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>

정신분열병에 대한 리스페리돈의 효과 및 안정성

이민수,김용구,김영훈,연병길,오병훈,윤도준,윤진상,이철,정희연,강병조,김광수,김동언,김명정,김상훈,김희철,나철,노승호,민경준,박기창,박두병,백기청,백인호,손봉기,손진욱,양병환,양창국,우행원,이정호,이종범,이홍식,임기영,전태연,정영조,정영철,정인과,정인원,지익성,채정호,한상익,한선호,한진희,서광윤 大韓神經精神醫學會 1998 신경정신의학 Vol.37 No.1

연구목적 : 본 시험의 목적은 임상시험 시작전에 연구자들을 대상으로 PANSS Workshop을 통하여 PANSS, ESRS에 대한 국내에서의 표준화 작업을 구축하고 새로운 정신병 치료제인 리스페리돈의 효과와 안정성을 재확인하여 리스페리돈 사용에 대한 적정화를 이루는데 있다. 연구방법 : 1996년 4월부터 1996년 9월까지 국내 39개 대학병원 정신과에 입원중인 혹은 증상이 악화되어 입원하는 정신분열병 환자 377명을 대상으로 다시설 개방 연구를 시행하였다. 1주일간의 약물 배설기간을 가진후, 리스페리돈을 8주간 투여하였고, 기준점, 1주, 2주, 4주, 그리고 8주후에 평가되었다. 용량은 제1일에는 리스페리돈 1mg씩 1일 2회, 제2일에는 2mg씩 1일 2회, 제3∼7일에는 3mg씩 1일 2회 투여하였다. 이후 환자의 임상상태에 따라 임의로 증량할 수 있으며, 최대 일일 16mg을 초과하지 않도록 하였다. 추체외로 증상을 조절하기 위한 투약을 허용하였다. 임상증상 및 부작용의 평가는 PANSS(Positive and Negative Syndrome Scale), CGI(Clinical Global Impression) 그리고 ESRS(Extrapyramidal Symptom Rating Scale)을 사용하였다. 연구결과 : 377명중 343명(91%)이 8주간의 연구를 완결하였다. 치료 종결시점인 8주후 PANSS 총점수가 20% 이상 호전된 경우를 약물 반응군으로 정의할때, 약물반응군은 81.3%였다. 리스페리돈에 반응하는 예측인자로는 발병연령, 이전의 입원 횟수, 유병기간이 관련 있었다. 리스페리돈은 1주후부터 PANSS양성, 음성, 및 일반정신병리 점수상에 유의한 호전을 보여 효과가 빨랐다. CGI의 경우도 기준점에 비해 1주후부터 유의한 감소를 나타내었다. ESRS의 경우, 파킨슨 평가점수는 기준점과 비교해 투여 1주, 2주, 4주후 유의하게 증가되었다가 8주후 기준점과 차이가 없었다. Dystonia 평가점수는 1주후만 유의한 증가를 보였으며, dyskinesia 평가점수는 유의한 차이가 없었다. 혈압, 맥박수의 생명징후 및 일반 혈액학 검사, 생화학적 검사, 심전도 검사에서 유의한 변화는 없었다. 결 론 : 이상의 다시설 개방 임상 연구를 통해 리스페리돈은 정신분열병 환자에서 양성증상뿐만 아니라 음성증상 및 전반적인 증상에도 효과적인 것으로 사료된다. 보다 명확한 평가를 위해서는 다른 항정신병약물과의 이중맹검 연구가 필요할 것으로 생각되며, 또한 장기적 치료에 대한 평가도 함께 이루어져야 하겠다. Objective : The purpose of this study was to investigate the efficacy and safety of risperidone in the treatment of Korean schizophrenic patients. Method : This multicenter open study included 377 schizophrenic patients drawn from 39 university hospitals. After a wash-out period of 1 week, the schizophrenic patients were treated with risperidone for 8 weeks and evaluated at 5 points ; at baseline, and 1, 2, 4 and 8 weeks of treatment. The dose was increased from 2mg/day(1mg twice daily) to 6mg/day(3mg twice daily) during the first week and adjusted to a maximum of 16mg/day over the next 7 weeks according to the patient's clinical response. Medication to control extrapyramidal symptoms was permitted. The psychiatric and neurological status of the patients was assessed by PANSS, CGI, and ESRS scales. Results : 343(91%) of 377 patients completed the 8-week trial period. Clinical improvement, as defined by a 20% or more reduction in total PANSS score at end point, was shown by 81.3% of patients. The predictors of response to risperidone were associated older age, shorter duration of illness, fewer previous hospitalization. Risperidone had rapid onset of action ; a significant decrease of the total PANSS and three PANSS factor(positive, negative, general), and CGI was already noticed at the end of first week. For the ESRS, parkinsonism rating scores were significantly increased until week 4 comparing with baseline. Dystonia rating scores were significantly increased until week 1, and dyskinesia rating scores were not significantly changed during the study. Laboratory parameters including vital sign, EKG, hematological, and biochemical values showed no significant changes during the trial. Conclusions : This study suggests that risperidone is generally safe and effective against both the positive and negative symptoms in our group of patients.

Investigation of the April 2000 forest fire damage in Kang-won Province, Korea, using RADARSAT data

Kang, Sung Chul,Seo, Jin Won,Lee, Tae Hee,Park, Sang Eun,Hong, Suk Young,Moon, Wooil M. 대한원격탐사학회 2000 International Symposium on Remote Sensing Vol.16 No.1

The series of forest Fires in Kangwon Province in April, 2000, were one of the mast serious ones in the Kang-won Province in recent years. The fire damaged areas are extensive and this paper investigates the utility of the satellite image data, particularly the RADARSAT SAR data. One of the main objectives of this study included evaluation of potential usefulness of the C-band RADARSAT data in the detection of forest fires in mountainous areas. Among several fire damaged sites, the area near Samchuk (city) was selected as the main study area and mufti-temporal RADARSAT(raw) data were acquired and the processed results were comparatively investigated with the IRS-1c data acquired shortly after the fire. To identify the burnt area from the undamaged background in the optical imagery, supervised classification and NDVI processing were carried out and tested with the IRS-1C data. For this experiment, several sets of raw RADARSAT standard and Fine mode (S4, F3, ascending orbit) data were processed and the final image was formed. In addition to the final image, sigma nought (σ°) was catnputed and compared for the burnt area against the undamaged areas. Because of the steep slopes in the study area and subsequent deviation from the flat surface scattering models, the fire scars in the sigma nought (σ°) image were not apparent. However, fire scars are slightly detected in the difference and ratio images obtained from the signal intensity data acquired at different dates (bath before and after fire). Texture analysis of the image data including the burnt areas were carried out using the Multiplicative Markov Random-Field (MMRF) algorithm. The detection of the fire damaged area from both standard mode and fine mode RADARSAT was not as straightforward as in optical data. However, Previous studies with ERS-1 S_AR and RADARSAT data in Indonesia and in the North American Plains indicate that C-band SAR data provide us with an effective tool for studying the forest fire damages. However, the application of C-band SAR data to the analysis of the forest fire areas requires careful processing of the data with realistic scattering models.

조기 발병한 정신증적 장애에서 자기공명영상을 이용한 측뇌실에 대한 구조적인 예비연구

이윤희,강민희,김철응,이정섭,배재남,홍강의 대한소아청소년정신의학회 2001 소아청소년정신의학 Vol.12 No.2

연구목적:측뇌실의 확장은 성인기의 정신분열병에서 잘 확립되는 소견이지만, 조기에 발병한 정신증적 장애에서는 아직 논란이 있다. 본 연구에서는 자기공명영상을 이용한 후향적인 방법을 통하여 지금까지 비교적 연구가 많이 시행되지 않았던 조기발병한 정신분열증·양극성 장애 환아들을 대상으로 측뇌실의 구조적인 이상을 연구하여, 이러한 뇌의 구조적 이상이 병의 초기부터 시작되어 정상과는 다른 경과로 진행되는 것인가를 알아보고자 하였다 방법:정신분열병과 양극성 장애의 DSM-Ⅲ-R 진단 기준에 부합하는 14명의 환아(평균 연령 14.0세,표준편차 2.1)와 26명의 두통 대조군에서 뇌자기공명 영상상을 후향적으로 모집하였다. 분석을 위하여 측뇌실이 가장 잘 보이는 축 영상(axial image)를 선택하였다. 뇌자기공명영상상은 평판형 스캐너로 읽어들여서 NIH IMAGE 프로그램을 통하여 분석하였다. 결과:환자군에서는 측뇌실 크기, 측뇌실확장지수가 연령의 증가에 따라 함께 증가하는 상관관계를 나타내었으나, 대조군에서는 연령과 측뇌실 크기, 측뇌실확장지수 등이 유의한 상관관계를 보이지 않았다. 환자군에서는 정상군에서 보이는 좌우 측뇌실 비대칭성이 소실된 결과를 보였다. 그리고 통계적으로 유의한 정도는 아니었으나 환자군이 대조군에 비해 측뇌실과 측뇌실확장지수가 큰 경향을 보였다. 결론:정신증적 환자에서의 뇌의 구조적 이상은 병의 비교적 초기 경과에서부터 시작되며, 정상과는 다소 다른 경과를 취하여 진행한다는 것을 시사하는 결과라 할 수 있다. Objective : The enlargement of the lateral ventricle is well established finding in adult-onset schizophrenia, but in the patients with early-onset psychotic disorder(EOPD) is still controversal. To identify structural abnormalities of the lateral ventricle in patients with EOPD and difference of the brain developmental course in EOPD group, planimetrical assessment of the lateral ventricle was conducted by means of retrospective quantitative neuroimaging. Methods : The brain MR images of 14 patients with EOPD(mean age 14.0±2.1 years) who met the DSM-Ⅲ-R diagnostic criteria for schizophrenia and bipolar disorder and 24 control subjects with simple headache(mean age 10.0±2.1 years) were collected. Single best view for the lateral ventricle, one axial slice was selected for analysis. MR images were redigitalized with flatbed scanner and data were analyzed with NIH IMAGE software. Results : In the patients with EOPD, there were significant correlations between aging and lateral ventricular sizes and between aging and ventricular brain ratio(VBR). The statistical significance of normal asymmetry of the lateral ventricle was not observer for the EOPD group. The EOPD group had larger lateral ventricular sizes and VBR than control group, but these results were not statistically significant. Conclusion : These findings suggest that the brain abnormalities in patients with EOPD progress from the earlier course of the disorders and the course of brain development in EOPD group is different from control group.

Comparison of Food Consumption Pattern, Nutrient and Dietary Fiber Intakes between Female College Students and Middle Aged Women in Korea

Lee,Kang-Hee,Chyun,Jong-Hee 韓國營養學會 1997 Journal of Nutrition and Health Vol.30 No.9

Gilbert 증후군에서 열량 제한 시험과 Phenobarbital 자극 시험의 의의(14예)

이헌영,채경훈,정재훈,강윤세,김연수,문희석,박기오,이엄석,김선문,김석현,성재규,이병석,이강욱 충남대학교 의학연구소 2003 충남의대잡지 Vol.30 No.2

Gilbert 증후군은 인구의 7%에서까지 나타날 수 있는 매우 흔한 증후군으로서 비진행성인 양성의 만성적 경과를 치하며, 간질환의 증상과 징후가 없는 경한 비포합형 고빌리루빈혈증이 특징인 일종의 체질적인 증상으로서 혈장 빌리루빈 농도에 대한 사춘기의 영향 때문에 10대와 20대에 자주 진단이 된다. 따라서 임상적인 중요성은 미약하지만 높은 빈도가 예상되는 점에 그 중요성이 부여되어야 할 것이다. 따라서 적정한 임상적 진단법으로 기왕에 소개된 열량제한 시험과 phenobarbital 유도 시험을 시행하고 이들의 진단적 가치를 알아보기 위하여 본 연구를 시행하였다. 1990년 7월부터 1999년 4월까지 충남대학교병원에 내원하여 HBsAg, IgG anti-HBc 및 anti-HCV가 음성이고, 간 초음파 스캔에서 이상이 없으며, 혈청 AST, ALT 및 AP가 정상인 비음주자에서 경한 비포합형 고빌리루빈혈증이 있는 14예의 환자들을 대상으로 ^(99m)Tc-DISID 스캔을 시행하였으며, 기저 치 총빌리루빈 및 포합형 빌리루빈 치를 측정한 다음에 하루에 400Kcal로 48시간동안 제한한 열량 제한 시험을 시행하였고, phenobarbital을 하루 60mg씩 5일간 투여한 후에도 각각 총빌리루빈과 포합형 빌리루빈 치를 검사하여 비포합형을 구하였다. 대상 환자들은 모두 14예로서 남자가 11예(78.6%)였고 여자가 3예(21.4%)여서 3.7:1로 남자에서 많았으며, 20대가 6예(42.9%), 30대가 역시 6예(42.9%) 및 40대가 2예(14.2%)로서 2,30대가 대부분(85.8%)이었다. 열량 제한 시험 후의 총빌리루빈 치, 비포합형 및 포합형 빌리루빈 치들은 평균 각각 5.5±2.7, 4.2±2.3 및 1.3±10mg/dL 로서, 시험 전 치들인 3.0±0.8, 2.2±0.8 및 0.7±0.4mg/dL 보다 유의하게(p=0.001, p=0.001, p=0.023) 상승하였다. 포합형 빌리루빈 치도 유의하게 상승하였으나 비포합형의 상승보다는 훨씬 낮아서 주로 비포합형이 증가하였다. phenobarbital 투여 중 설사가 발생하여 중단한 1예를 제외한 13예에서 열량 제한 시험 후에 상승하였던 총, 비포합형 및 포합형 빌리루빈 치가 phenobarbital 유도 시험후에는 2.0±1.1, 1.5±0.8 및 0.5±0.4mg/dL로서 열량 제한 시험 결과보다 유의하게 낮아졌고(p=0.00, p=0.000, p=0.001), 열량 제한 시험 전의 기초치들인 3.0±0.8, 2.2±0.8 및 0.7±0.4mg.dL 보다도 더욱 낮아졌으며 유의한 차이(p=0.001, p=0.02, p=0.005)를 나타내었다. 14예에서 시행한 ^(99m)-Tc DISIDA 스캔에서 9예(64.3%)가 정상이었고, 5예(35.7%)에서는 심장 및 신장으로의 간외 섭취가 3예였고, 60분까지 소장 배출이 없는 배설 지연 예와 담낭 수축 불량 예가 각각 1예 씩 발견되었다. Phenobarbital 투여시험에서 민감도가 열량제한시험에 비해 더 높았다(92.3%와 50.0%). Gilbert 증후군에서 1일 400 Kcal로 48시간의 열량제한 시험과 1일 60mg의 phenobarbital을 5일간 투여하는 유도 시험은 편리하고 유용한 임상적인 진단법으로 이용할 수 있다고 생각된다. 그러나 열량 제한 시험에서는 증가 기준의 통일이 필요하다고 유추되며 phenobarbital 유도 시험이 민감도가 더 높은 것으로 생각된다. Gilbert's syndrome is very frequent and benign chronic process characterized by mild, intermittent, unconjugated hyperbilirubinemia without any symptom and sign of liver disease. Previously intoduced caloric restriction test and phenobarbital stimulation test as two appropriate clinical tests had been examined and their diagnostic values were reevaluated. Fourteen patients with mild, persistent, unconjugated hyperbilirubinemia were included. Subsequently caloric restriction has been applicated by 400 Kcal/day for 48 hours and phenobarbital has been prescribed by 60 mg/day for 5 days. Therafter serum levels of total and direct bilirubin were measured. Most of the patients were third and fourth decade(85.8%) and male predominant. Each basal serum levels of total, indirect and direct bilirubin were 3.0±0.8, 2.2±0.8 and 0.7±0.4 mg/dL. After caloric restriction test, each levels were increased significantly to 5.5±2.7, 4.2±2.3 and 1.3±1.0 mg/dL(p=0.001, p=0.001, p=0.023). After phenobarbital stimulation test for 13 patients had been practiced, increased levels of each bilirubin after caloric restriction test were decreased significantly to 2.0±1.0, 1.5±0.8 and 0.5±0.4 mg/dL(p=0.000, p=0.000, p=0.001) and these levels were significantly lower than basal levels(p=0.001, p=0.02, p=0.005). The sensitivities of caloric restriction test were 85.7%, 50.0%, and 71.4%, 35.7%(1.0, 1.5 mg increase of total bilirubin and 1.0, 1.5 mg/dL increase of indirect bilirubin). The sensitivities of phenobarbital stimulation test were 93.2% and 92.3% at criteria of 1.5 mg/dL increase of total bilirubin and indirect bilirubin. On the diagnosis of Gilbert syndrome, caloric restriction test and phenobarbital stimulation test are convenient and useful diagnostic tools in clinical face. And also phenobarbital stimulation test has higher sensitivity than caloric restriction test. Furthermore, standardization of bilirubin increment would be necessary in caloric restriction test.

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.

전류 비유 모델에 의한 초등학생의 전류 개념 변화 분석

유병길,강인석,김병철,남만희,박선희,소하연,윤희정,이영아,이하룡,전병문,정승호 부산교육대학교 과학교육연구소 2000 科學敎育硏究 Vol.25 No.-

There exists a major impediment to learning electricity which may illuminate why direct presentation of scientists' ideas is too aggressive a strategy. This impediment lies in thinking that electricity is used up and in envisaging the light bulb as a consumer. This view is based on a powerful idea which summarises much of our experience; it declares that 'things get used up', 'you cannot get something for nothing', and 'intuitive thinking'. To replace this view with scientific view, we made the analogy model. It is suggested that the analogy model is more effective in teaching electricity circuits than conventional teaching method.

저장 온도 및 상대습도가 비타민 정제 중 지용성 비타민 함량의 변화에 미치는 영향

김동섭,이재황,김세곤,이동언,박석준,이진희,이강표,최성원,백무열 경희대학교식량자원개발연구소 2007 硏究論文集 Vol.26 No.1