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>

노인의 갑상선기능저하증에 대한 임상적 연구

정윤석,남문석,이은직,김경래,이현철,김현승,허갑범 한국노화학회 1993 한국노화학회지 Vol.3 No.1

Glycated albumin is a useful glycation index for monitoring fluctuating and poorly controlled type 2 diabetic patients

Lee, Eun Young,Lee, Byung-Wan,Kim, Daham,Lee, Yong-ho,Kim, Kwang Joon,Kang, Eun Seok,Cha, Bong-Soo,Lee, Eun Jig,Lee, Hyun Chul Springer-Verlag 2011 Acta diabetologica Vol.48 No.2

다낭성 난소증후군 환자에서 L - dopa 및 Pyridostigmine 자극에 대한 성장호르몬 분비

이경미,배희동,이병석,허갑범,이현철,임승길,이은직,김경래,정윤석,박기현 대한내분비학회 1993 Endocrinology and metabolism Vol.8 No.3

Polycystic ovary syndrome (PCOS) is the combination of ovulatory failure, infertility, hirsutism, obesity, bilateral polycystic ovaries and large numbers of endocrine dysfunctions. In 12 women with PCOS and 9 control women with regular cycle, the Ghrespose to L-dopa and insulin response to oral glucose tolerence test were investigated. In PCOS, L-dopa test with phridostigmine pretreatment was also performed. GH response and GH response area under the curve(AUC) to L-dopa were significantly lower in PCOS (basal(ng/ml), maximum(ng/ml), GH resonse AUC(ng/mlxh), 0.5±0.2, 1.6±0.7, 2.1±0.7) than those(1.4±0.2, 6.9±1.1, 9.7±1.0) of controls (p$lt;0.05). Pyridostigmine pretreatment had significantly enbhanced the GH response to L-dopa (1.4±0.4, 7.7±1.3, 9.6±1.4) in PCOS (p$lt;0.05). Insulin response (uU/ml) and insulin response AUC (uU/mlxh) to glucose load were significantly higher in PCOS(8.0±1.8, 142.1±59.5, 1`94.3±73.7) than those (5.3±1.2, 24.9±2.6, 35.9±2.8) of controls(p$lt;0.05). Plasma IGF-1 levels of ug/L) were significantly higher than controls(287.3±27.1) (p$lt;0.05). BMI had a positive correlation with insulin response AUC (p$lt;0.01). Insulin respponse AUC had a positive correlation with plasma IGF-1 levels (p$lt;0.001) but inverse correlation with GH response AUC in PCOS and controls(p$lt;0.05). These data suggest that decreased GH secretion of PCOS may be associated with a high somatostatin activity and a high plasma IGF-1 level (J Kor Soc Endocrinol 8: 265~272, 1993)

Absence of activating mutations of <i>CXCR4</i> in pituitary tumours

Lee, Yong-ho,Noh, Tae Woong,Lee, Mi Kyung,Jameson, J. Larry,Lee, Eun Jig Blackwell Publishing Ltd 2010 Clinical endocrinology Vol.72 No.2

<P>Summary</P><P>Objective </P><P>Mutations of the <I>gsp</I> oncogene are responsible for 30–40% of GH-producing pituitary adenomas and 10% of nonfunctioning pituitary adenomas (NFPAs). However, the pathogenetic mechanism of the remaining pituitary tumours still remains to be identified. Recently, the interaction between the chemokine stromal cell-derived factor 1 and its receptor CXCR4 was found to play an important role in GH production and cell proliferation in various pituitary adenoma cell lines. As CXCR4 is a Gi-coupled chemokine receptor, its constitutive activating mutations may be involved in pituitary tumour formation by cyclic adenosine monophosphate (cAMP)-independent, ERK-related pathways.</P><P>Patients and methods </P><P>We investigated whether somatic activating-mutations of <I>CXCR4</I> might be a possible tumourigenic mechanism for <I>gsp</I>-negative GH-secreting pituitary adenomas and NFPAs. Direct sequencing of polymerase chain reaction-amplified products for coding exons of <I>CXCR4</I> were performed using genomic deoxyribonucleic acid samples from 37 GH-producing pituitary tumour tissues that were negative for the <I>gsp</I> mutation and 14 CXCR4 expressing NFPAs.</P><P>Results </P><P>Immunohistochemical analyses and double immunofluorescent staining of sectioned paraffin-embedded pituitary tissues revealed that CXCR4 is highly expressed in GH-producing pituitary adenomas and NFPAs. Direct sequencing showed that two synonymous mutations in exon 2 (87 C > T and 414 C > T) were detected in 4 out of 51 pituitary tumours.</P><P>Conclusion </P><P>Our results indicate that an activating mutation of the <I>CXCR4</I> may not be a common pathogenetic mechanism in GH-producing pituitary tumours and NFPAs.</P>

Association Between Obesity and BRAFV600E Mutation Status in Patients with Papillary Thyroid Cancer

Lee, Jandee,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Shin, Dong Yeob,Nam, Kee-Hyun,Jung, Sang Geun,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Springer - Society of Surgical Oncology 2015 Annals of Surgical Oncology Vol.22 No.suppl3

Aberrant Expression of COT Is Related to Recurrence of Papillary Thyroid Cancer

Lee, Jandee,Jeong, Seonhyang,Park, Jae Hyun,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Nam, Kee-Hyun,Shin, Dong Yeob,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Williams & Wilkins Co 2015 Medicine Vol.94 No.6

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.</P><P>The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n = 167) and analyze the clinical implications of aberrant expression of these genes.</P><P>Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).</P><P>qPCR data showed that the relative mRNA expression of <I>A-</I>, <I>B-</I>, <I>C-RAF</I> and <I>COT</I> of PTC were higher than normal tissues (all <I>P</I> < 0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (<I>r</I> = 0.4083, <I>P</I> < 0.001), B- (<I>r</I> = 0.2773, <I>P</I> = 0.0003), and C-RAF (<I>r</I> = 0.5954, <I>P</I> < 0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all <I>P</I> < 0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (<I>P</I> < 0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF<SUP>V600E</SUP>-positive PTC (<I>P</I> < 0.001, <I>P</I> = 0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (<I>P</I> = 0.045) and higher recurrence rate (<I>P</I> = 0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF<SUP>V600E</SUP> mutation (odds ratio, 4.662; 95% confidence interval 1.066 − 21.609; <I>P</I> = 0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2 ± 4.1 years; <I>P</I> = 0.0403). GSEA indicated that gene sets related to B-RAF-RAS (<I>P</I> < 0.0001, false discovery rate [FDR] <I>q</I>-value = 0.000) and thyroid differentiation (<I>P</I> = 0.048, FDR <I>q</I>-value = 0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, <I>P</I> < 0.0001, FDR <I>q</I>-value = 0.000).</P><P>Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.</P></▼2>

폐경전, 후 여성에서의 체조직분포와 골밀도의 상관성

이경미,박기현,이병석,허갑범,이현철,임승길,이은직,김경래,정윤석,남문석 대한내분비학회 1993 Endocrinology and metabolism Vol.8 No.2

Bone minearal density (BMD) is generally known to decrease with age, especially in postmenoopausal women. We examined the correlation between the body composition and BMD with dual energy x-ray absorptiometry (DEXA) in 36 premenopausal and 96 postmenopausal women. There were no statistical differences in total lean body mass (TLBM), total body fat mass(TBRM) and % body fat between pre-and body mass index(BMI), but no correlation with TBFM. In postmenopausal women, BMD had a negative correlation with age and postmenopausal period, but positive correlation with BMI, TBRM and TLBM by simple regression analysis. Multiple regression analysis revealed that positive correlation was found between TBFM and BMD of lumbar spine and femoral neck in postmenopausal women but not in premenopausal women. We concluded that TBFM in postmenopausal women is an iportant factor in maintaining the BMD, however the mechanism unerlying this relationship will be further clarified. (J Kor Soc Endocrinol 8: 180~186, 1993)

Distinct Features of Nonthyroidal Illness in Critically Ill Patients With Infectious Diseases

Lee, Woo Kyung,Hwang, Sena,Kim, Daham,Lee, Seul Gi,Jeong, Seonhyang,Seol, Mi-Youn,Kim, Hyunji,Ku, Cheol Ryong,Shin, Dong Yeop,Chung, Woong Youn,Lee, Eun Jig,Lee, Jandee,Jo, Young Suk Wolters Kluwer Health 2016 Medicine Vol.95 No.14

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Nonthyroidal illness (NTI), often observed in critically ill patients, arises through diverse alterations in the hypothalamus-pituitary-thyroid (HPT) axis. However, the causal relationship between underlying disease and NTI diversity in critically ill patients is poorly understood.</P><P>The aim of this study was to examine NTI severity and adverse outcomes in critically ill patients with respect to their underlying disease(s).</P><P>The medical records of 616 patients admitted to the intensive care unit (ICU) between January 2009 and October 2014 were retrospectively reviewed. Patients with known diseases or taking medications that affect thyroid function were excluded. All-cause mortality (ACM) and length of stay (LOS) in the ICU were assessed as adverse outcomes.</P><P>The enrolled patients (n = 213) were divided into the following 4 groups according to the severity of NTI at the nadir of their thyroid function test (TFT): normal (n = 11, 5.2%), mild NTI (n = 113, 53.1%), moderate NTI (n = 78, 36.6%), and severe NTI (n = 11, 5.2%). There was no significant difference between the groups in terms of age and gender. NTI severity showed a significantly strong association with ACM (<I>P</I> < 0.0001) and a significant positive association with LOS in the ICU (<I>P</I> = 0.031). After adjusting for age, gender, and current medications affecting TFT, increasing NTI severity led to increased ACM (odds ratio = 3.101; 95% confidence interval = 1.711–5.618; <I>P</I> < 0.0001). Notably, the prevalence of moderate-to-severe NTI was markedly higher in patients with infectious disease than in those with noninfectious disease (<I>P</I> = 0.012). Consistent with this, serum C-reactive protein levels were higher in patients with moderate-to-severe NTI (<I>P</I> = 0.016).</P><P>NTI severity is associated with increased ACM, LOS, and underlying infectious disease. Future studies will focus on the biological and clinical implications of infectious disease on the HPT axis.</P></▼2>

인슐린비의존형 당뇨병 환자에서의 β3-adrenergic 수용체 유전자 다형성

이상원,이지현,허갑범,이현철,임승길,이은직,김경래,송영득,남문석,남수연,차봉수,원영준,이해일 대한당뇨병학회 1997 Diabetes and Metabolism Journal Vol.21 No.2