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1.  Predictors of False-Negative Results from Percutaneous Transthoracic Fine-Needle Aspiration Biopsy: An Observational Study from a Retrospective Cohort 
Yonsei Medical Journal  2016;57(5):1243-1251.
We investigated factors predictive of false-negative pulmonary lesions with nonspecific benign cytology results on percutaneous transthoracic fine-needle aspiration biopsy (FNAB).
Materials and Methods
We included 222 pulmonary lesions that had a nonspecific benign result from percutaneous transthoracic FNAB between March 2005 and December 2012, and were confirmed by subsequent pathologic results or adequate clinical follow up over at least 2 years. Clinical, imaging, and biopsy procedure-related findings were compared between lesions with a final diagnosis of malignancy (false-negative) and lesions with a benign diagnosis (true-negative). Multivariate logistic regression analysis was performed to identify significant predictors of false-negatives.
Of 222 lesions, 115 lesions were proved to be false-negatives, and 107 were true-negatives. Compared with the true-negatives, false-negative lesions showed significantly older age (p=0.037), higher maximum standardized uptake value (SUVmax) on positron emission tomography (p=0.001), larger lesion size (p=0.007), and lesion characteristics of a subsolid nodule (p=0.007). On multivariate logistic regression analysis, SUVmax, lesion size, and lesion characteristics were significant predictors of false-negative results.
Among the clinical, radiologic, and procedure-related factors analyzed, high SUVmax, large lesion size, and subsolid lesions were useful for predicting malignancy in pulmonary lesions with nonspecific benign cytology results on FNAB.
PMCID: PMC4960393  PMID: 27401658
Fine needle aspiration; lung cancer; positron-emission tomography
2.  Structural modulation of lithium metal-electrolyte interface with three-dimensional metallic interlayer for high-performance lithium metal batteries 
Scientific Reports  2016;6:30830.
The use of lithium (Li) metal anodes has been reconsidered because of the necessity for a higher energy density in secondary batteries. However, Li metal anodes suffer from ‘dead’ Li formation and surface deactivation which consequently form a porous layer of redundant Li aggregates. In this work, a fibrous metal felt (FMF) as a three-dimensional conductive interlayer was introduced between the separator and the Li metal anode to improve the reversibility of the Li metal anode. The FMF can facilitate charge transfer in the porous layer, rendering it electrochemically more active. In addition, the FMF acted as a robust scaffold to accommodate Li deposits compactly in its interstitial sites. The FMF-integrated Li metal (FMF/Li) electrode operated with a small polarisation even at a current density of 10 mA cm−2, and it exhibited a seven times longer cycle-life than that of an FMF-free Li electrode in a symmetric cell configuration. A Li metal battery (LMB) using the FMF/Li electrode and a LiFePO4 electrode exhibited a two-fold increase in cycling stability compared with that of a bare Li metal electrode, demonstrating the practical effectiveness of this approach for high performance LMBs.
PMCID: PMC4971473  PMID: 27484160
3.  Inhaled Corticosteroids Use Is Not Associated With an Increased Risk of Pregnancy-Induced Hypertension and Gestational Diabetes Mellitus 
Medicine  2016;95(22):e3627.
There have been concerns that systemic corticosteroid use is associated with pregnancy-induced hypertension (PIH) and diabetes mellitus. However, the relationship between inhaled corticosteroids (ICSs) and the risk of PIH has not been fully examined, and there was no study investigating the association between ICS use and the development of gestational diabetes mellitus (GDM). The aims of the study are to determine whether the use of ICSs during pregnancy increases the risk of PIH and GDM in women.
We conducted 2 nested case-control studies utilizing the nationwide insurance claims database of the Health Insurance Review and Assessment Service (Seoul, Republic of Korea), in which 1,306,281 pregnant women who delivered between January 1, 2009 and December 31, 2011 were included. Among them, PIH cases and GDM cases were identified and matched controls were included. Conditional logistic regression analyses adjusted by other concomitant drugs use during and before pregnancy and confounding covariates including comorbidities were performed.
Total 43,908 PIH cases and 219,534 controls, and 34,190 GDM cases and 170,934 control subjects were identified. When other concomitant drugs use during pregnancy was adjusted, ICS use was associated with an increased rate of PIH (adjusted odds ratio, 1.40 [95% CI, 1.05–1.87]). ICS medication possession ratios and cumulative doses were associated with an increased risk of PIH. However, the statistical significance was not found in other models. In both unadjusted and adjusted multivariable models, ICSs use was not associated with increase in the risk of GDM.
ICSs use is not associated with an increased risk of PIH and GDM.
PMCID: PMC4900701  PMID: 27258493
4.  Association of Metformin Use With Cancer-Specific Mortality in Hepatocellular Carcinoma After Curative Resection 
Medicine  2016;95(17):e3527.
Many preclinical reports and retrospective population studies have shown an anticancer effect of metformin in patients with several types of cancer and comorbid type 2 diabetes mellitus (T2DM). In this work, the anticancer effect of metformin was assessed in hepatocellular carcinoma (HCC) patients with T2DM who underwent curative resection.
A population-based retrospective cohort design was used. Data were obtained from the National Health Insurance Service and Korea Center Cancer Registry in the Republic of Korea, identifying 5494 patients with newly diagnosed HCC who underwent curative resection between 2005 and 2011. Crude and adjusted hazard ratios (HRs) were calculated using Cox proportional hazard models to estimate effects. In the sensitivity analysis, we excluded patients who started metformin or other oral hypoglycemic agents (OHAs) after HCC diagnosis to control for immortal time bias.
From the patient cohort, 751 diabetic patients who were prescribed an OHA were analyzed for HCC-specific mortality and retreatment upon recurrence, comparing 533 patients treated with metformin to 218 patients treated without metformin. In the fully adjusted analyses, metformin users showed a significantly lower risk of HCC-specific mortality (HR 0.38, 95% confidence interval [CI] 0.30–0.49) and retreatment events (HR 0.41, 95% CI 0.33–0.52) compared with metformin nonusers. Risks for HCC-specific mortality were consistently lower among metformin-using groups, excluding patients who started metformin or OHAs after diagnosis.
In this large population-based cohort of patients with comorbid HCC and T2DM, treated with curative hepatic resection, metformin use was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events.
PMCID: PMC4998724  PMID: 27124061
5.  ESCRT-III activation by parallel action of ESCRT-I/II and ESCRT-0/Bro1 during MVB biogenesis 
eLife  null;5:e15507.
The endosomal sorting complexes required for transport (ESCRT) pathway facilitates multiple fundamental membrane remodeling events. Previously, we determined X-ray crystal structures of ESCRT-III subunit Snf7, the yeast CHMP4 ortholog, in its active and polymeric state (Tang et al., 2015). However, how ESCRT-III activation is coordinated by the upstream ESCRT components at endosomes remains unclear. Here, we provide a molecular explanation for the functional divergence of structurally similar ESCRT-III subunits. We characterize novel mutations in ESCRT-III Snf7 that trigger activation, and identify a novel role of Bro1, the yeast ALIX ortholog, in Snf7 assembly. We show that upstream ESCRTs regulate Snf7 activation at both its N-terminal core domain and the C-terminus α6 helix through two parallel ubiquitin-dependent pathways: the ESCRT-I-ESCRT-II-Vps20 pathway and the ESCRT-0-Bro1 pathway. We therefore provide an enhanced understanding for the activation of the spatially unique ESCRT-III-mediated membrane remodeling.
PMCID: PMC4865371  PMID: 27074665
ESCRT-III; Snf7; activation; Bro1; ESCRT-I; ESCRT-II; S. cerevisiae
6.  What Must a Vocabulary Editing Interface Offer? 
Creating, modifying, and maintaining a vocabulary is a new task that more healthcare enterprises are having to take on. There are today essentially no readily available vocabulary editing systems. This poster sets out a basic list of editing functions that knowledge workers will require - a minimal functionality list. Functions are explained and illustrated.
PMCID: PMC2232096
7.  Correlation between EGFR gene mutation, cytologic tumor markers, 18F-FDG uptake in non-small cell lung cancer 
BMC Cancer  2016;16:224.
EGFR mutation-induced cell proliferation causes changes in tumor biology and tumor metabolism, which may reflect tumor marker concentration and 18F-FDG uptake on PET/CT. Direct aspirates of primary lung tumors contain different concentrations of tumor markers than serum tumor markers, and may correlate better with EGFR mutation than serum tumor markers.
The purpose of this study is to investigate an association between cytologic tumor markers and FDG uptake with EGFR mutation status in non-small cell lung cancer (NSCLC).
We prospectively collected tumor aspirates of 61 patients who underwent EGFR mutation analysis. Serum and cytologic CYFRA 21-1, CEA, and SCCA levels were measured and correlated with EGFR gene mutations. FDG PET/CT was performed on 58 patients for NSCLC staging, and SUV was correlated with EGFR mutation status.
Thirty (50 %) patients had EGFR mutation and 57 patients had adenocarcinoma subtype. Univariate analysis showed that female gender, never smoker, high levels of cytologic CYFRA 21-1 (c-CYFRA) and lower maximum standard uptake value (SUVmax) were correlated with EGFR mutations. ROC generated cut-off values of 20.8 ng/ml for c-CYFRA and SUVmax of 9.6 showed highest sensitivity for EGFR mutation detection. Multivariate analysis revealed that female gender [hazard ratio (HR): 18.15, p = 0.025], higher levels of c-CYFRA (HR: 7.58, and lower SUVmax (HR: 0.08, p = 0.005) were predictive of harboring EGFR mutation.
The cytologic tumor marker c-CYFRA was positively associated with EGFR mutations in NSCLC. EGFR mutation-positive NSCLCs have relatively lower glycolysis compared with NSCLCs without EGFR mutation.
PMCID: PMC4793740  PMID: 26979333
EGFR mutation; Cytologic CYFRA 21-1; Cytologic tumor marker; 18F-FDG PET/CT
8.  Healthcare utilisation by pregnant patients with asthma in South Korea: a cohort study using nationwide claims data 
BMJ Open  2015;5(11):e008416.
Few nationwide population-based studies have examined the burden of asthma during pregnancy. Here, we investigated the burden and medical treatment of asthma during pregnancy requiring healthcare utilisation in South Korea.
Cohort study.
Nationwide insurance claims database.
A total of 1 306 281 pregnant women who delivered in South Korea in 2009–2011.
The prevalence and exacerbation rates of asthma requiring healthcare utilisation, and the prescription of antiasthmatic drugs during pregnancy.
The prevalence of asthma requiring healthcare utilisation was 0.43% among pregnant women. Among those with asthma requiring healthcare utilisation, 6.9% were hospitalised and treated with systemic steroids and short-acting β2-agonists during pregnancy. Oral drugs were prescribed less during the third trimester than during the first trimester (all p values for trends were <0.001). A significant number of patients with asthma were likely to stop taking antiasthmatic drugs after becoming pregnant.
The prevalence of asthma requiring healthcare utilisation during pregnancy was not very high. However, a significant number of women were likely to stop taking antiasthmatic drugs, and those who did tended to experience exacerbations.
PMCID: PMC4636627  PMID: 26546138
EPIDEMIOLOGY; pregnancy; inhaled respiratory drugs
9.  Measurement of Opening and Closing Angles of Aortic Valve Prostheses In Vivo Using Dual-Source Computed Tomography: Comparison with Those of Manufacturers' in 10 Different Types 
Korean Journal of Radiology  2015;16(5):1012-1023.
The aims of this study were to compare opening and closing angles of normally functioning mechanical aortic valves measured on dual-source computed tomography (CT) with the manufacturers' values and to compare CT-measured opening angles according to valve function.
Materials and Methods
A total of 140 patients with 10 different types of mechanical aortic valves, who underwent dual-source cardiac CT, were included. Opening and closing angles were measured on CT images. Agreement between angles in normally functioning valves and the manufacturer values was assessed using the interclass coefficient and the Bland-Altman method. CT-measured opening angles were compared between normal functioning valves and suspected dysfunctioning valves.
The CT-measured opening angles of normally functioning valves and manufacturers' values showed excellent agreement for seven valve types (intraclass coefficient [ICC], 0.977; 95% confidence interval [CI], 0.962-0.987). The mean differences in opening angles between the CT measurements and the manufacturers' values were 1.2° in seven types of valves, 11.0° in On-X valves, and 15.5° in ATS valves. The manufacturers' closing angles and those measured by CT showed excellent agreement for all valve types (ICC, 0.953; 95% CI, 0.920-0.972). Among valves with suspected dysfunction, those with limitation of motion (LOM) and an increased pressure gradient (PG) had smaller opening angles than those with LOM only (p < 0.05).
Dual-source cardiac CT accurately measures opening and closing angles in most types of mechanical aortic valves, compared with the manufacturers' values. Opening angles on CT differ according to the type of valve dysfunction and a decreased opening angle may suggest an elevated PG.
PMCID: PMC4559772  PMID: 26356549
Mechanical aortic valve; Opening and closing angles; Measurement; Dual-source computed tomography
10.  Inhibitory Effects of Epigallocatechin-3-Gallate on Microsomal Cyclooxygenase-1 Activity in Platelets 
Biomolecules & Therapeutics  2013;21(1):54-59.
In this study, we investigated the effect of (–)-epigallocatechin-3-gallate (EGCG), a major component of green tea catechins from green tea leaves, on activities of cyclooxygenase (COX)-1 and thromboxane synthase (TXAS), thromboxane A2 (TXA2) production associated microsomal enzymes. EGCG inhibited COX-1 activity to 96.9%, and TXAS activity to 20% in platelet microsomal fraction having cytochrome c reductase (an endoplasmic reticulum marker enzyme) activity and expressing COX-1 (70 kDa) and TXAS (58 kDa) proteins. The inhibitory ratio of COX-1 to TXAS by EGCG was 4.8. These results mean that EGCG has a stronger selectivity in COX-1 inhibition than TXAS inhibition. In special, a nonsteroid anti-inflammatory drug aspirin, a COX-1 inhibitor, inhibited COX-1 activity by 11.3% at the same concentration (50 μM) as EGCG that inhibited COX-1 activity to 96.9% as compared with that of control. This suggests that EGCG has a stronger effect than that of aspirin on inhibition of COX-1 activity. Accordingly, we demonstrate that EGCG might be used as a crucial tool for a strong negative regulator of COX-1/TXA2 signaling pathway to inhibit thrombotic disease-associated platelet aggregation.
PMCID: PMC3762306  PMID: 24009859
(–)-Epigallocatechin-3-gallate (EGCG); Aspirin; Microsomal fraction; Cyclooxygenase-1; Thromboxane synthase
11.  Hepatocellular Carcinoma in the Elderly: Clinical Characteristics, Treatment, Survival Analysis in Korean Patients Older than 70 Years 
Journal of Korean Medical Science  2012;27(10):1147-1154.
The prevalence of hepatocellular carcinoma (HCC) has increased in recent years. However, HCC remains poorly characterized in elderly patients, and comprehensive data are limited. This study aimed to investigate the clinical characteristics, prognostic features and survival outcome of elderly HCC patients. We retrospectively analyzed 992 HCC patients treated at Dongsan Hospital from January 2003 to December 2007. The patients were divided into two age groups: < 70 yr (n = 813) and ≥ 70 yr (n = 179). Elderly HCC patients, compared to younger patients, had significantly higher incidence of females (31.3% vs 18.9%, P = 0.001), hepatitis C-related disease (HCV antibody positivity 26.3% vs 9.2%, P = 0.001) and comorbid condition (53.6% vs 32.1%), but lower rates of hepatitis B-related disease (HBs antigen positivity 31.3% vs 69.4%, P = 0.001). There were no significant differences in underlying liver function, stage and survival outcomes. Factors significantly influencing the prognosis of HCC were Child-Pugh grade, number of HCC, level of alpha-fetoprotein, presence of metastasis. The survival outcome of older patients with HCC was not different from that of younger patients. There were no differences between groups in independent factors influencing the prognosis of HCC. Therefore, determining the optimal management strategy for elderly HCC patients is important to improve survival and long-term outcomes.
PMCID: PMC3468749  PMID: 23091310
Hepatocellular Carcinoma; Elderly; Survival; Prognosis
12.  Rapid normalization of alanine aminotransferase predicts viral response during combined peginterferon and ribavirin treatment in chronic hepatitis C patients 
The treatment for chronic hepatitis C (CHC) is removal of the virus in order to prevent progression to liver cirrhosis and hepatocellular carcinoma (HCC). Few data have been presented regarding the clinical significance of changes in the alanine aminotransferase (ALT) level in this context. We analyzed the patterns of changes in ALT level and investigated the relationship between the rapid normalization of ALT and sustained virologic response (SVR) after combined treatment with peginterferon and ribavirin.
CHC patients (n=370) were classified into four groups according to the initial ALT level and subsequent changes: (1) initially abnormal ALT level and sustained abnormal ALT level during treatment, (2) initially abnormal ALT level but achievement of ALT normalization, (3) initially normal ALT level and variable ALT abnormality during treatment, and (4) initially normal ALT level and sustained normalization of ALT level during treatment. We subdivided groups 1 and 2 into those with patterns of decreased and normalization of ALT, with or without rapid normalization. We checked the end-treatment response (ETR) and SVR rates in each group and the factors associated with SVR, including patterns of changes in ALT level.
A total of 168 patients completed the therapy (age=54.34±10.64 years [mean±SD], 95 males [56.5%], genotype 1:82 [48.8%]). SVR was achieved in 115 (68.45%) of the completely treated patients. The SVR rate was significantly lower in group 1 than in group 2 (37.8 vs. 81.6%, P<0.001), and significantly higher in the rapid normalization group than in the group without rapid normalization (78.5% vs. 41.2%, P<0.001). Multiple logistic regression analysis revealed that age (odds ratio [OR]=0.94, 95% confidence interval [CI]=0.91-0.98, P=0.005), viral genotype (OR=2.76, 95% CI=1.20-6.38, P=0.017), and initial hepatitis C virus RNA titer (OR=0.28, 95% CI=0.10-0.75, P=0.012) were identified as independent significant predictive factors for SVR.
The SVR rate is significantly associated with normalization, and especially rapid normalization of ALT. Rapid normalization of ALT by 4 weeks after treatment might be a useful response factor that is readily available in clinical practice, and especially for genotype 1 patients.
PMCID: PMC3326992  PMID: 22511902
Hepatitis C; Chronic; Ribavirin; Alanine transaminase; Peginterferon
13.  Prevalence of Human Papilloma Virus Infections and Cervical Cytological Abnormalities among Korean Women with Systemic Lupus Erythematosus 
Journal of Korean Medical Science  2010;25(10):1431-1437.
We performed a multicenter cross-sectional study of 134 sexually active systemic lupus erythematosus (SLE) patients to investigate the prevalence of and risk factors for high risk human papilloma virus (HPV) infection and cervical cytological abnormalities among Korean women with SLE. In this multicenter cross-sectional study, HPV testing and routine cervical cytologic examination was performed. HPV was typed using a hybrid method or the polymerase chain reaction. Data on 4,595 healthy women were used for comparison. SLE patients had greater prevalence of high-risk HPV infection (24.6% vs. 7.9%, P<0.001, odds ratio 3.8, 95% confidence interval 2.5-5.7) and of abnormal cervical cytology (16.4 vs. 2.8%, P<0.001, OR 4.4, 95% CI 2.5-7.8) compared with controls. SLE itself was identified as independent risk factors for high risk HPV infection among Korean women (OR 3.8, 95% CI 2.5-5.7) along with ≥2 sexual partners (OR 8.5, 95% CI 1.2-61.6), and Pap smear abnormalities (OR 97.3, 95% CI 6.5-1,456.7). High-risk HPV infection and cervical cytological abnormalities were more common among Korean women with SLE than controls. SLE itself may be a risk factor for HPV infection among Korean women, suggesting the importance of close monitoring of HPV infections and abnormal Pap smears in SLE patients.
PMCID: PMC2946651  PMID: 20890422
Systemic Lupus Erythematosus, Human Papilloma Virus; Cervical Cytological Abnormalities
14.  Behavioral Changes as the Earliest Clinical Manifestation of Progressive Supranuclear Palsy 
The clinical and pathological heterogeneity of progressive supranuclear palsy (PSP) is well established. Even with a well-defined clinical phenotype and a thorough laboratory workup, PSP can be misdiagnosed, especially in its early stages.
Case Report
A 52-year-old woman, who we initially diagnosed with a behavioral variant of frontotemporal dementia developed parkinsonian features, which then progressed to gait instability and gaze abnormality.
We report herein a pathologically confirmed case of PSP presenting with behavioral changes including agitation and irritability, which eventually led to the cardinal symptoms of progressive supranuclear palsy.
PMCID: PMC2950920  PMID: 20944816
frontotemporal dementia; parkinsonism; progressive supranuclear palsy
15.  High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups 
Arthritis and rheumatism  2009;60(4):1085-1095.
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
PMCID: PMC2776081  PMID: 19333953
16.  A mixture of the aqueous extract of Garcinia cambogia, soy peptide and l-carnitine reduces the accumulation of visceral fat mass in rats rendered obese by a high fat diet 
Genes & Nutrition  2007;2(4):353-358.
The aim of the present study was to investigate the anti-obesity effect of a mixture composed of Garcinia cambogia extract, soypeptide, and l-carnitine (1.2:0.3:0.02, w/w/w) in rats rendered obese by a high-fat diet (HFD). Sprague-Dawley rats were fed either the high-fat control diet (CD) or the 0.38% mixture-supplemented HFD (CD + M) for 9 weeks. The mixture significantly reduced body weight gain and the accumulation of visceral fat mass in a rat model of HFD-induced obesity. Moreover, the mixture effectively lowered blood and hepatic lipid concentrations and serum glucose, insulin, c-peptide, and leptin levels in rats with HFD-induced obesity. Results from real-time reverse transcription-polymerase chain reaction analyses indicated that the expression levels of leptin, tumor necrosis factor-alpha (TNF-α), and sterol regulatory element binding protein 1c (SREBP1c) genes in the epididymal fat tissue of rats fed the CD + M diet were 0.4-, 0.6-, and 0.48-fold, respectively, of those found in the CD rats (P  < 0.05), while expression of the uncoupling protein 2 (UCP2) gene in epididymal adipose tissue was 1.25-fold (P  < 0.05) of that found in CD rats. In conclusion, a mixture composed of G. cambogia extract, soy peptide, and l-carnitine attenuated visceral fat accumulation and improved dyslipidemia in a rat model with HFD-induced obesity.
PMCID: PMC2478482  PMID: 18850230
Garcinia cambogia; Soypeptide; l-carnitine; Anti-obesity effect; High-fat-diet-induced obesity rats; Obesity-related genes

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