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대한내분비학회> Endocrinology and Metabolism(구 대한내분비학회지)> Frequency of TERT Promoter Mutations in Real-World Analysis of 2,092 Thyroid Carcinoma Patients

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Frequency of TERT Promoter Mutations in Real-World Analysis of 2,092 Thyroid Carcinoma Patients

Heera Yang , Hyunju Park , Hyun Jin Ryu , Jung Heo , Jung-sun Kim , Young Lyun Oh , Jun-ho Choe , Jung Han Kim , Jee Soo Kim , Hye Won Jang , Tae Hyuk Kim , Sun Wook Kim , Jae Hoon Chung
  • : 대한내분비학회
  • : Endocrinology and Metabolism(구 대한내분비학회지) 37권4호
  • : 연속간행물
  • : 2022년 08월
  • : 652-669(18pages)
Endocrinology and Metabolism(구 대한내분비학회지)

DOI


목차

INTRODUCTION
METHODS
RESULTS
DISCUSSION
CONFLICTS OF INTEREST
ACKNOWLEDGMENTS
AUTHOR CONTRIBUTIONS
ORCID
REFERENCES

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Background: Telomerase reverse transcriptase (TERT) promoter mutations are associated with increased recurrence and mortality in patients with thyroid carcinoma. Previous studies on TERT promoter mutations were retrospectively conducted on a limited number of patients.
Methods: We prospectively collected data on all consecutive patients who underwent thyroid carcinoma surgery between January 2019 and December 2020 at the Samsung Medical Center, Seoul, Korea. We included 2,092 patients with thyroid carcinoma.
Results: Of 2,092 patients, 72 patients (3.4%) had TERT promoter mutations. However, the frequency of TERT promoter mutations was 0.5% in papillary thyroid microcarcinoma (PTMC) ≤1 cm and it was 5.8% in papillary thyroid carcinoma (PTC) >1 cm. The frequency of TERT promoter mutations was significantly associated with older age at diagnosis (odds ratio [OR], 1.12; P<0.001), larger primary tumor size (OR, 2.02; P<0.001), and aggressive histological type (OR, 7.78 in follicular thyroid carcinoma; OR, 10.33 in poorly differentiated thyroid carcinoma; OR, 45.92 in anaplastic thyroid carcinoma; P<0.001). Advanced T stage, advanced N stage, and distant metastasis at diagnosis were highly prevalent in mutated thyroid cancers. However, initial distant metastasis was not present in patients with TERT promoter mutations in PTMC. Although the C228T mutation was more highly detected than the C250T mutation (64 cases vs. 7 cases), there were no significant clinicopathological differences.
Conclusion: This study is the first attempt to investigate the frequency of TERT promoter mutations in a real-world setting. The frequency of TERT promoter mutations in PTC was lower than expected, and in PTMC, young patients, and female patients, the frequency was very low.

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간행물정보

  • : 의약학분야  > 내과학
  • : KCI등재
  • : SCOPUS
  • : 격월
  • : 2093-596X
  • : 2093-5978
  • : 학술지
  • : 연속간행물
  • : 1986-2022
  • : 2677


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1Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Maternal Thyroid Dysfunction, and Child Autism Spectrum Disorder

저자 : Hyeong-moo Shin , Jiwon Oh , Rebecca J. Schmidt , Elizabeth N. Pearce

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 819-829 (11 pages)

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Autism spectrum disorder (ASD), with its high economic and societal costs, is a growing public health concern whose prevalence has risen steadily over the last two decades. Although actual increased incidence versus improved diagnosis remains controversial, the increased prevalence of ASD suggests non-inherited factors as likely contributors. There is increasing epidemiologic evidence that abnormal maternal thyroid function during pregnancy is associated with increased risk of child ASD and other neurodevelopmental disorders. Prenatal exposure to endocrine-disrupting chemicals such as per- and polyfluoroalkyl substances (PFAS) is known to disrupt thyroid function and can affect early brain development; thus, thyroid dysfunction is hypothesized to mediate this relationship. The concept of a potential pathway from prenatal PFAS exposure through thyroid dysfunction to ASD etiology is not new; however, the extant literature on this topic is scant. The aim of this review is to evaluate and summarize reports with regard to potential mechanisms in this pathway.

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2Preclinical Models of Follicular Cell-Derived Thyroid Cancer: An Overview from Cancer Cell Lines to Mouse Models

저자 : Min Ji Jeon , Bryan R. Haugen

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 830-838 (9 pages)

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The overall prognosis of thyroid cancer is excellent, but some patients have grossly invasive disease and distant metastases with limited responses to systemic therapies. Thus, relevant preclinical models are needed to investigate thyroid cancer biology and novel treatments. Different preclinical models have recently emerged with advances in thyroid cancer genetics, mouse modeling and new cell lines. Choosing the appropriate model according to the research question is crucial to studying thyroid cancer. This review will discuss the current preclinical models frequently used in thyroid cancer research, from cell lines to mouse models, and future perspectives on patient-derived and humanized preclinical models in this field.

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3Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society

저자 : Hyemi Kwon , Eun Roh , Chang Ho Ahn , Hee Kyung Kim , Cheol Ryong Ku , Kyong Yeun Jung , Ju Hee Lee , Eun Heui Kim , Sunghwan Suh , Sangmo Hong , Jeonghoon Ha , Jun Sung Moon , Jin Hwa Kim , Mi-kyung Ki

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 839-850 (12 pages)

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Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

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4Forty Years Together, New Leap Forward! The 40th Anniversary of the Korean Endocrine Society

저자 : Jong Chul Won , Ki-hyun Baek

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 851-857 (7 pages)

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5DPP-4 Inhibitor in Type 2 Diabetes Mellitus Patient with Non-Alcoholic Fatty Liver Disease: Achieving Two Goals at Once?

저자 : Ji Cheol Bae

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 858-860 (3 pages)

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6Efficacy and Safety of Long-Term Methimazole versus Radioactive Iodine in the Treatment of Toxic Multinodular Goiter

저자 : Fereidoun Azizi , Navid Saadat , Mir Alireza Takyar , Hengameh Abdi , Ladan Mehran , Atieh Amouzegar

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 861-869 (9 pages)

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Background: This study compared the degree of sustained control of hyperthyroidism in patients with toxic multinodular goiter (TMNG) treated with long-term methimazole (LT-MMI) or radioactive iodine (RAI).
Methods: In this clinical trial, 130 untreated patients with TMNG were randomized to either LT-MMI or RAI treatment. Both groups were followed for 108 to 148 months, with median follow-up durations of 120 and 132 months in the LT-MMI and RAI groups, respectively. Both groups of patients were followed every 1 to 3 months in the first year and every 6 months thereafter.
Results: After excluding patients in whom the treatment modality was changed and those who were lost to follow-up, 53 patients in the LT-MMI group and 54 in the RAI group completed the study. At the end of the study period, 50 (96%) and 25 (46%) patients were euthyroid, and two (4%) and 25 (46%) were hypothyroid in LT-MMI and RAI groups, respectively. In the RAI group, four (8%) patients had subclinical hyperthyroidism. The mean time to euthyroidism was 4.3±1.3 months in LT-MMI patients and 16.3±15.0 months in RAI recipients (P<0.001). Patients treated with LT-MMI spent 95.8%±5.9% of the 12-year study period in a euthyroid state, whereas this proportion was 72.4%±14.8% in the RAI-treated patients (P<0.001). No major treatment-related adverse events were observed in either group.
Conclusion: In patients with TMNG, LT-MMI therapy is superior to RAI treatment, as shown by the earlier achievement of euthyroidism and the longer duration of sustained normal serum thyrotropin.

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7Identification of Mutations in the Thyroxine-Binding Globulin (TBG) Gene in Patients with TBG Deficiency in Korea

저자 : Jung Heo , Sang-mi Kim , Hyun Jin Ryu , Hyunju Park , Tae Hyuk Kim , Jae Hoon Chung , Hyung-doo Park , Sun Wook Kim

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 870-878 (9 pages)

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Background: Thyroxine-binding globulin (TBG) is a major transporter protein for thyroid hormones. The serpin family A member 7 (SERPINA7) gene codes for TBG, and mutations of the SERPINA7 gene result in TBG deficiency. Although more than 40 mutations have been reported in several countries, only a few studies of TBG deficiency and SERPINA7 gene mutation have been performed in Korea. The aim of this study is to review the clinical presentations and laboratory findings of patients with TBG deficiency and to investigate the types of SERPINA7 gene mutation.
Methods: Five unrelated Korean adults with TBG deficiency attending endocrinology clinic underwent SERPINA7 gene sequencing. Four patients harbored a SERPINA7 gene mutation. Serum thyroid hormones, anti-microsomal antibodies, and TBG were measured. Genomic DNA was extracted from whole blood. All exons and intron-exon boundaries of the TBG gene were amplified and sequencing was performed.
Results: Two patients were heterozygous females, and the other two were hemizygous males. One heterozygous female had coexisting hypothyroidism. The other heterozygous female was erroneously prescribed levothyroxine at a local clinic. One hemizygous male harbored a novel mutation, p.Phe269Cysfs*18, which caused TBG partial deficiency. Three patients had the p.Leu372Phefs*23 mutation, which is known as TBG-complete deficiency Japan (TBG-CDJ) and was also presented in previous mutation analyses in Korea.
Conclusion: This study presents four patients diagnosed with TBG deficiency and provides the results of SERPINA7 gene sequencing. One novel mutation, p.Phe269Cysfs*18, causing TBD-partial deficiency and three cases of TBG-CDJ were demonstrated. It is necessary to identify TBG deficiency to prevent improper treatment. Also, sequencing of the SERPINA7 gene would provide valuable information about the TBG variants in Korea.

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8BRAFV600E Mutation Enhances Estrogen-Induced Metastatic Potential of Thyroid Cancer by Regulating the Expression of Estrogen Receptors

저자 : Minjun Kim , Su-jin Kim , Seong Yun Ha , Zhen Xu , Youngjin Han , Hyeon-gun Jee , Sun Wook Cho , Young Joo Park , Kyu Eun Lee

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 879-890 (12 pages)

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Background: Cross-talk between mitogen-activated protein kinase and estrogen has been reported; however, the role of BRAFV600E in the estrogen responsiveness of thyroid cancer is unknown. We elucidated the effect of BRAFV600E on the estrogen-induced increase in metastatic potential in thyroid cancer.
Methods: Using a pair of cell lines, human thyroid cell lines which harbor wild type BRAF gene (Nthy/WT) and Nthy/BRAFV600E (Nthy/V600E), the expression of estrogen receptors (ERs) and estrogen-induced metastatic phenotypes were evaluated. Susceptibility to ERα- and ERβ-selective agents was evaluated to confirm differential ER expression. ESR expression was analyzed according to BRAFV600E status and age (≤50 years vs. >50 years) using The Cancer Genome Atlas (TCGA) data.
Results: Estradiol increased the ERα/ERβ expression ratio in Nthy/V600E, whereas the decreased ERα/ERβ expression ratio was found in Nthy/WT. BRAFV600E-mutated cell lines showed a higher E2-induced increase in metastatic potential, including migration, invasion, and anchorage-independent growth compared with Nthy/WT. An ERα antagonist significantly inhibited migration in Nthy/V600E cells, whereas an ERβ agonist was more effective in Nthy/WT. In the BRAFV600E group, ESR1/ESR2 ratio was significantly higher in younger age group (≤50 years) compared with older age group (>50 years) by TCGA data analysis.
Conclusion: Our data show that BRAFV600E mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulating ER expression. Therefore, BRAFV600E might be used as a biomarker when deciding future hormone therapies based on estrogen signaling in thyroid cancer patients.

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9Metabolite Changes during the Transition from Hyperthyroidism to Euthyroidism in Patients with Graves' Disease

저자 : Ho Yeop Lee , Byeong Chang Sim , Ha Thi Nga , Ji Sun Moon , Jingwen Tian , Nguyen Thi Linh , Sang Hyeon Ju , Dong Wook Choi , Daiki Setoyama , Hyon-seung Yi

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 891-900 (10 pages)

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Background: An excess of thyroid hormones in Graves' disease (GD) has profound effects on systemic energy metabolism that are currently partially understood. In this study, we aimed to provide a comprehensive understanding of the metabolite changes that occur when patients with GD transition from hyperthyroidism to euthyroidism with methimazole treatment.
Methods: Eighteen patients (mean age, 38.6±14.7 years; 66.7% female) with newly diagnosed or relapsed GD attending the endocrinology outpatient clinics in a single institution were recruited between January 2019 and July 2020. All subjects were treated with methimazole to achieve euthyroidism. We explored metabolomics by performing liquid chromatography-mass spectrometry analysis of plasma samples of these patients and then performed multivariate statistical analysis of the metabolomics data.
Results: Two hundred metabolites were measured before and after 12 weeks of methimazole treatment in patients with GD. The levels of 61 metabolites, including palmitic acid (C16:0) and oleic acid (C18:1), were elevated in methimazole-naïve patients with GD, and these levels were decreased by methimazole treatment. The levels of another 15 metabolites, including glycine and creatinine, were increased after recovery of euthyroidism upon methimazole treatment in patients with GD. Pathway analysis of metabolomics data showed that hyperthyroidism was closely related to aminoacyl-transfer ribonucleic acid biosynthesis and branched-chain amino acid biosynthesis pathways.
Conclusion: In this study, significant variations of plasma metabolomic patterns that occur during the transition from hyperthyroidism to euthyroidism were detected in patients with GD via untargeted metabolomics analysis.

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10Inhibition of miR-146a-5p and miR-8114 in Insulin-Secreting Cells Contributes to the Protection of Melatonin against Stearic Acid-Induced Cellular Senescence by Targeting Mafa

저자 : Shenghan Su , Qingrui Zhao , Lingfeng Dan , Yuqing Lin , Xuebei Li , Yunjin Zhang , Chunxiao Yang , Yimeng Dong , Xiaohan Li , Romano Regazzi , Changhao Sun , Xia Chu , Huimin Lu

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 6호 발행 연도 : 2022 페이지 : pp. 901-917 (17 pages)

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Background: Chronic exposure to elevated levels of saturated fatty acids results in pancreatic β-cell senescence. However, targets and effective agents for preventing stearic acid-induced β-cell senescence are still lacking. Although melatonin administration can protect β-cells against lipotoxicity through anti-senescence processes, the precise underlying mechanisms still need to be explored. Therefore, we investigated the anti-senescence effect of melatonin on stearic acid-treated mouse β-cells and elucidated the possible role of microRNAs in this process.
Methods: β-Cell senescence was identified by measuring the expression of senescence-related genes and senescence-associated β-galactosidase staining. Gain- and loss-of-function approaches were used to investigate the involvement of microRNAs in stearic acid-evoked β-cell senescence and dysfunction. Bioinformatics analyses and luciferase reporter activity assays were applied to predict the direct targets of microRNAs.
Results: Long-term exposure to a high concentration of stearic acid-induced senescence and upregulated miR-146a-5p and miR-8114 expression in both mouse islets and β-TC6 cell lines. Melatonin effectively suppressed this process and reduced the levels of these two miRNAs. A remarkable reversibility of stearic acid-induced β-cell senescence and dysfunction was observed after silencing miR-146a-5p and miR-8114. Moreover, V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa) was verified as a direct target of miR-146a-5p and miR-8114. Melatonin also significantly ameliorated senescence and dysfunction in miR-146a-5p- and miR-8114-transfected β-cells.
Conclusion: These data demonstrate that melatonin protects against stearic acid-induced β-cell senescence by inhibiting miR-146a-5p and miR-8114 and upregulating Mafa expression. This not only provides novel targets for preventing stearic acid-induced β-cell dysfunction, but also points to melatonin as a promising drug to combat type 2 diabetes progression.

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발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 559-574 (16 pages)

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Taurine, a cysteine-derived zwitterionic sulfonic acid, is a common ingredient in energy drinks and is naturally found in fish and other seafood. In humans, taurine is produced mainly in the liver, and it can also be obtained from food. In target tissues, such as the retina, heart, and skeletal muscle, it functions as an essential antioxidant, osmolyte, and antiapoptotic agent. Taurine is also involved in energy metabolism and calcium homeostasis. Taurine plays a considerable role in bone growth and development, and high-profile reports have demonstrated the importance of its metabolism for bone health. However, these reports have not been collated for more than 10 years. Therefore, this review focuses on taurine-bone interactions and covers recently discovered aspects of taurine's effects on osteoblastogenesis, osteoclastogenesis, bone structure, and bone pathologies (e.g., osteoporosis and fracture healing), with due attention to the taurine-cartilage relationship.

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2Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia

저자 : Joon Ho Moon , Kyuho Kim , Sung Hee Choi

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 575-586 (12 pages)

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High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)-lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.

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3Long-Term Outcomes of Congenital Adrenal Hyperplasia

저자 : Anna Nordenström , Svetlana Lajic , Henrik Falhammar

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A plethora of negative long-term outcomes have been associated with congenital adrenal hyperplasia (CAH). The causes are multiple and involve supra-physiological gluco- and mineralocorticoid replacement, excess adrenal androgens both intrauterine and postnatal, elevated steroid precursor and adrenocorticotropic hormone levels, living with a congenital condition as well as the proximity of the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene to other genes. This review aims to discuss the different long-term outcomes of CAH.

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4Clinical and Technical Aspects in Free Cortisol Measurement

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발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 599-607 (9 pages)

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Accurate measurement of cortisol is critical in adrenal insufficiency as it reduces the risk associated with misdiagnosis and supports the optimization of stress dose. Comprehensive assays have been developed to determine the levels of bioactive free cortisol and their clinical and analytical efficacies have been extensively discussed because the level of total cortisol is affected by changes in the structure or circulating levels of corticoid-binding globulin and albumin, which are the main reservoirs of cortisol in the human body. Antibody-based immunoassays are routinely used in clinical laboratories; however, the lack of molecular specificity in cortisol assessment limits their applicability to characterize adrenocortical function. Improved specificity and sensitivity can be achieved by mass spectrometry coupled with chromatographic separation methods, which is a cutting-edge technology to measure individual as well as a panel of steroids in a single analytical run. The purpose of this review is to introduce recent advances in free cortisol measurement from the perspectives of clinical specimens and issues associated with prospective analytical technologies.

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5Advances in Pituitary Surgery

저자 : Yoon Hwan Byun , Ho Kang , Yong Hwy Kim

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 608-616 (9 pages)

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Pituitary surgery has advanced considerably in recent years with the exploration and development of various endoscopic approaches and techniques. Different endoscopic skull base approaches are being applied to access sellar tumors in different locations. Moreover, extracapsular dissection and cavernous sinus exploration have enabled gross total resection of sellar tumors where it could not have been achieved in the past. Techniques for skull base reconstruction have also progressed, allowing surgeons to remove larger and more complicated tumors than before. This review article discusses different endoscopic skull base approaches, surgical techniques for removing pituitary adenomas, and reconstruction methods for repairing postoperative low-flow and high-flow cerebrospinal fluid leakage.

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6A Meaningful Journey to Predict Fractures with Deep Learning

저자 : Jeonghoon Ha

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 617-619 (3 pages)

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7The Effects of Irisin on the Interaction between Hepatic Stellate Cell and Macrophage in Liver Fibrosis

저자 : Dinh Vinh Do , So Young Park , Giang Thi Nguyen , Dae Hee Choi , Eun-hee Cho

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 620-630 (11 pages)

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Background: Hepatic stellate cells (HSCs) are the central players interacting with multiple cell types in liver fibrosis. The crosstalk between HSCs and macrophages has recently become clearer. Irisin, an exercise-responsive myokine, was known to have a potentially protective role in liver and renal fibrosis, especially in connection with stellate cells. This study investigated the effects of irisin on the interaction between HSCs and macrophages.
Methods: Tamm-Horsfall protein-1 (THP-1) human monocytes were differentiated into macrophages, polarized into the inflammatory M1 phenotype with lipopolysaccharide. Lieming Xu-2 (LX-2) cells, human HSCs, were treated with conditioned media (CM) from M1 macrophages, with or without recombinant irisin. HSCs responses to CM from M1 macrophages were evaluated regarding activation, proliferation, wound healing, trans-well migration, contractility, and related signaling pathway.
Results: CM from M1 macrophages significantly promoted HSC proliferation, wound healing, transwell migration, and contractility, but not activation of HSCs. Irisin co-treatment attenuated these responses of HSCs to CM. However, CM and irisin treatment did not induce any changes in HSC activation. Further, irisin co-treatment alleviated CM-induced increase of phopho-protein kinase B (pAKT), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1).
Conclusion: These findings suggested that irisin may play a protective role in the pathogenesis of liver fibrosis, especially when working in the crosstalk between HSCs and macrophages.

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8High Cardiorespiratory Fitness Protects against Molecular Impairments of Metabolism, Heart, and Brain with Higher Efficacy in Obesity-Induced Premature Aging

저자 : Patcharapong Pantiya , Chanisa Thonusin , Natticha Sumneang , Benjamin Ongnok , Titikorn Chunchai , Sasiwan Kerdphoo , Thidarat Jaiwongkam , Busarin Arunsak , Natthaphat Siri-angkul , Sirawit Sriwichaiin , Nipon Ch

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 630-660 (31 pages)

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Background: High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats.
Methods: Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a high-fat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies.
Results: The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer's disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats.
Conclusion: The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

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9Characteristics of Glycemic Control and Long-Term Complications in Patients with Young-Onset Type 2 Diabetes

저자 : Han-sang Baek , Ji-yeon Park , Jin Yu , Joonyub Lee , Yeoree Yang , Jeonghoon Ha , Seung Hwan Lee , Jae Hyoung Cho , Dong-jun Lim , Hun-sung Kim

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 641-651 (11 pages)

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Background: The prevalence of young-onset diabetes (YOD) has been increasing worldwide. As the incidence of YOD increases, it is necessary to determine the characteristics of YOD and the factors that influence its development and associated complications.
Methods: In this retrospective study, we recruited patients who were diagnosed with type 2 diabetes mellitus between June 2001 and December 2021 at a tertiary hospital. The study population was categorized according to age: YOD (age <40 years), middle-age-onset diabetes (MOD, 40≤ age <65 years), and late-onset diabetes (LOD, age ≥65 years). We examined trends in glycemic control by analyzing fasting glucose levels during the first year in each age group. A Cox proportional-hazards model was used to determine the relative risk of developing complications according to glycemic control trends.
Results: The fasting glucose level at the time of diagnosis was highest in the YOD group (YOD 149±65 mg/dL; MOD 143±54 mg/dL; and LOD 140±55 mg/dL; P=0.009). In the YOD group, glucose levels decreased at 3 months, but increased by 12 months. YOD patients and those with poor glycemic control in the first year were at a higher risk of developing complications, whereas the risk in patients with LOD was not statistically significant.
Conclusion: YOD patients had higher glucose levels at diagnosis, and their glycemic control was poorly maintained. As poor glycemic control can influence the development of complications, especially in young patients, intensive treatment is necessary for patients with YOD.

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10Frequency of TERT Promoter Mutations in Real-World Analysis of 2,092 Thyroid Carcinoma Patients

저자 : Heera Yang , Hyunju Park , Hyun Jin Ryu , Jung Heo , Jung-sun Kim , Young Lyun Oh , Jun-ho Choe , Jung Han Kim , Jee Soo Kim , Hye Won Jang , Tae Hyuk Kim , Sun Wook Kim , Jae Hoon Chung

발행기관 : 대한내분비학회 간행물 : Endocrinology and Metabolism(구 대한내분비학회지) 37권 4호 발행 연도 : 2022 페이지 : pp. 652-669 (18 pages)

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Background: Telomerase reverse transcriptase (TERT) promoter mutations are associated with increased recurrence and mortality in patients with thyroid carcinoma. Previous studies on TERT promoter mutations were retrospectively conducted on a limited number of patients.
Methods: We prospectively collected data on all consecutive patients who underwent thyroid carcinoma surgery between January 2019 and December 2020 at the Samsung Medical Center, Seoul, Korea. We included 2,092 patients with thyroid carcinoma.
Results: Of 2,092 patients, 72 patients (3.4%) had TERT promoter mutations. However, the frequency of TERT promoter mutations was 0.5% in papillary thyroid microcarcinoma (PTMC) ≤1 cm and it was 5.8% in papillary thyroid carcinoma (PTC) >1 cm. The frequency of TERT promoter mutations was significantly associated with older age at diagnosis (odds ratio [OR], 1.12; P<0.001), larger primary tumor size (OR, 2.02; P<0.001), and aggressive histological type (OR, 7.78 in follicular thyroid carcinoma; OR, 10.33 in poorly differentiated thyroid carcinoma; OR, 45.92 in anaplastic thyroid carcinoma; P<0.001). Advanced T stage, advanced N stage, and distant metastasis at diagnosis were highly prevalent in mutated thyroid cancers. However, initial distant metastasis was not present in patients with TERT promoter mutations in PTMC. Although the C228T mutation was more highly detected than the C250T mutation (64 cases vs. 7 cases), there were no significant clinicopathological differences.
Conclusion: This study is the first attempt to investigate the frequency of TERT promoter mutations in a real-world setting. The frequency of TERT promoter mutations in PTC was lower than expected, and in PTMC, young patients, and female patients, the frequency was very low.

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