ThyroidPub Date : 2024-10-01Epub Date: 2024-09-23DOI: 10.1089/thy.2024.0178
Ju-Yeun Lee, Min Kyung Lee, Jae Hyuk Lee, Kyungsik Kim, Kunho Bae, Seo Young Sohn
{"title":"Cancer Risks of Patients with Graves' Disease Who Received Antithyroid Drugs as Initial Treatment: A Nationwide Population-Based Analysis.","authors":"Ju-Yeun Lee, Min Kyung Lee, Jae Hyuk Lee, Kyungsik Kim, Kunho Bae, Seo Young Sohn","doi":"10.1089/thy.2024.0178","DOIUrl":"10.1089/thy.2024.0178","url":null,"abstract":"<p><p><b><i>Background:</i></b> Population-based studies that examine the associations between hyperthyroidism and cancer risk have yielded inconsistent results. It remains unclear whether the risks of different cancers increase in patients with Graves' disease (GD) who received antithyroid drugs (ATDs) as initial treatment. We aimed to determine whether cancer risk increases in patients with GD, compared with controls. <b><i>Methods:</i></b> This nationwide retrospective cohort study utilized data from the National Health Information Database of South Korea. We included 29,502 patients aged >20 years with GD, who received ATDs as initial treatment, and 57,173 age- and sex-matched controls. The primary outcome was the incidence of various types of cancers. Hazard ratios (HRs) with confidence intervals (CIs) for cancer risk were estimated using Cox proportional hazards models. We also analyzed HR by follow-up period since the diagnosis of GD, accounting for surveillance effect. <b><i>Results:</i></b> The risk of biliary tract and pancreatic cancers (HR: 1.41, CI: 1.24-1.60), thyroid cancer (HR: 15.51, CI: 12.29-19.57), prostate cancer (HR: 1.48, CI: 1.28-1.71), and ovarian cancer (HR: 1.31, CI: 1.13-1.52) was elevated in the GD group than in the control group even after the first year of follow-up was excluded. The increased risk of these cancers persisted after a follow-up period of more than 5 years. The risk of thyroid cancer in patients with GD was higher during the initial follow-up period (1 to <2 years) (HR: 19.35, CI: 7.66-48.87) compared with that in the follow-up period exceeding 2 years. The cancer risk estimates remained significant after excluding patients with GD who underwent subsequent radioactive iodine therapy. <b><i>Conclusion:</i></b> In this large-scale population-based study, GD was associated with increased risks of biliary tract and pancreatic, prostate, ovarian, and thyroid cancers. The increased risk of thyroid cancer, particularly during the initial follow-up period, may be a surveillance effect.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1271-1279"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-09-27DOI: 10.1089/thy.2024.0188
Karolina Mastnikova, Barbora Bulanova Pekova, Vlasta Kuklikova, Eliska Vaclavikova, Jitka Carkova, Rami Katra, Lucie Fialova, Petr Vlcek, Daniela Kodetova, Martin Chovanec, Jana Drozenova, Radoslav Matej, Petra Pacesova, Zdenek Novak, Kristyna Procykova, Josef Vcelak, Bela Bendlova
{"title":"<i>DICER1</i> Variants in Pediatric and Young Adult Thyroid Nodules.","authors":"Karolina Mastnikova, Barbora Bulanova Pekova, Vlasta Kuklikova, Eliska Vaclavikova, Jitka Carkova, Rami Katra, Lucie Fialova, Petr Vlcek, Daniela Kodetova, Martin Chovanec, Jana Drozenova, Radoslav Matej, Petra Pacesova, Zdenek Novak, Kristyna Procykova, Josef Vcelak, Bela Bendlova","doi":"10.1089/thy.2024.0188","DOIUrl":"10.1089/thy.2024.0188","url":null,"abstract":"<p><p><b><i>Background:</i></b> Recent studies have suggested that pathogenic variants of the <i>DICER1</i> gene could be a driver of alterations in some pediatric thyroid nodules, but data are still limited. The aim of this study was to detect variants in the <i>DICER1</i> gene in a large cohort of pediatric thyroid nodules and then correlate them with clinicopathological data, with a focus on the disease prognosis in patients with thyroid carcinoma. <b><i>Methods:</i></b> This retrospective cohort study consisted of 350 pediatric and young adult patients (aged 2-21 years) with thyroid nodules, from whom 275 fresh-frozen thyroid nodule samples and 92 fine-needle aspiration biopsy (FNAB) samples were collected. After an analysis of variants in major genetic alterations of thyroid tumors, variants in the <i>DICER1</i> gene were identified using next-generation sequencing and multiplex ligation-dependent probe amplification methods. Peripheral blood was analyzed from patients with <i>DICER1</i>-positive tumors. The results of genetic analysis were then correlated with clinicopathological data. <b><i>Results:</i></b> Variants in the <i>DICER1</i> gene were detected in a total of 24/350 (6.9%; 95%CI [4.4;10.0]) pediatric and young adult patients, respectively, in 10/119 (8.4%; [4.1;14.9]) patients with benign fresh-frozen tissue, in 8/141 (5.7%; [1.9;9.5]) with papillary thyroid carcinoma (PTC) and in 6/86 (7.0%; [4.1;14.6]) patients with FNAB. No other gene alteration was found in <i>DICER1</i>-positive samples. Germline <i>DICER1</i> variants were identified in 11/24 (45.8%; [25.6;67.2]) patients. Two somatic (biallelic) variants in the <i>DICER1</i> gene were found in 9/24 (37.5%; [18.8;59.4]) thyroid nodules. Somatic deletions of at least 3 Mbp long were revealed in 2/24 (8.3%; [1.0;27.0]) cases. <i>DICER1</i>-positive PTCs were significantly associated with the follicular subtype of PTC (<i>p</i> = 0.001), encapsulation (<i>p</i> = 0.006) and were larger in size (<i>p</i> = 0.035), but with no extrathyroidal extension (<i>p</i> = 0.039), and less frequent lymph node metastases (<i>p</i> = 0.003) compared with <i>DICER1</i>-negative PTCs. Patients with <i>DICER1-</i>positive PTC had an excellent response to treatment in 75% of cases. <b><i>Conclusions:</i></b> Variants of the <i>DICER1</i> gene are frequently found in the thyroid nodules of pediatric and young adult patients. In our patients, <i>DICER1</i>-positive PTCs showed low invasiveness. Our findings support considering more conservative management for <i>DICER1</i>-positive low-risk PTCs.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1225-1233"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-09-25DOI: 10.1089/thy.2024.0109
Aleksandra Kropinska, Aleksandra Ledwon, Ewa Paliczka Cieslik, Tomasz Olczyk, Aleksandra Blewaska, Marcela Krzempek, Agata Wilk, Alexander Cortez, Agnieszka Czarniecka, Barbara Jarzab, Daria Handkiewicz Junak
{"title":"Changing Clinical Presentation of Pediatric Differentiated Thyroid Cancer in Poland: A Retrospective Cohort Study Spanning 45 Years.","authors":"Aleksandra Kropinska, Aleksandra Ledwon, Ewa Paliczka Cieslik, Tomasz Olczyk, Aleksandra Blewaska, Marcela Krzempek, Agata Wilk, Alexander Cortez, Agnieszka Czarniecka, Barbara Jarzab, Daria Handkiewicz Junak","doi":"10.1089/thy.2024.0109","DOIUrl":"10.1089/thy.2024.0109","url":null,"abstract":"<p><p><b><i>Background:</i></b> Differentiated thyroid carcinoma (DTC) in children is uncommon; clinical presentation over recent decades is incompletely characterized. <b><i>Methods:</i></b> This retrospective cohort study analyzed demographic and disease characteristics of consecutive juveniles with DTC treated from 1970 to 2015 at Poland's largest pediatric DTC referral center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, who had available records. Sex, age, histopathological characteristics, and DTC stage were documented. We aimed to identify changes in these variables over time and independent risk factors for lymph node or distant metastases. Trends in these variables were assessed using the Cochran-Armitage test and Spearman correlation. Multivariable logistic regression was performed to identify risk factors associated with lymph node or distant metastases. <b><i>Results:</i></b> 475 of 479 patients (99.2%) were included in the analysis; roughly half were age ≥15 years, 10%, <10 years. Papillary thyroid carcinoma (PTC) represented 88% of cases and follicular thyroid carcinoma (FTC) 11%. Tumors ≤2 cm constituted 56% of cases with relevant data; those >4 cm accounted for 12%. Multifocality was observed in 37% and extrathyroidal invasion in 22%. Lymph node metastases were noted in 59% and distant metastases in 16%. Over the observation period, significant trends among new cases included: increased proportion of adolescents >15 years; increased frequency of tumors ≤2 cm, decreased multifocality rates, and increased proportion of PTC versus FTC. Extrathyroidal invasion rates remained appreciable throughout, ranging from 17 to 28% during the 5-year study subperiods after 1990. Lymph node metastases significantly increased in frequency in the central neck, remaining consistently common in lateral sites; presence of distant metastases significantly decreased. In multivariable analysis, multifocality, extrathyroidal invasion, and tumor size were independently associated with lateral lymph node metastases and multifocality, larger tumor size, and N1b metastases with distant spread. <b><i>Conclusions:</i></b> Our observations of a rising proportion of diagnoses in adolescence, reductions in primary tumor size, and decreased frequency of multifocality and distant metastases may reflect increased detection of patients with less aggressive DTC at earlier disease stages. Nonetheless, we found persistently substantial rates of locoregionally advanced disease features (multifocality, extrathyroidal invasion, and lymph node metastases), which multivariable analyses suggested have significant associations with lateral lymph node and/or distant metastases.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1234-1245"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-08-13DOI: 10.1089/thy.2024.0274
Arthur B Schneider, Jay H Lubin, Michael M Kaplan, Dan V Mihailescu
{"title":"Reflections on the American Academy of Oral and Maxillofacial Radiology and the American Dental Association Guidelines for Patient Shielding During Dentomaxillofacial Radiography.","authors":"Arthur B Schneider, Jay H Lubin, Michael M Kaplan, Dan V Mihailescu","doi":"10.1089/thy.2024.0274","DOIUrl":"10.1089/thy.2024.0274","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1314-1316"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-09-04DOI: 10.1089/thy.2024.0240
Antonio Prinzi, Evert F S van Velsen, Antonino Belfiore, Francesco Frasca, Pasqualino Malandrino
{"title":"Brain Metastases in Differentiated Thyroid Cancer: Clinical Presentation, Diagnosis, and Management.","authors":"Antonio Prinzi, Evert F S van Velsen, Antonino Belfiore, Francesco Frasca, Pasqualino Malandrino","doi":"10.1089/thy.2024.0240","DOIUrl":"10.1089/thy.2024.0240","url":null,"abstract":"<p><p><b><i>Background:</i></b> Brain metastases (BM) are the most common intracranial neoplasms in adults and are a significant cause of morbidity and mortality. The brain is an unusual site for distant metastases of thyroid cancer; indeed, the most common sites are lungs and bones. In this narrative review, we discuss about the clinical characteristics, diagnosis, and treatment options for patients with BM from differentiated thyroid cancer (DTC). <b><i>Summary:</i></b> BM can be discovered before initial therapy due to symptoms, but in most patients, BM is diagnosed during follow-up because of imaging performed before starting tyrosine kinase inhibitors (TKI) or due to the onset of neurological symptoms. Older male patients with follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and distant metastases may have an increased risk of developing BM. The gold standard for detection of BM is magnetic resonance imaging with contrast agent administration, which is superior to contrast-enhanced computed tomography. The treatment strategies for patients with BM from DTC remain controversial. Patients with poor performance status are candidates for palliative and supportive care. Neurosurgery is usually reserved for cases where symptoms persist despite medical treatment, especially in patients with favorable prognostic factors and larger lesions. It should also be considered for patients with a single BM in a surgically accessible location, particularly if the primary disease is controlled without other systemic metastases. Additionally, stereotactic radiosurgery (SRS) may be the preferred option for treating small lesions, especially those in inaccessible areas of the brain or when surgery is not advisable. Whole brain radiotherapy is less frequently used in treating these patients due to its potential side effects and the debated effectiveness. Therefore, it is typically reserved for cases involving multiple BM that are too large for SRS. TKIs are effective in patients with progressive radioiodine-refractory thyroid cancer and multiple metastases. <b><i>Conclusions:</i></b> Although routine screening for BM is not recommended, older male patients with FTC or PDTC and distant metastases may be at higher risk and should be carefully evaluated for BM. According to current data, patients who are suitable for neurosurgery seem to have the highest survival benefit, while SRS may be appropriate for selected patient.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1194-1204"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-09-13DOI: 10.1089/thy.2024.0209
Julia Maier, Riccardo Dore, Rebecca Oelkrug, Annika Glatzel, Anna-Lena Cremer, Sonja Binder, Markus Schwaninger, Henrik Oster, Heiko Backes, Jens Mittag
{"title":"Inhibition of Thyroid Hormone Signaling in the Zona Incerta Alters Basal Metabolic Rate, Behavior, and Serum Glucocorticoids in Male Mice.","authors":"Julia Maier, Riccardo Dore, Rebecca Oelkrug, Annika Glatzel, Anna-Lena Cremer, Sonja Binder, Markus Schwaninger, Henrik Oster, Heiko Backes, Jens Mittag","doi":"10.1089/thy.2024.0209","DOIUrl":"10.1089/thy.2024.0209","url":null,"abstract":"<p><p><b><i>Background:</i></b> It has long been known that thyroid disease can lead to changes in energy metabolism, thermoregulation, and anxiety behavior. While these actions have been partially attributed to thyroid hormone (TH) receptor α1 (TRα1) action in the brain, the precise neuroanatomical substrates have remain elusive. <b><i>Methods:</i></b> We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the <i>zona incerta</i> (ZI), a still mysterious region previously implicated in thermogenesis and anxiety. To this end, we used an adeno-associated virus (AAV) expressing a dominant-negative TRα1R384C in wild-type mice and phenotyped the animals. Finally, we used tyrosine hydroxylase-Cre mice to test specifically the contribution of ZI dopaminergic neurons. <b><i>Results:</i></b> Our data showed that AAV-mediated inhibition of TRα1 signaling in the ZI lead to increased energy expenditure at thermoneutrality, while body temperature regulation remained unaffected. Moreover, circulating glucocorticoid levels were increased, and a mild habituation problem was observed in the open field test. No effects were observed when TRα1 signaling was selectively inhibited in dopaminergic neurons. <b><i>Conclusions:</i></b> Our findings suggest that altered TH signaling in the ZI is not involved in body temperature regulation but can affect basal metabolism and modulates stress responses.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1280-1291"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-08-23DOI: 10.1089/thy.2024.0087
Ling Tian, Xing Li, Xiaojiao Zeng, Yuanyuan Han, Ming Qian, Yan Ye, Laixiang Lin, Yongmei Li, Jingyun Zhang, Yuanjun Liu, Yina Sun
{"title":"Increased Thyroid Hormone Action Alleviates Hippocampal Damage by Downregulating Neuronal Type I Interferon Signaling/Necroptosis in Diabetes-Associated Cognitive Dysfunction.","authors":"Ling Tian, Xing Li, Xiaojiao Zeng, Yuanyuan Han, Ming Qian, Yan Ye, Laixiang Lin, Yongmei Li, Jingyun Zhang, Yuanjun Liu, Yina Sun","doi":"10.1089/thy.2024.0087","DOIUrl":"10.1089/thy.2024.0087","url":null,"abstract":"<p><p><b><i>Background:</i></b> Thyroid dysfunction plays an important role in the pathology of diabetes-associated cognitive dysfunction (DACD). However, thyroid hormone (TH) signaling and action changes in DACD brains remain unknown. This study evaluated the alternations in TH signaling and action in the brains of DACD mice and explored the beneficial effects of levothyroxine (L-T4) treatment. <b><i>Methods:</i></b> KK-Ay mice, serving as a spontaneous type 2 diabetes mellitus model, underwent intragastric administration of 10 ng/g and 20 ng/g of L-T4 solution or normal saline for 8 weeks. Age-matched C57BL/6J mice were used as normal controls. Cognitive and memory functions were examined through the open field and Morris water maze tests. Hippocampal TH signaling and pathogenic status were evaluated. The potential signaling pathways involved in the neuroprotective action of L-T4 were investigated through RNA sequencing and further verified through quantitative real-time PCR (qPCR), Western blotting (WB), immunofluorescence (IF), and fluorescent multiplex immunohistochemistry (mIHC) <i>in vivo</i> and vitro. <b><i>Results:</i></b> The expressions of hippocampal TH transporters (Mct8 and Oatp1c1), Dio2, and TH receptor were upregulated, whereas Dio3 as well as the TH-positive regulated genes MBP, Enpp2, and Klf9 were downregulated in DACD mice. Exogenous L-T4 partially alleviated cognitive and memory dysfunction and restored hippocampal neuronal activity by optimizing TH signaling. RNA sequencing provided insights into the role of type I interferon (IFN-I) signaling and necroptosis on the amelioration of hippocampal damage after L-T4 treatment. WB and qPCR further confirmed that the levels of key proteins for IFN-I signaling and necroptosis (p-STAT1, p-STAT2, IRF9, ZBP1, p-RIP3, and p-MLKL) were increased, but largely returned after L-T4 administration <i>in vivo</i> and T3 treatment <i>in vitro</i>. IF and mIHC revealed that IRF9 and p-MLKL colocalized in neurons, but not in astrocytes or microglia, of the hippocampus in DACD mice. The diabetes mellitus group had an increased number of IRF9<sup>+</sup> p-MLKL<sup>+</sup> NeuN<sup>+</sup> cells, which decreased after L-T4 treatment. The elevated IFN-I signaling-mediated necroptosis in HT22 cells was also decreased by T3. <b><i>Conclusion:</i></b> We demonstrated abnormal hippocampal TH signaling and action in DACD. Promoting TH action with exogenous L-T4 ameliorated hippocampal impairment through inhibiting IFN-I signaling-induced necroptosis.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1292-1307"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-07-05DOI: 10.1089/thy.2024.0357
Catherine B Jensen, Susan C Pitt
{"title":"<i>Letter to the Editor:</i> Molecular Testing: Adoption and Disparities in Utilization Across the United States.","authors":"Catherine B Jensen, Susan C Pitt","doi":"10.1089/thy.2024.0357","DOIUrl":"10.1089/thy.2024.0357","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1317-1318"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-09-27DOI: 10.1089/thy.2023.0700
Shi-Shuai Wen, Yi-Jun Wu, Jia-Yang Wang, Zhao-Xian Ni, Shuai Dong, Xiao-Jun Xie, Yu-Ting Wang, Yu Wang, Nai-Si Huang, Qing-Hai Ji, Ben Ma, Ning Qu
{"title":"BRAF<sup>V600E</sup>/p-ERK/p-DRP1(Ser616) Promotes Tumor Progression and Reprogramming of Glucose Metabolism in Papillary Thyroid Cancer.","authors":"Shi-Shuai Wen, Yi-Jun Wu, Jia-Yang Wang, Zhao-Xian Ni, Shuai Dong, Xiao-Jun Xie, Yu-Ting Wang, Yu Wang, Nai-Si Huang, Qing-Hai Ji, Ben Ma, Ning Qu","doi":"10.1089/thy.2023.0700","DOIUrl":"10.1089/thy.2023.0700","url":null,"abstract":"<p><p><b><i>Background:</i></b> Papillary thyroid cancer (PTC) with the BRAF<sup>V600E</sup> mutation is associated with a poorer prognosis. BRAF inhibitors may demonstrate limited efficacy due to emerging drug resistance. The Warburg effect may have cancer therapeutic implications. It is not known if the BRAF<sup>V600E</sup> mutation is associated with altered glucose metabolism in PTC. <b><i>Methods:</i></b> This study examined the effect of BRAF<sup>V600E</sup> and dynamin-related protein 1 (DRP1) on various cellular processes in PTC cells, including cell proliferation, migration, invasion, mitochondrial fission, glucose metabolism, reactive oxygen species (ROS) generation, and apoptosis. We used RT-qPCR to assess the expression of key glycolytic enzymes in thyroid cancer tissues. Additionally, the regulatory interaction between BRAF<sup>V600E</sup> and DRP1 was investigated through Western blot and immunohistochemical staining. We further evaluated the impact of DRP1 in PTC and the inhibitory effects of dabrafenib and 2-deoxy-d-glucose (2-DG) <i>in vitro</i> and <i>in vivo</i>. <b><i>Results:</i></b> We found that the BRAF<sup>V600E</sup> mutation significantly augments aerobic glycolysis while suppressing oxidative phosphorylation in PTC. We identified the BRAF<sup>V600E</sup>/p-ERK/p-DRP1(Ser616) signaling pathway as a critical mediator in PTC progression. First, the BRAF<sup>V600E</sup>/p-ERK/p-DRP1(Ser616) signaling pathway enhances cell proliferation by upregulating hexokinase 2 expression and thereby increasing aerobic glycolysis. Second, it inhibits apoptosis by promoting mitochondrial fission and reducing ROS levels. Moreover, we demonstrated that the combination therapy of 2-DG and dabrafenib markedly impedes the progression of BRAF<sup>V600E</sup>-positive PTC. <b><i>Conclusion:</i></b> The BRAF<sup>V600E</sup>/p-ERK/p-DRP1(Ser616) signaling pathway plays a pivotal role in glucose metabolism reprogramming, contributing to the aggressiveness and progression of BRAF<sup>V600E</sup>-positive PTC. Our findings suggest that a combined therapeutic approach using 2-DG and dabrafenib has the potential to improve the outcome of PTC patients with BRAF<sup>V600E</sup>.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1246-1259"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ThyroidPub Date : 2024-10-01Epub Date: 2024-09-18DOI: 10.1089/thy.2024.0358
Matthew D Ettleson, Kelly Karavolos, Sherri-Ann M Burnett-Bowie, Lynda H Powell, Imke Janssen
{"title":"The Association Between Hypothyroidism and Cognitive Function Change in Women across the Menopause Transition: The Study of Women's Health Across the Nation.","authors":"Matthew D Ettleson, Kelly Karavolos, Sherri-Ann M Burnett-Bowie, Lynda H Powell, Imke Janssen","doi":"10.1089/thy.2024.0358","DOIUrl":"10.1089/thy.2024.0358","url":null,"abstract":"<p><p><b><i>Background:</i></b> Patients treated for hypothyroidism with levothyroxine (LT4) monotherapy may present with persistent hypothyroidism symptoms, including cognitive symptoms, despite having a normal thyroid stimulating hormone (TSH) level. It remains unclear whether LT4 monotherapy is sufficient to normalize cognitive function outcomes over time. <b><i>Methods:</i></b> This is a multisite longitudinal study of a diverse group of women during midlife representing 5 ethnic/racial groups from 7 enrollment sites across the United States in the Study of Women's Health Across the Nation. Women were screened for a history of thyroid disease and the use of LT4. The study consisted of two primary groups: women with LT4-treated hypothyroidism and control women without thyroid disease. Each participant completed up to 9 cognitive assessments over the study period testing processing speed, working memory, and episodic memory (immediate and delayed recall). Multivariable generalized linear mixed models of scores for each cognitive assessment were developed to determine the association between LT4-treated hypothyroidism and cognitive function trajectories. Covariates included sociodemographic, clinical characteristics, and menopausal status (pre/early peri, late peri, and surgical/post). Sensitivity analyses were conducted to assess the impact of abnormal TSH levels and practice effects (i.e., improvements in scoring after repeated testing). <b><i>Results:</i></b> Of the 2033 women who were included in the study, 227 (11.2%) met criteria for LT4-treated hypothyroidism. At baseline, both processing speed and working memory scores were higher in LT4-treated women (mean processing speed scores: 56.5 vs 54.4; <i>p</i> value = 0.006; mean working memory scores: 6.8 vs 6.4; <i>p</i> value = 0.018). However, when considering the effect of LT4-treated hypothyroidism over time, there were no significant differences in the rate of cognitive decline (in any measure) between the hypothyroidism and control groups with or without covariate adjustment. The results were similar when considering LT4-treated women with abnormal TSH levels or after minimizing practice effects. <b><i>Conclusions:</i></b> We observed no difference in cognitive decline between women with LT4-treated hypothyroidism and women without thyroid disease. For similar aged patients with cognitive complaints, if thyroid function testing is normal, clinicians should consider causes other than inadequate thyroid hormone treatment to explain these symptoms.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"1205-1213"},"PeriodicalIF":5.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}