Decreased efficacy of drugs targeting the vascular endothelial growth factor pathway by the epigenetic silencing of <i>FLT1</i> in renal cancer cells

Kim, Jee Yeon,Hwang, Junha,Lee, Seo Hyun,Lee, Hyo Jin,Jelinek, Jaroslav,Jeong, Hyeseon,Lim, Jae Sung,Kim, Jin Man,Song, Kyu Sang,Kim, Byung Hoon,Lee, Sukhoon,Kim, Jei BioMed Central 2015 Clinical epigenetics Vol.7 No.-

<P><B>Background</B></P><P>The vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling pathway is involved in cancer-related biological functions and is a therapeutic target in cancer. However, the influence of epigenetic regulation of VEGF-VEGFR signaling-related genes remains unclear. Here, we evaluated the effects of <I>FLT1</I> and <I>KDR</I> promoter hypermethylation combined with drugs targeting VEGF-VEGFR signaling on cancer-related phenotypes in renal cancer cells (RCCs) and examined changes in <I>FLT1</I> and <I>KDR</I> promoter hypermethylation in tissues from patients with renal cancer.</P><P><B>Results</B></P><P>In vitro experiments were performed to evaluate the effects of beavacizumab (an anti-VEGF antibody), an anti-FLT1 peptide, an anti-KDR antibody, and the VEGFR tyrosine kinase inhibitors (TKIs) sunitinib and axitinib in 13 RCC lines with different levels of <I>FLT1</I> and/or <I>KDR</I> promoter methylation and in 2 FLT1 or KDR in vitro knockdown models. The synergistic effects of sunitinib and axitinib treatment were also evaluated in four RCC lines having different levels of <I>FLT1</I> and/or <I>KDR</I> methylation. In our in vitro experiments, bevacizumab and an anti-KDR antibody did not affect the proliferation of RCCs having <I>FLT1</I> and/or <I>KDR</I> hypermethylation. In contrast, in RCCs with <I>FLT1</I> hypermethylation, proliferation inhibition was counteracted by treatment with an anti-FLT1 peptide and both VEGF-TKIs (sunitinib and axitinib). Demethylation with sunitinib or axitinib synergistically increased proliferation inhibition in the RCCs exhibiting <I>FLT1</I> hypermethylation. Using in vitro <I>FLT1</I> or <I>KDR</I> knockdown models, decreased proliferation inhibition following anti-FLT1 peptide, sunitinib, and axitinib treatment was observed only in <I>FLT1</I>-knockdown cells. In patients with renal cancer who received sunitinib, <I>FLT1</I> promoter methylation was higher in renal cancer tissues from eight nonresponders (stable or progressive disease assessed by the Response Evaluation Criteria in Solid Tumors) than in cancer tissues from five responders (complete response or partial response).</P><P><B>Conclusions</B></P><P>The present data showed that hypermethylated <I>FLT1</I> was important for the efficacy of anti-VEGF/VEGFR drugs targeting FLT1 or intracellular VEGFR signaling. <I>FLT1</I> hypermethylation causing alterations of FLT1 function could serve as a useful biomarker for predicting changes in <I>FLT1</I> status in RCCs.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13148-015-0134-9) contains supplementary material, which is available to authorized users.</P>

Comparison of Three-dimensional Kinematic Changes of the Lower Extremity between the Two Different Braking Distances of Snowplow in Alpine Skiing

Kim, Joo-Nyeon,Kim, Jin-Hae,Ryu, Jiseon,Yoon, Sukhoon,Park, Sang-Kyoon Korean Society of Sport Biomechanics 2016 한국운동역학회지 Vol.26 No.4

Objective: The aim of this study was to compare three-dimensional kinematic changes of the lower extremity between the two different braking distances during snowplow in alpine skiing. Method: Six alpine ski instructors (age: $25.3{\pm}1.5yr$, height: $169.3{\pm}2.9cm$, weight: $66.2{\pm}5.9kg$, career: $4.2{\pm}2.9yr$) participated in this study. Each skier was asked to perform snowplow on the two different braking distances (2 and 4 m). Results: Snowplow and edging angles (p = .006 and p = .005), ankle adduction and inversion (p = .033 and p = .002), knee extension (p = .003), and hip abduction and internal rotation (p = .043 and p = .006) were significantly greater in the 2 m than in the 4 m braking distance. Conclusion: Based on our results, we suggest that skiers should make greater snowplow and edging angles on the shorter braking distance. In this situation, ankle joint adduction/inversion angle and hip joint internal-rotation make greater snowplow angle, and hip joint abduction make greater edging angle. In addition, greater knee joint extension angle may lead to more posteriorly positioned center of mass.

Mechanical effects of polishing pad in copper electrochemical mechanical deposition for planarization?

Sukhoon Jeong,Sangjik Lee,Boumyoung Park,Hyoungjae Kim,Sungryul Kim,정해도 한국물리학회 2010 Current Applied Physics Vol.10 No.1

ECMD (electrochemical mechanical deposition) process consists of a traditional ECP (electrochemical plating) mechanism and a mechanical component. That is, this technique involves both electrochemical plating and mechanical sweeping of the material surface by the polishing pad. The mechanism of the ECMD process may be achieved through two mechanisms. The first mechanism may be the electrochemical plating on the surface where mechanical sweeping of polishing pad does not reach, and the second mechanism may be that the plating rate in the area that is mechanically swept may be reduced by the polishing pad. In this study, the effects of the mechanical component were investigated through various polishing pad types and hole ratios. In comparison to various polishing pad types using the manufactured the ECMD system, the plating rate and WIWNU (within wafer non-uniformity) using the experimental non-pore polishing pad were better than those of the experiments using other polishing pads.

Web과 혼합된 형태의 통계수업의 교육적 효과

김종우,김주한,김홍기,박래현,박석윤,이낙영,이석훈,이주호,정현용 충남대학교 기초과학연구소 1999 忠南科學硏究誌 Vol.26 No.1

In the 1998 academic year, 33 college junior in the department of statistics who are taking the course of sample theory are divided into 7 groups. And each group conducts a survey which contains all the process of sampling design, such as typing text, customizing color, using icons and clip art and even adding their favorite link The result is an attractive colorful website. [http://stat.chungnam.ac.kr/~sypark]

Suggestion on Screening-out Method of Radionuclides to be Considered for the Offsite Consequence Analysis of Nuclear Power Plants

Sukhoon Kim,Sung-yeop Kim 한국방사성폐기물학회 2023 한국방사성폐기물학회 학술논문요약집 Vol.21 No.1

As a result of various generation, transmutation, and decay schemes, a wide variety of radionuclides exist in the reactor prior to accident occurrence. Considering all of the radionuclides as the accident source term in an offsite consequence analysis will inevitably take up excessive computer resources and time. Calculation time can be reduced with minimal impact on the accuracy of the results by considering only the nuclides that have a significant effect on the calculation among the potential radioactive sources that may be released into the environment. In earlier studies related to offsite consequence analysis, it is shown that the principal criteria for the radionuclide screening applied are as follows; radionuclide inventory in the reactor, radioactive half-life, radionuclide release fraction to the environment, relative dose contribution of nuclides within a specific group, and radiobiological importance. As a result, it is confirmed that 54, 60, and 69 nuclides are applied to the risk assessment performed in WASH-1400, NUREG-1150, and SOARCA (State-of-the-Art Reactor Consequence Analyses) project in the United States, respectively. In addition, in this study, the technical consultations with domestic and foreign experts were carried out to confirm details on criteria and process for screening out radionuclides in offsite consequence analysis. In this paper, based on the literature survey and technical consulting, we derived the screening process of selecting a list of radionuclides to be considered in the offsite consequence analysis. The first step is to eliminate radionuclides with little core inventory (less than specific threshold) or very short half-lives. However, important decay products of radionuclides that have short half-lives should not be excluded by this process. The next step is to further eliminate radionuclides by considering contribution to offsite impact, which is defined as a product of radioactivity released to the environment (i.e. ‘inventory in the reactor’ times ‘release fraction to offsite’) and comprehensive dose (or risk) coefficient taking into account all exposure pathways to be included. The final step is to delete isotopes that contribute less than certain threshold to any important dose metric through additional computer runs for each important source term. Even though it is presumed that this process is applicable to existing light water reactors and the set of accidents that would be considered in PSA, some of the assumptions or specific recommendations may need to be reconsidered for other reactor types or set of accident categories.

Effects of Counter-rotation Position on Knee/Hip Angulation, Center of Mass Inclination, and Edging Angle in Simulated Alpine Skiing

( Sukhoon Yoon ),( Jin-hae Kim ),( Jae-hyeon Park ),( Jiseon Ryu ),( Sang-kyoon Park ),( Joo-nyeon Kim ) 한국운동역학회 2017 한국운동역학회지 Vol.27 No.2

Objective: To investigate rotation movement of segment for performing each position and its effect on knee/hip angulation, COM inclination, and edging angle changes. Method: Twelve Alpine skiers (age: 25.8±4.8 years, height: 173.8±5.9 cm, weight: 71.4±7.4 kg, length of career: 9.9±4.6 years) participated in this study. Each skier was asked to perform counter-rotation, neutral, and rotation positions. Results: Shank and thigh were less rotated in the counter-rotation position than in other positions, whereas the trunk and pelvis were more counter-rotated (p<.05). Hip angulation, COM inclination, and edging angle were significantly greater in the counter-rotation position than in other positions (p<.05). Conclusion: Our finding proved that the counter-rotation position increases hip angulation, COM inclination, and edging angle. Consequently, we suggest that skiers should perform counter-rotation of the trunk and pelvis relative to the ski direction in the vertical axis for the counter-rotation position. Further analysis will continue to investigate the effects of the counter-rotation position in real ski slope with kinetic analysis.

Suggestion on Design Alternative for Backfilling Solution of the Disposal Tunnel in the Deep Geological Repository for High-Level Radioactive Waste: Focusing on the Finnish Case

Sukhoon Kim,Heekwon Ku,Jongchan Lee 한국방사성폐기물학회 2023 한국방사성폐기물학회 학술논문요약집 Vol.21 No.2

In 2012, POSIVA selected a bentonite-based (montmorillonite) block/pellet as the backfilling solution for the deposition tunnel in the application for a construction license for the deep geological repository of high-level radioactive waste in Finland. However, in the license application (i.e. SC-OLA) for the operation submitted to the Finnish Government in 2021, the design for backfilling was changed to a granular mixture consisting of bentonite (smectite) pellets crushed to various sizes, based on NAGRA’s buffer solution. In this study, as part of the preliminary design of the deep geological repository system in Korea, we reviewed history and its rationale for the design change of Finland’s deposition tunnel backfilling solution. After the construction license was granted by the Finnish Government in 2015, POSIVA conducted various lab- and full-scale in-situ tests to evaluate the producibility and performance of two design alternatives (i.e. block/pellet type and granular type) for backfilling. Principal demonstration tests and their results are summarized as follows: (a) Manufacturing of blocks using three types of materials (Friedland, IBeco RWC, and MX-80): Cracking and jointing under higher pressing loads were found. Despite adjusting the pressing process, similar phenomena were observed. (b) 1:6 scale experiment: Confirmation of density difference inhomogeneity due to the swelling of block/pellet backfill and void filling due to swelling behavior into the mass loss area of block/pellet. (c) FISST (Full-Scale In situ system Test): Identification of technical unfeasibility due to the inefficient (too manual) installation process of blocks/pellets and development of an efficient granular in-situ backfilling solution to resolve the disadvantage. (d) LUCOEX-FE (Large Underground Concept Experiments – Full-scale Emplacement) experiment: Confirmation of dense/homogeneous constructability and performance of granular backfilling solution. In conclusion, the simplified granular backfill system is more feasible compared to the block/ pellet system from the perspective of handling, production, installation, performance, and quality control. It is presumed that various experimental and engineering researches should be preceded reflecting specific disposal conditions even though these results are expected to be applied as key data and/or insights for selecting the backfilling solution in the domestic deep geological repository.

Development of an Analytical Solution-Based Thermal Evolution Analysis Program for the Deep Geological Repository of High-Level Radioactive Waste in Korea

Sukhoon Kim,Jeehee Lee,Seong-Su Jeon 한국방사성폐기물학회 2023 한국방사성폐기물학회 학술논문요약집 Vol.21 No.2

With the importance of permanent disposal of high-level radioactive waste (HLW) generated in Korea, the deep geological disposal system based on the KBS-3 type is being developed. Since the deep geological repository must provide the long-term isolation of HLW from the surface environment and normal habitats for humans, plants, and animals, it is essential to assess the longterm performance of the disposal facility considering thermal-hydraulic-mechanical-chemical (TH- M-C) evolution. Decay heat dissipated from HLW contained in the canister causes an increase in temperature in the adjacent area. The requirement for the maximum temperature is established in consideration of the possibility of bentonite degradation. Therefore, when designing the repository, the temperature in the region of interest should be identified in detail through the thermal evolution assessment to ensure that the design requirement is satisfied. In the thermal evolution analysis, it is needed to evaluate the temperature distribution over the entire area of the disposal panel to consider the heat generated from both a single canister and adjacent canisters. Computational fluid dynamics (CFD) codes are widely used for detailed temperature analysis but are limited to simulating a wide range. Accordingly, in this study, we developed an analytical solution-based program for efficiently calculating the temperature distribution throughout the deposition panel, which is based on threedimensional heat conduction equations. The code developed can assess the temperature distribution of engineered and natural barrier systems. Principal parameters to be inputted are as follows: (a) geometry of the panel (e.g. width, length, height, spacing between canisters), (b) geometry of the canister (e.g. diameter, height), (c) thermal properties of bentonite and host-rock, (d) initial conditions (e.g. residual heat, temperature), and (e) time information (e.g. canister emplacement rate, time-interval, period). Through the calculation for the conceptual problem of a deposition panel capable of accommodating 900 (i.e. 30×30) canisters, it was confirmed that the program can adequately predict when and where the maximum temperature will occur. It is expected that the overall temperature distribution within the panel can be obtained by the evaluation of the entire region using this program reflecting the detailed design of the repository to be developed in the future. In addition, the thermal evolution analysis considering the influence of other canisters can be performed by applying the results as boundary conditions in the CFD analysis.

Suggestion on What to Prepare for the Performance Assessment for the Deep Geological Facility in Korea: Focusing on Buffer Mass Loss

Gitae Kim,Seong-Su Jeon,Sukhoon Kim,Jeong-Hwan Lee,Haeryong Jung 한국방사성폐기물학회 2023 한국방사성폐기물학회 학술논문요약집 Vol.21 No.1

In buffer, a main component of engineering barrier system (EBS) in the deep geological repository, mass loss is mainly caused by upheave and mechanical erosion. The former is a phenomenon that bentonite in the upper part of the buffer moves to the backfill region due to groundwater intake and swelling. And, the latter is a phenomenon that bentonite on the surface of the buffer moves to the backfill region due to groundwater flow at the interface with host rock as the buffer saturates. Buffer mass loss adversely affects the fulfilment of the safety function of the buffer that is to limit and retard radionuclide release in the event of canister failure. Accordingly, in this paper, we reviewed how to consider this phenomenon in the performance assessment for the operating license application in Finland, and tentatively summarized data required to conduct the analysis for the domestic facility based on the review results. Regarding buffer mass loss, the previous studies carried out in Finland are categorized as follows: 1) experiment on the amount of buffer upheave with groundwater inflow rate (before backfilling), 2) analysis for the amount of buffer upheave with groundwater inflow rate (after backfilling), 3) analysis of buffer erosion rate with groundwater inflow rate, 4) analysis for distribution of the groundwater inflow rate into the buffer for all deposition holes (using ConnectFlow modeling results), and 5) analysis of buffer mass loss with groundwater salinity. Finally, the buffer mass loss distribution table was derived from the results of 1) through 3) by combining with that of 4). Given these studies, the following will be required for the performance assessment for buffer mass loss in the domestic disposal facility: a) distribution table of buffer mass loss for combined interactions taking into account effect of 5) (i.e. 1), 2), 3), and 5) + 4)), and b) Threshold for buffer mass loss starting to negatively affect the fulfilment of the safety function of the buffer. Even though it is judged that the results of this study could be directly applied to developing the design concept of EBS and to conducting the performance assessment in the domestic disposal facility, it is essential to prepare a set of input data reflecting the site-specific design features (e.g. dimension, material used, site, etc.), which include saturation time and groundwater salinity.

Improvement on Conceptual Model for Post-closure Safety Assessment of Rock-cavern Type Disposal Facility

Hyejin Kim,Seunghee Lee,Sukhoon Kim 한국방사성폐기물학회 2020 한국방사성폐기물학회 학술논문요약집 Vol.2020 No.07