Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

Pathogenesis of cancers derived from thyroid follicular cells.

The genomic simplicity of differentiated cancers derived from thyroid follicular cells offers unique insights into how oncogenic drivers impact tumour phenotype. Essentially, the main oncoproteins in thyroid cancer activate nodes in the receptor tyrosine kinase-RAS-BRAF pathway, which constitutively induces MAPK signalling to varying degrees consistent with their specific biochemical mechanisms of action. The magnitude of the flux through the MAPK signalling pathway determines key elements of thyroid cancer biology, including differentiation state, invasive properties and the cellular composition of the tumour microenvironment. Progression of disease results from genomic lesions that drive immortalization, disrupt chromatin accessibility and cause cell cycle checkpoint dysfunction, in conjunction with a tumour microenvironment characterized by progressive immunosuppression. This Review charts the genomic trajectories of these common endocrine tumours, while connecting them to the biological states that they confer.

Simulation Model for Hashimoto Autoimmune Thyroiditis Disease.

Hashimoto thyroiditis (HT) is a pathology that often causes a gradual thyroid insufficiency in affected patients due to the autoimmune destruction of this gland. The cellular immune response mediated by T helper lymphocytes TH1 and TH17 can induce the HT disease. In this pathologic condition, there is an imbalance between the TH17 and Treg lymphocytes as well as a gut microbiota dysfunction. The objective of this work was to describe the interactions of the cell subpopulations that participate in HT. To achieve this goal, we generated a mathematical model that allowed the simulation of different scenarios for the dynamic interaction between thyroid cells, the immune system, and the gut microbiota. We used a hypothetical-deductive design of mathematical modeling based on a system of ordinary differential equations, where the state variables are the TH1, TH17, and Treg lymphocytes, the thyrocytes, and the bacteria from gut microbiota. This work generated a compartmental model of the cellular immune response occurring in the thyroid gland. It was observed that TH1 and TH17 lymphocytes could increase the immune cells' activity, as well as activate effector cells directly and trigger the apoptosis and inflammation processes of healthy thyrocytes indirectly. Likewise, the model showed that a reduction in Treg lymphocytes could increase the activity of TH17 lymphocytes when an imbalance of the gut microbiota composition occurred. The numerical results highlight the TH1, TH17, and bacterial balance of the gut microbiota activities as important factors for the development of HT disease.

Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells.

Stromal interaction molecule 1 (STIM1) and the ORAI1 calcium channel mediate store-operated calcium entry (SOCE) and regulate a multitude of cellular functions. The identity and function of these proteins in thyroid cancer remain elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared to primary thyroid cells. Knock-down of STIM1 or ORAI1 attenuated SOCE, reduced invasion, and the expression of promigratory sphingosine 1-phosphate and vascular endothelial growth factor-2 receptors in thyroid cancer ML-1 cells. Cell proliferation was attenuated in these knock-down cells due to increased G1 phase of the cell cycle and enhanced expression of cyclin-dependent kinase inhibitory proteins p21 and p27. STIM1 protein was upregulated in thyroid cancer tissue, compared to normal tissue. Downregulation of STIM1 restored expression of thyroid stimulating hormone receptor, thyroid specific proteins and increased iodine uptake. STIM1 knockdown ML-1 cells were more susceptible to chemotherapeutic drugs, and significantly reduced tumor growth in Zebrafish. Furthermore, STIM1-siRNA-loaded mesoporous polydopamine nanoparticles attenuated invasion and proliferation of ML-1 cells. Taken together, our data suggest that STIM1 is a potential diagnostic and therapeutic target for treatment of thyroid cancer.

Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death.

Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.

Cell competition between anaplastic thyroid cancer and normal thyroid follicular cells exerts reciprocal stress response defining tumor suppressive effects of normal epithelial tissue.

The microenvironment of an early-stage tumor, in which a small number of cancer cells is surrounded by a normal counterpart milieu, plays a crucial role in determining the fate of initiated cells. Here, we examined cell competition between anaplastic thyroid cancer cells and normal thyroid follicular cells using co-culture method. Cancer cells were grown until they formed small clusters, to which normal cells were added to create high-density co-culture condition. We found that co-culture with normal cells significantly suppressed the growth of cancer cell clusters through the activation of Akt-Skp2 pathway. In turn, cancer cells triggered apoptosis in the neighboring normal cells through local activation of ERK1/2. A bi-directional cell competition provides a suppressive mechanism of anaplastic thyroid cancer progression. Since the competitive effect was negated by terminal growth arrest caused by radiation exposure to normal cells, modulation of reciprocal stress response in vivo could be an intrinsic mechanism associated with tumor initiation, propagation, and metastasis.

Pathological thyroid findings in amiodarone-induced thyrotoxicosis.

Amiodarone (AMD) is a class III antiarrhythmic drug whose chronic or high dosage administration alters the tests of thyroid function. AMD is also associated with hypothyroidism or thyrotoxicosis. Total thyroidectomy is an efficient treatment of AMD-induced thyrotoxicosis in cases resistant to medical therapy, worsening of cardiac function and/or severe thyrotoxicosis. Although AMD is a widely used drug, its pathological consequences are not well known. We describe the pathological findings in the thyroid gland of a patient who underwent total thyroidectomy due to AMD-induced thyrotoxicosis. The surgical specimen was macroscopically normal, but histologically showed multiple follicles totally or partially invaded by clear vacuolated (foamy) histiocytes, sometimes multinucleated. Loss of thyrocytes, breaks in the follicular basal membrane and stromal fibrosis could also be appreciated but no lymphocytic infiltrates were found. An awareness of these histopathological features is particularly important for surgical pathologists, especially as there are very few published reports describing these alterations.

Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer.

The primary cilium is well-preserved in human differentiated thyroid cancers such as papillary and follicular carcinoma. Specific thyroid cancers such as Hürthle cell carcinoma, oncocytic variant of papillary thyroid carcinoma (PTC), and PTC with Hashimoto's thyroiditis show reduced biogenesis of primary cilia; these cancers are often associated the abnormalities in mitochondrial function. Here, we examined the association between primary cilia and the mitochondria-dependent apoptosis pathway. Tg-Cre;Ift88flox/flox mice (in which thyroid follicles lacked primary cilia) showed irregularly dilated follicles and increased apoptosis of thyrocytes. Defective ciliogenesis caused by deleting the IFT88 and KIF3A genes from thyroid cancer cell lines increased VDAC1 oligomerization following VDAC1 overexpression, thereby facilitating upregulation of mitochondria-dependent apoptosis. Furthermore, VDAC1 localized with the basal bodies of primary cilia in thyroid cancer cells. These results demonstrate that loss-of-function of primary cilia results in apoptogenic stimuli, which are responsible for mitochondrial-dependent apoptotic cell death in differentiated thyroid cancers. Therefore, regulating primary ciliogenesis might be a therapeutic approach to targeting differentiated thyroid cancers.

The impact of repeat fine-needle aspiration in thyroid nodules categorized as atypia of undetermined significance or follicular lesion of undetermined significance: A single center experience.

BACKGROUND: Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) is the most controversial category of the Bethesda System. The present study was conducted to compare the histological findings in a series of thyroid nodules diagnosed with AUS/FLUS after single or repeat fine needle aspiration (FNA) cytology. METHODS: Retrospective analysis of our institution's series of 514 patients with an initial diagnosis of AUS/FLUS between 11/2011 and 02/2020. RESULTS: Of 4887 FNA samples, 11.8% were classified as AUS/FLUS. Of patients with an initial AUS/FLUS diagnosis, 11.5% (59/514) underwent surgery after a single FNA, 55.4% (285/514) had a repeat FNA, and 32.7% (168/514) were either observed or lost to follow-up. Surgical pathology was available in 123 cases (23.9%), and malignancy was confirmed in 32.5% (40/123) cases, with similar rates in the single 32.2% (19/59) and repeat FNA 32.8% (21/64) groups. Repeat FNA reclassified 78.9% of the AUS/FLUS cases to a different category: 57.2% were reclassified as benign, 10.5% as follicular neoplasm, and 5.6% as suspicious for malignancy or malignant. The rates of nonneoplastic benign lesions were 52.5% (31/59) and 31.2% (20/64) in the single and repeat FNA groups, respectively (P = .018). The rates of follicular adenomas were higher when repeat FNA was performed (23/64, 35.9%) compared with a single FNA (9/59; 15.2%) (P = .013). CONCLUSION: In this series, a repeat FNA in cases of AUS/FLUS increased detection of follicular adenomas but not the detection of malignancy. Repeat FNA reduced the rate of benign nonneoplastic lesions by 40% in the surgical samples.

Pro64His (rs4644) Polymorphism Within Galectin-3 Is a Risk Factor of Differentiated Thyroid Carcinoma and Affects the Transcriptome of Thyrocytes Engineered via CRISPR/Cas9 System.

Background: Galectin-3 (LGALS3) is an important glycoprotein involved in the malignant transformation of thyrocytes acting in the extracellular matrix, cytoplasm, and nucleus where it regulates TTF-1 and TCF4 transcription factors. Within LGALS3 gene, a common single-nucleotide polymorphism (SNP) (c.191C>A, p.Pro64His; rs4644) encoding for the variant Proline to Histidine at codon 64 has been extensively studied. However, data on rs4644 in the context of thyroid cancer are lacking. Thus, the aim of the present work was to evaluate the role of the rs4644 SNP as risk factor for differentiated thyroid cancer (DTC) and to determine the effect on the transcriptome in thyrocytes. Methods: A case/control association study in 1223 controls and 1142 unrelated consecutive DTC patients was carried out to evaluate the association between rs4644-P64H and the risk of DTC. We used the nonmalignant cell line Nthy-Ori (rs4644-C/A) and the CRISPR/Cas9 technique to generate isogenic cells carrying either the rs4644-A/A or rs4644-C/C homozygosis. Then, the transcriptome of the derivative and unmodified parental cells was analyzed by RNA-seq. Genes differentially expressed were validated by quantitative reverse transcription PCR and further tested in the parental Nthy-Ori cells after LGALS3 gene silencing, to investigate whether the expression of target genes was dependent on galectin-3 levels. Results: rs4644 AA genotype was associated with a reduced risk of DTC (compared with CC, ORadj = 0.66; 95% confidence interval = 0.46-0.93; Pass = 0.02). We found that rs4644 affects galectin-3 as a transcriptional coregulator. Among 34 genes affected by rs4644, HES1, HSPA6, SPC24, and NHS were of particular interest since their expression was rs4644-dependent (CC>AA for the first and AA>CC for the others), also in 574 thyroid tissues of Genotype-Tissue Expression (GTEx) biobank. Moreover, the expression of these genes was regulated by LGALS3-silencing. Using the proximity ligation assay in Nthy-Ori cells, we found that the TTF-1 interaction was genotype dependent. Conclusions: Our data show that in thyroid, rs4644 is a trans-expression quantitative trait locus that can modify the transcriptional expression of downstream genes, through the modulation of TTF-1.

Thyroid parafollicular cell hyperplasia and carcinoma in a sheep with enzootic calcinosis due to Nierembergia rivularis poisoning / [Hiperplasia e carcinoma de células parafoliculares da tireóide em ovino com calcinose enzoótica associada a intoxicação por Nierembergia rivularis]

Calcinose enzoótica, causada por Nierembergia rivularis, no Uruguai, e Nierembergia veitchii, no Brasil, é uma doença caracterizada por mineralização de tecidos moles, hiperplasia das células parafoliculares da tireoide e elevação nos níveis de cálcio e fósforo. Descreve-se um caso de hiperplasia e carcinoma de células parafoliculares bilateral em um ovino de quatro anos, com calcinose enzoótica associada à intoxicação por Nierembergia rivularis. O diagnóstico histológico de hiperplasia e carcinoma de células parafoliculares é suportado pelas marcações imuno-histoquímicas positivas para calcitonina, peptídeo relacionado ao gene da calcitonina e enolase neurônio específica. Como a hiperplasia de células parafoliculares é uma lesão pré-neoplásica induzida por hipercalcemia, sugere-se que a hipercalcemia crônica causada pela intoxicação por N. rivularis pode ter induzido hiperplasia de células parafoliculares seguida de transformação em carcinoma, neste caso. Os efeitos carcinogênicos das plantas calcinogênicas no sistema endócrino devem ser melhor explorados.(AU)

Relevance of rosette patterns in variants of papillary thyroid carcinoma.

INTRODUCTION: The detection of rosette-like clusters (RLC) of follicular cells in thyroid carcinoma has been reported mostly in the columnar cell variant of papillary thyroid carcinoma (PTC). Despite the fact that diagnosing variants of PTC is no longer encouraged by The Bethesda System for Reporting Thyroid Cytopathology, the identification of cytomorphological features such as RLC linked with these tumours might help reduce possible misinterpretation in thyroid fine needle aspiration (FNA) cytology. We accordingly investigated the potential correlation of architectural patterns including RLC with PTC variants. METHODS: We analysed 225 thyroid FNA cytology cases diagnosed as suspicious for malignancy (SFM) and positive for malignancy (M) over a 1-year time where all samples had corresponding histology. We also included 150 benign lesions from the same period. The presence of RLC vs similar appearing solid clusters, papillary structures and microfollicles were evaluated. We also performed immunocytochemistry and molecular testing for BRAFV600E. RESULTS: We included 100 (44.4%) SFM favouring PTC and 125 (55.6%) M cases with cyto-histological correlation. On histology, all SFM and M cases showed malignancy including 140 (62.2%) classic PTC and 85 (37.8%) PTC variants. The cytomorphological patterns in all FNA samples included solid (74%), papillary (89%), microfollicular (70%), and pseudo-RLC morphology (25.7%). We identified only pseudo-RLC in 33 FNA specimens from PTC variant cases that included tall cell variant (42.4%), hobnail variant (21.2%) and miscellaneous variants (36.3%) of PTC. No definitive RLC were detected in our series. Immunocytochemistry and BRAFV600E were not specifically linked with an RLC pattern. CONCLUSIONS: These findings demonstrate that in our dataset the architectural pattern of RLC was not recognised within PTC variants. However, we did identify a pseudo-RLC pattern that was observed in association with tall cell variant and hobnail variant cases of PTC.

Diagnóstico endoscópico de carcinoma pulmonar de célula pequeña y neoplasia folicular de tiroides / Endoscopic Diagnosis of Small Cell Lung Carcinoma and Follicular Thyroid Cancer

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Thyroid Follicular Cell Loss of Differentiation Induced by MicroRNA miR-17-92 Cluster Is Attenuated by CRISPR/Cas9n Gene Silencing in Anaplastic Thyroid Cancer.

Background: Loss of the expression of thyroid differentiation markers such as sodium iodide symporter (NIS) and, consequently, radioiodine refractoriness is observed in aggressive papillary thyroid cancer and anaplastic thyroid cancer (ATC) that may harbor the BRAFV600E mutation. Activation of the BRAFV600E oncogene in thyroid follicular cells induces the expression of the miR-17-92 cluster that comprises seven mature microRNAs (miRNAs). miRNAs are a class of endogenous small RNAs (∼22 nt) that regulate gene expression post-transcriptionally. Indeed, miR-17-92 is overexpressed in ATC, and in silico prediction shows the potential targeting of thyroid transcription factors and tumor suppressor pathways. In this study, we aimed to investigate the role of the miR-17-92 cluster in thyroid cell differentiation and function. Methods:miR-17-92 silencing was performed using CRISPR/Cas9n-guided genomic editing of the miR-17-92 gene in the KTC2 ATC cell line, and miR-17-92 cluster or individual miRNAs were overexpressed in PCCl3 thyroid cells to evaluate the influence in thyroid cell differentiation and cell function. Results: In this study, we demonstrate that CRISPR/Cas9n gene editing of the miR-17-92 cluster results in promotion of thyroid follicular cell differentiation (NIS, thyroperoxidase, thyroglobulin, PAX8, and NKX2-1 expression) in the KTC2 ATC cell line and inhibits cell migration and proliferation by restoring transforming growth factor beta (TGF-ß) signaling pathway responsiveness. Moreover, induction of the miR-17-92 cluster in normal thyroid follicular cells strongly impairs thyroid differentiation and induces a pro-oncogenic effect by blocking TGF-ß signaling and increasing cell migration. Conclusions:miR-17-92 is a potent regulator of thyroid follicular cell differentiation, and CRISPR/Cas9n-mediated editing of the miR-17-92 gene efficiently blocks miR-17-92 expression in the KTC2 ATC cell line, resulting in improvement of thyroid differentiation. Thus, targeting miR-17-92 could provide a potential molecular approach to restoring thyroid cell differentiation and NIS expression in aggressive thyroid cancer.

Immune cell infiltrate-associated dysregulation of DNA repair machinery may predispose to papillary thyroid carcinogenesis.

BACKGROUND: An altered immune microenvironment may contribute to papillary thyroid cancer development, as immune infiltrates are identified postoperatively in many papillary thyroid cancer cases with or without diagnosed thyroiditis. Oxygen radicals, endogenous or inflammation-induced, can generate DNA damage, which causes mutations when repaired incorrectly. We hypothesized that infiltrating immune cells might promote aberrant DNA repair, predisposing thyrocytes to papillary thyroid cancer. METHODS: Quantitative reverse-transcriptase polymerase chain reaction assays measured gene expression in fresh-frozen samples (n = 55). RNA-seq data was obtained for papillary thyroid cancer and normal thyroid samples from the Cancer Genome Atlas (n = 564), and Hashimoto's-affected and normal thyroids from the Genotype-Tissue Expression project (n = 279). Immune cell marker expression levels were compared to histological estimates and to selected DNA repair genes. Immunohistochemistry localized gene expression to specific cell types. RESULTS: DNA polymerase theta expression by quantitative reverse-transcriptase Polymerase chain reaction was higher in papillary thyroid cancer and papillary thyroid cancer-adjacent samples than in benign normal thyroid (P < .001). Immune markers including CD4 correlated with DNA polymerase theta expression (r = 0.50) but not other DNA repair genes examined. Benign tissue with Hashimoto's exhibited increased DNA polymerase theta (P < .0001) and CD3E (P < .0001) expression. DNA polymerase theta localized to thyrocytes, not lymphocytes. CONCLUSION: We identified a strong correlation between immune cell infiltrate and dysregulated thyrocyte DNA repair genes, likely reflecting a pathway to papillary thyroid cancer development.

Survival with Follicular and Hurthle Cell Microcarcinoma Compared to Papillary Thyroid Microcarcinoma: A Population Study of 84,532 Patients.

BACKGROUND: This study compares survival in patients with the rare subtypes of follicular (FTmC) and Hurthle cell (HCmC) microcarcinoma compared to that of papillary thyroid (PTmC) microcarcinoma. METHODS: Patients with FTmC and HCmC were selected from the National Cancer Database 2004-2015 and compared with PTmC. Patient clinicopathological characteristics and overall survival (OS) were analyzed. Multivariable logistic and Cox regression analysis evaluated binary outcomes and predictors of survival. A propensity score matched analysis using age, gender, race, extrathyroidal extension (ETE), nodal status, distant metastasis, radiation, and operation was performed to evaluate the difference in OS with FTmC, HCmC, and PTmC. RESULTS: We identified 858 FTmC, 476 HCmC, and 82,056 PTmC. FTmC was less likely to have macroscopic ETE compared to PTmC (2.6% vs. 3.1% p = 0.03), but more likely to have distant metastasis (2.3% vs. 0.2%, p < 0.01). FTmC and HCmC were less likely to have nodal metastasis (2.7%, 2.5% vs. 10.9%, p < 0.01). Ten-year OS was decreased in patients with FTmC (91.4%, p = 0.04) and HCmC (89.8%, p < 0.01) compared to PTmC (93.5%). On multivariable analysis, histology was not associated with OS. With HCmC, older age (OR 1.13, p < 0.01) and male gender (OR 2.72, p = 0.03) were associated with decreased OS. In propensity matched analysis, there was no difference in 10-year OS with FTmC and PTmC (91.4% vs. 93.7%, p = 0.54), but HCmC had decreased OS compared to PTmC (89.8% vs. 94.3%, p = 0.04). CONCLUSIONS: Patients with FTmC have comparable OS to those with PTmC, but HCmC has decreased OS especially in older and male patients.

Immunocytochemical characteristics of thyrocytes in radioiodine refractory metastases of papillary thyroid cancer.

The aim of the work was to carry out an immunocytochemical (ICC) study of thyroid peroxidase (TPO) and thyroglobulin (Tg) expression in the punctates of the radioiodine (RI) refractory and RI uptake metastases of thyroid papillary carcinoma (PTC), on the basis of which it is possible to develop new methods of preoperative prediction of RI resistance and RI therapy efficiency for thyroid papillary carcinoma metastases. MATERIALS AND METHODS: The ICC research was carried out on a fine needle aspiration biopsy material of 104 metastases that were found after thyroidectomy and RI therapy, i.e. in postoperative period (79 - radioiodine-refractory metastases, 25 - radioiodine-uptake metastases). The ICC analysis of TPO and Tg expression in PTC was performed with the use of monoclonal antibodies against TPO and Tg. RESULTS: RI-refractory (RIRM) and RI-uptake metastases of PTC significantly differ by the percentage of cells expressing TPO and Tg (p < 0.05, and p < 0.05 respectively). The effectiveness of RI therapy was different for patients with different percentages of TPO-positive cells. CONCLUSION: A statistically significant difference was demonstrated in the expression of TPO in a punctates of RI-resistant and RI-sensitive metastatic TPC, based on which a new method for preoperative prediction of RI resistance and RI therapy efficiency was developed. It was shown that ICC determination of Tg expression in metastases is effective in preoperative monitoring of RI resistance of PTC if the part of Tg-positive cells in punctates is lower than 56%. The comprehensive study of the ICC profile of thyrocytes in RI-uptake metastases punctates allows us to develop a personified approach to prediction, monitoring and therapy of patients with PTC.

Bilateral thyroid follicular compact-cellular carcinoma in a llama.

An 18-y-old female llama (Lama glama) in Saskatoon, Saskatchewan was examined during a routine herd check, and a mass was detected in the ventral cervical area just below the angle of the jaw. No clinical signs were evident except for the mass and chronic loss of body condition. Postmortem examination revealed bilateral enlargement of the thyroid gland with multiple cysts. Histopathology of the thyroid gland revealed follicular compact-cellular carcinoma lesions, with infiltration of neoplastic thyroid follicular cells in regional lymph nodes.

Basal Autophagy Deficiency Causes Thyroid Follicular Epithelial Cell Death in Mice.

Autophagy is a catabolic process that involves the degradation of cellular components through the lysosomal machinery, relocating nutrients from unnecessary processes to more pivotal processes required for survival. It has been reported that systemic disruption of the Atg5 or Atg7 gene, a component of autophagy, is lethal and that its tissue-specific disruption causes tissue degeneration in several organs. However, the functional significance of autophagy in the thyroid glands remains unknown. Our preliminary data imply the possible involvement of dysfunctional autophagy in radiation-induced thyroid carcinogenesis. Therefore, we evaluated the effect of Atg5 gene knockout (KO) on thyroid morphology and function. To this end, Atg5flox/flox mice were crossed with TPO-Cre mice, yielding the thyroid follicular epithelial cell (thyrocyte)‒specific ATG5-deficient mice (Atg5thyr-KO/KO). Atg5 gene KO was confirmed by a lack of ATG5 expression, and disruption of autophagy was demonstrated by a decrease in microtubule-associated protein 1 light chain 3-II puncta and an increase in p62. Atg5thyr-KO/KO mice were born normally, and thyroid morphology, thyroid weights, and serum T4 and TSH levels were almost normal at 4 months. However, at 8 and 12 months, a decrease in the number of thyrocytes and an increase in TUNEL+-thyrocytes were observed in Atg5thyr-KO/KO mice even though thyroid function was still normal. The number of irregularly shaped (gourd-shaped) follicles was also increased. Excess oxidative stress was indicated by increased 8-hydroxy-2'-deoxyguanosine and 53BP1 foci in Atg5thyr-KO/KO mice. These data demonstrate that thyrocytes gradually undergo degradation/cell death in the absence of basal levels of autophagy, indicating that autophagy is critical for the quality control of thyrocytes.