To evaluate the application value of recurrent laryngeal nerve tunnel dissection combined with mesangectomy in en-bloc resection for thyroid cancer. A retrospective analysis was conducted on 174 patients with thyroid cancer diagnosed by preoperative fine-needle aspiration cytology who underwent surgery at Shaoxing Central Hospital from January 2020 to May 2024. These patients (modified surgery group) received en-bloc resection using recurrent laryngeal nerve tunnel dissection combined with mesangectomy, including 143 cases of unilateral radical thyroidectomy, 24 cases of bilateral radical thyroidectomy, and 7 cases of isthmus thyroidectomy. A total of 178 patients diagnosed by preoperative fine-needle aspiration cytology who underwent conventional two-step surgery by the same surgical team during the same period were selected as the conventional surgery group, including 160 cases of unilateral radical thyroidectomy and 18 cases of bilateral radical thyroidectomy. All surgeries were completed successfully. Compared with the conventional surgery group, the modified surgery group showed superior outcomes in terms of operation time, intraoperative blood loss, postoperative drainage duration, and postoperative drainage volume in patients undergoing unilateral radical thyroidectomy; temporary recurrent laryngeal nerve palsy and autologous parathyroid gland transplantation rate in patients undergoing bilateral radical thyroidectomy; as well as length of hospital stay, number of central lymph nodes dissected, and number of level IVB lymph nodes dissected (all P<0.05). As of May 25, 2026, the follow-up period ranged from 15 to 77 months. No adverse events such as recurrence of thyroid cancer were reported in any patient. The modified en-bloc resection of thyroid cancer using recurrent laryngeal nerve tunnel dissection combined with mesangectomy is convenient to perform, achieves thorough lymph node dissection with less intraoperative bleeding, and provides reliable protection of the recurrent laryngeal nerve and parathyroid glands. It is worthy of clinical application. 目的: 探讨喉返神经隧道解剖法结合系膜切除在甲状腺癌整块切除术中的应用价值。方法: 回顾性分析绍兴市中心医院2020年1月至2024年5月共174例经术前穿刺明确诊断为甲状腺癌的手术病例作为改良手术组，术中均采用喉返神经隧道解剖法结合系膜切除开展整块切除术，其中单侧甲状腺癌根治术143例，双侧甲状腺癌根治术24例，峡部癌甲状腺根治7例。选取在同期相同团队进行的共178例经术前穿刺明确诊断为甲状腺癌且采用传统二步法进行手术的病例作为传统手术组，其中单侧甲状腺癌根治术160例，双侧甲状腺癌根治术18例。结果: 两组手术均顺利完成。与传统手术组比较，改良手术组单侧甲状腺癌根治术患者的手术时间、术中出血量、术后引流时间和引流量，双侧甲状腺癌根治术患者的术后暂时性喉返神经麻痹、自体旁腺移植，以及住院时间、中央区淋巴结、ⅣB区淋巴结清扫数等指标均更优（均P<0.05）。截至2026年5月25日，患者随访时间为15~77个月。所有患者均未报告甲状腺癌复发等不良情况。结论: 喉返神经隧道解剖法结合系膜切除行甲状腺癌整块切除术操作方便，创面出血少，淋巴结清扫彻底，可以保护喉返神经及甲状旁腺，值得推广应用。.
The physiological demands of pregnancy substantially alter iodine metabolism and thyroid function. This critical period heightens the requirement for iodine, making deficiency a significant risk factor for both maternal and fetal thyroid dysfunction. This study aimed to evaluate the iodine nutritional status of pregnant women in Hubei Province, explore the relationship between serum iodine concentration (SIC) and thyroid function, and determine the prevalence of thyroid disorders. The eligible participants underwent a face-to-face interview and completed questionnaire surveys to collect baseline information and dietary intake data. Serum thyroid hormones, thyroid antibodies, SIC, and urine iodine concentration (UIC) were measured. The 95% reference intervals of SIC were established and ROC analysis was applied to compare the predictive ability of SIC and UIC for thyroid dysfunction. Hubei Province, China. 1197 eligible pregnant women were included in this study. This study revealed a thyroid dysfunction prevalence of 28.40%, with hypothyroxinemia being the most prevalent thyroid function abnormality, accounting for 79.7% of all thyroid dysfunction cases. Significant differences in hypothyroxinemia prevalence were noted across pregnancy trimesters (P < 0.001), with the highest prevalence in the first trimester and the lowest in the third. In the first trimester, SIC was negatively correlated with TSH (r = -0.195, P < 0.001) and positively correlated with FT3 (r = 0.294, P < 0.001). Additionally, SIC demonstrated a positive correlation with FT4 in each trimester (all P < 0.001). Finally, the SIC reference intervals for pregnant women in the first, second, and third trimesters were 50.08∼118.61 µg/L, 59.16∼127.44 µg/L, and 53.61∼118.67 µg/L, respectively. SIC can serve as a reliable indicator for evaluating individual iodine nutritional status and predicting thyroid dysfunction.
Sphingosine-1-phosphate (S1P) is a versatile immunomodulatory lipid mediator that affects both immune and cardiovascular health. S1P has been linked to thyroid health, for example by affecting inflammatory reactions found in Graves' disease. In our study, we explored associations of S1P with thyroid markers obtained from laboratory tests (thyrotropin [TSH], free triiodothyronine [fT3], and free thyroxine [fT4]) and ultrasound examination. We quantified S1P by LC-MS/MS in participants from the population-based 'Study of Health in Pomerania' conducted in Northeast Germany. Serum levels of TSH, fT3 and fT4 were measured using chemiluminescent immunoassays. Thyroid volume, thyroid nodules, and echogenic patterns were assessed by ultrasonography. Cross-sectional associations between serum S1P and thyroid biomarkers were evaluated using multivariable linear regression models adjusted for confounding. The total study population consisted of 4,034 participants (51.6% women aged 20 to 84 years). A one µmol/L higher S1P level was associated with a 0.17 mIU/L lower TSH level (95% confidence interval [CI]: -0.32; -0.04) and a 0.52 pmol/L [0.42; 0.63] higher fT3 level. These associations persisted after excluding individuals with high or low serum TSH levels and those taking thyroid medication. S1P levels were not significantly associated with serum fT4 levels. Higher S1P levels were associated with a larger thyroid volume, the presence of thyroid nodules, and a hypoechogenic thyroid pattern. Circulating S1P is inversely associated with TSH and positively associated with fT3, suggesting a potential modulatory role of S1P in thyroid function.
Although it is extremely rare, papillary thyroid carcinoma (PTC) can exhibit unexpected behavior, with the potential to transform into more lethal forms in metastatic sites. This report describes 2 cases in which PTC transformed within metastatic lymph nodes. Case 1: A 57-year-old woman with a progressively enlarging right neck mass was found on imaging to have cervical lymphadenopathy and small right thyroid nodules. She underwent total thyroidectomy with neck dissection. Histopathology revealed metastatic PTC with squamous dedifferentiation in cervical nodes. Immunohistochemistry confirmed thyroid origin. Case 2: A 45-year-old woman presented with right submandibular swelling. Ultrasound revealed a left thyroid nodule with suspicious cervical lymphadenopathy. She underwent total thyroidectomy with neck dissection. Histopathology showed conventional PTC with high-grade transformation in 1 metastatic lymph node, consistent with differentiated high-grade thyroid carcinoma. Seven cases of PTC transformation in metastatic sites were reviewed. Ages ranged from 56 to 79 years. Symptoms were neck masses, respiratory, and systemic symptoms. Most cases were conventional PTC. Transformation predominantly resulted in squamous cell carcinoma, though rarer transformations were present. The transformations were mainly regional, but distant metastatic sites such as the lung were also reported. Management included total thyroidectomy and neck dissections with radioactive iodine, often combined with chemoradiation or targeted therapy for advanced cases. Lymph node metastases originating from the thyroid may undergo histological transformation and exhibit aggressive behavior. Total thyroidectomy combined with radioiodine ablation and hormone therapy might yield favorable outcomes, but regional and distant metastases may still develop.
Maternal hypothyroidism, characterized by insufficient thyroid hormone levels during pregnancy, is linked to adverse outcomes including preeclampsia, intrauterine growth restriction, and miscarriage. Beyond supporting fetal neurodevelopment, thyroid hormones are essential for maintaining maternal immune tolerance to the semi-allogeneic fetus. Regulatory T (Treg) cells, particularly those expressing Forkhead box P3 (FoxP3), are key mediators of this tolerance. Although reduced FoxP3+ Tregs have been associated with pregnancy complications, their role in maternal hypothyroidism remains unclear. Exosomes, important mediators of immune signaling, may also influence FoxP3+ Tregs, but their function in hypothyroid placentas is poorly understood. Placentas from hypothyroid and healthy pregnancies were analyzed. FoxP3 and the exosome marker CD63 were evaluated by immunohistochemistry and ELISA, with FoxP3 and the trophoblast marker CK7 also assessed by immunofluorescence. Histomorphological alterations were examined using H&E staining. Histomorphological analysis revealed pathological changes in hypothyroid placentas. A significant reduction in FoxP3+ cells was detected in hypothyroid placentas compared to controls, while CD63 expression showed no difference between groups. Immunofluorescence confirmed FoxP3 expression in trophoblasts. This study is the first to demonstrate an association between maternal hypothyroidism and FoxP3 expression and suggests that a reduction in FoxP3+ cells may contribute to impaired feto-maternal immune tolerance. The detection of FoxP3 in trophoblasts provides novel insight into their potential immunomodulatory role. These findings suggest that FoxP3 may act as a mediator in the pathophysiology of maternal hypothyroidism and highlight the need for further mechanistic and clinical studies.
Hydroxychloroquine (HCQ) is a commonly used immunomodulatory drug in various autoimmune diseases; however, its role in autoimmune thyroid diseases (AITDs) remains unclear. This study aimed to evaluate the potential effects of HCQ in autoimmune thyroiditis using both naïve and experimental autoimmune thyroiditis (EAT) mouse models. Mice were administered HCQ via drinking water. Plasma levels of free thyroxine (FT4), anti-thyroglobulin antibody (ATA), B-cell activating factor (BAFF), and interferon-α (IFN-α), along with thyroid histopathology, were assessed. Thyroid tissues were subjected to next-generation sequencing (NGS), followed by over-representation analysis (ORA) and gene set enrichment analysis (GSEA) for functional enrichment evaluation. In EAT mice, HCQ treatment did not significantly affect FT4 or ATA levels, nor did it alter thyroid histological features. However, HCQ reduced human thyroglobulin stimulated splenocyte metabolic activity and plasma BAFF levels, indicating a systemic immunomodulatory effect. NGS of thyroid tissues revealed widespread upregulation of immune and inflammatory genes in EAT mice, which were partially attenuated by HCQ. GSEA also confirmed downregulation of immune-related pathways, including IL-6-JAK-STAT3 signaling and allograft rejection. No significant changes were observed in naïve mice treated with HCQ. In the context of autoimmune thyroiditis, HCQ showed preliminary immunomodulatory effects on certain immunological markers without recovering histological damage in the short term. Further long-term and mechanistic studies are warranted to clarify HCQ's therapeutic potential in autoimmune thyroiditis.
The thyroid gland is a highly vascularized organ in vertebrates. However, the information on the vascular pattern of this gland in pigs remains limited. This study elucidates the morphoanatomy and arterial supply of the gland in three breeds: Landrace (L), Large White (W), and Crossbreed (LWD). Two hundred twelve pigs were used and dissected to observe the arteries supplying blood to the gland. As a result, the gland was classified into three types based on its appearance: pear-shaped, butterfly-shaped, or partially separated. Moreover, the arteries supplying the gland were observed and then compared among breeds. The arterial supply of the thyroid gland on the cranial side consisted of branches from the cranial laryngeal artery, cranial thyroid artery, superficial cervical artery, and common carotid artery. Otherwise, the caudal side was supplied by the caudal thyroid artery, superficial cervical artery, bicarotid trunk, internal thoracic artery, and external thoracic artery. Furthermore, significant differences were identified between L and LWD, as well as between W and LWD, in the pattern of arterial origin on the cranial right side of the thyroid gland. Similarly, on the left side, significant differences were observed not only between L and W but also between W and LWD. On the caudal side, significant differences were found between L and W, as well as between W and LWD. These anatomical variations provide important insights for research and clinical applications involving the thyroid gland in pigs.
To explore the active components and potential molecular mechanisms of Xiangsha Liujunzi decoction (XSLJZ) in the treatment of thyroid cancer. Active components and corresponding targets of XSLJZ were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Thyroid cancer-related targets were collected from seven bioinformatics databases, including GeneCards, OMIM, DisGeNET, DrugBank, TCGA, GEO, and TTD. A protein-protein interaction (PPI) network and a multi-level "XSLJZ-medicinal materials-active components-potential targets-thyroid cancer" network were constructed to identify core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed, followed by molecular docking to assess binding affinities. In vitro, CCK-8, flow cytometry, colony formation, Transwell, and Western blotting assays were used to evaluate cell proliferation, death, colony formation, migration, and protein expression in 8505C and TPC-1 thyroid cancer cells. In vivo, a subcutaneous xenograft model was established in female BALB/c nude mice (6-8 weeks old, 15-16 g) by injecting 2×106 8505C cells. Mice were randomly divided into model control (vehicle), low-dose XSLJZ (2 mg/kg), and high-dose XSLJZ (4 mg/kg) groups (n=6 per group), receiving daily gavage for 24 days. Tumor volume and body weight were measured every four days. Histopathological changes were observed by HE and immunohistochemical staining. Five major active components of XSLJZ (isoliquiritigenin, naringenin, baicalein, nobiletin, and glycyrrhetinic acid) and 45 core targets for thyroid cancer were identified. XSLJZ and these five components significantly inhibited the proliferation of 8505C and TPC-1 cells without notable toxicity to normal thyroid cells, with isoliquiritigenin showing the most prominent effect. Flow cytometry revealed that XSLJZ (16 mg/mL) induced up to 84.91% death in TPC-1 cells. Molecular docking showed low binding energies between isoliquiritigenin and Akt1, Caspase-3, Caspase-9, and PARP (lowest: －9.9 kcal/mol with PARP). XSLJZ and isoliquiritigenin dose-dependently suppressed colony formation and migration, downregulated RAGE, p-PI3K, and p-Akt, upregulated Bax and mitochondrial cytochrome c, and activated Caspase-3/9-mediated apoptosis and GSDME-dependent pyroptosis via the AGE-RAGE→PI3K/Akt axis. In vivo, both low and high doses of XSLJZ significantly inhibited tumor growth, reduced Akt and Ki-67 expression in tumor tissues (all P<0.05), and showed no obvious toxicity to the heart, liver, or kidneys. XSLJZ inhibits thyroid cancer cell proliferation and induces cell death through multi-component, multi-target synergistic regulation of the AGE-RAGE→PI3K/Akt signaling pathway. 目的: 探究香砂六君子汤（XSLJZ）治疗甲状腺癌的活性成分及潜在分子机制。方法: 利用中药系统药理学数据库与分析平台（TCMSP）筛选XSLJZ的药物有效活性成分及其靶点。运用GeneCards、在线人类孟德尔遗传（OMIM）、DisGENET、DrugBank、癌症基因组图谱（TCGA）、基因表达综合（GEO）数据库及治疗靶点数据库（TTD）等七个生物信息学数据库筛选甲状腺癌相关靶点。通过构建蛋白-蛋白相互作用（PPI）网络和“XSLJZ-药材-活性成分-潜在靶点-甲状腺癌”多层次网络筛选核心靶点，并通过基因本体（GO）功能注释、京都基因和基因组数据库（KEGG）通路进行富集分析，分子对接分析XSLJZ活性成分与靶点的结合能力。体外试验中，通过CCK-8检测细胞活性，流式细胞术检测甲状腺癌细胞死亡情况，克隆形成实验检验甲状腺癌细胞增殖能力，Transwell实验检验甲状腺癌细胞迁移能力，蛋白质印迹法检测目标蛋白表达。取6~8周龄雌性BALB/c裸鼠（体重15~16g）建立皮下移植瘤模型，于裸鼠侧腹部皮下注射2×10⁶/100 µL的8505C细胞悬浮液。一周后，将小鼠随机分为模型对照组（给予赋形剂）、XSLJZ小剂量组（给予XSLJZ 2 mg/kg）和XSLJZ大剂量组（给予XSLJZ 4 mg/kg），均每日一次灌胃，持续24 d，每组6只。每四天测量一次小鼠的体重和肿瘤大小。HE染色和免疫组织化学染色观察组织病理学变化。结果: 筛选出XSLJZ的五种主要活性成分（异甘草素、柚皮素、黄芩素、川陈皮素、甘草次酸）及45个XSLJZ治疗甲状腺癌的核心靶点。CCK-8实验显示，XSLJZ及五种活性成分可显著抑制8505C、TPC-1细胞增殖，对正常甲状腺细胞无明显毒性，以异甘草素抑癌效果最突出。流式细胞术结果显示，XSLJZ及五种活性成分能诱导甲状腺癌细胞死亡，其中16 mg/mL XSLJZ处理后TPC-1细胞死亡率达84.91%;分子对接结果显示异甘草素与Akt1、Caspase-3、Caspase-9及PARP的结合能较低，其中与PARP的结合能低至－9.9 kcal/mol。XSLJZ及异甘草素可呈剂量依赖性抑制甲状腺癌细胞克隆形成与迁移能力，通过阻断AGE-RAGE→PI3K/Akt信号轴下调RAGE、磷酸化PI3K及磷酸化Akt表达，上调促凋亡蛋白Bax与线粒体细胞色素C，同时激活Caspase-3/9介导的凋亡与GSDME依赖的焦亡。体内试验显示，小、大剂量XSLJZ均抑制移植瘤裸鼠的肿瘤生长，下调肿瘤组织Akt和Ki-67表达（均P<0.05），且对小鼠心、肝、肾无明显毒性。结论: XSLJZ通过多成分-多靶点协同调控AGE-RAGE→PI3K/Akt通路抑制甲状腺癌细胞增殖并诱导细胞死亡。.
Radioactive iodine (RAI) is a crucial treatment for refractory pediatric and adolescent Graves' disease (GD) cases characterized by poor response to antithyroid drug (ATD), recurrence, adverse effects, or excessive thyroid enlargement. Compared to adults, pediatric and adolescent patients currently lack effective efficacy prediction models tailored to this specific population. Furthermore, the applicability of existing adult dose calculation standards to children remains controversial. This study aims to develop a predictive model and explore the cutoff values of key variables influencing treatment efficacy, thereby providing a new adjunctive tool for the clinical management of pediatric and adolescent GD patients. A total of 95 children and adolescents with GD who received RAI therapy at the Department of Nuclear Medicine, the Second Affiliated Hospital of Nanchang University, between January 2020 and May 2025 were initially screened. Following the exclusion of 13 patients who had undergone prior thyroid surgery, received non-initial RAI treatment, or lacked regular follow-up, 83 patients (aged 9-19 years; 58 females) were finally enrolled. Based on thyroid function status 6 months post-treatment, patients were categorized into the cured group (Clinical Cure and Hypothyroidism) and the uncured group (Ineffective and Partial Improvement). Univariate analysis and LASSO regression were employed for preliminary variable screening to identify predictive indicators. A multivariate logistic regression model was subsequently constructed based on these selected variables. Model performance was evaluated using the area under the curve (AUC), calibration curves, and decision curve analysis (DCA), with internal validation performed via Bootstrap (2000 resamplings). The optimal cutoff values were determined using the Youden index. The proposed dose per gram of thyroid tissue was a protective factor (OR = 1.048, 95% CI (1.01-1.09), P = 0.018); Thyroid weight (OR = 0.956, 95% CI (0.924-0.983), P = 0.004) and TRAb (OR = 0.914, 95% CI (0.861-0.963), P = 0.001) were risk factors. The model achieved an AUC of 0.833 on the original dataset, and an adjusted AUC of 0.810, After model establishment, further analysis of key variables revealed significantly reduced cure rates in patients with thyroid weight > 55.52 g, TRAb > 13.8 IU/L, and the proposed dose per gram of thyroid tissue < 97.5 µCi/g (3.61 MBq/g). A model incorporating the proposed dose per gram of thyroid tissue, TRAb, and thyroid weight effectively predicts treatment efficacy. For high-risk patients (thyroid weight > 55.52 g, TRAb > 13.8 IU/L), increasing the proposed dose (≥ 97.5 µCi/g or 3.61 MBq/g) is recommended to enhance treatment outcomes.
Thyroid cancer (TC), the most common endocrine malignancy, is closely linked to aging. In this study, we estimated DNA methylation (DNAm) age in TC tissues versus adjacent non-cancerous thyroid tissues using TCGA and GSE97466 datasets. We employed multi-tissue DNAm age estimators, specifically Horvath's clock and the Bayesian Neural Network (BNN) clock, to quantify epigenetic aging in TC and adjacent normal tissues from the TCGA and GSE97466 cohorts. We further integrated genomic, transcriptomic, and mutational analyses, including assessments of senescence-associated secretory phenotype (SASP), immune cell infiltration, and thyroid differentiation, to elucidate the associations between DNAm age acceleration and various cancer-related features. Our results revealed marked DNAm age acceleration in TC tissues relative to controls, with both models yielding significantly higher DNAm age estimates in tumors. Although DNAm age correlated strongly with chronological age in control tissues (R ≈ 0.94), this association was notably diminished in TC tissues (R ≈ 0.62). Moreover, TC tissues with accelerated DNAm age exhibited higher telomerase-associated gene expression score, heightened SASP signaling, and distinct immune profiles characterized by elevated M2 macrophages and reduced activated NK cells. Genomic analysis further showed a higher prevalence of BRAF mutations and lower thyroid differentiation scores (TDS) in the accelerated subgroup. No significant associations were detected between DNAm age and clinicopathological parameters or overall survival. Our findings provide valuable insights into the complex interplay between epigenetic regulation, immune dysfunction, and genomic instability in thyroid cancer, highlighting promising avenues for future research and therapeutic intervention.
A substantial number of thyroid surgeries are performed annually, and most patients are of working age. Research on the impact of thyroid surgery on patient quality of life (QoL) remains limited. This study evaluated changes in QoL within 1 year after thyroid surgery and identified risk factors for poor postoperative QoL. The prevalence of depressive symptoms and their association with QoL outcomes were examined. A prospective cohort study including all consecutive patients (n = 314) who underwent lobectomy or total thyroidectomy at Oulu University Hospital in Finland between September 2021 and December 2022. QoL was assessed using the RAND-36 questionnaire, and depressive symptoms were measured with the Beck Depression Inventory (BDI) before surgery and at 6 and 12 months postoperatively. Poor QoL was defined as a RAND-36 score more than two standard deviations below the age-adjusted population mean. Overall QoL improved, particularly in mental well-being, but remained below the Finnish population norms across all domains in patients with complete QoL data across all time points (n = 143). Preoperative depressive symptoms were present in 42% of patients who completed the baseline BDI questionnaire (n = 162). Among these patients, QoL improved in the same domains but remained below the baseline level of the overall cohort. At 12 months (n = 157), 64% of patients had good QoL and 36% had poor QoL. In multivariable analysis, female gender, poor baseline QoL, and preoperative depressive symptoms independently predicted poor QoL at 12 months. Thyroid surgery improves QoL over 12 months, especially in mental health, but remains below the general population. Depressive symptoms are common and predict worse recovery, indicating that patients may benefit from preoperative psychological assessment and support.Clinical trial registrationN/A.
LncRNAs emerge as critical regulators of gene expression and epigenetic modulation in human cancer. However, the biological and clinical significance of the lncRNA GAS8-AS1 in differentiated thyroid cancers (DTCs) remains poorly understood. GAS8-AS1 expression in normal tissues was evaluated using LncExpDB. Quantitative RT-PCR was performed on 21 DTCs with matched adjacent normal tissues. RNA-seq data from TCGA (507 DTCs) were analyzed to assess GAS8-AS1 expression and clinicopathological associations. Independent validation was conducted using ENCORI (510 thyroid cancer, 58 normal) and TNMplot datasets. Expression profiles of GAS8-AS1-associated genes were analyzed in TCGA and were corroborated with ENCORI dataset. Co-expression analyses were performed to identify regulatory relationships. Functional characterization was conducted using siRNA-mediated knockdown of GAS8-AS1 in HEK293T and BCPAP cells, and overexpression studies in papillary thyroid cancer cell lines (K1 and BCPAP). Cell proliferation, migration, and invasion assays were performed. Pathway enrichment analyses were used to identify GAS8-AS1-mediated biological processes. GAS8-AS1 expression was significantly downregulated in DTCs compared with matched normal tissues (p < 0.0001). TCGA analysis confirmed lower GAS8-AS1 expression, which was markedly associated with early-stage disease (p = 0.03) and lymph node metastasis (p = 0.03). GAS8-AS1 downregulation was remarkably consistent in thyroid cancer (ENCORI, p = 0.004). A dramatic downregulation of GAS8-AS1 was also observed across pan-cancer, including thyroid cancer (TNMplot, p = 2.01 × 10-128). Expression analysis of GAS8-AS1-associated genes revealed frequent deregulation in DTCs (24%), including downregulation of ATF2, ATG5, ATG7, and BECN1, and upregulation of NEAT1 and UCA1. Co-expression analysis revealed that GAS8-AS1 and ATG5 expression levels were positively correlated with ATF2, whereas NEAT1 showed a negative association, suggesting ATF2-dependent transcriptional regulation of GAS8-AS1, ATG5, and NEAT1. Functional characterizations demonstrated that GAS8-AS1 knockdown significantly increased proliferation, migration, and invasion, whereas GAS8-AS1 overexpression markedly suppressed tumor cell proliferation. Pathway enrichment analyses implicated GAS8-AS1-related genes in autophagy, apoptosis, proliferation, invasion, and metastasis. These findings demonstrate that GAS8-AS1 may function as a tumor suppressor in DTCs, with its downregulation associated with disease progression and metastasis. The consistent loss of GAS8-AS1 expression and its functional impact on tumor progression suggest that it may serve as a valuable diagnostic and prognostic biomarker in DTCs.
Western diet (WD) is strongly associated with obesity and metabolic dysfunction and often co-occurs with human exposure to widely used herbicides such as glyphosate (GLP) and 2,4-dichlorophenoxyacetic acid (2,4-D). Both compounds have been suggested as potential endocrine disruptors, including effects on thyroid homeostasis. However, no studies have examined their combined impact in the context of WD-related metabolic disturbances. Here, we investigated the long-term effects of GLP and/or 2,4-D exposure on thyroid-related parameters in male C57BL/6J mice fed a WD for 6 months. Animals received GLP (0.05 or 5 mg/kg/day), 2,4-D (0.02 or 2 mg/kg/day), or their mixtures via intragastric administration, in doses spanning environmentally relevant exposures near the acceptable daily intake (ADI) to levels approaching, but still below, established no-observed-adverse-effect levels (NOAEL). WD feeding successfully induced obesity, glucose intolerance, and hypercholesterolemia; none of these parameters were significantly modified by herbicide exposure. However, GLP at 5 mg/kg increased serum triiodothyronine (T3) levels and promoted thyroid follicular changes, including increased follicle diameter, area, and the area of follicles within the 0-100 μm2 range. TSH levels remained unchanged. Additionally, low-dose GLP (0.05 mg/kg) elevated the percentage of PCNA-positive follicular cells, indicating enhanced cell proliferation. These findings suggest that chronic GLP exposure may exacerbate thyroid morphological and functional alterations even in the absence of changes in systemic metabolic outcomes. Our study provides the first evidence that GLP exposure within toxicologically relevant doses and under a WD setting can modulate thyroid parameters, highlighting the need to consider real-life scenarios in endocrine toxicity assessment.
The American Joint Committee on Cancer Eighth Edition reclassified level VII lymph node metastasis from N1b to N1a in medullary thyroid cancer. However, the prognostic implications of this change remain debated. Using 1,983 medullary thyroid cancer patients (Surveillance, Epidemiology, and End Results, 2004-2015), participants were categorized into N0, N1a (level VI), N1b (level I-V), and level VII groups. Disease-specific survival was evaluated using hazard ratios and 10-year disease-specific survival. We first evaluated the prognostic impact of level VII lymph node metastasis as a distinct category. We then compared the discriminative ability of the American Joint Committee on Cancer Eighth Edition with a modified N classification that reclassifies level VII into the N1b category, using the concordance index and proportion of variation explained. Sensitivity analyses were conducted using overall survival. Level VII lymph node metastasis, 4.7% of medullary thyroid cancer patients, exhibited the most aggressive features: poor differentiation, size >40 mm, extrathyroidal extension, and distant metastasis. Level VII group conferred the poorest disease-specific survival (adjusted hazard ratio versus N0: 4.59; 95% confidence interval, 2.95-7.13), significantly worse than N1b (adjusted hazard ratio, 3.29; 95% confidence interval, 2.33-4.64) and N1a (adjusted hazard ratio, 2.46; 95% confidence interval, 1.63-3.71). Adjusted 10-year disease-specific survival was 72.7% (level VII) vs 78.5% (N1b). However, under the American Joint Committee on Cancer Eighth Edition, there was no significant difference in disease-specific survival between N1a and N1b (adjusted hazard ratio, 1.02; 95% confidence interval, 0.79-1.31), whereas the modified system achieved superior stratification: N0 (91.8%), N1a (82.8%), and N1b (77.4%) with enhanced discrimination (concordance index: 0.726 vs 0.715; proportion of variation explained, 0.104 vs 0.096) and improved stage III/IVA separation (adjusted hazard ratio, 1.75; 95% confidence interval, 1.23-2.50 versus American Joint Committee on Cancer adjusted hazard ratio, 1.26; 95% confidence interval, 0.92-1.73). Level VII lymph node metastasis represents a distinct, highly aggressive medullary thyroid cancer subgroup with the worst prognosis. Reclassifying it into N1b improves prognostic discrimination and optimizes the American Joint Committee on Cancer system.
There are multiple studies reporting the impact of social determinants of health on survival of well differentiated thyroid cancer. Many studies utilized national databases, but few have examined the effect at an institutional level. We hypothesized that assessing survival at our urban safety-net hospital would identify disparities among gender, race, and insurance status. We examined records from our institutional cancer registry for patients diagnosed with thyroid cancer from 2000 to 2023. We obtained data regarding their demographics and cancer stage at diagnosis. A survival analysis was performed using Kaplan-Meier estimates and Cox proportional hazards regression models. A total of 336 patients were diagnosed during this time. Most patients were female 285 (84%) and 215 (63%) under age 55. We compared survival among our White 155 (54%) and Black populations 127 (45%). Insurance status was stratified into non-insured/VA insurance/other 116 (34%), Medicaid 107 (32%), private insurance 64 (19%), and Medicare 49 (15%). Five-year survival was worse in those age > 55 (p < .001), White individuals (p=.019), and Medicaid beneficiaries (p=.003). Mortality risk was higher in males (p=.012, confidence interval (CI): 0.13-0.78), age > 55 (p<.001, CI: 0.13-0.78), Whites (p=.026, CI: 0.21-0.91), and Medicaid insured (p=.002, CI: 0.08-0.56). Our study demonstrates there are significant factors associated with disparities in survival for thyroid cancer. Interestingly, our White population is at increased risk which is contrary to other studies at either a national or institutional level. Further investigation is required to identify how to target this group to alleviate any modifiable factors impacting outcomes.
The relationship between liver-related metabolic markers and thyroid nodules (TNs) has attracted increasing interest. However, whether the Fibrosis-4 (FIB-4) index is independently associated with TN prevalence in women, particularly after accounting for the age embedded in the score, remains unclear. We investigated the association between FIB-4 and prevalent TNs in a female health-check cohort and assessed its robustness in age-stratified and age-adjusted analyses. We conducted a cross-sectional analysis of 695 women from a health examination cohort at The Second Affiliated Hospital of Anhui Medical University. TNs were defined as ultrasound-detected thyroid nodules. Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for prevalent TNs according to standardized FIB-4 levels. Prespecified age-stratified analyses were performed for women aged ≤ 60 years and > 60 years. Within each age stratum, an additional model adjusted for continuous age. Age-adjusted within-stratum results were considered the main basis for interpretation. In the full female cohort, the association between FIB-4 and prevalent TNs was attenuated after additional adjustment for continuous age (OR 1.104, 95% CI 0.822-1.484; P = 0.511). In age-adjusted within-stratum analyses, FIB-4 was not significantly associated with prevalent TNs in either women aged ≤ 60 years (OR 1.211, 95% CI 0.837-1.751; P = 0.310) or women aged > 60 years (OR 0.567, 95% CI 0.289-1.113; P = 0.099). The corresponding base model estimates before additional continuous-age adjustment were OR 1.564 (95% CI 1.086-2.253; P = 0.016) and OR 0.576 (95% CI 0.278-1.193; P = 0.138), respectively. The interaction between FIB-4 and age group was not statistically significant (P for interaction = 0.239). After additional adjustment for continuous age within age strata, the association between FIB-4 and prevalent thyroid nodules in women was attenuated and no longer statistically significant. These findings suggest that the apparent relationship between FIB-4 and TN prevalence in this health-check population may be substantially influenced by age handling and should be interpreted cautiously. Not applicable.
Complementary and alternative medicine (CAM) therapies are increasingly popular; however, comprehensive data on their usage patterns and types remain limited, especially in South Korea. We investigated the patterns and economic impact of CAM use in thyroid cancer after lobectomy. We utilized data from the MASTER study, a prospective, multicenter, randomized, controlled trial on patients with differentiated thyroid cancer post-lobectomy. Data on CAM usage in 1,166 patients at baseline and at 3, 6, and 12 months postoperatively were included. Logistic regression quantified the effect of levothyroxine treatment on CAM usage. CAM use was reported by 58% of participants. Dietary nutritional products were the most used CAM modality, with usage rates of 42.5% at baseline, decreasing to 37.7% at 12 months. Exercise and physical therapies also showed significant differences, with 19.2% using these modalities at baseline, increasing to 27.1% at 12 months. The median cost for CAM varied, with dietary products consistently costing 144 USD (200,000 KRW) and exercise costs rising from 144 USD (200,000 KRW) to 288 USD (400,000 KRW) over time. Patients on levothyroxine were less likely to use CAM, with an odds ratio (OR) of 0.57 (95% confidence interval [CI] = 0.45-0.72, P < 0.001). However, levothyroxine users who did use CAM were more likely to use multiple CAM modalities, with an OR of 3.66 (95% CI = 1.88-7.14, P = 0.001) at baseline, though this association did not remain significant later. CAM is integrated into thyroid cancer treatment, indicating a need for healthcare professionals to discuss its safety and effective care integration.
Oxyphil cells are a primary cellular component of the parathyroid gland. Due to the limitations of techniques for separating oxyphil cells from chief cells, the characteristics and functions of oxyphil cells in uremic secondary hyperparathyroidism (SHPT) remain largely unclear. Therefore, we integrated spatial transcriptomics and single-cell transcriptomics to investigate the characteristics of oxyphil cells and the association between oxyphil cells and calcitriol resistance in SHPT. 6 uremic SHPT samples and 3 normal parathyroid samples were used for single-cell transcriptomics, while the most suitable SHPT sample was used for spatial transcriptomics. By integrating spatial transcriptomics with single-cell transcriptomics data (93073 cells), we identified a subset of 7653 cells with high confidence as oxyphil cells. Both transcriptomic data indicated a higher mitochondrial transcript proportion in oxyphil cells, and further investigation revealed that the transcription factor estrogen related receptor alpha (ESRRA), participated in mitochondrial biogenesis in these cells. Meanwhile, lower VDR expression and calcitriol resistance were observed in oxyphil cells. Further investigation demonstrated that the transcription factor JUNB promoted the transcription of VDR gene by binding to the promoter area of VDR gene, thus ameliorating calcitriol resistance of oxyphil cells in SHPT. These findings offer reliable evidence and new insights into the characteristics of oxyphil cells and their potential role in SHPT, and provide JUNB as a potential target for calcitriol resistance in SHPT.
Antiangiogenic and targeted therapies represent the most effective systemic options for advanced thyroid cancers. In this setting, toxicity management is essential to ensure treatment adherence. Among hematological toxicities, erythrocytosis has been rarely investigated, and its clinical pattern and management remain unclear. We conducted a retrospective cohort study including patients with any advanced thyroid cancer histology treated with antiangiogenic or targeted therapies between 2012 and 2023 at two Italian referral centers. Therapies included RET inhibitors (RETi: selpercatinib, pralsetinib), cabozantinib, the BRAF/MEK inhibitor combination dabrafenib + trametinib, lenvatinib, sorafenib, and vandetanib. Erythrocytosis, defined according to 2022 World Health Organization criteria, was assessed through serial hemoglobin and hematocrit measurements up to 36 months from treatment start. Associations with clinical variables, event-free survival (EFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and acute vascular events were assessed using Fisher's exact and regression models, as appropriate. Among 173 screened patients, 135 were included in the final analysis (median follow-up 68.5 months). Erythrocytosis occurred in 24 patients (17.8%), with 16/24 (66.6%) experiencing recurrent events (total: 50). Median time to onset was 1.28 months (Q1-Q3: 0.76-5.14). RETi showed the highest incidence (46.7%), followed by vandetanib (20.7%). Among 14/24 tested patients, no JAK2 V617F or exon 12 alterations were detected. Management involved temporary treatment interruption in 60.0% (30/50) of events, with 53.3% (16/30) resuming at a reduced dose; in selected cases (4/9, 44.4%), hematology-guided phlebotomy was performed without drug discontinuation. Erythrocytosis was not associated with EFS, OS, or ORR, but was associated with higher DCR (p = 0.031). Incidence of acute vascular events was comparable among patients with (8.3%) and without (14.4%) erythrocytosis. Erythrocytosis represents an underrecognized, early, recurrent, and indolent adverse event of antiangiogenic and targeted therapies, particularly RETi, in advanced thyroid cancer. Its biological mechanisms and optimal management strategies warrant further investigation.
N7-methylguanosine (m7G) modification plays a critical role in RNA metabolism and is increasingly recognized for its implications in cancer biology. It can influence RNA stability, translation efficiency, and gene expression regulation. However, the specific role of m7G modification and its downstream genes in thyroid carcinoma (THCA) is not well understood. To comprehensively explore the impact of m7G methylation modification and the m7G-related gene ZNF831 on THCA, this study aims to identify key genes influencing m7G modification in THCA, with a particular focus on clarifying the role of ZNF831. This study is expected to further elucidate the pathological mechanisms of THCA and fill the current research gap in this field. Weighted gene co-expression network (WGCNA) analysis was used to evaluate the expression of m7G-related genes in the THCA expression data from the GEO (Gene Expression Omnibus) datasets. Machine learning algorithms, including the least absolute shrinkage and selection operator (LASSO), gradient boosting decision tree (XGBoost), and random forest (RF), were used to identify the feature genes, including GPSM3 and ZNF831, in the TCGA-THCA dataset. Immunohistochemistry was used to identify the expression difference of ZNF831 in 3 THCA tissues and 3 normal tissues. Finally, the changes of proliferation and migration of THCA cells after overexpression of ZNF831 were investigated. This study investigated m7G-related genes in THCA, focusing on ZNF831 as a key tumor suppressor. Differential expression analysis revealed significant dysregulation of m7G-related genes in THCA. Functional and bioinformatics analyses, including gene set enrichment analysis and protein-protein interaction network construction, identified ZNF831 as a candidate gene. Experimental validation demonstrated that ZNF831 overexpression significantly reduced the proliferation and migration of THCA cells. Additionally, tumor microenvironment analysis showed a positive correlation between ZNF831 expression and immune cell infiltration, indicating its potential role in enhancing anti-tumor immunity. These findings underscore the importance of m7G modifications and m7G-related gene ZNF831 in THCA pathogenesis, highlighting their potential as therapeutic targets. Further research is needed to elucidate the molecular mechanisms and explore clinical applications of these findings.