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2.  Effects of Takju intake and moderate exercise training on brain acetylcholinesterase activity and learning ability in rats 
Nutrition Research and Practice  2011;5(4):294-300.
Takju is a Korean alcoholic beverage made from rice, and is brewed with the yeast Saccharomyces cerevisiae. This study was conducted to evaluate the effects of exercise training and moderate Takju consumption on learning ability in 6-week old Sprague-Dawley male rats. The rats were treated with exercise and alcohol for 4 weeks in six separate groups as follows: non-exercised control (CC), exercised control (EC), non-exercised consuming ethanol (CA), exercised consuming ethanol (EA), non-exercised consuming Takju (CT), and exercised consuming Takju (ET). An AIN-93M diet was provided ad libitum. Exercise training was performed at a speed of 10 m/min for 15 minutes per day. Ethanol and Takju were administered daily for 6-7 hours to achieve an intake of about 10 ml after 12 hours of deprivation, and, thereafter, the animals were allowed free access to deionized water. A Y-shaped water maze was used from the third week to understand the effects of exercise and alcohol consumption on learning and memory. After sacrifice, brain acetylcholinesterase (AChE) activity was analyzed. Total caloric intake and body weight changes during the experiment were not significantly different among the groups. AChE activity was not significantly different among the groups. The number of errors for position reversal training in the maze was significantly smaller in the EA group than that in the CA and ET groups, and latency times were shorter in the EA group than those in the CC, EC, CT, and ET groups. The latency difference from the first to the fifth day was shortest in the ET group. The exercised groups showed more errors and latency than those of the non-exercised groups on the first day, but the data became equivalent from the second day. The results indicate that moderate exercise can increase memory and learning and that the combination of exercise and Takju ingestion may enhance learning ability.
doi:10.4162/nrp.2011.5.4.294
PMCID: PMC3180679  PMID: 21994523
Takju intake; exercise training; water maze; AChE; learning ability
3.  Synergistic enhancement of NK cell-mediated cytotoxicity by combination of histone deacetylase inhibitor and ionizing radiation 
Background
The overexpression of histone deacetylase (HDAC) and a subsequent decrease in the acetylation levels of nuclear histones are frequently observed in cancer cells. Generally it was accepted that the deacetylation of histones suppressed expression of the attached genes. Therefore, it has been suggested that HDAC might contribute to the survival of cancer cells by altering the NKG2D ligands transcripts. By the way, the translational regulation of NKG2D ligands remaines unclear in cancer cells. It appears the modulation of this unclear mechanism could enhance NKG2D ligand expressions and the susceptibility of cancer cells to NK cells. Previously, it was reported that irradiation can increase the surface expressions of NKG2D ligands on several cancer cell types without increasing the levels of NKG2D ligand transcripts via ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related (ATM-ATR) pathway, and suggested that radiation therapy might be used to increase the translation of NKG2D ligands.
Methods
Two NSCLC cell lines, that is, A549 and NCI-H23 cells, were used to investigate the combined effects of ionizing radiation and HDAC inhibitors on the expressions of five NKG2D ligands. The mRNA expressions of the NKG2D ligands were quantitated by multiplex reverse transcription-PCR. Surface protein expressions were measured by flow cytometry, and the susceptibilities of cancer cells to NK cells were assayed by time-resolved fluorometry using the DELFIA® EuTDA cytotoxicity kit and by flow cytometry.
Results
The expressions of NKG2D ligands were found to be regulated at the transcription and translation levels. Ionizing radiation and HDAC inhibitors in combination synergistically increased the expressions of NKG2D ligands. Furthermore, treatment with ATM-ATR inhibitors efficiently blocked the increased translations of NKG2D ligands induced by ionizing radiation but did not block the increased ligand translations induced by HDAC inhibitors. The study confirms that increased NKG2D ligand levels by ionizing radiation and HDAC inhibitors could synergistically enhance the susceptibilities of cancer cells to NK-92 cells.
Conclusions
This study suggests that the expressions of NKG2D ligands are regulated in a complex manner at the multilevel of gene expression, and that their expressions can be induced by combinatorial treatments in lung cancer cells.
doi:10.1186/1748-717X-9-49
PMCID: PMC3923253  PMID: 24512718
NKG2D ligands; HDAC inhibitors; Ionizing radiation; Radioresistance
4.  Effects of poly-γ-glutamic acid on serum and brain concentrations of glutamate and GABA in diet-induced obese rats 
Poly-gamma-glutamic acid (γ-PGA) is a mucilaginous and biodegradable compound produced by Bacillus subtilis from fermented soybeans, and is found in the traditional Korean soy product, cheongkukjang. This study was carried out to evaluate the effects of γ-PGA from a food source on the concentration of the neurotransmitter GABA and its metabolic precursor glutamate in diet-induced obese rats. Eight-week old male Sprague-Dawley rats (n=60) were used. The rats were divided into two groups and obesity was induced by providing either a 10% control fat or 45% high fat diet for 5 weeks. The rats were then blocked into 6 groups and supplemented with a 0.1% γ-PGA diet for 4 weeks. After sacrifice, brain and serum GABA and glutamate concentrations were analyzed by high performance liquid chromatography with fluorometric detection. The rats fed the high fat diet had significantly increased body weights. γ-PGA supplementation significantly increased serum concentrations of glutamate and GABA in the control fat diet groups while this effect was not found in the high fat groups. In the brain, glutamate concentrations were significantly higher in the γ-PGA supplemented groups both in rats fed the normal and high fat diets than in the no γ-PGA controls. GABA concentrations showed the same tendency. The results indicated that γ-PGA intake increased GABA concentrations in the serum and brain. However, the effects were not shown in obese rats.
doi:10.4162/nrp.2010.4.1.23
PMCID: PMC2830410  PMID: 20198205
Poly-gamma-glutamic acid (γ-PGA); glutamate; γ-aminobutyric acid (GABA)
5.  Neuropathic truncal pain in patients with type 2 diabetes mellitus relieved by topical cream and nerve block 
doi:10.3904/kjim.2014.29.1.120
PMCID: PMC3932384  PMID: 24574843
Diabetes; Nerve block; Neuropathy
6.  A novel PRF1 gene mutation in a fatal neonate case with type 2 familial hemophagocytic lymphohistiocytosis 
Korean Journal of Pediatrics  2014;57(1):50-53.
Hemophagocytic lymphohistiocytosis (HLH) occurs in the primary form (genetic or familial) or secondary form (acquired). The familial form of HLH (FHL) is a potentially fatal autosomal recessive disorder that occurs because of constitutional defects in cell-mediated cytotoxicity. Here, we report a fatal neonatal case of type 2 FHL (FHL2) that involved a novel frameshift mutation. Clinically, the newborn presented with severe sepsis-like features and required mechanical ventilation and continuous venovenous hemodiafiltration. Flow cytometry analysis showed marked HLH and complete absence of intracytoplasmic perforin expression in cytotoxic cells; therefore, we performed molecular genetic analyses for PRF1 mutations, which showed that the patient had a compound heterozygous mutation in PRF1, that is, c.65delC (p.Pro22Argfs*2) and c.1090_1091delCT (p.Leu364Glufs*93). Clinical and genetic assessments for FHL are required for neonates with refractory fever and progressive multiple organ failure, particularly when there is no evidence of microbiological or metabolic cause.
doi:10.3345/kjp.2014.57.1.50
PMCID: PMC3935114  PMID: 24578718
FHL2; PRF1; Mutation; Neonate
7.  Factors Associated With the Time to Next Attack in Neuromyelitis Optica: Accelerated Failure Time Models With Random Effects 
PLoS ONE  2013;8(12):e82325.
Background and Objective
Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system with a relapsing and remitting course. We aimed to identify factors associated with the time to next attack, including the effect of the natural disease course and the diverse treatment regimens, by applying a longitudinal statistical analysis to the individual attacks of each patient.
Methods
In total, 184 acute attacks among 58 patients with either NMO or NMO spectrum disorder with anti-aquaporin-4 antibody were assessed retrospectively. Patient demographics, clinical characteristics at each attack, and type of treatment during inter-attack periods were assessed. The dependent variable was defined as the time from each attack to the next attack (inter-attack interval). An exponential accelerated failure time model with shared gamma frailty was adapted for statistical analysis.
Results
A multivariable analysis revealed that the time from each attack to the next attack in NMO increased independently by 1.31 times (95% confidence interval (CI), 1.02–1.67; p = 0.035) with each additional cumulative attack experienced, by 5.34 times (95% CI, 1.57–18.13; p = 0.007) with combined azathioprine treatment and continued oral prednisolone, and by 4.26 times (95% CI, 1.09–16.61; p = 0.037) with rituximab treatment.
Conclusion
The time to next attack in NMO can increase naturally in the later stages of the disease as the number of cumulative attacks increases. Nevertheless, both combined azathioprine treatment with continued oral prednisolone and rituximab treatment were also associated with a longer time to next attack, independently of the natural disease course of NMO.
doi:10.1371/journal.pone.0082325
PMCID: PMC3864949  PMID: 24358171
9.  Molecular Cytogenetic Analysis of Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia 
The aims of this study were to estimate the incidences of BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions in childhood acute lymphoblastic leukemia (ALL), to identify new abnormalities, and to demonstrate the usefulness of interphase fluorescence in situ hybridization (FISH). We performed G-banding analysis and FISH using probes for BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions on 65 childhood ALL patients diagnosed and uniformly treated at a single hospital. Gene rearrangements were identified in 73.8% of the patients using the combination of G-banding and FISH, while the chromosomal abnormalities were identified in 49.2% using G-banding alone. Gene rearrangements were disclosed by FISH in 24 (72.7%) of 33 patients with normal karyotype or no mitotic cell in G-banding. Among the gene rearrangements detected by FISH, the most common gene rearrangement was p16 deletion (20.3%) and the incidences of others were 14.1% for TEL/AML1, 11.3% for MLL, and 1.8% for BCR/ABL translocations. Infrequent or new aberrations such as AML1 amplification, MLL deletion, ABL deletion, and TEL/AML1 fusion with AML1 deletion were also observed. We established the rough incidences of gene rearrangements in childhood ALL, found new abnormalities and demonstrated the diagnostic capability of interphase FISH to identify cryptic chromosome aberrations.
doi:10.3346/jkms.2005.20.1.36
PMCID: PMC2808572  PMID: 15716599
In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Acute; Childhood; Gene Rearrangements
10.  De novo CD5 Positive Diffuse Large B-cell Lymphomas with Bone Marrow Involvement in Korean 
Journal of Korean Medical Science  2004;19(6):815-819.
In CD5 positive (CD5+) mature B-cell lymphomas, newly recognized CD5+ diffuse large B-cell lymphoma (DLBCL) has been characterized by aggressive features. We studied twenty-five cases with CD5+ lymphomas involving bone marrow. Eleven cases were diagnosed as chronic lymphocytic leukemia, six cases were diagnosed as mantle cell lymphoma (MCL), and three cases with morphologic characteristics of MCL and without both the cyclin D1 expression and IGH/CCND1 rearrangement were unclassifiable. The remaining five cases, showing large to medium-sized lym-phoid cells with prominent nucleoli and a moderate amount of cytoplasm, were diagnosed as DLBCL. Five DLBCL cases were positive for CD5, CD20, surface immuno-globulin, but negative for CD23. Patients with CD5+ DLBCL showed a high age of onset (median, 68 yr) and two patients expired one month after the diagnosis. Since CD5+ DLBCL forms a distinct subgroup of DLBCL, a study of CD5 expression in DLBCL would be helpful to predict prognosis and to determine future therapeutic strategy. To the best of our knowledge, this is the first report on de novo CD5+ DLBCL in Koreans.
doi:10.3346/jkms.2004.19.6.815
PMCID: PMC2816303  PMID: 15608391
Antigens, CD5; Leukemia, Lymphocytic, Chronic; Lymphoma, Mantle-Cell; Lymphoma, Large-Cell, Diffuse
11.  Sequence variation data of F8 and F9 genes in functionally validated control individuals: implications on the molecular diagnosis of hemophilia 
Blood research  2013;48(3):206-210.
Background
The F8 and F9 genes encode for coagulation factor VIII (FVIII) and FIX, respectively, and mutations in these genes are the genetic basis of hemophilia A/B. To determine whether a sequence variation in F8/F9 is a disease-causing mutation, frequency data from a control population is needed. This study aimed to obtain data on sequence variation in F8/F9 in a set of functionally validated control chromosomes of Korean descent.
Methods
We re-sequenced F8 and F9 from DNA samples of 100 Korean male control individuals with normal PT, aPTT, and FVIII activity. PCR and direct sequencing analyses were performed using primer pairs to cover all coding regions and the flanking intronic sequences.
Results
Thirteen individuals (13%) were hemizygous for sequence variations in the coding region of F8. Six (6%) had c.3780C>G (p.Asp1260Glu), five (5%) had c.3864A>C (p.Ser1288=). One each individual (1%) had c.4794G>T (p.Glu1598Asp) and c.5069 A>G (p.Glu1690Gly). Asp1260Glu and Ser1288= were known SNPs (rs1800291 and rs1800292, respectively). Glu1598Asp was assigned as a missense mutation in public databases (HGMD and HAMSTeRS), and Glu1690Gly was a novel variation. Based on the normal FVIII activities in control individuals carrying these variations (109% and 148%, respectively), they were considered to be rare SNPs. No variation was observed in F9 of control individuals.
Conclusion
A significant proportion of control individuals carried sequence variations in F8, but not in F9. These results can be used as a reference dataset for molecular diagnosis of hemophilia A and B, particularly in Korea.
doi:10.5045/br.2013.48.3.206
PMCID: PMC3786281  PMID: 24086941
Hemophilia; F8; F9; Sequence variation; Control population; Korea
12.  Accuracy of Diagnostic Methods and Surveillance Sensitivity for Human Enterovirus, South Korea, 1999–2011 
Emerging Infectious Diseases  2013;19(8):1268-1275.
The epidemiology of enteroviral infection in South Korea during 1999–2011 chronicles nationwide outbreaks and changing detection and subtyping methods used over the 13-year period. Of 14,657 patients whose samples were tested, 4,762 (32.5%) samples were positive for human enterovirus (human EV); as diagnostic methods improved, the rate of positive results increased. A seasonal trend of outbreaks was documented. Genotypes enterovirus 71, echovirus 30, coxsackievirus B5, enterovirus 6, and coxsackievirus B2 were the most common genotypes identified. Accurate test results correlated clinical syndromes to enterovirus genotypes: aseptic meningitis to echovirus 30, enterovirus 6, and coxsackievirus B5; hand, foot and mouth disease to coxsackievirus A16; and hand, foot and mouth disease with neurologic complications to enterovirus 71. There are currently no treatments specific to human EV infections; surveillance of enterovirus infections such as this study provides may assist with evaluating the need to research and develop treatments for infections caused by virulent human EV genotypes.
doi:10.3201/eid.1908.130496
PMCID: PMC3739515  PMID: 23876671
human enterovirus; surveillance; prevalence; genotype; cell culture; RT-PCR; real time RT-PCR; the Republic of Korea; South Korea; Korea Centers for Disease Control and Prevention; viruses
14.  The improvement of ginsenoside accumulation in Panax ginseng as a result of γ-irradiation 
Journal of Ginseng Research  2013;37(3):332-340.
In this study, gamma rays were used to irradiate embryogenic calli induced from cotyledon explants of Panax ginseng Meyer. After the embryogenic calli were irradiated, they were transferred to adventitious roots using an induction medium; next, mutated adventitious root (MAR) lines with a high frequency of adventitious root formations were selected. Two MAR lines (MAR 5-2 and MAR 5-9) from the calli treated with 50 Gy of gamma rays were cultured on an NH4NO3-free Murashige and Skoog medium with indole-3-butyric acid 3 mg/L. The expression of genes related to ginsenoside biosynthesis was analyzed using reverse transcription polymerase chain reaction with RNA prepared from native ginseng (NG), non-irradiated adventitious root (NAR) and 2 MAR lines. The expression of the squalene epoxidase and dammarenediol synthase genes was increased in the MAR 5-2 line, whereas the phytosterol synthase was increased in the MAR 5-9 line. The content and pattern of major ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1) were analyzed in the NG, NAR, and 2 MAR lines (MAR 5-2 and MAR 5-9) using TLC and HPLC. In the TLC analysis, the ginsenoside patterns in the NG, NAR, and 2 MAR lines were similar; in contrast, the MAR 5-9 line showed strong bands of primary ginsenosides. In the HPLC analysis, compared with the NG, one new type of ginsenoside was observed in the NAR and 2 MAR lines, and another new type of ginsenoside was observed in the 2 MAR lines irradiated with gamma rays. The ginsenoside content of the MAR 5-9 line was significantly greater in comparison to the NG.
doi:10.5142/jgr.2013.37.332
PMCID: PMC3818960  PMID: 24198659
Panax ginseng; Gamma irradiation; Ginsenoside; HPLC; TLC
15.  Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells 
Background. Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. Methodology/Principal Findings. Combined treatment of decursin and doxorubicin significantly exerted significant cytotoxicity compared to doxorubicin or decursin in U266, RPMI8226, and MM.1S cells. Furthermore, the combination treatment enhanced the activation of caspase-9 and -3, the cleavage of PARP, and the sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment downregulated the phosphorylation of mTOR and its downstream S6K1 and activated the phosphorylation of ERK in three multiple myeloma cells. Furthermore, the combined treatment reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells. Conversely, tyrosine phosphatase inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activation induced by combined treatment of doxorubicin and decursin in U266 cells. Conclusions/Significance. Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.
doi:10.1155/2013/506324
PMCID: PMC3684033  PMID: 23818927
16.  Increasing and Worsening Late Effects in Childhood Cancer Survivors during Follow-up 
Journal of Korean Medical Science  2013;28(5):755-762.
Recent advances in childhood cancer treatment have increased survival rates to 80%. Two out of three survivors experience late effects (LEs). From a group of 241 survivors previously described, 193 were followed at the long-term follow-up clinic (LTFC) of Severance Hospital in Korea; the presence of LEs was confirmed by oncologists. We reported the change in LEs during 3 yr of follow-up. The median follow-up from diagnosis was 10.4 yr (5.1-26.2 yr). Among 193 survivors, the percentage of patients with at least one LE increased from 63.2% at the initial visit to 75.1% at the most recent visit (P = 0.011). The proportion of patients having multiple LEs and grade 2 or higher LEs increased from the initial visit (P = 0.001 respectively). Forty-eight non-responders to the LTFC were older and had less frequent and severe LEs than responders at initial visit (all P < 0.05). In multivariate analysis, younger age at diagnosis, older age at initial visit, a diagnosis of a brain tumor or lymphoma, and use of radiotherapy were significant risk factors for LEs (all P < 0.05). Adverse changes in LEs were seen among the survivors, regardless of most clinical risk factors. They need to receive comprehensive, long-term follow up.
doi:10.3346/jkms.2013.28.5.755
PMCID: PMC3653090  PMID: 23678269
Complications; Health; Late Effects; Morbidity; Neoplasms; Survivors
17.  Coercively Adjusted Auto Regression Model for Forecasting in Epilepsy EEG 
Recently, data with complex characteristics such as epilepsy electroencephalography (EEG) time series has emerged. Epilepsy EEG data has special characteristics including nonlinearity, nonnormality, and nonperiodicity. Therefore, it is important to find a suitable forecasting method that covers these special characteristics. In this paper, we propose a coercively adjusted autoregression (CA-AR) method that forecasts future values from a multivariable epilepsy EEG time series. We use the technique of random coefficients, which forcefully adjusts the coefficients with −1 and 1. The fractal dimension is used to determine the order of the CA-AR model. We applied the CA-AR method reflecting special characteristics of data to forecast the future value of epilepsy EEG data. Experimental results show that when compared to previous methods, the proposed method can forecast faster and accurately.
doi:10.1155/2013/545613
PMCID: PMC3655454  PMID: 23710252
18.  Therapeutic Potential of Dioscorea Extract (DA-9801) in Comparison with Alpha Lipoic Acid on the Peripheral Nerves in Experimental Diabetes 
Journal of Diabetes Research  2013;2013:631218.
DA-9801, a mixture of extracts from Dioscorea japonica Thunb. and Dioscorea nipponica Makino, was reported to have neurotrophic activity. Therefore, we investigated the therapeutic potential of DA-9801, in comparison with alpha lipoic acid (ALA), for peripheral nerves preservation in experimental diabetes. Experimental animals were divided into 4 groups, and each group was designated according to the type of treatment administered as follows: normal, DM, DM+DA-9801, and DM+ALA. After 16 weeks, response thresholds to tactile and thermal stimuli were higher in DM+DA-9801 group than in nontreated DM group. This degree of increase in DM+DA-9801 group indicates more therapeutic potency of DA-9801 than ALA. Western blot analysis showed more significant increase in NGF and decrease in TNF-α and IL-6 in DM+DA-9801 group than in DM or DM+ALA groups (P < 0.05). IENF density was reduced less significantly in the DM+DA-9801 group than in other DM groups (7.61 ± 0.32, 4.2 ± 0.26, and 6.5 ± 0.30 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Mean myelinated axonal area in the sciatic nerves was significantly greater in DM+DA-9801 group than in other DM groups (69.2 ± 5.76, 54.0 ± 6.32, and 63.1 ± 5.41 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Results of this study demonstrated potential therapeutic applications of DA-9801 for the treatment of diabetic peripheral neuropathy.
doi:10.1155/2013/631218
PMCID: PMC3647555  PMID: 23671883
19.  Therapy-Related Myeloid Neoplasms in 39 Korean Patients: A Single Institution Experience 
Annals of Laboratory Medicine  2013;33(2):97-104.
Background
Therapy-related myeloid neoplasms (t-MN) occur as late complications of cytotoxic therapy. This study reviewed clinical and cytogenetic characteristics of patients with t-MN at a single institution in Korea.
Methods
The study subjects included 39 consecutive patients diagnosed with t-MN. Each subject's clinical history of previous diseases, treatments, and laboratory data was reviewed, including cytogenetics. The primary diagnosis was hematologic malignancy in 14 patients and solid tumor in 25 patients.
Results
Therapy-related acute myeloid leukemia (t-AML, 66.7%) was found to be more common than therapy-related myelodysplastic syndrome (t-MDS). Primary hematologic malignancies that were commonly implicated included mature B-cell neoplasm and acute leukemia. Breast cancer was the most common primary solid tumor. The mean time interval from cytotoxic therapy initiation to t-MN detection was 49 months. Chromosomal aberrations were observed in 35 patients, and loss of chromosome 5, 7, or both accounted for 41% of all cases. Balanced rearrangements occurred in 13 patients; these patients showed shorter latency intervals (mean, 38 months) than patients with loss of chromosome 5 or 7 (mean, 61 months).
Conclusions
In this study, we determined the clinical and cytogenetic characteristics of Korean patients with t-MN. Although our results were generally consistent with those of previous reports, we found that t-MN resulting from de novo leukemia was common and that t-AML was more common than t-MDS at presentation. Multi-institutional studies involving a larger number of patients and additional parameters are required to investigate the epidemiology, genetic predisposition, and survival rate of t-MN in Korea.
doi:10.3343/alm.2013.33.2.97
PMCID: PMC3589647  PMID: 23483787
Therapy-related neoplasms; Myelodysplastic syndrome; Acute myeloid leukemia; Cytogenetics; Korea
20.  ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression 
Cancer research  2011;71(22):7010-7020.
Prostaglandin E2 (PGE2), the most abundant COX-2–derived prostaglandin found in colorectal cancer, promotes tumor cell proliferation and survival via multiple signaling pathways. However, the role of PGE2 in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE2 and hypoxia on enhancing ANGPTL4 expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE2 induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE2 receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by its antagonist inhibits PGE2 induction of ANGPTL4 under hypoxic conditions. Importantly, over-expression of ANGPTL4 promotes cell proliferation and tumor growth in vitro and in vivo. In addition, treatment with ANGPTL4 recombinant protein increases colorectal carcinoma cell proliferation through effects on STAT1 signaling. The MAPK and Src pathways mediate ANGPTL4-induced STAT1 expression and activation. These results are relevant to human disease since we found that the expression of ANGPTL4 and STAT1 are elevated in 50% of human colorectal cancers tested and there is a positive correlation between COX-2 and ANGPTL4 as well STAT1 expression in colorectal carcinomas. Collectively, these findings suggest that PGE2 plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions.
doi:10.1158/0008-5472.CAN-11-1262
PMCID: PMC3217078  PMID: 21937683
PGE2; hypoxia; ANGPTL4; colorectal cancer; proliferation
21.  Prostaglandin E2 promotes intestinal tumor growth via DNA methylation 
Nature Medicine  2012;18(2):224-226.
Although DNA methylation is one of the critical ways for silencing tumor suppressor and DNA repair genes during tumor initiation and progression, the mechanisms underlying DNA methylation in cancer remain unclear. Here we show that prostaglandin E2 (PGE2) silences certain tumor suppressor and DNA repair genes via DNA methylation to promote tumor growth. These findings uncover a previously unrecognized role for PGE2 in the promotion of tumor progression.
doi:10.1038/nm.2608
PMCID: PMC3274627  PMID: 22270723
22.  The antihypertensive effect of ethyl acetate extract of radish leaves in spontaneously hypertensive rats 
Nutrition Research and Practice  2012;6(4):308-314.
Radish (Raphanus sativus L.) is a cruciferous vegetable, and its leaves have antioxidant and anticancer properties. This study was conducted to evaluate the effects of ethyl acetate extracts from radish leaves on hypertension in 11-week-old spontaneously hypertensive rats (SHRs). The SHRs were randomly divided into 3 groups of 6 rats each on the basis of initial systolic blood pressure (SBP) and were treated with oral administration of radish leaf extract (0, 30, or 90 mg/kg body weight [bw], respectively) for 5 weeks. Six Wistar rats were used as normotensive controls. The amount of the radish leaf extract had no effect on body weight. The SBP of the SHRs showed a decreasing trend with the consumption of the radish leaf extract. In the third week, the SBP of the group fed 90 mg extract/kg bw reduced from 214 mmHg to 166 mmHg and was significantly lower than that of the normotensive and hypertensive controls. The extract did not show a significant effect on the angiotensin-converting enzyme (ACE) activity in the serum, kidney, and lung. The extract increased the concentration of NO in serum and the activities of antioxidant enzymes such as glutathione peroxidase and catalase in red blood cells (RBCs). The serum concentrations of Na+ and K+ were not significantly different between all groups. However, the fecal concentrations of Na+ and K+ increased; the fecal concentrations of Na+ and K+ for the normotensive and hypertensive controls were not different. Urinary excretion of Na+ was higher in the normotensive Wistar rats than in the SHRs, while that of K+ was not significantly different. These findings indicate that consumption of radish leaves might have had antihypertensive effects in SHRs by increasing the serum concentration of NO and fecal concentration of Na+ and enhancing antioxidant activities.
doi:10.4162/nrp.2012.6.4.308
PMCID: PMC3439574  PMID: 22977684
Radish (Raphanus sativus L.) leaf ethyl acetate extract; spontaneous hypertension; ACE; antioxidant enzyme activity
23.  MYC Rearrangement Involving a Novel Non-immunoglobulin Chromosomal Locus in Precursor B-cell Acute Lymphoblastic Leukemia 
Annals of Laboratory Medicine  2012;32(4):289-293.
MYC rearrangement, a characteristic cytogenetic abnormality of Burkitt lymphoma and several subsets of other mature B-cell neoplasms, typically involves an immunoglobulin gene partner. Herein, we describe a case of precursor B-cell lymphoblastic leukemia harboring a MYC rearrangement with a novel non-immunoglobulin partner locus. The patient was a 4-yr-old Korean boy with ALL of the precursor B-cell immunophenotype. At the time of the second relapse, cytogenetic analyses revealed t(4;8)(q31.1;q24.1) as a clonal evolution. The MYC rearrangement was confirmed by FISH analysis. He died 3 months after the second relapse without achieving complete remission. To our knowledge, this is the first report of a case of MYC rearrangement with a non-immunoglobulin partner in precursor B-cell lymphoblastic leukemia.
doi:10.3343/alm.2012.32.4.289
PMCID: PMC3384811  PMID: 22779071
Precursor B-cell acute lymphoblastic leukemia; MYC gene rearrangement; Non-immunoglobulin partner
24.  Adipose-tissue-derived Stem Cells Enhance the Healing of Ischemic Colonic Anastomoses: An Experimental Study in Rats 
Purpose
This experimental study verified the effect of adipose-tissue-derived stem cells (ASCs) on the healing of ischemic colonic anastomoses in rats.
Methods
ASCs were isolated from the subcutaneous fat tissue of rats and identified as mesenchymal stem cells by identification of different potentials. An animal model of colonic ischemic anastomosis was induced by modifying Nagahata's method. Sixty male Sprague-Dawley rats (10-week-old, 370 ± 50 g) were divided into two groups (n = 30 each): a control group in which the anastomosis was sutured in a single layer with 6-0 polypropylene without any treatment and an ASCtreated group (ASC group) in which the anastomosis was sutured as in the control group, but then ASCs were locally transplanted into the bowel wall around the anastomosis. The rats were sacrificed on postoperative day 7. Healing of the anastomoses was assessed by measuring loss of body weight, wound infection, anastomotic leakage, mortality, adhesion formation, ileus, anastomotic stricture, anastomotic bursting pressure, histopathological features, and microvascular density.
Results
No differences in wound infection, anastomotic leakage, or mortality between the two groups were observed. The ASC group had significantly more favorable anastomotic healing, including less body weight lost, less ileus, and fewer ulcers and strictures, than the control group. ASCs augmented bursting pressure and collagen deposition. The histopathological features were significantly more favorable in the ASC group, and microvascular density was significantly higher than it was in the control group.
Conclusion
Locally-transplanted ASCs enhanced healing of ischemic colonic anastomoses by increasing angiogenesis. ASCs could be a novel strategy for accelerating healing of colonic ischemic risk anastomoses.
doi:10.3393/jksc.2012.28.3.132
PMCID: PMC3398108  PMID: 22816056
Colonic anastomosis; Ischemia; Anastomotic healing; Adipose-tissue-derived stem cell; Angiogenesis
25.  Hereditary Thrombophilia in Korean Patients with Idiopathic Pulmonary Embolism 
Yonsei Medical Journal  2012;53(3):571-577.
Purpose
Hereditary thrombophilia (HT) is a major risk factor for idiopathic pulmonary embolism (iPE) and shows different prevalence among ethnic groups. The prevalence and clinical characteristics of HT in Korean patients with iPE were investigated.
Materials and Methods
Patients with PE on computed tomography (CT) scan were recruited, and those with malignancy were excluded. Patients were divided into iPE and provoked PE (pPE) groups. The presence of HT in the iPE group was assessed by DNA sequencing of the corresponding gene in patients who had low levels of natural anticoagulants. The clinical characteristics of iPE with HT (iPE/HT+) were compared with those of iPE without HT (iPE/HT-) and pPE.
Results
Out of 161 patients, 84 patients had iPE and 77 patients had pPE. Among 54 patients in the iPE group whose coagulation profiles were tested, 28 patients were diagnosed with HT (51.9%; 28/54). Compared with the iPE/HT- and pPE groups, the iPE/HT+ group showed the highest proportion of male patients (71.4%; p<0.001); the youngest mean age (44±14 years; p<0.001); and the highest frequencies for history of venous thromboembolism (64.3%; p<0.001), concurrent deep vein thrombosis (75.0%; p=0.021), and adverse clinical outcomes (42.9%, p<0.001). Protein C deficiency was the most common HT. On molecular genetic tests, causative mutation was identified in 13 patients.
Conclusion
In this study of Korean patients, about half of the patients with iPE had HT. Patients with iPE and HT were mostly young males with deep venous thrombosis (DVT), previous venous thromboembolism (VTE), and frequent adverse clinical outcomes. Therefore, Korean patients with iPE should be tested for HT.
doi:10.3349/ymj.2012.53.3.571
PMCID: PMC3343445  PMID: 22477002
Pulmonary embolism; hereditary thrombophilia; protein C deficiency; Korea

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