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Objective
Previous reports suggest that a high body mass index (BMI) increases the risk of thyroid carcinoma. However, it remains unclear whether a high BMI is associated with the risk of the BRAFV600E mutation. We aimed to assess whether a high BMI is associated with an increased risk of the BRAFV600E mutation.
Design and Methods
We screened 6558 PTC patients who had undergone BRAFV600E mutation testing between January 2009 and December 2017. After exclusion, 6438 PTC patients were enrolled. We used logistic regression, and restricted cubic spline plots of the adjusted odds ratios (ORs) were illustrated to model the relationship between BMI and the BRAFV600E mutation.
Results
Of the 6438 patients, 5102 (79.2%) had the BRAFV600E mutation, and 4954 (76.9%) were female. The median BMI was 23.8 (21.6–26.2) kg/m2. The primary tumor size was ≤1 cm in 4226 patients (65.6%) and >1 cm in 2212 patients (34.4%). The BRAFV600E mutation was significantly associated with high BMI only in patients with a primary tumor size >1 cm (OR: 1.034; 95% CI: 1.003–1.065; P = 0.029), whereas no clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; 95% CI: 0.984–1.030; P = 0.570). Gender was not a significant factor in either group.
Conclusions
Our study found that a higher BMI was positively associated with the BRAFV600E mutation in patients with a primary tumor size >1 cm. These results suggest that the association between BMI and the BRAFV600E mutation status differs depending on primary tumor size.
Significance Statement
Obesity has been suggested as a potential risk factor for thyroid carcinoma. The aim of this study was to assess the association between BMI and the BRAFV600E mutation. In this study, the BRAFV600E mutation was significantly associated with a high BMI only in a primary tumor size >1 cm (OR: 1.034; P = 0.029). No clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; P = 0.570). The association between BMI and the BRAFV600E mutation status differs depending on the primary tumor size.
Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, South Korea
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Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
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Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
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Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
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Department of Pediatrics, Gyeongsang National University College of Medicine, Jinju, South Korea
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Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
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Objective
This study examined the effect of sirtuin 4 (SIRT4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC).
Methods
Data from The Cancer Genome Atlas (TCGA) were analyzed to identify SIRT4 expression in thyroid cancer. Subsequently, the correlation between SIRT4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated SIRT4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model.
Results
Gene Expression Omnibus (GEO) and TCGA data indicated that SIRT4 expression is lower in thyroid cancer and SIRT4 downregulation is associated with poor overall survival. In PTC tissues, positive SIRT4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of SIRT4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. SIRT4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial–mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model.
Conclusion
This study provides novel insight into the potential contribution of SIRT4 to the regulation of the pathological progression of PTC. The data suggest that SIRT4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of SIRT4.
Research Institute Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, the Netherlands
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Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, Massachusetts, USA.
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Department of Pediatric Endocrinology. Emma children’s hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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The Pulmonary Center and Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
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The Pulmonary Center and Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
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Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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Research Institute Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, the Netherlands
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Background
Mutations in TBL1X, part of the NCOR1/SMRT corepressor complex, were identified in patients with hereditary X-linked central congenital hypothyroidism and associated hearing loss. The role of TBL1X in thyroid hormone (TH) action, however, is incompletely understood. The aim of the present study was to investigate the role of TBL1X on T3-regulated gene expression in two human liver cell models.
Methods
A human hepatoma cell line (HepG2) wherein TBL1X was downregulated using siRNAs, and human-induced pluripotent stem cell-derived hepatocytes (iHeps) generated from individuals with a TBL1X N365Y mutation. Both cell types were treated with increasing concentrations of T3. The expression of T3-regulated genes was measured by qPCR.
Results
KLF9, CPT1A, and PCK1 mRNA expression were higher upon T3 stimulation in the HepG2 cells with decreased TBL1X expression compared to controls, while DIO1 mRNA expression was lower. Hemizygous TBL1X N365Y iHeps exhibited decreased expression of CPT1A, G6PC1, PCK1, FBP1, and ELOVL2 compared to cells with the heterozygous TBL1X N365Y allele, but KLF9 and HMGCS2 expression was unaltered.
Conclusion
Downregulation of TBL1X in HepG2 cells and the TBL1X N365Y variant in iHeps have differential effects on T3-regulated gene expression. This suggests that TBL1X may play a gene context role in TH action.
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Objective. The ultrasound evaluation of thyroid nodules (TN) in patient selection for fine needle aspiration (FNA) requires both uniformly accepted definitions of each nodule characteristic and extensive experience of the examiner. We hypothesized that nodule echogenicity alone may provide comparable performance to the more complex approaches, in patient selection for FNA.
Patients and Methods. Seven highly experienced investigators from four countries evaluated, online, the ultrasound (US) video recordings of 123 histologically verified TN, by answering 17 nodule characteristics-related questions. The diagnostic performances of five TN image reporting and data systems (TIRADS) were compared to making decisions based alone on echogenicity of the nodule, for indicating FNA in 110 nodules ≥10 mm.
Results. In the 10 to 20 mm size range, the sensitivities and specificities of the five TIRADS systems in identifying malignant nodules was 80.5%-91.0%, and 31.4-50.9%, respectively. Had FNA been recommended in all hypoechoic nodules, disregarding other US characteristics, comparable sensitivity and specificity (87.5% and 43.4%, respectively) were obtained. Compared to nodules >20mm, a higher proportion of cancers were hypoechoic in the 10 to 20 mm size range (87.2% vs. 77.8%, p=0.05). In the 10-20 mm size range, compared to hypoechoic nodules, a significantly lower proportion of isoechoic nodules demonstrated suspicious findings (70.7% vs. 30.0%, p<0.05).
Conclusion. In contrast to >20 mm diameter nodules, the recommendation of FNA may rely on a single US feature, echogenicity, in the 10-20 mm size range. If independently confirmed in larger cohorts, this may simplify nodule evaluation in this size range.
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Objectives: When exposed to iodine contrast medium (ICM), thyroid dysfunction may develop, due to excess amounts of iodide. The incidence of contrast-induced thyroid dysfunction has been difficult to interpret, because of the observational and retrospective designs of most previous studies. With the Swedish CArdioPulmonary bioImage Study (SCAPIS), where randomly selected individuals aged 50–65 years, underwent contrast-enhanced coronary CT angiography (CCTA), we were able to prospectively assess the incidence, magnitude and clinical impact of contrast-induced thyroid dysfunction.
Methods: In 422 individuals, thyroid hormone levels were analysed before and 4–12 weeks after CCTA. Thyroid-related patient-reported outcome questionnaires (ThyPRO) at the time of pre and post CCTA blood samplings were provided by 368 of those individuals. Thyroid peroxidase antibodies (TPOab) were analysed and ultrasound of the thyroid gland was performed to detect any thyroid nodules.
Results: There was a small statistically significant effect on thyroid hormone levels but no cases of overt hypo- or hyperthyroidism after ICM. Subclinical hypo- or hyperthyroidism or isolated low/high levels of free thyroxine (fT4) developed in 3.5% of the population with normal hormone levels pre-CCTA, but without any increased thyroid-related symptoms compared to the remaining cohort. Elevated TPOab and being born outside Sweden were risk factors of developing subclinical hypothyroidism. Presence of thyroid nodules was not associated with ICM-induced thyroid dysfunction.
Conclusion: The results of this prospective study support the notion that in iodine-sufficient countries, ICM associated thyroid dysfunction is rare, usually mild, self-limiting and oligo/asymptomatic in subjects aged 50–65 years.
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Objective
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis, and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signaling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized that epigenetic mechanisms may be involved in modulating hepatic TH action.
Methods
Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2 cells were used to validate the functional binding of miRNA to predicted targets. DNA methylation was analyzed by bisulfite pyrosequencing.
Results
miR-34a-5p was upregulated in MASH patients and correlated positively with the clinical parameters of MASH. Using in silico and in vitro analysis, we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by the functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2 cells reduced the expression of THRA, THRB, DIO1, and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As an additional regulatory mechanism, DNA methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression.
Conclusion
miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB-specific DNA methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.
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Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70-year-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment, and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.
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Objective:
Hyperthyroidism increases cardiovascular morbidity and mortality, but the underlying mechanisms are not fully understood. In this study we compared non-invasive haemodynamics between 20 hyperthyroid patients and 60 euthyroid subjects.
Methods:
The measurements were performed median 6 days after the initiation of antithyroid medication when the patients were still hyperthyroid. Three controls matched for age, sex, body mass index, and smoking status were selected for each patient. Recordings were performed during rest and passive head-up tilt using whole-body impedance cardiography, radial pulse wave analysis, and finger blood pressure measurements.
Results:
Systolic and diastolic blood pressures in the aorta and radial artery were similar in hyperthyroid and euthyroid subjects, while finger blood pressure was 16/12 mmHg lower in hyperthyroidism (p<0.001). Pulse wave velocity and aortic pulse pressure were similar, but radial pulse pressure was ~5 mmHg higher in hyperthyroidism (p=0.040) due to augmented amplification (p=0.045). Systemic vascular resistance was reduced (-18%), whereas heart rate (+19 beats/min), cardiac index (+28%), and left cardiac work (+31%) were increased in hyperthyroidism (p<0.001). Subendocardial viability ratio, reflecting the balance between coronary perfusion and pressure load, was reduced by 19% in hyperthyroidism (p<0.001). Compared with euthyroid subjects, hyperthyroid patients presented with reductions in systolic and diastolic finger blood pressures (p<0.001), and higher increase in heart rate (p=0.014) during upright posture.
Conclusions:
Hyperthyroid patients exhibited hyperdynamic circulation, reduced vascular resistance, reduced peripheral but not central blood pressure, and higher pulse pressure amplification. Furthermore, left cardiac workload was increased in parallel with unfavourable changes in coronary perfusion conditions.
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