SCI 발표논문

1. 9582012

   제1저자 최의근 · 교신저자 Peng-Sheng Chen

   Choi EK, Chang PC, Lee YS, Lin SF, Zhu W, Maruyama M, Fishbein MC, Chen Z, Rubart-von der Lohe M, Field LJ, Chen PS

   Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-β1.

   Circ J. 2012;76(6):1354-62.

   Abstract

   BACKGROUND Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Ca(i)) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1).

   METHODS AND RESULTS MHC-TGFcys(33)ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Ca(i)transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Ca(i) transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca(2+)-ATPase 2a.

   CONCLUSIONS Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Ca(i) transient, EAD and triggered activity. Inhibition of Ca(2+) release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.

   PubMed IF 5.8 순환기내과
2. 9572012

   제1저자 김경희 · 교신저자 김용진

   Kim KH, Kim YJ, Ohn JH, Yang J, Lee SE, Lee SW, Kim HK, Seo JW, Sohn DW

   Long-term effects of sildenafil in a rat model of chronic mitral regurgitation: benefits of ventricular remodeling and exercise capacity.

   Circulation. 2012;125(11):1390-401.

   Abstract

   BACKGROUND We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR).

   METHODS AND RESULTS MR was created in Sprague-Dawley rats by making a hole on the mitral leaflet. Two weeks after MR creation, MR and LV dilatation were confirmed by echocardiography, and rats were randomly assigned to sildenafil treatment (MR+sildenafil group; 50 mg/kg PO twice a day; n=16) or normal saline only (MR group; n=16) and continued for 4 months. Sixteen sham rats were compared with MR rats. After 4 months, LV size was smaller in the MR+sildenafil compared with the MR group (LV end-systolic dimension, 4.7±0.3 for sham versus 5.9±0.3 for MR+sildenafil versus 7.4±0.5 mm for MR; P<0.05; LV end-diastolic dimension, 8.3±0.4 versus 10.5±0.2 versus 11.7±0.61 mm, respectively; P<0.05). LV ejection fraction was greater in the MR+sildenafil group than in the MR group (70.2±2.2 for sham versus 67.0±4.2 for MR+sildenafil versus 58.9±2.5 for MR; P=0.01). Serial treadmill test revealed that exercise capacity was reduced in the MR but not in the MR+sildenafil group. Transcriptional profiling of cardiac apical tissues revealed that gene sets related to inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed that perivascular fibrosis was more prominent in the MR than in the MR+sildenafil group and that the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells was 2-fold greater in the MR compared with the MR+sildenafil group.

   CONCLUSIONS Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit may be associated with the antiapoptotic, anti-inflammatory effects of sildenafil.

   PubMed IF 41.3 순환기내과
3. 9562012

   제1저자 김준규 · 교신저자 김태유

   Kim JG, Kang MJ, Yoon YK, Kim HP, Park J, Song SH, Han SW, Park JW, Kang GH, Kang KW, Oh DY, Im SA, Bang YJ, Yi EC, Kim TY

   Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody.

   PLoS One. 2012;7(3):e33322.

   Abstract

   BACKGROUND Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer.

   METHODOLOGY/PRINCIPAL FINDINGS In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity.

   CONCLUSION AND SIGNIFICANCE The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells.

   PubMed IF 2.8 혈액종양내과
4. 9552012

   제1저자 강시혁 · 교신저자 최동주

   Kang SH, Suh JW, Yoon CH, Cho MC, Kim YJ, Chae SC, Yoon JH, Gwon HC, Han KR, Kim JH, Ahn YK, Jeong MH, Kim HS, Choi DJ, KAMIR/KorMI Registry

   Sex differences in management and mortality of patients with ST-elevation myocardial infarction (from the Korean Acute Myocardial Infarction National Registry).

   Am J Cardiol. 2012;109(6):787-93.

   Abstract

   There has been controversy over the disparity between men and women with regard to the management and prognosis of acute myocardial infarction. Analyzing nationwide multicenter prospective registries in Korea, the aim of this study was to determine whether female gender independently imposes a risk for mortality. Data from 14,253 patients who were hospitalized for ST-segment elevation myocardial infarction from November 2005 to September 2010 were extracted from registries. Compared to men, women were older (mean age 56 ± 12 vs 67 ± 10 years, p < 0.001), and female gender was associated with a higher frequency of co-morbidities, including hypertension, diabetes, and dyslipidemia. Women had longer pain-to-door time and more severe hemodynamic status than men. All-cause mortality rates were 13.6% in women and 7.0% in men at 1 year after the index admission (hazard ratio for women 2.01, 95% confidence interval 1.80 to 2.25, p < 0.001). The risk for death after ST-segment elevation myocardial infarction corresponded highly with age. Although the risk remained high after adjusting for age, further analyses adjusting for medical history, clinical performance, and hemodynamic status diminished the gender effect (hazard ratio 1.00, 95% confidence interval 0.86 to 1.17, p = 0.821). Propensity score matching, as a sensitivity analysis, corroborated the results. In conclusion, this study shows that women have a comparable risk for death after ST-segment elevation myocardial infarction as men. The gender effect was accounted for mostly by the women's older age, complex co-morbidities, and severe hemodynamic conditions at presentation.

   PubMed IF 2.5 순환기내과
5. 9542012

   제1저자 강효재 · 교신저자 임재준

   Kang HJ, Park JS, Kim DW, Lee J, Jeong YJ, Choi SM, Lee SM, Yang SC, Yoo CG, Kim YW, Han SK, Yim JJ

   Adverse pulmonary reactions associated with the use of monoclonal antibodies in cancer patients.

   Respir Med. 2012;106(3):443-50.

   Abstract

   BACKGROUND The incidence and clinical characteristics of adverse pulmonary reactions resulting from anticancer monoclonal antibody (mAbs) therapy have not been well described. We determined the incidence and clinical characteristics of adverse pulmonary reactions in patients treated with anticancer chemotherapy including mAbs.

   METHODS A retrospective cohort study was performed including patients who were treated with a chemotherapeutic regimen that included rituximab, trastuzumab, cetuximab, or bevacizumab at Seoul National University Hospital between January 1, 2004 and December 31, 2008. Rates of adverse pulmonary reactions classified as non-infectious and infectious complications were compared with those among patients treated with comparable regimens without mAbs.

   RESULTS In total, 1078 patients were included (418 for rituximab, 329 for trastuzumab, 122 for cetuximab, 209 for bevacizumab). Adverse pulmonary reactions were identified in 36 patients (3.5%) and the incidence differed among agents: cetuximab (9%), rituximab (5.3%), trastuzumab (0.6%), bevacizumab (0.5%). Infectious pulmonary complications occurred in 28 patients, and eight patients experienced non-infectious pulmonary complications, most commonly interstitial lung disease (6 patients). In a multivariate analysis, low serum albumin level was associated with the development of pulmonary complications. The incidence of overall adverse pulmonary reactions did not differ between the mAbs users and the 1012 patients treated with comparable regimens other than mAbs (3.5% vs. 2.8%, P=0.53).

   CONCLUSIONS Infectious and non-infectious adverse pulmonary reactions occur in patients with cancer who are administered a regimen including mAbs. Clinicians should be alert for the possibility of pulmonary adverse reactions, particularly among patients with low serum albumin levels.

   PubMed IF 3.3 호흡기내과
6. 9532012

   제1저자 김민혜 · 교신저자 장윤석

   Kim MH, Park CH, Kim DI, Kim KM, Kim HK, Lim KH, Song WJ, Lee SM, Kim SH, Kwon HS, Park HW, Yoon CJ, Cho SH, Min KU, Kim YY, Chang YS

   Surveillance of contrast-media-induced hypersensitivity reactions using signals from an electronic medical recording system.

   Ann Allergy Asthma Immunol. 2012;108(3):167-71.

   Abstract

   BACKGROUND Contrast-media (CM) hypersensitivity is a well-known adverse drug reaction. Surveillance of adverse drug reactions usually depends on spontaneous reports. However, the rate of spontaneous reports is low. Recent progress in information technology enables the electronic search on signals of adverse drug reactions from electronic medical recording (EMR) systems.

   OBJECTIVES To analyze the incidence and clinical characteristics of CM hypersensitivity using an EMR-based surveillance system.

   METHODS The surveillance system used signals from standardized terms within the international classification of nursing practice terms that can indicate symptoms of CM hypersensitivity and from the order codes for procedures that used contrast media, antihistamine, and epinephrine. The search strategy was validated by allergists comparing the electronic search strategy versus manually reviewing medical charts over one month. The main study covered for one year period.

   RESULTS Detection rate of the electronic search method was 0.9% (7/759), while that of the manual search method was 0.8% (6/759). EMR-based electronic search method was highly efficient: reduced the charts that needed to be reviewed by 96% (28/759). The sensitivity of electronic screening was 66.7%, specificity was 99.6%, and the negative predictive value was 99.7%. CM hypersensitivity reactions were noted in 266 among 12,483 cases (2.1%). Urticaria was the most frequent symptom (74.4%). CT was the most frequent procedure (3.6%) that induced CM hypersensitivity.

   CONCLUSION A surveillance system using EMR may be a useful tool in the study of drug hypersensitivity epidemiology and may be used in an adverse drug reaction alarm system and as a clinical, decision making support system.

   PubMed IF 7.1 알레르기내과
7. 9522012

   제1저자 김의석 · 교신저자 김백남

   Kim ES, Park SW, Lee CS, Gyung Kwak Y, Moon C, Kim BN

   Impact of a national hospital evaluation program using clinical performance indicators on the use of surgical antibiotic prophylaxis in Korea.

   Int J Infect Dis. 2012;16(3):e187-92.

   Abstract

   OBJECTIVES Clinical performance measurement in surgical antibiotic prophylaxis (SAP) was implemented as part of a national hospital evaluation program (NHEP) in Korea in 2007. This study investigated changes in SAP quality before and after the implementation of clinical performance measurement.

   METHODS The medical records of patients who underwent three types of surgery that were included for assessment in the NHEP (NHEP surgery) - arthroplasty, gastrectomy, and hysterectomy - and two other types of non-NHEP assessment surgery - craniotomy and spine surgery (non-NHEP surgery) - at six hospitals, from August to October in 2006-2008, were retrospectively reviewed. Three clinical indicators of SAP (antibiotic selection, timing of administration of the first dose, and duration) and the development of surgical site infections (SSIs) were compared before and after implementation.

   RESULTS A total of 1949 patients were enrolled: 356 arthroplasty, 273 gastrectomy, 615 hysterectomy, 168 craniotomy, and 537 spinal surgery. There were no significant changes in age, gender, wound class, or ASA score for each surgery during the study period. From 2007, SAP quality was significantly improved in NHEP surgery for the three clinical indicators. The timing of administration of the first dose was most markedly improved. SAP quality was also improved in non-NHEP surgery, but not as much as in NHEP surgery. Changes in the SSI rates for each surgery were not significant.

   CONCLUSIONS Hospital evaluation using clinical performance indicators can considerably improve the use of SAP. Further studies are warranted to investigate whether this hospital evaluation will decrease the development of SSIs.

   PubMed IF 4.6 감염내과
8. 9512012

   제1저자 윤창환 · 교신저자 최동주

   Yoon CH, Youn TJ, Ahn S, Choi DJ, Cho GY, Chae IH, Choi J, Cho H, Han S, Cho MC, Jeon ES, Chae SC, Kim JJ, Ryu KH, Oh BH, Korean Heart Failure Registry

   Low serum total cholesterol level is a surrogate marker, but not a risk factor, for poor outcome in patients hospitalized with acute heart failure: a report from the Korean Heart Failure Registry.

   J Card Fail. 2012;18(3):194-201.

   Abstract

   BACKGROUND Hypercholesterolemia is a major risk factor for incident coronary artery disease and the prevalence of heart failure (HF). The causal relationship between low total cholesterol (TC) levels and poor clinical outcome in patients with acute HF has not been investigated. This study evaluated the effect of cholesterol levels on the long-term outcome in patients hospitalized due to acute HF.

   METHODS AND RESULTS We analyzed a cohort of 2,797 HF patients who were eligible for analysis in 3,200 patients of the Korean Heart Failure Registry. Patients were stratified into quartiles of TC (Q1 <133, Q2 133-158, Q3 159-190, and Q4 >190 mg/dL). Propensity score matching was performed with the patients in Q1 and Q4. Patients with lower serum TC had lower blood pressure, lower hemoglobin, lower serum sodium, and higher natriuretic peptide levels than patients with higher TC levels. Low TC was associated with increased risks for death and readmission due to HF; the adjusted hazard ratio (HR) of Q1 compared with Q4 was 1.57 (95% confidence interval [CI] 1.30-1.90). However, propensity score matching analysis revealed that low cholesterol itself did not affect outcome (HR 1.12, 95% CI 0.85-1.48).

   CONCLUSIONS Low TC is strongly associated with mortality and morbidity in patients with HF. However, low TC seemed to be a secondary result of the patient's state rather than an independent risk factor for poor outcome.

   PubMed IF 9.9 순환기내과
9. 9502012

   제1저자 정성수 · 교신저자 박경수

   Chung SS, Lee JS, Kim M, Ahn BY, Jung HS, Lee HM, Kim JW, Park KS

   Regulation of Wnt/β-catenin signaling by CCAAT/enhancer binding protein β during adipogenesis.

   Obesity (Silver Spring). 2012;20(3):482-7.

   Abstract

   Activation of the Wnt/β-catenin signaling pathway inhibits adipogenesis, while disruption of Wnt signaling leads to spontaneous adipogenesis. CCAAT/enhancer binding protein β (C/EBPβ) is rapidly induced in early stages of adipogenesis and is responsible for transcriptional induction of two major adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα. In this study, we examined whether C/EBPβ is involved in the suppression of Wnt/β-catenin signaling during adipogenesis. Knockdown of C/EBPβ expression not only inhibited adipogenesis but also maintained active Wnt/β-catenin signaling, after addition of adipogenic inducers. In contrast, overexpression of C/EBPβ substantially inhibited Wnt signaling. Interestingly, our data showed that C/EBPβ is involved in the expression of Wnt10b, a major Wnt ligand in preadipocytes, even though C/EBPβ is not an essential factor to regulate Wnt10b expression during adipogenesis, and that C/EBPβ inhibits Wnt10b promoter activity by directly binding to specific regions of the promoter. These results suggest a dual function of C/EBPβ: stimulating expression of adipogenic genes and inhibiting Wnt signaling.

   PubMed IF 4.9 내분비대사내과
10. 9492012

    제1저자 오세원 · 교신저자 나기영

    Oh SW, Ahn JM, Lee YM, Kim S, Chin HJ, Chae DW, Na KY

    Activation of hypoxia-inducible factor by cobalt is associated with the attenuation of tissue injury and apoptosis in cyclosporine-induced nephropathy.

    Tohoku J Exp Med. 2012;226(3):197-206.

    Abstract

    Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses. Despite the therapeutic benefits of cyclosporine A (CsA) in organ transplantation, its clinical use is limited due to chronic nephropathy. We investigated whether HIF activation by cobalt could improve CsA-induced nephropathy, and investigated the related mechanism. In animal experiments, rats were kept on a 0.05% low-salt diet and administered CsA subcutaneously for 28 days (15 mg/kg/day). They also received cobalt (10 mg/kg/day) during the entire experimental period. The administration of cobalt significantly increased HIF-1α expression in the kidney. The increased expression of HIF-1α ameliorated CsA-induced afferent arteriolopathy and tubulointerstitial injury in the kidney. Cobalt significantly reduced the infiltration of macrophages/monocytes into the renal tubulointerstitium. In addition, HIF activation by cobalt reduced the number of CsA-induced apoptotic cells in the kidney. Subsequently, HK-2 human renal tubular epithelial cells were used for in vitro experiments. They were pre-treated with 150 µM of cobalt to activate HIF, and then exposed to 10 µM CsA. HIF activation by cobalt decreased the CsA-induced apoptosis in HK-2 cells, as judged by the decreases in the number of apoptotic cells, pro-apoptotic caspase-3 activity, and the expression level of cleaved caspase-3, together with the increase in the expression of anti-apoptotic bcl-2. Cobalt pretreatment also reduced the CsA-induced phosphorylation of NF-κB and the CsA-induced expression of vimentin and α-smooth muscle actin, suggesting the attenuation of inflammation and fibrosis. In conclusion, the activation of HIF by cobalt may ameliorate the CsA-induced nephropathy by inhibiting apoptosis, inflammation, and fibrosis.

    PubMed IF 1.5 신장내과
11. 9482012

    제1저자 신철민 · 교신저자 김나영

    Shin CM, Kim N, Park JH, Kang GH, Kim JS, Jung HC, Song IS

    Prediction of the risk for gastric cancer using candidate methylation markers in the non-neoplastic gastric mucosae.

    J Pathol. 2012;226(4):654-65.

    Abstract

    Aberrant DNA methylation is frequently found during gastric carcinogenesis. Recently, we identified potential methylation markers important for Helicobacter pylori-induced gastric carcinogenesis using an Illumina methylation chip assay. In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK, and VAV1 was evaluated in non-neoplastic gastric specimens using quantitative methylation-specific PCR in patients with GC (n = 207) and their age- and gender-matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy-based tests (CLOtest, histology, and culture), H. pylori serology, and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS, and VAV1 but decreased methylation levels in PTPN6 (all p < 0.05); the methylation levels in MOS remained increased in patients with past H. pylori infection compared to H. pylori-negative subjects (p < 0.001). Methylation levels in MOS in non-neoplastic gastric mucosae increased in the presence of GC, regardless of H. pylori infection status (p < 0.01). Methylation levels in all genes but DCC decreased significantly in GC specimens compared to neoplastic gastric mucosae (p < 0.01); however, methylation levels in GC tissues were not correlated with those in their background gastric mucosae. Hypomethylation of MOS in GC tissues was associated with tumour invasion, nodal metastasis, and undifferentiated histology (p < 0.05). To summarize, among the candidate genes, DNA methylation of MOS may reflect the duration of H. pylori exposure and may be a marker for the development of GC.

    PubMed IF 5.4 소화기내과
12. 9472012

    제1저자 김혜진 · 교신저자 방영주

    Kim HJ, Kim HP, Yoon YK, Kim MS, Lee GS, Han SW, Im SA, Kim TY, Oh DY, Bang YJ

    Antitumor activity of HM781-36B, a pan-HER tyrosine kinase inhibitor, in HER2-amplified breast cancer cells.

    Anticancer Drugs. 2012;23(3):288-97.

    Abstract

    HM781-36B is an orally administered pan-human epidermal growth factor receptor (HER) inhibitor. To explore the role of pan-HER inhibitor in breast cancer, we investigated the antitumor effect and mechanisms of HM781-36B in breast cancer cell lines. Six breast cancer cell lines (BT474, MDA-MB-453, SK-BR-3, T47D, MCF-7, and MDA-MB-231) were tested. The growth inhibitory effect was assessed using the tetrazolium bromide [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide] assay. The cell cycle at various concentrations of HM781-36B was analyzed by flow cytometry, and analysis of downstream molecules was performed by western blot analysis. Interaction of HM781-36B with cytotoxic chemotherapeutic agents was analyzed by combination index using CalcuSyn. The HER2-amplified cells (SK-BR-3, BT474, and MDA-MB-453) were sensitive to HM781-36B (IC50=0.001 μmol/l, 0.0012 μmol/l, and 0.0095 μmol/l, respectively). HM781-36B induced G1 arrest and resulted in apoptosis. It reduced the level of p-HER2, p-AKT, p-ERK, and p-STAT3. HM781-36B combined with 5-fluorouracil, cisplatin, paclitaxel, or gemcitabine showed a synergistic inhibitory effect on the HER2-amplified and on some of the HER2-nonamplified breast cancer cells. HM781-36B could be a promising treatment for HER2-amplified breast cancer as a single agent or in combination with cytotoxic agents and can be a candidate for treatment of HER2-nonamplified breast cancer in combination with cytotoxic agents.

    PubMed IF 2 혈액종양내과
13. 9462012

    제1저자 오홍상 · 교신저자 이동호

    Oh HS, Lee DH, Seo JY, Cho YR, Kim N, Jeoung SH, Kim JW, Hwang JH, Park YS, Lee SH, Shin CM, Cho HJ, Jung HC, Song IS

    Ten-day sequential therapy is more effective than proton pump inhibitor-based therapy in Korea: a prospective, randomized study.

    J Gastroenterol Hepatol. 2012;27(3):504-9.

    Abstract

    BACKGROUND AND AIMS The eradication rate of proton pump inhibitor (PPI)-based triple therapy for Helicobacter pylori (H. pylori) infection has decreased, mainly due to increasing antibiotic resistance, especially against clarithromycin. It has been reported that a 10-day sequential strategy can produce good outcomes. The aim of this prospective study was to assess the efficacy of sequential therapy as the first-line treatment for the eradication of H. pylori in Korea.

    METHODS A total of 116 patients with proven H. pylori infection received 10-day sequential therapy (20 mg rabeprazole and 1 g amoxicillin, twice daily for the first 5 days, followed by 20 mg rabeprazole, 500 mg clarithromycin, and 500 mg metronidazole, twice daily for the remaining 5 days); 130 patients received 7-day triple therapy (20 mg rabeprazole, 500 mg clarithromycin, and 1 g amoxicillin, twice daily for 7 days). Eradication was evaluated by the (13) C-urea breath test, 4 weeks after the completion of treatment. Compliance and adverse events were assessed.

    RESULTS The eradication rates of 10-day sequential therapy and PPI-based triple therapy were 79.3% (92/116) and 63% (82/130) by intention-to-treat analysis, respectively (P = 0.005), and 81.9% (91/111) and 64.5% (82/127) by per protocol analysis, respectively (P = 0.003). Mild adverse events occurred in both therapy groups (27.5% vs 23.8%), but both treatments were well tolerated.

    CONCLUSION The eradication rate of the 10-day sequential therapy regimen was significantly higher than that of PPI-based triple therapy in the Korean population. Ten-day sequential therapy might be effective as a first-line treatment for H. pylori infection in Korea.

    PubMed IF 3.5 소화기내과
14. 9452012

    제1저자 김재환 · 교신저자 류지곤

    Kim J, Ryu JK, Ahn DW, Park JK, Yoon WJ, Kim YT, Yoon YB

    Results of repeat endoscopic retrograde cholangiopancreatography after initial biliary cannulation failure following needle-knife sphincterotomy.

    J Gastroenterol Hepatol. 2012;27(3):516-20.

    Abstract

    BACKGROUND AND AIM After failed biliary cannulation with needle knife sphincterotomy (NKS), endoscopic retrograde cholangiopancreatography (ERCP) is sometimes repeatedly performed in clinically stable patients; however, there are few reports about the results. This study assessed the results of repeated ERCPs after failure with NKS.

    METHODS After failed NKS, patients who underwent repeated ERCP for the same purpose within 3 days were retrospectively identified. Success was defined as deep placement of a catheter into the common bile duct.

    RESULTS Sixty-nine patients underwent a second ERCP procedure and, of those, six underwent a third ERCP. Of the 69 patients, cannulation was successful in 76.8% (53/69): 46 of 58 patients without additional NKS and 7 of 11 with additional NKS. Success increased to 79.7% (55/69) after the results of the third ERCP were included. Common causes of failed NKS were biliary deep cannulation failure (78.3%) and blocking of the endoscopic view due to bleeding (13.0%). There was a significant difference in success rates between the one day (65.7%) and the combined 2-3 day (88.2%) cases (P = 0.027). Except for the interval between ERCPs, there were no other factors associated with success rates. Complications occurred in 8, 11, and one patient after initial, second, and third ERCP and there was no difference of complication rates between each ERCPs.

    CONCLUSIONS In cases with biliary cannulation failure with NKS, it is more worthwhile repeating ERCP 2 or 3 days after such failure than one day after, if the patient's condition permits delay of procedure.

    PubMed IF 3.5 소화기내과
15. 9442012

    제1저자 주경돈 · 교신저자 오국환

    Ju KD, Shin EK, Cho EJ, Yoon HB, Kim HS, Kim H, Yang J, Hwang YH, Ahn C, Oh KH

    Ethyl pyruvate ameliorates albuminuria and glomerular injury in the animal model of diabetic nephropathy.

    Am J Physiol Renal Physiol. 2012;302(5):F606-13.

    Abstract

    Pyruvate is an endogenous antioxidant and anti-inflammatory substance. The present study was implemented to investigate the protective effect of ethyl pyruvate (EP) against the development and progression of diabetic nephropathy in an in vivo and in vitro model. Diabetic rats were prepared by injecting streptozotocin (65 mg/kg). Those that developed diabetes after 72 h were treated with EP (40 mg/kg) intraperitoneally. Diabetic rats without pyruvate treatment and nondiabetic rats were used for control. As an in vitro experiment, rat mesangial cells cultured primarily from Sprague-Dawley rats were treated in high-glucose (HG; 50 mM) or normal-glucose (NG; 5 mM) conditions and with or without pyruvate. Pyruvate-treated diabetic rats exhibited decreased albuminuria and attenuated NADPH-dependent reactive oxygen species generation. Immunohistochemistry showed reduced laminin, type IV collagen, and fibronectin deposition in the glomeruli compared with nontreated diabetic rats. Parallel changes were shown in tissue mRNA and protein expression levels of monocyte chemoattractant protein-1, transforming growth factor-β1, laminin, fibronectin, and type IV collagen in the kidney. Concordantly, protective effects were also exhibited in the mesangial cell culture system. These findings suggest that pyruvate protects against kidney injury via NADPH oxidase inhibition. The present study established that activation of NADPH oxidase plays a crucial role in diabetes-induced oxidative stress, glomerular hypertrophy, and ECM molecule expression. Pyruvate exhibited a renoprotective effect in the progression of experimental diabetic nephropathy. Future research is warranted to investigate the protective mechanism of pyruvate more specifically in relation to NADPH oxidase in diabetic nephropathy.

    PubMed IF 3.6 신장내과
16. 9432012

    제1저자 윤영광 · 교신저자 김태유

    Yoon YK, Kim HP, Song SH, Han SW, Oh DY, Im SA, Bang YJ, Kim TY

    Down-regulation of mitogen-inducible gene 6, a negative regulator of EGFR, enhances resistance to MEK inhibition in KRAS mutant cancer cells.

    Cancer Lett. 2012;316(1):77-84.

    Abstract

    Previously, we found that KRAS mutant cancer cells showed variable response to AZD6244, a MEK inhibitor through differential activation of EGFR/AKT. To investigate its mechanism, we performed cDNA microarray using four KRAS mutant cancer cells. We found that treatment with AZD6244 reduced the expression of mitogen-inducible gene 6 (MIG6), a negative feedback regulator for EGFR, in AZD6244-resistant cells, while activity of EGFR and AKT was increased in these cells. Reconstitution or knockdown of MIG6 expression affected cancer cell responses to AZD6244. Treatment with a combination of EGFR inhibitor and AZD6244 inhibited cell proliferation synergistically without activation of AKT in AZD6244-resistant cells. Our study provides a mechanism of differential response to MEK inhibition in KRAS mutant cancer.

    PubMed IF 11.8 혈액종양내과
17. 9422012

    제1저자 이연주 · 교신저자 유철규

    Lee YJ, Lee SM, Park JS, Yim JJ, Yang SC, Kim YW, Han SK, Lee JH, Lee CT, Yoon HI, Yoo CG

    The clinical implications of bronchoscopy in hemoptysis patients with no explainable lesions in computed tomography.

    Respir Med. 2012;106(3):413-9.

    Abstract

    INTRODUCTION Hemoptysis is observed frequently in patients, although chest computed tomography (CT) shows no explainable lesion as the cause of hemoptysis. However, the clinical course of these patients has not been reported fully.

    METHODS This study included patients who visited Seoul National University Hospital and Seoul National University Bundang Hospital to be treated for hemoptysis from January 2003 through October 2009 and who had no lesion causing hemoptysis in chest CT. We retrospectively analyzed their bronchoscopic and clinical findings.

    RESULTS A total of 228 patients were included, and the mean follow-up duration was 781 days. All patients underwent bronchoscopy. The bronchoscopic findings of 191 patients (83.8%) were negative for hemoptysis and showed the possible causes of bleeding in 37 patients (16.2%). Forty-three of the 191 patients with negative bronchoscopic findings had oronasopharyngeal problems or were using anticoagulants. After excluding these 43 patients, hemoptysis recurred in 29 (19.6%) of the remaining patients. Thirteen of the patients whose bronchoscopic findings identified the possible causes of bleeding (35.1%) experienced recurrence. Only one patient (0.4%) was diagnosed with lung cancer by the initial bronchoscopy, and no patient developed malignancy during the follow-up period.

    CONCLUSION The recurrence rate was higher in the patients with positive findings than in the patients with negative findings on bronchoscopy. Although about 20% of patients with negative bronchoscopy findings experienced recurrence, the clinical course of those in whom recurrent bleeding occurred was usually benign.

    PubMed IF 3.3 호흡기내과
18. 9412012

    제1저자 이정훈 · 교신저자 윤정환

    Lee JH, Yoon JH, Cho EJ, Yang HJ, Jang ES, Kwak MS, Hwang SY, Yu SJ, Lee CH, Kim YJ, Kim CY, Lee HS

    Simple scoring system predicting genotypic resistance during rescue therapy for Lamivudine-resistant chronic hepatitis B.

    J Clin Gastroenterol. 2012;46(3):243-50.

    Abstract

    GOAL In this study, we aimed to devise a simple scoring system predicting the risk of genotypic resistance (GR) to current rescue therapies for patients with lamivudine (LAM)-resistant chronic hepatitis B.

    BACKGROUND LAM and adefovir (ADV) combination therapy should be recommended for an initial rescue therapy against LAM-resistant hepatitis B virus (HBV). However, there still are many LAM-resistant patients being treated with entecavir (ETV) or ADV monotherapy.

    STUDY This retrospective cohort study included consecutive patients treated for LAM-resistant chronic hepatitis B with ETV or ADV monotherapy, or LAM/ADV combination therapy. The cumulative probabilities of GR and virological responses and breakthrough according to clinical variables were analyzed by survival analyses and derived an index for future GR.

    RESULTS A total of 224 patients were included (median treatment duration=117.9 wk). Using risk factors indentified on multivariable analyses, a simple index for future GR (Antiviral Resistance Prediction Index, ARPI) was developed with 3 clinical variables: the rescue therapy regimens (+0, ADV; +1, ETV; +2, LAM/ADV), HBV DNA reduction at 12 weeks (+0, <3 log10 copies/mL; +1, >3 log10 copies/mL), and the initial HBV DNA level (+0, >10 copies/mL; +1, <10 copies/mL). No patient with ARPI ≥2 exhibited GR, whereas 47% of the patients with an ARPI <2 developed GR by week 144 (P=0.005).

    CONCLUSIONS The results of this study suggest that the ARPI is a simple and early index that can be used to determine the risk for subsequent GR during rescue therapy for LAM-resistant chronic hepatitis B.

    PubMed IF 2.7 소화기내과
19. 9402012

    제1저자 곽민선 · 교신저자 윤정환

    Kwak MS, Lee JH, Yoon JH, Yu SJ, Cho EJ, Jang ES, Kim YJ, Lee HS

    Risk factors, clinical features, and prognosis of the hepatocellular carcinoma with peritoneal metastasis.

    Dig Dis Sci. 2012;57(3):813-9.

    Abstract

    BACKGROUND The clinical features and prognosis of hepatocellular carcinoma (HCC) with peritoneal metastasis have not been fully evaluated.

    AIMS This study aimed to investigate the risk factors, clinical features, and prognosis of HCC with peritoneal metastasis.

    METHODS Patients who were diagnosed as HCC with peritoneal metastasis and the same number of randomly selected, risk factor-matched HCC controls without peritoneal metastasis were included. The risk factors and overall survival were compared between peritoneal metastasis-positive and -negative groups after adjustment of other variables.

    RESULTS HCC rupture was an independent risk factor for peritoneal metastasis in HCC patients (P = 0.008). When the risk factors (age, sex, Child-Pugh score, and intrahepatic tumor stage) were matched, peritoneal metastasis failed to independently affect overall survival (P = 0.511). In the peritoneal metastasis-positive group, advanced Child-Pugh class [hazard ratio (HR), 1.99; 95% confidence interval (CI), 1.07-3.72; P = 0.030] and progressive intrahepatic HCC status (HR, 19.04; 95% CI, 2.55-142.13; P = 0.004) were independent risk factors for early death. Complications such as ileus, bleeding, and hydronephrosis due to rectovesical mass were reported in 1.5-7.4% in the peritoneal metastasis-positive group.

    CONCLUSIONS Peritoneal metastasis was not found to be an independent prognostic factor of HCC, and among HCC patients with peritoneal metastasis, those with advanced Child-Pugh class and with uncontrolled intrahepatic HCC showed poor survival. Therefore, the maintenance of favorable hepatic function and control of intrahepatic HCC should still be emphasized in HCC patients with peritoneal metastasis.

    PubMed IF 2.8
20. 9392012

    제1저자 이상협 · 교신저자 김혜령

    Lee SH, Kim H, Hwang JH, Lee HS, Cho JY, Yoon YS, Han HS

    Breast cancer resistance protein expression is associated with early recurrence and decreased survival in resectable pancreatic cancer patients.

    Pathol Int. 2012;62(3):167-75.

    Abstract

    The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismal even after complete resection, with most recurrences occurring within 1-2 years postoperatively. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been demonstrated to play major roles in multidrug resistance (MDR) of cancers. In this study, we evaluated the expression statuses and the clinical significance of MDR1 (ABCB1), MDR-associated proteins (MRPs/ABCC) 1, 2 and 3, and breast cancer resistance protein (BCRP/ABCG2) in 67 surgically resected PDACs by immunohistochemistry. MDR1, MRP1, MRP2, MRP3 and BCRP were expressed in 35 (52.2%), 56 (83.6%), 61 (91.0%), 49 (73.1%) and 49 (73.1%) out of 67 cases, respectively. The expression statuses of the MDR-related proteins were positively correlated with each other (P < 0.05). Tumors expressing MRP1 (P= 0.015), MRP2 (P= 0.022) and MRP3 (P < 0.001) demonstrated more frequent perineural invasion. MDR1 expression was significantly correlated with lymphatic invasion (P= 0.047). High BCRP expression in PDAC was a significant prognostic factor for early tumor recurrence (HR = 2.43, P= 0.003) and poor survival (HR = 2.63, P= 0.001). MDR-related proteins are frequently expressed in PDAC, and high BCRP expression is a significant independent predictor for early recurrence and poor survival. Immunohistochemical analysis for BCRP expression in PDAC may be a useful test in identifying a subgroup of patients with a poor prognosis.

    PubMed IF 1.9 소화기내과
21. 9382012

    제1저자 양효준 · 교신저자 이효석

    Yang HJ, Lee JH, Kim YJ, Yoon JH, Lee HS

    Antiviral efficacy of combination therapy with entecavir and adefovir for entecavir/lamivudine-resistant hepatitis B virus with or without adefovir resistance.

    J Med Virol. 2012;84(3):424-30.

    Abstract

    There is little clinical information on the management of hepatitis B virus (HBV) that is resistant to multiple drugs including entecavir (ETV). The present retrospective cohort study assessed the antiviral efficacy of ETV/adefovir dipivoxil (ADV) combination therapy for ETV-resistant HBV with prior lamivudine (LAM) resistance, and either with or without previous ADV resistance. The cumulative probability of achieving a virological response (undetectable serum HBV DNA) was compared by Kaplan-Meier analysis and the Breslow method. Seventeen patients with ETV-resistant HBV who were treated with ETV/ADV combination therapy for at least 6 months at a tertiary care center, were included; seven had dual resistance to ETV and LAM [ADV-r(-) group] and 10 had triple resistance to ETV, LAM, and ADV [ADV-r(+) group]. The median follow-up period was 9 months (range, 6-23). A virological response was noted in seven patients after a median of 3 months (range, 3-12) of treatment; five in the ADV-r(-) group and two in the ADV-r(+) group. The cumulative probability of a virological response was significantly higher in the ADV-r(-) group than in the ADV-r(+) group (6 months cumulative probability, 57.1% vs. 11.1%). In conclusion, ETV/ADV combination therapy led to virological responses in five of seven patients with resistance to ETV and LAM, but a significantly poorer response in patients with prior ADV resistance than in those without prior ADV resistance. Therefore, ETV/ADV combination therapy could be a useful therapeutic option for ETV- and LAM-resistant HBV without prior ADV resistance.

    PubMed IF 3.7 소화기내과
22. 9372012

    제1저자 허진 · 교신저자 김효수

    Hur J, Yang JM, Choi JI, Yun JY, Jang JH, Kim J, Kim JY, Oh IY, Yoon CH, Cho HJ, Park YB, Kim HS

    New method to differentiate human peripheral blood monocytes into insulin producing cells: Human hematosphere culture.

    Biochem Biophys Res Commun. 2012;418(4):765-9.

    Abstract

    Strategy to differentiate stem cells into insulin producing cells (IPCs) in vitro has been a promising one to get cell source of β-cell replacement therapy for diabetes. It has been suggested that islets and neurons share features and nestin-positive cells could differentiate into IPCs. We have recently developed a three-dimensional culture system using human peripheral blood cells named as blood-born hematosphere (BBHS). Here we showed that most of BBHS were composed of nestin-positive cells. Under the four-stage differentiation protocol for IPCs, we plated nestin-positive BBHS onto fibronectin-coated dish. These cells form islet-like clusters and most of them expressed insulin. Pancreatic specific genes were turned on, such as transcription factors (Pdx-1, Ngn3 and Nkx6.1), genes related to endocrine function (Glut-2 and PC2) or β cell function (Kir6.2, SUR1). Furthermore islet differentiation was confirmed by dithizone (DTZ) staining to detect zinc ion which binds insulin protein within the cells. Finally, IPCs derived from BBHS showed capability to secrete insulin in response to glucose stimulation. Taken together, our novel protocol successfully induced islet-like human insulin producing cells out of BBHS. This strategy of ex vivo expansion of IPCs using BBHS provides an autologous therapeutic cell source for the treatment of diabetes.

    PubMed IF 2.5 순환기내과
23. 9362012

    제1저자 임수, 최형진 · 교신저자 장학철

    Lim S, Choi HJ, Shin H, Khang AR, Kang SM, Yoon JW, Choi SH, Jeong IK, Cho SI, Park KS, Jang HC

    Subclinical atherosclerosis in a community-based elderly cohort: the Korean Longitudinal Study on Health and Aging.

    Int J Cardiol. 2012;155(1):126-33.

    Abstract

    BACKGROUND Early detection of atherosclerosis in elderly people is important because of high cardiovascular mortality. However, only few studies have evaluated the prevalence of subclinical atherosclerosis in Asian elderly people. We evaluated subclinical atherosclerosis using various methods in a population-based cohort study, the Korean Longitudinal Study on Health and Aging (KLoSHA).

    METHODS Subjects aged over 65 years without symptomatic chest pain were recruited for the KLoSHA in 2006 by random stratified sampling (439 men and 561 women). Anthropometrics, biochemical parameters, body composition, and abdominal fat by computed tomography (CT) were measured. Multidetector-row cardiac CT for coronary artery calcium score (CACS) and severity of stenosis, and carotid sonography for intima-media thickness (IMT) were used to detect subclinical atherosclerosis. Pulse wave velocity (PWV) and ankle-brachial index (ABI) were also measured.

    RESULTS The prevalence of subclinical atherosclerosis defined by coronary stenosis >50%, CACS >100, PWV >9m/s, carotid-IMT >0.8mm, or ABI <0.9 was 17.6%, 28.1%, 37.9%, 39.2%, and 29.6%, respectively. There were significant, but modest correlations among parameters. Although male sex, diabetes mellitus, hypertension, abnormal BMI, and higher insulin resistance were associated with subclinical atherosclerosis, older age was found to be the most robust predictor after controlling for multiple factors.

    CONCLUSION Our results suggest that proactive screening with multiple measurements in elderly subjects, particularly in men and those with diabetes mellitus or hypertension, may help to identify asymptomatic patient with atherosclerosis. Further studies exploring the predictive value of diagnostic tools can determine the most appropriate measurement for predicting future cardiovascular events.

    PubMed IF 3.3 내분비대사내과
24. 9352012

    제1저자 박효은 · 교신저자 김형관

    Park HE, Kim JH, Kim HK, Lee SP, Choi EK, Kim YJ, Oh S, Cho GY, Sohn DW

    Ventricular dyssynchrony of idiopathic versus pacing-induced left bundle branch block and its prognostic effect in patients with preserved left ventricular systolic function.

    Am J Cardiol. 2012;109(4):556-62.

    Abstract

    The extent of left ventricular (LV) dyssynchrony might not be comparable between right ventricular pacing-induced left bundle branch block (RV-LBBB) and idiopathic LBBB (iLBBB), despite the morphologic analogy on the electrocardiogram. The objectives of the present study were to elucidate the differences in the LV dyssynchrony index (LVdys) between RV-LBBB and iLBBB, and to assess the prognostic implication of LV dyssynchrony. The conventional echocardiographic parameters, LVdys, and LV end-systolic wall stress were evaluated in 20 healthy volunteers and 21 patients with iLBBB and 20 with RV-LBBB with preserved LV systolic function. Three types of LVdys were evaluated: LVdys-6, LVdys-2, and LVdys-standard deviation. The patients were clinically followed up for about 3 years. The prevalence of LV dyssynchrony was not rare in those with either iLBBB or RV-LBBB, but it was more prevalent in the patients with iLBBB than in those with RV-LBBB. The patients with iLBBB had greater LVdys than those with RV-LBBB (84 ± 55 vs 55 ± 50 for LVdys-6, 51 ± 49 vs 31 ± 40 for LVdys-2, 37 ± 24 vs 24 ± 22 for LVdys-standard deviation in iLBBB vs RV-LBBB). LVdys displayed significant correlations with QRS duration, LV volumes, LV ejection fraction, LV end-systolic wall stress, and mitral inflow E/mitral annular E' velocity ratio. Multivariate logistic regression analysis showed that the LV end-diastolic volume and LV end-systolic wall stress were independent determinants of the presence of LV dyssynchrony. During follow-up, no cardiovascular death or hospitalization for heart failure was reported in either group. In conclusion, despite similarities in electrocardiographic morphology, the extent of LV dyssynchrony were greater in patients with iLBBB, with LV preload and afterload the main determinants. No association was found between the presence of LV dyssynchrony and prognosis.

    PubMed IF 2.5 순환기내과
25. 9342012

    제1저자 고진신/박재홍 · 교신저자 연태진

    Koh JS, Park JH, Shin DH, Youn TJ, Oh IY, Yoon CH, Suh JW, Cho YS, Cho GY, Chae IH, Choi DJ

    Risk factors and effects on long-term outcomes of cardiac troponin I elevation after drug-eluting stent implantation in patients with stable coronary artery disease.

    Am J Cardiol. 2012;109(4):461-5.

    Abstract

    This study evaluated the risk factors of postprocedure cardiac troponin I (cTnI) increase and its effects on repeat revascularization and on overall clinical outcomes in patients with angina and normal preprocedural cTnI levels who underwent successful drug-eluting stent implantation. Postprocedure cTnI increase (≥0.5 ng/ml) was observed in 207 of 802 patients (25.8%). Patients with cTnI increase had more extensive coronary disease than patients without cTnI increase, which necessitated for the cTnI group more multilesion interventions and a longer total stent length. In multivariate analysis, total stent length (odds ratio 1.02, 1.01 to 1.03, p = 0.001) and use of glycoprotein IIb/IIIa inhibitors (3.07, 1.54 to 6.11, p <0.001) were identified as independent predictors of cTnI increase. During a median follow-up of 42 months, however, there were no significant between-group differences in Kaplan-Meier estimates of any repeat revascularization (24.8% vs 18.4%, hazard ratio 1.085, 0.723 to 1.627, p = 0.694) and major adverse cardiovascular events (27.0% vs 22.4%, 1.022, 0.703 to 1.485, p = 0.911). In conclusion, patients with postprocedure cTnI increase had more severe baseline coronary disease and received more complex interventional procedures. However, cTnI increase after successful drug-eluting stent implantation was not associated with an increased risk of repeat revascularization or of other adverse events.

    PubMed IF 2.5 순환기내과
26. 9332012

    제1저자 유수종 · 교신저자 윤정환

    Yu SJ, Yoon JH, Yang JI, Cho EJ, Kwak MS, Jang ES, Lee JH, Kim YJ, Lee HS, Kim CY

    Enhancement of hexokinase II inhibitor-induced apoptosis in hepatocellular carcinoma cells via augmenting ER stress and anti-angiogenesis by protein disulfide isomerase inhibition.

    J Bioenerg Biomembr. 2012;44(1):101-15.

    Abstract

    3-bromopyruvate (3-BP), a hexokinase (HK) II inhibitor, promotes tumor cell death by inducing endoplasmic reticulum (ER) stress in human hepatocellular carcinoma (HCC) cell lines. Protein disulfide isomerase (PDI) is an essential folding catalyst and attenuates ER stress by folding the misfolded proteins. We examined if PDI is expressed in hypoxic HCC cells, and evaluated its inhibition potentiated HK II inhibitor-induced ER stress in hypoxic HCC cells. HCC apoptotic cell death was assessed by DAPI staining and apoptotic signaling pathways were explored by immunoblot analysis. An in vivo model of HCC was established in C3H mice intradermally with implanted MH134 cells. 3-BP with/without a PDI inhibitor (bacitracin) was subsequently administered. The anti-tumor efficacies were evaluated by measuring tumor volumes and quantifying apoptotic cells and microvessel densities (MVDs). HCC cells were found to express PDI in a hypoxia-inducible manner. The simultaneous treatment of bacitracin and 3-BP enhanced 3-BP-induced apoptosis. This enhancement was attributed to increased ER stress and JNK activation compared to the cells treated with just 3-BP. In an in vivo model of HCC, tumor growth was significantly suppressed in mice co-treated with bacitracin and 3-BP, and the percentages of apoptotic cells significantly increased and MVDs significantly decreased. These results demonstrated that PDI was induced in hypoxic HCC tissue and that PDI inhibition enhanced HK II inhibitor-induced anti-tumor efficacy synergistically via augmenting ER stress and anti-angiogenesis in vivo. Thus, blockage of PDI activity in combination with HK II inhibitor may be therapeutically useful in HCCs.

    PubMed IF 3.7 소화기내과
27. 9322012

    제1저자 심성훈 · 교신저자 허대석

    Sim SH, Ahn YO, Yoon J, Kim TM, Lee SH, Kim DW, Heo DS

    Influence of chemotherapy on nitric oxide synthase, indole-amine-2,3-dioxygenase and CD124 expression in granulocytes and monocytes of non-small cell lung cancer.

    Cancer Sci. 2012;103(2):155-60.

    Abstract

    There is no specific marker to evaluate the immuno-suppressive status of cancer patients. Several markers, such as CD124, latency-associated peptide (LAP), arginase I, indole-amine-2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS), are known to be associated with immune suppression. However, there is little research regarding the change in these parameters after chemotherapy. The present study enrolled 23 chemo-naïve non-small cell lung cancer (NSCLC) patients and 19 healthy donors. From the 23 NSCLC patients, 11 post-chemotherapy samples were collected. Surface and functional markers were analyzed by flow-cytometry. The mean fluorescence intensities (MFI) of iNOS were higher and the MFI of LAP were lower in NSCLC patient than in healthy donors (P < 0.05). In a comparison of pre-chemotherapy and post-chemotherapy groups with NSCLC, the MFI of iNOS on granulocytes and monocytes and IDO on monocytes were significantly lower in the post-chemotherapy group than in the pre-chemotherapy group (P < 0.05). In a serial analysis with 10 patients who had paired samples and who showed clinical benefits from chemotherapy, the MFI of iNOS for both cell types, and of IDO and CD124 for monocytes decreased significantly after chemotherapy, compared with those before chemotherapy (iNOS, 4.79 ± 1.75 vs 2.83 ± 0.77, P = 0.005, for granulocytes and 6.15 ± 2.94 vs 2.76 ± 1.05, P = 0.005 for monocytes; IDO, 6.81 ± 3.43 vs 4.64 ± 1.55, P = 0.012 for monocytes; CD124, 2.31 ± 0.39 vs 1.94 ± 0.43, P = 0.008 for monocytes). The changes in arginase I and LAP expression were not significant. The changes in iNOS, IDO and CD124 expression were significant after chemotherapy in NSCLC. Further evaluation of the possibility of immune status monitoring using these parameters is needed.

    PubMed IF 4.9 혈액종양내과
28. 9312012

    제1저자 남현진 · 교신저자 방영주/오도연

    Nam HJ, Ching KA, Kan J, Kim HP, Han SW, Im SA, Kim TY, Christensen JG, Oh DY, Bang YJ

    Evaluation of the antitumor effects and mechanisms of PF00299804, a pan-HER inhibitor, alone or in combination with chemotherapy or targeted agents in gastric cancer.

    Mol Cancer Ther. 2012;11(2):439-51.

    Abstract

    Recently, HER2-directed treatment, such as trastuzumab, has shown clinical benefit in HER2-amplified gastric cancer. On the basis of recent studies about epidermal growth factor receptor (EGFR) or HER2-targeting agents (including gefitinib, lapatinib, and trastuzumab) in gastric cancer, the potent effects of pan-HER inhibitors targeting the HER family are anticipated. In this study, we evaluated the activity and mechanisms of PF00299804, an irreversible pan-HER inhibitor, in gastric cancer in vitro and in vivo models. PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033. PF00299804 induced apoptosis and G(1) arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal-regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF00299804 also blocked EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular-targeted agents including trastuzumab (an anti-HER2 monoclonal antibody), CP751871 (an IGF1R inhibitor), PD0325901 (an ERK1/2 inhibitor), and PF04691502 (a PI3K/mTOR inhibitor) produced synergistic effects. These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of HER2-amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and/or molecular-targeted agents.

    PubMed IF 6.9 혈액종양내과
29. 9302012

    제1저자 김진원 · 교신저자 오도연

    Kim JW, Cha Y, Kim SJ, Han SW, Oh DY, Lee SH, Kim DW, Im SA, Kim TY, Heo DS, Bang YJ

    Association of oral mucositis with quality of life and symptom clusters in patients with solid tumors receiving chemotherapy.

    Support Care Cancer. 2012;20(2):395-403.

    Abstract

    PURPOSE The study aims to determine whether or not oral mucositis (OM) during active chemotherapy in patients with solid tumors is representative of the patient's quality of life (QOL) and the suffering from adverse effects.

    METHODS From October 2007 to September 2008, we prospectively enrolled 344 consecutive patients with solid tumors who initiated a new chemotherapy regimen. OM, other adverse effects, and the QOL were surveyed by face-to-face interviews and patient diaries.

    RESULTS OM developed during 175 of 633 cycles (27.7%). Forty-five percent of the patients experienced OM during two cycles of chemotherapy. The QOL in patients with OM was significantly lower than patients without OM, as evaluated by the Functional Assessment of Cancer Therapy-General (70.26 ± 15.36 and 75.09 ± 13.12, respectively; p < 0.001). Specifically, the physical and emotional well-being was lower in patients with OM compared with patients without OM. Moreover, other adverse effects were more frequent in chemotherapy cycles with OM compared with chemotherapy cycles without OM (amount of food intake, activity, nausea, vomiting, fever, myalgias, and sensory neuropathy; p < 0.001, p = 0.008, p < 0.001, p = 0.001, p = 0.002, p < 0.001, and p < 0.001, respectively).

    CONCLUSIONS OM represents poor QOL and is a basic symptom of symptom clusters in patients with solid tumors receiving active chemotherapy.

    PubMed IF 3.4 혈액종양내과
30. 9292012

    제1저자 차명진 · 교신저자 오세일

    Cha MJ, Oh GC, Hahn S, Choi EK, Oh S

    Thromboembolic risk evaluation in patients with atrial fibrillation using a modified CHADS(2) scoring system.

    J Cardiovasc Electrophysiol. 2012;23(2):155-62.

    Abstract

    BACKGROUND Antithrombotic recommendations for relatively low risk patients with atrial fibrillation (AF) are not well established. Some patients with CHADS(2) score = 0 have a CHA(2) DS(2) -VASc score of 2, which indicated warfarin therapy in the latter system. We evaluated the thromboembolic risk in AF patients with a CHADS(2) score of 0 or 1.

    METHODS A total of 695 patients with AF that were followed for ≥ 12 months (median 65.6 months, range 12-138 months), were analyzed retrospectively. The modified CHADS(2) score (MCS) was applied as follows. Each CHADS(2) score group was divided into 2 groups, A and B (i.e., MCS 0A vs 0B, and MCS 1A vs 1B) according to the number of nonmajor risk factors (female gender, chronic kidney disease, coronary artery disease, age 65-74 years). Group A had 0 or 1, and group B had 2 or more nonmajor risk factors.

    RESULTS In patients with CHADS(2) score = 1, there were 13 thromboembolic events (0.65%/year) in 343 MCS 1A patients, and 12 thromboembolic events (1.90%/year) in 108 MCS 1B patients. Thromboembolic risk was significantly higher in the MCS 1B compared to the MCS 1A patients (P = 0.006). In 244 patients with CHADS(2) score = 0, the thromboembolic risk of MCS 0B was similar to that of MCS 0A (P = 0.095), and 26 patients had a CHA(2) DS(2) -VASc score of 2.

    CONCLUSION Patients with MCS 1B had a higher thromboembolic risk than patients with MCS 1A. Antithrombotic strategies for patients with a CHA(2) DS(2) -VASc score of 2 but a CHADS(2) score of 0 need further investigation.

    PubMed IF 2.4 순환기내과

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