET-CT) have limitations in their sensitivity and specificity. There are a number of benign causes of false positive lymph node such as anthracosis or anthracofibrosis, pneumoconiosis, old or active tuberculosis, interstitial lung disease, and other infectious conditions including pneumonia. The purpose of this study was to evaluate possible causes of false positive lymph node detected in chest CT or PET-CT.

Methods: Two hundred forty-seven patients who were initially diagnosed with lung cancer between May 2009 and December 2012, and underwent EBUS-TBNA to confirm suspicious lymph node involvement by chest CT or PET-CT were analyzed for the study.

Results: Of 247 cases, EBUS-TBNA confirmed malignancy in at least one lymph node in 189. The remaining 58 patients whose EBUS-TBNA results were negative were analyzed. Age ≥65, squamous cell carcinoma as the histologic type, and pneumoconiosis were related with false-positive lymph node involvement on imaging studies such as chest CT and PET-CT.

Conclusion: These findings suggest that lung cancer staging should be done more carefully when a patient has clinically benign lymph node characteristics including older age, squamous cell carcinoma, and benign lung conditions.
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http://dx.doi.org/10.4046/trd.2017.0121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148105PMC
October 2018

Effect of the anti-IL-17 antibody on allergic inflammation in an obesity-related asthma model.

Korean J Intern Med 2018 Nov 19;33(6):1210-1223. Epub 2018 Apr 19.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.

Background/aims: The co-occurrence of obesity aggravates asthma symptoms. Diet-induced obesity increases helper T cell (TH) 17 cell differentiation in adipose tissue and the spleen. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin can potentially be used to treat asthma in obese patients by inhibiting interleukin 17 (IL-17) expression. This study investigated the combined effects of pravastatin and anti-IL-17 antibody treatment on allergic inflammation in a mouse model of obesity-related asthma.

Methods: High-fat diet (HFD)-induced obesity was induced in C57BL/6 mice with or without ovalbumin (OVA) sensitization and challenge. Mice were administered the anti-IL-17 antibody, pravastatin, or both, and pathophysiological and immunological responses were analyzed.

Results: HFD exacerbated allergic airway inflammation in the bronchoalveolar lavage fluid of HFD-OVA mice as compared to OVA mice. Blockading of the IL-17 in the HFD-OVA mice decreased airway hyper-responsiveness (AHR) and airway inflammation compared to the HFD-OVA mice. Moreover, the administration of the anti-IL-17 antibody decreased the leptin/adiponectin ratio in the HFD-OVA but not the OVA mice. Co-administration of pravastatin and anti-IL-17 inhibited airway inflammation and AHR, decreased goblet cell numbers, and increased adipokine levels in obese asthmatic mice.

Conclusion: These results suggest that the IL-17-leptin/adiponectin axis plays a key role in airway inflammation in obesity-related asthma. Our findings suggest a potential new treatment for IL-17 as a target that may benefit obesity-related asthma patients who respond poorly to typical asthma medications.
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http://dx.doi.org/10.3904/kjim.2017.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234391PMC
November 2018

Falcarindiol inhibits LPS-induced inflammation via attenuating MAPK and JAK-STAT signaling pathways in murine macrophage RAW 264.7 cells.

Mol Cell Biochem 2018 Aug 24;445(1-2):169-178. Epub 2018 Jan 24.

Department of Forest Products and Biotechnology, College of Science and Technology, Kookmin University, 861-1 Chongnung-dong, Songbuk-gu, Seoul, 136-702, South Korea.

Falcarindiol (FAD) is a natural polyacetylene compound found rich in many plants of the Umbelliferae family. Previously, we isolated FAD from the rhizome of Cnidium officinale Makino, which belongs to the Umbelliferae family and found it to have a significant inhibitory effect on lipopolysaccharide (LPS)-induced production of nitric oxide, a pro-inflammatory molecule in murine macrophage RAW 264.7 cells. In this study, we investigated its effect on the expression of other major pro-inflammatory molecules as well as the mechanism underlying these effects. Pre-treatment of RAW 264.7 cells with FAD suppressed LPS-stimulated mRNA expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) and thereby reduced the respective protein levels. Mechanistic studies demonstrated that FAD attenuated the LPS-induced activation of JNK, ERK, STAT1, and STAT3 signaling molecules. Moreover, we found that FAD did not influence LPS-induced activation of p38 and NFκB signaling pathways. Collectively, this study provides evidence that FAD inhibits the production of major pro-inflammatory molecules in LPS-challenged murine macrophages via suppression of JNK, ERK, and STAT signaling pathways.
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http://dx.doi.org/10.1007/s11010-017-3262-zDOI Listing
August 2018

Current status of asthma care in South Korea: nationwide the Health Insurance Review and Assessment Service database.

J Thorac Dis 2017 Sep;9(9):3208-3214

Division of Pulmonology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.

Background: Quality control is important for patients with asthma because of its prevalence and because the social burden is substantial. This study analyzed the Health Insurance Review and Assessment Service (HIRA) database to assess asthma quality control in South Korea.

Methods: We investigated the HIRA nationwide database for reimbursed insurance claims from all medical institutions in South Korea from July 2013 to June 2014. The number of patients with asthma were evaluated and the medical institutions were categorized by type of medical institution. Asthma care quality was assessed by measuring the performance rate on pulmonary function test (PFT) and investigating prescriptions for asthma medications.

Results: A total of 16,804 medical institutions and 831,613 patients were included in this study. Among them, primary health clinics accounted for 87.75% of all medical institutions and 82.50% of patients were treated in a primary health clinic. The overall PFT performance rate was 23.47%, which was highest in tertiary hospitals (80.59%) and relatively lower in primary health clinics (17.06%). Oral agents were prescribed to 93.96% of patients, whereas inhaled agents were prescribed to only 30.34%. Oral corticosteroids were prescribed to 40.61% of patients, leukotriene antagonists to 48.78%, and inhaled corticosteroids (ICS) to 25.37% of patients by drug category.

Conclusions: Most patients with asthma were treated in primary health clinics rather than higher class medical institutions. Asthma quality control was poor regarding usage of diagnostic measures and prescribed medications.
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http://dx.doi.org/10.21037/jtd.2017.08.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708454PMC
September 2017

The leukotriene receptor antagonist pranlukast attenuates airway remodeling by suppressing TGF-β signaling.

Pulm Pharmacol Ther 2018 02 13;48:5-14. Epub 2017 Oct 13.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Background/objective: Asthma is a chronic airway disease characterized by airway eosinophilic inflammation and remodeling, which are associated with a loss in lung function. Although both contribute significantly to asthma pathogenesis, mechanistic studies and drug discovery have focused on inflammatory targets. In this study, we investigated the effect of the leukotriene receptor antagonist pranlukast on allergic airway inflammation and remodeling in vivo and in vitro.

Method: Four groups of female BALB/c mice (control; ovalbumin [OVA]-sensitized and -challenged; dimethyl sulfoxide [DMSO]-treated OVA; and pranlukast-treated OVA) were examined. Lung pathology, cytokine production, and airway hyperresponsiveness (AHR) measurements were compared among these groups. A human fetal lung fibroblast HFL-1 cell line was used in the peribranchial fibrosis analysis.

Results: OVA-sensitized and -challenged mice exhibited allergic airway inflammation and significant increases in Th2 cytokines. Pranlukast-treated mice showed significant attenuation of allergic airway inflammation. The pranlukast treatment decreased AHR and attenuated airway remodeling to goblet cell hyperplasia, collagen deposition, α-smooth muscle actin expression, and pro-fibrotic gene expression. We further demonstrated that pranlukast not only inhibited transforming growth factor-beta 1 (TGF-β1)-induced Smad signaling in human fetal lung fibroblast cells but also simultaneously reduced collagen synthesis and pro-fibrotic gene expression.

Conclusions: The leukotriene receptor antagonist pranlukast can reduce airway inflammation and remodeling by inhibiting TGF-β/Smad signaling in an OVA-sensitized and -challenged asthma mouse model, thus suppressing AHR.
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http://dx.doi.org/10.1016/j.pupt.2017.10.007DOI Listing
February 2018

Comparison of World Health Organization and Asia-Pacific body mass index classifications in COPD patients.

Int J Chron Obstruct Pulmon Dis 2017 21;12:2465-2475. Epub 2017 Aug 21.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Introduction: A low body mass index (BMI) is associated with increased mortality and low health-related quality of life in patients with COPD. The Asia-Pacific classification of BMI has a lower cutoff for overweight and obese categories compared to the World Health Organization (WHO) classification. The present study assessed patients with COPD among different BMI categories according to two BMI classification systems: WHO and Asia-Pacific.

Patients And Methods: Patients with COPD aged 40 years or older from the Korean COPD Subtype Study cohort were selected for evaluation. We enrolled 1,462 patients. Medical history including age, sex, St George's Respiratory Questionnaire (SGRQ-C), the modified Medical Research Council (mMRC) dyspnea scale, and post-bronchodilator forced expiratory volume in 1 second (FEV) were evaluated. Patients were categorized into different BMI groups according to the two BMI classification systems.

Result: FEV and the diffusing capacity of the lung for carbon monoxide (DLCO) percentage revealed an inverse "U"-shaped pattern as the BMI groups changed from underweight to obese when WHO cutoffs were applied. When Asia-Pacific cutoffs were applied, FEV and DLCO (%) exhibited a linearly ascending relationship as the BMI increased, and the percentage of patients in the overweight and obese groups linearly decreased with increasing severity of the Global Initiative for Chronic Obstructive Lung Disease criteria. From the underweight to the overweight groups, SGRQ-C and mMRC had a decreasing relationship in both the WHO and Asia-Pacific classifications. The prevalence of comorbidities in the different BMI groups showed similar trends in both BMI classifications systems.

Conclusion: The present study demonstrated that patients with COPD who have a high BMI have better pulmonary function and health-related quality of life and reduced dyspnea symptoms. Furthermore, the Asia-Pacific BMI classification more appropriately reflects the correlation of obesity and disease manifestation in Asian COPD patients than the WHO classification.
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http://dx.doi.org/10.2147/COPD.S141295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571887PMC
May 2018

Pinus densiflora needle supercritical fluid extract suppresses the expression of pro-inflammatory mediators iNOS, IL-6 and IL-1β, and activation of inflammatory STAT1 and STAT3 signaling proteins in bacterial lipopolysaccharide-challenged murine macrophages.

Daru 2017 Aug 4;25(1):18. Epub 2017 Aug 4.

Department of Forest Products and Biotechnology, College of Forest Science, Kookmin University, 861-1 Chongnung-dong, Songbuk-gu, Seoul, 136-702, South Korea.

Background: Regulation of a persistently-activated inflammatory response in macrophages is an important target for treatment of various chronic diseases. Pine needle extracts are well known to have potent immunomodulatory effects. The current study was designed to evaluate the effects of Pinus densiflora needle supercritical fluid extract (PDN-SCFE) on bacterial lipopolysaccharide (LPS)-induced inflammatory response in RAW 264.7 murine macrophages.

Methods: Cytotoxic effect of PDN-SCFE was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The levels of nitric oxide (NO) and the corresponding enzyme, inducible nitric oxide synthase (iNOS), were quantified by Griess and immunoblotting methods, respectively. The levels of cytokines were quantified using commercial ELISA kits. Quantitative real-time PCR (qRT-PCR) analysis was performed to assess the mRNA expression of iNOS and cytokines. To elucidate the mechanism of action, the involvement of nuclear transcription factor-kappa B (NFκB), mitogen activated protein kinases (MAPKs) and Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways were examined by an immunoblotting method. In addition, the cellular localization of NFκB was analyzed by immunofluorescence staining.

Results: MTT assay results indicated that PDN-SCFE is non-toxic to RAW 264.7 cells up to a maximum assayed concentration of 40 μg/mL. The PDN-SCFE exhibited a concentration-dependent inhibitory effect on LPS-induced NO production by down regulating the expression of iNOS. In addition, the extract suppressed the LPS-induced expression of interleukin-6 (IL-6) and interleukin-1β (IL-1β) but not tumour necrosis factor-α (TNFα). Mechanistic studies revealed that PDN-SCFE does not influence the NFκB and MAPK pathways. However, it showed a significant inhibitory effect on LPS-induced activation of STAT1 and STAT3 proteins in macrophages.

Conclusion: The present findings revealed that the anti-inflammatory activity of PDN-SCFE in LPS-challenged RAW 264.7 macrophages is probably caused by the suppression of the JAK-STAT signaling pathway.
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http://dx.doi.org/10.1186/s40199-017-0184-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544993PMC
August 2017
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