PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI–Resistant Metastatic Clear Cell Renal Cell Carcinoma

정세운,황희상,박자민,윤선영,신수진,고현정,이재련,정고운,조영미 대한암학회 2023 Cancer Research and Treatment Vol.55 No.1

Purpose Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism.Materials and Methods To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib.Results Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway.Conclusion These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.

기억신뢰가 확인행동에 미치는 영향: 책임감의 조절효과

정세운,박준호 한국건강심리학회 2016 한국심리학회지 건강 Vol.21 No.3

It has been found that memory confidence and responsibility are the cause of checking behavior, one of the representative symptoms of obsessive-compulsive disorder based on previous research studies. The purpose of this study was to examine the effect of memory confidence on the checking behavior according to the level of responsibility. The main hypothesis of present study was as follows: The effect of memory confidence on the checking behavior would be significant under the condition of high level of responsibility. Such effect would be in, significant under the condition of low level of responsibility. To test the hypotheses, a 2×2 analysis of variance(ANOVA) with memory confidence(high/low) and responsibility(high/low) as between-participants factors was performed on the checking behavior. Sixty nine undergraduates were randomly assigned to one of the four experimental conditions. The results of the analysis supported the main hypothesis. The interaction between factors was significant. Under condition of higher responsibility, the checking behavior was higher with lower memory confidence. However, under the condition with lower responsibility, the checking behavior was not different between lower and higher memory confidence. These results suggest that the effect of memory confidence on checking behavior is moderated by the level of responsibility only when the level of responsibility is high. The implication and limitation of this study and direction for future studies are also disussed. 강박장애의 대표적 증상 중 하나인 확인행동의 원인으로 책임감과 기억신뢰가 선행연구들을 통해밝혀져 왔다. 본 연구에서는 기억신뢰가 확인행동에 미치는 영향이 책임감의 수준에 따라 달라질수 있다는 가정 하에 책임감과 기억신뢰가 상호작용하여 확인행동에 어떻게 영향을 미치는지 실험적으로 검증하였다. 본 연구는 2(책임감: 고/저)×2(기억신뢰: 고/저)의 완전무선설계였으며 대학생 69명이 참가하였다. 먼저 지시문을 통해 책임감 고/저를 조작하고 첫 번째 알약모형 분류과제를 실시하였다. 그다음에 참가자들은 분류과제에서 자신이 선택하였던 알약모형들을 재인하는 기억검사를 실시하였다. 그 이후 실제의 검사점수가 아닌 가상의 검사점수를 통해 기억신뢰를 조작하고 두 번째 알약모형 분류과제를 실시하였으며 과제 수행 중 나타나는 확인행동의 횟수와 시간을 측정하였다. 분석 결과, 확인행동 횟수와 시간 모두에서 이원상호작용이 유의하게 나타나 가설이 지지되었다. 구체적으로 책임감이 낮은 조건에서는 기억신뢰가 낮은 집단과 높은 집단 모두확인행동 횟수와 시간에서 유의한 차이가 없었다. 반면 책임감이 높은 조건에서는 기억신뢰가 낮은 집단이 높은 집단보다 확인행동 시간이 더 길었고 횟수 또한 더 많았다. 이 결과는 기억신뢰가 확인행동에 미치는 영향에서 책임감의 수준을 고려해야 함을 시사한다. 그리고 본 연구의 시사점과 제한점 및 장래연구 방향을 논의하였다.

Diverse Immunoprofile of Ductal Adenocarcinoma of the Prostate with an Emphasis on the Prognostic Factors

정세운,조영미,Anuja Kashikar Kekatpure,박자민,한민규,황희상,정휘정,고현정 대한병리학회 2017 Journal of Pathology and Translational Medicine Vol.51 No.5

Background: Ductal adenocarcinoma (DAC) of the prostate is an uncommon histologic subtype whose prognostic factors and immunoprofile have not been fully defined. Methods: To define its prognostic factors and immunoprofile, the clinicopathological features, including biochemical recurrence (BCR), of 61 cases of DAC were analyzed. Immunohistochemistry was performed on tissue microarray constructs to assess the expression of prostate cancer-related and mammalian target of rapamycin (mTOR) signaling-related proteins. Results: During the median follow-up period of 19.3 months, BCR occurred in 26 cases (42.6%). DAC demonstrated a wide expression range of prostate cancer-related proteins, including nine cases (14.8%) that were totally negative for pan-cytokeratin (PanCK) immunostaining. The mTOR signaling-related proteins also showed diverse expression. On univariate analysis, BCR was associated with high preoperative serum levels of prostate-specific antigen (PSA), large tumor volume, predominant ductal component, high Gleason score (GS), comedo-necrosis, high tumor stage (pT), lymphovascular invasion, and positive surgical margin. High expressions of phospho-mTOR (p-mTOR) as well as low expressions of PSA, phospho-S6 ribosomal protein (pS6) and PanCK were associated with BCR. On multivariable analysis, GS, pT, and immunohistochemical expressions of PanCK and p-mTOR remained independent prognostic factors for BCR. Conclusions: These results suggest GS, pT, and immunohistochemical expressions of PanCK and p-mTOR as independent prognostic factors for BCR in DAC. Since DAC showed diverse expression of prostate cancer–related proteins, this should be recognized in interpreting the immunoprofile of DAC. The diverse expression of mTOR-related proteins implicates their potential utility as predictive markers for mTOR targeted therapy.

IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma

정세운,박자민,윤선영,황희상,고현정,신동명,주혜인,성창옥,이재련,정고운,조용미 대한비뇨의학회 2024 Investigative and Clinical Urology Vol.65 No.1

Purpose: Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. Materials and Methods: To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. Results: Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. Conclusions: These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.

수리온 인체진동 영향성 평가

정세운,곽동일,김세희,황유상 한국항공우주학회 2015 한국항공우주학회 학술발표회 논문집 Vol.2015 No.4

헬리콥터의 진동은 조종사와 승객의 안락함을 결정하는 주요인이며, 점차 높아지는 안락함에 대한 요구 수준에 대응하기 위한 진동저감 관련 연구가 꾸준히 진행되고 있다. 인체진동은 진동에 노출된 조종사와 승객에 대한 안락함과 건강에 미치는 영향을 평가하기 위해 활용되고 있다. 또한, 진동에 노출된 인체에 대한 평가는 인체진동을 향상시키기 위한 연구에 활용하고 있다. 국내 최초로 개발된 수리온 헬리콥터에서도 다양한 진동저감장치가 적용되어 있으며, 국제표준 ISO 2631-1(Mechanical vibration and shock-Evaluation of human exposure to whole body vibration)을 적용하여 수리온에 대한 인체진동 평가를 수행하였다. 본 논문에서는 수리온 진동에 노출된 인체에 대한 평가 방법과 결과를 제시한다. The major factor for pilot and passenger comfortable in cockpit and cabin is vibration of the helicopter, and the research for helicopter vibration reduction is in progress corresponding to the demand for increased comfort level. The human vibration has been used to evaluate comfort and health for pilot and passenger who are exposed to vibration. Also, the evaluation of human exposure to vibration has been used to improve comfort and health with regards of human vibration. For Surion that is first korean-developed helicopter and has appropriate vibration-reduction devices, the evaluation of human vibration was conducted according to ISO 2631-1(Mechanical vibration and shock-Evaluation of human exposure to whole body vibration). This paper presents the evaluation method and results of human exposure to Surion vibration.

헬리콥터 시스템 식별 알고리즘 모델 시험 및 검증

정세운(Se Un Jung),임형찬(Hyoung-Chan Lim),송민호(Min-Ho Song),곽동일(Dong-Il Kwak) 한국항공우주학회 2017 한국항공우주학회 학술발표회 논문집 Vol.2017 No.4

자이로콥터의 동적 유한요소모델링 및 구조진동해석

정세운(Se-Un Jung),김동현(Dong-Hyun Kim),양용준,김현정(Hyun-Jung Kim),제상언(Sang-Eon Je),조태환(Tae-Hwan Cho) 한국소음진동공학회 2005 한국소음진동공학회 학술대회논문집 Vol.2005 No.5

헬리콥터 시스템 식별 알고리즘 설계

정세운(Se-Un Jung),곽동일(Dong-Il Kwak),임형찬(Hyoung-Chan Lim),송민호(Min-Ho Song) 한국항공우주학회 2016 한국항공우주학회 학술발표회 논문집 Vol.2016 No.11

한국형기동헬기 진동저감장치

정세운(Se-Un Jung),곽동일(Dong-Il Kwak),김세희(Se-hee Kim),최종호(Jong-ho Choi),심대성(Dai-Sung Shim) 한국항공우주학회 2013 韓國航空宇宙學會誌 Vol.41 No.12

한국형기동헬기(KUH)는 국내 최초로 개발된 헬기로서, 2010년 3월 초도 비행을 시작으로 2012년 6월 체계 개발을 성공적으로 종료하였다. 비행시험 단계에서 다양한 진동문제가 발생하였으며 이를 제어하기 위해 적절한 진동저감장치를 설계하고 적용하였다. 한국형 기동헬기의 주요 진동 성분인 4Ω 주파수 진동 저감을 위해 주로터 블레이드, 주기어박스 지지부, 조종실, 승객실 그리고 조종좌석에 진동저감장치를 적용하였다. 또한, 테일-쉐이크 진동 제어를 위해 돔페어링을 적용하였다. 본 논문에서는 한국형 기동헬기에 적용된 진동저감장치들의 해석 및 설계 기법과 비행시험 결과를 제시한다. Korean Utility Helicopter(KUH) is the first korean-developed helicopter. Its first flight was performed in March 2010 and then its development was completed successfully by June 2012. During flight test phase, KUH faced various vibration problems and appropriate vibration-reduction devices were designed and applied to solve the problems. The vibration-reduction devices were applied to main rotor blades, main gear box(MGB) supporting structure, cockpit, cabin and pilot seats to reduce rotor-induced 4/rev vibration. Also, dome-fairing was introduced in order to reduce the tail-shake vibration. This paper shows design technique and flight test results for vibration-reduction devices that have been incorporated into KUH.

소형민수헬기 능동진동제어시스템 인증계획

정세운(Se-Un Jung),하광태(Gwang-Tae Ha),송민호(Min-Ho Song),곽동일(Dong-il Kwak),백승길(Seung-Kil Paek) 한국항공우주학회 2016 한국항공우주학회 학술발표회 논문집 Vol.2016 No.4