SCI 발표논문

1. 19182015

   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
2. 19172015

   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
3. 19162015

   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
4. 19152015

   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
5. 19142015

   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
6. 19132015

   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
7. 19122015

   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
8. 19112015

   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
9. 19102015

   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
10. 19092015

    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
11. 19082015

    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
12. 19072015

    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
13. 19062015

    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
14. 19052015

    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
15. 19042015

    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
16. 19032015

    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
17. 19022015

    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
18. 19012015

    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
19. 19002015

    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
20. 18992015

    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
21. 18982015

    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
22. 18972015

    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
23. 18962015

    제1저자 이세원 · 교신저자 김효수

    Lee SW, Won JY, Yang J, Lee J, Kim SY, Lee EJ, Kim HS

    AKAP6 inhibition impairs myoblast differentiation and muscle regeneration: Positive loop between AKAP6 and myogenin.

    Sci Rep. 2015;5:16523.

    Abstract

    Skeletal muscle regeneration occurs continuously to repair muscle damage incurred during normal activity and in chronic disease or injury. Herein, we report that A-kinase anchoring protein 6 (AKAP6) is important for skeletal myoblast differentiation and muscle regeneration. Compared with unstimulated skeletal myoblasts that underwent proliferation, differentiated cells show significant stimulation of AKAP6 expression. AKAP6 knockdown with siRNA effectively halts the formation of myotubes and decreases the expression of the differentiation markers myogenin and myosin heavy chain. When shAKAP6-lentivirus is delivered to mice with cardiotoxin (CTX)-induced muscle injury, muscle regeneration is impaired compared with that of mice injected with control shMock-lentivirus. The motor functions of mice infected with shAKAP6-lentivirus (CTX+shAK6) are significantly worse than those of mice infected with shMock-lentivirus (CTX+shMock). Mechanistic analysis showed that AKAP6 promotes myogenin expression through myocyte enhancer factor 2A (MEF2A). Notably, myogenin increases AKAP6 expression as well. The results of chromatin immunoprecipitation and luciferase assays showed that myogenin binds to an E-box site on the AKAP6 promoter. Taken together, our findings demonstrate a novel interplay between AKAP6 and myogenin, and we suggest that AKAP6 is an important regulator of myoblast differentiation, myotube formation, and muscle regeneration.

    PubMed IF 4.9 순환기내과
24. 18952015

    제1저자 이창훈 · 교신저자 윤호일

    Lee CH, Kim J, Jang EJ, Kim YJ, Choi S, Lee JH, Kim DK, Yim JJ, Yoon HI

    Healthcare utilisation by pregnant patients with asthma in South Korea: a cohort study using nationwide claims data.

    BMJ Open. 2015;5(11):e008416.

    Abstract

    OBJECTIVES Few nationwide population-based studies have examined the burden of asthma during pregnancy. Here, we investigated the burden and medical treatment of asthma during pregnancy requiring healthcare utilisation in South Korea.

    DESIGN Cohort study.

    SETTING Nationwide insurance claims database.

    PARTICIPANTS A total of 1,306,281 pregnant women who delivered in South Korea in 2009-2011.

    OUTCOMES The prevalence and exacerbation rates of asthma requiring healthcare utilisation, and the prescription of antiasthmatic drugs during pregnancy.

    RESULTS The prevalence of asthma requiring healthcare utilisation was 0.43% among pregnant women. Among those with asthma requiring healthcare utilisation, 6.9% were hospitalised and treated with systemic steroids and short-acting β2-agonists during pregnancy. Oral drugs were prescribed less during the third trimester than during the first trimester (all p values for trends were <0.001). A significant number of patients with asthma were likely to stop taking antiasthmatic drugs after becoming pregnant.

    CONCLUSIONS The prevalence of asthma requiring healthcare utilisation during pregnancy was not very high. However, a significant number of women were likely to stop taking antiasthmatic drugs, and those who did tended to experience exacerbations.

    PubMed IF 2.5 호흡기내과
25. 18942015

    제1저자 강지연 · 교신저자 김태유

    Kang JY, Song SH, Yun J, Jeon MS, Kim HP, Han SW, Kim TY

    Disruption of CTCF/cohesin-mediated high-order chromatin structures by DNA methylation downregulates PTGS2 expression.

    Oncogene. 2015;34(45):5677-84.

    Abstract

    The CCCTC-binding factor (CTCF)/cohesin complex regulates gene transcription via high-order chromatin organization of the genome. De novo methylation of CpG islands in the promoter region is an epigenetic hallmark of gene silencing in cancer. Although the CTCF/cohesin complex preferentially targets hypomethylated DNA, it remains unclear whether the CTCF/cohesin-mediated high-order chromatin structure is affected by DNA methylation during tumorigenesis. We found that DNA methylation downregulates the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), which is an inducible, rate-limiting enzyme for prostaglandin synthesis, by disrupting CTCF/cohesin-mediated chromatin looping. We show that the CTCF/cohesin complex is enriched near a CpG island associated with PTGS2 and that the PTGS2 locus forms chromatin loops through methylation-sensitive binding of the CTCF/cohesin complex. DNA methylation abolishes the association of the CTCF/cohesin complex with the PTGS2 CpG island. Disruption of chromatin looping by DNA methylation abrogates the enrichment of transcriptional components, such as positive elongation factor b, at the transcriptional start site of the PTGS2 locus. These alterations result in the downregulation of PTGS2. Our results provide evidence that CTCF/cohesin-mediated chromatin looping of the PTGS2 locus is dynamically influenced by the DNA methylation status.

    PubMed IF 9.1 혈액종양내과
26. 18932015

    제1저자 곽민선 · 교신저자 이창훈

    Kwak MS, Kim E, Jang EJ, Kim HJ, Lee CH

    The efficacy and safety of triple inhaled treatment in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis using Bayesian methods.

    Int J Chron Obstruct Pulmon Dis. 2015;10:2365-76.

    Abstract

    PURPOSE Although tiotropium (TIO) and inhaled corticosteroid (ICS)/long-acting β-agonists are frequently prescribed together, the efficacy of "triple therapy" has not been scientifically demonstrated. We conducted a systematic review and meta-analysis using Bayesian methods to compare triple therapy and TIO monotherapy.

    METHODS We searched the MEDLINE, EMBASE, and Cochrane Library databases for randomized controlled trials comparing the efficacy and safety of triple therapy and TIO monotherapy in patients with chronic obstructive pulmonary disease (COPD). We conducted a meta-analysis to compare the effectiveness and safety of triple therapy and TIO monotherapy using Bayesian random effects models.

    RESULTS Seven trials were included, and the risk of bias in the majority of the studies was acceptable. There were no statistically significant differences in the incidence of death and acute exacerbation of disease in the triple therapy and TIO monotherapy groups. Triple therapy improved the prebronchodilator forced expiratory volume in 1 second (mean difference [MD], 63.68 mL; 95% credible interval [CrI], 45.29-82.73), and patients receiving triple therapy showed more improvement in St George Respiratory Questionnaire scores (MD, -3.11 points; 95% CrI, -6.00 to -0.80) than patients receiving TIO monotherapy. However, both of these differences were lower than the minimal clinically important difference (MCID). No excessive adverse effects were reported in triple therapy group.

    CONCLUSION Triple therapy with TIO and ICSs/long-acting β-agonists was only slightly more efficacious than TIO monotherapy in treating patients with COPD. Further investigations into the efficacy of new inhaled drugs are needed.

    PubMed IF 4.1 소화기내과
27. 18922015

    제1저자 안정남, 김영훈 · 교신저자 이정표

    An JN, Kim YH, Park JB, Hwang JH, Yoo KD, Park JY, Kim CT, Kim HL, Kim YJ, Han DJ, Lim CS, Kim YS, Lee JP

    The reciprocal interaction between LV remodelling and allograft outcomes in kidney transplant recipients.

    Heart. 2015;101(22):1826-33.

    Abstract

    OBJECTIVE This study aimed to investigate the incidence and related clinical factors of LV hypertrophy (LVH) regression after kidney transplantation and its effect on graft outcome.

    METHODS Among the 3373 kidney transplant recipients who were enrolled in a multicentre cohort from 1997 to 2012, a total of 767 patients who underwent echocardiography before and after transplantation were included in this study followed for a median of 7.5 years.

    RESULTS LVH regression steadily increased from 7.4% at 1 year to 35.4% at 5 year over the 5-year post-transplantation period. The probability of LVH regression decreased in the patients who received a kidney transplant due to end-stage renal disease of unknown aetiology (p=0.041) or who underwent pretransplant haemodialysis (p=0.020). The probability of LVH regression also decreased as the pretransplant LV mass index (p<0.001) and post-transplant systolic blood pressure increased (p=0.005). Conversely, LVH regression was significantly associated with the highest tertile of the pretransplant haemoglobin level (p=0.029). Furthermore, in the 5th year after transplantation, persistent LVH was independently associated with allograft failure (HR 1.95; 95% CI 1.14 to 3.33; p=0.015) and the LV mass index reliably predicted graft outcome.

    CONCLUSIONS LVH consistently regressed after kidney transplantation in most patients. Persistent LVH, low haemoglobin levels and elevated blood pressure were associated with an increased risk of allograft failure in kidney transplant recipients.

    PubMed IF 4.4 신장내과
28. 18912015

    제1저자 박흥우 · 교신저자 Tantisira KG

    Park HW, Ge B, Tse S, Grundberg E, Pastinen T, Kelly HW, Tantisira KG

    Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts.

    J Allergy Clin Immunol. 2015;136(5):1240-6.e1-8.

    Abstract

    BACKGROUND Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA).

    OBJECTIVE We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma.

    METHODS We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblasts.

    RESULTS We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. The rs9896933 variant met the criteria for genome-wide significance (P = 3.15 × 10(-8) in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant (P = 2.74 × 10(-4) in the GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblasts (P = 8.64 × 10(-4)). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased.

    CONCLUSIONS We have identified 2 novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.

    PubMed IF 11.2 알레르기내과
29. 18902015

    제1저자 곽민선, 유수종 · 교신저자 윤정환

    Kwak MS, Yu SJ, Yoon JH, Lee SH, Lee SM, Lee JH, Kim YJ, Lee HS, Kim CY

    Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model.

    J Cancer Res Clin Oncol. 2015;141(11):2037-45.

    Abstract

    PURPOSE A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model.

    METHODS An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then, doxorubicin with or without flavopiridol was injected. The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism.

    RESULTS Tumor growth was significantly suppressed in the doxorubicin + flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression.

    CONCLUSIONS These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression.

    PubMed IF 3.3 소화기내과
30. 18892015

    제1저자 권유욱 · 교신저자 김효수

    Kwon YW, Jang S, Paek JS, Lee JW, Cho HJ, Yang HM, Kim HS

    E-Ras improves the efficiency of reprogramming by facilitating cell cycle progression through JNK-Sp1 pathway.

    Stem Cell Res. 2015;15(3):481-494.

    Abstract

    We have previously shown that pluripotent stem cells can be induced from adult somatic cells which were exposed to protein extracts isolated from mouse embryonic stem cells (mESC). Interestingly, generation of induced pluripotent stem (iPS) cells depended on the background of ES cell lines; possible by extracts from C57, but not from E14. Proteomic analysis of two different mES cell lines (C57 and E14) shows that embryonic Ras (E-Ras) is expressed differently in two mES cell lines; high level of E-Ras only in C57 mESC whose extracts allows iPS cells production from somatic cells. Here, we show that E-Ras augments the efficiency in reprogramming of fibroblast by promoting cell proliferation. We found that over-expression of E-Ras in fibroblast increased cell proliferation which was caused by specific up-regulation of cyclins D and E, not A or B, leading to the accelerated G1 to S phase transition. To figure out the common transcription factor of cyclins D and E, we used TRANSFAC database and selected SP1 as a candidate which was confirmed as enhancer of cyclins D and E by luciferase promoter assay using mutants. As downstream signaling pathways, E-Ras activated only c-Jun N-terminal kinases (JNK) but not ERK or p38. Inhibition of JNK prevented E-Ras-mediated induction of pSP1, cyclins D, E, and cell proliferation. Finally, E-Ras transduction to fibroblast enhanced the efficiency of iPS cell generation by 4 factors (Oct4/Klf4/Sox2/C-myc), which was prevented by JNK inhibitor. In conclusion, E-Ras stimulates JNK, enhances binding of Sp1 on the promoter of cyclins D and E, leading to cell proliferation. E-Ras/JNK axis is a critical mechanism to generate iPS cells by transduction of 4 factors or by treatment of mESC protein extracts.

    PubMed IF 0.6 순환기내과

서울대학교병원 내과 교실이 발표한 SCI 논문입니다. 제목을 누르면 Abstract · 그림 등을, 저자 이름을 누르면 소속 · PubMed · ORCID 를 볼 수 있습니다. 굵은 이름은 동문과 연결된 저자입니다.