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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>
Lee, Eun Jig,Ahn, Jung Yong,Noh, Taewoong,Kim, Se Hun,Kim, Tai Seung,Kim, Sun Ho WilliamsWilkins Co 2009 Neurosurgery Vol.64 No.3
<P>The microsurgical pseudocapsule can be found in the transition zone between an adenoma and the surrounding normal pituitary tissue. We investigated the precise histology of the pseudocapsule. Furthermore, we evaluated the remission rate, the changes in pituitary function, and the recurrence rate after intensive resection of the pseudocapsule.</P>
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>
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>
Lee, Sung Jun,Rim, Tyler Hyung Taek,Jang, Sun Young,Kim, Chan Yun,Shin, Dong Yeob,Lee, Eun Jig,Lee, Sang Yeul,Yoon, Jin Sook Springer-Verlag 2013 Graefe’s archive for clinical and experimental oph Vol.251 No.1
<P>To evaluate the efficacy of subconjunctival triamcinolone injection for treating upper eyelid retraction caused by thyroid-associated ophthalmopathy (TAO).</P>
Lee, Jandee,Seol, Mi-Youn,Jeong, Seonhyang,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Shin, Dong Yeob,Nam, Kee-Hyun,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Wolters Kluwer Health 2015 Medicine Vol.94 No.2
<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Metabolic reprogramming has been regarded as an essential component of malignant transformation. However, the clinical significance of metabolic heterogeneity remains poorly characterized.</P><P>The aim of this study was to characterize metabolic heterogeneity in thyroid cancers via the analysis of the expression of mitochondrial ribosomal proteins (MRPs) and genes involved in oxidative phosphorylation (OxPhos), and investigate potential prognostic correlations.</P><P>Gene set enrichment analysis (GSEA) verified by reverse transcription polymerase chain reaction and gene network analysis was performed using public repository data. Cross-sectional observational study was conducted to classify papillary thyroid cancer (PTC) by the expression of MRP L44 (MRPL44) messenger RNA (mRNA), and to investigate the clinicopathological features.</P><P>GSEA clearly showed that the expression of OxPhos and MRP gene sets was significantly lower in primary thyroid cancer than in matched normal thyroid tissue. However, 8 of 49 primary thyroid tumors (16.3%) in the public repository did not show a reduction in OxPhos mRNA expression. Remarkably, strong positive correlations between MRPL44 expression and those of OxPhos and MRPs such as reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 α subcomplex, 5; succinate dehydrogenase complex, subunit D; cytochrome c, somatic; adenosine triphosphate synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9); and MRP S5 (MRPS5) (<I>P</I> < 0.0001) were clearly denoted, suggesting that MRPL44 is a representative marker of OxPhos and MRP expressions. In laboratory experiments, metabolic heterogeneity in oxygen consumption, extracellular acidification rates (ECARs), and amounts of OxPhos complexes were consistently observed in BCPAP, TPC1, HTH-7, and XTC.UC1 cell lines. In PTCs, metabolic phenotype according to OxPhos amount defined by expression of MRPL44 mRNA was significantly related to lymph node metastasis (LNM) (<I>P</I> < 0.001). Furthermore, multivariate analysis clearly indicated that expression of MRPL44 is associated with an increased risk of lateral neck LNM (odds ratio 9.267, 95% confidence interval 1.852–46.371, <I>P</I> = 0.007).</P><P>MRPL44 expression may be a representative marker of metabolic phenotype according to OxPhos amount and a useful predictor of LNM.</P></▼2>
GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers
Lee, Jandee,Jeong, Seonhyang,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Nam, Kee-Hyun,Shin, Dong Yeob,Chung, Woong Youn,Lee, Eun Jig,Jo, Young Suk Williams & Wilkins Co 2015 Medicine Vol.94 No.25
<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated.</P><P>The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC.</P><P>Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing.</P><P>Among 137 patients with PTC, glioma-associated oncogene homolog 1 (<I>GLI1</I>) group III (patients in whom the ratio of <I>GLI1</I> messenger ribonucleic acid (mRNA) level in tumor tissue to <I>GLI1</I> mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414–13.569, <I>P</I> = 0.01) and LNM (OR 5.627, 95% CI 1.674–18.913, <I>P</I> = 0.005). Glioma-associated oncogene homolog 2 (<I>GLI2</I>) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292–13.342, <I>P</I> = 0.017) and LNM (OR 3.924, 95% CI 1.097–14.042, <I>P</I> = 0.036). GSEA suggested that higher <I>GLI1</I> expression is associated with expression of the <I>KEGG</I> gene set related to axon guidance (<I>P</I> = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.</P><P><I>GLI1</I> and <I>GLI2</I> expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers, as well as novel therapeutic targets.</P></▼2>