SCI 발표논문

전체 4,588편

21882017

제1저자 하태훈 · 교신저자 고성준

, , , , , , , , , ,
Alcoholic Liver Disease Is Associated with an Increased Risk of Gastric Cancer.
Dig Dis Sci. 2017;62(1):273-279.

Abstract
BACKGROUND Little information is available regarding the relationship between alcoholic liver diseases (ALD) and the development of gastric neoplasia.
AIM The aim of this study was to examine whether ALD is associated with the increased risk of gastric neoplasia.
METHODS We reviewed the medical records 514 patients diagnosed with ALD at Seoul Metropolitan Government Boramae Hospital between January 2000 and December 2011. Control subjects were selected by using propensity score matching (age, sex, and body mass index) from 8190 members of the general population who underwent EGD for screening for gastric neoplasia at Boramae Health Promotion Center during the study period. We compared the frequency of gastric neoplasia between the two groups and evaluated the risk factors for the development of gastric cancer in patients with ALD. In addition, we compared the frequency of gastric cancer between patients with ALD and those with nonalcoholic steatohepatitis (NASH).
RESULTS Of the 514 patients with ALD, 16 patients (3.1 %) had gastric neoplasia, including 14 gastric cancers (2.7 %). The odds of detecting a gastric cancer in ALD patients were approximately 4.77 times greater than in healthy controls [odds ratio (OR) 4.77; 95 % confidence interval (CI) 1.36-16.69; P = 0.007]. ALD (OR 5.32, 95 % CI 1.51-18.68, P = 0.009) was found to be an independent risk factor by multivariate logistic analysis. However, there were no significant differences in the prevalence of gastric adenoma and gastric cancer between patients with ALD and those with NASH.
CONCLUSIONS The rate of gastric cancer was significantly higher in patients with ALD than in healthy controls, suggesting that strict endoscopic surveillance is warranted in patients with ALD.
PubMed IF 2.8 소화기내과
21872017

제1저자 김학령 · 교신저자 김명아

, , , , , , , , , , , , , ,
Sex Difference in the Association Between Brachial Pulse Pressure and Coronary Artery Disease: The Korean Women's Chest Pain Registry (KoROSE).
J Clin Hypertens (Greenwich). 2017;19(1):38-44.

Abstract
This study was performed to investigate the association between brachial pulse pressure (PP) and the presence/extent of obstructive coronary artery disease (CAD) in men and women. Study data were obtained from a nation-wide registry composed of 632 patients (173 men and 459 women, 58.1±10.5 years) with suspected CAD who underwent invasive coronary angiography. PP was higher in patients with obstructive CAD (≥50% stenosis) than those without CAD in both sexes (P=.032 in men; P<.001 in women). However, PP increased proportionally with the increasing number of obstructed coronary arteries in women (P<.001) but not in men (P=.070). Multiple logistic-regression analyses demonstrated that higher PP (≥50.5 mm Hg) was an independent factor for determining obstructive CAD even after controlling for potential confounders in women (odds ratio, 2.83; 95% confidence interval, 1.40-5.73; P=.004). These results were consistent in 173 selected women matched with 173 men based on age and CAD severity. In conclusion, the association between brachial PP and obstructive CAD was more pronounced in women than in men. Brachial PP can be a simple and useful indicator of CAD especially in women.
PubMed IF 2.9 순환기내과
21862017

제1저자 옥찬영 · 교신저자 오도연

, , , , , , , , ,
Signature of cytokines and angiogenic factors (CAFs) defines a clinically distinct subgroup of gastric cancer.
Gastric Cancer. 2017;20(1):164-174.

Abstract
BACKGROUND Little is known about cytokine and angiogenic factors (CAFs) in gastric cancer (GC) in terms of tumor classification and prognostic value. Here, we aimed to correlate CAF signature with overall survival (OS) in GC.
METHODS We measured pretreatment serum levels of 52 kinds of CAFs in 68 GC patients who were treated with fluoropyrimidine and platinum combination chemotherapy using multiplex bead immunoassays and enzyme-linked immunosorbent assay. We evaluated correlations between CAF levels and pathological features and OS.
RESULTS Three distinct patient groups were identified: one with high levels of proangiogenic factors, another with high levels of proinflammatory factors, and the other with high levels of both factors. Eleven CAFs [interleukin (IL)-2 receptor-alpha, growth-regulated alpha protein, hepatocyte growth factor, macrophage colony-stimulating factor, stromal cell-derived factor, IL-6, IL-8, IL-10, interferon-gamma, vascular endothelial growth factor, and osteopontin] were independently correlated with poor OS. Clustering analysis of these 11 CAFs revealed distinct high and low 11-CAF signature groups. High 11-CAF signature was associated with shorter OS (10.1 vs. 17.9 months, p = 0.026) along with poor performance status, and the presence of signet ring cell components in multivariate analysis of OS (HR 1.76, p = 0.029). The patients' traditional clinicopathological characteristics were not significantly different between the high and low 11-CAF signature groups.
CONCLUSION Serum CAF profiling differentiated GC patient groups. A high 11-CAF signature could identify GC patients with a poor prognosis when treated with standard chemotherapy who need urgent new treatment strategies.
PubMed IF 6.1 혈액종양내과
21852017

제1저자 임수 · 교신저자 이문규

, , , , , , , , , , , , , , ,
Efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes: A double-blind randomized controlled trial (INICOM study).
Diabetes Obes Metab. 2017;19(1):87-97.

Abstract
BACKGROUND Gemigliptin is a new dipeptidyl peptidase-IV inhibitor. We investigated the efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes (T2D).
METHODS A total of 433 T2D patients with a glycosylated haemoglobin (HbA1c) level of 7.5% to 11.0% and a fasting plasma glucose (FPG) concentration <270 mg/dL were randomly assigned to 3 groups: (1) gemigliptin 50 mg qd + metformin 1000 to 2000 mg qd (titrated individually), (2) gemigliptin 50 mg qd, or (3) metformin 1000 to 2000 mg qd. The primary end-point was the change in HbA1c level after 24 weeks. Secondary end-points were the changes in FPG, insulin, proinsulin and C-peptide levels. The percentages of responders who achieved an HbA1c level <7% (or <6.5%) were compared between treatment groups.
RESULTS Baseline HbA1c levels were 8.7% in all groups. The mean changes in HbA1c level from baseline to week 24 were -2.06%, -1.24% and -1.47% in the combination, gemigliptin monotherapy and metformin monotherapy groups, respectively. The 95% confidence intervals for between-group differences in HbA1c changes were -1.02 to -0.63 in the combination group vs the gemigliptin group and -0.82 to -0.41 vs the metformin group, which confirmed the superiority of combination therapy. A significantly higher percentage of patients in the combination therapy group reached the target HbA1c level <7% (or <6.5%) compared with the monotherapy groups. No severe side effects were observed.
CONCLUSIONS In T2D patients, the initial combination of gemigliptin and metformin had superior efficacy without safety concerns compared with monotherapy with either drug.
PubMed IF 6.1 내분비대사내과
21842017

제1저자 김연욱, 김정희 · 교신저자 박영식

, , , , , ,
Vertebral bone attenuation on low-dose chest CT: quantitative volumetric analysis for bone fragility assessment.
Osteoporos Int. 2017;28(1):329-338.

Abstract
UNLABELLED This study evaluated the use of low-dose chest computed tomography (LDCT) for detecting bone fragility. LDCT-measured vertebral bone attenuation by volumetric methods showed good correlation with bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DXA, and good diagnostic performance for identifying osteoporosis and compression fractures. The results of this study suggest the feasibility of obtaining comprehensive information on bone health in subjects undergoing LDCT.
INTRODUCTION Osteoporosis is a prevalent but underdiagnosed disease that increases fracture risk. This study evaluated the utility of vertebral attenuation derived from low-dose chest computed tomography (LDCT) compared to dual-energy x-ray absorptiometry (DXA) for detecting bone fragility.
METHODS A total of 232 subjects (78 men and 154 women) aged above 50 years who underwent both LDCT and DXA within 30 days were evaluated. LDCT-measured bone attenuation in Hounsfield units (HU) of four vertebrae (T4, T7, T10, and L1) was evaluated using volumetric methods for correlation with DXA-measured bone mineral density (BMD) and for the diagnosis of compression fractures, osteoporosis, and low BMD (osteoporosis or osteopenia) in men and women, with DXA measurements as the reference standard.
RESULTS The average attenuation of the four vertebrae showed strong correlation with DXA-measured BMD of the lumbar spine (r = 0.726, p < 0.05). In receiver-operating characteristic (ROC) analyses, the area under the curve (AUC) across LDCT-measured thresholds of the average attenuation to distinguish compression fractures was 0.827, and a threshold of 129.5 HU yielded 90.9 % sensitivity and 64.4 % specificity. Similarly, average attenuation showed high AUCs and good diagnostic performance for detecting osteoporosis and low BMD in both men and women. Among 44 subjects with compression fractures, the average bone attenuation showed strong negative correlation with both the worst fracture grade (r = -0.525, p < 0.05) and cumulative fracture grade score (r = -0.633, p < 0.05).
CONCLUSION LDCT-measured bone attenuation by volumetric methods showed good correlation with BMD measured by DXA and good diagnostic performance for identifying bone fragility.
PubMed IF 5.4 호흡기내과
21832017

제1저자 민세희 · 교신저자 한서경, 조영민

, , ,
Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis.
Diabetes Metab Res Rev. 2017;33(1).

Abstract
BACKGROUND Both sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors can be used to treat patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with insulin therapy, and yet there has been no direct comparison of these two inhibitors.
METHODS We searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through June 2015. Randomized controlled trials published in English that compare SGLT2 inhibitor plus insulin (SGLT2i/INS) with placebo plus insulin or DPP4 inhibitor plus insulin (DPP4i/INS) with placebo plus insulin in patients with T2DM were selected. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between SGLT2i/INS and DPP4i/INS indirectly with covariates adjustment. Risk of potential bias was assessed.
RESULTS Fourteen eligible randomized controlled trials comprising 6980 patients were included (five SGLT2 inhibitor studies and nine DPP4 inhibitor studies). Covariate-adjusted indirect comparison using meta-regression analyses revealed that SGLT2i/INS achieved greater reduction in HbA_1c [weighted mean difference (WMD) -0.24%, 95% confidence interval (CI) -0.43 to -0.05%], fasting plasma glucose (WMD -18.0 mg/dL, 95% CI -28.5 to -7.6 mg/dL) and body weight (WMD -2.38 kg, 95% CI -3.18 to -1.58 kg) from baseline than DPP4i/INS without increasing the risk of hypoglycaemia (relative risks 1.19, 95% CI 0.78 to 1.82).
CONCLUSIONS Sodium glucose cotransporter 2 inhibitors achieved better glycaemic control and greater weight reduction than DPP4 inhibitors without increasing the risk of hypoglycaemia in patients with T2DM that is inadequately controlled with insulin. There has been no direct comparison of SGLT2 inhibitors and DPP4 inhibitors in patients with T2DM inadequately controlled with insulin therapy. In this study, we performed indirect meta-analysis comparing SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy. Without increasing hypoglycaemia, SGLT2 inhibitors showed better glycaemic control and greater weight reduction than DPP4 inhibitors in patients with T2DM inadequately controlled with insulin. The results of the current study could serve as the best available evidence in selecting oral agents to improve glycaemic control in insulin-treated T2DM patients. Copyright © 2016 John Wiley & Sons, Ltd.
PubMed IF 8.3 내분비대사내과
21822017

제1저자 안정남 · 교신저자 이정표

, , , , , , , , , , , ,
Chronic Kidney Disease After Acute Kidney Injury Requiring Continuous Renal Replacement Therapy and Its Impact on Long-Term Outcomes: A Multicenter Retrospective Cohort Study in Korea.
Crit Care Med. 2017;45(1):47-57.

Abstract
OBJECTIVES Severe acute kidney injury requiring continuous renal replacement therapy is associated with a high risk of early mortality. Our objectives were to identify a cohort of early survivors and to follow their renal progress and long-term mortality.
DESIGN Multicenter, observational, retrospective cohort study.
SETTING ICUs in tertiary academic hospitals in Korea.
PATIENTS From 2009 to 2013, we identified 1,764 severe acute kidney injury patients who were started on continuous renal replacement therapy at four hospitals. Of these, we identified 331 survivors for whom we could identify renal function at baseline and at 3 months.
INTERVENTIONS None.
MEASUREMENTS AND MAIN RESULTS The 331 patients were separated into two groups based on their renal function at 3 months after the start of continuous renal replacement therapy. Those who displayed significant deterioration in renal function compared to baseline, defined as greater than or equal to 50% increase in serum creatinine or greater than or equal to 35% decrease in the estimated glomerular filtration rate, or those who continued to receive renal replacement therapy were designated as a "3-month chronic kidney disease progression" group. Those with a return to baseline, less than 50% increase in serum creatinine or less than 35% decrease in the estimated glomerular filtration rate, were designated as a "3-month chronic kidney disease nonprogression" group. The acute kidney injury patients requiring continuous renal replacement therapy showed a higher risk of progression to end-stage renal disease compared to that of stage 3 chronic kidney disease patients who did not undergo an acute kidney injury episode, even if the acute kidney injury was recovered at 3 months after continuous renal replacement therapy initiation. Furthermore, "3-month chronic kidney disease progression" was associated with a high risk of progression to end-stage renal disease and long-term mortality over a median follow-up period of 12.7 (3.8-33.2) and 20.4 (7.5-39.7) months, respectively. Older age, higher baseline serum creatinine levels, and higher blood urea nitrogen concentrations at continuous renal replacement therapy initiation, and lower 24-hour urine output after continuous renal replacement therapy initiation are associated with an increased risk of "3-month chronic kidney disease progression."
CONCLUSIONS Renal functional assessment at 3 months after continuous renal replacement therapy initiation can be useful in predicting progression to end-stage renal disease and long-term mortality. Furthermore, continuous close monitoring and management of acute kidney injury patients requiring continuous renal replacement therapy are required, even in those with recovered renal function.
PubMed IF 7.5 신장내과
21812017

제1저자 차용준, 김유정 · 교신저자 이세훈

, , , , , , , , , , , , ,
Post-bevacizumab Clinical Outcomes and the Impact of Early Discontinuation of Bevacizumab in Patients with Recurrent Malignant Glioma.
Cancer Res Treat. 2017;49(1):129-140.

Abstract
PURPOSE Bevacizumab±irinotecan is effective for treatment of recurrent malignant gliomas. However, the optimal duration of treatment has not been established.
MATERIALS AND METHODS Ninety-four consecutive patients with recurrent malignant glioma who were treated with bevacizumab at our institutions were identified. Patients who continued bevacizumab until tumor progression were enrolled in a late discontinuation (LD) group, while those who stopped bevacizumab before tumor progression were enrolled in an early discontinuation (ED) group. Landmark analyses were performed at weeks 9, 18, and 26 for comparison of patient survival between the two groups.
RESULTS Among 89 assessable patients, 62 (69.7%) and 27 (30.3%) patients were categorized as the LD and ED groups, respectively. According to landmark analysis, survival times from weeks 9, 18, and 26 were not significantly different between the two groups in the overall population. However, the LD group showed a trend toward increased survival compared to the ED group among responders. In the ED group, the median time from discontinuation to disease progression was 11.4 weeks, and none of the patients showed a definite rebound phenomenon. Similar median survival times after disease progression were observed between groups (14.4 weeks vs. 15.7 weeks, p=0.251). Of 83 patients, 38 (45.8%) received further therapy at progression, and those who received further therapy showed longer survival in both the LD and ED groups.
CONCLUSION In recurrent malignant glioma, duration of bevacizumab was not associated with survival time in the overall population. However, ED of bevacizumab in responding patients might be associated with decreased survival.
PubMed IF 4.2 혈액종양내과
21802017

제1저자 정고은 · 교신저자 임정윤

, , , , , , ,
Associations between hemoglobin concentrations and the development of incidental metabolic syndrome or nonalcoholic fatty liver disease.
Dig Liver Dis. 2017;49(1):57-62.

Abstract
AIMS Hemoglobin (Hb) is known to be associated with both nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS). We evaluated the relationship between serum Hb levels and the development of MS or NAFLD.
METHODS A retrospective cohort study was conducted. We recruited participants who underwent abdominal ultrasonography and blood samplings in both 2005 and 2010.
RESULTS Graded independent relationships were observed between higher Hb levels and the incidence of MS and NAFLD. After adjusting for age, body mass index, and fasting glucose, high-density lipoprotein cholesterol and triglyceride levels, the risk of developing MS was significantly higher according to the Hb quartiles in men (P for trend=0.027). The adjusted odds ratio (OR) and 95% confidence intervals (CIs) for the highest Hb quartile was 1.81 (1.06-3.10) for women and 1.43 (1.00-2.05) for men. The risk of developing NAFLD was also significantly higher according to the Hb quartiles in men (P for trend=0.03). The adjusted OR and 95% CI for the highest Hb quartile was 1.18 (0.73-1.91) in women and 1.76 (1.16-2.66) in men.
CONCLUSIONS The risk of developing either MS or NAFLD was significantly associated with serum Hb levels in men. These findings have implications in the clinical availability of serum Hb as a predictor of MS and NAFLD.
PubMed IF 4.9 소화기내과
21792017

제1저자 차문용,권유욱,안효숙,정효빈 · 교신저자 김효수,묵인희

, , , , , , , , , , , ,
Protein-Induced Pluripotent Stem Cells Ameliorate Cognitive Dysfunction and Reduce Aβ Deposition in a Mouse Model of Alzheimer's Disease.
Stem Cells Transl Med. 2017;6(1):293-305.

Abstract
Transplantation of stem cells into the brain attenuates functional deficits in the central nervous system via cell replacement, the release of specific neurotransmitters, and the production of neurotrophic factors. To identify patient-specific and safe stem cells for treating Alzheimer's disease (AD), we generated induced pluripotent stem cells (iPSCs) derived from mouse skin fibroblasts by treating protein extracts of embryonic stem cells. These reprogrammed cells were pluripotent but nontumorigenic. Here, we report that protein-iPSCs differentiated into glial cells and decreased plaque depositions in the 5XFAD transgenic AD mouse model. We also found that transplanted protein-iPSCs mitigated the cognitive dysfunction observed in these mice. Proteomic analysis revealed that oligodendrocyte-related genes were upregulated in brains injected with protein-iPSCs, providing new insights into the potential function of protein-iPSCs. Taken together, our data indicate that protein-iPSCs might be a promising therapeutic approach for AD. Stem Cells Translational Medicine 2017;6:293-305.
PubMed IF 5.9 순환기내과
21782017

제1저자 권지현 · 교신저자 윤성수

, , , , , , , , , , , , , , , ,
Efficacy and toxicity of the combination chemotherapy of thalidomide, alkylating agent, and steroid for relapsed/refractory myeloma patients: a report from the Korean Multiple Myeloma Working Party (KMMWP) retrospective study.
Cancer Med. 2017;6(1):100-108.

Abstract
We analyzed the treatment responses, toxicities, and survival outcomes of patients with relapsed or refractory multiple myeloma who received daily thalidomide, cyclophosphamide, and dexamethasone (CTD) or daily thalidomide, melphalan, and prednisolone (MTP) at 17 medical centers in Korea. Three-hundred and seventy-six patients were enrolled. The combined chemotherapy of thalidomide, corticosteroid, and an alkylating agent (TAS) was second-line chemotherapy in 142 (37.8%) patients, and third-line chemotherapy in 135 (35.9%) patients. The response rate overall was 69.4%. Patients who were not treated with bortezomib and lenalidomide before TAS showed a higher response rate compared to those who were exposed to these agents. The estimated median progression-free survival and overall survival times were 10.4 months and 28.0 months, respectively. The adverse events during TAS were generally tolerable, but 39 (10.4%) patients experienced severe infectious complications. There were no differences in terms of efficacy between CTD and MTP, but infectious complications were more common in CTD group. TAS is an effective treatment regimen which induces a high response rate in relapsed or refractory multiple myeloma patients. Due to the high incidence of grade 3 or 4 infection, proper management of infection is necessary during the TAS treatment, especially the CTD.
PubMed IF 3.5 혈액종양내과
21772017

제1저자 구보경 · 교신저자 김원, 김동희

, , , , , , ,
Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis.
J Hepatol. 2017;66(1):123-131.

Abstract
BACKGROUND & AIMS We explored whether sarcopenia is associated with the histological severity of non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis (NASH) and significant fibrosis.
METHODS In a biopsy-proven NAFLD cohort, the appendicular skeletal muscle mass (ASM) was measured. Sarcopenia was defined as a ASM/body weight (ASM%) value beyond two standard deviations below the mean for healthy young adults.
RESULTS Among the entire set of 309 subjects, the prevalence of sarcopenia in subjects without NAFLD, with non-alcoholic fatty liver (NAFL), and with NASH were 8.7%, 17.9%, and 35.0%, respectively (p<0.001). ASM% was inversely correlated with the severity of fibrosis (p<0.001), and the prevalence of significant fibrosis (⩾F2) was higher in subjects with sarcopenia than in those without (45.7% vs. 24.7%; p<0.001). A crude analysis revealed that sarcopenia was associated with NAFLD (odds ratio [OR], 3.82; 95% confidence interval [CI], 1.58-9.25), which became insignificant after adjustment for body mass index (BMI), diabetes, and hypertension. Among NAFLD subjects, subjects with sarcopenia were more likely to have NASH than those without sarcopenia through a multivariate analysis adjusted for age, gender, BMI, hypertension, diabetes, and smoking status (OR, 2.28; 95% CI, 1.21-4.30), and this finding was obtained even after adjustment for insulin resistance (OR, 2.30; 95% CI, 1.08-4.93). Sarcopenia was also associated with significant fibrosis independent of BMI and insulin resistance (OR, 2.05; 95% CI, 1.01-4.16).
CONCLUSIONS In this large biopsy-proven NAFLD cohort, sarcopenia was significantly associated with NASH and significant fibrosis.
LAY SUMMARY Low muscle mass was found to be associated with histological severity in non-alcoholic fatty liver disease, and sarcopenia was significantly associated with non-alcoholic steatohepatitis and significant fibrosis, independent of obesity, inflammation, and insulin resistance. Clinical trial number: NCT 02206841.
PubMed IF 40.1 소화기내과
21762017

제1저자 이승표, 임형준 · 교신저자 정재민, 김용진

, , , , , , , , , , , , ,
Noninvasive Imaging of Myocardial Inflammation in Myocarditis using 68Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography.
Theranostics. 2017;7(2):413-424.

Abstract
The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized ⁶⁸Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with ⁶⁸Ga. The efficacy of ⁶⁸Ga-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue. ⁶⁸Ga-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31~0.33) for normal versus 1.02 (0.86~1.06) for myocarditis (median (range), SUV); n=4~6 per group, p-value=0.01). ⁶⁸Ga-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42~3.40) for normal versus 4.18 (3.43~6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value<0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59~3.86) for myocarditis versus 2.28 (1.76~2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value<0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA. ⁶⁸Ga-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with ⁶⁸Ga-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocarditis.
PubMed IF 14.9 순환기내과
21752017

제1저자 김학령 · 교신저자 조주희

, , , , , ,
Association between arterial stiffness and left ventricular diastolic function in relation to gender and age.
Medicine (Baltimore). 2017;96(1):e5783.

Abstract
Left ventricular (LV) diastolic dysfunction and subsequent overt heart failure are more prevalent in elderly women. Close interaction between arterial stiffness and LV morphology/function has been reported. The aim of this study was to investigate whether there is an age- and gender-dependent relationship between arterial stiffness and LV diastolic function. A total of 819 subjects (58.6 ± 13.3 years, 50.2% men) without structural heart disease (LV ejection fraction ≥50%) were retrospectively analyzed. All participants underwent transthoracic echocardiography and brachial-ankle pulse wave velocity (baPWV) measurement on the same day. The association of baPWV with septal e' velocity and average E/e' was assessed. In the total study subjects, baPWV was negatively correlated with septal e' velocity (r = 0.383, P < 0.001), and positively correlated with E/e' (r = -0.266, P < 0.001). These linear correlations remained significant even after stratificaion of the study subjects by age (<65 years vs ≥65 years) and genders (P < 0.05 for each). There were obvious differences in baPWV according to groups with normal LV diastolic function, intermediate profile and LV diastolic dysfunction in young (P = 0.010) and elderly (≥65 years) women (P < 0.001) and eldery men (P = 0.012) but not in elderly men (P = 0.270). There was a significant association of baPWV with septal e' velocity (β = -0.258, P = 0.020) and E/e' (β = 0.122, P = 0.030) in elderly women even after controlling for multiple clinical covariates. This independent association was not seen in younger women and men (P > 0.05 for each). In conclusion, baPWV was independently associated with septal e' velocity and E/e' in elderly women but not in younger women or men. The results of this study provide additional evidence that increased arterial stiffness plays an important role in the development of heart failure with preserved ejection fraction as well as LV diastolic dysfunction in elderly women.
PubMed IF 2 순환기내과
21742017

제1저자 이진솔 · 교신저자 윤성수

, , , , ,
MCM7 polymorphisms associated with the AML relapse and overall survival.
Ann Hematol. 2017;96(1):93-98.

Abstract
The minichromosome maintenance complex component 7 (MCM7) encodes a member of MCM complex, which plays a critical role in the initiation of gene replication. Due to the importance of MCM complex, MCM7 gene has been regarded as a candidate gene for cancer development. In the present study, seven MCM7 polymorphisms were genotyped in 344 subjects composed of 103 acute myeloid leukemia (AML) patients and 241 normal controls to examine the possible associations between MCM7 polymorphisms and the risk of AML. MCM7 polymorphisms were not associated with the risk of AML (P > 0.05). However, MCM7 polymorphisms were significantly related to the relapse of AML and overall survival. The rs2070215 (N144S) showed a protective effect to the risk of AML relapse (OR = 0.37; P ^corr = 0.02). In haplotype analyses, the ht1 and ht2 showed significant associations with the risk of AML relapse (P ^corr = 0.02-0.03). In addition, rs1534309 showed an association with the overall survival of AML patients. Patients with major homozygote genotype (CC) of rs1534309 showed a higher survival rate than the patients with other genotypes (CG and GG). The results of the present study indicate that MCM7 polymorphisms may be able to predict the prognosis of AML patients.
PubMed IF 2.3 혈액종양내과
21732016

제1저자 최승진, 박상원 · 교신저자 오명돈

, , , , , , , , , , , , , , , , , , , , ,
Severe Fever with Thrombocytopenia Syndrome in South Korea, 2013-2015.
PLoS Negl Trop Dis. 2016;10(12):e0005264.

Abstract
BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was recently identified in China, South Korea and Japan. The objective of the study was to evaluate the epidemiologic and clinical characteristics of SFTS in South Korea.
METHODS/PRINCIPAL FINDINGS SFTS is a reportable disease in South Korea. We included all SFTS cases reported to the Korea Centers for Disease Control and Prevention (KCDC) from January 2013 to December 2015. Clinical information was gathered by reviewing medical records, and epidemiologic characteristics were analyzed using both KCDC surveillance data and patient medical records. Risk factors for mortality in patients with SFTS were assessed. A total of 172 SFTS cases were reported during the study period. SFTS occurred throughout the country, except in urban areas. Hilly areas in the eastern and southeastern regions and Jeju island (incidence, 1.26 cases /105 person-years) were the main endemic areas. The yearly incidence increased from 36 cases in 2013 to 81 cases in 2015. Most cases occurred from May to October. The overall case fatality ratio was 32.6%. The clinical progression was similar to the 3 phases reported in China: fever, multi-organ dysfunction, and convalescence. Confusion, elevated C-reactive protein, and prolonged activated partial thromboplastin times were associated with mortality in patients with SFTS. Two outbreaks of nosocomial SFTS transmission were observed.
CONCLUSIONS SFTS is an endemic disease in South Korea, with a nationwide distribution and a high case-fatality ratio. Confusion, elevated levels of C-reactive protein, and prolonged activated partial thromboplastin times were associated with mortality in patients with SFTS.
PubMed IF 3.6 감염내과
21722016

제1저자 박준원 · 교신저자 이은영

, , , , , ,
Impact of Dose Tapering of Tumor Necrosis Factor Inhibitor on Radiographic Progression in Ankylosing Spondylitis.
PLoS One. 2016;11(12):e0168958.

Abstract
OBJECTIVE To investigate the impact of dose reduction of tumor necrosis factor inhibitor (TNFi) on radiographic progression in ankylosing spondylitis (AS).
METHODS One hundred and sixty-five patients treated with etanercept or adalimumab were selected from a consecutive single-center observational cohort based on the availability of radiographs at baseline and after two- and/or four-years of follow up. Radiographs were assessed by two blinded readers using the modified Stokes AS Spinal Score (mSASSS). Radiographic progression in patients treated with standard-dose TNFi (standard-dose group, n = 49) was compared with patients whose dosage was tapered during the treatment (tapering group, n = 116) using linear mixed models.
RESULTS Baseline characteristics between two groups were comparable except for higher BASDAI (7.1 vs. 6.3, p = 0.003) in the standard-dose group. At two years after the treatment, mean dose quotient (S.D.) of the tapering group was 0.59 (0.17). During follow up, rate of radiographic progression in overall patients was 0.90 mSASSS units/year. Radiographic progression over time between the two groups was similar at the entire group level. However, in the subgroup of patients with baseline syndesmophytes, progression occurred significantly faster in the tapering group after the adjustment for baseline status (1.23 vs. 1.72 mSASSS units/year, p = 0.023). Results were consistent when radiographic progression was assessed by the number of newly developed syndesmophytes (0.52 vs. 0.73/year, p = 0.047). Sensitivity analysis after multiple imputation of missing radiographs also showed similar results.
CONCLUSION A dose tapering strategy of TNFi is associated with more rapid radiographic progression in AS patients who have syndesmophytes at baseline.
PubMed IF 2.8 류마티스내과
21712016

제1저자 김경영 · 교신저자 김정희

, , , , , , , ,
Disentangling of Malignancy from Benign Pheochromocytomas/Paragangliomas.
PLoS One. 2016;11(12):e0168413.

Abstract
OBJECTIVE Many malignant tumors initially appear benign but subsequently exhibit extensive metastases. Early identification of malignant pheochromocytomas and paragangliomas (PPGLs) before metastasis is important for improved prognosis. However, there are no robust prognostic indices of recurrence and malignancy. The aim of this study was to identify the clinical and histopathological factors that predict malignant PPGLs.
DESIGN Retrospective follow-up study.
METHODS In this study, we included 223 patients with pathologically confirmed PPGLs who were treated between 2000 and 2015 at the Seoul National University Hospital in South Korea.
RESULTS Of these patients, 29 were diagnosed with malignancy, 12 of whom presented with metastatic lesions at the initial diagnosis while 17 developed metastases during follow-up. Nineteen patients with recurrent PPGLs consisted of ones with malignant PPGLs (n = 17) and multifocal PPGLs (n = 2) who had VHL and RET mutations. The mean age at presentation for malignant PPGLs was significantly younger than that for benign PPGLs (43.0 vs. 49.0 years, respectively; p = 0.023). Tumor size was not a distinguishing factor between malignant and benign PPGLs (5.0 vs. 4.5 cm, respectively; p = 0.316) nor did it predict recurrence. Of 119 patients with available pheochromocytoma of adrenal gland scaled score (PASS) data, those with malignant PPGLs presented PASS values ≥4. Of 12 parameters of PASS, necrosis, capsular invasion, vascular invasion, cellular monotony, high mitosis, atypical mitotic figures, and nuclear hyperchromasia were significant predictors of malignancy.
CONCLUSIONS Tumor size did not predict malignancy or recurrence of PPGLs. PPGL patients with characteristic pathologic findings and PASS ≥4 or germline mutations require close follow-up.
PubMed IF 2.8 내분비대사내과
21702016

제1저자 이지은 · 교신저자 임수

, , , , , , , , ,
Comprehensive assessment of lipoprotein subfraction profiles according to glucose metabolism status, and association with insulin resistance in subjects with early-stage impaired glucose metabolism.
Int J Cardiol. 2016;225:327-331.

Abstract
BACKGROUND Early detection of atherogenic dyslipidemia is crucial. We investigated lipoprotein subfraction parameters according to glucose metabolism status.
METHODS We recruited 1255 lipid-lowering drug-naïve subjects with normal fasting glucose (NFG; n=200, 15.9%), impaired fasting glucose (IFG; n=443, 35.3%), or type 2 diabetes (T2D; n=612, 48.8%). Lipoprotein subfractions (1-7) were determined by polyacrylamide gel electrophoresis, separating low-density lipoprotein (LDL) into large buoyant LDL (lbLDL, LDL1-2) and small dense LDL (sdLDL, LDL3-7). Lipoprotein subfraction parameters including the sdLDL% (LDL3-7/LDL1-7), the sdLDL/lbLDL ratio (LDL3-7/LDL1-2), and weighted LDL subfraction (LDLSF) scores, were compared between groups. Their associations with insulin resistance, estimated using the homeostasis model assessment of insulin resistance, were examined.
RESULTS The concentrations of sdLDL particles were significantly higher in subjects with T2D and IFG than in those with NFG (15.78±13.47mg/dl and 14.60±14.33mg/dl, respectively, vs. 12.22±12.31mg/dl). Compared with those with NFG, subjects with IFG or T2D had significantly a higher sdLDL% (15.98±15.26% vs. 19.50±16.21% or 21.46±16.81%, respectively), a higher sdLDL/lbLDL ratio (0.24±0.30 vs. 0.31±0.37 or 0.35±0.39), and a higher LDLSF score (2.08±0.91 vs. 2.30±1.14 or 2.36±1.17). These lipoprotein subfraction parameters had stronger associations with insulin resistance compared to conventional lipid profiles in the IFG and T2D groups.
CONCLUSIONS Atherogenic dyslipidemia is initiated in an early stage of impaired glucose metabolism, when early intervention might be required.
PubMed IF 3.3 내분비대사내과
21692017

제1저자 김선욱 · 교신저자 김광일

, , , , , , ,
Clinical implication of frailty assessment in older patients with atrial fibrillation.
Arch Gerontol Geriatr. 2017;70:1-7.

Abstract
BACKGROUND We aimed to show the frailty status in older AF patients, and to find the association between frailty and the scores of CHA₂DS₂-VASc and HAS-BLED. Ultimately, we sought to investigate the impact of frailty on cardiovascular and all-cause mortality in older AF patients.
METHODS We retrospectively evaluated 365 patients (≥65years old) with AF, who underwent comprehensive geriatric assessment (CGA) between 2007 and 2014 in a single tertiary hospital. The CHA₂DS₂-VASc and HAS-BLED scores were calculated based on the electronic medical records and the frailty index was computed from the CGA data. The primary outcomes were cardiovascular and all-cause mortality.
RESULTS Frailty status was positively associated with the CHA₂DS₂-VASc score (P<0.001) and the HAS-BLED score (P=0.01). Patients with high CHA₂DS₂-VASc and HAS-BLED scores were more likely to be treated with anticoagulants rather than antiplatelet agents. However, frailty status was not associated with antithrombotic therapy. During the follow-up period (median [interquartile range], 22.9 [8.4-42.2] months), 141 patients (38.6%) died, of which 48 were due to cardiovascular events. CHA₂DS₂-VASc score could predict cardiovascular mortality, but not all-cause mortality. In contrast, frailty status was the independent predictor for both cardiovascular and all-cause mortality after adjusting for possible confounders (hazard ratio for all-cause mortality, 4.549; 95% CI, 2.756-7.509; P<0.001).
CONCLUSION Frailty assessment can be used to predict mortality in older AF patients, and provides additional prognostic value, along with the CHA₂DS₂-VASc and HAS-BLED scores.
PubMed IF 4.7 순환기내과
21682016

제1저자 이상훈 · 교신저자 박무석

, , , , , , , , , , , , ,
Characterization of microbiome in bronchoalveolar lavage fluid of patients with lung cancer comparing with benign mass like lesions.
Lung Cancer. 2016;102:89-95.

Abstract
OBJECTIVES Disruption in the stability of respiratory microbiota is known to be associated with many chronic respiratory diseases. However, only few studies have examined microbiomes in lung cancer. Therefore, we characterized and compared the microbiomes of patients with lung cancer and those with benign mass-like lesions.
MATERIALS AND METHODS Bronchoalveolar fluid was collected prospectively to evaluate lung masses in patients who had undergone bronchoscopies from May to September 2015. Twenty-eight patients (20 male, 8 female) were enrolled: 20 diagnosed with lung cancer and 8 diagnosed with benign diseases. Samples were analysed by 16S rRNA-based next-generation sequencing.
RESULTS The participants' mean age was 64±11years. Bacterial operational taxonomic units were classified into 26 phyla, 44 classes, 81 orders, 153 families, 288 genera, and 797 species. The relative abundance of two phyla (Firmicutes and TM7) was significantly increased in patients with lung cancer (p=0.037 and 0.035, respectively). Furthermore, two genera (Veillonella and Megasphaera) were relatively more abundant in lung cancer patients (p=0.003 and 0.022, respectively). The area under the curve of a combination of these two genera used to predict lung cancer was 0.888 (sensitivity=95.0%, specificity=75.0% and sensitivity=70.0%, specificity=100.0%; p=0.002).
CONCLUSION The results indicate that differences exist in the bacterial communities of patients with lung cancer and those with benign mass-like lesions. The genera Veillonella and Megasphaera showed the potential to serve as biomarkers to predict lung cancer. Thus, the lung microbiota may change the environment in patients with lung cancer.
PubMed IF 5.3 호흡기내과
21672016

제1저자 이승아 · 교신저자 윤연이

, , , , , , , , , , , , , , , ,
Long-Term Prognostic Value of Late Gadolinium-Enhanced Magnetic Resonance Imaging in Patients With and Without Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Grafting.
Am J Cardiol. 2016;118(11):1647-1654.

Abstract
The value of late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) for the prediction of functional recovery after surgical revascularization has been previously established. However, the impact of LGE-MRI on the long-term prognosis after coronary artery bypass grafting (CABG) remains incompletely understood. Therefore, we aimed to evaluate the long-term prognostic value of LGE-MRI, based on the presence or absence of left ventricular (LV) dysfunction, in patients with coronary artery disease undergoing CABG. One hundred forty-six consecutive patients underwent cine- and LGE-MRI before CABG. Adverse cardiac events included cardiac death, nonfatal myocardial infarction, heart failure, and unstable angina. A 3-year landmark analysis of the primary end point was also performed for patients surviving beyond 3 years after CABG. During a median follow-up of 9.4 years, 44 patients (30%) experienced adverse cardiac events. Although a LV ejection fraction <50% was associated only with adverse cardiac events at 3 years after CABG, LGE was associated with a worse outcome both at and beyond 3 years after CABG. In the overall study population, LGE presence (adjusted hazard ratio [HR] 2.58; p = 0.027), score (adjusted HR 1.06; p <0.001), and extent (adjusted HR 1.08; p <0.001) were independent predictors of adverse cardiac events. Moreover, in both the LV ejection fraction <50% and ≥50% groups, the LGE extent was an independent predictor of adverse cardiac events. In conclusion, our qualitative and quantitative analyses of LGE-MRI provide long-term prognostic information after surgical revascularization. The LGE extent was a strong predictor of adverse cardiac events, independent of the LV function.
PubMed IF 2.5 순환기내과
21662016

제1저자 김학령 · 교신저자 김명아

, , , , , , , , ,
Sex Difference in the Association Between Metabolic Syndrome and Left Ventricular Diastolic Dysfunction.
Metab Syndr Relat Disord. 2016;14(10):507-512.

Abstract
BACKGROUND Sex-related differences in the influence of metabolic syndrome (MetS) on various cardiovascular diseases have been suggested. The aim of this study was to investigate the effect of sex on the association between MetS and left ventricular (LV) diastolic dysfunction in patients with suspected coronary artery disease (CAD).
METHODS Two hundred ten patients (105 men and age-matched 105 women; mean age: 56.5 ± 10.9 years) undergoing elective coronary angiography for the evaluation of CAD were studied. MetS was defined according to the International Diabetes Federation criteria. LV diastolic function was assessed using transthoracic echocardiography.
RESULTS The incidence of MetS was 23.8% in men and 14.3% in women (P = 0.079). The incidence of LV diastolic dysfunction was significantly different by MetS in women, but not in men. In multiple linear regression analyses, the number of MetS components was independently associated with septal e' velocity, E/e', and left atrial (LA) diameter in women (P < 0.05 for each). In men, the number of MetS components was associated with only LA size in this analysis. As the number of components of MetS increased, septal e' velocity decreased proportionally in women (P < 0.001), but not in men (P = 0.117).
CONCLUSIONS Among middle-aged and elderly Korean patients at high risk of CAD, the impact of MetS on LV diastolic dysfunction was more pronounced in women than in men. This suggests the important role of sex hormonal effects in the development of LV diastolic dysfunction in relation to MetS in this population.
PubMed IF 1.6 순환기내과
21652016

제1저자 강아름 · 교신저자 김정희

, , , , , , , , ,
Sex differences in the prevalence of metabolic syndrome and its components in hypopituitary patients: comparison with an age- and sex-matched nationwide control group.
Pituitary. 2016;19(6):573-581.

Abstract
PURPOSE Hypopituitary patients have a reduced life expectancy owing to cardiovascular events. We investigated the prevalence of metabolic syndrome in hypopituitary patients for a follow-up period of at least 1 year in comparison with an age- and sex-matched nationwide control group.
METHODS A total of 515 patients with hypopituitarism who visited Seoul National University Hospital between January 2000 and December 2010 were included. Data for an age- and sex-matched control group were obtained from the Korean National Health and Nutrition Examination Surveys (KNHANES) (n = 1545). Metabolic syndrome was defined according to the modified National Cholesterol Education Program (NCEP-ATPIII).
RESULTS The prevalence of metabolic syndrome did not differ significantly between the hypopituitary and control groups for men (34.9 versus 30.3 %), but the risk of metabolic syndrome was higher in hypopituitary women than in controls (39.8 versus 28.5 %). In both sexes, the risks of central obesity and dyslipidemia were higher in the hypopituitary group than in the control group. Men had lower risks of hypertension and hyperglycemia in the hypopituitary group, which attenuated the risk of metabolic syndrome. Age greater than 40 years and obesity (BMI ≥25 kg/m²) contributed to a higher risk of metabolic syndrome.
CONCLUSIONS The metabolic syndrome prevalence was higher in the hypopituitry group than in the control group in Korean women, and this was attributed to an increased risk of central obesity and dyslipidemia. Accordingly, early intervention to reduce metabolic syndrome needed in hypopituitary patients, i.e. women.
PubMed IF 3.8 내분비대사내과
21642016

제1저자 오수연 · 교신저자 김나영

, , , , , ,
Effect of Helicobacter pylori Eradication and ABO Genotype on Gastric Cancer Development.
Helicobacter. 2016;21(6):596-605.

Abstract
BACKGROUND Evidence is lacking regarding how Helicobacter pylori infection status, eradication history, and ABO blood type affect the development of gastric cancer (GC) given the multifactorial and distinctive etiology according to cancer location (noncardia vs cardia) and histologic type (intestinal vs diffuse-type). We evaluated the effect of H. pylori infection status incorporated with H. pylori eradication history and ABO genotype on GC development according to cancer location and histologic type.
METHODS A case-control study of 997 patients with noncardia GC (NCGC) and 1147 control subjects was performed using risk analyses with 14 factors including H. pylori infection with eradication history and ABO genotype. As final analyses, multivariable logistic regression models were fitted. Additionally, H. pylori infection status with eradication history was tested for its association with age, atrophic gastritis (AG), and intestinal metaplasia (IM).
RESULTS The ABO genotype with the B allele was associated with a significantly lower risk of NCGC of both histologic types. The reduction in risk for NCGC by adding the B allele was more prominent in diffuse-type than that in the intestinal-type. H. pylori infection with eradication history was associated with a significantly lower risk of NCGC of both histologic types, compared with those without eradication history (odds ratio (OR), 0.22; 95% confidence interval (CI), 0.14-0.34) approaching that of uninfected subjects. Past infection status without an eradication history was associated with older age, AG, and IM.
CONCLUSIONS H. pylori eradication and the B allele decreased the risks of the intestinal and diffuse-types of NCGC. H. pylori eradication revealed a strong association against developing NCGC. Therefore, it should be considered as a primary measure in NCGC prevention.
PubMed IF 4.6 소화기내과
21632016

제1저자 곽낙원 · 교신저자 임재준

, , , , , ,
Non-tuberculous mycobacterial lung disease: diagnosis based on computed tomography of the chest.
Eur Radiol. 2016;26(12):4449-4456.

Abstract
OBJECTIVES To elucidate the accuracy and inter-observer agreement of non-tuberculous mycobacterial lung disease (NTM-LD) diagnosis based on chest CT findings.
METHODS Two chest radiologists and two pulmonologists interpreted chest CTs of 66 patients with NTM-LD, 33 with pulmonary tuberculosis and 33 with non-cystic fibrosis bronchiectasis. These observers selected one of these diagnoses for each case without knowing any clinical information except age and sex. Sensitivity and specificity were calculated according to degree of observer confidence. Inter-observer agreement was assessed using Fleiss' κ values. Multiple logistic regression was performed to elucidate which radiological features led to the correct diagnosis.
RESULTS The sensitivity of NTM-LD diagnosis was 56.4 % (95 % CI 47.9-64.7) and specificity 80.3 % (73.1-86.0). The specificity of NTM-LD diagnosis increased with confidence: 44.4 % (20.5-71.3) for possible, 77.4 % (67.4-85.0) for probable, 95.2 % (87.2-98.2) for definite (P < 0.001) diagnoses. Inter-observer agreement for NTM-LD diagnosis was moderate (κ = 0.453). Tree-in-bud pattern (adjusted odds ratio [aOR] 6.24, P < 0.001), consolidation (aOR 1.92, P = 0.036) and atelectasis (aOR 3.73, P < 0.001) were associated with correct NTM-LD diagnoses, whereas presence of pleural effusion (aOR 0.05, P < 0.001) led to false diagnoses.
CONCLUSIONS NTM-LD diagnosis based on chest CT findings is specific but not sensitive.
KEY POINTS • Diagnosis of NTM-LD based on radiological findings showed high specificity. • Sensitivity of NTM-LD diagnosis was around 50 %. • Inter- observer agreement was moderate. • Identification of tree-in-bud pattern, consolidation and atelectasis led to correct diagnoses.
PubMed IF 6 호흡기내과
21622016

제1저자 유정주 · 교신저자 윤정환

, , , , , , , ,
Differential sensitivity of hepatocellular carcinoma cells to suppression of hepatocystin transcription under hypoxic conditions.
J Bioenerg Biomembr. 2016;48(6):581-590.

Abstract
Mutations in the gene encoding hepatocystin/80 K-H (PRKCSH) cause autosomal dominant polycystic liver disease. Hepatocystin deficiency impairs glucosidase II activity, which is critical for processing and folding glycoproteins in the endoplasmic reticulum (ER). Hypoxia is known as a strong stimulus for generating survival signals in hepatocellular carcinoma (HCC) cells. However, hypoxia may induce cell apoptosis under conditions of severe ER stress. Thus, we hypothesized that suppression of hepatocystin transcription induces HCC cell death under hypoxic conditions due to excessive ER stress. A new human HCC cell line, SNU-3058, was established following primary culture of tumor cells harvested from a Korean patient with rapidly growing hypovascular HCC. In cell culture, human HCC cells (Huh-7, SNU-761, and SNU-3058) were treated with control siRNA or hepatocystin siRNA with or without doxorubicin under hypoxic conditions. Cell viability, ER stress, unfolded protein response (UPR), and apoptosis were assessed using the MTS assay, immunoblot assay, and RT-PCR. Suppression of hepatocystin transcription attenuated proliferation in Huh-7 and SNU-761 cells, while proliferation was amplified in SNU-3058 cells. Similar results were observed following treatment with doxorubicin. Hepatocystin siRNA transfection increased cell death in Huh-7 and decreased cell death in SNU-3058. In SNU-3058, hepatocystin siRNA amplified GRP78, known as a pro-survival and cyto-protective signal, and attenuated the pro-apoptotic signal CHOP. These findings suggest that suppression of hepatocystin transcription induce the UPR, which alleviates damage associated with ER stress in SNU-3058. UPR had a limited role in protecting SNU-761 cells, resulting in cell death through apoptosis. In addition, blocking of pro-survival UPR signal by bacitracin or GRP78 knockdown, attenuated hepatocystin siRNA-induced proliferation in SNU-3058 cells under hypoxia. In this study, we demonstrated that different sensitivities to hepatocystin siRNA among human HCC cell lines are dependent on appropriate UPRs to hypoxia-induced ER stress following hepatocystin siRNA transfection. Because UPR is the main evasive mechanism for apoptosis induced by suppression of hepatocystin, targeting hepatocystin via UPR suppression could be a strategy for treating HCC.
PubMed IF 3.7 소화기내과
21612016

제1저자 석기태, 윤정환 · 교신저자 배시현, 백순구

, , , , , , , , , , , , , , , , , , ,
Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial.
Hepatology. 2016;64(6):2185-2197.

Abstract
UNLABELLED Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has been suggested as an effective therapy for liver cirrhosis. The efficacy and safety of autologous BM-MSC transplantation in the treatment of alcoholic cirrhosis were investigated. Seventy-two patients with baseline biopsy-proven alcoholic cirrhosis who had been alcohol-abstinent for more than 6 months underwent a multicenter, randomized, open-label, phase 2 trial. Patients were randomly assigned to three groups: one control group and two autologous BM-MSC groups that underwent either one-time or two-time hepatic arterial injections of 5 × 10⁷ BM-MSCs 30 days after BM aspiration. A follow-up biopsy was performed 6 months after enrollment, and adverse events were monitored for 12 months. The primary endpoint was improvement in fibrosis quantification based on picrosirius red staining. The secondary endpoints included liver function tests, Child-Pugh score, and Model for End-stage Liver Disease score. Outcomes were analyzed by per-protocol analysis. In terms of fibrosis quantification (before versus after), the one-time and two-time BM-MSC groups were associated with 25% (19.5 ± 9.5% versus 14.5 ± 7.1%) and 37% (21.1 ± 8.9% versus 13.2 ± 6.7%) reductions in the proportion of collagen, respectively (P < 0.001). In the intergroup comparison, two-time BM-MSC transplantation in comparison with one-time BM-MSC transplantation was not associated with improved results in fibrosis quantification (P > 0.05). The Child-Pugh scores of both BM-MSC groups (one-time 7.6 ± 1.0 versus 6.3 ± 1.3 and two-time 7.8 ± 1.2 versus 6.8 ± 1.6) were also significantly improved following BM-MSC transplantation (P < 0.05). The proportion of patients with adverse events did not differ among the three groups.
CONCLUSION Autologous BM-MSC transplantation safely improved histologic fibrosis and liver function in patients with alcoholic cirrhosis. (Hepatology 2016;64:2185-2197).
PubMed IF 18 소화기내과
21602016

제1저자 하혜림 · 교신저자 오도연

, , , , , , , , , ,
Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy.
Oncotarget. 2016;7(47):76604-76612.

Abstract
Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (≥0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p<0.001). In multivariate analysis, high sPDL1 and NLR were independent poor prognostic factors. In conclusion, serum sPDL1 can be measured and has significant role on the prognosis of advanced BTC patients treated with palliative chemotherapy.
PubMed IF 5.008 혈액종양내과
21592016

제1저자 이주연 · 교신저자 송영욱

, , , ,
Circulating exosomes from patients with systemic lupus erythematosus induce an proinflammatory immune response.
Arthritis Res Ther. 2016;18(1):264.

Abstract
BACKGROUND Exosomes are involved in intercellular communication. The aim of this study was to investigate whether circulating exosomes effectively contribute to the inflammatory response in systemic lupus erythematosus (SLE).
METHODS Exosomes were purified from SLE patients and healthy controls (HCs). Healthy peripheral blood mononuclear cells (PBMCs) were stimulated with exosomes isolated from SLE patients and HCs in the presence or absence of Toll-like receptor (TLR) inhibitors. Production of interferon (IFN)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured. Correlation between exosome levels and SLE disease activity was examined.
RESULTS The serum exosomes levels were significantly higher in SLE patients than in HCs. SLE exosomes induced a higher production of IFN-α, TNF-α, IL-1β, and IL-6 compared to healthy exosomes. SLE serum that was depleted of exosomes and SLE exosomes that were mechanically disrupted failed to induce any significant cytokine production. Exosome-mediated production of TNF-α, IL-1β, and IL-6 was decreased by the TLR4 antagonist, whereas that of IFN-α was suppressed by the TLR1/2, TLR7, and TLR9 antagonists. Exosome levels correlated with disease activity in SLE patients (rho = 0.846, p = 0.008).
CONCLUSIONS The circulating exosomes are immunologically active and their levels correlate with disease activity in SLE patients. The circulating exosomes might serve as novel biomarkers of SLE disease activity.
PubMed IF 5.4 류마티스내과

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