A selective cyclin-dependent kinase 4, 6 dual inhibitor, Ribociclib (LEE011) inhibits cell proliferation and induces apoptosis in aggressive thyroid cancer

Lee, Hyun Joo,Lee, Woo Kyung,Kang, Chan Woo,Ku, Cheol Ryong,Cho, Yoon Hee,Lee, Eun Jig Elsevier 2018 Cancer letters Vol.417 No.-

<P><B>Abstract</B></P> <P>The RB-E2F1 pathway is an important mechanism of cell-cycle control, and deregulation of this pathway is one of the key factors contributing to tumorigenesis. Cyclin-dependent kinases (CDKs) and Cyclin D have been known to increase in aggressive thyroid cancer. However, there has been no study to investigate effects of a selective CDK 4/6 inhibitor, Ribociclib (LEE011), in thyroid cancer. Performing Western blotting, we found that RB phosphorylation and the expression of Cyclin D are significantly higher in papillary thyroid cancer (PTC) cell lines as well as anaplastic thyroid cancer (ATC) cell lines, compared with normal thyroid cell line and follicular thyroid cancer cell line. LEE011 dose-dependently inhibited RB phosphorylation and also decreased the expressions of its target genes such as <I>FOXM1, Cyclin A1,</I> and <I>Myc</I> in ATC. Furthermore, LEE011 induced cell cycle arrest in G0-G1 phase and cell apoptosis, and inhibited cell proliferation in ATC. Consistently, oral administration of LEE011 to ATC xenograft models strongly inhibited tumor growth with decreased expressions of pRB, pAKT and Ki-67, and also significantly increased tumor cell apoptosis. Taken together, our data support the rationale for clinical development of the CDK4/6 inhibitor as a therapy for patients with aggressive thyroid cancer.</P> <P><B>Highlights</B></P> <P> <UL> <LI> pRB and Cyclin D were expressed high in aggressive thyroid cancer. </LI> <LI> LEE011 suppressed pRB and also decreased the expressions of its target genes in ATC. </LI> <LI> LEE011 induced cell cycle G1 arrest and apoptosis, and inhibited cell proliferation. </LI> <LI> LEE011 inhibited in vivo tumor growth with decreased expressions of pRB and Ki-67. </LI> <LI> We could explain the anticancer effects with the RB-E2F pathway. </LI> </UL> </P>

Key Ethical Issues and Hindrances to Ethical Behavior in Korean Insurance Industry

Lee, Kyung-Lyong,Lee, Bong-Joo,Lee, Han-Duck 서강대학교 경영연구소 2004 서강경영논총 Vol.15 No.2

The purpose of this paper is to investigate key ethical issues and hindrances to ethical behavior faced by professionals working in Korean insurance industry. For this purpose, conducted is a survey of actuaries in a variety of positions in insurance companies and insurance related institutions. The findings also are compared to those of American studies. Actuaries' perceptions of the key ethical issues tend to be restricted to actuarial aspects such as insufficient legal authority to perform professional services in an ethical manner and failure to get adequate ethics training program. But some issues arising in marketing are considered significant similar to the U.S. As a whole, key ethical issues and challenges are not significantly different from the viewpoints of actuaries working in the life and non-life insurance business. Regarding key hindrances to ethical behavior, the 15 factors are presented such as competitive pressures, performance-based evaluation and unethical demand made by clients. These findings are generally similar to those of the U.S. studies.

강남경희한방병원에 내원한 냉증을 호소하는 여성의 Heart Rate Variability 특성 연구

이미주 ( Mi Joo Lee ),김은경 ( Eun Kyung Kim ),이진무 ( Jin Moo Lee ),조정훈 ( Jung Hoon Cho ),장준복 ( Jun Bock Jang ),이경섭 ( Kyung Sub Lee ),이창훈 ( Chang Hoon Lee ) 대한한방부인과학회 2011 大韓韓方婦人科學會誌 Vol.24 No.3

Fluoxetine이 Schedule-Induced Polydipsia가 유발된 백서 뇌에서 Tyrosine Hydroxylase 발현에 미치는 영향

이기철,이정호,최영민,정주호,정홍경,이용민,김도형,이대환 大韓神經精神醫學會 2001 신경정신의학 Vol.40 No.2

연구목적: Fluoxetine은 serotonin을 매개하여 간접적으로 dopamine 신경전달기능을 억제한다고 추정되고 있다. 또한 운동장애에서 운동기능의 악화를 유발한다고 알려져 있다. 그러나 신경세포체에서 fluoxetine이 dopamine에 어떠한 영향을 주는지는 아직까지 확실치 않다. 저자들은 schedule-induced polydipsia를 유발시킨 백서 뇌의 흑질, 복부피개영역, 미상핵에서 tyrosine hydroxylase(TH) 발현이 저하됨을 발견하였다. 이를 통해서 fluoxetine이 백서 뇌의 dopamine 기능에 긍정적인지 혹은 부정적인지를 규명하고자 하였다. 방법: 4주간의 schedule-induced polydipsia 과정을 거친 백서에서 면역죄치화학적인 방법으로 흑질, 복부피개영역, 미상핵의 tyrosine hydroxylase 발현이 저하됨을 확인한 후, 실험동물들에게 fluoxetine 10mg/kg를 3주간 복강내 주사하였다. 실험백서들을 희생시켜 뇌 조직을 적출하여, TH 면역조직화학 염색법을 이용하여 흑질, 복부피개영역, 그리고 미상핵의 TH 면역반응세포를 관찰하고 이를 정상백서와 비교하였다. 결과: 1) 다갈증이 유발된 백서의 흑질, 복부피개영역, 미상핵에서 tyrosine hydroxylase 발현이 정상백서 보다 저하됨을 관찰하였다. 2) 3주간에 걸친 fluoxetine 투여후 흑질, 복부피개영역, 미상핵의 tyrosin hydroxylase 발현이 다시 증가하는 소견을 보였다. 결론: Fluoxetine 만성투여가 흑질, 복부피개영역 그리고 미상핵의 tyrosin hydroxylase를 증가시키는 소견을 얻었다. 이러한 결과는 임상에서 dopamine 결핍과 연관된 질환들에서 fluoxetine을 만성투여하면 운동기능을 포함한 증상들의 개선을 가져올 수도 있다고 추정된다. Objective: It has been suggested that fluoxetine inhibits the dopaminergic neurotransmission by serotonergic mediation. And also, it has been shown to inhibit synthesis of DOPA in dopamine-rich areas of the rat forebrain. These dopamine-antagonistic capacity of fluoxetine is only supported by anecdotal report that the increased amount of motor disability in patients with idiopathic Parkinson's disease after exposure to fluoxetine. However, there is still no evidence of the direct effect of fluoxetine on dopaminergic neuronal cell body in the substantia nigra, VTA, caudate & putamen. This study was designed to evaluate the effects of fluoxetine in rat brain which showed decreased numbers of dopaminergic neuronal cell body induced by schedule-induced polydipsia(SIP). Method: We incidentally found that 4 weeks of schedule-induced polydipsic rats revealed the suppression of tyrosine hydroxylase expression in the substantia nigra, VTA, caudate & putamen with the immunohistochemistric measures. After 3 weeks of intraperitoneal injection of 10mg/kg of fluoxetine to the schedule induced polydipsic rats, the tyrosine hydroxylase expression was also measured with immunohistochemistry. We compared the tyrosine hydroxylase expression among the normal control, the polydipsic rats, and the rats with fluoxetine treatment. Results: 1) By contrast with the control, the polydipsic rats revealed the evidence of decreased tyrosine hydroxylase expression in the substantia nigra, VTA, caudate & putamen. 2)After daily injection of fluoxetine for 3 weeks, the polydipsic rats showed increment of tyrosine hydroxyase expression in those areas. Conclusions: In previous studies, a great deal of results suggest that fluoxetine negatively influence the dopaminergic systems indirectly via serotonergic activation such as inhibition of dopamine synthesis or transport system. Although our results are obtained from rodents, we suggest that fluoxetine directly and positively enhance the dopamine system in the substantia nigra, VTA, caudate & putamen. The chronic adminstration of fluoxetine may be helpful to dopamine-depleted condition in clinical situations. We anticipate the replication studies of our findings and well-controlled clinical trial.

Chiari Ⅳ 기형:1예 보고

이경주,박동우,이승로,함창곡,주경빈 한양대학교 의과대학 2001 한양의대 학술지 Vol.21 No.2

The Chiari IV malformation is a very rare condition which is characterized by severe cerebellar hypoplasia or aplasia. Morphologic findings include aplastic or severely hypoplastic cerebellum, small brainstem and relatively large cerebrospinal fluid space in the posterior cranial fossa. We recently experienced Chiari IV malformation and report radiologic findings of the case.

에탄올이 백서의 해마에서 Neuropeptide Y 발현에 미치는 영향

정홍경,이기철,이정호,이희제,정주호,이주영 대한생물치료정신의학회 2002 생물치료정신의학 Vol.8 No.1

에탄올을 장기간 섭취한 백서에서 Acamprosate 투여가 Nitric Oxide Synthase 발현에 미치는 영향

정홍경,이기철,이정호,이승휘,이희제,정주호 대한생물치료정신의학회 2002 생물치료정신의학 Vol.8 No.1

BEZ235 (PIK3/mTOR inhibitor) Overcomes Pazopanib Resistance in Patient-Derived Refractory Soft Tissue Sarcoma Cells

Kim, Hee Kyung,Kim, Sun Young,Lee, Su Jin,Kang, Mihyeon,Kim, Seung Tae,Jang, Jiryeon,Rath, Oliver,Schueler, Julia,Lee, Dong Woo,Park, Woong Yang,Kim, Sung Joo,Park, Se Hoon,Lee, Jeeyun Neoplasia Press 2016 Translational oncology Vol.9 No.3

<P><I>BACKGROUND:</I> Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients. <I>METHODS:</I> Patient derived tumor cells were collected from ascites at the time of progression to pazopanib and a 13-drug panel was tested for drug sensitivity. We confirmed the results using <I>in vitro</I> cell viability assay and immunoblot assay. We also performed the genomic profiling of PDX model. <I>RESULTS:</I> The growth of patient derived tumor cells was significantly reduced by exposure to 1.0 μM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, <I>P</I> = .0435). Similarly, 1.0 μM BEZ235 profoundly inhibited tumor cell growth <I>in vitro</I> when compared to control (control versus BEZ235, mean growth = 100.0% vs 7.308%, difference = 92.69%, 95% CI = 78.87% to 106.5%, <I>P</I> < .0001). Despite the presence of CDK4 amplification in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control vs LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, <I>P</I> = .0377). The immunoblot analysis showed that BEZ235 treatment decreased pAKT, pmTOR and pERK whereas AZD2014 decreased only pmTOR. <I>CONCLUSION:</I> Taken together, upregulation of mTOR/AKT pathway in sarcoma patient derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235). These molecules may be considered as treatment option in STS patient who have failed to pazopanib in the context of clinical trials.</P>

Purge & Trap-GC를 이용한 의약품 필름코팅 정제 중 잔류용제에 관한 연구

장준식,이명자,소유섭,문춘선,이주헌,박희라,김진숙,강경모,이선옥,방성연,유미자,유문균,금오성,이병욱 식품의약품안전청 2000 식품의약품안전청 연보 Vol.4 No.-

의약품은 약물을 생체에 적풋하기 위하여 유효성분의 효과가 언제나 일정하게 확보되고 사응에 편리하도록 만들어지는 것이므로 유효썽분 이외에 약효에 영향을 주지 않는 성분이 첨가되는 경운가 많다. 이 때 사용되는 용매들은 제피의 광택 및 건쪼시간의 단축 등을 위하여 휘발점이 낮을 용매들이 주로 사용되어진다. 본 연구는 의약품 필름코팅정제 중 잔류용매 4종(chlorofonr benzen, trichloro ethylen, 1,4-dioxane)에 대한 변형된 pirge & trap-GC 장치를 이용한 동시분석방법을 개발하였으며, 각 표준품의 RSD 값은 chloroform 3.03%, benzen 3.17%, trichloroethylen 3.69% and 1,4-dioxane 3.41%였다. 또한 시중 유통중인 의약품 50종에 대하여 잔류웅매 양을 측정하였으며, 검출되는 잔류용매는 한 건도 없었다. This study nras carried out to develope the analytical method for the mixture of chlorefonn, benzen, trichloroethylen and 1,4-dioxane simultaneously and determine the remainingorgauic solvents in coating tablets by Purge & Trap-GC. The results were as follouFs ; 1. Chloroform, benzen, trio:tloroethylen and 1,4-dioxane separated by tenax #5 trap by HP-624GC column by terrlperature programming. The peaks were separated completely at retentiontime of 6.88min for chloroform, 8.21min for benzen, 10.38miu for trichloroethylen and 11.95minfor 1,4-dioxane. 2. Standard RSD were individually chloroform 3.03%, benzen 3.17%, trichloroethylen 3.69%and 1,4-diorane 3.41%. 3. 60 samples were not detrcted chloroform, benzen, trichloroethylen and 1,4-dioxane.

실리카흄을 흔입한 고강도 콘크리트 개발

홍창우,김태경,김경진,김성환,김남윤,심도식,이정호,윤청호,백민경,원치문,박제선,이주형,정경일 강원대학교 석재복합신소재제품연구센터 1996 석재연 논문집 Vol.1 No.-

콘크리트 구조물이 대형화됨에 따라 설계단면이 증대되어 상대적으로 많은 경제적 손실을 부담하게 된다. 따라서 단면을 감소시키면서도 소요의 하중에 안전한 구조물을 건설하기 위해서는 우선적으로 구조물 건설에 기초가 되는 고품질, 고내구성의 고강도 콘크리트 개발이 절실히 요구된다 본 연구에서는 일정 시멘트비 및 혼화재 비율하에서 소요의 워커빌리티가 확보되는 고강도 콘크리트를 시간과 온도의 변화에 따라 증기 양생하여, 압축, 인장, 휨강도 뿐만 아니라 파괴특성을 실험적으로 연구하였다. 시료 제작시 시멘트 입자 사이의 공극 및 불연속 영역을 충전하여 고밀도화하기 위한 콘크리트용 혼화재로 시멘트 비표면적이 상당히 작은 초미립 분말인 실리카흄을 이용하였다. 또한 AE감수제 및 고성능 유동화제를 사용하여 혼화재의 첨가에 의하여 발생될 수 있는 워커빌리티의 감소를 방지하였다. 실험결과에 의하면 일정 양생 지속 시간하에서 온도의 증가에 따라 콘크리트의 압축, 인장 및 휨강도가 전반적으로 증가하였다. 동일하게 일정 온도하에서 양생 지속시간이 커짐에 따라 강도들이 증가됨을 알 수 있었다. 따라서 상대적으로 높은 온도와 긴 지속 양생 조건하에서 파괴에 대한 저항력이 크게 나타났다. The compressible, tensible, and flexibleresistance of the high strength concrete is analyzed by the experimentation in the present study. For the test, we cure several samples with the silica fume as a mixture being become dense the spaces between the particle of cement under the variation of both the temperature and the curing-interval. Then, the superplasticizer and the ezcon are also used to satisfy the required workability for construction. The compressible, tensible, and flexible resistances to a stress are increased as increasing the temperature and the time interval for the curing. Therefore it is concluded that the overal fractural and mechanical properties is improved by mixing the silica fume into the cement.