• Journal of Life Science
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• v.29 no.1
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• pp.9-17
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• 2019

As tumors develop, they encounter microenvironmental stress, such as hypoxia and glucose depletion, due to poor vascular function, thereby leading to necrosis, which is observed in solid tumors. Necrotic cells are known to release cellular cytoplasmic contents, such as high mobility group box 1 (HMGB1), into the extracellular space. The release of HMGB1, a proinflammatory and tumor-promoting cytokine, plays an important role in promoting inflammation and metabolism during tumor development. Recently, HMGB1 was shown to induce the epithelial-mesenchymal transition (EMT) and metastasis. However, the underlying mechanism of the HMGB1-induced EMT, invasion, and metastasis is unclear. In this study, we showed that noninvasive breast cancer cells MCF-7 formed tightly packed, rounded spheroids and that the cells in the inner regions of a multicellular tumor spheroid (MTS), an in vitro model of a solid tumor, led to necrosis due to an insufficient supply of O2 and glucose. In addition, after 7 d of MTS culture, the EMT was induced via the transcription factor Snail. We also showed that HMGB1 receptors, including RAGE, TLR2, and TLR4, were induced by MTS culture. RAGE, TLR2, and TLR4 shRNA inhibited MTS growth, supporting the idea that RAGE/TLR2/TLR4 play critical roles in MTS growth. They also prevented MTS culture-induced Snail expression, pointing to RAGE/TLR2/TLR4-dependent Snail expression. RAGE, TLR2, and TLR4 shRNA suppressed the MTS-induced EMT. In human cancer tissues, high levels of RAGE, TLR2, and TLR4 were detected. These findings demonstrated that the HMGB-RAGE/TLR2/TLR4-Snail axis played a crucial role in the growth of the MTS and MTS culture-induced EMT.

• Journal of the Korean Society of Radiology
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• v.83 no.1
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• pp.149-161
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• 2022

Purpose To investigate the correlation between computer-aided diagnosis (CAD) parameters in 3-tesla (T) MRI and pathologic immunohistochemical (IHC) markers in invasive carcinoma of no special type (NST). Materials and Methods A total of 94 female who were diagnosed with NST carcinoma and underwent 3T MRI using CAD, from January 2018 to April 2019, were included. The relationship between angiovolume, curve peak, and early and late profiles of dynamic enhancement from CAD with pathologic IHC markers and molecular subtypes were retrospectively investigated using Dwass, Steel, Critchlow-Fligner multiple comparison analysis, and univariate binary logistic regression analysis. Results In NST carcinoma, a higher angiovolume was observed in tumors of higher nuclear and histologic grades and in lymph node (LN) (+), estrogen receptor (ER) (-), progesterone receptor (PR) (-), human epidermal growth factor 2 (HER2) (+), and Ki-67 (+) tumors. A high rate of delayed washout and a low rate of delayed persistence were observed in Ki-67 (+) tumors. In the binary logistic regression analysis of NST carcinoma, a high angiovolume was significantly associated with a high nuclear and histologic grade, LN (+), ER (-), PR (-), HER2 (+) status, and non-luminal subtypes. A high rate of washout and a low rate of persistence were also significantly correlated with the Ki-67 (+) status. Conclusion Angiovolume and delayed washout/persistent rate from CAD parameters in contrast enhanced breast MRI correlated with predictive IHC markers. These results suggest that CAD parameters could be used as clinical prognostic, predictive factors.

• The korean journal of orthodontics
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• v.33 no.6 s.101
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• pp.485-497
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• 2003

The form and function of the craniofacial structure critically depend on genetic information. With recent advances in the molecular technology, genes that are important for normal growth and morphogenesis of the craniofacial skeleton are being rapidly uncovered, shaping up modem craniofacial biology. One of them is fibroblast growth factor receptor 2 (FGFR2). Specific point mutations in the. FGFR2 gene have been linked to Apert syndrome, which is characterized by premature closure of cranial sutures and craniofacial anomalies as well as limb deformities. To study pathogenic mechanisms underlying craniosynostosis phenotype of Apert syndrome, we used a transgenic approach; an FGFR2 minigene construct containing an Apert mutation (a point mutation that substitute proline at the position 253 to arginine; P253R) was introduced into fertilized mouse germ cells by DNA microinjection. The injected cells were then allowed to develop into transgenic mice. We used a bone-specific promoter (a DNA fragment from the type I collagen gene) to confine the expression of mutant FGFR2 gene to the bone tissue, and asked whether expression of mutant FGFR2 in bone is sufficient to cause the craniosynostosis phenotype in mice. Initial characterization of these mice shows prematurely closed cranial sutures with facial deformities expected from Apert patients. We also demonstrate that the transgene produces mutant FGFR2 protein with increased functional activities. Having this useful mouse model, we now can ask questions regarding the role of FGFR2 in normal and abnormal development of cranial bones and sutures.

• Tuberculosis and Respiratory Diseases
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• v.47 no.3
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• pp.347-355
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• 1999

Background: Phospholipase C(PLC) plays a central role in cellular signal transduction and is important in cellular growth, differentiation and transformation. There are currently ten known mammalian isozymes of PLC reported to this date. Hydrolysis of phosphatidylinositol 4,5-bisphosphate($PIP_2$) by PLC produces two important second messengers, inositol 1,4,5-trisphosphate($IP_3$) and diacylglycerol. PLC-${\gamma}1$, previously, was known to be activated mainly through growth factor receptor tyrosine kinase. Other mechanisms of activating PLC-yl have been reported such as activation through tau protein in the presence of arachidonic acid in bovine brain and activation by $IP_3$, phosphatidic acid, etc. Very recently, another PLC-${\gamma}1$ activator protein such as tau has been found in bovine lung tissue, which now is considered to be AHNAK protein. But there has been no report concerning AHNAK and its associated disease to this date. In this study, we examined the expression of the PLC-${\gamma}1$ activator, AHNAK, in lung cancer specimens and their paired normal. Methods: From surgically resected human lung cancer tissues taken from twenty-eight patients and their paired normal counterparts, we evaluated expression level of AHNAK protein using immunoblot analysis of total tissue extract Immunohistochemical stain was performed with primary antibody against AHNAK protein. Results: Twenty-two among twenty-eight lung cancer tissues showed overexpression of AHNAK protein (eight of fourteen squamous cell lung cancers, all of fourteen adenocarcinomas). The resulting bands were multiple ranging from 70 to 200 kDa in molecular weight and each band was indistinct and formed a smear, reflecting mobility shift mainly due to proteolysis during extraction process. On immunohistochemistry, lung cancer tissues showed a very heavy, dense staining with anti-AHNAK protein antibody as compared to the surrounding normal lung tissue, coresponding well with the results of the western blot Conclusion: The overexpression of PLC-${\gamma}1$ activator protein, AHNAK in lung cancer may provide evidence that the AHNAK protein and PLC-${\gamma}1$ act in concerted manner in carcinogenesis.

• The korean journal of orthodontics
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• v.36 no.4
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• pp.284-294
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• 2006

Objective: Activating mutations in the fibroblast growth factor receptor-2 (FGFR2) have been shown to cause syndromic craniosynostosis such as Apert and Crouzon syndromes. The purpose of this pilot study was to investigate the resultant phenotypes induced by the two distinctive bone-targeted gene constructs of FGFR2, Pro253Arg and Cys278Phe, corresponding to human Apert and Crouzon syndromes respectively. Methods: Wild type and a transgenic mouse model with normal FGFR2 were used as controls to examine the validity of the microinjection. Micro-CT and morphometric analysis on the skull revealed the following results. Results: Both Apert and Crouzon mutants of FGFR2 induced fusion of calvarial sutures and anteroposteriorly constricted facial dimension, with anterior crossbite present only in Apert mice. Apert mice differed from Crouzon mice and transgenic mice with normal FGFR2 in the anterior cranial base flexure and calvarial flexure angle which implies a possible difference in the pathogenesis of the two mutations. In contrast, the transgenic mice with normal FGFR2 displayed normal craniofacial phenotype. Conclusion: Apert and Crouzon mutations appear to lead to genotype-specific phenotypes, possibly causing the distinctive sites and sequence of synostosis in the calvaria and cranial base. The exact function of the altered FGFR2 at each suture needs further investigation.

• Tuberculosis and Respiratory Diseases
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• v.58 no.5
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• pp.473-479
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• 2005

Background : Gefitinib targets the epidermal growth factor receptor r(EGFR), and Gefitinib has antitumor activity in patient with non-small cell lung cancer (NSCLC). However, only 10 to 20 percent of patients show a clinical response to this drug, and the molecular mechanisms underlying patient sensitivity to gefitinib are unknown. PTEN (Phosphatase and tensin homolog deleted on chromosome Ten) plays a role for the modulation of the phosphatidylinositol 3-kinase pathway (PI3K), which is involved in cell proliferation and survival, so that it can inhibit cell cycle progression and induce G1 arrest. Therefore, we analyzed the relationship between PTEN expression and gefitinib's responsiveness in patients having advanced non small cell lung cancer that had progressed after previous chemotherapy. Methods : The expression of PTEN was studied by immunohistochemistry in paraffin-embedded tumor blocks that were obtained from 22 patients who had been treated with gefitinib from JAN, 2001 to AUG. 2004. For the evaluation of the relationships between the PTEN expression, the clinical stage and the basal characteristics, those cases that showed the respective antigen expression in >50% of the tumor cells were considered positive. Results : The positive rate of PTEN staining was 55% of the total of 22 patients. There was a significant relationship between the increased expression of PTEN and the response group (p=0.039). However, there was no significant relationship between the expression of PTEN and other clinicopathologic characteristics. Conclusion: The expression of PTEN in patients with advanced non small cell lung cancer that has progressed after previous chemotherapy may play a role in gefitinib's responsiveness.

• Journal of Life Science
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• v.28 no.1
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• pp.17-25
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• 2018

In this study, we examined the efficacy of the immune regulation of ${\beta}$-1,3/1,6-glucan and Lactobacillus plantarum LM1004 on atopic dermatitis models. The oral administration of ${\beta}$-1,3/1,6-glucan and L. plantarum LM1004 on mice significantly decreased the amount of scratching, leakage to evans blue, and concentrations of serum immunoglobulin E (IgE) and histamine compared with the atopic dermatitis - induced group. When atopic dermatitis was induced, the transcription factors (GATA-3, retinoic acid-related orphan receptor ${\gamma}$ T [$ROR{\gamma}T$]) and cytokines (interleukin-4 [IL-4], IL-17) of Th2 and Th17 cells were overexpressed at the transcriptional level, and they significantly decreased with oral administration of ${\beta}$-1,3/1,6-glucan and L. plantarum LM1004. In addition, ${\beta}$-1,3/1,6-glucan and L. plantarum LM1004 were shown to modulate the immune balance by increasing the expression of Th1 and Treg transcription (T-bet, forkhead box p3 [Foxp3]) and cytokines (interferon-${\gamma}$ [IFN-${\gamma}$], transforming growth factor-${\beta}$ [TGF-${\beta}$]). Galectin-9 and filaggrin were significantly lower in the atopic dermatitis - induced group and significantly higher in the ${\beta}$-1,3/1,6-glucan-treated group. In contrast, thymic stromal lymphopoietin (TSLP) was highest in the atopic dermatitis-induced group, while mice that were orally administered ${\beta}$-1,3/1,6-glucan and L. plantarum LM1004 showed similar TSLP levels to the control group. These results indicate that ${\beta}$-1,3/1,6-glucan and L. plantarum LM1004 have immunomodulatory effects and atopic dermatitis improvement effects in an animal model of atopic dermatitis. Therefore, it is expected that ${\beta}$-1,3/1,6-glucan and L. plantarum LM1004 can be used as natural materials in the treatment of atopic dermatitis.

• Journal of Life Science
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• v.19 no.11
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• pp.1581-1590
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• 2009

Hizikia fusiforme is a kind of brown edible seaweed that mainly grows in the temperate seaside areas of the northwest pacific, including Korea, Japan and China, and has been widely used as a health food for hundreds of years. Recently, H. fusiforme has been known to exert pharmacological activities including antioxidant, antimutagenic and anticoagulant activities. However, the molecular mechanisms of H. fusiforme in malignant cells have not been clearly elucidated yet. In this study, the effects of ethyl alcohol extract of H. fusiforme (EAHF) on the anti-proliferative effects of MDA-MB-231 and MCF-7 human breast cancer cells were investigated. EAHF treatment resulted in a concentration-dependent growth inhibition by including apoptosis in MDA-MB-231 cells and G1 phase arrest in MCF-7 cells, which could be proved by MTT assay, DAPI staining, agarose gel electrophoresis and flow cytometry analysis. In MDA-MB-231 cells, the increase in apoptosis induced by EAHF treatment correlated with up-regulation of pro-apoptotic Bax expression. EAHF treatment induced the proteolytic activation of caspase-3 and caspase-9, and a concomitant inhibition of poly (ADP-ribose) polymerase, $\beta$-catenin, phospholipase-${\gamma}1$ protein and DNA fragmentation factor 45/inhibitor of caspase-activated DNase. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of H. fusiforme.

• The korean journal of orthodontics
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• v.31 no.1 s.84
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• pp.121-136
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• 2001

This study was performed to analyse the expression of VEGF and it's receptor(VEGFR) in the tension side of the periodontal ligament following orthodontic tooth movement. Upper first molars of Sprague-Dawley rats were moved medially using closed coil spring for 1, 2, 24 hours and 3, 7, 14 days. H&E staining, immunohistochemical staining and in situ hybridization methods were used to analyse the change of the expression of VEGF and VEGFR. The results from this study were as follows : 1. Following tensional force, periodontal ligament showed elongation of fibers, compression and congestion of vessels and regional hemorrhage. These tissue changes were recovered within 3 days of force application. New bone formation was seen after 3 days of force application and continued for the remaining experimental periods. 2. Following tensional force, VEGF and VEGF mRNA expression was increased in the periodontal ligament cells, osteoblasts and cementoblasts. This change was followed by increased vasculature in the periodontal ligament. 3. After 3 days of tensional force, VEGF and VEGF mRNA expression was confined mainly to the osteopaths and the periodontal ligament cells adjacent to the alveolar bone. After 2 weeks of force application, VEGF and VEGF mRNA expression was reduced to the level of control sample. 4. VEGFRs(Flt-1, Flk-1) showed similar expression pattern and it's expression was mainly seen in the endothelial cells and osteoblasts. Following tensional force VEGFR expression was increased in the endothelial cells and osteoblasts. In conclusion, in the tension side of the penodontal ligament, ligament cells, osteoblast and cementoblast showed increased expression of VEGF & VEGF mRNA. It preceded the increase of vasculature and new bone formation. The increased expression of VEGF mRNA in cementoblast may induce periodontal vessels, which distribute mainly the bone side half of periodontal ligament, grow in the direction of tensional force. Increased expression of VEGFR & VEGFR mRNA not only in endothelial cell but in osteoblast, osteocyte and periodontal cells showed VEGF acts not only in paracrine manner but in autocrine one.

• Korean Journal of Clinical Laboratory Science
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• v.51 no.3
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• pp.360-369
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• 2019

Cadherins are essential transmembrane proteins that promote cell-cell adhesion and maintain the corpus luteum structure in the ovary. This study examined the influence of prostaglandin F2 alpha ($PGF2{\alpha}$) on E-cadherin, N-cadherin, and adhesion in luteal theca cells (LTCs). The luteal cells were isolated from the mid-phase corpus luteum, and the LTCs were cultured separately from the luteal heterogeneous cells according to the morphology of the mesenchymal cells and to determine if steroidogenic and endothelial cells of LTCs, 3beta-hydroxysteroid dehydrogenase ($3{\beta}$-HSD), and vascular endothelial growth factor receptor 2 (VEGFR2) mRNA were used. The LTCs were then incubated in the culture medium supplemented with 0.01, 0.1, and 1.0 mM $PGF2{\alpha}$ for 24 h, and the E-cadherin and N-cadherin proteins in the LTCs were detected by confocal laser scanning microscopy. The results revealed $3{\beta}$-HSD mRNA expression in the LTC but no VEGF2R mRNA expression. The E-cadherin and N-cadherin proteins of the LTCs were damaged in the 0.01, 0.1, and 1.0 mM $PGF2{\alpha}$ treatment groups, and the expression of the N-cadherin protein was reduced significantly in 0.01 mM $PGF2{\alpha}$ compared to the 0 mM $PGF2{\alpha}$ treatment groups (P<0.05). In addition, the number of attached LTCs were significantly lower in the 0.01 mM $PGF2{\alpha}$ treatment group than in the 0 mM $PGF2{\alpha}$ treatment group (P<0.05). In conclusion, $PGF2{\alpha}$ affected the disruption of cadherin proteins and cell adhesion in LTCs. These results may help better understand the cadherin and adhesion mechanism during corpus luteum regression in the ovary.