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1.  Effects of Exercise Type on Hemodynamic Responses and Cardiac Events in ACS Patients 
[Purpose] This study investigated the effects of mid, and high exercise intensities on hemodynamic responses and cardiac events during two exercise types of treadmill exercise (TM) and cycle ergometer exercises (CE) in patients with acute coronary syndrome (ACS). [Subjects] Patients who had percutaneous coronary intervention (PCI) for ACS and were participating in cardiac rehabilitation program were included. [Methods] The patients were assessed for hemodynamic responses, cardiac events, and rate of perceived exertion (RPE) with target heart rates of 60% and 85% heart rate reserve (HRR) during TM and CE. [Results] Maximum systolic blood pressure (SBP), diastolic blood pressure (DBP), RPE, and rate pressure product (RPP) measured during CE were significantly higher than their values in TM at the same exercise intensities. The highest SBP was shown at 85% HRR during CE. SBPmax to SBPmax ratios obtained during the graded exercise test (GXT) showed that all %SBPmax were significantly greater in CE than in TM at the same exercise intensities. Out of 102 patients, cardiac events occurred in 8 at 85% HRR during CE, and 1 at 85% HRR during TM. Patients with cardiac events (CE-E) had significantly higher %SBP, %RPP, and RPE at 85% HRR than those without events (CE-NE) during CE. [Conclusion] Prescribing exercise based on the intensity obtained in a treadmill GXT may expose patients to cardiovascular complications such as higher RPP, higher exercise intensity, and cardiac events during CE.
PMCID: PMC3996432  PMID: 24764644
Treadmill; Cycle ergometer; Rate pressure product
3.  Structural importance of the C-terminal region in pig aldo-keto reductase family 1 member C1 and their effects on enzymatic activity 
Pig aldo-keto reductase family 1 member C1 (AKR1C1) belongs to AKR superfamily which catalyzes the NAD(P)H-dependent reduction of various substrates including steroid hormones. Previously we have reported two paralogous pig AKR1C1s, wild-type AKR1C1 (C-type) and C-terminal-truncated AKR1C1 (T-type). Also, the C-terminal region significantly contributes to the NADPH-dependent reductase activity for 5α-DHT reduction. Molecular modeling studies combined with kinetic experiments were performed to investigate structural and enzymatic differences between wild-type AKR1C1 C-type and T-type.
The results of the enzyme kinetics revealed that Vmax and kcat values of the T-type were 2.9 and 1.6 folds higher than those of the C-type. Moreover, catalytic efficiency was also 1.9 fold higher in T-type compared to C-type. Since x-ray crystal structures of pig AKR1C1 were not available, three dimensional structures of the both types of the protein were predicted using homology modeling methodology and they were used for molecular dynamics simulations. The structural comparisons between C-type and T-type showed that 5α-DHT formed strong hydrogen bonds with catalytic residues such as Tyr55 and His117 in T-type. In particular, C3 ketone group of the substrate was close to Tyr55 and NADPH in T-type.
Our results showed that 5α-DHT binding in T-type was more favorable for catalytic reaction to facilitate hydride transfer from the cofactor, and were consistent with experimental results. We believe that our study provides valuable information to understand important role of C-terminal region that affects enzymatic properties for 5α-DHT, and further molecular mechanism for the enzyme kinetics of AKR1C1 proteins.
PMCID: PMC4310174  PMID: 25583233
Aldo-keto reductase; Homology modeling; Molecular dynamic simulation; NADPH-dependent reduction; Steroid hormone
4.  Reference Values of Body Composition Indices: The Korean National Health and Nutrition Examination Surveys 
Yonsei Medical Journal  2014;56(1):95-102.
An increase in the prevalence of obesity has been observed in children and adolescents. As remarkable changes in body composition occur with growth during the adolescent period, it is important that changes in body composition be monitored. The purpose of this study was to propose reference percentile values for body composition indices including body mass index (BMI) in children and adolescents in Korea.
Materials and Methods
This study was performed using data from the Fourth and Fifth Korea National Health and Nutrition Examination Surveys. Body composition data were obtained using dual-energy X-ray absorptiometry. The percentile curves of body composition indices were constructed by the LMS method.
A total of 2123 children and adolescents between the ages of 10 and 19 years were included in this study. We obtained the percentile curves for BMI and body composition indices.
The reference values for body composition from this study could help with assessing body composition in Korean adolescents.
PMCID: PMC4276783  PMID: 25510752
Body mass index; percent body fat; fat mass index; fat-free mass index; adolescent
5.  Impact of hemoglobin A1c-based criterion on diagnosis of prediabetes: The Korea National Health and Nutrition Examination Survey 2011 
To examine the impact of hemoglobin A1c (HbA1c) criterion on the diagnosis of prediabetes in Koreans, we analyzed nationally representative cross-sectional data of 5,845 Korean adults aged ≥20 years from the Fifth Korea National Health and Nutrition Examination Survey 2011. Standardized prevalence rates of prediabetes in Korean adults by fasting plasma glucose (FPG; 5.6–6.9 mmol/L), HbA1c (5.7–6.4% [39–46 mmol/mol]), and combined criteria were 16.9, 28.4 and 33.8%, respectively. Among the subjects with prediabetes, 16% met FPG criteria only, 55% met HbA1c criteria only and 29% met both criteria. Prediabetic subjects who met HbA1c criteria only were significantly older, more likely to be women, and had lower hemoglobin and serum iron concentrations, whereas those who met FPG criteria only had higher body mass index, waist circumference, systolic and diastolic blood pressure. In conclusion, introduction of HbA1c criterion markedly increased the prevalence of prediabetes in Koreans, and the two criteria identified people with different characteristics.
PMCID: PMC4296703  PMID: 25621133
Fasting plasma glucose; Hemoglobin A1c; Prediabetes
6.  Epimedium koreanum Nakai Displays Broad Spectrum of Antiviral Activity in Vitro and in Vivo by Inducing Cellular Antiviral State 
Viruses  2015;7(1):352-377.
Epimedium koreanum Nakai has been extensively used in traditional Korean and Chinese medicine to treat a variety of diseases. Despite the plant’s known immune modulatory potential and chemical make-up, scientific information on its antiviral properties and mode of action have not been completely investigated. In this study, the broad antiviral spectrum and mode of action of an aqueous extract from Epimedium koreanum Nakai was evaluated in vitro, and moreover, the protective effect against divergent influenza A subtypes was determined in BALB/c mice. An effective dose of Epimedium koreanum Nakaimarkedly reduced the replication of Influenza A Virus (PR8), Vesicular Stomatitis Virus (VSV), Herpes Simplex Virus (HSV) and Newcastle Disease Virus (NDV) in RAW264.7 and HEK293T cells. Mechanically, we found that an aqueous extract from Epimedium koreanum Nakai induced the secretion of type I IFN and pro-inflammatory cytokines and the subsequent stimulation of the antiviral state in cells. Among various components present in the extract, quercetin was confirmed to have striking antiviral properties. The oral administration of Epimedium koreanum Nakai exhibited preventive effects on BALB/c mice against lethal doses of highly pathogenic influenza A subtypes (H1N1, H5N2, H7N3 and H9N2). Therefore, an extract of Epimedium koreanum Nakai and its components play roles as immunomodulators in the innate immune response, and may be potential candidates for prophylactic or therapeutic treatments against diverse viruses in animal and humans.
PMCID: PMC4306843  PMID: 25609307
Epimedium koreanum Nakai; herbal medicine; quercetin; antiviral effect; anti-influenza Effect
7.  Overexpression of sphingosine-1-phosphate receptor 1 and phospho-signal transducer and activator of transcription 3 is associated with poor prognosis in rituximab-treated diffuse large B-cell lymphomas 
BMC Cancer  2014;14(1):911.
Sphingosine-1-phosphate receptor-1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) play important roles in immune responses with potential oncogenic roles.
We analyzed S1PR1/STAT3 pathway activation using immunohistochemistry in rituximab-treated diffuse large B-cell lymphomas (DLBCL; N = 103).
Nuclear expression of pSTAT3 (but not S1PR1) was associated with non-GCB phenotype (p = 0.010). In univariate survival analysis, S1PR1 expression (S1PR1+) was a poor prognostic factor in total DLBCLs (p = 0.018), as well as in nodal (p = 0.041), high-stage (III, IV) (p = 0.002), and high-international prognostic index (IPI; 3–5) (p = 0.014) subgroups, while nuclear expression of pSTAT3 (pSTAT3+) was associated with poor prognosis in the low-stage (I, II) subgroup (p = 0.022). The S1PR1/pSTAT3 risk-categories, containing high-risk (S1PR1+), intermediate-risk (S1PR1-/pSTAT3+), and low-risk (S1PR1-/pSTAT3-), predicted overall survival (p = 0.010). This prognostication tended to be valid in each stage (p = 0.059 in low-stage; p = 0.006 in high-stage) and each IPI subgroups (p = 0.055 [low-IPI]; p = 0.034 [high-IPI]). S1PR1 alone and S1PR1/pSTAT3 risk-category were significant independent prognostic indicators in multivariate analyses incorporating IPI and B symptoms (S1PR1 [p = 0.005; HR = 3.0]; S1PR1/pSTAT3 risk-category [p = 0.019: overall; p = 0.024, HR = 2.7 for S1PR1-/pSTAT3+ vs. S1PR1+; p = 0.021, HR = 3.8 for S1PR1-/pSTAT3- vs. S1PR1+]).
Therefore, S1PR1 and S1PR1/pSTAT3 risk-category may contribute to risk stratification in rituximab-treated DLBCLs, and S1PR1 and STAT3 might be therapeutic targets for DLBCL.
PMCID: PMC4265452  PMID: 25472725
S1PR1; pSTAT3; Diffuse large B-cell lymphoma; Prognosis
8.  Dietary Magnesium Intake and Metabolic Syndrome in the Adult Population: Dose-Response Meta-Analysis and Meta-Regression 
Nutrients  2014;6(12):6005-6019.
Increasing evidence has suggested an association between dietary magnesium intake and metabolic syndrome. However, previous research examining dietary magnesium intake and metabolic syndrome has produced mixed results. Our objective was to determine the relationship between dietary magnesium intake and metabolic syndrome in the adult population using a dose-response meta-analysis. We searched the PubMed, Embase and the Cochrane Library databases from August, 1965, to May, 2014. Observational studies reporting risk ratios with 95% confidence intervals (CIs) for metabolic syndrome in ≥3 categories of dietary magnesium intake levels were selected. The data extraction was performed independently by two authors, and the quality of the studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). Based on eight cross-sectional studies and two prospective cohort studies, the pooled relative risks of metabolic syndrome per 150 mg/day increment in magnesium intake was 0.88 (95% CI, 0.84–0.93; I2 = 36.3%). The meta-regression model showed a generally linear, inverse relationship between magnesium intake (mg/day) and metabolic syndrome. This dose-response meta-analysis indicates that dietary magnesium intake is significantly and inversely associated with the risk of metabolic syndrome. However, randomized clinical trials will be necessary to address the issue of causality and to determine whether magnesium supplementation is effective for the prevention of metabolic syndrome.
PMCID: PMC4277012  PMID: 25533010
magnesium intake; metabolic syndrome; meta-analysis; meta-regression
9.  Effect of recombinant human bone morphogenetic protein-2 on bisphosphonate-treated osteoblasts 
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphophonate therapy that has been reported in recent years. Osteoclastic inactivity by bisphosphonate is the known cause of BRONJ. Bone morphogenetic protein-2 (BMP-2) plays an important role in the development of bone. Recombinant human BMP-2 (rhBMP-2) is potentially useful as an activation factor for bone repair. We hypothesized that rhBMP-2 would enhance the osteoclast-osteoblast interaction related to bone remodeling.
Materials and Methods
Human fetal osteoblast cells (hFOB 1.19) were treated with 100 µM alendronate, and 100 ng/mL rhBMP-2 was added. Cells were incubated for a further 48 hours, and cell viability was measured using an MTT assay. Expression of the three cytokines from osteoblasts, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF), were analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay.
Cell viability was decreased to 82.75%±1.00% by alendronate and then increased to 110.43%±1.35% after treatment with rhBMP-2 (P<0.05, respectively). OPG, RANKL, and M-CSF expression were all decreased by alendronate treatment. RANKL and M-CSF expression were increased, but OPG was not significantly affected by rhBMP-2.
rhBMP2 does not affect OPG gene expression in hFOB, but it may increase RANKL and M-CSF gene expression.
PMCID: PMC4279973  PMID: 25551094
Bone morphogenetic protein-2; Alendronate; Osteoblasts; Macrophage colony-stimulating factor; RANK ligand
10.  Cardiac Rehabilitation After Acute Myocardial Infarction Resuscitated From Cardiac Arrest 
Annals of Rehabilitation Medicine  2014;38(6):799-804.
To examine the safety and effectiveness of cardiac rehabilitation on patients resuscitated from cardiac arrest due to acute myocardial infarction.
The study included 23 subjects, including 8 with history of cardiac arrest and 15 without history of cardiac arrest. Both groups underwent initial graded exercise test (GXT) and subsequent cardiac rehabilitation for 6 weeks. After 6 weeks, both groups received follow-up GXT.
Statistically significant (p<0.05) increase of VO2peak and maximal MVO2 but significant (p<0.05) decrease of submaximal MVO2 and resting heart rate were observed in both groups after 6 weeks of cardiac rehabilitation. An increasing trend of maximal heart rates was observed in both groups. However, the increase was not statistically significant (p>0.05). There was no statistically significant change of resting heart rate, maximal heart rate, maximal MVO2, or submaximal MVO2 in both groups after cardiac rehabilitation. Fatal cardiac complications, such as abnormal ECG, cardiac arrest, death or myocardial infarction, were not observed. All subjects finished the cardiac rehabilitation program.
Improvement was observed in the exercise capacity of patients after aerobic exercise throughout the cardiac rehabilitation program. Therefore, cardiac rehabilitation can be safely administered for high-risk patients with history of cardiac arrest. Similar improvement in exercise capacity can be expected in patients without cardiac arrest experience.
PMCID: PMC4280376  PMID: 25566479
Cardiac arrest; Myocardial infarction; Rehabilitation
11.  Clinical Characteristics and Metabolic Features of Patients with Adrenal Incidentalomas with or without Subclinical Cushing's Syndrome 
Endocrinology and Metabolism  2014;29(4):457-463.
The aim of this study was to examine the clinical characteristics of adrenal incidentalomas discovered by computed tomography (CT) and to investigate metabolic features of subclinical Cushing's syndrome (SCS) in patients with adrenal incidentalomas in a tertiary hospital in Korea.
This retrospective study examined the clinical aspects of 268 patients with adrenal incidentalomas discovered by CT at Soonchunhyang University Bucheon Hospital. Clinical data and endocrine function of the patients as well as histological findings were obtained from medical records, while anatomic characteristics were analyzed by reviewing imaging studies. Hormonal tests for pheochromocytoma, Cushing's syndrome, and aldosterone-secreting adenoma were performed.
Most (n=218, 81.3%) cases were nonfunctioning tumors. Of the 50 patients with functioning tumors (18.7%), 19 (7.1%) were diagnosed with SCS, nine (3.4%) with overt Cushing's syndrome, 12 (4.5%) with primary aldosteronism, and 10 (3.7%) with pheochromocytoma. Malignant tumors (both primary and metastatic) were rare (n=2, 0.7%). Body mass index, fasting glucose, hemoglobin A1c, and total cholesterol were significantly higher in patients with SCS in comparison with those with nonfunctioning tumors. The prevalence of type 2 diabetes mellitus and hypertension were significantly higher in patients with SCS compared with those with nonfunctioning tumors.
Functioning tumors, especially those with subclinical cortisol excess, are commonly found in patients with adrenal incidentalomas, although malignancy is rare. In addition, patients with SCS in adrenal incidentalomas have adverse metabolic and cardiovascular profiles.
PMCID: PMC4285048  PMID: 25325264
Adrenal incidentalomas; Metabolic features; Subclinical Cushing's syndrome
12.  The ACTN3 R577X variant in sprint and strength performance 
The aim of this study is to examine the association between the distribution of ACTN3 genotypes and alleles in power, speed, and strength-oriented athletics.
ACTN3 genotyping was carried out for a total of 975 Korean participants: top-level sprinters (n = 58), top-level strength athletes (n = 63), and healthy controls (n = 854).
Genetic associations were evaluated by chi-squire test or Fisher’s exact test. In the power-oriented group composed of sprinters and strength athletes, the frequency of the XX genotype was significantly underrepresented (11.6%) in comparison to its representation in the control group (11.6% versus 19.1%, P < 0.05). When the power-oriented group was divided into strength-oriented and speed-oriented groups, no significant difference in the ACTN3 XX genotype was found between the strength-oriented athletes and the controls (15.9% versus 19.1%, P < 0.262). Only the speed-oriented athletes showed significant differences in the frequency distributions of the ACTN3 XX genotype (6.9% versus 19.1%, P < 0.05) from that of the controls.
The ACTN3 genotype seems to mainly affect sports performance and especially speed.
PMCID: PMC4322025  PMID: 25671201
α-actinin-3; human performance; population genetics; fast-twitch muscle fibers; contractile property
13.  Primary percutaneous coronary intervention ameliorates complete atrioventricular block complicating acute inferior myocardial infarction 
Complete atrioventricular block (CAVB) in acute inferior ST-segment elevation myocardial infarction (STEMI) is associated with poor clinical outcomes after noninvasive treatment. This study was designed to determine the effect of primary percutaneous coronary intervention (PCI) in patients with CAVB complicating acute inferior STEMI, at a single center.
We enrolled 138 consecutive patients diagnosed with STEMI involving the inferior wall; of these, 27 patients had CAVB. All patients received primary PCI. The clinical characteristics, procedural data, and clinical outcomes were compared in patients with versus without CAVB.
Baseline clinical characteristics were similar between patients with and without CAVB. Patients with CAVB were more likely to present with cardiogenic shock, and CAVB was caused primarily by right coronary artery occlusion. Door-to-balloon time was similar between those two groups. After primary PCI, CAVB was reversed in all patients. The peak creatinine phosphokinase level, left ventricular ejection fraction and in-hospital mortality rate were similar between the two groups. After a median follow up of 318 days, major adverse cardiac events did not differ between the groups (8.1% in patients without CAVB; 11.1% in patients with CAVB) (P=0.702).
We conclude that primary PCI can ameliorate CAVB-complicated acute inferior STEMI, with an acceptable rate of major adverse cardiac events, and suggest that primary PCI should be the preferred reperfusion therapy in patients with CAVB complicating acute inferior myocardial infarction.
PMCID: PMC4246926  PMID: 25473274
major adverse cardiac events; PCI-capable hospital
14.  RNA-Seq Analysis and De Novo Transcriptome Assembly of Jerusalem Artichoke (Helianthus tuberosus Linne) 
PLoS ONE  2014;9(11):e111982.
Jerusalem artichoke (Helianthus tuberosus L.) has long been cultivated as a vegetable and as a source of fructans (inulin) for pharmaceutical applications in diabetes and obesity prevention. However, transcriptomic and genomic data for Jerusalem artichoke remain scarce. In this study, Illumina RNA sequencing (RNA-Seq) was performed on samples from Jerusalem artichoke leaves, roots, stems and two different tuber tissues (early and late tuber development). Data were used for de novo assembly and characterization of the transcriptome. In total 206,215,632 paired-end reads were generated. These were assembled into 66,322 loci with 272,548 transcripts. Loci were annotated by querying against the NCBI non-redundant, Phytozome and UniProt databases, and 40,215 loci were homologous to existing database sequences. Gene Ontology terms were assigned to 19,848 loci, 15,434 loci were matched to 25 Clusters of Eukaryotic Orthologous Groups classifications, and 11,844 loci were classified into 142 Kyoto Encyclopedia of Genes and Genomes pathways. The assembled loci also contained 10,778 potential simple sequence repeats. The newly assembled transcriptome was used to identify loci with tissue-specific differential expression patterns. In total, 670 loci exhibited tissue-specific expression, and a subset of these were confirmed using RT-PCR and qRT-PCR. Gene expression related to inulin biosynthesis in tuber tissue was also investigated. Exsiting genetic and genomic data for H. tuberosus are scarce. The sequence resources developed in this study will enable the analysis of thousands of transcripts and will thus accelerate marker-assisted breeding studies and studies of inulin biosynthesis in Jerusalem artichoke.
PMCID: PMC4222968  PMID: 25375764
15.  Nonthermal Plasma Induces Apoptosis in ATC Cells: Involvement of JNK and p38 MAPK-Dependent ROS 
Yonsei Medical Journal  2014;55(6):1640-1647.
To determine the effects of nonthermal plasma (NTP) induced by helium (He) alone or He plus oxygen (O2) on the generation of reactive oxygen species (ROS) and cell death in anaplastic thyroid cancer cells.
Materials and Methods
NTP was generated in He alone or He plus O2 blowing through a nozzle by applying a high alternating current voltage to the discharge electrodes. Optical emission spectroscopy was used to identify various excited plasma species. The apoptotic effect of NTP on the anaplastic thyroid cancer cell lines, such as HTH83, U-HTH 7, and SW1763, was verified with annexin V/propidium staining and TUNEL assay. ROS formation after NTP treatment was identified with fluorescence-activated cell sorting with DCFDA staining. The mitogen-activated protein kinase pathways and caspase cascade were investigated to evaluate the molecular mechanism involved and cellular targets of plasma.
NTP induced significant apoptosis in all three cancer cell lines. The plasma using He and O2 generated more O2-related species, and increased apoptosis and intracellular ROS formation compared with the plasma using He alone. NTP treatment of SW1763 increased the expression of phosphor-JNK, phosphor-p38, and caspase-3, but not phosphor-ERK. Apoptosis of SW1763 as well as expressions of elevated phosphor-JNK, phosphor-p38, and caspase-3 induced by NTP were effectively inhibited by intracellular ROS scavengers.
NTP using He plus O2 induced significant apoptosis in anaplastic cancer cell lines through intracellular ROS formation. This may represent a new promising treatment modality for this highly lethal disease.
PMCID: PMC4205706  PMID: 25323903
Nonthermal plasma; ROS; anaplastic thyroid cancer; apoptosis; helium; oxygen
16.  Expression of Nuclear Factor Erythroid 2 Protein in Malignant Cutaneous Tumors 
Archives of Plastic Surgery  2014;41(6):654-660.
Reactive oxygen species (ROS) damages cell molecules, and modifies cell signaling. The nuclear factor E2-related factor (Nrf2) is a critical transcription regulator, which protects cells against oxidative damage. Nrf2 expression is increased in a large number of cancers. However, little information has been reported regarding the expression of Nrf2 in skin cancers. Hence, we explored the expression of Nrf2 protein in skin cancers.
The Nrf2 protein expression in 24 specimens, including 6 malignant melanomas (MM), 6 squamous cell carcinomas (SCC), 6 basal cell carcinomas (BCC), and 6 normal skin tissues, was evaluated by western blotting. Immunohistochemical staining was performed. The expression of Kelch-like ECH-associated protein 1 (Keap1), the key regulator of Nrf2, was also analyzed by western blotting.
Small interfering RNA transfection to the melanoma cell line G361 confirmed that an approximately 66 kDa band was the true Nrf2 band. The western blot revealed that the Nrf2 protein was definitely expressed in normal skin tissues, but the Nrf2 expression was decreased in MM, SCC, and BCC. Immunohistochemical examination showed that expression of Nrf2 was decreased in all skin cancer tissues compared to the normal skin tissues. Keap1 was not expressed in all malignant skin tumors and normal skin tissues by western blot.
ROS was increased in various types of cancers which proteins were highly expressed or underexpressed. This study demonstrated that the expression of Nrf2 protein was down-regulated in human malignant skin tumors. We suggest that decreased expression of Nrf2 is related to skin cancers.
PMCID: PMC4228206  PMID: 25396176
NF-E2-related factor 2; Reactive oxygen species; Skin neoplasms
17.  Effect of Endogenous Bone Marrow Derived Stem Cells Induced by AMD-3100 on Expanded Ischemic Flap 
Journal of Korean Medical Science  2014;29(Suppl 3):S237-S248.
The purpose of this study was to devise an expanded ischemic flap model and to investigate the role of AMD-3100 (Plerixafor, chemokine receptor 4 inhibitor) in this model by confirming its effect on mobilization of stem cells from the bone marrow. Male Sprague-Dawley rats were used as an animal research model. The mobilization of stem cells from the bone marrow was confirmed in the AMD-3100-treated group. The fractions of endothelial progenitor cells (EPC) and the vascular endothelial growth factor receptor (VEGFR) 2+ cells in the peripheral blood were increased in groups treated with AMD-3100. The expression of vascular endothelial growth factor (VEGF) was increased in response to expansion or AMD injection. The expression of stromal cell derived factor (SDF)-1 and VEGFR2 were increased only in unexpanded flap treated with AMD-3100. Treatment with AMD-3100 increased both the number and area of blood vessels. However, there were no statistically significant differences in the survival area or physiologic microcirculation in rats from the other groups. This endogenous neovascularization induced by AMD-3100 may be a result of the increase in both the area and number of vessels, as well as paracrine augmentation of the expression of VEGF and EPCs. However, the presence of a tissue expander under the flap could block the neovascularization between the flap and the recipient regardless of AMD-3100 treatment and expansion.
Graphical Abstract
PMCID: PMC4248011  PMID: 25473215
Endothelial Progenitor Cell; Hematopoietic Stem Cell; Tissue Expansion; Ischemic Flap; AMD-3100; CXCR4 Inhibitor; Plerixafor
18.  Comparative Analysis of the Mitochondrial Physiology of Pancreatic β Cells 
Bioenergetics : open access  2014;3(1):110-.
The mitochondrial metabolism of β cells is thought to be highly specialized. Its direct comparison with other cells using isolated mitochondria is limited by the availability of islets/β cells in sufficient quantity. In this study, we have compared mitochondrial metabolism of INS1E/β cells with other cells in intact and permeabilized states. To selectively permeabilize the plasma membrane, we have evaluated the use of perfringolysin-O (PFO) in conjunction with microplate-based respirometry. PFO is a protein that binds membranes based on a threshold level of active cholesterol. Therefore, unless active cholesterol reaches a threshold level in mitochondria, they are expected to remain untouched by PFO. Cytochrome c sensitivity tests showed that in PFO-permeabilized cells, the mitochondrial integrity was completely preserved. Our data show that a time-dependent decline of the oligomycin-insensitive respiration observed in INS1E cells was due to a limitation in substrate supply to the respiratory chain. We predict that it is linked with the β cell-specific metabolism involving metabolites shuttling between the cytoplasm and mitochondria. In permeabilized β cells, the Complex l-dependent respiration was either transient or absent because of the inefficient TCA cycle. The TCA cycle insufficiency was confirmed by analysis of the CO2 evolution. This may be linked with lower levels of NAD+, which is required as a co-factor for CO2 producing reactions of the TCA cycle. β cells showed comparable OxPhos and respiratory capacities that were not affected by the inorganic phosphate (Pi) levels in the respiration medium. They showed lower ADP-stimulation of the respiration on different substrates. We believe that this study will significantly enhance our understanding of the β cell mitochondrial metabolism.
PMCID: PMC4190029  PMID: 25309834
Mitochondrial metabolism; Oxidative phosphorylation; OxPhos; Respiratory chain; Perfringolysin-O; Respirometry
19.  A Phase II Study of Ifosfamide, Methotrexate, Etoposide, and Prednisolone for Previously Untreated Stage I/II Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Multicenter Trial of the Korean Cancer Study Group 
The Oncologist  2014;19(11):1129-1130.
Combination chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) was active as first-line and second-line treatment for extranodal natural killer/T-cell lymphoma (NTCL).
Forty-four patients with chemo-naïve stage I/II NTCL were enrolled in a prospective, multicenter, phase II study and received six cycles of IMEP (ifosfamide 1.5 g/m2 on days 1–3; methotrextate 30 mg/m2 on days 3 and 10; etoposide 100 mg/m2 on days 1–3; and prednisolone 60 mg/m2 per day on days 1–5) followed by involved field radiotherapy (IFRT).
Overall response rates were 73% (complete remission [CR] in 11 of 41 evaluable patients [27%]) after IMEP chemotherapy and 78% (CR 18 of 27 evaluable patients [67%]) after IMEP followed by IFRT. Neutropenia and thrombocytopenia were documented in 33 patients (75%) and 7 patients (16%), respectively. Only 8 patients (18%) experienced febrile neutropenia. Three-year progression-free survival (PFS) and overall survival (OS) were 66% and 56%, respectively. High Ki-67 (≥70%) and Ann Arbor stage II independently reduced PFS (p = .004) and OS (p = .001), respectively.
Due to the high rate of progression during IMEP chemotherapy, IFRT needs to be introduced earlier. Moreover, active chemotherapy including an l-asparaginase-based regimen should be use to reduce systemic treatment failure in stage I/II NTCL.
PMCID: PMC4221378  PMID: 25280488
20.  ARS-Interacting Multi-Functional Protein 1 Induces Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Accumulation of β-Catenin via Fibroblast Growth Factor Receptor 2-Mediated Activation of Akt 
Stem Cells and Development  2013;22(19):2630-2640.
ARS-Interacting Multi-functional Protein 1 (AIMP1) is a cytokine that is involved in the regulation of angiogenesis, immune activation, and fibroblast proliferation. In this study, fibroblast growth factor receptor 2 (FGFR2) was isolated as a binding partner of AIMP peptide (amino acids 6–46) in affinity purification using human bone marrow-derived mesenchymal stem cells (BMMSCs). AIMP1 peptide induced the proliferation of adult BMMSCs by activating Akt, inhibiting glycogen synthase kinase-3β, and thereby increasing the level of β-catenin. In addition, AIMP1 peptide induced the translocation of β-catenin to the nucleus and increased the transcription of c-myc and cyclin D1 by activating the β-catenin/T-cell factor (TCF) complex. By contrast, transfection of dominant negative TCF abolished the effect of AIMP1. The inhibition of Akt, using LY294002, abolished the accumulation and nuclear translocation of β-catenin induced by AIMP1, leading to a decrease in c-myc and cyclin D1 expression, which decreased the proliferation of BMMSCs. An intraperitoneal injection of AIMP1 peptide into C57/BL6 mice increased the colony formation of fibroblast-like cells. Fluorescence activated cell sorting analysis showed that the colony-forming cells were CD29+/CD44+/CD90+/CD105+/CD34−/CD45−, which is characteristic of MSCs. In addition, the fibroblast-like cells differentiated into adipocytes, chondrocytes, and osteocytes. Taken together, these data suggest that AIMP1 peptide promotes the proliferation of BMMSCs by activating the β-catenin/TCF complex via FGFR2-mediated activation of Akt, which leads to an increase in MSCs in peripheral blood.
PMCID: PMC3780312  PMID: 23672191
21.  Acanthopanax sessiliflorus stem confers increased resistance to environmental stresses and lifespan extension in Caenorhabditis elegans 
Nutrition Research and Practice  2014;8(5):526-532.
Acanthopanax sessiliflorus is a native Korean plant and used as traditional medicine or an ingredient in many Korean foods. The free radical theory of aging suggests that cellular oxidative stress caused by free radicals is the main cause of aging. Free radicals can be removed by cellular anti-oxidants.
Here, we examined the anti-oxidant activity of Acanthopanax sessiliflorus extract both in vitro and in vivo. Survival of nematode C. elegans under stress conditions was also compared between control and Acanthopanax sessiliflorus extract-treated groups. Then, anti-aging effect of Acanthopanax sessiliflorus extract was monitored in C. elegans.
Stem extract significantly reduced oxidative DNA damage in lymphocyte, which was not observed by leaves or root extract. Survival of C. elegans under oxidative-stress conditions was significantly enhanced by Acanthopanax sessiliflorus stem extract. In addition, Acanthopanax sessiliflorus stem increased resistance to other environmental stresses, including heat shock and ultraviolet irradiation. Treatment with Acanthopanax sessiliflorus stem extract significantly extended both mean and maximum lifespan in C. elegans. However, fertility was not affected by Acanthopanax sessiliflorus stem.
Different parts of Acanthopanax sessiliflorus have different bioactivities and stem extract have strong anti-oxidant activity in both rat lymphocytes and C. elegans, and conferred a longevity phenotype without reduced reproduction in C. elegans, which provides conclusive evidence to support the free radical theory of aging.
PMCID: PMC4198965  PMID: 25324932
Acanthopanax sessiliflorus; Caenorhabditis elegans; lifespan; stress response; fertility
22.  Multicenter Validation Study of a Prognostic Index for Portal Vein Tumor Thrombosis in Hepatocellular Carcinoma 
We previously reported on a staging system and prognostic index (PITH) for portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) patients treated with radiotherapy (RT) at a single institution. The aim of this study is to validate the PITH staging system using data from patients at other institutions and to compare it with other published staging systems.
Materials and Methods
A total of 994 HCC patients with PVTT who were treated with RT between 1998 and 2011 by the Korean Radiation Oncology Group were analyzed retrospectively. All patients were staged using the Cancer of the Liver Italian Program (CLIP), Japanese Integrated Staging (JIS), Okuda, and PITH staging systems, and survival data were analyzed. The likelihood ratio, Akaike information criteria (AIC), time-dependent receiver operating characteristics, and prediction error curve analysis were used to determine discriminatory ability for comparison of staging systems.
The median survival was 9.2 months. Compared with the other staging systems, the PITH score gave the highest values for likelihood ratio and lowest AIC values, demonstrating that PITH may be a better prognostic model. Although the values were not significant and differences were not exceptional, the PITH score showed slightly better performance with respect to time-dependent area under curve and integrated Brier score of prediction error curve.
The PITH staging system was validated in this multicenter retrospective study and showed better stratification ability in HCC patients with PVTT than other systems.
PMCID: PMC4206074  PMID: 25036573
Hepatocellular carcinoma; Portal vein; Radiotherapy; Multicenter study; Validation
23.  Metastasis of Colon Cancer to Medullary Thyroid Carcinoma: A Case Report 
Journal of Korean Medical Science  2014;29(10):1432-1435.
Metastasis to the primary thyroid carcinoma is extremely rare. We report here a case of colonic adenocarcinoma metastasis to medullary thyroid carcinoma in a 53-yr old man with a history of colon cancer. He showed a nodular lesion, suggesting malignancy in the thyroid gland, in a follow-up examination after colon cancer surgery. Fine needle aspiration biopsy (FNAB) of the thyroid gland showed tumor cell clusters, which was suspected to be medullary thyroid carcinoma (MTC). The patient underwent a total thyroidectomy. Using several specific immunohistochemical stains, the patient was diagnosed with colonic adenocarcinoma metastasis to MTC. To the best of our knowledge, the present patient is the first case of colonic adenocarcinoma metastasizing to MTC. Although tumor-tumor metastasis to primary thyroid carcinoma is very rare, we still should consider metastasis to the thyroid gland, when a patient with a history of other malignancy presents with a new thyroid finding.
Graphical Abstract
PMCID: PMC4214946  PMID: 25368499
Colorectal Neoplasms; Thyroid Neoplasms; Neoplasm Metastasis
24.  Pathobiological features of a novel, highly pathogenic avian influenza A(H5N8) virus 
The endemicity of highly pathogenic avian influenza (HPAI) A(H5N1) viruses in Asia has led to the generation of reassortant H5 strains with novel gene constellations. A newly emerged HPAI A(H5N8) virus caused poultry outbreaks in the Republic of Korea in 2014. Because newly emerging high-pathogenicity H5 viruses continue to pose public health risks, it is imperative that their pathobiological properties be examined. Here, we characterized A/mallard duck/Korea/W452/2014 (MDk/W452(H5N8)), a representative virus, and evaluated its pathogenic and pandemic potential in various animal models. We found that MDk/W452(H5N8), which originated from the reassortment of wild bird viruses harbored by migratory waterfowl in eastern China, replicated systemically and was lethal in chickens, but appeared to be attenuated, albeit efficiently transmitted, in ducks. Despite predominant attachment to avian-like virus receptors, MDk/W452(H5N8) also exhibited detectable human virus-like receptor binding and replicated in human respiratory tract tissues. In mice, MDk/W452(H5N8) was moderately pathogenic and had limited tissue tropism relative to previous HPAI A(H5N1) viruses. It also induced moderate nasal wash titers in inoculated ferrets; additionally, it was recovered in extrapulmonary tissues and one of three direct-contact ferrets seroconverted without shedding. Moreover, domesticated cats appeared to be more susceptible than dogs to virus infection. With their potential to become established in ducks, continued circulation of A(H5N8) viruses could alter the genetic evolution of pre-existing avian poultry strains. Overall, detailed virological investigation remains a necessity given the capacity of H5 viruses to evolve to cause human illness with few changes in the viral genome.
PMCID: PMC4217095
avian influenza virus; genetic evolution; HPAI A(H5N8); migratory waterfowl; reassortment
25.  Elective tracheostomy scoring system for severe oral disease patients 
The purpose of this research was to create a scoring system that provides comprehensive assessment of patients with oromaxillofacial cancer or odontogenic infection, and to statistically reevaluate the results in order to provide specific criteria for elective tracheostomy.
Materials and Methods
All patients that had oral cancer surgery (group A) or odontogenic infection surgery (group B) during a period of 10 years (2003 to 2013) were subgrouped according to whether or not the patient received a tracheostomy. After a random sampling (group A: total of 56, group B: total of 60), evaulation procedures were observed based on the group classifications. For group A, four factors were evaluated: TNM stage, reconstruction methods, presence of pathologic findings on chest posterior-anterior (PA), and the number of systemic diseases. Scores were given to each item based on the scoring system suggested in this research and the scores were added together. Similarly, the sum score of group B was counted using 5 categories, including infection site, C-reactive protein level on first visit, age, presence of pathologic findings on chest PA, and number of systemic diseases.
The scoring system rendered from this research shows that there is a high correlation between the scores and TNM stage in oral cancer patients, or infection sites in odontogenic infection patients. However, no correlation between pathologic findings on chest PA could be found in either group. The results also indicated that for both groups, the hospital day increased with the tracheostomy score. The tracheostomy score cutoff value was 5 in oral cancer patients and 6 in odontogenic infection patients which was used for elective tracheostomy indication.
The elective tracheostomy score system suggested by this research is a method that considers both the surgical and general conditions of the patient, and can be very useful for managing patients with severe oral disease.
PMCID: PMC4217265  PMID: 25368833
Tracheostomy; Scoring system; Airway management; Mouth neoplasms; Odontogenic infection

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