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Kim J.-W.,Seoul National University | Kim D.K.,Seoul International School | Min A.,Seoul National University | Lee K.-H.,Seoul National University | And 6 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2016

Purpose: Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer. Methods: Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results. Results: The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment. Conclusions: High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin. © 2015, Springer-Verlag Berlin Heidelberg.


Kim J.,Seoul National University | Hong D.,Seoul International School | Lee H.,Seoul National University | Shin Y.,Samsung | And 4 more authors.
Journal of Physical Chemistry C | Year: 2013

We report the large-scale fabrication of high-performance field effect transistors (FETs) based on pristine semiconducting single-walled carbon nanotube (s-SWCNT) networks without bundles or organic impurities, thus exhibiting its intrinsic characteristics. Here, the solution of pristine s-SWCNTs without bundles or organic impurities was prepared in nonpolar solvent via filtration and centrifugation processes, and the s-SWCNTs in the solution were selectively assembled onto specific regions on the solid substrates via a directed assembly strategy. The fabricated FET devices based on such pristine s-SWCNT networks could exhibit a rather large on-off ratio up to over ∼106 and a subthreshold swing as small as ∼490 mV/dec, which are comparable to those of a single s-SWCNT-based device with the same device structure. Importantly, the s-SWCNT devices exhibited anomalous gating behaviors such as an on-current saturation at a large gate bias and unconventional scaling behaviors, which are quite different from those of previous SWCNT network-based devices. Such anomalous behaviors can be explained by a simple model based on the networks of contact and CNT resistances, which implies that the anomalous behaviors are, in fact, the intrinsic characteristics of pristine s-SWCNT network-based devices. Our work provides a new insight about the intrinsic characteristics of pristine s-SWCNT network-based devices and, thus, should be an important guideline for the future research and applications of high-performance s-SWCNT network-based devices. © 2013 American Chemical Society.


Min A.,Seoul National University | Im S.-A.,Seoul National University | Kim D.K.,Seoul International School | Song S.-H.,Seoul National University | And 8 more authors.
Breast Cancer Research | Year: 2015

Introduction: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway. Methods: We determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These in vitro data were validated in vivo using a human breast cancer xenograft model. Results: Triple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both in vitro and in vivo. Conclusion: Our findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA. © Min et al.; licensee BioMed Central.


Min A.,Seoul National University | Im S.-A.,Seoul National University | Kim D.K.,Seoul International School | Song S.-H.,Seoul National University | And 7 more authors.
Breast Cancer Research | Year: 2015

Introduction: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway. Methods: We determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These in vitro data were validated in vivo using a human breast cancer xenograft model. Results: Triple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both in vitro and in vivo. Conclusion: Our findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA. © 2015 Min et al.; licensee BioMed Central.


Park J.,Seoul National University | Hong D.,Seoul International School | Kim D.,Seoul National University | Byun K.-E.,Samsung | Hong S.,Seoul National University
Journal of Physical Chemistry C | Year: 2014

The diffusion of lipids and proteins in cell membranes is involved in various cellular processes such as cell adhesion and cellular signaling. We report the anisotropic molecular diffusion in the membranes of human mesenchymal stem cells on aligned single-walled carbon nanotube networks. In this study, the cells were first cultured on the surfaces of glass, graphene, and carbon nanotube networks with random or aligned orientations. Then, the molecular diffusion constants of the cell membranes were measured using a fluorescence-recovery-after-photobleaching technique. The cells on graphene exhibited a diffusion constant comparable to that on glass substrate, while those on the rough surface of randomly oriented carbon nanotube networks exhibited a rather low diffusion constant. On the aligned carbon nanotube networks, the molecules in the cell membrane were found to diffuse faster along the direction parallel to the aligned carbon nanotubes than along the direction orthogonal to the nanotubes. These results indicate that the nanoscale properties of nanostructured materials may significantly affect the molecular diffusion in cell membranes and, possibly, related cellular processes. © 2014 American Chemical Society.


PubMed | Seoul International School, Astrazeneca and Seoul National University
Type: | Journal: Breast cancer research : BCR | Year: 2015

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway.We determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These in vitro data were validated in vivo using a human breast cancer xenograft model.Triple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both in vitro and in vivo.Our findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA.


Kim J.H.,Korea University | Choi H.,Korea University | Suh M.J.,Seoul International School | Shin J.H.,Korea University | And 2 more authors.
Spine | Year: 2013

Study Design: Human annulus fibrosus (AF) cells were stimulated in vitro with interleukin (IL)-1β and exposed to biphasic electrical currents. Objective: To identify the effect of biphasic electrical currents on the production of the extracellular matrix-modifying enzymes and inflammatory mediators in IL-1β-stimulated AF cells. Summary of Background Data: Symptomatic disc degeneration is an important cause of chronic intractable lumbar pain and is associated with macrophage-mediated inflammation in the AF. The inflammatory reaction relationship has not been studied in the AF. Methods: Human AF cells were treated with 1 ng/mL IL-1β and cultured in a microcurrent generating chamber system. The levels of matrix metalloproteinase (MMP)-1, MMP-3, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, IL-6, IL-8, vascular endothelial growth factor (VEGF), insulin-like growth factor, and nitric oxide (NO) were measured. Expression of cyclooxygenase 2 and type I collagen mRNA was analyzed. Results: Compared with unstimulated cells, IL-1β-stimulated AF cells produced significantly higher levels of MMP-1, MMP-3, IL-6, IL-8, NO, and VEGF, and lower levels of TIMP-1 and TIMP-2. Exposure to a 250-mV/mm field induced time-dependent increases in IL-6, NO, MMP-1, TIMP-1, VEGF, and insulin-like growth factor-1 production. The cells exposed to 500-mV/mm field produced significantly less MMP-1, TIMP-1, IL-6, and VEGF than unexposed cells (MMP-1, 17.2 ± 4.7 ng/mL vs. 27.3 ± 3.9 ng/mL, P< 0.05; TIMP-1, 12.4 ± 3.3 ng/mL vs. 22.3 ± 2.1 ng/mL, P< 0.02; IL-6, 2.5 ± 0.9 ng/mL vs. 6.39 ± 1.90 ng/mL, P< 0.05; and VEGF, 0.1 ± 0.04 ng/mL vs. 0.44 ± 0.15 ng/mL, P< 0.03). NO production was markedly increased at 500 mV/mm (P< 0.0001). Conclusion: We showed that exposure of IL-1β-stimulated AF cells to a 500 mV/mm inhibited MMP-1, IL-6, VEGF, and TIMP-1 production. The results suggest that biphasic electrical current stimulation may have efficacy in diminishing symptomatic disc degeneration. © 2013 Lippincott Williams & Wilkins.


Suh B.,Korea University | Kim Y.,Korea University | Kim T.,Seoul International School | Jeon S.,Korea University
Journal of Electromagnetic Waves and Applications | Year: 2013

This paper presents a CMOS wideband miniature balun operating over the full K- and Ka-bands. The balun is based on a single spiral coupled structure where two symmetric spiral lines are stacked vertically (i.e. broadside-coupled) in an antipodal manner. The proposed structure provides ultra-wideband balun performance while occupying a minimal chip area compared with conventional spiral baluns. In order to offset residual inductance of the spirals, a compensation capacitor is shunted at the end of an unbalanced input line, which further improves the bandwidth. The proposed balun is implemented in a bulk 0.13-μm CMOS process. The measured insertion loss is less than 6.5 dB from 14 to 40 GHz. The amplitude and phase imbalances are less than 1 dB and 10°, respectively, over the entire bandwidth. The balun occupies an area of only 0.0095 mm2, which, to the authors knowledge, is significantly smaller than any previously reported CMOS baluns at similar frequency bands. © 2013 Copyright Taylor and Francis Group, LLC.


Ji C.,Ajou University | Kim J.,Ajou University | Lee J.-Y.,Seoul International School | Hong M.,Ajou University
2015 12th International Conference and Expo on Emerging Technologies for a Smarter World, CEWIT 2015 | Year: 2015

One-time signatures are known to be one of the most promising solution for time-critical multicast authentication in environments with resource-constrained devices such as smart grid. There have been several solutions for multicast applications and TV-OTS has been known to be the most efficient scheme so far. However, there still exists several challenges for one-time signatures to be deployed in practice. We review existing onetime signatures for multicast authentication and address several challenges such as key management and storage cost problems that can inevitably arise when they are actually deployed in practice. © 2015 IEEE.


Choi A.,University of Texas Health Science Center at Houston | Rim Y.,University of Texas Health Science Center at Houston | Mun J.S.,Seoul International School | Kim H.,University of Texas Health Science Center at Houston
Bio-Medical Materials and Engineering | Year: 2014

Alterations of normal mitral valve (MV) function lead to mitral insufficiency, i.e., mitral regurgitation (MR). Mitral repair is the most popular and most efficient surgical intervention for MR treatment. An annuloplasty ring is implanted following complex reconstructive MV repairs to prevent potential reoccurrence of MR. We have developed a novel finite element (FE)-based simulation protocol to perform patient-specific virtual ring annuloplasty following the standard clinical guideline procedure. A virtual MV was created using 3D echocardiographic data in a patient with mitral annular dilation. Proper type and size of the ring were determined in consideration of the MV apparatus geometry. The ring was positioned over the patient MV model and annuloplasty was simulated. Dynamic simulation of MV function across the complete cardiac cycle was performed. Virtual patient-specific annuloplasty simulation well demonstrated morphologic information of the MV apparatus before and after ring implantation. Dynamic simulation of MV function following ring annuloplasty demonstrated markedly reduced stress distribution across the MV leaflets and annulus as well as restored leaflet coaptation compared to pre-annuloplasty. This novel FE-based patient-specific MV repair simulation technique provides quantitative information of functional improvement following ring annuloplasty. Virtual MV repair strategy may effectively evaluate and predict interventional treatment for MV pathology. © 2014 - IOS Press and the authors. All rights reserved.

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