Su-Hyeon Kim

Genistein Inhibits Cell Growth by Modulating Various Mitogen-Activated Protein Kinases and AKT in Cervical Cancer Cells

Genistein, a soy‐derived isoflavone, inhibits growth of tumor cells from various malignancies. Here we investigated the effect of genistein on the growth of cervical cancer cells (HeLa and CaSki) and its possible mechanism. Genistein significantly suppressed cell growth of HeLa and CaSki cells at concentrations of 20 and 60 μmol/L, respectively, for 24 h. Western blotting analysis showed that genistein reduced phosphorylation of AKT and extracellular signal–regulated kinase (ERK)‐1/2 and induced phosphorylation of p38 mitogen‐activated protein kinase (MAPK) and c‐Jun N‐terminal kinase (JNK). Moreover, inhibition of ERK1/2 activity enhanced cell growth inhibition by genistein, whereas inhibition of p38 MAPK activity rescued from genistein‐mediated growth inhibition. Interestingly, inhibition of AKT activity recovered genistein‐induced growth inhibition in CaSki cells but did not in HeLa cells. However, inhibition of JNK activity seemed to have little effect on cell growth inhibition by genistein. Taken together, these results suggest that genistein could inhibit cell growth by inhibiting ERK1/2 activity and activating p38 MAPK.

Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Apoptosis Induced by Genistein in Human Cervical Cancer Cells

Genistein, a naturally occurring isoflavonoid abundant in soy products, has anticancer activity in multiple tumor cells. In this study, we evaluated the apoptotic effect of genistein on cervical cancer cells and its mechanism of apoptosis. Genistein inhibited the proliferation of cervical cancer cells (HeLa, CaSki, and C33A). HeLa cells were the most sensitive to genistein, whereas CaSki and C33A cells were less sensitive. Sub‐G1 analysis showed that genistein increased apoptotic cells up to 45% at a concentration of 60 μmol/L in HeLa cells, whereas it produced 21% and 17% apoptotic cells in CaSki and C33A cells, respectively, at the same concentration. To determine the apoptotic pathway induced by genistein in the cervical cancer cells, we assessed activation of caspase‐3, ‐8, and ‐9 by immunoblotting. Procaspase‐3, ‐8, and ‐9 were decreased and PARP cleavage increased in a time‐dependent manner after the treatment of genistein in HeLa cells. Also, inhibition of caspase‐3, ‐8, and ‐9 with pharmacological inhibitors reduced genistein‐mediated apoptosis. Interestingly, inhibition of caspase‐8 resulted in remarkable reduction of genistein‐induced apoptosis. Bax expression was increased and total bid decreased, whereas bcl‐2 level was not changed by genistein. Taken together, these results suggest that genistein could induce apoptosis through both extrinsic and intrinsic pathways in human cervical cancer cells.

Recrystallization of alumina dispersion strengthened copper strips

Abstract A study has been made of recrystallization behavior of boron added alumina dispersion strengthened copper strips subjected to single-pass cold rolling and multi-pass warm rolling. The cold and warm rolled strips had the microstructure characterized by a band-like substructure and the texture characterized by a well developed rolling texture with high intensities of Brass {011}〈211〉 and S components {123}〈634〉, though the warm rolled strip had the larger band boundary disorientation and the smaller fraction of low angle boundaries than the cold rolled strip. Upon annealing at 1123 K, the cold rolled strip underwent recrystallization. The recrystallization texture was approximated by the {112}〈312〉 orientation, which is supposed to result from a superposition of recrystallization texture of Brass component, {236}〈385〉, and S texture, {123}〈634〉. The warm rolled strip, which must have assumed a particle stabilized structure, retained the deformation microstructure and texture after annealing at 1123 K. Annealing at 1318 K transformed the warm rolled strip to assume a recrystallized grain structure through continuous recrystallization accompanied by particle coarsening without texture change.

Transportation Network Design Considering Travel Time Reliability

Fluctuations in roadway capacity due to non-recurrent traffic incidents is a source of uncertainty of travel time. Travel time reliability, as a transportation performance measure, which may reflect travel time uncertainty was applied to network analysis. Recently, research which applies network reliability concepts to transportation network design has been undertaken. In this study, a continuous network design problem (CNDP) with a travel time reliability constraint was formulated as a bi-level model. A simulation-based genetic algorithm with penalty method was used to obtain the optimal capacity enhancement of each link, combined with a routine which estimates travel time reliability under fluctuations of link capacity. The effect of the travel time constraint on a CNDP was analyzed through a numerical experiment using a simple network. Additionally, the effect of budget allocation and factors to be specified in the model on the results were analyzed.

Two-step infiltration of aluminum melts into Al-Ti-B4C-CuO powder mixture pellets

Aluminum matrix composites with a high volume fraction of B4C and TiB2 were fabricated by a novel processing technique - a quick spontaneous infiltration process. The process combines a pressureless infiltration with the combustion reaction of Al-Ti-B4C-CuO in molten aluminum. The process is realized in a simple and economical way in which the whole process is performed in air in a few minutes. To verify the rapidity of the process, the infiltration kinetics was calculated based on the Washburn equation in which melt flows into a porous skeleton. However, there was a noticeable deviation from the calculated results with the experimental results. Considering the cross-sections of the samples at different processing times, a new infiltration model (two step infiltration) consisting of macro-infiltration and micro-infiltration is suggested. The calculated kinetics results in light of the proposed model agree well with the experimental results.

Abstract 2607: Antitumor activity of the selective RAF inhibitor HM95573 in solid tumors and hematologic malignancies

The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF, NRAS and KRAS is considered one of the causes of solid tumors (NSCLC, CRC,HCC, andthyroid cancers) and hematologic malignancies. HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM). HM95573 potently inhibited the growth of BRAFmutation CRC cell lines (e.g. IC50: 118nM for Colo-205) and thyroid cancer cell lines (43nM for B-CPAP); KRAS mutation NSCLC cell lines(297nM for Calu-6),CRC cell lines(65nM for HCT-116) and thyroid cancer cell lines(479nM for CAL-62); and NRAS mutation HCC cell lines(28nM for HepG2) andleukemia cell lines (39nM for HL-60). HM95573 effectively inhibited the phosphorylations of MEK and ERK, downstream kinases associated with cell proliferation in tumor cell lines mutated in BRAF, KRAS and NRAS. In addition, the phosphorylation of downstream kinases of RAF such as MEK and ERK was effectively inhibited with treatment of HM95573 in mutant KRAS NSCLC and CRC cells. HM95573 showed the excellent antitumor activity in mouse models xenografted with BRAF mutation cell line (Colo-205), KRAS mutation cell lines (Calu-6 and HCT-116)and NRAS mutation cell line (HepG2)two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. The in vivo antitumor activity of HM95573 was potentiated with MEK inhibitors. Now, HM95573 is currently in phase I development in patients with advanced solid tumors including KRAS mutation NSCLC in Korea. Citation Format: Young-Mi Lee, InHwan Bae, Namgoong Gwang Mo, Jae Ho Lee, Suhyeon Kim, Ji Yeon Song, Kyu Hang Lee, Tae Hun Song, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in solid tumors and hematologic malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2607. doi:10.1158/1538-7445.AM2015-2607

Abstract 2606: Antitumor activity of the selective RAF inhibitor HM95573 in melanoma

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF and NRAS is considered one of the causes of melanoma. HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM). HM95573 potently inhibited the growth of mutant BRAF melanoma cell lines such asA375 (IC50: 57nM) and SK-MEL-28 (69nM) and of mutant NRAS melanoma cell lines such asSK-MEL-2 (53nM) and SK-MEL-30 (24nM). In addition, the phosphorylations of MEK and ERK downstream kinases associated with cell proliferation were effectively inhibited with treatment of HM95573in mutant BRAF and mutant NRAS melanoma cells.HM95573inhibited the downstream signaling in melanoma cells even in the presence of HGF which is known to mediate innate resistance to RAF inhibitors. HM95573 showed the excellent antitumor activity in mouse models xenografted with both of BRAF mutation cell lines (e.g. A375 and SK-MEL-28) and NRAS mutation cell lines (such as SK-MEL-2 and SK-MEL-30) compared to two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. Furthermore, HM95573 did not show a potential to paradoxical activation inducing tumor growth in mouse xenograft study using A431 cuSCC (cutaneous squamous cell carcinoma)cancer cell. Now, HM95573 is currently in phase I development in patients with advanced solid tumors including melanoma in Korea. Citation Format: InHwan Bae, YoungGil Ahn, Namgoong GwangMo, SuHyeon Kim, JiYeon Song, TaeHun Song, JaeHo Lee, KyuHang Lee, Young-Mi Lee, YoungHoon Kim, KweeHyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2606. doi:10.1158/1538-7445.AM2015-2606

Multimodal Freight Transportation Network Design Problem for Reduction of Greenhouse Gas Emissions

At the strategic level, multimodal freight network design problems are limited in that they reflect the costs and constraints associated with emissions. The network design problem (NDP) addressed in this study determines investment alternatives for minimizing total system cost, including costs related to greenhouse gas (GHG) emissions, while satisfying the emissions constraint. The NDP can accommodate improvement alternatives in transfer terminals as well as in road and railroad links. In this study, mode-specific travel time functions were used to represent the differences between the modes explicitly, even for the transfer facility. Emission factors were calculated by link travel speed and level of facilities. The empirical application to a container freight network from the Port of Pusan in southeastern South Korea showed the optimal investment strategy for meeting emissions reduction policy objectives. The conclusion is that investment should concentrate on railroad and terminal facilities to induce modal shift. In contrast, investment in congested roads might be a better option for corridors in which the level of railroad service is low and short-distance freight demands are dominant. These results indicate that the proposed network design problem can provide the appropriate investment strategy for reducing GHG emissions and therefore can be a useful approach with regard to GHG emissions reduction policy.

In situ Synthesis of Al/TiC Composites by Combustion Reaction in an Aluminium Melt

In situ Al/TiC composites with a homogeneous distribution of TiC reinforcements were prepared by adding a reactant mixture of Al-Ti-C to an Al melt. A certain amount of CuO addition to the Al-Ti-C system dramatically increases the adiabatic temperature and thereby enables to form in situ TiC in an Al melt at a temperature range of 750~920 °C. TiC particles with a size of 1~2 urn synthesised by self-propagating high-temperature synthesis (SHS) are present in an Al matrix along with Al3Ti. Increase in the melt temperature up to 920 °C with CuO addition promotes the synthesis of TiC with increasing its volume fraction while less Al3Ti phases are observed.

Abstract LB-168: Genistein sensitizes radio-resistant cancer cells through regulation of NF-kappaB

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: NF-kappaB is a key transcription factor involved in the control of normal cellular and organismal processes, such as immune and inflammatory responses, developmental processes, cellular growth, and apoptosis. However, NF-kappaB is persistently active in a number of disease states, including cancer. It has been reported that chemo- or radio- resistant cancer cells had elevated NF-kappaB activity. Recent studies including ours have showed that genistein, a soy-derived isoflavonoid, has antitumor activity in various cancer cells. Objective: In this study, we evaluated whether genistein could sensitize ionizing radiation resistance of cervical cancer cells through regulation of NF-kappaB. Methods: Six cervical cancer cell lines (HeLa, CaSki, C33A, ME180, SiHa, HeLa229) were treated by 20 Gy radiation with 50 M genistein or not. Cell growth rate was measured by MTT assay and protein expression level was analyzed by western blotting. Protein localization was observed by confocal microscopic analysis. NF-kappaB transcriptional activity was measured by luciferase reporter gene assay. NF-kappaB DNA binding activity was evaluated by electophoretic mobility shift assay. Results: Among six cervical cancer cells, HeLa and HeLa229 cells showed radio-resistance accompanied by elevated NF-kappaB activity. Ionizing radiation induced NF-kappaB nuclear transclocation and stimulated NF-kappaB DNA binding and transcriptional activities. However, pretreatment with genistein inhibited radiation induced transcriptional activity coincident to decreased radio-resistancy. Genistein also inhibited radiation-induced NF-kappaB regulated anti-apoptotic gene expression including c-myc, Survivin, XIAP, Bcl-2, IAP-1, TRAF, A1/Bfl-1 and FLIP. Conclusion: Taken together, genistein can sensitize radio-resistant cancer cells through regulation of NF-kappaB and could be used as a radio-sensitizer for the treatment of cervical cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-168.