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1.  Brown Pine Leaf Extract and Its Active Component Trans-Communic Acid Inhibit UVB-Induced MMP-1 Expression by Targeting PI3K 
PLoS ONE  2015;10(6):e0128365.
Japanese red pine (Pinus densiflora) is widely present in China, Japan, and Korea. Its green pine leaves have traditionally been used as a food as well as a coloring agent. After being shed, pine leaves change their color from green to brown within two years, and although the brown pine leaves are abundantly available, their value has not been closely assessed. In this study, we investigated the potential anti-photoaging properties of brown pine leaves for skin. Brown pine leaf extract (BPLE) inhibited UVB-induced matrix metalloproteinase-1 (MMP-1) expression to a greater extent than pine leaf extract (PLE) in human keratinocytes and a human skin equivalent model. HPLC analysis revealed that the quantity of trans-communic acid (TCA) and dehydroabietic acid (DAA) significantly increases when the pine leaf color changes from green to brown. BPLE and TCA elicited reductions in UVB-induced MMP-1 mRNA expression and activator protein-1 (AP-1) transactivation by reducing DNA binding activity of phospho-c-Jun, c-fos and Fra-1. BPLE and TCA also inhibited UVB-induced Akt phosphorylation, but not mitogen activated protein kinase (MAPK), known regulators of AP-1 transactivation. We additionally found that BPLE and TCA inhibited phosphoinositide 3-kinase (PI3K), the upstream kinase of Akt, in vitro. In summary, both BPLE and its active component TCA exhibit protective effects against UVB-induced skin aging. Taken together, these findings underline the potential for BPLE and TCA to be utilized as anti-wrinkling agents and cosmetic ingredients, as they suppress UVB-induced MMP-1 expression.
doi:10.1371/journal.pone.0128365
PMCID: PMC4465834  PMID: 26066652
2.  Results of Gender-Specific Total Knee Arthroplasty: Comparative Study with Traditional Implant in Female Patients 
Purpose
To compare the incidence of overhang between two distinct femoral components and whether there is clinical and radiological benefit of gender-specific implants in short-term follow-up.
Materials and Methods
One hundred and four knees in consecutive 66 female patients who underwent primary total knee arthroplasty due to primary osteoarthritis were included in this study. Overhang was measured and recorded in every cut surface of femur with both gender-specific and traditional trial femoral components respectively in every patient. Then, the knees were divided into two groups according to the type of the permanent femoral component they received. Clinical and radiological outcomes were compared between 2 groups at minimum 3 years after operation.
Results
Mean follow-up duration was 41.3 months (range, 36 to 50 months). Sixty two knees (59.6%) showed femoral overhang at least in one area with a traditional trial component, while 26 knees (25.0%) did with a gender-specific trial component (p<0.001). In terms of range of motion, Hospital for Special Surgery knee score, radiographic result, patella tilt angle and displacement, no significant difference was observed between two groups.
Conclusions
The use of gender-specific implants substantially reduced the incidence of femoral overhang but did not demonstrate any clinical, functional or radiologic benefit in short-term follow-up.
doi:10.5792/ksrr.2015.27.1.17
PMCID: PMC4349641  PMID: 25750890
Knee; Osteoarthritis; Arthroplasty; Gender; Female
3.  Licochalcone A, a Polyphenol Present in Licorice, Suppresses UV-Induced COX-2 Expression by Targeting PI3K, MEK1, and B-Raf 
Licorice is a traditional botanical medicine, and has historically been commonly prescribed in Asia to treat various diseases. Glycyrrhizin (Gc), a triterpene compound, is the most abundant phytochemical constituent of licorice. However, high intake or long-term consumption of Gc has been associated with a number of side effects, including hypertension. However, the presence of alternative bioactive compounds in licorice with anti-carcinogenic effects has long been suspected. Licochalcone A (LicoA) is a prominent member of the chalcone family and can be isolated from licorice root. To date, there have been no reported studies on the suppressive effect of LicoA against solar ultraviolet (sUV)-induced cyclooxygenase (COX)-2 expression and the potential molecular mechanisms involved. Here, we show that LicoA, a major chalcone compound of licorice, effectively inhibits sUV-induced COX-2 expression and prostaglandin E2 PGE2 generation through the inhibition of activator protein 1 AP-1 transcriptional activity, with an effect that is notably more potent than Gc. Western blotting analysis shows that LicoA suppresses sUV-induced phosphorylation of Akt/ mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinases (ERK)1/2/p90 ribosomal protein S6 kinase (RSK) in HaCaT cells. Moreover, LicoA directly suppresses the activity of phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase kinase (MEK)1, and B-Raf, but not Raf-1 in cell-free assays, indicating that PI3K, MEK1, and B-Raf are direct molecular targets of LicoA. We also found that LicoA binds to PI3K and B-Raf in an ATP-competitive manner, although LicoA does not appear to compete with ATP for binding with MEK1. Collectively, these results provide insight into the biological action of LicoA, which may have potential for development as a skin cancer chemopreventive agent.
doi:10.3390/ijms16034453
PMCID: PMC4394430  PMID: 25710724
Licochalcone A; Solar ultraviolet; Cyclooxygenase-2; PI3K; MEK1; B-Raf
4.  Ginseng total saponin attenuates myocardial injury via anti-oxidative and anti-inflammatory properties 
Journal of Ginseng Research  2014;39(3):206-212.
Background
Ginseng total saponin (GTS) contains various ginsenosides. These ginsenosides are widely used for treating cardiovascular diseases in Asian communities. The aim of this study was to study the effects of GTS on cardiac injury after global ischemia and reperfusion (I/R) in isolated guinea pig hearts.
Methods
Animals were subjected to normothermic ischemia for 60 minutes, followed by 120 minutes of reperfusion. GTS significantly increased aortic flow, coronary flow, and cardiac output. Moreover, GTS significantly increased left ventricular systolic pressure and the maximal rate of contraction (+dP/dtmax) and relaxation (−dP/dtmax). In addition, GTS has been shown to ameliorate electrocardiographic changes such as the QRS complex, QT interval, and RR interval.
Results
GTS significantly suppressed the biochemical parameters (i.e., lactate dehydrogenase, creatine kinase-MB fraction, and cardiac troponin I levels) and normalized the oxidative stress markers (i.e., malondialdehyde, glutathione, and nitrite). In addition, GTS also markedly inhibits the expression of interleukin-1β (IL-1β), IL-6, and nuclear factor-κB, and improves the expression of IL-10 in cardiac tissue.
Conclusion
These data indicate that GTS mitigates myocardial damage by modulating the biochemical and oxidative stress related to cardiac I/R injury.
doi:10.1016/j.jgr.2014.12.001
PMCID: PMC4506374  PMID: 26199551
antioxidative enzymes; cardioprotection; hemodynamics; myocardial infarction; Panax ginseng
5.  Engraftment Potential of Spheroid-Forming Hepatic Endoderm Derived from Human Embryonic Stem Cells 
Stem Cells and Development  2013;22(12):1818-1829.
Transplantation and drug discovery programs for liver diseases are hampered by the shortage of donor tissue. While recent studies have shown that hepatic cells can be derived from human embryonic stem cells (hESCs), few cases have shown selective enrichment of hESC-derived hepatocytes and their integration into host liver tissues. Here we demonstrate that the dissociation and reaggregation procedure after an endodermal differentiation of hESC produces spheroids mainly consisted of cells showing hepatic phenotypes in vitro and in vivo. A combined treatment with Wnt3a and bone morphogenic protein 4 efficiently differentiated hESCs into definitive endoderm in an adherent culture. Dissociation followed by reaggregation of these cells in a nonadherent condition lead to the isolation of spheroid-forming cells that preferentially expressed early hepatic markers from the adherent cell population. Further differentiation of these spheroid cells in the presence of the hepatocyte growth factor, oncostatin M, and dexamethasone produced a highly enriched population of cells exhibiting characteristics of early hepatocytes, including glycogen storage, indocyanine green uptake, and synthesis of urea and albumin. Furthermore, we show that grafted spheroid cells express hepatic features and attenuate the serum aspartate aminotransferase level in a model of acute liver injury. These data suggest that hepatic progenitor cells can be enriched by the spheroid formation of differentiating hESCs and that these cells have engraftment potential to replace damaged liver tissues.
doi:10.1089/scd.2012.0401
PMCID: PMC3668500  PMID: 23373441
6.  Prevalence of Anti-Ganglioside Antibodies and Their Clinical Correlates with Guillain-Barré Syndrome in Korea: A Nationwide Multicenter Study 
Background and Purpose
No previous studies have investigated the relationship between various anti-ganglioside antibodies and the clinical characteristics of Guillain-Barré syndrome (GBS) in Korea. The aim of this study was to determine the prevalence and types of anti-ganglioside antibodies in Korean GBS patients, and to identify their clinical significance.
Methods
Serum was collected from patients during the acute phase of GBS at 20 university-based hospitals in Korea. The clinical and laboratory findings were reviewed and compared with the detected types of anti-ganglioside antibody.
Results
Among 119 patients, 60 were positive for immunoglobulin G (IgG) or immunoglobulin M antibodies against any type of ganglioside (50%). The most frequent type was IgG anti-GM1 antibody (47%), followed by IgG anti-GT1a (38%), IgG anti-GD1a (25%), and IgG anti-GQ1b (8%) antibodies. Anti-GM1-antibody positivity was strongly correlated with the presence of preceding gastrointestinal infection, absence of sensory symptoms or signs, and absence of cranial nerve involvement. Patients with anti-GD1a antibody were younger, predominantly male, and had more facial nerve involvement than the antibody-negative group. Anti-GT1a-antibody positivity was more frequently associated with bulbar weakness and was highly associated with ophthalmoplegia when coupled with the coexisting anti-GQ1b antibody. Despite the presence of clinical features of acute motor axonal neuropathy (AMAN), 68% of anti-GM1- or anti-GD1a-antibody-positive cases of GBS were diagnosed with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) by a single electrophysiological study.
Conclusions
Anti-ganglioside antibodies were frequently found in the serum of Korean GBS patients, and each antibody was correlated strongly with the various clinical manifestations. Nevertheless, without an anti-ganglioside antibody assay, in Korea AMAN is frequently misdiagnosed as AIDP by single electrophysiological studies.
doi:10.3988/jcn.2014.10.2.94
PMCID: PMC4017025  PMID: 24829594
Guillain-Barré syndrome; ganglioside; antibodies; Korea; acute motor axonal neuropathy
8.  Heritabilities of Facial Measurements and Their Latent Factors in Korean Families 
Genomics & Informatics  2013;11(2):83-92.
Genetic studies on facial morphology targeting healthy populations are fundamental in understanding the specific genetic influences involved; yet, most studies to date, if not all, have been focused on congenital diseases accompanied by facial anomalies. To study the specific genetic cues determining facial morphology, we estimated familial correlations and heritabilities of 14 facial measurements and 3 latent factors inferred from a factor analysis in a subset of the Korean population. The study included a total of 229 individuals from 38 families. We evaluated a total of 14 facial measurements using 2D digital photographs. We performed factor analysis to infer common latent variables. The heritabilities of 13 facial measurements were statistically significant (p < 0.05) and ranged from 0.25 to 0.61. Of these, the heritability of intercanthal width in the orbital region was found to be the highest (h2 = 0.61, SE = 0.14). Three factors (lower face portion, orbital region, and vertical length) were obtained through factor analysis, where the heritability values ranged from 0.45 to 0.55. The heritability values for each factor were higher than the mean heritability value of individual original measurements. We have confirmed the genetic influence on facial anthropometric traits and suggest a potential way to categorize and analyze the facial portions into different groups.
doi:10.5808/GI.2013.11.2.83
PMCID: PMC3704931  PMID: 23843774
facial bones; genetic research; statistical factor analysis
9.  A Case of Isolated Middle Cerebral Artery Stenosis with Hemichorea and Moyamoya Pattern Collateralization 
Journal of Movement Disorders  2013;6(1):13-16.
Isolated middle cerebral artery (MCA) stenosis in young patients with no other medical condition may be a unique pathologic entity with a benign long-term course. Generally, moyamoya disease shows a progression of stenosis from internal cerebral artery (ICA) to other intracranial vessel. A 26-year-old woman was admitted for choreic movements of the right arm and leg. Brain magnetic resonance imaging showed no stroke. Conventional angiography revealed 48% stenosis of the left M1 without ICA stenosis. Single photon emission computed tomography revealed perfusion asymmetry after acetazolamide injection, suggesting decreased uptake in the left basal ganglia and the cerebral cortex. Her hemichorea was mildly decreased with risperidone. One year later, follow-up angiography showed complete occlusion of the left M1 with neovascularization suggestive of moyamoya disease. The patient underwent bypass surgery and her hemichorea disappeared. This may be an atypical presentation of moyamoya disease. The bypass surgery was an effective measure for restoring the vascular insufficiency and, resultantly, controlling her hemichorea.
doi:10.14802/jmd.13003
PMCID: PMC4027648  PMID: 24868419
Middle cerebral artery stenosis; Hemichorea; Moyamoya
10.  Complete Genome Sequence of Brucella abortus A13334, a New Strain Isolated from the Fetal Gastric Fluid of Dairy Cattle 
Journal of Bacteriology  2012;194(19):5444.
Brucella abortus is a major pathogen that infects livestock and humans. A new strain of B. abortus (A13334) was isolated from the fetal gastric fluid of a dairy cow, with the aim of using it to compare genetic properties, analyze virulence factor, and survey the epidemiological relationship to other Brucella species. Here, we report the complete and annotated genome sequence of B. abortus A13334.
doi:10.1128/JB.01124-12
PMCID: PMC3457244  PMID: 22965076
11.  Complete Genome Sequence of Brucella canis Strain HSK A52141, Isolated from the Blood of an Infected Dog 
Journal of Bacteriology  2012;194(18):5134.
Brucella canis infection can be clinically inapparent in dogs, and when infection goes unnoticed, there is a chance for dog-to-human transmission. A new strain of B. canis was isolated from the blood of an infected dog in order to analyze the pathogenic mechanism, compare genetic properties, and develop new genetic tools for early diagnosis of canine brucellosis. Herein, we report the complete genome sequence of the strain B. canis HSK A52141. This is the second complete genome sequence and biological annotation available for a member of B. canis.
doi:10.1128/JB.01125-12
PMCID: PMC3430308  PMID: 22933762
12.  Adiaspiromycosis of an Apodemus agrarius captured wild rodent in Korea 
Laboratory Animal Research  2012;28(1):67-69.
Adiaspiromycosis is caused by pulmonary infection with Emmonsia. Inhalated spores of Emmonsia cause asymptomatic infection to necrogranulomatous pneumonia, depending on the burden of adiaspore and host immunity. For disease monitoring of wild rodents captured on Jeju Island in Korea, we examined the lung tissue of wild rodents histopathologically. Spores composed of thick three-layered walls were found following histopathological examination and were diagnosed as adiaspiromycosis. Adiaspiromycosis has been found in mammals in many parts of the world. To our knowledge, this is the first report of adiaspiromycosis of an Apodemus agrarius captured in Korea.
doi:10.5625/lar.2012.28.1.67
PMCID: PMC3315196  PMID: 22474477
Adiaspiromycosis; Emmonisia crescens; wild rodent
13.  Detection of sarcocystic infection in a wild rodent (Apodemus agrarius chejuensis) captured on Jeju island 
Laboratory Animal Research  2011;27(4):357-359.
Sarcocystis spp is a causative agent of sarcocystosis. They have a characteristic life cycle infecting both prey and predator. Sarcocystis can cause myositis, atrophy of the adjacent cells and abortion in cattle. In mice, sarcocystosis causes mild cellular reactions without clinical disease. Severe haemorrhage and abortion were also reported. For monitoring the disease in wild rodents of the Korean peninsula, we captured Apodemus agrarius chejuensis on Jeju island and examined the specimen histopathologically. Intramuscular cysts were found and diagnosed as Sarcocystis. Sarcocystic infection has been reported in worldwide. There have been many reported infections in cattle and pigs in Korea. To our knowledge, this is the first report of Sarcocystis in Apodemus agrarius chejuensis captured in Korea.
doi:10.5625/lar.2011.27.4.357
PMCID: PMC3251769  PMID: 22232647
Sarcocystis; Apodemus agrarius chejuensis; Jeju island
14.  Genome-wide association of serum bilirubin levels in Korean population 
Human Molecular Genetics  2010;19(18):3672-3678.
A large-scale, genome-wide association study was performed to identify genetic variations influencing serum bilirubin levels using 8841 Korean individuals. Significant associations were observed at UGT1A1 (rs11891311, P = 4.78 × 10−148) and SLCO1B3 (rs2417940, P = 1.03 × 10−17), which are two previously identified loci. The two single-nucleotide polymorphisms (SNPs) were replicated (rs11891311, P = 3.18 × 10−15) or marginally significant (rs2417940, P = 8.56 × 10−4) in an independent cohort of 1096 individuals. In a conditional analysis adjusted for the top UGT1A1 variant (rs11891311), another variant in UGT1A1 (rs4148323, P = 1.22 × 10−121) remained significant; this suggests that in UGT1A1 at least two independent genetic variations influence the bilirubin levels in the Korean population. The protein coding variant rs4148323, which is monomorphic in European-derived populations, may be specifically associated with serum bilirubin levels in Asians (P = 2.56 × 10−70). The SLCO1B3 variant (rs2417940, P = 1.67 × 10−18) remained significant in a conditional analysis for the top UGT1A1 variant. Interestingly, there were significant differences in the associated variations of SLCO1B3 between Koreans and European-derived populations. While the variant rs2417940 at intron 7 of SLCO1B3 was more significantly associated in Koreans, variants rs17680137 (P = 0.584) and rs2117032 (P = 2.76 × 10−5), two of the top-ranked SNPs in European-derived populations, did not reach the genome-wide significance level. Also, variants in SLCO1B1 did not reach genome-wide significance in Koreans. Our result supports the idea that there are considerable ethnic differences in genetic association of bilirubin levels between Koreans and European-derived populations.
doi:10.1093/hmg/ddq281
PMCID: PMC2928134  PMID: 20639394
15.  Cordycepin inhibits UVB-induced matrix metalloproteinase expression by suppressing the NF-κB pathway in human dermal fibroblasts 
Experimental & Molecular Medicine  2009;41(8):548-554.
Cordycepin (3'-deoxyadenosine) has been shown to exhibit many pharmacological activities, including anti-cancer, anti-inflammatory, and anti-infection activities. However, the anti-skin photoaging effects of cordycepin have not yet been reported. In the present study, we investigated the inhibitory effects of cordycepin on matrix metalloproteinase-1 (MMP-1) and -3 expressions of the human dermal fibroblast cells. Western blot analysis and real-time PCR revealed cordycepin inhibited UVB-induced MMP-1 and -3 expressions in a dose-dependent manner. UVB strongly activated NF-κB activity, which was determined by IκBα degradation, nuclear localization of p50 and p65 subunit, and NF-κB binding activity. However, UVB-induced NF-κB activation and MMP expression were completely blocked by cordycepin pretreatment. These findings suggest that cordycepin could prevent UVB-induced MMPs expressions through inhibition of NF-κB activation. In conclusion, cordycepin might be used as a potential agent for the prevention and treatment of skin photoaging.
doi:10.3858/emm.2009.41.8.060
PMCID: PMC2739894  PMID: 19381070
cordycepin; matrix metalloproteinases; NF-κB; skin aging; ultraviolet rays
16.  Plant growth promotion and Penicillium citrinum 
BMC Microbiology  2008;8:231.
Background
Endophytic fungi are known plant symbionts. They produce a variety of beneficial metabolites for plant growth and survival, as well as defend their hosts from attack of certain pathogens. Coastal dunes are nutrient deficient and offer harsh, saline environment for the existing flora and fauna. Endophytic fungi may play an important role in plant survival by enhancing nutrient uptake and producing growth-promoting metabolites such as gibberellins and auxins. We screened roots of Ixeris repenes (L.) A. Gray, a common dune plant, for the isolation of gibberellin secreting endophytic fungi.
Results
We isolated 15 endophytic fungi from the roots of Ixeris repenes and screened them for growth promoting secondary metabolites. The fungal isolate IR-3-3 gave maximum plant growth when applied to waito-c rice and Atriplex gemelinii seedlings. Analysis of the culture filtrate of IR-3-3 showed the presence of physiologically active gibberellins, GA1, GA3, GA4 and GA7 (1.95 ng/ml, 3.83 ng/ml, 6.03 ng/ml and 2.35 ng/ml, respectively) along with other physiologically inactive GA5, GA9, GA12, GA15, GA19, GA20 and, GA24. The plant growth promotion and gibberellin producing capacity of IR-3-3 was much higher than the wild type Gibberella fujikuroi, which was taken as control during present study. GA5, a precursor of bioactive GA3 was reported for the first time in fungi. The fungal isolate IR-3-3 was identified as a new strain of Penicillium citrinum (named as P. citrinum KACC43900) through phylogenetic analysis of 18S rDNA sequence.
Conclusion
Isolation of new strain of Penicillium citrinum from the sand dune flora is interesting as information on the presence of Pencillium species in coastal sand dunes is limited. The plant growth promoting ability of this fungal strain may help in conservation and revegetation of the rapidly eroding sand dune flora. Penicillium citrinum is already known for producing mycotoxin citrinin and cellulose digesting enzymes like cellulase and endoglucanase, as well as xylulase. Gibberellins producing ability of this fungus and the discovery about the presence of GA5 will open new aspects of research and investigations.
doi:10.1186/1471-2180-8-231
PMCID: PMC2631606  PMID: 19099608
17.  Preliminary Report of Multisession Gamma Knife Radiosurgery for Benign Perioptic Lesions: Visual Outcome in 22 Patients 
Objective
Radiosurgery may be contraindicated for lesions adjacent to the optic pathways because of the substantial risk of visual complication. Multisession radiosurgery has been tried as a compromise between single session radiosurgery and fractionated radiotherapy. The purpose of this study is to evaluate the outcomes of multisession gamma knife radiosurgery (GKRS) in 22 patients with perioptic lesions of benign pathology.
Methods
In all 22 cases, the lesions were within 1 mm of the optic apparatus and were therefore not considered suitable for single session radiosurgery. Radiation was delivered in 3 to 4 fractions with a median cumulated marginal dose of 20 Gy (range, 15-20 Gy).
Results
During a mean follow-up of 29 months (range, 14-44 months), tumor control was achieved in 21 patients. Visual function improved in 7 patients, remained unchanged in 14 patients, and deteriorated in 1 patient with tumor progression. No other complication was observed.
Conclusion
This preliminary result supports the idea that multisession GKRS may be an effective and safe alternative for treatment in perioptic lesions that are unsuitable for single session radiosurgery.
doi:10.3340/jkns.2008.44.2.67
PMCID: PMC2588338  PMID: 19096695
Multisession radiosurgery; Gamma knife; Visual complication
18.  Spinal Cord Hemangioblastoma : Diagnosis and Clinical Outcome after Surgical Treatment 
Objective
Spinal cord hemangioblastoma is an uncommon vascular neoplasm with a benign nature and is associated with von Hippel-Lindau (VHL) disease in 20-30% of patients. Total removal of these tumors without significant neurological deficit remains a great challenge. The purpose of this study was to investigate the efficacy of VHL mutation analysis and to evaluate surgical outcome of patients with spinal cord hemangioblastomas.
Methods
This study included nine patients treated for spinal cord hemangioblastomas at our institute between December 1994 and March 2006. There were four male and five female patients. Mean age was 37.8 years. The mean follow-up period was 22.4 months. Magnetic resonance imaging (MRI) of the complete neuraxis was done in all cases and VHL mutation analysis was performed in three cases for a definite diagnosis.
Results
Six patients had intramedullary tumor, and the remaining patients had intradural extramedullary lesions. Five patients were associated with VHL disease. The von Hippel-Lindau mutation analysis was done in three patients and two of them showed VHL gene abnormality. Tumors were located in the cervical cord in five cases and in the thoracic cord in four cases. All patients underwent surgical intervention, and total removal was achieved in six cases. All patients showed improvement or, at least, clinically stationary state. Surgical complications did not develop in any cases.
Conclusion
Spinal hemangioblastoma in this series has been safely and effectively removed via a posterior approach. Postoperatively, clinical outcome was excellent in the majority of cases. The VHL mutation analysis was useful in patients with family history and in those with multiple hemangioblastomas.
doi:10.3340/jkns.2007.42.6.436
PMCID: PMC2588179  PMID: 19096585
Hemangioblastoma; Von Hippel-Lindau disease; Mutation analysis
19.  Simple Tests to Predict Hepatic Fibrosis in Nonalcoholic Chronic Liver Diseases 
Gut and Liver  2007;1(2):145-150.
Background/Aims
Several simple tests for hepatic fibrosis employ indirect markers. However, the efficacy of using direct and indirect serum markers to predict significant fibrosis in clinical practice is inconclusive. We analyzed the efficacy of a previously reported indirect marker of hepatic fibrosis - the aspartate aminotransferase to platelet ratio index (APRI) - in patients with nonalcoholic chronic liver diseases (CLDs).
Methods
A total of 134 patients who underwent a percutaneous liver biopsy with a final diagnosis of chronic hepatitis B (n=93), chronic hepatitis C (n=18), or nonalcoholic fatty liver disease (n=23) were enrolled. A single-blinded pathologist staged fibrosis from F0 to F4 according to the METAVIR system, with significant hepatic fibrosis defined as a METAVIR fibrosis score of ≥2.
Results
The mean area under the receiver operating characteristic curve (AUROC) of APRI for predicting significant fibrosis in nonalcoholic CLDs was 0.84 [95% confidence interval (CI), 0.78-0.91]. APRI yielded the highest mean AUROC in the patients with chronic hepatitis B (0.85; 95% CI, 0.771-0.926). The positive predictive value of APRI ≥1.5 for predicting significant fibrosis was 89%. The negative predictive value of APRI <0.5 for excluding significant fibrosis was 80%.
Conclusions
APRI might be a simple and noninvasive index for predicting significant fibrosis in nonalcoholic CLDs.
doi:10.5009/gnl.2007.1.2.145
PMCID: PMC2871633  PMID: 20485631
Aspartate aminotransferase; Fibrosis; Hepatitis B
20.  Rhythmic Serotonin N-Acetyltransferase mRNA Degradation Is Essential for the Maintenance of Its Circadian Oscillation 
Molecular and Cellular Biology  2005;25(8):3232-3246.
Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase [AANAT]) is the key enzyme in melatonin synthesis regulated by circadian rhythm. To date, our understanding of the oscillatory mechanism of melatonin has been limited to autoregulatory transcriptional and posttranslational regulations of AANAT mRNA. In this study, we identify three proteins from pineal glands that associate with cis-acting elements within species-specific AANAT 3′ untranslated regions to mediate mRNA degradation. These proteins include heterogeneous nuclear ribonucleoprotein R (hnRNP R), hnRNP Q, and hnRNP L. Their RNA-destabilizing function was determined by RNA interference and overexpression approaches. Expression patterns of these factors in pineal glands display robust circadian rhythm. The enhanced levels detected after midnight correlate with an abrupt decline in AANAT mRNA level. A mathematical model for the AANAT mRNA profile and its experimental evidence with rat pinealocytes indicates that rhythmic AANAT mRNA degradation mediated by hnRNP R, hnRNP Q, and hnRNP L is a key process in the regulation of its circadian oscillation.
doi:10.1128/MCB.25.8.3232-3246.2005
PMCID: PMC1069600  PMID: 15798208
21.  Population Structure of the Bacillus cereus Group as Determined by Sequence Analysis of Six Housekeeping Genes and the plcR Gene  
Infection and Immunity  2004;72(9):5253-5261.
The population structure of the Bacillus cereus group (52 strains of B. anthracis, B. cereus, and B. thuringiensis) was investigated by sequencing seven gene fragments (rpoB, gyrB, pycA, mdh, mbl, mutS, and plcR). Most of the strains were classifiable into two large subgroups in six housekeeping gene trees but not in the plcR tree. In addition, several consistent clusters were identified, which were unrelated to species distinction. Moreover, interrelationships among these clusters were incongruent in each gene tree. The incongruence length difference test and split decomposition analyses also showed incongruences between genes, suggesting horizontal gene transfer. The plcR gene was observed to have characteristics that differed from those of the other genes in terms of phylogenetic topology and pattern of sequence diversity. Thus, we suggest that the evolutionary history of the PlcR regulon differs from those of the other chromosomal genes and that recombination of the plcR gene may be frequent. The homogeneity of B. anthracis, which is depicted as an independent lineage in phylogenetic trees, is suggested to be of recent origin or to be due to the narrow taxonomic definition of species.
doi:10.1128/IAI.72.9.5253-5261.2004
PMCID: PMC517475  PMID: 15322020
22.  Identification of Bacillus anthracis by rpoB Sequence Analysis and Multiplex PCR 
Journal of Clinical Microbiology  2003;41(7):2908-2914.
Comparative sequence analysis was performed upon Bacillus anthracis and its closest relatives, B. cereus and B. thuringiensis. Portions of rpoB DNA from 10 strains of B. anthracis, 16 of B. cereus, 10 of B. thuringiensis, 1 of B. mycoides, and 1 of B. megaterium were amplified and sequenced. The determined rpoB sequences (318 bp) of the 10 B. anthracis strains, including five Korean isolates, were identical to those of Ames, Florida, Kruger B, and Western NA strains. Strains of the “B. cereus group” were separated into two subgroups, in which the B. anthracis strains formed a separate clade in the phylogenetic tree. However, B. cereus and B. thuringiensis could not be differentiated. Sequence analysis confirmed the five Korean isolates as B. anthracis. Based on the rpoB sequences determined in the present study, multiplex PCR generating either B. anthracis-specific amplicons (359 and 208 bp) or cap DNA (291 bp) in a virulence plasmid could be used for the rapid differential detection and identification of virulent B. anthracis.
doi:10.1128/JCM.41.7.2908-2914.2003
PMCID: PMC165277  PMID: 12843020
23.  Lipocalin-2 deficiency attenuates neuroinflammation and brain injury after transient middle cerebral artery occlusion in mice 
Lipocalin-2 (LCN2) is a secreted protein of the lipocalin family, but little is known about the expression or the role of LCN2 in the central nervous system. Here, we investigated the role of LCN2 in ischemic stroke using a rodent model of transient cerebral ischemia. Lipocalin-2 expression was highly induced in the ischemic brain and peaked at 24 hours after reperfusion. After transient middle cerebral artery occlusion, LCN2 was predominantly expressed in astrocytes and endothelial cells, whereas its receptor (24p3R) was mainly detected in neurons, astrocytes, and endothelial cells. Brain infarct volumes, neurologic scores, blood–brain barrier (BBB) permeabilities, glial activation, and inflammatory mediator expression were significantly lower in LCN2-deficient mice than in wild-type animals. Lipocalin-2 deficiency also attenuated glial neurotoxicity in astrocyte/neuron cocultures after oxygen-glucose deprivation. Our results indicate LCN2 has a critical role in brain injury after ischemia/reperfusion, and that LCN2 may contribute to neuronal cell death in the ischemic brain by promoting neurotoxic glial activation, neuroinflammation, and BBB disruption.
doi:10.1038/jcbfm.2014.83
PMCID: PMC4126090  PMID: 24780901
astrocyte; blood–brain barrier; ischemia/reperfusion; lipocain-2; microglia; neuroinflammation
24.  3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium 
Nature communications  2014;5:3329.
Means for high-density multiparametric physiological mapping and stimulation are critically important in both basic and clinical cardiology. Current conformal electronic systems are essentially 2D sheets, which cannot cover the full epicardial surface or maintain reliable contact for chronic use without sutures or adhesives. Here we create 3D elastic membranes shaped precisely to match the epicardium of the heart via the use of 3D printing, as a platform for deformable arrays of multifunctional sensors, electronic and optoelectronic components. Such integumentary devices completely envelop the heart, in a form-fitting manner, and possess inherent elasticity, providing a mechanically stable bioti-/abiotic interface during normal cardiac cycles. Component examples range from actuators for electrical, thermal and optical stimulation, to sensors for pH, temperature and mechanical strain. The semiconductor materials include silicon, gallium arsenide and gallium nitride, co-integrated with metals, metal oxides and polymers, to provide these and other operational capabilities. Ex vivo physiological experiments demonstrate various functions and methodological possibilities for cardiac research and therapy.
doi:10.1038/ncomms4329
PMCID: PMC4521772  PMID: 24569383
25.  Predictors and patterns of recurrence after curative liver resection in intrahepatic cholangiocarcinoma, for application of postoperative radiotherapy: a retrospective study 
Background
The majority of patients with intrahepatic cholangiocarcinoma (IHCC) who undergo complete tumor resection subsequently develop tumor recurrence. The objectives of this study were to determine the risk factors for IHCC recurrence after curative (R0) liver resection and to identify the feasibility about postoperative adjuvant radiation therapy (RT).
Methods
We retrospectively reviewed patients who underwent liver resection for IHCC between April 1995 and December 2012 at Samsung Medical Center. Cox regression analysis was performed to determine risk factors of recurrence. Patients with a recurrence in remnant liver within 2 cm from the resection margin, with or without locoregional lymph node (LN) metastases, were considered as potential RT candidates. Center-of-mass (COM) distances between the recurrent cancers and the cut surface were measured with MATLAB.
Results
We included 153 out of 198 patients who underwent partial liver resection for IHCC. About two thirds (n = 93, 60.8 %) of patients developed recurrent disease. The median recurrence-free survival (RFS) was 14 months (range, 0–204). Tumor size ≥4.0 cm, LN metastasis and multiple tumors were significant predictors of IHCC recurrence on multivariate analysis. Tumor size ≥5.0 cm was the only factor associated with recurrence beyond the RT field in patients with recurrence. Among 93 patients with recurrence, 16 (17.2 %) patients were recurred in the RT field.
Conclusion
After curative resection in IHCC, more than 60 % of patients recurred, and among recurred patients, 17.2 % were recurred within the RT field. Consequently, for control of locoregional recurrence, adjuvant RT could be carefully considered in patients with recurrence factors. Especially, patients with a tumor size larger than 5 cm should be judiciously selected for adjuvant RT.
doi:10.1186/s12957-015-0637-z
PMCID: PMC4517555  PMID: 26216347
Intrahepatic cholangiocarcinoma; Recurrence; Hepatectomy; Adjuvant radiotherapy

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