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Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid malignancy with high mortality rate. This malignancy arises in thyroid follicular cells either denovo or with an associated differentiated thyroid carcinoma component. Clinically, it usually presents as a rapidly enlarging mass, pain and locally compressive symptoms. Histopathologic variability and heterogeneity often pose diagnostic challenges, especially in scant and paucicellular specimens. This article describes the clinical, histopathologic and molecular features of ATC and also addresses the associated diagnostic limitations and challenges.

Stem cell-based therapies to reconstitute in vivo organ function hold great promise for future clinical applications to a variety of diseases. Hypothyroidism resulting from congenital lack of functional thyrocytes, surgical tissue removal, or gland ablation, represents a particularly attractive endocrine disease target that may be conceivably cured by transplantation of long-lived functional thyroid progenitors or mature follicular epithelial cells, provided a source of autologous cells can be generated and a variety of technical and biological challenges can be surmounted. Here we review the emerging literature indicating that thyroid follicular epithelial cells can now be engineered in vitro from the pluripotent stem cells (PSCs) of mice, normal humans, or patients with congenital hypothyroidism. We review the in vivo embryonic development of the thyroid gland and explain how emerging discoveries in developmental biology have been utilized as a roadmap for driving PSCs, which resemble cells of the early embryo, into mature functional thyroid follicles in vitro. Finally, we discuss the bioengineering, biological, and clinical hurdles that now need to be addressed if the goals of life-long cure of hypothyroidism through cell- and/or gene-based therapies are to be attained.

Thyroid cancer is the most frequent endocrine malignancy with the majority of cases derived from thyroid follicular cells and caused by sporadic mutations. However, when at least two or more first degree relatives present thyroid cancer, it is classified as familial non-medullary thyroid cancer (FNMTC) that may comprise 3–9% of all thyroid cancer. In this context, 5% of FNMTC are related to hereditary syndromes such as Cowden and Werner Syndromes, displaying specific genetic predisposition factors. On the other hand, the other 95% of cases are classified as non-syndromic FNMTC. Over the last 20 years, several candidate genes emerged in different studies of families worldwide. Nevertheless, the identification of a prevalent polymorphism or germinative mutation has not progressed in FNMTC. In this work, an overview of genetic alteration related to syndromic and non-syndromic FNMTC is presented.

Introduction: Thyroid disorders are very common all over India, more so in Kerala. Although definite histologic criteria exist for diagnosing various thyroid lesions, there is an overlap of many nuclear and cytoplasmic features like nuclear atypia, enlargement etc., between both non-neoplastic and neoplastic lesions. This sometimes leads to a diagnostic dilemma in differentiating these lesions. CD56 is expressed by many tissues in the body including normal thyroid follicular epithelium, this expressivity being absent or reduced in Papillary Thyroid Carcinoma (PTC). Normal thyroid follicular cells do not express p63. Aberrant expression of p63 on thyroid epithelium is thus a marker of proliferation and tumourigenesis. Aim: To assess the expression of CD56 and p63 in various nonneoplastic and neoplastic thyroid lesions and to calculate the percentage of positivity and negativity in these lesions. Materials and Methods: This was a prospective study of 100 thyroidectomy specimens submitted to the Department of Pathology, Govt. TD Medical College, Alappuzha from January 2016 to June 2017. H&E stained sections of these specimens were studied and Immunohistochemical (IHC) staining with CD56 and p63 markers was performed on all and their expressions, positive or negative, were evaluated and expressed as percentage values. Results: Out of 100 thyroidectomy specimens studied, total number of non-neoplastic cases was 58 and neoplastic lesions (benign and malignant) were 42. The most common nonneoplastic lesion was lymphocytic thyroiditis (39/58). Most common malignant thyroid neoplasm was PTC (35/42). CD56 showed membranous positivity in 53/58 (91.4%) non-neoplastic lesions and only 4/42 (9.5%) neoplastic lesions. Nuclear positivity for p63 was seen in only a small proportion (18/100, i.e., 18%) of all lesions. Conclusion: Significance of this study lies in the fact that CD56 is expressed in most non-neoplastic lesions of thyroid and is found negative in thyroid malignancies. The p63 even though considered to be a proliferation marker is negative in most of nonneoplastic as well as neoplastic lesions in the present study.

There are 5 main histological types of thyroid cancers (TCs): papillary, follicular (also known as differentiated), poorly differentiated, anaplastic (the most aggressive form), and medullary TC, and only the latter arises from thyroid C cells. These different forms of TCs show significant variability, both among and within tumours. This great variation is particularly notable among the first 4 types, which all originate from thyroid follicular cells. Importantly, this heterogeneity is not limited to histopathological diversity only but is also manifested as variation in several genetic and/or epigenetic alterations, the numbers of interactions between the tumour and surrounding microenvironment, and interpatient differences, for example. All these factors contribute to the great complexity in the development of a tumour from cancer cells. In the present review, we summarise the knowledge accumulated about the heterogeneity of TCs. Further research in this direction should help to gain a better understanding of the underlying mechanisms contributing to the development and diversity of TCs, paving the way toward more effective treatment strategies.

Follicular thyroid carcinoma (FTC), a form of differentiated thyroid carcinoma, is the second most common malignancy arising from thyroid follicular cells. Recently, the tumor-node-metastasis (TNM) classification for differentiated thyroid carcinoma was revised from the 7th to the 8th edition. The diagnostic criteria for poorly differentiated carcinoma (PDC) were also updated in the latest World Health Organization (WHO) classification. In this study, we investigated whether these changes are appropriate for accurately predicting prognosis. Three hundred and twenty-nine patients diagnosed with postoperative pathologically confirmed FTC, who underwent initial surgery at our hospital between 1984 and 2004, were enrolled. For this study, patients were re-evaluated and diagnosed with FTC (N = 285) or PDC (N = 44) without typical nuclear findings of papillary thyroid carcinoma. For FTC, the 8th TNM classification was a more accurate predictor of prognosis than the 7th TNM classification. In the 8th TNM classification, cause-specific survival became significantly poorer from Stage I to IVB. The cause-specific survival of PDC based on the latest WHO classification was worse than, but did not significantly differ from, that of PDC based only on the former WHO classification. For PDC, neither of the TNM classifications could accurately predict prognosis. Taken together, we conclude that (1) the 8th TNM classification more accurately reflects the prognosis of FTC than the 7th TNM classification; (2) PDC based on the former WHO classification should be retained, at least in Japan; and (3) the TNM classification may not be suitable for predicting the prognosis of PDC.

The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. Due to the limited number of representative model systems, there is limited understanding of fundamental thyroid biology as well as thyroid carcinogenesis. To fill the caveats in the understanding of thyroid cell biology, we aimed to develop an adult stem cell-derived three-dimensional (3D) organoid culture system using murine and human thyroid follicular cells (TFCs). We have succeeded to grow such an organoid culture system that harbours the complete machinery of hormone production visualised by the presence of colloid in the lumen and essential transporters and enzymes in a polarised cell layer. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1/TTF1. Moreover, the thyroid hormone precursor thyroglobulin is expressed in both cultures to similar levels as in tissue. Extensive characterisation furthermore identifies known and new biological insights in TFC subclassification, subcellular organisation and hormone production using state-of-the art techniques like single cell RNA sequencing, transmission electron microscopy and genome editing. These 3D in vitro cultures allow for a variety of thyroid-related studies including the progression of wild type cells towards cancer. Additionally, due to the success of generating patient-specific tumour organoids of primary differentiated thyroid carcinoma and metastasis, insights in drug resistance and metastases can be identified. In short, this newly developed organoid culture of murine and human wild type TFCs as well as tumour tissue opens up an extensive area of research that will help understand the drivers for growth and development of thyroid (cancer) cells and enable studies upon drug responsiveness.

Despite the availability of synthetic thyroid hormone (TH) for therapeutic use, many patients with hypothyroidism do not feel well on replacement doses of TH. Indeed, hypothyroid children may develop various behavioral issues if under- or overtreated for hypothyroidism, suggesting the need of better individualized therapy. The development of stem cell-based models of thyroid replacement would greatly facilitate the treatment of post-surgical and congenital hypothyroidism and our understanding of the causes of congenital hypothyroidism. To generate thyroid follicular cells from human induced pluripotent stem cells (hiPSCs), we utilize a directed differentiation approach by activating endogenous signaling pathways we have previously identified in the mouse. We are employing a hiPSC-line with a GFP reporter targeted to the NKX2-1 locus allowing us to identify and purify cells positive for the transcription factor NKX2-1. Using these cells, we confirmed that BMP4 and FGF2 led to the induction of thyroid progenitors from foregut endoderm, expressing the four transcription factors in thyroid development NKX2-1, PAX8, HHEX and FOXE1. Subsequent differentiation of the purified, NKX2-1-positive progenitors led to follicular cell maturation, expressing genes related to TH synthesis, such as TG, TSHR, NIS (SLC5A5) and TPO. To assess the in vivo function of these hiPSC-derived thyroid follicular cells, we grafted the cells under the kidney capsule of radioablated, immunocompromised mice. First, hypothyroidism was confirmed 4 weeks post-ablation by increased TSH and low T4 levels. Next, mice received matured hiPSC-derived follicular cells, undifferentiated hiPSCs or sham surgery and were monitored for 8 weeks. In this preliminary test, no difference in TH levels was detected between the three groups. However, the grafted follicular cells formed a distinct cell population with thyroid-like histology. In order to optimize our directed differentiation protocol further and obtain a purer thyroid progenitor population, we generated a hiPSC line carrying a tdTomato reporter targeted to the PAX8 locus in addition to the NKX2-1-GFP-reporter. After directed differentiation cells sorted for NKX2-1-GFP and PAX8-tdTomato showed high induction of NKX2-1, PAX8, HHEX and FOXE1 expression, as well as expression of TG and TPO. Utilizing this double-reporter hiPSC line will enhance our ability to generate mature follicular cells for transplantation.

Epidermal inclusion cyst (EIC) of the thyroid is extremely rare in the clinical practice. A handful of cases have been documented in the past in the world literature. A giant EIC of the thyroid is hitherto unreported. This lesion may arise from the squamous metaplasia of the thyroid follicular cells. Though non-neoplastic, giant forms can cause compression of the vital structures of the neck. In the present case, we have described a giant epidermal inclusion cyst successfully managed with surgical management.

Thyroid cancer incidence has been increasing over the past 40 years [1–4]. The histological and genetic profile distribution has been changing [3]. Majority of thyroid cancer are derived from thyroid follicular cells, consisting of papillary thyroid carcinoma (80%), follicular thyroid carcinoma (

The ability of thyroid follicular cells to take up iodine enables the use of radioactive iodine (RAI) for imaging and targeted killing of RAI-avid thyroid cancer following thyroidectomy. To facilitate identifying novel strategies to improveA customized mouse cradle was designed and used for microSPECT/CT image acquisition at 1 hour (t1) and 24 hours (t24) post injection ofThe customized mouse cradle facilitates consistent tissue configuration among image acquisitions such that rigid body registration can be applied to align serial images of the same mouse via the in-house CTViewer software. CTViewer is designed specifically to streamline SPECT/CT image analysis with functions tailored to quantify thyroid radioiodine uptake. Automatic segmentation of thyroid volumes of interest (VOI) from adjacent salivary glands in t1 images is enabled by superimposing the thyroid VOI from the t24 image onto the corresponding aligned t1 image. The extent of heterogeneity inMicroSPECT/CT image acquisition and analysis for thyroidal RAI uptake is greatly improved by the cradle and the CTViewer software, respectively. Furthermore, the approach of superimposing thyroid VOIs from t24 images to select thyroid VOIs on corresponding aligned t1 images can be applied to studies in which the target tissue has differential radiotracer retention from surrounding tissues.

In contrast to studies in women, male osteoporosis is poorly understood and strictly related to advancing age. Among the first antiresorptive substances used in the prevention and treatment of osteoporosis is calcitonin (CT), a hypocalcemic hormone that potently inhibits osteoclastic bone resorption. Natural CT is produced and secreted by thyroid C-cells. The other endocrine population of thyroid cells produces thyroid hormones (TH), which also affect bone turnover. The aim of this study was to evaluate the influence of salmon CT on trabecular bone microarchitecture with special reference to effects on the structure and function of both CT- and TH-producing thyroid cells in orchidectomized (Orx) middle-aged rats. Twenty-four male Wistar rats aged 15 months were randomly divided into Orx and sham-operated (SO) groups. One group of Orx animals received (s.c.) synthetic salmon CT (Orx + CT; 100 IU kg(-1) b.w.) subcutaneously every second day for 6 weeks. The second Orx group and SO rats were given the same volume of vehicle alone by the same schedule. Trabecular bone histomorphometrical parameters were: cancellous bone area (B.Ar), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp) were obtained with an ImageJ public-domain image-processing program. The peroxidase-antiperoxidase method was applied for localization of CT in C-cells. Anti-human CT antisera served as the primary antibodies. For immunohistochemical characterization of vascular endothelial growth factor (VEGF) in thyroid tissue, rabbit antisera against human VEGF, served as primary antibodies. CT-immunopositive thyroid C-cells, thyroid follicular epithelium, interstitium and colloid were evaluated morphometrically. Blood serum samples were analyzed for CT, osteocalcin (OC), and thyroxine (T4 ), and calcium (Ca(2+) ) concentration was determined in urine samples. Salmon CT application significantly increased B.Ar, TbTh and TbN, but markedly decreased Tb.Sp. Administration of exogenous CT significantly decreased mean volume (Vc) and relative volume density (Vv) of thyroid C-cells in relation to both SO and Orx groups. The Vv of the colloid was higher, whereas the VV of the follicular epithelium was lower after CT treatment compared with Orx alone. CT treatment markedly elevated serum CT, whereas serum OC, T4 and urinary Ca(2+) concentrations were lower than in the Orx group. These results indicate that salmon CT stimulates trabecular bone microarchitecture, strongly inhibits thyroid C-cells and changes the structure of the thyroid gland, indicating hypoactivity. This is the pre-peer reviewed version of the following article: Filipović B, Šošić-Jurjević B, Ajdžanović V, Živanović J, Ristić N, Trifunović S, Milošević V. Response of trabecular bone, thyroid C and follicular cells to synthetic salmon calcitonin in middle-aged orchidectomized male rats. J Anat. 2017, which has been published in final form at [http://doi.org/10.1111/joa.12600]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Journal of Anatomy (2017)

The transcription factor Pax8 is already known to be essential at very early stages of mouse thyroid gland development, before the onset of thyroid hormone production. In this paper we show, using a conditional inactivation strategy, that the removal of the Pax8 protein late in gland development results in severe hypothyroidism, consequent to a reduced gland size and a deranged differentiation. These results demonstrate that Pax8 is also an essential player in controlling survival and differentiation of adult thyroid follicular cells. © 2014 Elsevier Ireland Ltd.

Acromegaly is a rare chronic disease and associated with an increased risk of malignancy. The issue of the risk of thyroid cancer in these patients is a topic of debate, and the number of large case–control studies is very limited. Several studies indicated that a chronic excess insulin-like growth factor-1 stimulates the proliferation of various cell types and induces an antiapoptotic effect in thyroid follicular cells. In the literature, the risk of thyroid cancer was reported greater than five-fold. In this review, we will briefly summarize the studies available regarding thyroid cancer in patients with acromegaly and present three case reports.

We observed spontaneous dwarfism among Wistar Hannover GALAS rats, caused by primary hypothyroidism. The dwarf (D) rats showed markedly high serum thyroid-stimulating hormone (TSH) values. In this study, we investigated the incidence and histopathological characteristics of the proliferative lesions of the thyroid follicular cells in our D rats. Gross enlargement of thyroid and histological vacuolar change of the thyroid follicular cells with age-related progression suggesting diffuse hypertrophy/hyperplasia were seen in all the D rats. In addition, focal proliferative lesions—namely hyperplasias, activated hyperplasias, adenomas, and adenocarcinomas—were seen in D rats aged over 50 weeks. Taken together, these results suggested that the sustained stimulation of elevated levels of serum TSH caused and enhanced diffuse hypertrophy of thyroid follicular cells and subsequent development of focal proliferative lesions.

We evaluated the effects on the absorbed dose to thyroid follicular cells of self-absorption of 131I radiation (specifically, β-rays) in the follicular colloid. Methods: Thyroid follicles were modeled as colloid-filled spheres, containing a uniform concentration of 131I and surrounded by a concentric monolayer of cells. Assuming close packing of identical follicles, we used Monte Carlo simulation to assess the absorbed dose to follicular cells. Results: Because of β-ray self-absorption in colloidal spheres with radii larger than 50 μm, the absorbed dose to follicular cells is less than the average thyroid absorbed dose. Conclusion: For the same thyroid mass, radioiodine thyroid uptake, and effective half-life, patients with follicles with colloidal sphere radii of 100, 200, 300, and 400 μm should be administered 9%, 15%, 21%, and 30% more 131I, respectively, than patients with colloidal sphere radii of less than 50 μm, to yield the same absorbed dose to follicular cells.

Descrevem-se os achados clínicos e patológicos da intoxicação experimental por Sida carpinifolia em bovinos. Para a reprodução experimental da doença, folhas verdes da planta foram coletadas semanalmente na região do Alto Vale do Itajaí e fornecidas in natura diariamente para cinco bovinos nas doses de 10 e 20g/kg por 120 dias, 40g/kg por 30 dias, e 30 e 40g/kg de peso animal por 150 dias. Um bovino morreu e os outros foram eutanasiados ao final do período de consumo da planta. Os principais sinais clínicos consistiam de andar em marcha, olhar atento e tremores de cabeça e foram de intensidade leve a acentuado conforme a dose de planta e tempo de consumo. A lesão histológica predominante caracterizava-se por vacuolização e tumefação de neurônios (principalmente os de Purkinje), das células acinares pancreáticas e células foliculares da tireóide. Ultra-estruturalmente verificou-se vacúolos, por vezes, contendo material finamente granular em neurônios, células acinares pancreáticas e células foliculares da tireóide. S. carpinifolia causa doença de depósito lisossomal em bovinos quando consumida por período prolongado, mesmo em pequenas doses.

The paper is an analytical overview of the main results presented at the 3 rd Dosimetry Workshop in Hiroshima (9-11 of March 2005), where different aspects of the dose reconstruction around the Semipalatinsk nuclear test site (SNTS) were discussed and summarized. The results of the international intercomparison of the retrospective luminescence dosimetry (RLD) method for Dolon' village (Kazakhstan) were presented at the Workshop and good concurrence between dose estimations by different laboratories from 6 countries (Japan, Russia, USA, Germany, Finland and UK) was pointed out. The accumulated dose values in brick for a common depth of 10 mm depth obtained independently by all participating laboratories were in good agreement for all four brick samples from Dolon' village, Kazakhstan, with the average value of the local gamma dose due to fallout (near the sampling locations) being about 220 mGy (background dose has been subtracted). Furthermore, using a conversion factor of about 2 to obtain the free-in-air dose, a value of local dose ∼440 mGy is obtained, which supports the results of external dose calculations for Dolon': recently published soil contamination data, archive information and new models were used for refining dose calculations and the external dose in air for Dolon village was estimated to be about 500 mGy. The results of electron spin resonance (ESR) dosimetry with tooth enamel have demonstrated the notable progress in application of ESR dosimetry to the problems of dose reconstruction around the Semipalatinsk nuclear test site. At the present moment, dose estimates by the ESR method have become more consistent with calculated values and with retrospective luminescence dosimetry data, but differences between ESR dose estimates and RLD/calculation data were noted. For example mean ESR dose for eligible tooth samples from Dolon' village was estimated to be about 140 mGy (above background dose), which is less than dose values obtained by RLD and calculations. A possible explanation of the differences between ESR and RLD/calculations doses is the following: for interpretation of ESR data the "shielding and behaviour" factors for investigated persons should be taken into account. The "upper level" of the combination of "shielding and behaviour" factors of dose reduction for inhabitants of Dolon' village of about 0.28 was obtained by comparing the individual ESR tooth enamel dose estimates with the calculated mean dose for this settlement. The biological dosimetry data related to the settlements near SNTS were presented at the Workshop. A higher incidence of unstable chromosome aberrations, micronucleus in lymphocytes, nuclear abnormalities of thyroid follicular cells, T-cell receptor mutations in peripheral blood were found for exposed areas (Dolon', Sarjal) in comparison with unexposed ones (Kokpekty). The significant greater frequency of stable translocations (results of analyses of chromosome aberrations in lymphocytes by the FISH technique) was demonstrated for Dolon' village in comparison with Chekoman (unexposed village). The elevated level of stable translocations in Dolon' corresponds to a dose of about 180 mSv, which is close to the results of ESR dosimetry for this village. The importance of investigating specific morphological types of thyroid nodules for thyroid dosimetry studies was pointed out. In general the 3 rd Dosimetry Workshop has demonstrated remarkable progress in developing an international level of common approaches for retrospective dose estimations around the SNTS and in understanding the tasks for the future joint work in this direction. In the framework of a special session the problems of developing a database and registry in order to support epidemiological studies around SNTS were discussed. The results of investigation of psychological consequences of nuclear tests, which are expressed in the form of verbal behaviour, were presented at this session as well.

Because specification of duplicated genes is considered to be a major driving force for diversity and evolution, it is important to understand the function of the duplicated genes. In mammals, Nkx2.1 is essential for the differentiation of thyroid follicular cells and for the transcription of thyroid-specific genes. We have cloned four distinct Nkx2.1 cDNAs from the rainbow trout, Oncorhynchus mykiss. In the present article, we will characterize the trout Nkx2.1 mRNAs and show their tissue distribution, their transcriptional activities, and their expression during early development.

Hashimoto's thyroiditis (HT), a common thyroid disease, is now recognized as an autoimmune thyroid disorder. However, little is known about its discoverer, the man who first described this disease. He presented four patients with a chronic thyroid disorder, which he termed as struma lymphomatosa, characterized by diffuse lymphocytic infiltration with germinal centers, parenchymal atrophy and eosinophilic changes in some thyroid follicular cells. Dr. Hakaru Hashimoto was born in 1881 in Japan. Once he finished his studies, he started his training at the Surgery Department of Fukuoka Medical College. Professor Miyake, the head of the department, trained Dr. Hashimoto in the technique of assessing excised thyroid glands microscopically. In 1912, he published a paper, Zur Kenntnis der lymphomatosen Veranderung der Schilddruse (Struma lymphomatosa) in 'Archiv fur klinische Chirurgie', Berlin, 1912:97:219-248. Some years later, he studied pathology under the instruction of prof. Eduard Kaufmann in Gottingen. Hashimoto's struma lymphomatosa was then ignored and forgotten until 1931, when Mr. Allen Graham of Cleveland reported struma lymphomatosa and insisted that Mr. Hashimoto had first discovered the disease and wanted to name it after him - Hashimoto's thyroiditis (HT).

Experimental mutagenic effect of acrylamide on thyroid gland cells was studied by an extended micronucleus test. Acrylamide in doses corresponding to 0.004-0.1 LD(50) increased the incidence of thyroid follicular cells (A-cells) with micronuclei and other karyological parameters in exposed rats after hemithyroidectomy. This cytogenetic effect allows regarding acrylamide as a mutagen for the thyroid gland and as a carcinogen for this organ.

Huge vacuoles in the follicular epithelial cells distributing diffusely in the thyroid gland were seen in 2 out of 36 males and 8 out of 82 females of BrlHan: WIST@Jcl (GALAS) rats examined histopathologically. The vacuoles showed negative reactivity by periodic acid-Schiff reaction and thyroglobulin-immunohistochemistry. Corresponding to the vacuoles, remarkable dilatation of rough endoplasmic reticulum was seen in electron microscopic observation. The animals in which the thyroid lesion was found had shown no abnormalities in behavior, body weight, food consumption, or hematological and biochemical examinations. Plasma concentrations of thyroid-stimulating hormone (TSH) and thyroid hormones (T3 and T4) were not different from those of normal rats. From these results, thyroid functions seemed to be kept normal in spite of the severe morphological change. Based on the character and incidence of the thyroid lesion, it was presumed to be related with a certain genetic factor of one or several parents of breeding rats rather than food contamination or infection.

In order to assess morphological and functional plasticity of the thyroid gland in aging the effects of fasting and refeeding on the thyroid morphology and thyroid hormone serum levels were compared with morphometry and RIA in young and old rats. Young (4 months) and old (24 months) male Wistar rats were fasted for 40 h and sampled, or fasted and fed thereafter for 4 or 24 h. In control (fed) old animals the thyroid follicules were larger, the follicular epithelium was smaller and colloid resorption was smaller than in young rats. 'Thyroid activation index' (epithelial volume/colloid volume ratio) was almost twice lower in the thyroids of control old rats. As the result of fasting, height, surface area and volume of epithelial follicular cells decreased in the thyroids of fasted young rats but not in old ones. On the contrary, in thyroids of fasted old rats the dimensions of epithelial cells did not change and thyroid colloid resorption was increased. After 24 h of refeeding, thyroid morphology in both young and old rats did not differ significantly as compared with control animals. Upon fasting, serum levels of thyroxine (T4) and triiodothyronine (T3) decreased by 28 and 38% in young and by 35 and 46% in old rats, respectively. However, T4 and T3 serum concentrations did not differ significantly between age groups in both fed and fasted states. During refeeding the increase in serum thyroxine concentration was delayed in old rats as compared with young ones. The results of morphological, morphometric and hormonal investigations indicate the existence of age-related changes in the structure and function of thyroid follicular cells.

Bilateral Thyroid Follicular Atrophy in a Young Canadian Lynx (Lynx canadensis) A 1.5 year old intact male Canadian Lynx (Lynx canadensis) presented to the referring veterinarian with a 1 year history of poor appetite, lethargy, and weakness with eventual development of neurologic signs (vestibular signs, ataxia). At necropsy, gross lesions were few and non-specific. The lynx had decreased amounts of subcutaneous adipose stores and decreased skeletal muscle mass. Histologically, the thyroid glands were bilaterally decreased in size and approximately 75% of the thyroid gland was replaced by mature adipocytes. The remaining thyroid follicular cells are cuboidal and form follicles of varying sizes (10 µm-100 µm) with a mild amount of colloid.

Biological similarities between dogs and humans make the dog an appropriate preclinical model for gene therapy of many human disorders. Retroviral and adenoviral vectors have been used to successfully transfer a variety of gene constructs to canine hematopoietic progenitor cells, fibroblasts, hepatocytes, thyroid follicular cells, and other cells. Canine hemophilia B and mucopolysaccaridosis I are currently being used as models for gene therapy of inherited diseases, and several other models are potentially available. Neoplastic diseases, including canine lymphoma, osteosarcoma, and melanoma are potential models for gene therapy of cancer. Cloned canine genes and reagents are becoming more available as models are developed. Collaborative efforts between basic scientists, physicians, and veterinarians, involving both academic and private sectors, will probably lead to significant advances in human gene therapy.

Since TPO plays a cardinal role in regulating many cellular processes of thyroid hormone biosynthesis in thyrocytes, it is important to present a summary of the impact that TPO research on the basis of molecular structure has had on our understanding of thyroid diseases. This review has therefore been written to highlight the biochemical, molecular biological, immunological and clinical aspects of TPO in thyroid follicular cells. As for hormonogenesis, further details of the properties of the superoxide generating system remain unknown, but based on decisive evidence showing what active iodinating species are at initial and principal stages, a novel concept of the mechanism of two electron oxidation has been put forth. Recent progress in studies of analyses of TPO gene structure has also provided stimuli for renewed investigation into a much wider field of thyroidology, including thyroiditogenesis.

Over the last decade it has become evident that thyroid follicular cells express a number of immunologically active molecules in autoimmune thyroid disease that may endow them with the capacity to interact with cells of the classical immune system. Expression of major histocompatibility complex class II molecules is induced by gamma-interferon, but there is no evidence yet that thyroid follicular cells can concurrently express the costimulatory signals necessary for class II expression to result in T cell stimulation: in this situation, class II expression may have a protective role, inducing T cell anergy. Thyroid follicular cells also express a variety of cell surface proteins (in particular CD59) that may protect the cells from complement attack. On the other hand, the expression of adhesion molecules and cytokines by thyrocytes would seem to be harmful, as these are likely to exacerbate autoimmune injury. Further study of the immunological role of thyroid follicular cells will shed new light on the pathogenesis of Graves' disease and autoimmune hypothyroidism, and may lead to novel therapeutic approaches to these disorders.

Since the specific accumulation of iodide in thyroid was found in 1915, radioiodine has been widely applied to diagnose and treat thyroid cancer. Iodide uptake occurs across the membrane of the thyroid follicular cells and cancer cells through an active transporter process mediated by the sodium iodide symporter (NIS). The NIS coding genes were cloned and identified from rat and human in 1996. Evaluation of the NIS gene and protein expression is critical in the management of thyroid cancer, and several approaches have been tried to increase NIS levels. Identification of the NIS gene has provided a means of expanding its role in the radionuclide gene therapy of nonthyroidal cancers as well as thyroid cancer. In this article, we explain the relationship between NIS expression and the treatment of thyroid carcinoma with I-131, and we include a review of the results of our experimental and clinical trials.

Several genomics-based techniques have been applied in the last decade to the molecular characterization of cancer, which has led to a variety of applications suitable for improved diagnosis, prognosis and prediction of outcome to treatment. Proteomics-based approaches have also been seen as crucial to the discovery of biomarkers for early diagnosis and prognosis of tumors, as well as for a better understanding of the molecular bases of cancer. Accordingly, proteomic techniques have been used extensively for a better molecular characterization of thyroid tumors. In this field, three main directions have been preceded: first, proteomic studies of model systems; second, proteomics of thyroid tumor specimens; and third, serum proteomics. In this review, we describe the most relevant results that have been obtained for tumors derived from thyroid follicular cells using various proteomic approaches.

Pigmentation within thyroid follicular cells is common and its significance uncertain. While “black thyroid” pigment is associated with chronic minocycline therapy, similar pigments may simply be age related. Although a relationship between black thyroid pigment and neoplasia has been suggested, no study has proven increased tumor development with pigmentation. By comparing the incidence of thyroid pigmentation in thyroids with neoplasms …

Early- and late-passage cultures of Fischer rat thyroid cells differ in their growth properties and gap junction competency. Previous studies comparing early- and late-passage cultures exposed to gamma rays and proton beams revealed that differences in growth rate did not influence their responses; however, the presence of connexin 32 gap junctions conferred resistance to gamma radiation. To further assess differences in radiation quality, suspension cultures of early- and late-passage cells were exposed to accelerated iron ions, and their comparative biological responses were measured. The iron-ion-irradiated cells displayed sustained levels of incorporated dUTP, reflecting persistent DNA damage. These results were supported by the frequency of chromosomal damage measured by micronucleus formation. Iron-ion irradiation induced micronuclei at a rate of eight per gray per 100 binucleated cells scored in early-passage cells and nine per gray per 100 binucleated cells scored in late-passage cells. Relative to photons, the calculated radiobiological effectiveness for frequency of micronuclei was 5.7 and 6.4 for the early- and late-passage cultures, respectively (P0.05). Levels of apoptosis fluctuated as a function of dose, and modest increases above basal levels persisted throughout the 48-h period. The comparison of retained follicular structures revealed differences in the alpha components of the linear-quadratic dose-response curves (0.60 Gy(-1) for early-passage and 0.71 Gy(-1) for late-passage cultures, P0.014). Cell cycle phase redistribution resulted in a G2 arrest (P0.001) for both early- and late-passage cultures. In conclusion, the response of thyroid follicular cells to high-LET radiation was not influenced by the presence of gap junctions or the proliferative status of the target cells.

This chapter highlights immunological aspects of cancers arising from thyroid follicular cells, and examines the interplay between the immune system and abnormal thyroid follicular cells that could suppress transformed follicular cells from developing into carcinomas. The role of cytokines secreted by immune cells and how they modulate the function of thyroid carcinoma cells in a manner that could inhibit their growth is discussed, and potential difficulties in the immune response to thyroid carcinoma that could lead to the escape of immune containment are examined. Understanding these difficulties may lead to methods to augment or modify the immune response that could have therapeutic importance. Finally, in this chapter we identify potential routes of immune augmentation or modification of the immune response that could be used therapeutically to suppress thyroid carcinoma. Despite the excellent therapy that has been designed for thyroid carcinoma, many patients still suffer significant morbidity and mortality. Potential immunotherapeutic approaches are not merely conjectural but could have significant clinical importance. Therefore the examination of the immune interaction between effector cells and thyroid carcinoma is an important task to accomplish to define new therapeutic initiatives.

We thank Dr. Eterovic and colleagues for their interest and comments. Our work was aimed at showing the ability of the Monte Carlo code “CELLDOSE” to assess electron dose to specific cells in a complex environment [1]. This approach can be of considerable interest for comparing different radiopharmaceuticals as therapy agents in oncology. Eterovic et al. used the EGS5 code, with a predefined energy cut-off of 1 keV [2]. Our track structure code follows all primary and secondary electrons down to 7.4 eV (i.e. below the first ionisation potential of the water molecule ≅ 12.6 eV) [3]. This makes “CELLDOSE” a valuable tool to calculate energy deposited at the tissue, cellular as well as sub-cellular scale. We used a model of normal thyroid tissue as an example. The geometrical model assumed spherical thyroid follicles of 170 μm diameter with a cell height of 10 μm. Neighbouring follicles are 4 μm apart. Based on the specific geometry presented, it is found that when the average I electron dose to thyroid tissue is 1 Gy, the dose to the colloidal matter is 1.168 Gy, the dose specifically received by thyroid cells is 0.982 Gy and the dose to the inter-follicular tissue is 0.895 Gy [1]. Eterovic and colleagues suggest that the thyroid cell dose we found is overestimated because of small follicle diameter and a packing of spheres based on the simple cubic model [4]. We fully agree that thyroid follicles may vary in size according to age and pathological conditions. The follicle size we used is compatible with the average for normal thyroid [5]. In a recent study, Faggiano et al. found an average diameter for thyroid follicles of 171 μm in adults and smaller values in children

We argued that modeling the thyroid as composed of identical follicles, packed as inside the cubes that are aligned side to side is unrealistic since this leaves too much space between diagonal neighbors and in reality these spaces are occupied by relatively small follicles. This assumption leads to underestimation of self-absorption of 131I radiation in coloidal lumens of the thyroid follicles. We conclude that the degree of intrathyroidal inhomogeneity of 131I beta radiation dose may be larger than estimated by Hindie et al. due to close packing of follicles, which is especially important in cases of relatively large follicles.

Thyroid cancer is the ninth most common cancer in the United States, with an incidence that has been increasing sharply since the mid-1990s.1- 2 The majority of thyroid cancers are papillary thyroid cancers (PTC), which arise from thyroid follicular cells. Papillary thyroid tumors grow slowly and often retain sufficient characteristics of thyroid follicular cells to take up iodine, allowing for treatment with radioiodine to ablate residual thyroid cancer cells in cases requiring additional therapy beyond surgery

The existence of follicles with a "super flat" epithelium and the large number of primary and especially secondary lysosomes and lipofuscin granules in these cells are characteristic features of the thyroid gland of adult marmosets (Callithrix jacchus, new-world monkeys). It is supposed that these morphological findings are indications of a relatively low function and early ageing.

We have examined the results obtained from the stereological ultraestructural study of follicular cells in thyroid glands treated with IR laser (904 nm). We studied 40 wistar rats exposed to radiation with doses of 46,80 J/cm2. They were sacrificed 1 and 180 days after the treatment. A stereological study of the volume and surface density was made in mitochondria, rER. Gogi complex and cytoplasmic granules. In the rats sacrificed 1 day after exposure to laser radiation, the thyrocited showed minimal morphological changes. In the rats sacrificed after a long period (180 days) the thyrocites showed a significant increase of volume and surface densities of rER, that may mean decreased capacity of the cells to synthesize thyroglobulin. Volume and surface densities of the citoplasmic granules experienced a significant increase.© (1993) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

We describe studies in a canine model aimed at establishing methods for ex vivo gene delivery to thyroid follicular cells. Canine follicular cells were harvested from tissue obtained by unilateral lobectomy, grown in thyrotropin-containing media, and transduced with amphotropic retroviral vectors carrying Escherichia coli beta-galactosidase or Tn7 neomycin-resistance genes. Up to 30% of cells were transduced with retroviral vectors containing the neomycin resistance gene, and transduced cells could be selected with G418. Significantly, transduced and selected cells exhibited the morphology of thyroid follicular cells and continued to express thyroglobulin. To assess the viability of cultivated and transduced cells for transplantation, cells were stained with the vital fluorescent dye DiI, recovered by trypsinization, and transplanted into the contralateral thyroid lobe of autologous animals. Engraftment was demonstrated by fluorescence microscopy and identification of proviral sequences 7-10 days after transplantation. Proviral transcripts were evident using coupled reverse transcription and the polymerase chain reaction using total RNA from transplanted glands. Thyroid follicular cells may represent an attractive target for gene therapy due to their proliferative potential, their large protein synthetic and secretory capacity, and their susceptibility to regulation. The thyroid might be a target for therapy of congenital or acquired thyroid diseases as well as disorders requiring regulated expression of proteins in the circulation. This work demonstrates the feasibility of ex vivo gene delivery to thyroid follicular cells that may be used in future investigations.

The mitotic activity of the oesophageal epithelium of male rats maintained under carefully controlled conditions was studied, using the metaphase-arrest agent, vincristine sulphate. The accumulation of metaphases was linear (r = 0·97). In untreated rats there was a clear mitotic rhythm with a peak metaphase index (expressed as a percentage) of 12·4±0·86 (s.e.m.) at 12.00–15.00 h and a trough of 1·3±0·35 at 24.00 h. The overall mean metaphase index was 5·4±0·76. The effect of treatment with the antithyroid agent, carbimazole (0·1 g/100 ml in the drinking water), for 3 weeks was to depress the higher values at 12.00–18.00 h (P Carbimazole caused a significant (P The results are in contrast to those in previously described experiments on thyroid follicular cells which show a large increase in the first few days of treatment, followed by a steady decline towards control levels at 12 weeks. The metabolic activity of the animals is about 50% of normal at 12 weeks when both the oesophageal epithelium and the thyroid follicular cells begin to show a reduction in proliferative activity. Journal of Endocrinology (1990) 127, 311–315

Endocrine cells may become targets for autoimmune processes resulting in cellular dysfunction and diseases which cause considerable morbidity. The thyroid follicular cells, the parietal cells of the gastric mucosa, the insulin-producing islet cells and the adrenal cortical cells are most often affected. This rank order may indicate a relationship between antigen mass and prevalence of disease in a given organ (15).

C. Giordano et al . ([1][1]) reported evidence that the ligand for Fas antigen (FasL) is constitutively expressed on thyroid follicular cells from both normal and Hashimoto's thyroiditis (HT) tissue, and that normal thyrocytes express Fas antigen only after induction with interleukin-1β (IL-1β).

Summary The ultrastructure of experimentally induced thyroid follicular adenomas and carcinomas was studied in rats and hamsters by means of transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Diaminobensidintetrachlorid (DAB) method was applied for cytochemical demonstration of the thyroid peroxydase activity. No significant difference was found in the ultrastructure between thyroid follicular adenomas and carcinomas in rats and hamsters. However, the ultrastructural organisation of tumor cells in carcinomas presuppose a more limited functional activity than in adenomas. The peroxydase activity of tumor cells was preserved, despite the presence of methylthiouracil (MTU) in the circulation. It was further noticed that malignant transformation of thyroid follicular cells does not lead to changes in the ultrastructural distribution of peroxydase activity. Scanning electron-microscopical examination of the thyroid tumors reveals significant changes in the structural organisation of tumor cells and follicles. The changes in the surface properties of thyroid gland in the course of malignant transformation should be considered as result of irregular cell proliferation, degenerative processes and functional heterogeneity of tumor cells.