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Han Chen Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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Ming Ni Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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Yun Xu Department of Obstetrics and Gynaecology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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Li-Yong Zhong Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

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Children with intracranial germ cell tumors may present premature sexual development via either gonadotrophin-releasing hormone (GnRH)-dependent cause or GnRH-independent cause. We conducted a single-center retrospective study on 37 precocious puberty (PP) patients with intracranial germ cell tumors and 25 age-matched prepubertal patients with elevated human chorionic gonadotropin (hCG) levels. Classification of PP was derived from hCG, gonadotropin and sex steroid levels and their changes. Five boys were assigned to GnRH-dependent group (G1). Thirty-one boys and one girl were assigned to GnRH-independent group (G2) with a median hCG of 76.75 (8.29–2747) IU/L. Seven boys and 18 girls were conducted as controls, with a median hCG of 17.12 (2.91–1062) IU/L. Patients in G1 had constant pubertal LH and testosterone levels after tumor complete response. Patients in G2 had hCG levels that decreased simultaneously with testosterone/estradiol levels, prior to tumor regression. The differences in hCG levels and the gender ratio were significant between G2 and controls (P = 0.006 and P < 0.001, separately). Among intracranial germ cell tumor patients with positive hCG, boys with significantly higher hCG levels more easily developed PP. Our results suggest that GnRH-independent PP commonly regresses together with tumor regression. In comparison, results were inconclusive in tying tumor regression to the regression of GnRH-dependent PP.

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Hong-Jun Song Department of Nuclear Medicine, Postgraduate Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China

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Yan-Li Xue Department of Nuclear Medicine, Postgraduate Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China
Department of Nuclear Medicine, Postgraduate Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China

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Yan-Hong Xu Department of Nuclear Medicine, Postgraduate Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China
Department of Nuclear Medicine, Postgraduate Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China

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Zhong-Ling Qiu Department of Nuclear Medicine, Postgraduate Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China

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Quan-Yong Luo Department of Nuclear Medicine, Postgraduate Department, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China

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Differentiated thyroid cancer (DTC) is usually indolent with good prognosis and long-term survival. However, DTC distant metastasis is often a grave event and accounts for most of its disease-specific mortality. The major sites of distant metastases are the lung and bone. Metastases to the brain, breast, liver, kidney, muscle, and skin are rare or relatively rare. Nevertheless, recognizing rare metastases from DTC has a significant impact on the clinical decision making and prognosis of patients. 131I single photon emission computed tomography/computed tomography (131I-SPECT/CT) can provide both metabolic and anatomic information about a lesion; therefore, it can better localize and define the 131I-WBS findings in DTC patients. In this pictorial review, the imaging features of a range of rare metastases from DTC are demonstrated, with a particular emphasis on the 131I-SPECT/CT diagnostic aspect.

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Sijin Li Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China

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Zhen Chen Department of Thyroid Surgery, Guangzhou First People’s Hospital, Guangzhou, China

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Mengchu Liu School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, China

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Liang Li Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Wensong Cai Department of Thyroid Surgery, Guangzhou First People’s Hospital, Guangzhou, China

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Zhe-Xiong Lian Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Haixia Guan Department of Endocrinology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Bo Xu Department of Thyroid Surgery, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China

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The activation of Treg cell subsets is critical for the prognosis of tumor patients; however, their heterogeneity and disease association in papillary thyroid carcinoma (PTC) need further investigation. We performed high-dimensional flow cytometry for immunophenotyping on thyroid tissues and matched peripheral blood samples from patients with multinodular goiters or PTC. We analyzed CD4+ T cell and Treg cell phenotypes and compared the recurrence-free survival of PTC patients with different Treg cell subset characteristics using TCGA. Furthermore, PTC recurrent and non-recurrent group were compared by multiplex immunohistochemistry. High-dimensional flow cytometry and bioinformatics analysis revealed an enrichment of Tregs in tumors compared with multinodular goiters and peripheral blood specimens. Moreover, effector Tregs (e-Tregs) as well as FOXP3+ non-Tregs were enriched in tumor samples, and the expression of CD39, PD-1, and CD103 increased on tumor Tregs. TCGA data analysis showed that individuals with CD39hi PD-1loCD103loe-Treghi and CD39loPD-1loCD103hie-Treghi expression patterns had a high recurrence rate. According to the multiplex immunohistochemistry and analysis, compared with non-recurrent group, the proportion of high recurrence rate effector Treg clusters (CD39+PD-1CD103 plus CD39PD-1CD103+) was increased in recurrent patients. Overall, our results highlight the potential of e-Treg subsets as future immunotherapy targets for PTC recurrence.

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Jingqi Fu Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Hongzhi Zheng Department of Geriatric Endocrinology, The First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China

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Qi Cui Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Chengjie Chen Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Simeng Bao Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Jing Sun Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Lu Li Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Bei Yang Department of Histology and Embryology, School of Basic Medical Sciences, China Medical University, Shenyang, People’s Republic of China

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Huihui Wang Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Yongyong Hou Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Yuanyuan Xu Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Yuanhong Xu Department of Pancreatic Surgery, The First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China

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Qiang Zhang Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA

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Jingbo Pi Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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The transcription factor nuclear factor erythroid 2-like 1 (NFE2L1 or NRF1) is involved in various critical cell processes such as maintenance of ubiquitin-proteasome system and regulation of the cellular antioxidant response. We previously determined that pancreatic β-cell-specific Nfe2l1-knockout mice had hyperinsulinemia and that silencing of Nfe2l1 in mouse islets or MIN6 insulinoma β-cells induced elevated basal insulin release and altered glucose metabolism. Hypoglycemia is a major issue with aggressive insulinomas, although a role of NFE2L1 in this pathology is not defined. In the present work, we studied the tumorigenicity of Nfe2l1-deficient insulinoma MIN6 cells (Nfe2l1-KD) and sensitivity to chemotherapy. Nfe2l1-KD cells grew faster and were more aggressive than Scramble cells in vitro. In a mouse allograft transplantation model, insulinomas arising from Nfe2l1-KD cells were more aggressive and chemoresistant. The conclusion was amplified using streptozotocin (STZ) administration in an allograft transplantation model in diabetic Akita background mice. Furthermore, Nfe2l1-KD cells were resistant to damage by the chemotherapeutic drugs STZ and 5-fluorouracil, which was linked to binding of hexokinase 1 with mitochondria, enhanced mitochondrial membrane potential and closed mitochondrial potential transition pore. Overall, both in vitro and in vivo data from Nfe2l1-KD insulinoma cells provided evidence of a previously un-appreciated action of NFE2L1 in suppression of tumorigenesis. Nfe2l1 silencing desensitizes insulinoma cells and derived tumors to chemotherapeutic-induced damage, likely via metabolic reprograming. These data indicate that NFE2L1 could potentially play an important role in the carcinogenic process and impact chemosensitivity, at least within a subset of pancreatic endocrine tumors.

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Pei-Pei Xu Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Su Zeng Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Xiao-Tian Xia Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Zi-Heng Ye Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Mei-Fang Li Department of Emergency, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Ming-Yun Chen Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai, China

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Tian Xia CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

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Jing-Jing Xu Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China

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Qiong Jiao Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Liang Liu Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Lian-Xi Li Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai, China

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Ming-Gao Guo Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Our aims were to uncover the role of FAM172A (Family with sequence similarity 172 member A) in the pathogenesis of follicular thyroid carcinoma (FTC) and to evaluate its value in the differential diagnosis between malignant and benign thyroid follicular lesions. FAM172A expression was evaluated by q-PCR, immunoblotting and immunohistochemistry (IHC). The ability of proliferation, migration and invasion of cells were assessed by Cell Counting Kit-8 assay (CCK8), clone-formation and Transwell assays. Nude mouse tumorigenicity assays were used to investigate the role of FAM172A in the pathogenesis of FTC in vivo. The value of FAM172A in the differential diagnosis for FTC was assessed using 120 formalin-fixed paraffin-embedded (FFPE) tissues after the operation and 81 fine-needle aspiration biopsy (FNAB) samples before the operation. FAM172A was highly expressed in FTC tissues and FTC cell lines. Downregulation of FAM172A inhibited the proliferation, invasion and migration of FTC cells through Erk1/2 and JNK pathways. Subcutaneous tumorigenesis in nude mice showed that knockdown of FAM172A inhibited tumor growth and progression in vivo. The FAM172A IHC scores of 3.5 had 92% sensitivity and 63% specificity to separate FTC from benign/borderline thyroid follicular lesions, and 92% sensitivity and 80% specificity to discriminate FTC from benign thyroid follicular lesions in postoperative FFPE samples. The corresponding values were 75 and 78%, and 75 and 89% in preoperative FNA samples, respectively. FAM172A plays an important role in the pathogenesis of FTC through Erk1/2 and JNK pathways. FAM172A may be a potential marker for the preoperative diagnosis of FTC based on the IHC results of thyroid FNAB samples.

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W-D Han Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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Y-M Mu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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X-C Lu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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Z-M Xu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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X-J Li Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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L Yu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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H-J Song Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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M Li Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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J-M Lu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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Y-L Zhao Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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C-Y Pan Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People's Republic of China.

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LRP16 is a novel gene cloned from lymphocytic cells, and its function is not known. The expression level of LRP16 mRNA was up-regulated by estrogen in breast cancer MCF-7 cells based on the computed aided serial analysis of gene expression (SAGE) analysis. In this study, we investigate the effect of 17beta-estradiol (17beta-E(2)) on the expression of LRP16 mRNA and the effects of overexpression of LRP16 on the proliferation of cultured MCF-7 cells and the possible mechanisms involved. The expression level of LRP16 mRNA induced by 17beta-E(2) was determined by Northern blot analysis. LRP16 promoter-controlled luciferase expression vector (pGL3-S(0)) was co-transfected with various nuclear receptors, including estrogen receptor alpha and beta (ERalpha and ERbeta), glucocorticoid receptor alpha (GRalpha), androgen receptor (AR) and peroxisome-proliferator activated receptor gamma and alpha (PPARgamma and PPARgamma) into COS-7 cells, and the relative luciferase activity was measured using Dual-luciferase report assay systems. The effect of overexpression of LRP16 on MCF-7 proliferation was examined by the Trypan Blue exclusion method, and the cell cycle was analyzed by flow cytometry. The expression levels of cyclin E, p53 and p21(WAF1/CIP1) proteins were determined by Western blot analysis. The results showed (1) 17beta-E(2) induced a five- to eightfold increase in LRP16 mRNA levels in MCF-7 cells; (2) the relative luciferase activities in the COS-7 cells co-transfected by pGL3-S(0) and ERalpha or AR were 7.8-fold and 11-fold respectively of those in the control cells transfected by pGL3-S(0) alone; (3) overexpression of LRP16 stimulated MCF-7 cell proliferation, and the numbers of cells in the S-phase of the cell cycle in cells transfected with LRP16 increased about 10% compared with the control cells; and (4) cyclin E levels were much higher in cells with overexpression of LRP16 than in the control cells, while the expression levels of p53 and p21(WAF1/CIP1) were not different between the two groups of cells. From these results we concluded that estrogen up-regulates the expression level of LRP16 mRNA through activation of ERalpha and that overexpression of LRP16 promotes MCF-7 cell proliferation probably by increasing cyclin E.

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Wenwen Li Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, China
Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China

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Teng Wang Shandong University Cancer Center, Cheeloo College of Medicine, Jinan, Shandong Province, China

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Guobin Fu Department of Medical Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China

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Yuan Xu Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, China
Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China

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Nasha Zhang Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China

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Linyu Han Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China

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Ming Yang Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China

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Papillary thyroid cancer (PTC) is one of the histological subtypes of thyroid cancer which is the most common endocrine malignancy in the world. The disrupted balance of the adenosine-to-inosine (A-to-I) RNA editing due to dysregulation of the editing genes exists in thyroid cancer. However, it is still largely unknown how functional single-nucleotide polymorphisms (SNPs) in the A-to-I RNA editing genes contribute to PTC genetic susceptibility. In this study, we systematically annotated and investigated the role of 28 potential functional SNPs of ADAR, ADARB1, ADARB2 and AIMP2 in PTC. We identified ADARB2 rs904957 and rs1007147 genetic variants which are associated with significantly elevated PTC risk in two case–control sets consisting of 2020 PTC cases and 2021 controls. Further investigations disclosed that ADARB2 could inhibit cell viability and invasion capabilities of PTC cells as a novel tumor suppressor. The ADARB2 rs904957 thymine-to-cytosine (T-to-C) polymorphism in gene 3'-untranslated region enhances miR-1180-3p-binding affinity and represses ADARB2 expression through an allele-specific manner. In line with this, carriers with the rs904957 C allele correlated with decreased tumor suppressor ADARB2 expression in tissue specimens showed notably increased risk of developing PTC compared to the T allele carriers. Our findings highlight that the A-to-I RNA editing gene ADARB2 SNPs confer PTC risk. Importantly, these insights would improve our understanding for the general roles of RNA editing and editing genes during cancer development.

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Xi Wei Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Shang Cai Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA
Department of Radiotherapy and Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China

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Rebecca J Boohaker Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA

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Joshua Fried Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA

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Ying Li The Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Linfei Hu Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yi Pan Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Ruifen Cheng Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Sheng Zhang Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Ye Tian Department of Radiotherapy and Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China

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Ming Gao Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Bo Xu Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA
Department of Molecular Radiation Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

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Anaplastic thyroid cancer (ATC) is an aggressive cancer with poor clinical prognosis. However, mechanisms driving ATC aggressiveness is not well known. Components of the DNA damage response (DDR) are frequently found mutated or aberrantly expressed in ATC. The goal of this study is to establish the functional link between histone acetyltransferase lysine (K) acetyltransferase 5 (KAT5, a critical DDR protein) and ATC invasiveness using clinical, in vitro and in vivo models. We analyzed the expression of KAT5 by immunohistochemistry and assessed its relationship with metastasis and overall survival in 82 ATC patients. Using cellular models, we established functional connection of KAT5 expression and C-MYC stabilization. We then studied the impact of genetically modified KAT5 expression on ATC metastasis in nude mice. In clinical samples, there is a strong correlation of KAT5 expression with ATC metastasis (P = 0.0009) and overall survival (P = 0.0017). At the cellular level, upregulation of KAT5 significantly promotes thyroid cancer cell proliferation and invasion. We also find that KAT5 enhances the C-MYC protein level by inhibiting ubiquitin-mediated degradation. Further evidence reveals that KAT5 acetylates and stabilizes C-MYC. Finally, we prove that altered KAT5 expression influences ATC lung metastases in vivo. KAT5 promotes ATC invasion and metastases through stabilization of C-MYC, demonstrating it as a new biomarker and therapeutic target for ATC.

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Feng Xu National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Yali Ling National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Jingjing Yuan National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Qin Zeng National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Lusha Li National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Dexing Dai National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Xuedi Xia National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Ruoman Sun National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Ran Zhang Department of Medical Laboratory, Hunan Normal University School of Medicine, Changsha, Hunan, China

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Zhongjian Xie National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

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Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy and highly expresses the receptor for 1,25-dihydroxyvitamin D (1,25(OH)2D). However, it is unclear whether 1,25(OH)2D regulates DTC proliferation and differentiation. Here, we found that 1,25(OH)2D3 inhibited proliferation but not differentiation of the DTC cells. Notably, CYP27B1was elevated in DTC cells and 25-hydroxyvitamin D3 (25(OH)D3) reduced DTC cell proliferation. Knockdown of VDR did not affect the anti-proliferative effects of 1,25(OH)2D3. However, knockdown of CCAAT enhancer-binding protein β (C/EBPβ)abolished 1,25(OH)2D3-suppressed DTC cell proliferation. In addition, 1,25(OH)2D3 induced phosphorylation and translocation of C/EBPβto the nucleus from the cytoplasm. However, inhibition of p38 mitogen-activated protein kinases (MAPK) abrogated 1,25(OH)2D3-induced phosphorylation and nuclear translocation of C/EBPβas well as 1,25(OH)2D3-suppressed DTC cell proliferation. Knockdown of C/EBPβreduced the expression of Notch3. Knockdown of Notch3 blocked 1,25(OH)2D3-suppressed DTC cell proliferation. In the DTC cell-derived xenograft SCID mouse, knockdown of C/EBPβmarkedly increased tumor growth and proliferation and decreased apoptosis. In DTC patients, C/EBPβwas predominantly located in the cytoplasm of DTC cells in the tumor tissue when compared with adjacent non-cancerous tissue in which C/EBPβis located in the nucleus. In conclusion, C/EBPβstimulated Notch3signaling via the p38 MAPK-dependent pathway mediates the inhibitory effect of 1,25(OH)2D on DTC cell proliferation.

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Fei Li Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Guangqi Chen Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Chunjun Sheng Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Aaron M Gusdon Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Yueye Huang Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Zhongwei Lv Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Huixiong Xu Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Mingzhao Xing Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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Shen Qu Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Department of Endocrinology Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yan Chang Middle Road, Shanghai 200072, China

First Clinical Medical College Nanjing Medical University, Nanjing 210029, China

Jiangsu Institute of Nuclear Medicine Wuxi 214063, China

Department of Cardiology Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

Department of Neurology and Neuroscience Weill Cornell Medical College, New York, New York 10065, USA

Departments of Nuclear Medicine

Ultrasound Medicine Shanghai Tenth People's Hospital, Shanghai 200072, China

Thyroid Institute Tongji University, Shanghai 200072, China

Division of Endocrinology Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA

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The prognostic value of the BRAFV600E mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma, has been generally confirmed. However, the association of BRAFV600E with aggressive clinical behaviors of papillary thyroid microcarcinoma (PTMC) has not been firmly established in individual studies. We performed this meta-analysis to examine the relationship between BRAFV600E mutation and the clinicopathological features of PTMC. We conducted a systematic search in PubMed, EMBASE, and the Cochrane library for relevant studies. We selected all the studies that reported clinicopathological features of PTMC patients with information available on BRAFV600E mutation status. Nineteen studies involving a total of 3437 patients met these selection criteria and were included in the analyses. The average prevalence of the BRAFV600E mutation was 47.48%, with no significant difference with respect to patient sex (male versus female) and age (younger than 45 years versus 45 years or older). Compared with the WT BRAF gene, the BRAFV600E mutation was associated with tumor multifocality (odds ratio (OR) 1.38; 95% CI, 1.04–1.82), extrathyroidal extension (OR 3.09; 95% CI, 2.24–4.26), lymph node metastases (OR 2.43; 95% CI, 1.28–4.60), and advanced stage (OR 2.39; 95% CI, 1.38–4.15) of PTMC. Thus, our findings from this large meta-analysis definitively demonstrate that BRAFV600E-mutation-positive PTMC are more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the BRAFV600E mutation is likely to be useful in assisting the risk stratification and management of PTMC.

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