SCI 발표논문

1. 2762015

   제1저자 이동희 · 교신저자 오국환, 김중경

   Donghee Lee, Jeong Chul Kim, Eunkyoung Shin, Kyung Don Ju, Kook-Hwan Oh, Hee Chan Kim, Eungtaek Kang, Jung Kyung Kim.

   In Vivo Measurement of Site-Specific Peritoneal Solute Transport Using a Fiber-Optic-based Fluorescence Photobleaching Technique.

   J Optical Soc Korea. 2015;19(3):228-236.

   IF 1.179 신장내과
2. 2752015

   제1저자 이정훈 · 교신저자 김윤준

   Lee JH, Lee Y, Lee M, Heo MK, Song JS, Kim KH, Lee H, Yi NJ, Lee KW, Suh KS, Bae YS, Kim YJ

   A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma.

   Br J Cancer. 2015;113(12):1666-76.

   Abstract

   BACKGROUND To date, no adjuvant treatment has been shown to have a clear benefit in patients with hepatocellular carcinoma (HCC). In this prospective phase I/IIa study, we evaluated the safety and efficacy of adjuvant dendritic cell (DC) therapy in HCC patients who received primary treatment for HCC.

   METHODS Twelve HCC patients who had no viable tumour after primary treatments were included. Dendritic cell vaccines pulsed with cytoplasmic transduction peptide-attached alpha-fetoprotein, glypican-3 and melanoma-associated antigen 1 recombinant fusion proteins were injected subcutaneously near to inguinal lymph nodes. Adverse effects, time to progression (TTP), and associated immune responses were evaluated after DC vaccination.

   RESULTS Nine of 12 patients had no tumour recurrence up to 24 weeks after DC vaccination. Among a total of 144 adverse events, 129 events (89.6%) were regarded as adverse drug reactions, all of which were grade 1 or 2. The majority of patients showed enhanced anti-tumour immune responses after DC vaccination. Recurrence-free patients exhibited relatively stronger anti-tumour immune responses than patients who developed recurrence after DC vaccination, as evidenced by lymphocyte proliferation and IFN-γ ELISPOT assays. The median time of TTP was 36.6 months in the DC-vaccination group and 11.8 months in the control group (hazard ratio, 0.41; 95% confidence interval, 0.18-0.95; P=0.0031 by log-rank test).

   CONCLUSIONS Adjuvant DC vaccine for HCC was safe and well tolerated in phase I/IIa study, and preliminary efficacy data are encouraging to warrant further clinical study in patients with HCC after primary treatments.

   PubMed IF 7.8 소화기내과
3. 2742015

   제1저자 오근희 · 교신저자 박경수

   Oh K, Kim SR, Kim DK, Seo MW, Lee C, Lee HM, Oh JE, Choi EY, Lee DS, Gho YS, Park KS

   In Vivo Differentiation of Therapeutic Insulin-Producing Cells from Bone Marrow Cells via Extracellular Vesicle-Mimetic Nanovesicles.

   ACS Nano. 2015;9(12):11718-27.

   Abstract

   The current diabetes mellitus pandemic constitutes an important global health problem. Reductions in the mass and function of β-cells contribute to most of the pathophysiology underlying diabetes. Thus, physiological control of blood glucose levels can be adequately restored by replacing functioning β-cell mass. Sources of functional islets for transplantation are limited, resulting in great interest in the development of alternate sources, and recent progress regarding cell fate change via utilization of extracellular vesicles, also known as exosomes and microvesicles, is notable. Thus, this study investigated the therapeutic capacity of extracellular vesicle-mimetic nanovesicles (NVs) derived from a murine pancreatic β-cell line. To differentiate insulin-producing cells effectively, a three-dimensional in vivo microenvironment was constructed in which extracellular vesicle-mimetic NVs were applied to subcutaneous Matrigel platforms containing bone marrow (BM) cells in diabetic immunocompromised mice. Long-term control of glucose levels was achieved over 60 days, and differentiation of donor BM cells into insulin-producing cells in the subcutaneous Matrigel platforms, which were composed of islet-like cell clusters with extensive capillary networks, was confirmed along with the expression of key pancreatic β-cell markers. The resectioning of the subcutaneous Matrigel platforms caused a rebound in blood glucose levels and confirmed the source of functioning β-cells. Thus, efficient differentiation of therapeutic insulin-producing cells was attained in vivo through the use of extracellular vesicle-mimetic NVs, which maintained physiological glucose levels.

   PubMed IF 17.3 내분비대사내과
4. 2732015

   제1저자 조남한 · 교신저자 임수

   Cho NH, Oh TJ, Kim KM, Choi SH, Lee JH, Park KS, Jang HC, Kim JY, Lee HK, Lim S

   Neck Circumference and Incidence of Diabetes Mellitus over 10 Years in the Korean Genome and Epidemiology Study (KoGES).

   Sci Rep. 2015;5:18565.

   Abstract

   Neck circumference, a proxy for upper-body fat, may be a unique fat depot that indicates metabolic risk beyond whole body fat. We investigated whether neck circumference is associated with development of diabetes mellitus (DM) in a subset of data with Korean Genome and Epidemiology Study (n = 3521, age range = 42-71 years). Nondiabetic subjects at the baseline were categorized into 4 groups (Q1-Q4) according to their neck circumference. Parameters related with β-cell function and insulin resistance including Epworth sleepiness scale and snoring habit were examined. The development of DM was confirmed biannually based on a 75-g oral glucose tolerance test. Over the 10 years, 2623 (74.5%) among 3521 subjects were followed-up. Among them, 632 (24.1%) developed DM. The incidence of DM increased from 17.6% in Q1 to 18.2% in Q2, to 25.4% in Q3, and to 36.0% in Q4 (P < 0.001). After adjusting for most risk factors related with DM, the relative risks of DM development were 0.989 (95% confidence interval, 0.638-1.578), 1.660 (1.025-2.687), and 1.746 (1.037-2.942) in men and 0.939 (0.540-1.769), 1.518 (0.808-2.853), and 2.077 (1.068-4.038) in women in Q2, Q3, and Q4, respectively when compared to Q1. This finding indicates negative impact from large neck circumference in the development of DM.

   PubMed IF 4.9 내분비대사내과
5. 2722015

   제1저자 이동화, 박경선 · 교신저자 임수

   Lee DH, Park KS, Ahn S, Ku EJ, Jung KY, Kim YJ, Kim KM, Moon JH, Choi SH, Park KS, Jang HC, Lim S

   Comparison of Abdominal Visceral Adipose Tissue Area Measured by Computed Tomography with That Estimated by Bioelectrical Impedance Analysis Method in Korean Subjects.

   Nutrients. 2015;7(12):10513-24.

   Abstract

   We evaluated the concordance between visceral fat area (VFA) estimated by bioelectrical impedance analysis (BIA) or computed tomography (CT) in Korean subjects with a wide range in age and body mass index (BMI). In 1006 individuals (mean age 55.2 ± 11.8 (19-87) years, mean BMI 26.0 ± 3.5 (17-46) kg/m², 48.9% men), VFA quantified by CT was compared with VFA using multifrequency BIA machines within 15 days. Concordance rates were compared by age or BMI using correlation analysis, Bland-Altman plots, and intraclass correlation coefficient (ICC). Using BIA data, we established a regression formula to reflect CT-VFA. The mean VFAs by CT and BIA were 131.9 ± 57.3 cm² and 110.5 ± 33.9 cm², respectively (r = 0.605, p < 0.001). The mean difference was 21.4 ± 45.6 cm², tending to increase with BMI. In women with BMI <25 kg/m² or age <50 years, the VFAs by BIA were similar to those by CT (ICC = 0.496 in BMI <25 kg/m² and ICC = 0.638 in age <50 years). However, the difference was greater in men with BMI ≥25 kg/m² or age ≥50 years. Applying our formula, the difference between estimations decreased to 0.2 ± 38.2cm². VFA estimated by BIA correlated well with that by CT, but a more accurate formula is needed to match CT data, particularly in older men or subjects with a high BMI.

   PubMed IF 5.8 내분비대사내과
6. 2712015

   제1저자 임수, 오태정 · 교신저자 고광곤

   Lim S, Oh TJ, Koh KK

   Mechanistic link between nonalcoholic fatty liver disease and cardiometabolic disorders.

   Int J Cardiol. 2015;201:408-14.

   Abstract

   Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low-grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue can lead to NAFLD related with insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is one of the phenotypes of insulin resistance or metabolic syndrome. Many researchers have discovered a close association between NAFLD and insulin resistance, and focused on the role of NAFLD in the development of type 2 diabetes. Further, substantial evidence has suggested the association between NAFLD and cardiovascular disease (CVD). In the current review, we provide a plausible mechanistic link between NAFLD and CVD and the potential of the former as a therapeutic target based on pathophysiology. We also discuss in detail about the role of insulin resistance, oxidative stress, low-grade inflammation, abnormal lipid metabolism, gut microbiota, changes of biomarkers, and genetic predisposition in the pathological linking between NAFLD and cardiometabolic disorders.

   PubMed IF 3.3 내분비대사내과
7. 2702015

   제1저자 김경민 · 교신저자 임수

   Kim KM, Park KS, Lee HJ, Lee YH, Bae JS, Lee YJ, Choi SH, Jang HC, Lim S

   Efficacy of a New Medical Information system, Ubiquitous Healthcare Service with Voice Inception Technique in Elderly Diabetic Patients.

   Sci Rep. 2015;5:18214.

   Abstract

   We have demonstrated previously that an individualized health management system using advanced medical information technology, named ubiquitous (u)-healthcare, was helpful in achieving better glycemic control than routine care. Recently, we generated a new u-healthcare system using a voice inception technique for elderly diabetic patients to communicate information about their glucose control, physical activity, and diet more easily. In a randomized clinical trial, 70 diabetic patients aged 60-85 years were assigned randomly to a standard care group or u-healthcare group for 6 months. The primary end points were the changes in glycated hemoglobin (HbA1c) and glucose fluctuation assessed by the mean amplitude glycemic excursion (MAGE). Changes in body weight, lifestyle, and knowledge about diabetes were also investigated. After 6 months, the HbA1c levels decreased significantly in the u-healthcare group (from 8.6 ± 1.0% to 7.5 ± 0.6%) compared with the standard care group (from 8.7 ± 0.9% to 8.2 ± 1.1%, P < 0.01). The MAGE decreased more in the u-healthcare group than in the standard care group. Systolic blood pressure and body weight decreased and liver functions improved in the u-healthcare group, but not in the standard care group. The u-healthcare system with voice inception technique was effective in achieving glycemic control without hypoglycemia in elderly diabetic patients (Clinicaltrials.gov: NCT01891474).

   PubMed IF 4.9 내분비대사내과
8. 2692015

   제1저자 조선욱 · 교신저자 박영주

   Cho SW, Bae JH, Noh GW, Kim YA, Moon MK, Park KU, Song J, Yi KH, Park do J, Chung JK, Cho BY, Park YJ

   The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves' Disease.

   PLoS One. 2015;10(12):e0144599.

   Abstract

   Osteoporosis-related fractures are one of the complications of Graves' disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves' disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves' disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10). From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII) to the blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves' disease.

   PubMed IF 2.8 내분비대사내과
9. 2682015

   제1저자 김현숙 · 교신저자 안규리

   Kim H, Park HC, Ryu H, Kim K, Kim HS, Oh KH, Yu SJ, Chung JW, Cho JY, Kim SH, Cheong HI, Lee K, Park JH, Pei Y, Hwang YH, Ahn C

   Clinical Correlates of Mass Effect in Autosomal Dominant Polycystic Kidney Disease.

   PLoS One. 2015;10(12):e0144526.

   Abstract

   Mass effect from polycystic kidney and liver enlargement can result in significant clinical complications and symptoms in autosomal dominant polycystic kidney disease (ADPKD). In this single-center study, we examined the correlation of height-adjusted total liver volume (htTLV) and total kidney volume (htTKV) by CT imaging with hepatic complications (n = 461) and abdominal symptoms (n = 253) in patients with ADPKD. "Mass-effect" complications were assessed by review of medical records and abdominal symptoms, by a standardized research questionnaire. Overall, 91.8% of patients had 4 or more liver cysts on CT scans. Polycystic liver disease (PLD) was classified as none or mild (htTLV < 1,600 mL/m); moderate (1,600 ≤ htTLV <3,200 mL/m); and severe (htTLV ≥ 3,200 mL/m). The prevalence of moderate and severe PLD in our patient cohort was 11.7% (n = 54/461) and 4.8% (n = 22/461), respectively, with a female predominance in both the moderate (61.1%) and severe (95.5%) PLD groups. Pressure-related complications such as leg edema (20.4%), ascites (16.6%), and hernia (3.6%) were common, and patients with moderate to severe PLD exhibited a 6-fold increased risk (compared to no or mild PLD) for these complications in multivariate analysis. Similarly, abdominal symptoms including back pain (58.8%), flank pain (53.1%), abdominal fullness (46.5%), and dyspnea/chest-discomfort (44.3%) were very common, and patients with moderate to severe PLD exhibited a 5-fold increased risk for these symptoms. Moderate to severe PLD is a common and clinically important problem in ~16% of patients with ADPKD who may benefit from referral to specialized centers for further management.

   PubMed IF 2.8 신장내과
10. 2672015

    제1저자 전희중 · 교신저자 이정표

    Jeon HJ, Kim CT, An JN, Lee H, Kim H, Park SK, Joo KW, Lim CS, Jung IM, Ahn C, Kim YS, Kim YH, Lee JP

    Time-varying maximal proteinuria correlates with adverse cardiovascular events and graft failure in kidney transplant recipients.

    Nephrology (Carlton). 2015;20(12):945-51.

    Abstract

    AIM In the general population, proteinuria is associated with progression to kidney failure, cardiovascular disease, and mortality. Here, we analyzed the effects of proteinuria on outcomes in kidney transplant recipients.

    METHODS We performed a retrospective, multi-centre cohort study involving 2047 recipients to evaluate the effects of post-transplant proteinuria on adverse cardiovascular events, graft failure, and mortality. Patients were classified into two groups according to their levels of proteinuria: patients without proteinuria (<150 mg/day, n = 1113) and proteinuric patients (≥ 150 mg/day, n = 934). Multivariate Cox hazard model was conducted with using the maximal proteinuria as time-varying covariate.

    RESULTS During a median 55.3-month (range, 0.6-167.1) follow-up, there were 50 cases of major adverse cardiac events (cardiac death, nonfatal myocardial infarction, or coronary revascularization), 115 cases of graft failure, and 52 patient deaths. In multivariate Cox regression with time-varying covariate, proteinuric recipients were significantly associated with major adverse cardiac events (hazard ratio [HR] 8.689, 95% confidence interval [CI] 2.929-25.774, P < 0.001) compared to those without proteinuria. Recipients with proteinuria showed significantly higher incidences of acute rejection (23.1% vs. 9.4%, P < 0.001) and graft failure rate (HR 6.910, 95% CI 3.270-14.601, P < 0.001). In addition, mortality rate was also significantly higher in patients with proteinuria (HR 6.815, 95% CI 2.164-21.467, P = 0.001).

    CONCLUSION Post-transplant proteinuria correlates with adverse cardiovascular events, graft failure, and mortality. Therefore, proteinuria should be evaluated and managed to improve the outcomes of renal recipients.

    PubMed IF 2 신장내과
11. 2662015

    제1저자 최연정, 고성준 · 교신저자 김지원

    Choi Y, Koh SJ, Lee HS, Kim JW, Gwan Kim B, Lee KL, Kim JS

    Roxithromycin inhibits nuclear factor kappaB signaling and endoplasmic reticulum stress in intestinal epithelial cells and ameliorates experimental colitis in mice.

    Exp Biol Med (Maywood). 2015;240(12):1664-71.

    Abstract

    Roxithromycin is known to have anti-inflammatory and immunoregulatory activity. However, little information is available on the effect of roxithromycin in intestinal inflammation. The aim of this study was to investigate the effect of roxithromycin on NF- κB signaling and ER stress in intestinal epithelial cells (IECs) and the effect of roxithromycin on dextran sulfate sodium (DSS)-induced acute colitis in a murine model. HCT116 cells and COLO205 cells were pretreated with roxithromycin and then stimulated with tumor necrosis factor-α (TNF-α). Interleukin (IL)-8 expression was determined by real-time reverse transcription-polymerase chain reaction. Nuclear factor kappaB (NF-κB) DNA-binding activity and IκB phosphorylation/degradation were evaluated by electrophoretic mobility shift assay and Western blot analysis. The molecular markers of endoplasmic reticulum stress, including p-JNK, phosphorylated eukaryotic initiation factor 2 (p-eIF2α), C/EBP homologous protein (CHOP), and X-box binding protein 1 (XBP1) were evaluated using western blotting and PCR. Mice were given 4% DSS for five days with or without roxithromycin. Primary IECs were isolated from mice with DSS-induced colitis. Roxithromycin significantly inhibited the upregulated expression of IL-8. Pretreatment with roxithromycin markedly attenuated NF-κB DNA-binding activity and IκB phosphorylation/degradation. CHOP and XBP1 mRNA expression were enhanced in the presence of TNF-α, and it was dampened by pretreatment of roxithromycin. c-Jun-N-terminal kinase (JNK) phosphorylation and the level of p-eIF2α were also downregulated by the pretreatment of roxithromycin. Roxithromycin significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histology. In addition, the DSS-induced phospho-IκB kinase activation was significantly decreased in roxithromycin-pretreated mice. Finally, IκB degradation was reduced in primary IECs from mice treated with roxithromycin. These results suggest that roxithromycin may have potential usefulness in the treatment of inflammatory bowel disease.

    PubMed IF 3.8 소화기내과
12. 2652015

    제1저자 유정주 · 교신저자 김윤준

    Yoo JJ, Cho EJ, Cho YY, Lee M, Lee DH, Cho Y, Lee JH, Yu SJ, Yoon SS, Yoon JH, Kim YJ

    Efficacy of antiviral prophylaxis in HBsAg-negative, anti-HBc positive patients undergoing hematopoietic stem cell transplantation.

    Liver Int. 2015;35(12):2530-6.

    Abstract

    BACKGROUND & AIMS Hepatitis B virus (HBV) reactivation can occur in persons who are hepatitis B surface antigen (HBsAg)-negative but hepatitis B core antibody (anti-HBc) positive, especially following hematopoietic stem cell transplantation (HSCT). However, evidence supporting the routine use of prophylactic antiviral agents for such patients is scarce. The aim of this study was to compare the frequency of HBV reactivation between prophylactic and non-prophylactic groups in patients who underwent HSCT.

    METHODS This retrospective cohort study included 315 HBsAg-negative, anti-HBc positive patients who received autologous or allogenic stem cell transplantation from January 2008 to December 2013. Patients were categorized into prophylactic and non-prophylactic groups. The primary endpoint was the incidence of HBV reactivation.

    RESULTS Median follow-up duration was 21.4 months. Antiviral prophylaxis was not given to 219 patients, and 96 received prophylaxis. The median duration of prophylaxis was 7.0 months. HBV reactivated in 12 patients (prophylactic group, 4; non-prophylactic group, 8). The median time to reactivation was 20.5 months after starting chemotherapy. All patients who reactivated were promptly and successfully treated with rescue antiviral agents. The risk of reactivation did not differ between prophylactic and non-prophylactic groups (P = 0.061) but was increased significantly by the allogenic type of HSCT and the loss of recipient's antibodies against HBsAg (anti-HBs).

    CONCLUSIONS Short-term antiviral prophylaxis appears insufficient to decrease the risk of HBV reactivation. Therefore, either prophylaxis longer than 24 months or careful monitoring of HBV DNA combined with on-demand antiviral treatment may prove more effective than the routine short-term prophylaxis given to these patients.

    PubMed IF 6.2 소화기내과
13. 2642015

    제1저자 김태민, 송안아 · 교신저자 김동완

    Kim TM, Song A, Kim DW, Kim S, Ahn YO, Keam B, Jeon YK, Lee SH, Chung DH, Heo DS

    Mechanisms of Acquired Resistance to AZD9291: A Mutation-Selective, Irreversible EGFR Inhibitor.

    J Thorac Oncol. 2015;10(12):1736-44.

    Abstract

    INTRODUCTION AZD9291, a third-generation and mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is active against patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who failed prior treatment with EGFR TKIs. However, acquired resistance to AZD9291 is inevitable. In this study, we identified the mechanisms of acquired resistance to AZD9291 in EGFR-mutant NSCLC.

    METHODS Four NSCLC patients with both an EGFR exon 19 deletion and the EGFR mutation after developing acquired resistance to first-generation EGFR TKIs received AZD9291 at doses of 20 to 80 mg/day in a phase I trial (NCT01802632). Paired tumor samples before and after treatment were obtained to evaluate EGFR modifications, alternative pathway activation, and histologic transformation. Genetic alterations were analyzed using Sanger sequencing, fluorescence in situ hybridization, real-time polymerase chain reaction, and targeted exome sequencing.

    RESULTS All four patients achieved a partial response (median duration of response, 9 months [range, 9-11 months]) and subsequently showed resistance to AZD9291. EGFR-mutant clones depopulated AZD9291-resistant tumors to below 1% (baseline, 14%-36%) in three patients with progression: one with the loss of EGFR-double mutant clones and two accompanied by transformation to small-cell carcinoma and focal fibroblast growth factor receptor 1 (FGFR1) amplification, respectively. EGFR-mutant clones remained and the EGFR ligand was overexpressed in one patient with focal progression to AZD9291.

    CONCLUSION Acquired resistance mechanisms of AZD9291 in patients with EGFR-mutant NSCLC who failed treatment with first-generation EGFR TKIs include the loss of EGFR-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand-dependent activation.

    PubMed IF 23.3 혈액종양내과
14. 2632015

    제1저자 김영효 · 교신저자 신형두, 윤성수

    Hyo Kim L, Sub Cheong H, Koh Y, Ahn KS, Lee C, Kim HL, Doo Shin H, Yoon SS

    Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML.

    J Hum Genet. 2015;60(12):749-54.

    Abstract

    The cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of the cytarabine (AraC) into a 1-β-D-arabinofuranosyluracil (AraU), an inactive metabolite that plays a crucial role in lowering the amount of AraC, a key chemotherapeutic drug, in the treatment of patients with acute myeloid leukemia (AML). In this study, we hypothesized that CDA polymorphisms were associated with the AraC metabolism for AML treatment and/or related clinical phenotypes. We analyzed 16 polymorphisms of CDA among 50 normal karyotype AML (NK-AML) patients, 45 abnormal karyotype AML (AK-AML) patients and 241 normal controls (NC). Several polymorphisms and haplotypes, rs532545, rs2072671, rs471760, rs4655226, rs818194 and CDA-ht3, were found to have a strong correlation with NK-AML compared with NC and these polymorphisms also revealed strong linkage disequilibrium with each other. Among them, rs2072671 (79A>C), which is located in a coding region and the resultant amino acid change K27Q, showed significant associations with NK-AML compared with NC (P=0.009 and odds ratio=2.44 in the dominant model). The AC and CC genotypes of rs2072671 (79A>C) were significantly correlated with shorter overall survival rates (P=0.03, hazard ratio=1.84) and first complete remission duration (P=0.007, hazard ratio=3.24) compared with the AA genotype in the NK-AML patients. Our results indicate that rs2072671 in CDA may be an important prognostic marker in NK-AML patients.

    PubMed IF 2.3 혈액종양내과
15. 2622015

    제1저자 강시혁, 박진주 · 교신저자 최동주

    Kang SH, Park JJ, Choi DJ, Yoon CH, Oh IY, Kang SM, Yoo BS, Jeon ES, Kim JJ, Cho MC, Chae SC, Ryu KH, Oh BH, KorHF Registry

    Prognostic value of NT-proBNP in heart failure with preserved versus reduced EF.

    Heart. 2015;101(23):1881-8.

    Abstract

    OBJECTIVE Plasma level of N-terminal-pro-brain natriuretic peptide (NT-proBNP) is a reliable prognostic factor in patients with heart failure (HF). However, it is unclear how differently the biomarker predicts adverse outcomes in HF with preserved EF (HFpEF) versus HF with reduced EF (HFrEF).

    METHODS From the Korean Heart Failure registry, a prospective multicentre cohort for consecutive patients who were hospitalised for acute HF syndrome, those with available NT-proBNP and LVEF measurements were extracted. Patients with LVEF ≥50% were categorised as the HFpEF group (N=528) and those with ≤40% as the HFrEF group (N=1142).

    RESULTS Patients with HFpEF had significantly lower NT-proBNP level than those with HFrEF (median 2723 vs 5644 ng/L, p<0.001). Event-free survival did not differ between the two groups either in terms of death from any cause (88.4% vs 86.9%; p=0.471) or the composite of death or HF readmission at 1 year (73.8% vs 70.6%; p=0.225). High levels of NT-proBNP were significantly associated with poor outcomes. However, the relationship was not different among the HFpEF and HFrEF groups (interaction p=0.956 for all-cause death; p=0.351 for the composite of all-cause death or HF hospitalisation).

    CONCLUSIONS Plasma level of NT-proBNP is the most powerful prognostic factor in both HFpEF and HFrEF. Although patients with HFpEF have lower NT-proBNP levels, the prognosis of a patient with HFpEF expected from a given NT-proBNP level is similar with his/her counterpart with HFrEF.

    PubMed IF 4.4 순환기내과
16. 2612015

    제1저자 김유정 · 교신저자 Lois Ramondetta

    Kim YJ, Munsell MF, Park JC, Meyer LA, Sun CC, Brown AJ, Bodurka DC, Williams JL, Chase DM, Bruera E, Ramondetta LM

    Retrospective review of symptoms and palliative care interventions in women with advanced cervical cancer.

    Gynecol Oncol. 2015;139(3):553-8.

    Abstract

    OBJECTIVE The objective of this study was to delineate and measure the symptom distress experienced by patients with advanced cervical cancer at the time of palliative care (PC) referral.

    METHODS A total of 156 patients with advanced cervical cancer were referred to PC from 2010 to 2012. Of these, 88 patients had completed the Edmonton Symptom Assessment System (ESAS) and were included in the analysis.

    RESULTS The mean age was 45years (25-76), 47% were white, 18% were African American, and 33% were Hispanic. Fifty-one percent were married, 64% had no advance directives, and 75% had recurrent disease. Clinically significant symptoms recorded by patient reported outcome measurement (defined as ESAS scores ≥4) were pain (81%), anorexia (72%), a poor feeling of well-being (70%), fatigue (69%), and insomnia (54%). The chief complaint recorded for the visit was pain in 94% of patients. According to the PC specialists' assessment, pain (96%), emotional distress (77%), and constipation (50%) were predominant symptoms. Various PC interventions including opioids, laxatives, and expressive supportive counseling were provided. Clinically significant symptoms including nausea, depression, anxiety, and feeling of well-being were significantly improved at follow-up visits.

    CONCLUSION More than half of patients with advanced cervical cancer were significantly burdened with pain, anorexia, a poor feeling of well-being, fatigue, insomnia, and constipation at the time of PC referral. This research is an integral step towards developing a standardized tool for assessing symptoms in women diagnosed with cervical cancer and thus maximizing effectiveness of patient centered care.

    PubMed IF 4.5 혈액종양내과
17. 2602015

    제1저자 장현 · 교신저자 김나영

    Chang H, Kim N, Park JH, Nam RH, Choi YJ, Park SM, Choi YJ, Yoon H, Shin CM, Lee DH

    Helicobacter pylori Might Induce TGF-β1-Mediated EMT by Means of cagE.

    Helicobacter. 2015;20(6):438-48.

    Abstract

    BACKGROUND Epithelial-mesenchymal transition (EMT), in which polarized epithelial cells have mesenchymal cell phenotypes, is thought to be a key process of invasion and metastasis of cancer. Transforming growth factor beta-1 (TGF-β1) is known to be carcinogenic and Helicobacter pylori is a predominant carcinogen of gastric cancer. Our study aimed to determine whether TGF-β1 or H. pylori infection enhances EMT process and cytotoxin-associated gene E (CagE) is associated with EMT.

    MATERIALS AND METHODS Human gastric cancer cell AGS and MKN45 were treated with recombinant TGF-β1 or H. pylori including cagE-negative (ΔcagE) mutant. Besides the assessment of EMT-related markers expression levels by means of RT-qPCR, Western blot, and immunofluorescence assay, the induction of in vitro EMT on gastric cancer cells (AGS and MKN cell lines) was confirmed by wound-healing assay and invasion assay.

    RESULTS When gastric cancer cells were treated with TGF-β1 or various strains of cagE-positive H. pylori, EMT-related marker altered significantly. However, the ΔcagE mutant did not. Wound-healing assay and invasion assay showed enhanced migration ability of the cells treated with cagE-positive H. pylori but not in ΔcagE mutant.

    CONCLUSIONS EMT induction in gastric cancer cells by TGF-β1 was confirmed. Only infection with cagE-positive H. pylori upregulated the TGF-β1-mediated EMT pathway and consequently promotes EMT. Therefore, H. pylori might induce TGF-β1-mediated EMT associated with the cagE.

    PubMed IF 4.6 소화기내과
18. 2592015

    제1저자 박완범 · 교신저자 오명돈

    Park WB, Perera RA, Choe PG, Lau EH, Choi SJ, Chun JY, Oh HS, Song KH, Bang JH, Kim ES, Kim HB, Park SW, Kim NJ, Man Poon LL, Peiris M, Oh MD

    Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea.

    Emerg Infect Dis. 2015;21(12):2186-9.

    Abstract

    We investigated the kinetics of serologic responses to Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using virus neutralization and MERS-CoV S1 IgG ELISA tests. In most patients, robust antibody responses developed by the third week of illness. Delayed antibody responses with the neutralization test were associated with more severe disease.

    PubMed IF 7.9 감염내과
19. 2582015

    제1저자 안지현 · 교신저자 박영주, 임석아

    An JH, Hwangbo Y, Ahn HY, Keam B, Lee KE, Han W, Park DJ, Park IA, Noh DY, Youn YK, Cho BY, Im SA, Park YJ

    A Possible Association Between Thyroid Cancer and Breast Cancer.

    Thyroid. 2015;25(12):1330-8.

    Abstract

    BACKGROUND Several lines of evidence suggest that breast cancer (BC) and thyroid cancer (TC) occur together in the same female patients more frequently than would be expected by chance. This study investigated the prevalence and clinicopathological characteristics of second primary BC in TC patients and second primary TC in BC patients.

    METHODS A retrospective case-controlled study was performed in 4243 patients with differentiated TC and 6833 patients with BC. Age-matched control groups without second malignancies were selected.

    RESULTS Of the 4243 patients with TC, 55 patients developed subsequent BC during a five-year follow-up (range 2-40 years); the standardized incidence ratio (SIR) was 2.45 [confidence interval (CI) 1.83-2.96]. Among the 6833 patients with BC, 81 patients developed subsequent TC during a 6.2-year follow-up (range 2-40 years); the SIR was 2.18 [CI 1.43-2.82]. Subsequent second BC or TC diagnosed within five years of the initial primary malignancy showed more clinical characteristics consistent with early-stage cancer than did control BC or TC patients. Notably, the expression of both the estrogen and progesterone receptors was significantly higher in the tissues of BC patients with coexisting TC compared with those with BC alone.

    CONCLUSIONS The overall risk of second primary TC or BC is increased in patients with prior BC or TC, respectively. The early detection of second cancer might have contributed to these findings. However, BC that coexisted with TC had a higher expression of hormone receptors, suggesting an association between the molecular pathogenesis of TC and BC.

    PubMed IF 6.6 내분비대사내과
20. 2572015

    제1저자 임주현 · 교신저자 김상균

    Lim JH, Kim SG, Choi J, Im JP, Kim JS, Jung HC

    Risk factors of delayed ulcer healing after gastric endoscopic submucosal dissection.

    Surg Endosc. 2015;29(12):3666-73.

    Abstract

    BACKGROUND Although post-endoscopic submucosal dissection (ESD) iatrogenic ulcer is known to heal faster than peptic ulcer, some iatrogenic ulcers show delayed healing. The aim of this study was to clarify risk factors of delayed ulcer healing after gastric ESD.

    METHODS We retrospectively reviewed medical records of all patients who had ESD for gastric neoplasms (866 adenomas and 814 early gastric cancers) between January 2005 and February 2011.

    RESULTS Of 1680 subjects, 95 had delayed ulcer healing in 3-month follow-up. Multivariate analysis showed that diabetes (OR 1.743; 95% CI 1.017-2.989, p = 0.043), coagulation abnormality (OR 3.195; 95% CI 1.535-6.650, p = 0.002), specimen size greater than 4 cm (OR 2.999; 95% CI 1.603-5.611, p = 0.001), and electrocoagulation (OR 7.149; 95% CI 1.738-29.411, p = 0.006) were revealed to be independent risk factors of delayed ulcer healing. Meanwhile, persistent Helicobacter pylori infection was not related to the delayed ulcer healing.

    CONCLUSIONS Large iatrogenic ulcer by ESD with massive hemostasis, especially in patients with diabetes mellitus or coagulation abnormalities, tends to take more than 3 months to heal. For such cases, initial dosage increment of PPI or addition of other anti-ulcer agents after ESD may be beneficial.

    PubMed IF 3.3 소화기내과
21. 2562015

    제1저자 강현재 · 교신저자 Roe T. Matthew

    Kang HJ, Simon D, Wang TY, Alexander KP, Jeong MH, Kim HS, Bates ER, Henry TD, Peterson ED, Roe MT, National Cardiovascular Data Registry

    The Contemporary Use of Angiography and Revascularization Among Patients With Non-ST-Segment Elevation Myocardial Infarction in the United States Compared With South Korea.

    Clin Cardiol. 2015;38(12):708-14.

    Abstract

    BACKGROUND Practice guidelines recommend an early invasive strategy for high-risk non-ST-segment elevation myocardial infarction (NSTEMI) patients, but international differences in the use of invasive strategies are unknown.

    HYPOTHESIS Profiling NSTEMI patient management in the United States (U.S.) and South Korea could provide insight into how patients are triaged for an early invasive strategy in different health care environments and geographical regions.

    METHODS We evaluated the use of angiography and revascularization for NSTEMI patients treated at revascularization-capable hospitals (2007-2010) in both the ACTION Registry-GWTG (U.S.: n = 133,835; 433 hospitals) and KAMIR/KorMI Registry (South Korea: n = 7,901; 72 hospitals).

    RESULTS Compared with South Korean patients, U.S. NSTEMI patients more commonly had established cardiovascular risk factors, disease, and prior cardiovascular events and procedures. From 2007-2010, the use of angiography for NSTEMI patients rose steadily in both countries, but the use of revascularization only rose in South Korea. Patients from South Korea more commonly underwent angiography and revascularization. Percutaneous coronary intervention was the most common type of revascularization in both countries, but coronary artery bypass grafting was less common in South Korea. The use of both angiography and revascularization was incrementally lower with a higher predicted mortality risk for patients from both countries, but greater differences between low- and high-risk patients occurred in the U.S.

    CONCLUSIONS The profile, characteristics, and use of angiography and revascularization for NSTEMI patients in the U.S. vs South Korea differed substantially from 2007-2010, underscoring the heterogeneity of NSTEMI patients and treatment selection among different countries.

    PubMed IF 2.8 순환기내과
22. 2552015

    제1저자 송경호 · 교신저자 김홍빈

    Song KH, Kim HB, Kim HS, Lee MJ, Jung Y, Kim G, Hwang JH, Kim NH, Kim M, Kim CJ, Choe PG, Chung JY, Park WB, Kim ES, Park KU, Kim NJ, Kim EC, Oh MD

    Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia.

    Int J Antimicrob Agents. 2015;46(6):689-95.

    Abstract

    There have been few clinical studies on the association between the vancomycin 24-h area under the concentration-time curve (AUC24) to minimum inhibitory concentration (MIC) ratio and vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus (MRSA) infections. To examine this association and to establish a suitable cut-off value for AUC24/MIC, a multicentre prospective observational study was conducted in patients with MRSA bacteraemia. Data were collected on all patients aged ≥18 years with MRSA bacteraemia treated with vancomycin for ≥72 h without dialysis. The MIC was determined by broth microdilution (BMD) and Etest. Treatment failure was defined as (i) 30-day mortality, (ii) persistent bacteraemia (≥7 days) and (iii) recurrence (≤30 days after completion of therapy). AUC24 was estimated by a Bayesian approach based on individual vancomycin concentrations. The AUC24/MIC cut-off value for differentiating treatment success and failure was calculated by Classification and Regression Tree (CART) analysis. In total, 117 patients were enrolled, among which vancomycin treatment failure occurred in 38 (32.5%). In univariate analysis, high vancomycin MIC and low trough levels were unrelated to treatment outcomes. In the CART analysis, low vancomycin AUC24/MIC [<392.7 (BMD) and <397.2 (Etest)] was associated with treatment failure. In multivariate analysis, low AUC24/MIC was a risk factor for treatment failure [adjusted odds ratio (aOR)=3.50, 95% confidence interval (CI) 1.39-8.82 by BMD; aOR=5.61, 95% CI 2.07-15.24 by Etest]. AUC24/MIC is associated with vancomycin treatment outcomes in MRSA bacteraemia, and seeking individualised AUC24/MIC ratios above target (>400) may improve treatment outcomes.

    PubMed IF 5 감염내과
23. 2542015

    제1저자 이정원 · 교신저자 김나영

    Lee JW, Kim N, Nam RH, Kim JM, Park JY, Lee SM, Kim JS, Lee DH, Jung HC

    High Efficacy of Finafloxacin on Helicobacter pylori Isolates at pH 5.0 Compared with That of Other Fluoroquinolones.

    Antimicrob Agents Chemother. 2015;59(12):7629-36.

    Abstract

    Finafloxacin is a novel fluoroquinolone with improved antimicrobial efficacy, especially in an acidic environment. The efficacy of finafloxacin for the inhibition of Helicobacter pylori infection was compared with the efficacies of levofloxacin and moxifloxacin at neutral and acidic pH. The impacts of gyrA point mutation on the efficacy of those three fluoroquinolones were also investigated. A total of 128 clinical H. pylori strains were utilized. MICs of levofloxacin, moxifloxacin, and finafloxacin were determined at pH 5.0 and pH 7.0 by the agar dilution method. The impact of gyrA point mutations that are responsible for fluoroquinolone resistance was analyzed; the results showed 50 strains with an Asn-87 point mutation, 48 strains with an Asp-91 point mutation, and the remaining 30 strains with no gyrA mutations. The use of finafloxacin led to MIC values at pH 5.0 that were lower than the values seen at pH 7.0 for 112 strains (112/128, 87.5%), and this proportion was higher than that seen with moxifloxacin (21/128, 16.4%, P < 0.001). Finafloxacin also demonstrated a rate of susceptibility (MIC, <1 μg/ml) (37.5%, 48/128) at pH 5.0 that was higher than that seen with moxifloxacin (2.3%, 3/128) (P < 0.001). The trends were similar regardless of which of the Asn-87, Asp-91, and A2143 point mutations were present. In conclusion, the superior antimicrobial efficacy of finafloxacin against H. pylori in an acidic environment suggests the possible use of finafloxacin for treatment of H. pylori infection, as has been proposed by its developer, Merlion Pharma.

    PubMed IF 4.2 소화기내과
24. 2532015

    제1저자 김지원 · 교신저자 박완범, 김인호

    Kim JW, Min CK, Mun YC, Park Y, Kim BS, Nam SH, Koh Y, Kwon JH, Choe PG, Park WB, Kim I

    Varicella-zoster virus-specific cell-mediated immunity and herpes zoster development in multiple myeloma patients receiving bortezomib- or thalidomide-based chemotherapy.

    J Clin Virol. 2015;73:64-69.

    Abstract

    BACKGROUND The incidence of herpes zoster is substantial during bortezomib treatment in patients with multiple myeloma (MM).

    OBJECTIVES This study aimed to elucidate the effect of chemotherapy with or without bortezomib in MM patients on their herpes zoster incidence and varicella zoster virus (VZV)-specific cell-mediated immunity (CMI).

    STUDY DESIGN Peripheral blood mononuclear cells were collected at baseline and after 1 month of bortezomib-based or thalidomide-based chemotherapy and then analyzed using VZV-specific interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. The clinical data from these patients were analyzed in relation to the ELISPOT results.

    RESULTS Of 58 patients analyzed, 39 patients received bortezomib and the other 19 patients, thalidomide. Among them, 5 patients developed herpes zoster during chemotherapy; all 5 were being treated with the bortezomib-based regimen and were not receiving prophylactic anti-viral agents. The median onset of herpes zoster was 32 days (range, 15-95 days) from the initiation of chemotherapy. Among patients who received bortezomib therapy, acyclovir prophylaxis significantly reduced the risk for herpes zoster (100-day cumulative incidence, 0% vs. 49.5%; p<0.001). Spot-forming cell (SFC) counts in the IFN-γ ELISPOT assay decreased from baseline after bortezomib (p=0.011) or thalidomide (p=0.096) treatment. Patients with baseline SFCs greater than 20/10(6) mononuclear cells exhibited significantly higher incidence of herpes zoster (100-day cumulative incidence, 34.8% vs. 0%; p=0.040).

    CONCLUSIONS Bortezomib treatment significantly reduced VZV-specific CMI, and high baseline SFC counts in patients receiving this treatment without acyclovir prophylaxis were associated with a significantly increased risk for herpes zoster.

    PubMed IF 3.7 혈액종양내과
25. 2522015

    제1저자 이사민 · 교신저자 이승표

    Lee S, Lee SP, Park EA, Hong MK, Kim JH, Kim HK, Lee W, Kim YJ, Sohn DW

    Real-Time 3D TEE for Diagnosis of Subvalvular Pannus Formation in Mechanical Aortic Valves: Comparison With Multidetector CT and Surgical Findings.

    JACC Cardiovasc Imaging. 2015;8(12):1461-1464.

    PubMed IF 19 순환기내과
26. 2512015

    제1저자 박성열, 고재문 · 교신저자 김동완, 전윤경

    Park S, Koh J, Kim DW, Kim M, Keam B, Kim TM, Jeon YK, Chung DH, Heo DS

    MET amplification, protein expression, and mutations in pulmonary adenocarcinoma.

    Lung Cancer. 2015;90(3):381-7.

    Abstract

    OBJECTIVES MET amplification, protein expression, and splice mutations at exon 14 are known to cause dysregulation of the MET/HGF pathway. Our study aimed to confirm the relationship among MET amplification, protein expression, and mutations in pulmonary adenocarcinoma.

    MATERIALS AND METHODS MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH) were evaluated in 316 surgically resected lung adenocarcinomas. Patients were divided into 4 groups (IHC-negative/FISH-negative, IHC-negative/FISH-positive, IHC-positive/FISH-negative, and IHC-positive/FISH-positive), and 15-20 tumors in each group were randomly selected for mutation analyses to find splice mutations at exon 14.

    RESULTS An IHC score of 0-3 was found in 168 (53.2%), 71 (22.5%), 59 (18.7%), and 18 (5.7%) tumors, respectively. The mean gene copy number (GCN) was 3.56; MET FISH positivity was detected in 123 (38.9%) samples, and 26 (8.2%) of them were gene amplifications. MET amplification were significantly associated with the IHC score (P<0.001, χ(2) test). Splice mutations were identified in only 2 (2.9%) of 70 cases. One had a MET IHC score of 2 and negative FISH without amplification; The other had a MET IHC score of 0 and positive FISH without amplification. MET IHC or FISH results were not prognostic indicators of overall survival in multivariate analysis.

    CONCLUSION There is a significant relationship between MET amplification and protein expression, and selection of tumors with amplification using IHC was effective. However, because of its rarity, a selection strategy for mutated tumors is implausible using IHC or FISH.

    PubMed IF 5.3 혈액종양내과
27. 2502015

    제1저자 이윤석 · 교신저자 황진혁

    Lee YS, Kim H, Kim HW, Lee JC, Paik KH, Kang J, Kim J, Yoon YS, Han HS, Sohn I, Cho J, Hwang JH

    High Expression of MicroRNA-196a Indicates Poor Prognosis in Resected Pancreatic Neuroendocrine Tumor.

    Medicine (Baltimore). 2015;94(50):e2224.

    Abstract

    There is limited data on miRNA expression in pancreatic neuroendocrine tumors (PanNETs). In this study, we aimed to identify miRNAs that could be potential prognostic biomarkers of PanNETs in patients who underwent curative surgery. For miRNA target screening, 2 primary PanNETs and corresponding liver metastases were screened for miRNA expression by the NanoString nCounter analysis. Candidate miRNAs were selected by ≥2-fold difference of expression between metastatic versus primary tumor. For miRNA target validation, quantitative real-time PCR was performed for candidate miRNAs on 37 PanNETs and matched nonneoplastic pancreata, and the miRNA levels were correlated with the clinicopathological features and patient survival data. Eight miRNAs (miRNA-27b, -122, -142-5p, -196a, -223, -590-5p, -630, and -944) were selected as candidate miRNAs. Only miR-196a level was significantly associated with stage, and mitotic count. When PanNETs were stratified into high (n = 10) and low (n = 27) miRNA-196a expression groups, miRNA-196a-high PanNETs were significantly associated with advanced pathologic T stage (50.0% vs 7.4%), N stage (50.0% vs 3.7%), higher mitotic counts (60.0% vs 3.7%), and higher Ki-67-labeling indices (60.0% vs 22.2%). In addition, high miRNA-196a expression was significantly associated with decreased overall survival (P = 0.046) and disease-free survival (P < 0.001) during a median follow-up of 37.9 months with the hazard ratio for recurrence of 16.267 (95% confidence interval = 1.732-153.789; P = 0.015). MiRNA-196a level may be a promising prognostic marker of recurrence in resected PanNETs, although further experimental investigation would be required.

    PubMed IF 2 소화기내과
28. 2492015

    제1저자 오세진 · 교신저자 김동완, 김태우

    Oh SJ, Noh KH, Lee YH, Hong SO, Song KH, Lee HJ, Kim S, Kim TM, Jeon JH, Seo JH, Kim DW, Kim TW

    Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

    Oncotarget. 2015;6(37):40255-67.

    Abstract

    The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.

    PubMed IF 6.359 혈액종양내과
29. 2482015

    제1저자 이경희 · 교신저자 유철규

    Lee KH, Lee CH, Jeong J, Jang AH, Yoo CG

    Neutrophil Elastase Differentially Regulates Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF) Production by Cigarette Smoke Extract.

    J Biol Chem. 2015;290(47):28438-28445.

    Abstract

    Inflammation by IL-8-induced neutrophil recruitment and apoptosis of epithelial cells by decreased expression of VEGF have been suggested as one of the complicated pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). The role of neutrophil elastase (NE) in the development of COPD is also well known. However, little is known about how they interact. The objective of this study was to elucidate the effect of NE on cigarette smoke extract (CSE)-induced IL-8 and VEGF production and its molecular mechanism in bronchial epithelial cells. CSE increased both IL-8 and VEGF production in human bronchial epithelial cells (BEAS-2B). Although NE significantly enhanced CSE-induced IL-8 production, it suppressed VEGF production. This differential regulation was not CSE-specific. The effect of NE on IL-8 production, but not VEGF, was ERK-dependent. Interestingly, in contrast to decreased VEGF protein expression, NE accelerated VEGF transcription by CSE, suggesting post-translational modification. When cells were incubated with purified NE, it was detected in the cytoplasm, suggesting the intracellular translocation of NE. Furthermore, NE fragmented recombinant human VEGF in vitro but not recombinant human IL-8. These results indicate that VEGF down-regulation is due to direct degradation by NE, which is translocated into cells. Similar to in vitro cell experiments, elastase treatment increased CSE-induced IL-8; however, it suppressed VEGF production in bronchoalveolar lavage fluid of CSE-treated mice. Moreover, elastase treatment enhanced CSE-induced emphysema in mice. Considering the actions of IL-8 and VEGF, our results suggest that NE contributes to the pathogenesis of COPD by enhancing inflammation and apoptosis.

    PubMed IF 4.1 호흡기내과
30. 2472015

    제1저자 방영주 · 교신저자 방영주

    Bang YJ, Im SA, Lee KW, Cho JY, Song EK, Lee KH, Kim YH, Park JO, Chun HG, Zang DY, Fielding A, Rowbottom J, Hodgson D, O'Connor MJ, Yin X, Kim WH

    Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.

    J Clin Oncol. 2015;33(33):3858-65.

    Abstract

    PURPOSE Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel.

    PATIENTS AND METHODS In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS).

    RESULTS One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings.

    CONCLUSION Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

    PubMed IF 44.7 혈액종양내과

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