Endocrinology and Metabolism

Original Articles

Calcium & bone metabolism
Persistence with Denosumab in Male Osteoporosis Patients: A Real-World, Non-Interventional Multicenter Study: Chaiho Jeong, Jeongmin Lee, Jinyoung Kim, Jeonghoon Ha, Kwanhoon Jo, Yejee Lim, Mee Kyoung Kim, Hyuk-Sang Kwon, Tae-Seo Sohn, Ki-Ho Song, Moo Il Kang, Ki-Hyun Baek; Endocrinol Metab. 2023;38(2):260-268. Published online April 27, 2023; DOI: https://doi.org/10.3803/EnM.2023.1663

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Background
Persistence with denosumab in male patients has not been adequately investigated, although poor denosumab persistence is associated with a significant risk of rebound vertebral fractures.
Methods
We retrospectively evaluated 294 Korean male osteoporosis patients treated with denosumab at three medical centers and examined their persistence with four doses of denosumab injection over 24 months of treatment. Persistence was defined as the extent to which a patient adhered to denosumab treatment in terms of the prescribed interval and dose, with a permissible gap of 8 weeks. For patients who missed their scheduled treatment appointment(s) during the follow-up period (i.e., no-shows), Cox proportional regression analysis was conducted to explore the factors associated with poor adherence. Several factors were considered, such as age, prior anti-osteoporotic drug use, the treatment provider’s medical specialty, the proximity to the medical center, and financial burdens of treatment.
Results
Out of 294 male patients, 77 (26.2%) completed all four sequential rounds of the denosumab treatment. Out of 217 patients who did not complete the denosumab treatment, 138 (63.6%) missed the scheduled treatment(s). Missing treatment was significantly associated with age (odds ratio [OR], 1.03), prior bisphosphonate use (OR, 0.76), and prescription by non-endocrinologists (OR, 2.24). Denosumab was stopped in 44 (20.3%) patients due to medical errors, in 24 (11.1%) patients due to a T-score improvement over –2.5, and in five (2.3%) patients due to expected dental procedures.
Conclusion
Our study showed that only one-fourth of Korean male osteoporosis patients were fully adherent to 24 months of denosumab treatment.

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Denosumab

Reactions Weekly.2023; 1963(1): 206. CrossRef

Thyroid Big Data Articles (National Health Insurance Service Database)
Repeated Low High-Density Lipoprotein Cholesterol and the Risk of Thyroid Cancer: A Nationwide Population- Based Study in Korea: Jinyoung Kim, Mee Kyoung Kim, Ki-Hyun Baek, Ki-Ho Song, Kyungdo Han, Hyuk-Sang Kwon; Endocrinol Metab. 2022;37(2):303-311. Published online April 6, 2022; DOI: https://doi.org/10.3803/EnM.2021.1332

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Background
High-density lipoprotein cholesterol (HDL-C) plays an important role in the reverse cholesterol transport pathway and prevents atherosclerosis-mediated disease. It has also been suggested that HDL-C may be a protective factor against cancer. However, an inverse correlation between HDL-C and cancer has not been established, and few studies have explored thyroid cancer.
Methods
The study participants received health checkups provided by the Korean National Health Insurance Service from 2009 to 2013 and were followed until 2019. Considering the variability of serum HDL-C level, low HDL-C level was analyzed by grouping based on four consecutive health checkups. The data analysis was performed using univariate and multivariate Cox proportional hazard regression models.
Results
A total of 3,134,278 total study participants, thyroid cancer occurred in 16,129. In the crude model, the hazard ratios for the association between repeatedly measured low HDL-C levels and thyroid cancer were 1.243, 1.404, 1.486, and 1.680 (P for trend <0.01), respectively, which were significant even after adjusting for age, sex, lifestyle factors, and metabolic diseases. The subgroup analysis revealed that low HDL-C levels likely had a greater impact on the group of patients with central obesity (P for interaction= 0.062), high blood pressure (P for interaction=0.057), impaired fasting glucose (P for interaction=0.051), and hyperlipidemia (P for interaction=0.126).
Conclusion
Repeatedly measured low HDL-C levels can be considered a risk factor for cancer as well as vascular disease. Low HDL-C levels were associated with the risk of thyroid cancer, and this correlation was stronger in a metabolically unhealthy population.

Citations

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Association between total cholesterol levels and all-cause mortality among newly diagnosed patients with cancer
Seohyun Kim, Gyuri Kim, So Hyun Cho, Rosa Oh, Ji Yoon Kim, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Jae Hyeon Kim
Scientific Reports.2024;[Epub] CrossRef
Association between organophosphate flame retardant exposure and lipid metabolism: data from the 2013–2014 National Health and Nutrition Examination Survey
Fu-Jen Cheng, Kai-Fan Tsai, Kuo-Chen Huang, Chia-Te Kung, Wan-Ting Huang, Huey-Ling You, Shau-Hsuan Li, Chin-Chou Wang, Wen-Chin Lee, Hsiu-Yung Pan
Frontiers in Public Health.2024;[Epub] CrossRef
Low serum total cholesterol levels predict inferior prognosis of patients with POEMS syndrome
Jue Zhang, Ting Zhang, Ye Yao, Xuxing Shen, Yuanyuan Jin, Run Zhang, Lijuan Chen
Discover Oncology.2024;[Epub] CrossRef
Lipoprotein alterations in endocrine disorders - a review of the recent developments in the field
Michal Olejarz, Ewelina Szczepanek-Parulska, Marek Ruchala
Frontiers in Endocrinology.2024;[Epub] CrossRef
Carbohydrate, Lipid, and Apolipoprotein Biomarkers in Blood and Risk of Thyroid Cancer: Findings from the AMORIS Cohort
Xue Xiao, Yi Huang, Fetemeh Sadeghi, Maria Feychting, Niklas Hammar, Fang Fang, Zhe Zhang, Qianwei Liu
Cancers.2023; 15(2): 520. CrossRef
Altered serum lipid levels are associated with prognosis of diffuse large B cell lymphoma and influenced by utility of rituximab
Fei Wang, Luo Lu, HuiJuan Chen, Yanhua Yue, Yanting Sun, Feng Yan, Bai He, Rongrong Lin, Weiying Gu
Annals of Hematology.2023; 102(2): 393. CrossRef
Big Data Research in the Field of Endocrine Diseases Using the Korean National Health Information Database
Sun Wook Cho, Jung Hee Kim, Han Seok Choi, Hwa Young Ahn, Mee Kyoung Kim, Eun Jung Rhee
Endocrinology and Metabolism.2023; 38(1): 10. CrossRef
High-density lipoprotein cholesterol and carcinogenesis
Meijuan Tan, Shijie Yang, Xiequn Xu
Trends in Endocrinology & Metabolism.2023; 34(5): 303. CrossRef
Low Serum Cholesterol Level Is a Significant Prognostic Factor That Improves CLL-IPI in Chronic Lymphocytic Leukaemia
Rui Gao, Kaixin Du, Jinhua Liang, Yi Xia, Jiazhu Wu, Yue Li, Bihui Pan, Li Wang, Jianyong Li, Wei Xu
International Journal of Molecular Sciences.2023; 24(8): 7396. CrossRef
Do metabolic factors increase the risk of thyroid cancer? a Mendelian randomization study
Weiwei Liang, FangFang Sun
Frontiers in Endocrinology.2023;[Epub] CrossRef
Assessment of causal association between differentiated thyroid cancer and disordered serum lipid profile: a Mendelian randomization study
Qiang Ma, Yu Li, Lijuan An, Liang Guo, Xiaokang Liu
Frontiers in Endocrinology.2023;[Epub] CrossRef
Risk factors and diagnostic prediction models for papillary thyroid carcinoma
Xiaowen Zhang, Yuyang Ze, Jianfeng Sang, Xianbiao Shi, Yan Bi, Shanmei Shen, Xinlin Zhang, Dalong Zhu
Frontiers in Endocrinology.2022;[Epub] CrossRef
Exposure to multiple trace elements and thyroid cancer risk in Chinese adults: A case-control study
Jia-liu He, Hua-bing Wu, Wen-lei Hu, Jian-jun Liu, Qian Zhang, Wei Xiao, Ming-jun Hu, Ming Wu, Fen Huang
International Journal of Hygiene and Environmental Health.2022; 246: 114049. CrossRef

Bone Metabolism
Comparison of the Effects of Various Antidiabetic Medication on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus: Jeonghoon Ha, Yejee Lim, Mee Kyoung Kim, Hyuk-Sang Kwon, Ki-Ho Song, Seung Hyun Ko, Moo Il Kang, Sung Dae Moon, Ki-Hyun Baek; Endocrinol Metab. 2021;36(4):895-903. Published online August 9, 2021; DOI: https://doi.org/10.3803/EnM.2021.1026

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Background
Prospective comparative studies on the effects of various antidiabetic agents on bone metabolism are limited. This study aimed to assess changes in bone mass and biochemical bone markers in postmenopausal patients with type 2 diabetes mellitus (T2DM).
Methods
This prospective, multicenter, open-label, comparative trial included 264 patients with T2DM. Patients who had received a metformin, or sulfonylurea/metformin combination (Group 1); a thiazolidinedione combination (Group 2); a dipeptidyl peptidase-4 inhibitor (gemigliptin) combination (Group 3); or an sodium-glucose cotransporter 2 inhibitor (empagliflozin) combination (Group 4) were prospectively treated for 12 months; bone mineral density (BMD) and bone turnover marker (BTM) changes were evaluated.
Results
The femoral neck BMD percentage changes were −0.79%±2.86% (Group 1), −2.50%±3.08% (Group 2), −1.05%±2.74% (Group 3), and −1.24%±2.91% (Group 4) (P<0.05). The total hip BMD percentage changes were −0.57%±1.79% (Group 1), −1.74%±1.48% (Group 2), −0.75%±1.87% (Group 3), and −1.27%±1.72% (Group 4) (P<0.05). Mean serum BTM (C-terminal type 1 collagen telopeptide and procollagen type 1 amino-terminal propeptide) levels measured during the study period did not change over time or differ between groups.
Conclusion
Significant bone loss in the femoral neck and total hip was associated with thiazolidinedione combination regimens. However, bone loss was not significantly associated with combination regimens including gemigliptin or empagliflozin. Caution should be exercised during treatment with antidiabetic medications that adversely affect the bone in patients with diabetes at a high risk of bone loss.

Citations

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Meta-Analysis on the Association Between DPP-4 Inhibitors and Bone Mineral Density and Osteoporosis
Lili Huang, Wei Zhong, Xinghuan Liang, Huijuan Wang, Shi-en Fu, Zuojie Luo
Journal of Clinical Densitometry.2024; 27(1): 101455. CrossRef
A multicentre, double‐blind, placebo‐controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add‐on therapy in type 2 diabetic patients treated with metformin and dapagliflozin
Soo Lim, Seung‐Hwan Lee, Kyung‐Wan Min, Chang Beom Lee, Sang Yong Kim, Hye Jin Yoo, Nan Hee Kim, Jae Hyeon Kim, Seungjoon Oh, Jong Chul Won, Hyuk Sang Kwon, Mi Kyung Kim, Jung Hwan Park, In‐Kyung Jeong, Sungrae Kim
Diabetes, Obesity and Metabolism.2024;[Epub] CrossRef
Association of Bone Turnover Markers with Type 2 Diabetes Mellitus and Microvascular Complications: A Matched Case-Control Study
Yilin Hou, Xiaoyu Hou, Qian Nie, Qiuyang Xia, Rui Hu, Xiaoyue Yang, Guangyao Song, Luping Ren
Diabetes, Metabolic Syndrome and Obesity.2023; Volume 16: 1177. CrossRef
Complementary effects of dapagliflozin and lobeglitazone on metabolism in a diet-induced obese mouse model
Yun Kyung Lee, Tae Jung Oh, Ji In Lee, Bo Yoon Choi, Hyen Chung Cho, Hak Chul Jang, Sung Hee Choi
European Journal of Pharmacology.2023; 957: 175946. CrossRef

Clinical Study
Gemigliptin Inhibits Interleukin-1β–Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway: Oak-Kee Hong, Seong-Su Lee, Soon Jib Yoo, Min-Kyung Lee, Mee-Kyoung Kim, Ki-Hyun Baek, Ki-Ho Song, Hyuk-Sang Kwon; Endocrinol Metab. 2020;35(2):384-395. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.384

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Background
Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1β (IL-1β)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor.
Methods
We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1β/20 μM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins.
Results
Morphological changes showed gemigliptin blocked IL-1β-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1β activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1β induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1β-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1β. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1β-induced EndMT.
Conclusion
We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1β-induced EndMT.

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Injured Endothelial Cell: A Risk Factor for Pulmonary Fibrosis
Weiming Zhao, Lan Wang, Yaxuan Wang, Hongmei Yuan, Mengxia Zhao, Hui Lian, Shuaichen Ma, Kai Xu, Zhongzheng Li, Guoying Yu
International Journal of Molecular Sciences.2023; 24(10): 8749. CrossRef
Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances
Zuxiang Yu, Chaoyu Xu, Bin Song, Shihao Zhang, Chong Chen, Changlong Li, Shuyu Zhang
Journal of Translational Medicine.2023;[Epub] CrossRef
MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors
Mor Zaaroor Levy, Noa Rabinowicz, Maia Yamila Kohon, Avshalom Shalom, Ariel Berl, Tzipi Hornik-Lurie, Liat Drucker, Shelly Tartakover Matalon, Yair Levy
Biomedicines.2022; 10(3): 629. CrossRef
Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies
Li Li, Sainan Liu, Jianying Tan, Lai Wei, Dimeng Wu, Shuai Gao, Yajun Weng, Junying Chen
Journal of Tissue Engineering.2022; 13: 204173142210885. CrossRef
Vascular Calcification: New Insights Into BMP Type I Receptor A
Zhixing Niu, Guanyue Su, Tiantian Li, Hongchi Yu, Yang Shen, Demao Zhang, Xiaoheng Liu
Frontiers in Pharmacology.2022;[Epub] CrossRef
Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway
Zhuojing Tan, Yachen Si, Yan Yu, Jiarong Ding, Linxi Huang, Ying Xu, Hongxia Zhang, Yihan Lu, Chao Wang, Bing Yu, Li Yuan
Frontiers in Pharmacology.2022;[Epub] CrossRef
Panax notoginseng Suppresses Bone Morphogenetic Protein-2 Expression in EA.hy926 Endothelial Cells by Inhibiting the Noncanonical NF-κB and Wnt/β-Catenin Signaling Pathways
Tsu-Ni Ping, Shu-Ling Hsieh, Jyh-Jye Wang, Jin-Bor Chen, Chih-Chung Wu
Plants.2022; 11(23): 3265. CrossRef
Vascular calcification: New insights into endothelial cells
Cheng Yuan, Lihua Ni, Changjiang Zhang, Xiaorong Hu, Xiaoyan Wu
Microvascular Research.2021; 134: 104105. CrossRef
Concentrated small extracellular vesicles from menstrual blood-derived stromal cells improve intrauterine adhesion, a pre-clinical study in a rat model
Siwen Zhang, Qiyuan Chang, Pingping Li, Xiaoyu Tong, Yi Feng, Xinyao Hao, Xudong Zhang, Zhengwei Yuan, Jichun Tan
Nanoscale.2021; 13(15): 7334. CrossRef

Clinical Study
Consistency of the Glycation Gap with the Hemoglobin Glycation Index Derived from a Continuous Glucose Monitoring System: Han Na Joung, Hyuk-Sang Kwon, Ki-Hyun Baek, Ki-Ho Song, Mee Kyoung Kim; Endocrinol Metab. 2020;35(2):377-383. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.377

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Background
Discordances between glycated hemoglobin (HbA1c) levels and glycemic control are common in clinical practice. We aimed to investigate the consistency of the glycation gap with the hemoglobin glycation index (HGI).
Methods
From 2016 to 2019, 36 patients with type 2 diabetes were enrolled. HbA1c, glycated albumin (GA), and fasting blood glucose levels were simultaneously measured and 72-hour continuous glucose monitoring (CGM) was performed on the same day. Repeated tests were performed at baseline and 1 month later, without changing patients’ diabetes management. The HGI was calculated as the difference between the measured HbA1c and the predicted HbA1c that was derived from CGM. The glycation gap was calculated as the difference between the measured and GA-based predicted HbA1c levels.
Results
Strong correlations were found between the mean blood glucose (MBG)-based HGI and the prebreakfast glucose-based HGI (r=0.867, P<0.001) and between the glycation gap and the MBG-based HGI (r=0.810, P<0.001). A close correlation was found between the MBG-based HGI at baseline and that after 1 month (r=0.729, P<0.001), with a y-intercept of 0 and a positive slope.
Conclusion
The HGI and glycation gap were highly reproducible, and the magnitudes of repeated determinations were closely correlated. Patients with similar mean glucose levels may have significantly different HbA1c levels.

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Factors associated with hemoglobin glycation index in adults with type 1 diabetes mellitus: The FGM‐Japan study
Naoki Sakane, Yushi Hirota, Akane Yamamoto, Junnosuke Miura, Hiroko Takaike, Sari Hoshina, Masao Toyoda, Nobumichi Saito, Kiminori Hosoda, Masaki Matsubara, Atsuhito Tone, Satoshi Kawashima, Hideaki Sawaki, Tomokazu Matsuda, Masayuki Domichi, Akiko Suganu
Journal of Diabetes Investigation.2023; 14(4): 582. CrossRef
The Fast-Glycator Phenotype, Skin Advanced Glycation End Products, and Complication Burden Among People With Type 1 Diabetes
Alberto Maran, Mario Luca Morieri, Daniele Falaguasta, Angelo Avogaro, Gian Paolo Fadini
Diabetes Care.2022; 45(10): 2439. CrossRef
Hemoglobin glycation index, calculated from a single fasting glucose value, as a prediction tool for severe hypoglycemia and major adverse cardiovascular events in DEVOTE
Klara R Klein, Edward Franek, Steven Marso, Thomas R Pieber, Richard E Pratley, Amoolya Gowda, Kajsa Kvist, John B Buse
BMJ Open Diabetes Research & Care.2021; 9(2): e002339. CrossRef

Clinical Study
Comparison of Natural Course between Thyroid Cancer Nodules and Thyroid Benign Nodules: Kyun-Jin Yun, Jeonghoon Ha, Min-Hee Kim, Ye Young Seo, Mee Kyoung Kim, Hyuk-Sang Kwon, Ki-Ho Song, Moo Il Kang, Ki-Hyun Baek; Endocrinol Metab. 2019;34(2):195-202. Published online June 24, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.2.195

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Background

The natural course of thyroid cancer nodules and benign nodules is different. This study was to compare the changes in size between thyroid cancer nodules and thyroid benign nodules. The risk factors associated with the changes of thyroid cancer nodules were assessed.

Methods

This study contains retrospective observational and prospective analysis. A total of 113 patients with 120 nodules were recruited in the cancer group, and 116 patients with 119 nodules were enrolled in the benign group. Thyroid ultrasonography was performed at least two times at more than 1-year interval.

Results

The mean follow-up durations were 29.5±18.8 months (cancer group) and 31.9±15.8 months (benign group) (P=0.32). The maximum diameter change in length was 0.36±0.97 mm/year in the cancer group and –0.04±0.77 mm/year in the benign group (P<0.01). The volume was significantly increased in the cancer group compared with the benign group (0.06±0.18 mL/year vs. 0.004±0.05 mL/year, respectively, P<0.01; 26.9%±57.9%/year vs. 1.7%±26.0%/year, P<0.01). Initial maximum diameter (β=0.02, P<0.01) and initial volume (β=0.13, P<0.01) were significantly associated with volume change (mL)/year. Initial maximum standardized uptake value did not predict the nodule growth.

Conclusion

It is suggested that thyroid cancer nodules progress rapidly compared with benign nodules. Initial size and volume of nodule were independent risk factors for cancer nodule growth.

Citations

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RAS-Mutated Cytologically Indeterminate Thyroid Nodules: Prevalence of Malignancy and Behavior Under Active Surveillance
Hannah J. Sfreddo, Elizabeth S. Koh, Karena Zhao, Christina E. Swartzwelder, Brian R. Untch, Jennifer L. Marti, Benjamin R. Roman, Jared Dublin, Ronald S. Wang, Rong Xia, Jean-Marc Cohen, Bin Xu, Ronald Ghossein, Babak Givi, Jay O. Boyle, R. Michael Tuttl
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Ultrasound for the assessment of thyroid nodules: an overview for non-radiologists
Conor Hamill, Peter Ellis, Philip C Johnston
British Journal of Hospital Medicine.2022; 83(7): 1. CrossRef
Цитологічно підтверджений вузловий зоб у членів Українсько-Американського когортного дослідження: дескриптивний аналіз результатів обстеження за 1998- 2015 роки
M.D. Tronko, L.S. Strafun, H.M. Terekhova, H.A. Zamotayeva, I.P. Pasteur
Endokrynologia.2022; 27(1): 5. CrossRef
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José R. González, Charbel Damião, Maira Moran, Cristina A. Pantaleão, Rubens A. Cruz, Giovanna A. Balarini, Aura Conci
Sensors.2021; 21(13): 4459. CrossRef
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Sangeet Ghai, Ciara O’Brien, David P. Goldstein, Anna M. Sawka, Lorne Rotstein, Dale Brown, John de Almeida, Patrick Gullane, Ralph Gilbert, Douglas Chepeha, Jonathan Irish, Jesse Pasternak, Shereen Ezzat, James P. Brierley, Richard W. Tsang, Eric Monteir
Insights into Imaging.2021;[Epub] CrossRef
Association between various thyroid gland diseases, TSH values and thyroid cancer: a case–control study
Leif Schiffmann, Karel Kostev, Matthias Kalder
Journal of Cancer Research and Clinical Oncology.2020; 146(11): 2989. CrossRef
Combination of peroxisome proliferator–activated receptor gamma and retinoid X receptor agonists induces sodium/iodide symporter expression and inhibits cell growth of human thyroid cancer cells
Jui-Yu Chen, Jane-Jen Wang, Hsin-Chen Lee, Chin-Wen Chi, Chen-Hsen Lee, Yi-Chiung Hsu
Journal of the Chinese Medical Association.2020; 83(10): 923. CrossRef
Growth rates of malignant and benign thyroid nodules in an ultrasound follow-up study: a retrospective cohort study
Michael Cordes, Theresa Ida Götz, Karen Horstrup, Torsten Kuwert, Christian Schmidkonz
BMC Cancer.2019;[Epub] CrossRef

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