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1.  Mucosal Vaccination with Recombinant Lactobacillus casei-Displayed CTA1-Conjugated Consensus Matrix Protein-2 (sM2) Induces Broad Protection against Divergent Influenza Subtypes in BALB/c Mice 
PLoS ONE  2014;9(4):e94051.
To develop a safe and effective mucosal vaccine against pathogenic influenza viruses, we constructed recombinant Lactobacillus casei strains that express conserved matrix protein 2 with (pgsA-CTA1-sM2/L. casei) or without (pgsA-sM2/L. casei) cholera toxin subunit A1 (CTA1) on the surface. The surface localization of the fusion protein was verified by cellular fractionation analyses, flow cytometry and immunofluorescence microscopy. Oral and nasal inoculations of recombinant L. casei into mice resulted in high levels of serum immunoglobulin G (IgG) and mucosal IgA. However, the conjugation of cholera toxin subunit A1 induced more potent mucosal, humoral and cell-mediated immune responses. In a challenge test with 10 MLD50 of A/EM/Korea/W149/06(H5N1), A/Puerto Rico/8/34(H1N1), A/Aquatic bird /Korea/W81/2005(H5N2), A/Aquatic bird/Korea/W44/2005(H7N3), and A/Chicken/Korea/116/2004(H9N2) viruses, the recombinant pgsA-CTA1-sM2/L. casei provided better protection against lethal challenges than pgsA-sM2/L. casei, pgsA/L. casei and PBS in mice. These results indicate that mucosal immunization with recombinant L. casei expressing CTA1-conjugated sM2 protein on its surface is an effective means of eliciting protective immune responses against diverse influenza subtypes.
PMCID: PMC3979752  PMID: 24714362
2.  The Homologous Tripartite Viral RNA Polymerase of A/Swine/Korea/CT1204/2009(H1N2) Influenza Virus Synergistically Drives Efficient Replication and Promotes Respiratory Droplet Transmission in Ferrets 
Journal of Virology  2013;87(19):10552-10562.
We previously reported that influenza A/swine/Korea/1204/2009(H1N2) virus was virulent and transmissible in ferrets in which the respiratory-droplet-transmissible virus (CT-Sw/1204) had acquired simultaneous hemagglutinin (HAD225G) and neuraminidase (NAS315N) mutations. Incorporating these mutations into the nonpathogenic A/swine/Korea/1130/2009(H1N2, Sw/1130) virus consequently altered pathogenicity and growth in animal models but could not establish efficient transmission or noticeable disease. We therefore exploited various reassortants of these two viruses to better understand and identify other viral factors responsible for pathogenicity, transmissibility, or both. We found that possession of the CT-Sw/1204 tripartite viral polymerase enhanced replicative ability and pathogenicity in mice more significantly than did expression of individual polymerase subunit proteins. In ferrets, homologous expression of viral RNA polymerase complex genes in the context of the mutant Sw/1130 carrying the HA225G and NA315N modifications induced optimal replication in the upper nasal and lower respiratory tracts and also promoted efficient aerosol transmission to respiratory droplet contact ferrets. These data show that the synergistic function of the tripartite polymerase gene complex of CT-Sw/1204 is critically important for virulence and transmission independent of the surface glycoproteins. Sequence comparison results reveal putative differences that are likely to be responsible for variation in disease. Our findings may help elucidate previously undefined viral factors that could expand the host range and disease severity induced by triple-reassortant swine viruses, including the A(H1N1)pdm09 virus, and therefore further justify the ongoing development of novel antiviral drugs targeting the viral polymerase complex subunits.
PMCID: PMC3807396  PMID: 23864624
3.  The clinical usefulness of central hemodynamics to evaluate diastolic dysfunction in subjects without hypertension 
Diastolic dysfunction is associated with increased arterial stiffness in patients with hypertension. However, the role of arterial stiffness in diastolic dysfunction in subjects without hypertension has not been fully established.
Materials and methods
A total of 287 subjects (male:female ratio 121:166, mean age 53.0±14.4 years) without hypertension or any heart disease who simultaneously received transthoracic echocardiography and noninvasively semiautomated radial artery applanation tonometry (with an Omron HEM-9000AI) in the Department of Internal Medicine, St Vincent’s Hospital, from July 2011 to September 2012, were enrolled in this study.
A total of 147 subjects (male:female ratio 59:88, mean age 61.7±9.9 years), representing 51.2% of the 287 subjects, had diastolic dysfunction (defined as abnormal relaxation pattern of mitral inflow). There were significant differences in systolic blood pressure (BP), pulse pressure, late systolic peak pressure (SBP2), and radial augmentation index (RaAIx) between normal diastolic function and diastolic dysfunction. ΔBP was defined as systolic BP minus SBP2, because of the difference in systolic BP between the two groups. ΔBP (odds ratio [OR] 1.059, 95% confidence interval [CI] 1.005–1.115; P=0.032) and RaAIx (odds ratio 1.027, 95% CI 1.009–1.044, P=0.003) were associated with diastolic dysfunction. A receiver operating-characteristic curve showed that ΔBP (area under the curve 0.875, 95% CI 0.832–0.911) and RaAIx (area under the curve 0.878, 95% CI 0.835–0.914) were associated with diastolic dysfunction.
We found that ΔBP and increased RaAIx were associated with diastolic dysfunction in subjects without hypertension after adjustment for age and sex. Therefore, it is suggested that noninvasive estimation of central BP may be useful to reflect diastolic dysfunction in subjects with normal peripheral BP.
PMCID: PMC3974697
central blood pressure; augmentation index; diastolic dysfunction
4.  Non-Thermal Atmospheric Pressure Plasma Inhibits Thyroid Papillary Cancer Cell Invasion via Cytoskeletal Modulation, Altered MMP-2/-9/uPA Activity 
PLoS ONE  2014;9(3):e92198.
Plasma, the fourth state of matter, is defined as a partially or completely ionized gas that includes a mixture of electrons and ions. Advances in plasma physics have made it possible to use non-thermal atmospheric pressure plasma (NTP) in cancer research. However, previous studies have focused mainly on apoptotic cancer cell death mediated by NTP as a potential cancer therapy. In this study, we investigated the effect of NTP on invasion or metastasis, as well as the mechanism by which plasma induces anti-migration and anti-invasion properties in human thyroid papillary cancer cell lines (BHP10-3 and TPC1). Wound healing, pull-down, and Transwell assays demonstrated that NTP reduced cell migration and invasion. In addition, NTP induced morphological changes and cytoskeletal rearrangements, as detected by scanning electron microscopy and immunocytochemistry. We also examined matrix metalloproteinase (MMP)-2/-9 and urokinase-type plasminogen activator (uPA) activity using gelatin zymography, uPA assays and RT-PCR. FAK, Src, and paxillin expression was detected using Western blot analyses and immunocytochemistry. NTP decreased FAK, Src, and paxillin expression as well as MMP/uPA activity. In conclusion, NTP inhibited the invasion and metastasis of BHP10-3 and TPC1 cells by decreasing MMP-2/-9 and uPA activities and rearranging the cytoskeleton, which is regulated by the FAK/Src complex. These findings suggest novel actions for NTP and may aid in the development of new therapeutic strategies for locally invasive and metastatic cancers.
PMCID: PMC3965425  PMID: 24667444
5.  Functional Mechanism of C-Terminal Tail in the Enzymatic Role of Porcine Testicular Carbonyl Reductase: A Combined Experiment and Molecular Dynamics Simulation Study of the C-Terminal Tail in the Enzymatic Role of PTCR 
PLoS ONE  2014;9(3):e90712.
Porcine testicular carbonyl reductase, PTCR which is one of the short chain dehydrogenases/reductases (SDR) superfamily catalyzes the NADPH-dependent reduction of carbonyl compounds including steroids and prostaglandins. Previously we reported C- terminal tail of PTCR was deleted due to a nonsynonymous single nucleotide variation (nsSNV). Here we identified from kinetic studies that the enzymatic properties for 5α-dihydrotestosterone (5α-DHT) were different between wild-type and C-terminal-deleted PTCRs. Compared to wild-type PTCR, C-terminal-deleted PTCR has much higher reduction rate. To investigate structural difference between wild-type and C-terminal-deleted PTCRs upon 5α-DHT binding, we performed molecular dynamics simulations for two complexes. Using trajectories, molecular interactions including hydrogen bonding patterns, distance between 5α-DHT and catalytic Tyr193, and interaction energies are analyzed and compared. During the MD simulation time, the dynamic behavior of C-terminal tail in wild-type PTCR is also examined using essential dynamics analysis. The results of our simulations reveal that the binding conformation of 5α-DHT in C-terminal-deleted PTCR is more favorable for reduction reaction in PTCR, which shows strong agreement with kinetic data. These structural findings provide valuable information to understand substrate specificity of PTCR and further kinetic properties of enzymes belonging to the SDR superfamily.
PMCID: PMC3960098  PMID: 24646606
6.  The use of everolimus to target carcinogenic pathways in a patient with renal cell carcinoma and tuberous sclerosis complex: a case report 
An increased understanding of the genetic pathways involved in renal cell carcinoma has resulted in the development of various drugs that target relevant signaling cascades for the specific treatment of this disease. However, no validated predictive markers have been identified to guide the decision whether patients should receive vascular endothelial growth factor–targeted therapy or mammalian target of rapamycin–targeted therapy. We present what is, to the best of our knowledge, the first case of renal cell carcinoma in a patient with tuberous sclerosis complex who was successfully treated with everolimus.
Case presentation
The patient was a 49-year-old Korean woman with tuberous sclerosis complex and recurrent renal cell carcinoma. The patient was treated with the tyrosine kinase inhibitor sunitinib followed by the mammalian target of rapamycin inhibitor everolimus. This treatment resulted in a prolonged response and significant clinical benefit. Notably, everolimus ameliorated the symptoms related not only to renal cell carcinoma but also to tuberous sclerosis complex.
This case provides a rationale for the use of everolimus as first-line treatment for this specific patient population in order to target the correct pathway involved in carcinogenesis.
PMCID: PMC3976165  PMID: 24612911
Everolimus; Mammalian target of rapamycin inhibitor; Renal cell carcinoma; Tuberous sclerosis complex
7.  Transfer of Intracellular HIV Nef to Endothelium Causes Endothelial Dysfunction 
PLoS ONE  2014;9(3):e91063.
With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.
PMCID: PMC3946685  PMID: 24608713
8.  Impaired mitochondrial metabolism and mammary carcinogenesis 
Mitochondrial oxidative metabolism plays a key role in meeting energetic demands of cells by oxidative phosphorylation (OxPhos). Here, we have briefly discussed (i) the dynamic relationship that exists among glycolysis, the tricarboxylic acid (TCA) cycle, and OxPhos; (ii) the evidence of impaired OxPhos (i.e. mitochondrial dysfunction) in breast cancer; (iii) the mechanisms by which mitochondrial dysfunction can predispose to cancer; and (iv) the effects of host and environmental factors that can negatively affect mitochondrial function. We propose that impaired OxPhos could increase susceptibility to breast cancer via suppression of the p53 pathway, which plays a critical role in preventing tumorigenesis. OxPhos is sensitive to a large number of factors intrinsic to the host (e.g. inflammation) as well as environmental exposures (e.g. pesticides, herbicides and other compounds). Polymorphisms in over 143 genes can also influence OxPhos system. Therefore, declining mitochondrial oxidative metabolism with age due to host and environmental exposures could be a common mechanism predisposing to cancer.
PMCID: PMC3581737  PMID: 23269521
Mitochondrial metabolism; Oxidative phosphorylation; OxPhos; inflammation; tumor suppressor p53; breast cancer
9.  Relationship between the Severity of Diversion Colitis and the Composition of Colonic Bacteria: A Prospective Study 
Gut and Liver  2013;8(2):170-176.
Diversion colitis is the inflammation of the excluded segment of the colon in patients undergoing ostomy. It has been suggested that a change in colonic flora may lead to colitis; however, direct evidence for this disease progression is lacking. The aim of this study was to evaluate the relationship between the severity of diversion colitis and the composition of colonic bacteria.
We used culture methods and polymerase chain reaction to analyze the colonic microflora of patients who underwent rectal cancer resection with or without diversion ileostomy. In the diversion group, we also evaluated the severity of colonoscopic and pathologic colitis before reversal.
This study enrolled 48 patients: 26 in the diversion group and 22 in the control group. Significant differences were observed between the two groups in the levels of Staphylococcus (p=0.038), Enterococcus (p<0.001), Klebsiella (p<0.001), Pseudomonas (p=0.015), Lactobacillus (p=0.038), presence of anaerobes (p=0.019), and Bifidobacterium (p<0.001). A significant correlation between the severity of colitis and bacterial composition was only observed for Bifidobacterium (p=0.005, correlation coefficient=-0.531).
The colonic microflora differed significantly between the diversion and control groups. Bifidobacterium was negatively correlated with the severity of diversion colitis.
PMCID: PMC3964268  PMID: 24672659
Diversion colitis; Colonic bacteria; Rectal neoplasms; Polymerase chain reaction
10.  Syntenin increases the invasiveness of small cell lung cancer cells by activating p38, AKT, focal adhesion kinase and SP1 
Syntenin is a PDZ domain-containing adaptor protein that has been recently shown to regulate migration and invasion in several tumors. Small cell lung cancer (SCLC) is notorious for its invasiveness and strong potential for metastasis. We therefore studied the influence of syntenin on the invasiveness of SCLC. Immunohistochemistry in tumor tissues showed that syntenin was more frequently expressed in small cell carcinomas than other neuroendocrine tumors, such as carcinoids and neuroblastomas, suggesting that syntenin expression may be related to more aggressive forms of neuroendocrine tumors. In SCLC patients, syntenin overexpression in tumor cells was significantly associated with more extensive and advanced disease at the time of diagnosis (P=0.029). Overexpression of syntenin in SCLC cells that were intrinsically syntenin-low increased the invasiveness of cells and led to the induction of extracellular matrix (ECM)-degrading membrane type 1-matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase 2 (MMP2). In contrast, suppression of syntenin in syntenin-high cells was associated with the downregulation of MT1-MMP. Contrary to the results of previous studies using malignant melanomas and breast carcinomas, signaling cascades were shown to be further transduced through p38 MAPK and PI3K/AKT, with activation of SP1 rather than NF-κB, under circumstances not involving ECM interaction. In addition, the upstream molecule focal adhesion kinase was induced by syntenin activation, in spite of the absence of ECM interaction. These results suggest that syntenin might contribute to the invasiveness of SCLC and could be utilized as a new therapeutic target for controlling invasion and metastasis in SCLC.
PMCID: PMC3972791
MMP; p38 MAPK; PI3K/AKT; small cell lung cancer; syntenin
11.  Differential associations of central and brachial blood pressure with carotid atherosclerosis and microvascular complications in patients with type 2 diabetes 
We examined the relationship between central blood pressure (BP), brachial BP with carotid atherosclerosis and microvascular complications in type 2 diabetes mellitus (T2DM).
We recruited 201 patients who were evaluated for central BP, brachial BP, carotid ultrasonography, brachial-ankle pulse wave velocity (baPWV), ankle-brachial index (ABI) and microvascular complications. Central BP were calculated using a radial automated tonometric system.
Agreement between central BP and brachial BP was very strong (concordance correlation coefficient between central and brachial SBP = 0.889, between central and brachial PP = 0.816). Central pulse pressure (PP) was correlated with mean carotid intima-media thickness (CIMT), baPWV and ABI, whereas brachial PP was borderline significantly correlated with CIMT. The prevalence of nephropathy(DN) and retinopathy(DR) according to the brachial PP tertiles increased, the prevalences of microvascular complications were not different across central PP tertiles. In multivariate analysis, the relative risks (RRs) for the presence of DR were 1.2 and 4.6 for the brachial PP tertiles 2 and 3 when compared with the first tertile. Also, the RRs for the presence of DN were 1.02 and 3 for the brachial PP tertiles 2 and 3 when compared with the first tertile.
Agreement of central BP and brachial BP was very strong. Nonetheless, this study showed that higher brachial PP levels are associated with increased probability for the presence of microvascular complications such as DR/DN. However, there are no associations with central SBP and central PP with microvascular complications. Central BP levels than brachial BP are correlated with surrogate marker of macrovascular complications.
PMCID: PMC3936908  PMID: 24555866
Central blood pressure; Brachial blood pressure; Microvascular complications; Carotid atherosclerosis; Type 2 diabetes
12.  Heterosubtypic protective immunity against widely divergent influenza subtypes induced by fusion protein 4sM2 in BALB/c mice 
Virology Journal  2014;11:21.
Regular reformulation of currently available vaccines is necessary due to the unpredictable variability of influenza viruses. Therefore, vaccine based on a highly conserved antigen with capability of induction of effective immune responses could be a potential solution. Influenza matrix protein-2 (M2) is highly conserved across influenza subtypes and a promising candidate for a broadly protective influenza vaccine. For the enhancement of broad protection, four tandem copies of consensus M2 gene containing extracellular (ED) and cytoplasmic (CD) without the trans-membrane domain (TM) reconstituted from H1N1, H5N1 and H9N2 influenza viruses were linked and named as 4sM2. The construct was effectively expressed in Escherichia coli, purified and proteins were used to immunize BALB/c mice. Humoral and cell-mediated immune responses were investigated following administration.
Mice were intramuscularly immunized with 4sM2 protein 2 times at 2 weeks interval. Two weeks after the last immunization, first humoral and cell mediated immune response specific to sM2 protein were evaluated and the mice were challenged with a lethal dose (10MLD50) of divergent subtypes A/EM/Korea/W149/06(H5N1), A/PR/8/34(H1N1), A/Aquatic bird/Korea/W81/2005(H5N2), A/Aquatic bird/Korea/W44/2005(H7N3), and A/Chicken/Korea/116/2004(H9N2) viruses. The efficacy of 4sM2 was evaluated by determining survival rates, body weights and residual lung viral titers. Our studies demonstrate that the survival of mice immunized with 4sM2 was significantly higher (80–100% survival) than that of unimmunized mice (0% survival). We also examined the long lasting protection against heterosubtype H5N2 virus and found that mice vaccinated with 4sM2 displayed 80% of protection even after 6 months of final vaccination.
Taken together, these results suggest that prokaryotic expressed multimeric sM2 protein achieved cross protection against lethal infection of divergent influenza subtypes which are lasting for the long time.
PMCID: PMC3923897  PMID: 24502341
Broad protection; Humoral immunization; Influenza vaccine; Matrix protein-2
13.  Impaired Fasting Glucose and Risk of Cardiovascular Disease in Korean Men and Women 
Diabetes Care  2013;36(2):328-335.
The relationship between impaired fasting glucose (IFG) and risk of cardiovascular disease (CVD) or ischemic heart disease (IHD) varies widely according to sex and ethnicity. We evaluated the relationship between IFG and CVD or IHD among Korean men and women.
A total of 408,022 individuals who underwent voluntary private health examinations in 17 centers in South Korea were followed for 10 years. Data regarding CVD or IHD events were obtained from the Korean National Health Insurance database. IFG was categorized as grade 1 (fasting glucose 100–109 mg/dL) or grade 2 (110–125 mg/dL).
Incidence rates of CVD (per 100,000 person-years) were 2,203 for diabetes. Age-adjusted hazard ratios (HRs) for CVD were 1.17 (95% CI 1.13–1.20) for grade 1 IFG, 1.30 (1.24–1.35) for grade 2 IFG, and 1.81 (1.75–1.86) for diabetes. The increased risk for women was similar to that of men. Age-adjusted HRs for IHD and ischemic stroke were also significantly increased for men and women with IFG and diabetes. After multivariate adjustment of conventional risk factors (hypertension, dyslipidemia, smoking, obesity, and family history of CVD), the overall risk of CVD was greatly attenuated in all categories. However, the HRs for IHD and ischemic stroke remained significantly increased in men for grade 2 IFG but not in women.
In Korea, grade 2 IFG is associated with increased risk of IHD and ischemic stroke, independent of other conventional risk factors, in men but not in women.
PMCID: PMC3554281  PMID: 23002083
14.  Prevalence, Awareness, and Management of Obesity in Korea: Data from the Korea National Health and Nutrition Examination Survey (1998-2011) 
Diabetes & Metabolism Journal  2014;38(1):35-43.
Obesity is a risk factor for diabetes and several cardiovascular diseases. This study was to investigate the trends in the prevalence, awareness, and management status of obesity among the Korean population for recent 13 years.
The prevalence, subjective awareness, and management of obesity were investigated in adults aged ≥19 years by using the data from the Korea National Health and Nutrition Examination Surveys (KNHANES) 1998 to 2011.
The number of participants was 8,117, 5,826, 5,500, 3,025, 6,756, 7,506, 6,255, and 6,155 in the KNHANES in years 1998, 2001, 2005, 2007, 2008, 2009, 2010, and 2011, respectively. The prevalence of obesity was 26.9%, 29.2%, 32.9%, 32.5%, 32.0%, 32.6%, 32.0%, and 32.0% in 1998, 2001, 2005, 2007, 2008, 2009, 2010, and 2011, respectively, while the overall prevalence of obesity and abdominal obesity increased by 1.19-fold and 1.24-fold respectively in 2011 compared against 2001. In general, a gradual increase in the prevalence of severe obesity has been observed as years go by. Furthermore, trends of improvements in obesity awareness and management rates were visible over the period of surveys.
Although the management status of obesity has improved during the recent years, more effective strategy to control obesity is needed.
PMCID: PMC3950193  PMID: 24627826
Diabetes mellitus; Korea; Obesity; Prevalence
15.  Higher Prevalence and Awareness, but Lower Control Rate of Hypertension in Patients with Diabetes than General Population: The Fifth Korean National Health and Nutrition Examination Survey in 2011 
Diabetes & Metabolism Journal  2014;38(1):51-57.
We investigated the prevalence, awareness, treatment, and control rate of hypertension in Korean adults with diabetes using nationally representative data.
Using data of 5,105 adults from the fifth Korea National Health and Nutrition Examination Survey in 2011 (4,389 nondiabetes mellitus [non-DM]), 242 newly diagnosed with DM (new-DM), and 474 previously diagnosed with DM (known-DM), we analyzed the prevalence of hypertension (mean systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medication) and control rate of hypertension (blood pressure [BP] <130/80 mm Hg).
The prevalence of hypertension in diabetic adults was 54.6% (44.4% in new-DM and 62.6% in known-DM, P<0.0001 and P<0.0001, respectively) compared with non-DM adults (26.2%). Compared to non-DM, awareness (85.7%, P<0.001) and treatment (97.0%, P=0.020) rates were higher in known-DM, whereas no differences were found between new-DM and non-DM. Control rate among all hypertensive subjects was lower in new-DM (14.9%), compared to non-DM (35.1%, P<0.001) and known-DM (33.3%, P=0.004). Control rate among treated subjects was also lower in new-DM (25.2%), compared to non-DM (68.4%, P<0.0001) and known-DM (39.9%, P<0.0001).
Higher prevalence and low control rate of hypertension in adults with diabetes suggest that stringent efforts are needed to control BP in patients with diabetes, particularly in newly diagnosed diabetic patients.
PMCID: PMC3950195  PMID: 24627828
Blood pressure; Diabetes mellitus; Hypertension; Korea National Health and Nutrition Examination Survey
16.  Effects of Platelet Lysate Preparations on the Proliferation of HaCaT Cells 
Annals of Laboratory Medicine  2013;34(1):43-50.
Standard protocols are lacking for the preparation of platelet lysates (PL) as an alternative to using fetal bovine serum as a cell culture supplement. This study aimed to establish optimum conditions for preparing PL for use in cell cultures.
Cell density in three pooled platelet concentrates (PC) were adjusted to 1×1012/L and 2×1012/L. PL was prepared from PC by 1 to 3 freeze-thaw (FT) cycles. HaCaT cells were cultured in media supplemented with 5% or 10% PL. Cell numbers were estimated using a Cell Counting Kit-8 (CCK-8; Dojindo Laboratories, Japan). Growth factors were quantified by using the Luminex 200 system (Luminex Corporation, USA).
Cell proliferation rates in the presence of PLs were similar when prepared from PCs of both cell densities. The rates were higher in media containing 5% PL than 10% PL when prepared by two FT cycles. Concentrations of vascular endothelial growth factor (VEGF), platelet-derived growth factor-AB/BB (PDGF-AB/BB), PDGF-AA, and epidermal growth factor (EGF) were significantly higher in PL prepared from PC with a cell density of 2×1012/L than 1×1012/L PC. However, only VEGF and PDGF-AA concentrations in PLs were correlated with HaCaT cell counts.
The 5% PL from PC with a cell density of 1×1012/L prepared by two FT cycles treatment was the most effective condition that supported steady HaCaT cell proliferation. Our finding may be useful for preparing PL-supplemented cell culture media.
PMCID: PMC3885772  PMID: 24422195
Platelet lysate; Cell culture; Freeze-thaw; Growth factor; Cell proliferation
17.  Elevated Aurora Kinase A Protein Expression in Diabetic Skin Tissue 
Archives of Plastic Surgery  2014;41(1):35-39.
Aurora kinase A (Aurora-A) plays an important role in the regulation of mitosis and cytokinesis. Dysregulated Aurora-A leads to mitotic faults and results in pathological conditions. No studies on Aurora-A expression in human diabetic skin tissue have been reported. In light of this, we explored the expression of Aurora-A in human diabetic skin tissue.
Aurora-A protein was evaluated by western blotting in 6 human diabetic skin tissue and 6 normal skin specimens.
Increased expression of Aurora-A protein was detected in all diabetic skin tissue samples in both western blot analysis and immunohistochemical staining. However, in the case of the normal skin tissue, no bands of Aurora-A protein were detected in either the western blotting analysis or the immunohistochemical staining.
Thus far, there have been no studies on the expression of Aurora-A in diabetic skin tissue. However, we believe that oxidative DNA damage related to the expression of Aurora-A protein and Aurora-A could be involved inhuman diabetic skin tissue.
PMCID: PMC3915154  PMID: 24511492
Skin; Diabetes mellitus
18.  Mandibular Fracture Masking Hyoid Bone Fracture 
Archives of Plastic Surgery  2014;41(1):93-95.
PMCID: PMC3915166  PMID: 24511504
19.  Exosomes Derived from Mesenchymal Stem Cells Suppress Angiogenesis by Down-Regulating VEGF Expression in Breast Cancer Cells 
PLoS ONE  2013;8(12):e84256.
Exosomes are small membrane vesicles released by a variety of cell types. Exosomes contain genetic materials, such as mRNAs and microRNAs (miRNAs), implying that they may play a pivotal role in cell-to-cell communication. Mesenchymal stem cells (MSCs), which potentially differentiate into multiple cell types, can migrate to the tumor sites and have been reported to exert complex effects on tumor progression. To elucidate the role of MSCs within the tumor microenvironment, previous studies have suggested various mechanisms such as immune modulation and secreted factors of MSCs. However, the paracrine effects of MSC-derived exosomes on the tumor microenvironment remain to be explored. The hypothesis of this study was that MSC-derived exosomes might reprogram tumor behavior by transferring their molecular contents. To test this hypothesis, exosomes from MSCs were isolated and characterized. MSC-derived exosomes exhibited different protein and RNA profiles compared with their donor cells and these vesicles could be internalized by breast cancer cells. The results demonstrated that MSC-derived exosomes significantly down-regulated the expression of vascular endothelial growth factor (VEGF) in tumor cells, which lead to inhibition of angiogenesis in vitro and in vivo. Additionally, miR-16, a miRNA known to target VEGF, was enriched in MSC-derived exosomes and it was partially responsible for the anti-angiogenic effect of MSC-derived exosomes. The collective results suggest that MSC-derived exosomes may serve as a significant mediator of cell-to-cell communication within the tumor microenvironment and suppress angiogenesis by transferring anti-angiogenic molecules.
PMCID: PMC3877259  PMID: 24391924
20.  Association between Cardiac Autonomic Neuropathy, Diabetic Retinopathy and Carotid Atherosclerosis in Patients with Type 2 Diabetes 
Endocrinology and Metabolism  2013;28(4):309-319.
It is not clear whether microangiopathies are associated with subclinical atherosclerosis in type 2 diabetes mellitus (T2DM). We investigated the relation of cardiac autonomic neuropathy (CAN) and other microangiopathies with carotid atherosclerosis in T2DM.
A total of 131 patients with T2DM were stratified by mean carotid intima-media thickness (CIMT) ≥ or <1.0 mm and the number of carotid plaques. CAN was assessed by the five standard cardiovascular reflex tests according to the Ewing's protocol. CAN was defined as the presence of at least two abnormal tests or an autonomic neuropathy points ≥2. Diabetic microangiopathies were assessed.
Patients with CAN comprised 77% of the group with mean CIMT ≥1.0 mm, while they were 29% of the group with CIMT <1.0 mm (P=0.016). Patients with diabetic retinopathy (DR) comprised 68% of the group with CIMT ≥1.0 mm, while they were 28% of the group without CIMT thickening (P=0.003). Patients with CAN comprised 51% of the group with ≥2 carotid plaques, while they were 23% of the group with ≤1 carotid plaque (P=0.014). In multivariable adjusted logistic regression analysis, the patients who presented with CAN showed an odds ratio [OR] of 8.6 (95% confidence interval [CI], 1.6 to 44.8) for CIMT thickening and an OR of 2.9 (95% CI, 1.1 to 7.5) for carotid plaques. Furthermore, patients with DR were 3.8 times (95% CI, 1.4 to 10.2) more likely to have CIMT thickening.
These results suggest that CAN is associated with carotid atherosclerosis, represented as CIMT and plaques, independent of the traditional cardiovascular risk factors in T2DM. CAN or DR may be a determinant of subclinical atherosclerosis in T2DM.
PMCID: PMC3871040  PMID: 24396696
Cardiac autonomic neuropathy; Diabetic angiopathies; Carotid intima-media thickness; Carotid plaque; Diabetes mellitus, type 2
21.  A Case of Gastric Cancer Manifesting as a Solitary Brain Metastasis in the Cerebellopontine Angle That Mimicked Acoustic Neuroma 
Chonnam Medical Journal  2013;49(3):133-135.
At the time of diagnosis, about 20% of patients with gastric cancer have stage IV disease involving the liver, lung, and bone. Brain metastasis from gastric cancer is exceedingly rare, with an incidence of <1% of clinical cases. A 59-year-old man was admitted with hearing loss in the left ear and left facial palsy for 1 month. A magnetic resonance imaging scan revealed a tumor in the cerebellopontine angle that extended to the inner auditory canal and that was clinically diagnosed as acoustic neuroma. After complete resection, histological examination showed metastatic poorly differentiated carcinoma. Further investigation revealed advanced gastric cancer involving the antrum with no evidence of the involvement of other sites except the brain parenchyma. Palliative total gastrectomy was performed and the surgical specimen revealed a poorly cohesive carcinoma that was histopathologically identical to that of the resected brain tumor. Here we report this rare case of gastric cancer that initially presented as a solitary brain metastasis mimicking acoustic neuroma.
PMCID: PMC3881210  PMID: 24400217
Stomach Neoplasms; Brain; Neuroma, Acoustic
22.  Prevalence and Management of Dyslipidemia in Korea: Korea National Health and Nutrition Examination Survey during 1998 to 2010 
Diabetes & Metabolism Journal  2013;37(6):433-449.
Dyslipidemia is a major risk factor of cardiovascular disease. The aim of this study was to investigate the changing trends in the prevalence and management status of dyslipidemia among Korean adults.
The prevalence of dyslipidemia and the rates of awareness, treatment, and control of dyslipidemia were investigated in adults aged ≥20 years from the Korea National Health and Nutrition Surveys (KNHANES) 1998 to 2010. The updated National Cholesterol Education Program criteria was used, which define dyslipidemia as having one or more of the following lipid abnormalities: hypercholesterolemia (total cholesterol ≥240 mg/dL or diagnosis of dyslipidemia or use of lipid-lowering drugs), hypertriglyceridemia (≥150 mg/dL), hyper-low density lipoprotein (LDL) cholesterolemia (≥160 mg/dL or diagnosis of dyslipidemia or use of lipid-lowering drugs), and hypo-high density lipoprotein (HDL)-cholesterolemia (<40 mg/dL in men and <50 mg/dL in women).
The number of participants was 6,921, 4,894, 5,312, 2,733, 6,295, 6,900, and 5,738 in KNHANES 1998, 2001, 2005, 2007, 2008, 2009, and 2010, respectively. Age-standardized prevalence rates of dyslipidemia were 54.0%, 65.8%, 66.5%, 60.6%, 58.7%, 58.9%, and 59.0% in 1998, 2001, 2005, 2007, 2008, 2009, and 2010, respectively. Hypertriglyceridemia and hypo-HDL-cholesterolemia were the two most frequent lipid abnormalities. The overall prevalence of hypercholesterolemia and hyper-LDL-cholesterolemia increased by 1.36- and 1.35-fold in 2010 compared with 2007, respectively. Awareness, treatment, and control rates of dyslipidemia improved over the period of surveys in both sexes. In 2010, about 30% of dyslipidemic patients who received lipid-lowering treatment reached target levels.
Although the management status of dyslipidemia has improved during recent years, effective strategy is required for achieving better prevention, treatment, and control of dyslipidemia.
PMCID: PMC3881328  PMID: 24404515
Dyslipidemia, Korea; Prevalence
23.  Sequential chemotherapy followed by radiotherapy versus concurrent chemoradiotherapy in patients with stage I/II extranodal natural killer/T-cell lymphoma, nasal type 
Blood research  2013;48(4):274-281.
The purpose of this report is to summarize our clinical experience of patients with stage I/II extranodal natural killer (NK)/T-cell lymphoma, nasal type, treated using sequential chemotherapy followed by radiotherapy (SCRT) or concurrent chemoradiotherapy (CCRT).
Forty-three patients with stage I/II extranodal NK/T-cell lymphoma, nasal type, who received SCRT (16 patients) or CCRT (27 patients) were included in the present analysis.
The median follow-up time was 39 months (range, 4-171 months) for all patients, 77 months (range, 4-171 months) for the SCRT group, and 31 months (range, 6-132 months) for the CCRT group. There were no statistically significant differences between the SCRT and CCRT groups with regard to the 3-year progression-free survival (PFS) (56% vs. 41%, P=0.823) and 3-year overall survival (OS) (75% vs. 59%, P=0.670). Univariate analysis revealed that patients with tumors confined to the nasal cavity and patients achieved complete remission had better PFS and OS rates, regardless of the treatment sequence. Multivariate analysis revealed that patients with tumors confined to the nasal cavity and patients aged ≤60 years had better OS rates.
The effect of SCRT and CCRT are similar in terms of survival outcomes of patients with stage I/II extranodal NK/T-cell lymphoma, nasal type. Our results show that tumors confined to the nasal cavity and an age ≤60 years were associated with a better prognosis.
PMCID: PMC3894386  PMID: 24466552
Extranodal NK/T-cell lymphoma; Nasal type; Chemoradiotherapy; Treatment outcome
24.  The Influence of Previous Antipsychotic Polypharmacy Versus Monotherapy on the Effectiveness of Antipsychotic after Switching to Paliperidone Extended-release 
Although antipsychotic polypharmacy is widely used in the pharmacotherapy of schizophrenia, its effectiveness is controversial. In particular, clinicians tend to avoid switching to monotherapy in patients who have been prescribed polypharmacy. In the present study, the authors investigate whether there is difference in time to discontinuation of antipsychotics between patients on previous monotherapy or polypharmacy.
Pooled analysis was conducted on two 24-week, multicenter, open-label, non-comparative studies that were originally designed to investigate the effectiveness of switching to paliperidone extended-release (ER) in patients with schizophrenia. Patients were divided into two groups according to previously prescribed antipsychotics, that is, to a polypharmacy group or a monotherapy group. The primary outcome measure was time to discontinuation of paliperidone ER. In addition, the authors sought to identify clinical variables that influence time to discontinuation.
Before switching to paliperidone ER, 535 of 673 (79.5%) patients were prescribed antipsychotic monotherapy, and the remaining 138 (20.5%) patients were prescribed antipsychotic polypharmacy. No significant differences in time to discontinuation of paliperidone ER were observed between the polypharmacy and monotherapy groups. Personal and social performance scale score was the only factor found to influence time to discontinuation of paliperidone ER. No differences in psychopathology or adverse effects were found between the monotherapy and polypharmacy groups.
Our results suggest that number of antipsychotics prescribed before switching to monotherapy does not influence clinical prognosis in patients with schizophrenia.
PMCID: PMC3897764  PMID: 24465252
Schizophrenia; Antipsychotic agents; Polypharmacy; 9-Hydroxyrisperidone; Treatment outcome
25.  Influencing Factors and Predictors of Early Response in Schizophrenia Patients Receiving the Paliperidone Extended-Release Tablets (Paliperidone ER) 
Psychiatry Investigation  2013;10(4):407-416.
Paliperidone extended-release tablet (paliperidone ER) is a new oral psychotropic agent developed for schizophrenia treatment. There have been some studies about paliperidone's good efficacy and tolerability. Clinicians appear to change the antipsychotic medication to paliperidone ER. However, it is not known what patients are favorable responsive to paliperidone ER. The aim of this study was to evaluate the characteristics of early responders and investigate predictors of acute response when the medications changed to paliperidone ER.
Data were analyzed from schizophrenic patients who participated in a multi-center, open-label, non-comparative clinical trial. Total 320 patients were examined in this study. Sociodemographic, psychopathology, social function and metabolic data were evaluated. Unpaired t-test for continuous and χ2 for categorical data, respectively, were used to compare early responder and non-responders. Logistic regression analysis was used to establish a prediction model.
38.7% of study subjects (124 of 320) responded to paliperidone ER treatment. Logistic regression analysis showed that a good paliperidone ER response was more likely when patients were social drinkers, when patients had started medication at inpatient, when negative symptoms were less severe, and when patients' social relationship and self-care were better.
Early response to paliperidone ER treatment is associated with less negative symptoms and good social relationships and self-care. Strategies to reduce these symptoms may contribute to early response to paliperidone ER.
PMCID: PMC3902160  PMID: 24474991
Schizophrenia; Paliperidone ER; Early response; Predictors; Antipsychotics

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