A versatile nanoplatform carrying cascade Pt nanozymes remodeling tumor microenvironment for amplified sonodynamic/chemo therapy of thyroid cancer.

Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H2O2 to oxygen (O2) but also augmented intracellular ROS levels through the production of hydroxyl radicals (•OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant tumors.

Prevalencia de hipertirotropinemia neonatal comoindicador de deficiencia de yodo en la provincia de La Pampa: un análisis epidemiológico / Prevalence of high neonatal thyroid stimulating hormone levels as an indicator of iodine deficiency in the province of La Pampa: An epidemiological analysis

Introducción. El yodo desempeña un rol fundamental en el metabolismo, el crecimiento y el desarrollo humano. Durante el embarazo y la infancia, la demanda de este micronutriente aumenta considerablemente. La tirotropinemia neonatal (TSHn) aumentada, definida como TSHn ≥5 mUI/l, es un marcador que señala la deficiencia de yodo en una población cuando su prevalencia supera el 3 %. Objetivo. Determinar la prevalencia de TSHn ≥ 5 en La Pampa durante el período 2021-2022, analizar su correlación con diferentes variables y compararla con datos de una cohorte histórica. Población y métodos. Estudio transversal, de diseño descriptivo-analítico, sobre una población de neonatos nacidos en las cinco zonas sanitarias de la provincia de La Pampa durante los años 2021 y 2022. Resultados. De los 5778 neonatos evaluados, el 9,6 % presentó niveles de TSHn ≥5 mUI/l. El 70,4 % de estas mediciones fueron realizadas después del tercer día de vida. No se observaron diferencias significativas en la frecuencia de niveles elevados de TSHn según el año de nacimiento, peso al nacer o días hasta la extracción. Se registró una mayor prevalencia en el sexo masculino (10,6 % versus 8,5 %; p = 0,007) y entre los neonatos nacidos a término (9,8 % versus 6,6 %; p = 0,02). La prevalencia de hipertirotropinemia fue superior a la observada en una cohorte de 2001-2002. Conclusiones. La prevalencia de hipertirotropinemia neonatal en La Pampa durante los años 2021 y 2022 fue del 9,6 %, lo que indica un estado de deficiencia leve de yodo en la provincia, superior al reportado hace dos décadas.

Introduction. Iodine plays a key role in human metabolism, growth, and development. During pregnancy and childhood, the demand for this micronutrient increases notably. Increased neonatal thyroid stimulating hormone (nTSH) levels, defined as nTSH ≥ 5 mIUL, are a marker of iodine deficiency in a population if its prevalence is higher than 3%.Objective. To establish the prevalence of nTSH ≥ 5 in La Pampa in the 2021­2022 period, analyze its correlation with different variables, and compare it with data from a historical cohort.Population and methods. Cross-sectional, descriptive-analytical study in a population of newborn infants born in the 5 health regions of the province of La Pampa in 2021 and 2022. Results. Of  the  5778  assessed  newborn  infants,  9.6%  had  nTSH  levels  ≥  5  mIU/L. It was reported that 70.4% of these measurements were done after the third day of life. No significant differences were observed in the frequency of high nTSH levels by year of birth, birth weight, or days until samplecollection.A higher prevalence was observed among male infants (10.6% versus 8.5%; p = 0.007) and term infants (9.8% versus 6.6%; p = 0.02). The prevalence of high TSH levels was superior to that observed in the 2001­2002 cohort. Conclusions. The  prevalence of high nTSH levels in La Pampa during 2021 and 2022 was 9.6%, suggesting the presence of mild iodine deficiency in the population of this province, higher that what  had been reported 2 decades ago.

Posterior pituitary tumors and other rare entities involving the pituitary gland.

Non-neuroendocrine tumors account for around 10% of all primary neoplasms of the sella. If meningiomas, craniopharyngiomas, and germ cell tumors are excluded, the remaining lesions include a broad spectrum of uncommon, benign, and aggressive, often diagnostically challenging lesions. This review aims to summarize the essential clinicopathological features of tumors of the posterior pituitary gland, infundibulum spectrum expressing thyroid transcription factor 1, and primary sellar atypical rhabdoid teratoid tumor, and provide the criteria for their diagnosis and management.

Sonographic characteristics of thyroid nodules with a Halo.

OBJECTIVE: To investigate the sonographic characteristics of thyroid nodules with a halo, explore the value of contrast-enhanced ultrasound (CEUS) combined with fine needle aspiration (FNA) in identifying nodules with a halo, and predict the risk of metastasis by analyzing the pathological features of the halo. METHODS: A retrospective analysis was conducted on 185 postoperative cases of thyroid nodules accompanied by halos between January 2019 and December 2022. After describing the ultrasound characteristics of the thyroid nodules and their halos, all patients were divided into three groups, the first group (group I = CEUS only) of patients underwent CEUS, the second group (group II = CEUS + FNA) underwent FNA based on the first group, and the third group (group III = FNA only) underwent FNA directly. The CEUS and FNA results were graded using the Chinese Thyroid Imaging Report and Data System (C-TIRADS) and Bethesda Reporting System for Thyroid Cytopathology, respectively. Those graded below C-TIRADS 4b or Bethesda IV were defined as benign, and the results of FNA were referenced when the two methods were combined. The surgical pathology results were used as the gold standard. We plotted working curves to compare the diagnostic efficacy of CEUS and FNA alone and in combination in the diagnosis of thyroid nodules with halos. The pathological features of the halo were analyzed and the number of patients with cervical lymph node metastases was recorded. RESULTS: One hundred and sixty patients met the requirements. Benign nodules were mainly characterized by a thin (0.75 ± 0.31 mm) and uniform halo with good integrity, while malignant nodules had a thicker (1.48 ± 0.51 mm) halo with uneven and irregular margins (P < 0.05). The sensitivity and specificity were highest when the cutoff value was 1.09 mm, with 76.08% and 84.29%, respectively. The halos of benign nodules were mostly hyper- or iso-enhanced, whereas the halos of malignant nodules were predominantly hypo-enhanced (P < 0.05). The areas under the curve (AUCs) for CEUS, FNA, and CEUS + FNA were 0.751(95% CI = 0.642-0.841), 0.863(95% CI = 0.767-0.929), and 0.918(95% CI = 0.834-0.967), respectively. Cervical lymph node metastasis occurred in only 13 (11.5%) malignant nodes with halos. The primary pathological components of the halo around malignant nodules were almost reactive hyperplastic fibrous tissue. CONCLUSION: The halo surrounding malignant thyroid nodules is thicker, with uneven and irregular margins, and shows hypo-enhancement on CEUS. Combining CEUS with FNA improves the diagnostic efficacy of thyroid nodules with halos. The reactive hyperplastic fibrous halo may be one of the reasons why malignant nodules are less likely to metastasize.

Gut microbiota and autoimmune thyroid disease: a bidirectional Mendelian randomization study and mediation analysis.

Background: The gut microbiota (GM) plays a pivotal role in influencing various health outcomes, including immune-mediated conditions, but its potential association with autoimmune thyroid disease (AITD) remains underexplored. We aimed to investigate the potentially pathogenic or protective causal impacts of specific GM on two types of AITD, namely Graves' disease and Hashimoto's thyroiditis, and analyzed the mediating effect of 731 immune cell phenotypes. Methods: Leveraging pooled genome-wide association study (GWAS) data of 211 gut microbiota traits, 731 immune cell phenotypes, and two types of AITD (Hashimoto's thyroiditis and Graves' disease), we performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the GM and AITD. Subsequently, we employed a multivariable MR analysis to discover potential mediating immune cell traits. Additionally, sensitivity analyses were utilized to ensure the reliability of the outcomes. Results: Our analysis revealed that a total of 7 GM taxa were positively associated with AITD, and other 14 taxa showed a negative correlation with AITD. Furthermore, we identified several immune cell traits that mediated the effects of GM on AITD. Most notably, Actinobacteria (p) presented protective effects on Hashimoto's thyroiditis via CCR2 on myeloid Dendritic Cell (5.0%), and Bifidobacterium (g) showed facilitating effects on Graves' disease through CD39+ CD4+ T cell %CD4+ T cell (5.0%) and CD14 on CD33+ HLA DR+ CD14dim (12.2%). Conclusion: The current MR study provides evidence supporting the causal relationships between several specific GM taxa and AITD, and further identified potential mediating immunophenotypes.

Impact of Hashimoto's thyroiditis on the tumor microenvironment in papillary thyroid cancer: insights from single-cell analysis.

This study investigates the impact of Hashimoto's thyroiditis (HT), an autoimmune disorder, on the papillary thyroid cancer (PTC) microenvironment using a dataset of 140,456 cells from 11 patients. By comparing PTC cases with and without HT, we identify HT-specific cell populations (HASCs) and their role in creating a TSH-suppressive environment via mTE3, nTE0, and nTE2 thyroid cells. These cells facilitate intricate immune-stromal communication through the MIF-(CD74+CXCR4) axis, emphasizing immune regulation in the TSH context. In the realm of personalized medicine, our HASC-focused analysis within the TCGA-THCA dataset validates the utility of HASC profiling for guiding tailored therapies. Moreover, we introduce a novel, objective method to determine K-means clustering coefficients in copy number variation inference from bulk RNA-seq data, mitigating the arbitrariness in conventional coefficient selection. Collectively, our research presents a detailed single-cell atlas illustrating HT-PTC interactions, deepening our understanding of HT's modulatory effects on PTC microenvironments. It contributes to our understanding of autoimmunity-carcinogenesis dynamics and charts a course for discovering new therapeutic targets in PTC, advancing cancer genomics and immunotherapy research.

The long-term prognostic implications of free triiodothyronine to free thyroxine ratio in patients with obstructive sleep apnea and acute coronary syndrome.

Objective: Obstructive sleep apnea (OSA) and thyroid dysfunction frequently overlap clinically and are risk factors for cardiovascular disease. The free triiodothyronine to free thyroxine (FT3/FT4) ratio as a novel biomarker of cardiovascular disease prognosis, but the impact of the FT3/FT4 ratio on the prognosis of OSA in patients with acute coronary syndromes (ACS) remains uncertain. Methods: In this prospective cohort study, 2160 patients with ACS were recruited and underwent portable sleep monitoring at Beijing Anzhen Hospital from June 2015 to January 2020. OSA was diagnosed when apnea-hypopnea index of ≥15 events/h. Patients were further divided into tertiles according to FT3/FT4 ratio. All patients had scheduled follow-up visits at 1, 3, 6, 9 and 12 months after discharge, with subsequent outpatient visits or telephone follow-up visits every 6 months. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including cardiovascular death, myocardial infarction (MI), stroke, ischemia-driven revascularization, or hospitalization for unstable angina or heart failure. Results: Among 1,547 euthyroid patients enrolled (mean age, 56.0 ± 10.5 years), 812 patients (52.5%) had OSA. The FT3/FT4 ratio between OSA and non-OSA patients was not significantly different. During 2.8 (1.4, 3.5) years follow up, the risk of MACCE increased with the decreasing FT3/FT4 tertiles in patients with OSA (tertile3 as reference, tertile2: hazard ratio (HR) 1.26, 95% CI: 0.85-1.86, P = 0.255; tertile1: 1.60, 95% CI 1.11-2.32; P = 0.013). After adjustment for confounders, the lowest FT3/FT4 tertile was still independently associated with an increased risk of MACCE (adjusted HR 1.66, 95% CI 1.11-2.50, P = 0.015). Conclusion: Lower FT3/FT4 ratio associated with poor prognosis in patients with ACS and OSA.

Recurrent laryngeal nerve monitoring by flexible laryngoscopy during thyroid radiofrequency ablation in the awake patient.

Objective: Although radiofrequency ablation (RFA) is a safe and effective non-surgical treatment for benign thyroid nodules, injury to the recurrent laryngeal nerve (RLN), is a potential and feared complication. Intermittent voice checks have been proposed to monitor vocal cord (VC) function during RFA, but such assessment is highly subjective and effort-dependent. Methods: We are here reporting the methodological use of flexible laryngoscopy (FL) for VC monitoring during bilateral thyroid RFA treatment. The patient, a 35-year-old woman, was referred to the Endocrinology Unit for subclinical hyperthyroidism due to bilateral autonomously functioning thyroid nodules. Results: At the end of the treatment of the first nodule, the FL performed by an otorhinolaryngologist specialist allowed evaluating VC function and ruling out possible paralysis before proceeding with the contralateral RFA treatment. The patient was awake during the entire procedure and well tolerated the laryngoscopic examination. The TSH serum evaluations performed one month and 9 months after the procedure assessed an euthyroid state (TSH 3.2 mIU/L and 2.8 mIU/L, respectively). Conclusion: During bilateral thyroid RFA the use of FL for VC monitoring treatment resulted in a safe, easy-to-perform, and effective strategy to minimize and anticipate RLN injury risk in the awake patient. The prevention of RLN damage is advisable in the case of single RFA treatment, while it should be strongly recommended when RFA is performed on bilateral nodules.

Beyond malignancy risk stratification: FNAC report anticipates thyroid cancer staging. Insights from recent studies.

Fine-needle-aspiration-cytology (FNAC) is safe and cost-effective procedure for evaluating thyroid nodules. The non-negligible rate of indeterminate cytology (ITN), warrants diagnostic surgery for histological assessment, in some cases. Two recent studies (from Europe and the U.S.) reported that the clinical behavior of a histologically proven thyroid cancer (TC) varies according to its pre-surgical FNAC results. Despite differences in study design, inclusion criteria, and the use of different cytology classification systems (Italian and Bethesda), the overall results were comparable. In order to further discuss these results and to provide additional perspective on the topic, the senior authors of the two studies invited other thyroid experts and cytologists not involved in the previous studies to participate in the present commentary. The strong, consistent clinical message that emerges, especially regarding PTC, is that TC with an initial diagnosis of ITN has a less aggressive clinical presentation, lower rates of: i) lymph-node metastasis; ii) more aggressive variants; iii) BRAFV600E mutations, as compared with DTC with an initial diagnosis of "suspicious for malignancy" or "malignant". These results were consistent in both studies and strongly point toward a more indolent clinical phenotype of DTC with a preoperative diagnosis of ITN as opposed to suspicious for malignancy or malignant. Further understanding the clinical implications of these data appears of clinical relevance and will be discussed from both the endocrinologist and cytologist point of view. The here overviewed data provide the foundation for beginning to examine the impact of less aggressive therapies for TC with an initial ITN diagnosis.

Thyroid autoantibodies at baseline predict longer survival in non-small cell lung cancer patients treated with anti-programmed cell death-1 blockade: a prospective study.

The presence of anti-thyroid antibodies (ATAs) is a biomarker for the development of thyroid dysfunction induced by anti-programmed cell death-1 antibodies (PD-1-Abs). While patients with thyroid dysfunction reportedly showed better overall survival (OS), it remains unknown if ATAs at baseline can predict OS. Therefore, in this study, we examined the association of ATAs at baseline with OS in non-small cell lung cancer (NSCLC) patients with different levels of programmed cell death-1 ligand 1 (PD-L1) positivity associated with PD-1-Ab treatment efficacy. A total of 81 NSCLC patients treated with PD-1-Abs were evaluated for ATAs at baseline and prospectively for OS. Among the 81 patients, 49 and 32 patients had ≥50% (group A) and <50% (group B) PD-L1 positivity, respectively. Median OS did not differ significantly between patients with (n = 13) and without (n = 36) ATAs at baseline in group A. In contrast, median OS was significantly longer in patients with (n = 10) versus without (n = 22) ATAs at baseline in group B (not reached vs 378 days, respectively; 95% CI, 182 to 574 days, p = 0.049). These findings suggest that the presence of ATAs at baseline is a biomarker to predict better treatment efficacy of PD-1-Abs in NSCLC patients with low PD-L1 positivity, while the difference in OS in those with high PD-L1 positivity may be masked by increased tumor expression of PD-L1.

Detecting thyroid nodules along with surrounding tissues and tracking nodules using motion prior in ultrasound videos.

Ultrasound examination plays a crucial role in the clinical diagnosis of thyroid nodules. Although deep learning technology has been applied to thyroid nodule examinations, the existing methods all overlook the prior knowledge of nodules moving along a straight line in the video. We propose a new detection model, DiffusionVID-Line, and design a novel tracking algorithm, ByteTrack-Line, both of which fully leverage the prior knowledge of linear motion of nodules in thyroid ultrasound videos. Among them, ByteTrack-Line groups detected nodules, further reducing the workload of doctors and significantly improving their diagnostic speed and accuracy. In DiffusionVID-Line, we propose two new modules: Freq-FPN and Attn-Line. Freq-FPN module is used to extract frequency features, taking advantage of these features to reduce the impact of image blur in ultrasound videos. Based on the standard practice of segmented scanning by doctors, Attn-Line module enhances the attention on targets moving along a straight line, thus improving the accuracy of detection. In ByteTrack-Line, considering the characteristic of linear motion of nodules, we propose the Match-Line association module, which reduces the number of nodule ID switches. In the testing of the detection and tracking datasets, DiffusionVID-Line achieved a mean Average Precision (mAP50) of 74.2 for multiple tissues and 85.6 for nodules, while ByteTrack-Line achieved a Multiple Object Tracking Accuracy (MOTA) of 83.4. Both nodule detection and tracking have achieved state-of-the-art performance.

Assessing the Diagnostic Accuracy of TI-RADS in Pediatric Thyroid Nodules: A Multi-institutional Review.

PURPOSE: Thyroid nodules are uncommon in children and adolescents but carry an increased risk of malignancy when present. The Thyroid Imaging Reporting and Data System (TI-RADS) is an adult-validated ultrasound-based risk assessment providing a prediction of malignant potential for thyroid nodules, thereby guiding recommendations for fine needle aspiration biopsy (FNAB). Minimal data exist regarding the applicability of TI-RADS to predict malignancy in pediatric thyroid nodules. This study aims to analyze the performance of TI-RADS for children and adolescents with thyroid nodules, hypothesizing that applying TI-RADS criteria would improve accuracy and reduce the number of recommended FNAB compared to American Thyroid Association (ATA) size criteria alone. METHODS: A multi-institutional retrospective analysis was conducted including patients ≤21 years with a thyroid nodule by sonographic thyroid imaging between 2015 and 2020. TI-RADS scores were assigned at each institution by a pediatric radiologist trained in thyroid imaging and TI-RADS criteria. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy of TI-RADS scoring were compared to existing ATA size-based recommendation for performing a FNAB. Accounting for relative size differences between adults and children, a novel PED TI-RADS category was developed and tested, recommending FNAB for thyroid nodules with a TI-RADS 3 and ≥ 1.5 cm, TI-RADS 4 and ≥ 1.0 cm, and TI-RADS 5 any feasible size. RESULTS: 291 nodules from 260 patients (median age 14.9 years, 78.8% female) were assessed using TI-RADS. Applying adult TI-RADS criteria resulted in recommendation of FNAB for 35.1% of nodules, in contrast to 76.6% recommended by ATA guidelines (p < 0.0001) (Table). Utilizing the adult TI-RADS score ≥3 as an FNAB indicator resulted in 100% sensitivity and 28.5% specificity, with 0 cases of missed malignant nodules on pathology. When novel PED TI-RADS criteria were applied, 88 patients would have been spared an unnecessary FNAB with improved sensitivity and accuracy over ATA criteria. CONCLUSIONS: The application of adult and PED TI-RADS scoring to thyroid nodules in pediatric patients enhances the accuracy of malignancy prediction compared to current American Thyroid Association size criteria alone. The utilization of PED TI-RADS scoring eliminated unnecessary biopsies in many children while not missing a single thyroid malignancy. LEVEL OF EVIDENCE: Level III.

Impact of periodic neck ultrasonography on locoregional disease control in surveillance after total thyroidectomy for patients with low- and intermediate-risk papillary thyroid carcinoma: a propensity score-matched study.

This study aimed to evaluate the impact of periodic neck ultrasonography (US) on postoperative surveillance for locoregional disease control of patients with low- and intermediate-risk papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. This retrospective cohort study included patients with PTC who underwent total thyroidectomy and central neck dissection at our institution between January, 2000 and December, 2016. The patients were divided into two groups: the physical examination (PE) group (follow-up by PE without periodic US) and the US group (follow-up by PE with periodic US). Serum thyroglobulin levels were measured periodically in both groups. Propensity score matching was used to rigorously balance the significant variables and assess the 10-year postoperative outcomes between the groups. Of the 189 patients, 150 were included after matching (75 in each group). There were no significant differences between the two groups in terms of background characteristics. The median follow-up period was 127.9 months. There was no significant difference in locoregional relapse-free survival between the PE and US groups (97.0 vs. 98.7%, p = 0.541). The overall survival was 96.7% and 98.7% in the PE and US groups, respectively, with no significant difference (p = 0.364). This study demonstrated that the addition of periodic US to PE for postoperative surveillance of patients with low- and intermediate-risk PTC who underwent total thyroidectomy did not significantly affect locoregional control.

Establishing the TSH reference intervals for healthy adults aged over 70 years: the Australian ASPREE cohort study.

OBJECTIVES: As thyroid disorders are common amongst the elderly, this study aims to evaluate the reference interval (RI) for thyroid stimulating hormone (TSH) in healthy adults aged 70 years and over. METHODS: A proposed RI was determined from the Australian participants of the ASPirin in Reducing Events in the Elderly (ASPREE) randomised trial. Participants had no history of cardiovascular disease, thyroid cancer, dementia, or life-threatening illnesses. Participants prescribed with any thyroid-related medication at baseline were excluded. TSH levels were measured using a commercial chemiluminescence microparticle immunoassay. The RI was determined using the middle 95th percentile of the logarithmic transformed data of baseline TSH. Cox proportional hazard regression models were used to validate the RI by assessing disease incidence over time. RESULTS: A total of 10,995 participants had baseline TSH measures. Median (IQR) age was 73.9 (71.8-77.3) years. We propose a RI of 0.34-3.75 mU/L. TSH levels did not differ by age or sex. At baseline, there was no association between symptoms associated with thyroid disease and levels of TSH. Over the follow-up period of up to 11 years, no association was seen between baseline TSH levels and relevant disease outcomes for participants within the RI. CONCLUSIONS: From a group of initially healthy, community-dwelling adults aged >=70 years, we propose a RI of TSH to best represent euthyroidism. This concentration was not associated with an increased risk of thyroid related symptoms or outcomes, confirming its appropriateness for clinical use.

Diagnostic performance of ultrasound vs. ultrasound-guided FNAc in thyroid nodules: data from the ElaTION trial.

INTRODUCTION: ElaTION is a large multi-centre pragmatic randomised controlled trial, performed in 18 secondary/tertiary hospitals across England, comparing elastography ultrasound-guided fine needle aspiration cytology (EUS-FNAC) with ultrasound-guided FNAC (US-FNAC) alone in the diagnostic assessment of thyroid nodules. Secondary trial outcomes, reported here, assessed the accuracy of ultrasound-alone (US) compared with US-guided FNAC to inform and update current practice guidelines. METHODS: Adults with single or multiple thyroid nodules who had not undergone previous FNAC were eligible. Radiologists assessed all thyroid nodules using US alone, thereby enabling assessment of its accuracy (sensitivity and specificity) versus US-FNAC. RESULTS: Of the 982 participants, a final definitive diagnosis was obtained in 688, who were included in the final analyses. The sensitivity of US-alone was the same as US-FNAC (0.91, [95% CI 0.85, 0.97] vs 0.87 [95%CI 0.80-0.95], p=0.37). US alone had statistically significant lower specificity than US-FNAC alone (0.48 vs 0.67 respectively, p<0.0001). The malignancy rate on histology in a nodule classified as benign on ultrasound (U2) was 9/263 (3.42%) and on cytology (Thy2) was 15/353 (4.25%), whereas the malignancy rate in a nodule that was benign on both (U2, Thy2) was 3/210 (1.43%). Malignancy risk for U3, U4, and U5 nodules was 68/304 (22.4%), 43/83 (51.8%), and 29/38 (76.3%) respectively (p<0.0001). Yet 80/982 (8%) patients were discharged despite having U3-U5 scans with Thy1 (non-diagnostic) FNAC and no definitive diagnosis.Malignancy risk was higher in smaller nodules: <10mm 23/60 (38.3%), 10-20mm 46/162 (28.4 %), and >20mm 80/466 (17.2%) (p<0.0001). Nodules with indeterminate cytology with atypical features (Thy3a) carried a similar malignancy risk to those with indeterminate cytology (Thy3/3f): 27/95 (28.4%) versus 42/113 (37.2%) respectively (p=0.18). CONCLUSION: Ultrasound alone appears to be an effective diagnostic modality in thyroid nodules, confirming the recommendations of recent guidelines and the BTA classification. However, findings also suggest caution regarding existing recommendations for conservative management of non-diagnostic (Thy1/Bethesda I) and atypical (Thy3a/Bethesda III) nodules. In those cases, ultrasound (U3-5) features may help identify high-risk subgroups for more proactive management.

Overexpression of NR1D1 portends disease recurrence in thyroid cancer.

CONTEXT: Dysregulation of circadian rhythms has been linked to cancer susceptibility. Thyroid cancer cells demonstrate altered circadian oscillations in endogenous clock transcripts. OBJECTIVE: Our previous research identified NR1D1, a component of the circadian clock, as one of the recurrence-associated genes in papillary thyroid cancer. The objective of this study was to investigate the expression pattern of NR1D1 in thyroid cancer and explore its prognostic and translational implications. METHODS: We assessed NR1D1 expression using immunohistochemical analysis and examined its correlation with clinicopathological parameters. In vitro and in vivo experiments were performed to elucidate the oncogenic roles of NR1D1 and potential mechanisms. RESULTS: Nuclear NR1D1 expression was present in thyroid follicular epithelial-derived cancers, whereas normal thyroid tissue and benign nodular goiter showed no detectable NR1D1 immunoreactivity. Patients with high expression of NR1D1 had more advanced disease stages, extrathyroidal extension, lymphovascular invasion, and shorter recurrence-free survival compared to those with low levels of NR1D1. Through gain- and loss-of-function studies, we demonstrated that NR1D1 modulation affected the growth of organoids, resistance to anoikis, and the invasive and migratory capacity of thyroid cancer cells. The invasion-promoting effect of NR1D1 was regulated by the ß-catenin/ZEB1 axis. Moreover, the overexpression of NR1D1 accelerated xenograft growth and lung metastasis in vivo. CONCLUSION: NR1D1 is overexpressed in malignant thyroid tumors and has prognostic significance. Our findings suggest therapeutic potential in targeting NR1D1 for thyroid cancer.

Thyrotoxic Effects of Mixed Exposure to Perfluorinated Compounds: Integrating Population-Based, Toxicogenomic, Animal, and Cellular Evidence to Elucidate Molecular Mechanisms and Identify Potential Effector Targets.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are emerging environmental endocrine disruptors that may adversely affect the human endocrine system, particularly the thyroid gland, the largest endocrine gland in the human body. An epidemiologic survey was conducted involving 318 community residents in Shanghai, China, to assess PFAS exposure levels. The relationship between PFAS exposure and five thyroid function indicators was analyzed using Bayesian Kernel Regression (BKMR) and Weighted Quantile Sum Regression (WQS). Ten effector genes related to PFAS and thyroid diseases were identified through the Comparative Toxicogenomics Database (CTD) for bioinformatics analysis and pathways involved were explored through mediation analysis. In vivo validation of these effector genes was conducted using PCR, complemented by in vitro cellular experiments involving transcriptome sequencing and the construction of animal models to simulate mixed PFAS exposure in the general population. Mixed PFAS exposure was found to impact thyroid health primarily through pathways related to lipid metabolism in toxicogenomic studies and resulted in the upregulation of key genes associated with lipid metabolism in animal models. Our results demonstrate that PFAS exposure could affect the expression of lipid metabolism pathways through the modulation of transcription factors, contributing to the development of thyroid disease.

Glucose Transporter 1 Inhibitors Induce Autophagy and Synergize With Lenvatinib in Thyroid Cancer Cells.

BACKGROUND: Less differentiated thyroid cancer may upregulate the expression of glucose transporter 1 (GLUT1) and increase glycolytic activity. However, it is uncertain whether GLUT1 can be used as a target for therapy. METHODS: Thyroid cancer cell lines were treated with two different GLUT1 inhibitors, STF-31 and BAY-876. Functional assays were conducted to evaluate the effects of these inhibitors on cell biology. RESULTS: GLUT1 inhibitors dose-dependently decreased cell growth and clonogenicity of thyroid cancer cells. Cell cycle analysis showed that these inhibitors caused G2/M arrest instead of apoptosis. Additionally, treatment with GLUT1 inhibitors led to the activation of autophagy. In both the Transwell and spheroid models, GLUT1 inhibitors significantly suppressed cell invasiveness. Moreover, GLUT1 inhibitors demonstrated synergistic interactions when combined with lenvatinib. CONCLUSIONS: Treatment with GLUT1 inhibitors activates autophagy and provokes cell cycle arrest, accompanied by a decrease in colony formation and invasive capacity in thyroid cancer cells.

Sex differences in the influence of adult-onset hypothyroidism on hippocampal progenitor survival and neuronal differentiation in mice.

The ongoing production of newborn neurons in the adult hippocampus is reported to be sensitive to perturbations of thyroid hormone signaling, in male rats and mice. Here, we examined whether the neurogenic changes evoked by adult-onset hypothyroidism exhibit sex differences, using male and female C57BL/6N mice. We assessed the impact of goitrogen-induced, adult-onset hypothyroidism on the postmitotic survival and differentiation of hippocampal progenitors in male and female mice. Adult-onset hypothyroidism evoked a significant decline in the postmitotic survival and neuronal differentiation of adult-born progenitors within the dentate gyrus hippocampal subfield of male, but not female, mice. We observed a significant decrease in the number of immature neurons within the hippocampi of adult-onset hypothyroid male mice, whereas adult-onset hypothyroidism evoked by goitrogens using the same treatment paradigms did not evoke any change in immature neuron number in female mice. Gene expression analysis within the hippocampi of euthyroid male and female mice revealed sex-dependent, differential expression of thyroid hormone receptor genes, as well as genes linked to thyroid hormone metabolism and transport. Collectively, our findings highlight sex differences in the influence of goitrogen-induced, adult-onset hypothyroidism on hippocampal neurogenesis, with male, but not female, mice exhibiting a decline in postmitotic hippocampal progenitor survival and neuronal differentiation. These findings underscore the importance of sex as a vital variable when considering the impact of thyroid hormone signaling on the adult hippocampal neurogenic niche.