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1.  Prevalence of Trichomonas vaginalis in Women Visiting 2 Obstetrics and Gynecology Clinics in Daegu, South Korea 
This study explored epidemiological trends in trichomoniasis in Daegu, South Korea. Wet mount microscopy, PCR, and multiplex PCR were used to test for Trichomonas vaginalis in vaginal swab samples obtained from 621 women visiting 2 clinics in Daegu. Of the 621 women tested, microscopy detected T. vaginalis in 4 (0.6%) patients, PCR detected T. vaginalis in 19 (3.0%) patients, and multiplex PCR detected T. vaginalis in 12 (1.9%) patients. Testing via PCR demonstrated high sensitivity and high negative predictive value for T. vaginalis. Among the 19 women who tested positive for T. vaginalis according to PCR, 94.7% (18/19) reported vaginal signs and symptoms. Notably, more than 50% of T. vaginalis infections occurred in females younger than 30 years old, and 58% were unmarried. Multiplex PCR, which simultaneously detects pathogens from various sexually transmitted infections, revealed that 91.7% (11/12) of patients were infected with 2 or more pathogens. Mycoplasma hominis was the most prevalent co-infection pathogen with T. vaginalis, followed by Ureaplasma urealyticum and Chlamydia trachomatis. Our results indicate that PCR and multiplex PCR are the most sensitive tools for T. vaginalis diagnosis, rather than microscopy which has been routinely used to detect T. vaginalis infections in South Korea. Therefore, clinicians should take note of the high prevalence of T. vaginalis infections among adolescent and young women in order to prevent persistent infection and transmission of this disease.
doi:10.3347/kjp.2016.54.1.75
PMCID: PMC4792318  PMID: 26951983
Trichomonas vaginalis; trichomoniasis; PCR; multiplex PCR; multiple infection; sexually transmitted infection
2.  Comparison of the Epidemiological Aspects of Imported Dengue Cases between Korea and Japan, 2006–2010 
To compare the epidemiological characteristics of dengue cases imported by travelers or immigration in both Korea and Japan, we determined dengue incidence and related risk factors. During 2006–2010, 367 and 589 imported dengue cases were reported in Korea and Japan, respectively. In Korea, the presumptive origins for the dengue infections were Southeast Asia (82.6%), Southern Asia (13.9%), Eastern Asia (1.1%), South America (0.3%), Central America (0.3%), Africa (0.3%), and other countries (1.6%). In Japan, the origins of the infections were Southeast Asia (69.8%), Southern Asia (20.0%), Eastern Asia (1.7%), South America (2.5%), Central America (1.2%), Africa (1.2%), Oceania (2.4%), and other countries (1.2%). In both countries, more dengue cases were reported for men than for women (p < 0.01), and those aged 20–30 years accounted for > 60% of the total cases. The frequency of imported cases in summer and autumn (∼70% of total cases) was similar in both countries. This study demonstrates that there is a similar pattern of imported dengue cases in Korea and Japan. Therefore, there is a risk of an autochthonous dengue outbreak in Korea, as indicated by the recent outbreak in Japan in 2014.
doi:10.1016/j.phrp.2015.12.001
PMCID: PMC4776262  PMID: 26981346
dengue; epidemiology; Japan; Korea; travelers
3.  Prevalence of Trichomonas vaginalis by PCR in Men Attending a Primary Care Urology Clinic in South Korea 
Trichomonas vaginalis, a causative agent of trichomoniasis, may trigger symptomatic or asymptomatic nongonococcal urethritis and chronic prostatitis in men. Despite the availability of highly sensitive diagnostic tests, such as nucleic acid amplification tests, including PCR, few prospective studies present data on male T. vaginalis infection in South Korea. In the present study, the prevalence of T. vaginalis and associated clinical conditions were evaluated in 201 male patients from a primary care urology clinic in South Korea. The prevalence of T. vaginalis infection in our cohort was 4% (8/201) by PCR. T. vaginalis infection was common in men older than 40 years (median age, 52 years). Among the 8 Trichomonas-positive patients, 87.5% (7/8) had prostatic diseases, such as prostatitis and benign prostatic hyperplasia, and 25.0% (2/8) and 12.5% (1/8) were coinfected with Chlamydia trachomatis and Mycoplasma genitalium, respectively. Our results suggest that T. vaginalis infection is not rare in men attending primary care urology clinics in South Korea, especially in those older than 40 years, in whom it may explain the presence of prostatic disease. The possibility of T. vaginalis infection should be routinely considered in older male patients with prostatic diseases in South Korea.
doi:10.3347/kjp.2014.52.5.551
PMCID: PMC4210741  PMID: 25352707
Trichomonas vaginalis; sexually transmitted disease; diagnosis; PCR; multiplex PCR
4.  Aging Affects the Association Between Endothelial Nitric Oxide Synthase Gene Polymorphism and Acute Myocardial Infarction in the Korean Male Population 
Objectives
The aging process affects responsiveness and other functions of endothelium and vascular smooth muscle cells, predisposing the old vessels to the development of atherosclerotic lesions. Endothelial nitric oxide synthase (ecNOS) gene polymorphisms were shown to affect the occurrence of acute myocardial infarction (AMI). We hypothesized that aging may affect the association between the ecNOS gene polymorphism and AMI.
Methods
We investigated the age-related distribution of the ecNOS gene a/b polymorphism in 121 male AMI patients and 206 age-matched healthy male controls.
Results
The aa, ab and bb genotypes were found in 1, 49 and 156 cases among the control subjects and 5, 23 and 93 cases among the AMI patients, respectively. There was a significant correlation between the ecNOS polymorphism and AMI (p = 0.045). When the correlation was analyzed by age, the significance remained only in the group below the age of 51 (p = 0.009). The proportion of smokers was increased in the young patients when compared to the old patients (p = 0.033), indicating that smoking also has greater effect on the younger population. The incidences of hypertension and diabetes mellitus, however, were similar in both populations.
Conclusion
Our work provides the first evidence that links ecNOS polymorphism to the risk of AMI in relation to age. Young persons who smoke or have ecNOSaa genotype may have an increased risk of developing AMI. The functional as well as structural changes associated with aging in the vascular endothelium may mask the effect of the ecNOS polymorphism in the development of AMI in old persons.
doi:10.3904/kjim.2000.15.1.65
PMCID: PMC4531736  PMID: 10714094
Myocardial infarction; Nitric oxide synthase; DNA polymorphism; Smoking; Aging
5.  Epidemiology of Trichomoniasis in South Korea and Increasing Trend in Incidence, Health Insurance Review and Assessment 2009-2014 
PLoS ONE  2016;11(12):e0167938.
Trichomoniasis, which is caused by Trichomonas vaginalis, is one of the most common non-viral sexually transmitted infections; however, limited population-based data are available that describe patterns and trends of the disease. We summarized insurance claims of trichomoniasis cases reported during 2009–2014 to South Korea Health Insurance Review and Assessment Service. The average annual incidence in South Korea was 276.8 persons per 100,000 population, and a substantial sex-associated variation was observed. The incidence rate among female subjects trended upward over 6 years, that is, it increased from 501 in 2009 to 625.8 in 2014 per 100,000 female population, which indicates a 25% overall increase. This trend was sharpest in the ≥60 years group of female population. However, a 66% decrease in incidence rates was observed among male subjects (23.7 in 2009 to 15.7 in 2014 per 100,000 male population). Further, substantial decrease was observed in the ≥40 years groups of male population. The incidence of trichomoniasis varied across regions and was the highest in Jeju province of South Korea. Overall, as the incidence of trichomoniasis appears to have increased in South Korea during 2009–2014, the disease burden is increasing; hence, there is a need to better understand the disease transmission.
doi:10.1371/journal.pone.0167938
PMCID: PMC5148063  PMID: 27936227
6.  Epidemiological and Clinical Features of Severe Fever with Thrombocytopenia Syndrome during an Outbreak in South Korea, 2013–2015 
Since the first reported case of severe fever with thrombocytopenia syndrome (SFTS) in South Korea in 2013, between 2013 and 2015, we collected 1,697 serum samples from suspected patients who experienced symptoms of SFTS. We performed reverse transcriptase polymerase chain reaction using total RNA extracted from the patients' sera. When viral RNA was detected in the sera, SFTS was diagnosed. Among the 1,697 samples, 170 were positive for SFTS virus. We then analyzed the epidemiologic features of these 170 cases. As a result, we found that the annual number of cases increased steadily. However, the annual case fatality rate exhibited a downward trend. The majority of patients were aged ≥ 60 years, and most cases occurred during May–October in the eastern and southern parts of the country. These results may be useful for effective SFTS control by describing the clinical and epidemiologic features of the disease in South Korea.
doi:10.4269/ajtmh.16-0251
PMCID: PMC5154450  PMID: 27928084
7.  Identification of KIAA1199 as a Biomarker for Pancreatic Intraepithelial Neoplasia 
Scientific Reports  2016;6:38273.
Pancreatic cancer is one of the most aggressive cancers and has an extremely poor prognosis. Despite recent progress in both basic and clinical research, most pancreatic cancers are detected at an incurable stage owing to the absence of disease-specific symptoms. Thus, developing novel approaches for detecting pancreatic cancer at an early stage is imperative. Our in silico and immunohistochemical analyses showed that KIAA1199 is specifically expressed in human pancreatic cancer cells and pancreatic intraepithelial neoplasia, the early lesion of pancreatic cancer, in a genetically engineered mouse model and in human patient samples. We also detected secreted KIAA1199 protein in blood samples obtained from pancreatic cancer mouse models, but not in normal mice. Furthermore, we found that assessing KIAA1199 autoantibody increased the sensitivity of detecting pancreatic cancer. These results indicate the potential benefits of using KIAA1199 as a biomarker for early-stage pancreatic cancer.
doi:10.1038/srep38273
PMCID: PMC5138641  PMID: 27922049
8.  Validation of the 7th AJCC/UICC staging system for gastric cancer and a proposal for a new TNM system based on a prognostic score: a retrospective multicenter study 
Purpose
We validate the 7th American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system for gastric cancer and propose a new staging system that reflects the prognostic significances of each of T and N category.
Methods
Data from 5,957 patients who underwent curative gastrectomies from 2000 to 2007 at 4 university hospitals in Daegu Metropolitan city in Korea were analyzed for the validation of the 7th AJCC/UICC staging system for gastric cancer. The hazard ratios of the respective T and N categories were estimated and converted to weightings and summated to make prognostic score (P-score). Homogeneity and stage grouping were determined according to the P-scores.
Results
In the 7th AJCC/UICC staging system for gastric cancer, poor discrimination was noted between stages IIB and IIIA (P = 0.152). In addition, heterogeneity in stage IIB (P = 0.021) and a small gap in 5-year survival rates (1.7%) between stages IA and IB were noted. A new proposed staging system was generated on the basis of P-scores and demonstrated more discrimination between stages and more homogeneity within stages. The new staging system reflects the different prognostic impacts of N3a and N3b.
Conclusion
Several controversial issues of the 7th AJCC/UICC staging system for gastric cancer were reconfirmed in the present analysis. The TNM system based on P-score appears to be more scientifically accurate than the 7th AJCC/UICC staging system for gastric cancer.
doi:10.4174/astr.2016.91.6.295
PMCID: PMC5128375  PMID: 27904851
TNM classification; Stomach neoplasms
9.  Exendin-4 Inhibits Hepatic Lipogenesis by Increasing β-Catenin Signaling 
PLoS ONE  2016;11(12):e0166913.
The aim of this study is to investigate whether the beneficial effect of exendin-4 on hepatic steatosis is mediated by β-catenin signaling. After the HepG2 human hepatoma cells were treated with PA for 24 hours, total triglycerides levels were increased in a dose-dependent manner, and the expression levels of perilipin family members were upregulated in cells treated with 400 μM PA. For our in vitro model of hepatic steatosis, HepG2 cells were treated with 400 μM palmitic acid (PA) in the presence or absence of 100 nM exendin-4 for 24 hours. PA increased the expression of lipogenic genes, such as sterol regulatory element-binding protein 1c (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), stearoyl-CoA desaturase 1 (SCD1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) and triglyceride synthesis-involved genes, such as diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2) in HepG2 cells, whereas exendin-4 treatment significantly prevented the upregulation of SREBP-1c, PPARγ, SCD1, FAS, ACC, DGAT1 and DGAT2. Moreover, exendin-4 treatment increased the expression of phosphorylated glycogen synthase kinase-3 beta (GSK-3β) in the cytosolic fraction and the expression of β-catenin and transcription factor 4 (TCF4) in the nuclear fraction. In addition, siRNA-mediated inhibition of β-catenin upregulated the expression of lipogenic transcription factors. The protective effects of exendin-4 on intracellular triglyceride content and total triglyceride levels were not observed in cells treated with the β-catenin inhibitor IWR-1. These data suggest that exendin-4 treatment improves hepatic steatosis by inhibiting lipogenesis via activation of Wnt/β-catenin signaling.
doi:10.1371/journal.pone.0166913
PMCID: PMC5131969  PMID: 27907035
10.  Waist Circumference as a Marker of Obesity Is More Predictive of Coronary Artery Calcification than Body Mass Index in Apparently Healthy Korean Adults: The Kangbuk Samsung Health Study 
Endocrinology and Metabolism  2016;31(4):559-566.
Background
We aimed to assess the risk for coronary artery calcification (CAC) according to groups subdivided by body mass index (BMI) and waist circumference (WC) in apparently healthy Korean adults.
Methods
Thirty-three thousand four hundred and thirty-two participants (mean age, 42 years) in a health screening program were divided into three groups according to BMI: <23 kg/m2 (normal), 23 to 25 kg/m2 (overweight), and >25 kg/m2 (obese). In addition, the participants were divided into two groups according to WC. Coronary artery calcium score (CACS) was measured with multi-detector computed tomography in all participants. Presence of CAC was defined as CACS >0.
Results
When logistic regression analysis was performed with the presence of CAC as the dependent variable, the risk for CAC increased as BMI increased after adjusting for confounding variables (1.102 [95% confidence interval (CI), 1.000 to 1.216]; 1.284 [95% CI, 1.169 to 1.410]; in the overweight and obese groups vs. the normal weight group). When the participants were divided into six groups according to BMI and WC, the subjects with BMI and WC in the obese range showed the highest risk for CAC (1.321 [95% CI, 1.194 to 1.461]) and those with BMI in the overweight range and WC in the obese range showed the second highest risk for CAC (1.235 [95% CI, 1.194 to 1.461]).
Conclusion
Participants with obesity defined by both BMI and WC showed the highest risk for CAC. Those with BMIs in the overweight range but with WC in the obese range showed the second highest risk for CAC, suggesting that WC as a marker of obesity is more predictive of CAC than BMI.
doi:10.3803/EnM.2016.31.4.559
PMCID: PMC5195833  PMID: 28029026
Body mass index; Coronary artery calcium score; Waist circumference
11.  Unusual CD4+CD28− T Cells and Their Pathogenic Role in Chronic Inflammatory Disorders 
Immune Network  2016;16(6):322-329.
CD28 is a primary co-stimulatory receptor that is essential for successful T cell activation, proliferation, and survival. While ubiquitously expressed on naive T cells, the level of CD28 expression on memory T cells is largely dependent on the T-cell differentiation stage in humans. Expansion of circulating T cells lacking CD28 was originally considered a hallmark of age-associated immunological changes in humans, with a progressive loss of CD28 following replicative senescence with advancing age. However, an increasing body of evidence has revealed that there is a significant age-inappropriate expansion of CD4+CD28− T cells in patients with a variety of chronic inflammatory diseases, suggesting that these cells play a role in their pathogenesis. In fact, expanded CD4+CD28− T cells can produce large amounts of proinflammatory cytokines such as IFN-γ and TNF-α and also have cytotoxic potential, which may cause tissue damage and development of pathogenesis in many inflammatory disorders. Here we review the characteristics of CD4+CD28− T cells as well as the recent advances highlighting the contribution of these cells to several disease conditions.
doi:10.4110/in.2016.16.6.322
PMCID: PMC5195841  PMID: 28035207
CD28; Co-stimulatory receptor; CD4+CD28− T cells; Chronic inflammatory diseases; Cytotoxic potential
12.  Shear-Wave Elastography for the Differential Diagnosis of Breast Papillary Lesions 
PLoS ONE  2016;11(11):e0167118.
Objective
To evaluate the diagnostic performance of shear-wave elastography (SWE) for the differential diagnosis of breast papillary lesions.
Methods
This study was an institutional review board-approved retrospective study, with a waiver of informed consent. A total of 79 breast papillary lesions in 71 consecutive women underwent ultrasound and SWE prior to biopsy. Ultrasound features and quantitative SWE parameters were recorded for each lesion. All lesions were surgically excised or excised using an ultrasound-guided vacuum-assisted method. The diagnostic performances of the quantitative SWE parameters were compared using the area under the receiver operating characteristic curve (AUC).
Results
Of the 79 lesions, six (7.6%) were malignant and 12 (15.2%) were atypical. Orientation, margin, and the final BI-RADS ultrasound assessments were significantly different for the papillary lesions (p < 0.05). All qualitative SWE parameters were significantly different (p < 0.05). The AUC values for SWE parameters of benign and atypical or malignant papillary lesions ranged from 0.707 to 0.757 (sensitivity, 44.4–94.4%; specificity, 42.6–88.5%). The maximum elasticity and the mean elasticity showed the highest AUC (0.757) to differentiate papillary lesions.
Conclusion
SWE provides additional information for the differential diagnosis of breast papillary lesions. Quantitative SWE features were helpful to differentiate breast papillary lesions.
doi:10.1371/journal.pone.0167118
PMCID: PMC5125677  PMID: 27893857
13.  A Comparative Study of the Epidemiological Aspects of Legionnaires’ Disease: Outbreaks in Korea and Japan, 2010 - 2014 
Background
In the present study, we compared the epidemiological aspects of Legionnaire’ disease (LD) outbreaks in Korea and Japan by analyzing the current state from 2010 to 2014.
Methods
The following factors were analyzed: nationwide cumulative incidence rate (CIR) per 100,000 populations and case-fatality rate in percentage, epidemiological aspects (i.e., case related to gender), male to female morbidity ratio (MFMR), age, seasonality and habitat distribution of LD cases.
Results
In total, there were 134 cases of LD with the CIR of 0.05 per 100,000 populations in Korea from 2010 to 2014. During the same period in Japan, there were 4,840 cases of LD with a CIR of 0.76 per 100,000 populations. The CIR in Japan was significantly higher than that in Korea. However, the case-fatality rates were at similar levels (3.0% vs. 5.9%). Moreover, LD affects both sexes differently, accounting for 2.05 and 4.41 of MFMR in Korea and Japan, respectively. In both countries, the incidence mainly occurred among people aged 40 years or older, and peaked in summer (37.3% vs. 33.7% of total cases). Significant differences were observed in the incidence of LD cases between the capital city and county areas in both two countries. These differences in LD risk factors reflect the different influences of reservoir/host with natural or artificial aquatic environments.
Conclusion
This study provides a quantitative analysis of the epidemiological aspects and risk factors of LD outbreaks in Korea and Japan. We hope this study would be helpful for providing insight on effective future strategies to reduce LD outbreaks.
doi:10.14740/jocmr2811e
PMCID: PMC5127218  PMID: 27924178
Legionnaires’ disease; Epidemic aspects; Risk factors; Korea; Japan
14.  Evaluation of anti-tumorigenic activity of BP3B against colon cancer with patient-derived tumor xenograft model 
Background
KIOM-CRC#BP3B (BP3B) is a novel herbal prescription that is composed of three plant extracts. Our preliminary study identified that BP3B exhibited potent anti-proliferative activity against various types of cancer cell lines in vitro. Because the in vivo anti-tumor effect of BP3B is not evaluated before clinical trial, we want to test it using patient’s samples.
Methods
To confirm the in vivo anti-cancer effect of BP3B, we used genetically characterized patient-derived colon tumor xenograft (PDTX) mouse model. Anti-cancer activity was evaluated with apoptosis, proliferation, angiogenesis and histological analysis.
Results
Oral administration of BP3B significantly inhibited the tumor growth in two PDTX models. Furthermore, TUNEL assay showed that BP3B induced apoptosis of tumor tissues, which was associated with degradation of PARP and Caspase 8 and activation of Caspase 3. We also observed that BP3B inhibited cancer cell proliferation by down-regulation of Cyclin D1 and induction of p27 proteins. Inhibition of angiogenesis in BP3B-treated group was observed with immunofluorescence staining using CD31 and Tie-2 antibodies.
Conclusion
These findings indicated that BP3B has a strong growth-inhibitory activity against colon cancer in in vivo model and will be a good therapeutic candidate for treatment of refractory colon cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12906-016-1447-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12906-016-1447-8
PMCID: PMC5116142  PMID: 27863496
BP3B; Colon cancer; Patient-derived tumor xenograft; Medicinal plant
15.  Impact of carotid atherosclerosis detection on physician and patient behavior in the management of type 2 diabetes mellitus: a prospective, observational, multicenter study 
Background
This study compared carotid ultrasound (CUS) and traditional risk calculations in determining cardiovascular disease (CVD) risk in patients with type 2 diabetes mellitus (DM) and investigated whether awareness of CVD affects patient and/or physician behavior.
Methods
In this prospective, observational, multicenter study, 797 participants with type 2 diabetes were assessed using CUS, the United Kingdom Prospective Diabetes Study Risk Engine (UKPDSRE) calculator, and the Framingham Risk Score (FRS) algorithm. Health-related behaviors and physician treatments were compared at baseline and at 6 months after assessment.
Results
According to CUS, 43.5 % of the participants were at high risk (compared to 10.6 % and 4.3 % using the UKPDSRE and FRS approaches, respectively). Interestingly, 31.5 % of the patients with low risk scores according to the UKPDSRE calculator and 35.8 % of the patients with low risk scores according to the FRS algorithm were found to be at high risk according to CUS. The proportion of patients who achieved target LDL-C levels significantly increased after CUS. Moreover, increased awareness of atherosclerosis through CUS findings significantly altered physician treatment patterns and patient health-related behaviors.
Conclusions
Carotid atherosclerosis was detected in more than 30 % of all participants with low or intermediate risk stratification scores. Improved awareness of atherosclerosis through CUS findings had a positive impact on both patient and physician behavior, resulting in improved CV risk management.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-016-0401-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12872-016-0401-5
PMCID: PMC5109726  PMID: 27842497
Behavior; Cardiovascular disease; Carotid atherosclerosis; Diabetes mellitus; Type 2
16.  Functional screening of mammalian mechanosensitive genes using Drosophila RNAi library– Smarcd3/Bap60 is a mechanosensitive pro-inflammatory gene 
Scientific Reports  2016;6:36461.
Disturbed blood flow (d-flow) induces atherosclerosis by altering the expression of mechanosensitive genes in the arterial endothelium. Previously, we identified >580 mechanosensitive genes in the mouse arterial endothelium, but their role in endothelial inflammation is incompletely understood. From this set, we obtained 84 Drosophila RNAi lines that silences the target gene under the control of upstream activation sequence (UAS) promoter. These lines were crossed with C564-GAL4 flies expressing GFP under the control of drosomycin promoter, an NF-κB target gene and a marker of pathogen-induced inflammation. Silencing of psmd12 or ERN1 decreased infection-induced drosomycin expression, while Bap60 silencing significantly increased the drosomycin expression. Interestingly, knockdown of Bap60 in adult flies using temperature-inducible Bap60 RNAi (C564ts-GAL4-Bap60-RNAi) enhanced drosomycin expression upon Gram-positive bacterial challenge but the basal drosomycin expression remained unchanged compared to the control. In the mammalian system, smarcd3 (mammalian ortholog of Bap60) expression was reduced in the human- and mouse aortic endothelial cells exposed to oscillatory shear in vitro as well as in the d-flow regions of mouse arterial endothelium in vivo. Moreover, siRNA-mediated knockdown of smarcd3 induced endothelial inflammation. In summary, we developed an in vivo Drosophila RNAi screening method to identify flow-sensitive genes that regulate endothelial inflammation.
doi:10.1038/srep36461
PMCID: PMC5098218  PMID: 27819340
17.  Prognostic Significance of Preoperative Neutrophil-to-Lymphocyte Ratio in Nonmetastatic Renal Cell Carcinoma: A Large, Multicenter Cohort Analysis 
BioMed Research International  2016;2016:5634148.
Background. The prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) in nonmetastatic renal cell carcinoma (non-mRCC) is controversial, although NLR has been established as a prognostic factor in several cancers. The objective of our study was to assess the prognostic significance of preoperative NLR in non-mRCC, based on a large, multicenter cohort analysis. Methods. Totally, 1,284 non-mRCC patients undergoing surgery were enrolled from six institutions between 2000 and 2014. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were calculated, and the prognostic significance of NLR was evaluated. Results. Patients with higher NLR had larger tumors (p < 0.001), higher T stage (p < 0.001), worse Eastern Cooperative Oncology Group performance status (p < 0.001), worse symptoms (p = 0.003), sarcomatoid differentiation (p = 0.004), and tumor necrosis (p < 0.001). The 5-year RFS and CSS rates were significantly lower in patients with high NLR than in those with low NLR (each p < 0.001). Multivariate analysis identified NLR to be an independent predictor of RFS and CSS (each p < 0.05). Moreover, predictive accuracy of multivariate models for RFS and CSS increased by 2.2% and 4.2%, respectively, with NLR inclusion. Conclusions. Higher NLR was associated with worse clinical behavior of non-mRCC. Also, NLR was a significant prognostic factor of both RFS and CSS.
doi:10.1155/2016/5634148
PMCID: PMC5116355  PMID: 27891517
18.  Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase 
Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data.
doi:10.1016/j.bmcl.2015.06.074
PMCID: PMC4607639  PMID: 26166629
19.  Public Awareness of Stroke and Its Predicting Factors in Korea: a National Public Telephone Survey, 2012 and 2014 
Journal of Korean Medical Science  2016;31(11):1703-1710.
The aim of this study was to investigate time trends in the public awareness of stroke and its predicting factors. The target population was 9,600 community-dwelling adults, aged 19–79 years, in 16 metropolitan cities and provinces in Korea. The survey samples in 2012 and 2014 were selected separately (entirely different sets of subjects) using a proportionate quota sampling method. Information concerning knowledge of stroke and demographics was collected by trained telephone interviewers using random digit dialing. After excluding subjects with a non-response or refusal to answer any question, the analyses included 8,191 subjects in 2012 and 8,127 subjects in 2014. Respondents’ awareness of stroke warning signs (numbness or weakness, difficulty speaking or understanding speech, dizziness, visual impairment, and severe headache) was highest for difficulty speaking or understanding speech (80.9% in 2012 and 86.4% in 2014). There were significant increases in the proportion of respondents understanding the appropriate action (i.e., calling an ambulance) at the time of stroke occurrence (59.6% to 67.1%), and in the proportion aware of the general need for prompt treatment (86.7% to 89.8%). In multivariable logistic regression analysis, older age, higher education level, higher household income, current non-smoking, exposure to stroke-related public relations materials, and experience of stroke education were significantly associated with both high knowledge of stroke warning signs and awareness of the need for prompt treatment. Between 2012 and 2014, the public’s awareness of stroke increased significantly. More specialized interventions, including public relations materials and education, should focus on subgroups who have lower stroke knowledge.
Graphical Abstract
doi:10.3346/jkms.2016.31.11.1703
PMCID: PMC5056200  PMID: 27709846
Public; Awareness; Stroke; Warning Signs
20.  The Different Effect of VEGF Polymorphisms on the Prognosis of Non-Small Cell Lung Cancer according to Tumor Histology 
Journal of Korean Medical Science  2016;31(11):1735-1741.
Vascular endothelial growth factor (VEGF) contributes to tumor angiogenesis. The role of VEGF single nucleotide polymorphisms (SNPs) in lung cancer susceptibility and its prognosis remains inconclusive and controversial. This study was performed to investigate whether VEGF polymorphisms affect survival outcomes of patients with early stage non-small cell lung cancer (NSCLC) after surgery. Three potentially functional VEGF SNPs (rs833061T>C, rs2010963G>C, and rs3025039C>T) were genotyped. A total of 782 NSCLC patients who were treated with surgical resection were enrolled. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. In overall population, none of the three polymorphisms were significantly associated with OS or DFS. However, when the patients were stratified by tumor histology, squamous cell carcinoma (SCC) and adenocarcinoma (AC) had significantly different OS (Adjusted hazard ratio [aHR] = 0.76, 95% CI = 0.56–1.03 in SCC; aHR = 1.33, 95% CI = 0.98–1.82 in AC; P for heterogeneity = 0.01) and DFS (aHR = 0.75, 95% CI = 0.58–0.97 in SCC; aHR = 1.26, 95% CI = 1.00–1.60 in AC; P for heterogeneity = 0.004) according to the rs833061T>C genotypes. Our results suggest that the prognostic role of VEGF rs833061T>C may differ depending on tumor histology.
Graphical Abstract
doi:10.3346/jkms.2016.31.11.1735
PMCID: PMC5056204  PMID: 27709850
Non-Small Cell Lung Cancer; Survival; Angiogenesis; Polymorphisms; Histology
21.  Disability-adjusted Life Years for 313 Diseases and Injuries: the 2012 Korean Burden of Disease Study 
Journal of Korean Medical Science  2016;31(Suppl 2):S146-S157.
This study is part of a 5-year research project on the national burden of diseases, injuries, and risk factors in Korea. Using disability-adjusted life years (DALYs), a metric introduced by the 1990 Global Burden of Disease (GBD) project, we performed a comprehensive and detailed assessment of the magnitude and distribution of both fatal and non-fatal health problems in the Korean population. The concept and general approach were consistent with the original GBD study, with some methodological modifications to make the study more suitable for Korea. We computed DALYs for 313 causes in both sexes and nine age groups using the entire population's medical records and newly generated Korean disability weights. In 2012, the dominant disease burden was non-communicable diseases, which accounted for 85.21% of total DALYs, while injuries accounted for 7.77% and communicable, maternal, neonatal, and nutritional disorders for 7.02%. Of the total DALYs, 88.67% were from years lived with disability and 11.32% were from years of life lost due to premature mortality. Diabetes mellitus was the leading cause of DALYs, followed by low back pain, chronic obstructive pulmonary disease, ischemic heart disease, ischemic stroke, cirrhosis of the liver, falls, osteoarthritis, motorized vehicle with three or more wheels, and self-harm. The results reported here identify key health challenges and opportunities for future health interventions and policy changes, and provide information that will help assess the major public health issues in Korea, a nation faced with one of the world's most rapidly ageing populations.
Graphical Abstract
doi:10.3346/jkms.2016.31.S2.S146
PMCID: PMC5081296  PMID: 27775252
Burden of Disease; Disability-Adjusted Life Year (DALY); Population Health; Health Policy; Korea
22.  Disability-Adjusted Life Years (DALYs) for Injuries Using Death Certificates and Hospital Discharge Survey by the Korean Burden of Disease Study 2012 
Journal of Korean Medical Science  2016;31(Suppl 2):S200-S207.
A system for assessing the burdens imposed by disease and injury was developed to meet healthcare, priority setting, and policy planning needs. The first such system, the Global Burden of Disease (GBD), was implemented in 1990. However, problems associated with limited data and assumed disability weightings remain to be resolved. The purpose of the present study was to estimate national burdens of injuries in Korea using more reliable data and disability weightings. The incidences of injuries were estimated using the Korean National Hospital Discharge Survey and the mortality data from the Korean National Statistical Office in 2010. Additionally, durations of injuries and age at injury onset were used to calculate disability-adjusted life years (DALY) using disability weightings derived from the Korean Burden of Disease (KBD) study. Korea had 1,581,072 DALYs resulting from injuries (3,170 per 100,000), which was 22.9% higher than found by the GBD 2010 study. Males had almost twice as heavy an injury burden as females. Road injury, fall, and self-harm ranked 1st, 2nd, and 3rd in terms of burden of injury in 2010. Total injury burden peaked in the forties, while burden per person declined gradually from early adulthood. We hope that this study contributes to the reliable evaluation of injury burden and a better understanding of injury-related health status using nation-specific, dependable data.
Graphical Abstract
doi:10.3346/jkms.2016.31.S2.S200
PMCID: PMC5081302  PMID: 27775258
Injuries; Disease Burden; Disability-Adjusted Life Years (DALYs); Health Related Quality of Life
23.  The Combination of Periostin Overexpression and Microvascular Invasion Is Related to a Poor Prognosis for Hepatocellular Carcinoma 
Gut and Liver  2016;10(6):948-954.
Background/Aims
Periostin is an extracellular matrix protein and is known to be related to the metastatic potential and prognosis of cancer. However, few studies have investigated the expression level of periostin and its association with prognoses in hepatocellular carcinoma. Therefore, we analyzed periostin overexpression in hepatocellular carcinoma and its implication for prognoses.
Methods
We evaluated 149 patients who underwent surgical resection between 2006 and 2010. Tissue microarrays were constructed from hepatocellular carcinoma tissue and adjacent nontumor tissue, and immunohistochemistry was performed.
Results
A high periostin level was observed more frequently in cases of multiple tumors (odds ratio [OR], 2.826; 95% confidence interval [CI], 1.224 to 6.527; p=0.013), positive microvascular invasion (OR, 2.974; 95% CI, 1.431 to 6.181; p=0.003), and advanced stage disease (OR, 3.032; 95% CI, 1.424 to 6.452; p=0.003). Patients with high periostin expression had significantly (p=0.002) lower overall survival rates than those with low periostin expression (90.3%, 66.1%, and 56.2% vs 97.7%, 85.1%, and 77.5% at 1, 3, and 5 years).
Conclusions
We found that a combination of periostin overexpression and microvascular invasion in hepatocellular carcinoma was correlated with a poor prognosis and can be a good prognostic marker for hepatocellular carcinoma.
doi:10.5009/gnl15481
PMCID: PMC5087935  PMID: 27458178
Periostin; Microvascular invasion; Hepatocellular carcinoma; Tissue microarray analysis; Prognosis
24.  Disability-adjusted Life Years (DALYs) for Mental and Substance Use Disorders in the Korean Burden of Disease Study 2012 
Journal of Korean Medical Science  2016;31(Suppl 2):S191-S199.
The purpose of this study was to estimate the national burden of mental substance disorders on medical care utilization in Korea using National Health Insurance System (NHIS) data and updated disability weight, in terms of disability-adjusted life years (DALYs). For each of the 24 disorders, the incident years lived with disability (YLDs) was calculated, using NHIS data to estimate prevalence and incidence rates. The DisMod-II software program was used to model duration and remission. The years of life lost (YLLs) due to premature death were calculated from causes of death statistics. DALYs were computed as the sum of YLDs and YLLs, and time discounting and age weighting were applied. The year examined was 2012, and the subjects were divided into 9 groups according to age. In 2012, the Korean burden of mental and substance use disorders was 945,391 DALYs. More than 98% of DALYs were from YLDs, and the burden in females was greater than that in males, though the burden in males aged less than 19 years old was greater than that in females. Unipolar depressive disorders, schizophrenia, and anxiety disorders were found to be major diseases that accounted for more than 70% of the burden, and most DALYs occurred in their 30–59. Mental and substance use disorders accounted for 6.2% of the total burden of disease and were found to be the 7th greatest burden of disease. Therefore, mental and substance use disorders need to be embraced by mainstream health care with resources commensurate with the burden.
Graphical Abstract
doi:10.3346/jkms.2016.31.S2.S191
PMCID: PMC5081301  PMID: 27775257
Mental and Substance Use Disorders; Burden of Disease; Disability-adjusted Life Years (DALYs); Health-related Quality of Life
25.  Regeneration of Bovine Mammary Gland in Immunodeficient Mice by Transplantation of Bovine Mammary Epithelial Cells Mixed with Matrigel 
Background and Objectives
With the global demand for dairy protein for consumption growing annually, there has been increasing activity in the research field of dairy protein synthesis and production. From a manipulation perspective, it is more difficult to use live cattle for laboratory studies on the production of milk as well as of dairy protein such as casein, as compared with using laboratory animals like rodents. Therefore, we aimed to develop a mouse model of bovine mammary alveolar ducts for laboratory-scale studies. We studied the formation of the bovine mammary gland ductal structure by transplanting the MAC-T bovine alveolar cell line into mice.
Methods and Results
MAC-T cells (1×107) were suspended in Matrigel and injected into the dorsal tissue of 8-week-old male BALB/C nude mice. Histological analysis of tissue dissected from the MAC-T cell-transplanted mice after 6 weeks showed the typical morphology of the tubuloalveolar female gland, as well as glands made up of branching ducts that were surrounded by smooth muscle with small alveoli budding off the ducts. In addition, the epithelial markers CK14 and CK18 were expressed within the duct-like structure. Prolactin was detected in the duct interior in these CK14+ and CK18+ cells but not in the non-transplanted MAC-T cells.
Conclusions
These results showed that duct-like tissue had been successfully formed after 6 weeks of transplantation of the CK14+ and CK18+ MAC-T cells into mice dorsal tissue. This mouse model will be a useful tool for further research on the bovine mammary gland.
doi:10.15283/ijsc16044
PMCID: PMC5155714  PMID: 27788570
Bovine mammary gland; MAC-T cell; BALB/C nude mice; CK14; CK18; Prolactin

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