ResearchPad - no-longer-a-pain-in-the-neck—recent-insight-into-thyroid-growth-development-and-pathology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR28-01 Constitutive Activation of NRF2 Antioxidant Response Leads to Age-Dependent Goiter and Compensated Hypothyroidism in Male Mice]]> https://www.researchpad.co/article/elastic_article_7026 Background: Familial non-toxic multinodular goiter (MNG) is a rare disease. KEAP1 gene (Kelch-like ECH-associated protein 1) that encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses, has been found to be one of the mutated genes that lead to familial MNG. The proposed association of KEAP1 with familial MNG is based on only two loss-of-function mutations in respective Japanese families, only one of which included proper phenotyping and demonstration of co-segregation of phenotype and mutation. To date, there is no experimental evidence from model organisms to support that decreased Keap1 levels can cause goiter. Hypothesis: We hypothesized that enhanced Nrf2 signaling induced by loss of Keap1 function in mice can lead to goiter. Methods: To this end, male Keap1 hypomorphic C57BL/6J mice that express ~80% less Keap1 in their tissues (Keap1 knockdown mice:“Keap1KD”) were studied at 3 and 12 months of age and compared to wild-type mice (WT). Plasma, thyroids and pituitary glands were collected for assessment of thyroid function by radioimmunoassays and for histology as well as gene and protein expression by quantitative PCR and immunoblotting respectively. Results: Keap1KD showed diffuse goiter that began to develop in early adult life and became highly prominent at the age of 12 months when the thyroids of Keap1KD were 6-fold heavier than WT. Histomorphometry assessment of thyroids showed that Keap1KD had ~3-fold larger follicle area and colloid compartment but no thyroid nodules or hyperplasia was detected. Keap1KD also showed primary hypothyroidism already in early adult life that was eventually well-compensated over time by increased TSH levels (at age of 12 months: WT TSH=47.7±9.1 mU/L, Keap1KD TSH=460±74 mU/L). This was also reflected in the pituitary gland of Keap1KD where Tshb mRNA was ~3-fold higher than WT. Despite a known stimulatory effect of Nrf2 on Tg gene transcription and Tg protein abundance, these measures were decreased in the thyroid of Keap1KD mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, such as Duox1, Duoxa1, Duox2, Duoxa2, Tpo, Nis, Dio1, Dio2, Dehal1 mRNA levels, with the exception of Tg-processing and Tg-degrading cathepsins, including an increase in mature forms of cathepsins D, L and S. Conclusions: Keap1KD mice showed age-dependent diffuse goiter and compensated hypothyroidism. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation. This study unravels novel roles of the druggable Keap1/Nrf2 pathway in thyroid function and economy. Subclinical hypothyroidism in Keap1KD mice may have broader implications regarding their use in metabolic research.

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<![CDATA[OR28-05 Approaching Indeterminate Thyroid Nodules in the Absence of Molecular Markers. “The BETH-TR Score”]]> https://www.researchpad.co/article/N87cb2358-9968-4663-9f02-0c229da487a8 Context: Given the lack of easy access to molecular markers, for indeterminate thyroid nodules (Bethesda (BETH) category III, IV), the clinician can either decide to get a second opinion from an expert high volume thyroid cytopatholgist, re-do the FNAC after a period of 3-6 months or send the patient for a diagnostic hemithyroidectomy. Reviewing the sonographic risk features is also one way of triaging these nodules. The ACR-TIRADS (TR) is an objective method of sonographic risk assessment and is superior to other forms of sonographic classification. Aim: We propose combining the scoring of TR category and BETH category (both expressed as numerical value and summated) and look at the score which could potentially guide the clinician in deciding whom to send for surgery. Settings and Design: Observational Prospective collection of consecutive patient data from Thyroid FNAC clinic. Statistical analysis used: The BETH categories were represented numerically and summated with the TR category. The categorical outcome variables of Benign and Malignant nodules and the summated score was analysed using Kruskal-Wallis test. Results: We analysed 450 FNAC data, out of which 403 were thyroid nodule aspirates. Out of these nodules, 96 of them underwent surgery and 64% of these nodules were malignant on final histopathology (Malignant=62 and Benign=34). The mean (sd) size of the benign nodules was 3.6 (2.2)cm compared to 2.8 (1.8)cm of the malignant nodules. After excluding those with BETH 1 (n=4), the mean BETH-TR score for benign nodules was 6(1.4) and malignant nodules 9.4(2.1) (p<0.0001). The BETH-TR score progressively increased from 7.3(0.92) in Follicular thyroid cancers (FTC) to 8.6(1.4) in Follicular variant Papillary thyroid cancer (FVPTC) to 10(1.3) in classic Papillary thyroid cancers (PTC). Among the indeterminate nodules (BETH III & IV; n=40), the BETH-TR score of benign nodules was 6.75(1) and malignant nodules was 7.5(0.72) (p value=0.01). A BETH-TR score >=7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases (Likelihood ratio 3.5; ROC area: 0.8841; CI 0.79-0.94). Conclusion: A combined sono-cytological BETH-TR score is one way to triage management of indeterminate thyroid nodules. A BETH-TR score >=7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases.

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<![CDATA[OR28-03 Drug Repurposing Identifies Inhibitors of the Proteostasis Network to Augment Radioiodine Uptake in Combinatorial Approaches Targeting Thyroid Cancer]]> https://www.researchpad.co/article/Na41dbd79-642b-43a4-8149-dd36c6e45464 2 SD above mean. Categorisation of these revealed a high proportion of drugs that modulate the proteostasis network (19/48; ~40%), including key processes in protein homeostasis such as endoplasmic reticulum-associated protein degradation (ERAD) and autophagy. Secondary screening validated the activity of proteostasis modulators in enhancing iodide uptake after ranking 73 leading compounds based on their pharmacologic (AUC, EMAX and EC50) and specificity of response (NIS+ve vs NIS-ve YFP-thyroid cells) at ten different drug doses (0.1 to 50 μM). Of importance, several repurposed drugs (e.g. ebastine, Prestwick N, Prestwick C and clotrimazole) in combination with the HDAC inhibitor vorinostat induced a robust enhancement in RAI uptake in thyroid cancer cells (TPC-1 and 8505C NIS+ve cells, up to 11-fold vs DMSO, P<0.001), which was significantly greater than using vorinostat alone (up to 3-fold, P<0.01). For clotrimazole, we designed 7 new chemical derivatives, 3 of which showed enhanced aqueous solubility and retained the ability to significantly enhance RAI uptake. TaqMan RT-PCR revealed that, in contrast to vorinostat, our repurposed drugs failed to alter NIS mRNA expression, highlighting post-transcriptional mechanisms. Critically, 11 repurposed drugs induced significant gains in RAI uptake in human primary thyroid cells (up to 4.1-fold; P<0.05), the most physiological setting for NIS function. In conclusion, we performed high-throughput screening and identified proteostasis modulators, as well as other repurposed drugs, that markedly enhance radioiodine uptake. Further clinical investigation of these drugs might offer new combinatorial approaches, especially with existing therapies, to improve the treatment of thyroid cancer. ]]> <![CDATA[OR28-04 Identification of Novel and Rare Receptor Tyrosine Kinase Fusions in Thyroid Fine Needle Aspirates]]> https://www.researchpad.co/article/Nb67beab6-9bdf-41aa-b2bf-a66252e267ae 37,000 Bethesda III-VI samples were examined with STAR-fusion to determine gene/gene fusions. All samples were examined for NTRK1, NTRK3, RET, ALK, and BRAF fusions, regardless of fusion partner. Fusions were evaluated for being in-frame, with an intact kinase domain at the 3’ end of the fusion pair. Fusion pairs not currently reported by XA and not reported in thyroid TCGA fusion data are denoted “additional”. All fusion pairs were searched for in the literature and public fusion databases. Results: Examining the Veracyte clinical database revealed 7 additional NTRK1/3 fusions, with 3 NTRK fusions observed more than once - SQSTM1/NTRK3, VIM/NTRK3, and EML4/NTRK3. One of the 7 NTRK fusions had not been previously reported. Eight additional ALK fusions were identified, with 4 observed more than once- ITSN2/ALK, PPP1R21/ALK, PDE8B/ALK, NPAT/ALK. Five of these 8 ALK fusions had not been previously described. Seventeen additional RET fusions were identified, with 5 observed recurrently - KIAA1217/RET, AFAP1L2/RET, ACBD5/RET, SQSTM1/RET, and TFG/RET. Six of the 17 RET fusions had not been previously reported. Seventy-two additional BRAF fusions were identified, and 58 of them have not been previously reported. Eight of the 72 BRAF fusions were observed more than once. Examining >50,000 Afirma samples, NTRK1, NTRK3, RET, ALK, or BRAF fusions were not identified among the Afirma GSC Benign, and were present in 3.2% of 16,594 Bethesda III/IV Afirma GSC Suspicious samples, and 8.0% of 1,692 Bethesda V/VI samples. Correlation with surgical histology is unknown. Conclusions: By examining a large cohort of patients with an unbiased, whole-transcriptome RNA-seq assay, we identified potentially actionable kinase fusions in thyroid nodules beyond those described in TCGA. All fusions described here are either novel and not previously reported, rarely reported in one or two case studies, or not described in thyroid cancers. Additional NTRK, ALK, RET and BRAF fusions were found, all of which may be targeted with specific kinase inhibitors currently available. Future studies may determine genotype-phenotype correlations regarding the natural history of these neoplasms. Because of the potential clinical implications of these genomic markers for patient management, all 104 fusions described here are now included among the 235 gene pairs reported by the expanded Afirma XA. ]]> <![CDATA[OR28-06 Assessment of Long Term Quality of Life According to Treatment Options in Low Risk Papillary Thyroid Microcarcinoma Patients ‐ Active Surveillance or Immediate Surgery, (A Follow up Interim Analysis of Maestro)]]> https://www.researchpad.co/article/N5850de07-e96f-44bc-aae2-d792278e2d16 <![CDATA[OR28-07 Increased BMI Is Associated With Anti PD-1/PD-L1-Induced Thyroid Immune-Related Adverse Events]]> https://www.researchpad.co/article/N8dda55b7-93af-4ebf-9474-a26cf02bca8c