Thyroid最新文献

Background: 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). Summary: 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. Conclusions: 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.

Background: 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. Methods: We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the zona incerta (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. Results: 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. Conclusions: 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.

Background: 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. Methods: 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) in vivo and vitro. Results: 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 in vivo and T3 treatment in vitro. 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⁺ p-MLKL⁺ NeuN⁺ cells, which decreased after L-T4 treatment. The elevated IFN-I signaling-mediated necroptosis in HT22 cells was also decreased by T3. Conclusion: 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.

Background: Papillary thyroid cancer (PTC) with the BRAF^V600E 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^V600E mutation is associated with altered glucose metabolism in PTC. Methods: This study examined the effect of BRAF^V600E 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^V600E 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) in vitro and in vivo. Results: We found that the BRAF^V600E mutation significantly augments aerobic glycolysis while suppressing oxidative phosphorylation in PTC. We identified the BRAF^V600E/p-ERK/p-DRP1(Ser616) signaling pathway as a critical mediator in PTC progression. First, the BRAF^V600E/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^V600E-positive PTC. Conclusion: The BRAF^V600E/p-ERK/p-DRP1(Ser616) signaling pathway plays a pivotal role in glucose metabolism reprogramming, contributing to the aggressiveness and progression of BRAF^V600E-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^V600E.

Background: 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. Methods: 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). Results: 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; p value = 0.006; mean working memory scores: 6.8 vs 6.4; p 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. Conclusions: 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.