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.

경연 대회를 통한 초ㆍ중고생의 창의력 신장 효과에 관한 연구

이희복,육근철,류해일,김현섭,김희수,박달원,유병환,김선효,김여상,서광수,변두원,서명석,배성효,박종석,심규철,이성희 공주대학교 과학교육연구소 2001 과학교육연구 Vol.32 No.1

미래 사회를 대비하기 위한 개인의 개성을 존중과 창의적인 능력을 지닌 인간을 양성을 목적으로 충청남도 지역의 초 ㆍ 중고등학생들을 대상으로 한 창의력 경연대회가 공주대학교 과학교육연구소에서 개최되었다. 충청남도 초 ㆍ중 ㆍ 고등학생들을 대상으로 실시한 창의력 경연대회는 창조적 아이디어를 내어 스스로 문제를 해결해 나갈 수 있는 교육 프로그램을 제공하는 좋은 기회였음이 확인되었으나, 일부의 팀에서만 참신하고 재미있는 아이디어들이 제안되었다. 여학생의 참가자 수가 상당히 증가하였으며, 대체적으로 입상권의 학생들의 상당 부분이 여학생이라는 것이 특이할만하다. 학년이 올라감에 따라서 창의적인 아이디어를 내는 양이나 질에 있어서 뒤떨어지는 것으로 분석되었으며, 토론 학습의 적응력이 미흡하고 발표력 및 청취력에 있어서도 떨어지는 것으로 나타났다. 따라서 중 ㆍ고등학교의 학교교육에서도 학생들에게 프로젝트형 탐구학습 프로그램의 적용은 물론 토론식 수습을 통한 학생들의 사고의 전환의 기회를 제공해야 할 것으로 사료된다. The creativity competition was held to foster the creativity of elementary and secondary school students in the Institute of Science Education, Kongju national University. It was found that the creativity competition effected on the improvement of inventing creative ideas and problem solving activities. But, only some competitors participated in semifinal and final contests, presented original and interesting ideas. More female students participated in competition than last year. More female participants were awarded a prize than males. Totally, participants were defective in discussion and communication, and presentation and listening ideas. Increasing grades correlated inversely with creativity and originality. There is need of inquiry project teaming programs and presenting opportunities of conversion of thinking by discussing instructions in school

2003년 국내 중증급성호흡기증후군 진료 현황 및 문제점 분석

이진수,김은실,정문현,백제중,정선화,안주희,최영화,이선희,고철우,김성범,김민자,박승철,기현균,송재훈,최상호,김양수,이상오,조용균,박영훈,정숙인,김연숙,이흥범,손창희,장성희,정희진,김우주 대한감염학회 2004 감염과 화학요법 Vol.36 No.3

목적 : 2002년 말 중국에서 SARS가 발생한 이후 국내에서도 2003년 10월까지 총 3명의 추정환자, 17명의 의심환자가 보고되었다. 향후 추가적인 SARS의 유행이 우려되는 상황에서, 그간의 SARS 환자 진료에 있어서의 실질적인 준비사항, 진료 현황 등에 대한 조사를 통해 문제점을 파악하여, 향후 더 나은 대비가 될 수 있도록 개선점을 제시하고자 하였다. 재료 및 방법 : SARS로 의심되는 환자를 진료 경험이 있는 병원의료진을 대상으로 2003년 10월에 설문조사를 실시하였다. 설문에는 SARS 환자 진료 시의 실질적인 조치, 진료 현황, 병실, 응급실 및 외래에서의 격리 시설과 준비사항, 보건당국의 관리와 지원에 관한 사항을 포함하였다. 결과 : 대상이 되는 22개 병원 중 17개(17/22, 77.2%) 병원이 설문에 응하였다. SARS 환자를 위한 격리실은 응급실, 외래, 일반병실 및 중환자실에서 각각 9개(9/17, 52.9%), 5개(5/17, 29.4%), 15개(15/16, 93.7%), 4개(4/16, 25%) 병원에서 음압처리가 되어있지 않은 일인실 혹은 다인실이 사용되었고, 1개(1/16, 6.3%) 병원에서만 일반병실에서 음압격리실이 운영되었다. 입원환자의 진찰 시 개인보호구의 착용은 거의 모든 의료기관에서 이루어졌다. 보건당국에서 SARS지정병원의 시설 등을 사전에 확인한 곳은 1곳(1/12, 8.3%)이였고, 14개 병원(14/15, 93.3%)에서는 보건당국에 의뢰한 검사결과를 통하 받지 못하였다. 결론 : 의료기관에서 SARS 환자용 격리실뿐만 아니라 기존의 격리실 설비 등이 미흡하였으며, 특히 중환자실 및 외래의 준비가 더욱 부족하였다. 보건당국의 의료기관에 대한 종합적인 지원이 부족하였고, 병원과의 원활한 연계가 잘 이루어지지 않았다. SARS 만이 아닌 격리를 필요로 하는 질환의 적절한 진료를 위해 향후 병원 시설의 정비와 정부차원에서의 보다 구체적이고 실질적인 대책마련이 필요하다. Background : There was an worldwide outbreak of the Severe Acute Respiratory Syndrome (SARS) originated from China in late 2002. During that period three cases of suspected SARS and 17 cases of probable SARS were reported in Korea. With the concerns about the reemergence of SARS-coV transmission, it is important to be prepared for any possibility. So, this study is aimed to analysis the past measures in managing SARS and propose the amendatory plans to improve the preparedness. Materials & Methods : Questionnaires were collected among clinicians with any experience in managing the probable or suspected SARS cases in Oct. 2003. 17 out of 22 hospitals responded to the questionnaire. The contents in the questionnaire were practical activities, personal equipments, response plans, isolation facilities in emergency centers, outpatient clinics, general wards and intensive care units, and relationship with the public health department. Results : The dedicated isolation rooms in emergency centers, outpatient clinics, general wards, and intensive care units were prepared in 9 (9/17, 52.9%), 5 (5/17, 29.4%), 15 (15/16, 93.7%), and 4 (4/16, 25.0%) hospitals, respectively. Except for one hospital that newly made negative pressure room for SARS, single or multi-bed rooms without airborne infection control were used in all the other hospitals. The personal precaution principles were kept quite well in general wards. Before the designation of SARS hospital by the public health department prior evalution to see if the hospital was suitable for managing SARS was conducted in only 1 (1/12, 8.3%) hospital. The results of laboratory diagnosis were reported back in 1 (1/15, 6.6%) hospital. Conclusions : The isolation facilities which can control airborne infection were almost deficient not only for SARS but also for other respiratory transmissible diseases. For the infection control of transmissible diseases including SARS, more investment is needed on medical facilities and comprehensive support from the public health department required.

중환자에서 동맥혈 가스분석 횟수와 그로인한 실혈량에 대한 연구

이석열,전철우,정영수,오희숙,마분란,이정미,정혜영,이만복,이길노 순천향의학연구소;Soonchunhyang Medical Research Institute 2000 Journal of Soonchunhyang Medical Science Vol.6 No.1

Background : Arterial blood gas analysis is the most comon exam in intensive care unit. In this study, the frequency of blood gas analysis and the amount of blood loss after Blood Gas Analysis in Intensive Care Unit were observed. Methods : From November 1999 to February 2000, 115 patients admitted to intensive care unit at Soonchunhyang university Kumi hospital were studied prospectively for the frequency of blood gas analysis and the amount of blood loss after blood gas analysis in Intensive Care Unit. Results : The mean value of frequency of blood gas analysis was 6.41±6.49 and the mean value of amount of blood loss after blood gas analysis was 0.78ml. This was lower than that of other foreign reports. The patients with ventilator therapy above 24 hours showed higher frequency of blood gas analysis than that of not applied ventilator patients. Pulse oxymetry was applied to all patients and the frequency of blood gas analysis was decreased due to the use of strict pulse oxymetry. Conclusion : Doctors and nurses in intensive care unit keep in mind that adequate blood sampling is needed for the decrease of blood loss. Education and protocol for the decrease of blood loss after arterial blood gas analysis may be necessary.

GA 도포제와 염화칼슘 처리시기가 ‘신고’ 과실의 성숙 및 저장성에 미치는 영향

윤철구(Cheol Ku Youn),김선규(Seon Kyu Kim),임상철(Sang Cheol Lim),김학현(Hag Hyon Kim),김영호(Young Ho Kim),이철희(Cheol Hee1 Lee),최관순(Kwan Soon Choi) 한국원예학회 2000 원예과학기술지 Vol.18 No.2

조혈모세포이식 환자에서 침습성 진균 감염에 대한 Micafungin의 예방 효과 및 안전성

김시현,이동건,최수미,권재철,박선희,최정현,유진홍,이성은,조병식,김유진,이석,김희제,민창기,조석구,김동욱,이종욱,민우성,박종원 대한감염학회 2010 감염과 화학요법 Vol.42 No.3

Background: Micafungin, a potent inhibitor of 1,3-β-D-glucan synthase, is a novel antifungal agent of the echinocandin class. In vitro study showed that micafungin was effective against Aspergillus species as well as Candida species, but clinical data on the prophylactic efficacy against invasive fungal infections (IFIs) other than candidiasis are still lacking. Materials and Methods: We identified 60 consecutive adult hematopoietic stem cell transplantation (HSCT) recipients who received at least 3 doses of micafungin during neutropenic period. Micafungin was started as an alternative in patients who were intolerant or had adverse events (AEs) to primary prophylactic antifungal agents. We retrospectively reviewed the medical records and analyzed the efficacy and safety of micafungin for prophylaxis against IFIs. Results: The patients either had autologous (n=9) or allogeneic (n=51: 1 syngeneic, 24 sibling, 26 unrelated donor) HSCT. Itraconazole oral solution (n=58) was the most frequently used first line antifungal agent for prophylaxis and was administered for median 11 days. The most frequent cause of switch to micafungin was vomiting (n=42). The duration of neutropenia and micafungin administration was median 13 and 12 days, respectively. A successful outcome was achieved in 45 (75%) patients. Empirical antifungal therapy was initiated in 13 (22%) patients. There were 2 cases (3.3%) of breakthrough fungal infections which comprised a probable invasive pulmonary aspergillosis and a possible invasive fungal sinusitis. There was no case of invasive candidiasis. A total of 53 (88%) patients experienced at least one AE regardless of causality during micafungin administration. The most frequent AEs were hypokalemia, vomiting, diarrhea, and elevated serum aspartate aminotransferase or alanine aminotransferase. Among the aforementioned AEs, only 1 case of diarrhea could be classified as a probable relation with micafungin when causality was assessed. There was no AEs that caused discontinuation of micafungin. Conclusions: Micafungin seems to be a safe and effective agent for prophylaxis of IFIs including aspergillosis as well as candidiasis in HSCT recipients. However, further large, prospective, and randomized comparative studies are warranted for aspergillosis.

부산, 울산, 경남지역 직업병감시체계에서 나타난 수지진동증후근의 역학적 특성

최영희,유철인,이지호,이충렬,이헌,김영욱,채창호,고상백,김은아,이유진,김양호 大韓産業醫學會 2003 대한직업환경의학회지 Vol.15 No.3

목적: 국내에서도 국소진동에 의한 수지진동증후군이 다수 있을 것으로 추정하나 최근에 이에 대한 보고가 적어 부·울·경 직업병감시체계를 통하여 수지진동증후군에 대한 환례를 수집하여 이의 역학적 특성을 밝히고자 본 연구를 실시하였다. 방법: 2001년 44월부터 2002년 12월까지 부산, 울산, 경남지역에 있는 종합병원 9곳을 통하여 특수 건강진단과 산업의학과 외래를 방문한 근로자를 대상으로 진동폭로에 대한 설문조사를 실시하고 이들중에서 수지진동으로 인한 증상을 호소하는 근로자는 이학적 검사와 Stockholm workshop scale을 이용하여 수지진동증후군이 있는지 평가하였다. 결과: 남자 188명, 여자 4명 등 총 192례의 수진진동증후군이 의심되는 환례를 수집하였으며, 업종별로는 조선업에 종사하는 근로자들이 가장 많았다. 국소진동의 주된 폭로원은 그라인더가 가장 많았으며, 혈관장해로 인한 증상보다 감각신경성 장해로 인한 증상을 많이 호소하였다. 결론: 전국적으로 조선업종의 그라인더 사용자를 중심으로 많은 수의 수지진동증후군의 환자가 있을 것으로 추정되며, 이들에 대한 예방대책을 마련하기 위하여 전국규모의 정확한 유병률 조사 및 실태파악이 필요한 것으로 판단된다. Objects: The objectives of this study were to estimate the epidemiologic characteristics of hand-arm vibration syndrome (HAVS) due to occupational exposure of hand transmitted vibration and to identify the occupations and industries where such exposures arises, and the main sources of exposure. Methods: In April 2001 the Busan, Ulsan, and Kyung-Nam Province occupational disease surveillance system was established to measure the incidence and prevalence of work-relatd HAVS and other occipational diseases in these Korean provinces. Occupational physicians of nine hospitals in Busan, Ulsan, and Kyung-nam Province were involved in this project between April 2001 and November 2002. Physicians collected information through questionnaires and interviews. Information gathered included age, occupation, types of vibration tools used and presence of subkective symptoms such as vibration-induced white finger (VWF), numbness and tingling. Results: A total 192 cases were reported with 188 males and 4 females. The shipbuilding industry was the most common type of industry and grinders were the most common source of exposire. Symptoms of neurological disorder were more common than those of vascular disprder. Conclusions: The authors concluded that exposure to hand transmitted vibration is common and that HAVS is one of the most common occupational diseases in Korea. However, the range and extent of hand transmitted vibration and the overall prevalence of HAVS in Korea is still unknown. More extensive research on this syndrome in order to priorite necessary preventive measures is required.

크롬(Ⅵ)의 체내 흡수와 소실속도에 관한 연구

김현영,이성배,임철홍,이권섭,정용현,이종성,한정희,전윤석,황호순,이용묵 한국산업위생학회 2003 한국산업보건학회지 Vol.13 No.1

The CrO3 mostly used in plating. metal surface disposal, leather, cosmetic manufacturing, as an experiment material by repeatedly inhaling and exposure the male S.D. rats at a 0.00, 0.2., 0.50, 1.25 mg/㎡ concentration(particle size: 0.5-0.5 aerosol)6hours a day, 5day a week in 13weeks comparing with 2weeks, 8weeks of recovery group about the noxiousness of the experiment animal and the reduce scale of the CrO3 in the internal organ especially in blook and respiratory organ with the period of convalescent and clearance. The experiment results which we received are as follows. 1. In blood the RBC, HGB and HCT experiment, rats with 0.20, 0.50 mg/㎡ concentration showed that there were some decreases but not dependent. The kidneys absolute weight compared with control group was reduced intentionally(p〈0.05) and the lungs absolute weight compared with control group showed intentional increase(p〉0.05). 2. After the exposure of the experiment material, the whole blook, l\blood plasma and red blood cell in blood by (x): the period of convalescent, per (y); the decreasing of Cr concentration, was y=66.51 e -0.057x, y=67.2 e-0.101x, y=70.01 e-0.030 in 0.50 mg/㎡ exposure concentration by calculating the clearance coefficient of correlation, and the half life (day)was estimated 12.0, 6086, 23.0 each. 3, After the exposure of the experiment material, the experiment animals lung, liver and kidneys by(x); the period of convalescent, per (y); the decreasing of Cr conentration, was y=1808 e-0.00493x, y=12.02e-0.0297x, y=67.61 e-0.0292x in 0.50mg/㎡ exposure concentration by calculating the clearance coefficient of correlation, and the half life(day)was estimated 140.6, 23.3, 23.7, each, and including lung, liver with all of the experiment internal organs, the Cr clearance decreased as the exposure concentration increased.

SD Rats를 이용 1-hexene의 흡입독성 연구

김현영,임철홍,정용현,이권섭,이성배,이준연,한정희,전윤석,이용묵 한국환경독성학회 2001 환경독성보건학회지 Vol.16 No.4

The purpose of this study was to investigate the acute (4 hours) and repeated-dose (6 hours a day, 5 days a week, 4 weeks) toxic effects of I -hexene on Sprague- Dawley (SD) rats which were treated by inhalation. The results were as follows; I. The median lethal concentration (LC_(50)) was estimated 52,694 ppm (confidence limit 95%; 49,494~55,447 ppm) in acute inhalation. Abnormal clinical signs related to the l-Hexene were not observed with the acute inhalation dose. Gross findings of necropsy revealed on evidence of specific toxicity related to the 1-hexene, II. By repeated inhalation exposure the body weight of male were more or less reduced by the dose of 2,500 ppm and 5,000 ppm compared with control group. However there were no significant variation hematology and blood biochemistry for the exposed rats compared with the control rats. Abnormal clinical signs and gross findings of necropsy related to the 1-hexene were not shown. In conclusion when we exposed I-hexene to SD rats for 4 weeks, 5 days per week, 6 hours per day, the Lowest observed effect level (LOEL) was over 2,500 ppm and Non observed effect level (NOEL) was below 500 ppm.