Thyroid carcinomas are the most common endocrine tumors in humans. There are three major types of carcinomas of thyrocyte origin, including papillary, follicular, and anaplastic carcinomas. Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy accounting 80% of thyroid cancer cases, and present several histologic variants, namely classical (45%), follicular (18%), solid, diffuse-sclerosing, cribriform, … .Specific genetic events represent early initiating and late triggering events. Several genetic lesions have been identified in various thyroid carcinomas and some of them are specifically associated to one type thyroid cancer. For instance, RET/PTC is the most common molecular event in the radiation-associated PTC in childhood. <p>In the first part of the work, we studied two transgenic mouse models: the Tg-RET/PTC3 (Tg-RP3) mouse and the Tg-E7 mouse. Both strains express the human origin transgene (RET/PTC3 rearrangement or E7) exclusively in the thyroid under the control of the bovine thyroglobulin promoter. <p>Our study of these two models showed:<p>In both E7 and RET/PTC3 mouse models, the thyroids exhibited hyperplasia with own 'oncogene-dependent' follicular cell characteristics. Small follicular cells with hyperchromatic nuclei with an increased nucleus/cytoplasm ratio were numerous in the E7 mice, and large cells with convex apical border, a decreased nucleus/cytoplasm ratio, a pale nucleus and dispersed chromatin were found in the RET/PTC3 mice. <p>At 6, 10 months and later on, E7 mice developed huge heterogeneous, normal functional thyroid goiter, with no tumor formation. <p>As in previous studies on transgenic RET/PTC3 mouse models, the generally encountered features such as solid tumours were present. We also observed conventional variant of human PTC at late age (since 11 month-old) with quite low incidence (4%). In addition to solid and conventional variant PTCs, 28% of mice developed a peculiar big size thyroid tumor pattern with “proliferative papillary cystic changes with spindle cells and remodelling” and macrophage infiltration in the cysts at as early as 2 month of age; this kind of tumor histologically resembles the rare human young age 'diffused sclerosing' variant PTC (DSVP), but disappeared after 6 month. The other peculiar tumor exhibits morphological similarity with another rare human FAP-associated (Familial Adenomatous colonic polyposis) cribriform PTC, which showed a mixed architecture of several histological patterns (solid, follicular, cribriform). At 6 months, 26% of mice presented the cribriform tumor pattern.<p>From the analyse of the proliferation index in the two models, we conclude that RET/PTC3 fusion protein over stimulates MAPK and Akt/PKB-signalling pathways, through Ras-Raf-Mek-Erk, Ras-PI3-K/Akt/PKB, particularly in the large cells which were strongly positive for three proliferation markers. E7 bypasses these two pathways, by directly binding to Rb1 protein and releasing the E2F transcription factor which induces cell proliferation. <p>So RET/PTC3 and E7 mice present several morphologic features which mimic human PTC tumors; RET/PTC3 could therefore be used as a partial model for human PTCs. <p>Further investigation of gene expression will allow the characterization of the molecular phenotype of the observed variants.<p>In the second part of the work, we attempted to generate by xenobiotic administration an in vivo model of thyroid carcinoma. Chronic exposure of CD1 mice to acrylamide in the drinking water during 6 and 8 months at doses of 3mg/kg per day similar to those causing thyroid tumorigenesis after 2 years in rats, did not induce any thyroid tumors whatever the level of thyroid stimulation. <p><p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Afin d’assurer les échanges entre ses différents organites, la cellule eucaryote dispose d’un système ingénieux de trafic vésiculaire intracellulaire. Le transport directionnel de divers cargos tels que des organites membranaires et des complexes protéiques est assuré par des moteurs moléculaires auxquels appartiennent les protéines de la superfamille des kinésines (également appelées KIF pour KInesin Family). Celles-ci se servent des microtubules comme rails et se déplacent vers leur extrémité positive. Parmi elles, la kinésine II est composée de KIF3A et KIF3B, deux protéines motrices et de KAP3, une protéine de liaison au cargo à véhiculer. Ce moteur moléculaire est connu pour participer à l’assemblage du cil primaire à la surface des cellules ainsi qu’au trafic plus conventionnel tel que l’acheminement de protéines à la membrane. <p>Afin d’étudier le rôle précis de la kinésine II dans la glande thyroïde, nous avons invalidé spécifiquement le gène Kif3a dans cet organe chez la souris. Bien que cette inactivation ait conduit à un développement complet du tissu thyroïdien, les souris invalidées présentent une hypothyroïdie congénitale caractérisée par des concentrations sériques élevées de TSH et basses de T4. Par la suite, nous avons mis en évidence une expression fortement diminuée du transporteur d’iodure NIS chez ces souris, causant une déficience en iodure intracellulaire, une iodation insuffisante de la thyroglobuline et une sécrétion anormale de l’hormone T4 dans la circulation sanguine. De plus, ex vivo, nous avons montré que la réponse à la TSH en terme d’AMPc est altérée dans la thyroïde de ces souris. Ces observations nous ont permis d’émettre l’hypothèse que l’invalidation du gène Kif3a spécifiquement dans la glande thyroïde mène à une anomalie dans la voie de signalisation du récepteur de la TSH, en amont de la production d’AMPc. Finalement, in vitro, par l’utilisation de cellules Kif3a-/-, nous avons analysé l’expression à la membrane plasmique et la réponse à un agoniste du récepteur β2 adrénergique, un membre de la même sous-famille de récepteurs couplés aux protéines G que le récepteur de la TSH. De cette façon, nous avons obtenu des données indiquant que le transport de ce récepteur à la surface cellulaire était altéré en l’absence de Kif3a. <p>Au vu de ces éléments et de ceux de la littérature, nous suggérons que la kinésine II, et plus particulièrement sa sous-unité KIF3A, joue un rôle important dans le transport du récepteur de la TSH nouvellement synthétisé vers la membrane basale de la cellule de la thyroïde.<p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

No description available.

GenX, a newly synthesized per- and polyfluoroalkyl substance (PFAS), has gained attention as a supposedly safer replacement for the long-chain PFAS, PFOA. Given the thyroid gland being known to be a target organ for the health effects of PFOA, it is crucial to investigate GenX potential impact on the thyroid gland. Thyroid hormones play a critical role in normal development and metabolism, emphasizing the importance of assessing the thyroid-disrupting effects of GenX for future regulatory considerations.A review of the existing scientific literature revealed potential genotoxicity and cytotoxicity in thyroid cells, reduced postnatal survival rates, and altered levels of thyroid hormones following GenX exposure. Further research is needed to establish definitive conclusions regarding the thyroid-impairing effects of GenX. This study highlights the necessity for additional investigations to improve our understanding of the potential risks and effects associated with GenX exposure on thyroid function. / GenX, en nyligen framtagen PFAS, har uppmärksammats som en påstått säkrareersättning för PFOA, en av de långkedjiga PFAS. Sköldkörteln är känd som ettmålorgan för skadliga hälsoeffekter av PFOA vilket gör det intressant att undersöka GenX eventuella påverkan på sköldkörteln. Sköldkörtelhormoner är viktiga för normal utveckling och ämnesomsättning, vilket betonar vikten av att bedöma GenX potentiella störande effekter på sköldkörtelfunktionen för framtida regleringsåtgärder. En genomgång av befintlig vetenskaplig litteratur visade potentiell genotoxicitet och cytotoxicitet i sköldkörtelceller, minskad överlevnad efter födseln samt förändrade nivåer av sköldkörtelhormoner efter GenX-exponering. Vidare forskning behövs för att fastställa definitiva slutsatser angående GenX:s sköldkörtelpåverkande effekter. Denna studie belyser nödvändigheten av ytterligare undersökningar för att förbättra vår förståelse för de potentiella riskerna och effekterna som är förknippade medsköldkörtelfunktion och GenX-exponering.

A possible thyroidal control of water balance in the leopard frog, Rana pipiens, was investigated by (1) chemically thyroidectomizing intact animals by chronic injections of the goitrogen, 6-n-propyl-2-thiouracil (PTU ), or making animals hyperthyroid with thyroxine injections, and (2) dehydration of the frogs in a flow of air to enhance the rate of water loss through the skin, followed by rehydration in tap water until the animals regained their former weight. Radioiodine was employed in limited studies on the frog thyroid gland to ascertain the effects on thyroidal function caused by PTU. The frogs were dehydrated in desiccators in which there was a constant flow of clean, dry air over the animals. The cloacas cf the anurans were sutured closed during light etherization, and the frogs were weighed at regular intervals during dehydration and rehydration to determine the water loss and regain through the skin. PTU-treated frogs generally exhibited greater mean values for rates and total amounts of water loss and regain through the integument, and in one experiment, the PTU animals had a statistically greater rate of dehydration when compared to control frogs. The data indicated, however, that a goitrogen-induced, thyroxine depletion was not the cause for this increased, two-directional water movement through the frog skin, so several alternative proposals were therefore offered to explain the results obtained. The radioiodine studies demonstrated that the thyroid glands of normal, winter R. pipiens contained roughly 42 % 3-monoiodotyrosine, 28 % 3,5-diiodotyrosine, 21 % inorganic iodide, 6 % thyroxine, and 3 % origin material, and that the accumulation of radioiodine by these glands was approximately 2 % of the injected dose. PTU decreased the accumulative radioactivity of the frog thyroids to about 0.6 % of the injected quantity, markedly hindered the iodination of tyrosines, and depressed the level of thyroxine production, but this goitrogen did not completely inhibit thyroidal function.

Thyroid uptake and distribution of 125I, concentrations of T4 and T3 in serum and thyroids and concentrations of TSH in serum and pituitaries were measured to determine thyroid function of Uinta Ground Squirrels (Citellus armatus) native to 5,400 and 9,000 feet elevations to evaluate alterations in the state of the thyroid due to increased altitude. Uptake of 125I was 60 percent lower by squirrels from 9,000 feet. Incorporation of 125I into T3 was greater at the higher elevation, but absolute thyroid T3 concentrations were similar at both elevations. No significant differences were found in serum T3 concentrations, but squirrels living at 9,000 feet had higher serum T4 levels than those living at a lower elevation. Urinary excretion of T3 by squirrels from the 9,000 feet elevation was lower compared to excretion by squirrels native to 5,400 feet. Elevated pituitary TSH levels were also found in squirrels native to the higher altitude. These findings indicate a chronic hypothyroid state of squirrels living at 9,000 feet compared to those living at 5,400 feet.

It was the purpose of this thesis to establish the functional level of the thyroid gland in patients with chronic ulcerative colitis.

Thesis (M.Tech.)(Nuclear Medicine) -- Central University of Technology, free State, 2007 / In the South African Health Services (SAHS) it is each health worker’s responsibility to find ways to reduce health care cost and improve health service to the public. The measurement of radioactive iodine uptake (RAIU) by the thyroid gland for diagnostic purposes has been used as early as the 1940s. The 24-hour (hr) iodine-131 (131I) uptake measurement is traditionally used for the calculation of the 131I administered activity for therapy dosage. This entails that the patient’s hospitalisation is prolonged, which increases the costs. The literature also indicates that the 24-hr 131I uptake value can be discarded and only the 6-hr 131I uptake measurement is needed to calculate administered activity for therapeutic dosages for Graves’ patients. Therefore, if it can be confirmed that the 6-hr 131I uptake measurement alone is needed, the SAHS could decrease hospitalisation costs. The overall goal of the investigation was to analyse the 6-hr and 24-hr 131I uptake measurements of patients with Graves’ disease at the Universitas Hospital. The aim was to determine the relationship between the 6-hr and 24- hr RAIU values to establish the therapeutic dosage for Graves’ disease. To achieve the aim, three objectives were set. First, to serve as a background to the investigation, a literature survey relating to the RAIU measurements of patients with Graves’ disease was made. Second, a retrospective analysis was performed by collecting the 6-hr and 24-hr 131I uptake measurements of patients with proven Graves’ disease at the Universitas Nuclear Medicine Department (UNMD). Finally, the data obtained from the retrospective analysis was analysed, summarised and compared to answer the investigation questions. The investigation group included patients with confirmed Graves’ disease who had undergone both the 6- and 24-hr 131I RAIU at the Universitas Hospital from the beginning of 2004 to the end of 2005. Graves’ disease is confirmed by the following factors at the UNMD, namely: Suppressed TSH, elevated T4 and T3 values, an increased uptake on the 99mTc-pertechnetate scan and increased 6- and 24-hr 131I RAIU values. The UNMD statistics show that 178 patients were diagnosed with Graves’ disease during this period. The patients of the investigation group included both male and female patients from different races, ranging from 15-75 years. In order to increase the validity of the investigation, all factors that could influence the accuracy of the 131I thyroid uptake test were excluded. After the exclusion and inclusion criteria had been applied, the final investigation group was made up of 124 Graves’ disease patients. The data obtained from the patient files was noted on the different data sheets (see Appendix A) for further analysis. The information from these data sheets was then used to obtain the investigation results. The Department of Biostatistics of the University of the Free State (UFS) was consulted for recommendations regarding the management of data and the processing of results. All values were summarised by means and Standard Deviations (SD) or percentiles. Mean or median differences were calculated with a 95% Confidence Interval (CI). A regression analysis was made between the 6-hr and 24-hr 131I RAIU values. The highest RAIU value is the best to calculate the therapeutic dosage, as this gives a true reflection of the thyroid function of a Graves’ disease patient. In the investigation group the median of the 24-hr 131I RAIU values was higher than the 6-hr 131I RAIU values. The findings showed that the 24-hr 131I RAIU in most of the investigation group was the highest value and most effective to calculate the 131I therapeutic dosage. At a time when research-based practice is taking on an increasingly important role, it is essential for nuclear medicine departments to make evidence-based recommendations. This investigation found that the correlation between the 6-hr and 24-hr RAIU clearly justified the cost spent on Graves’ disease patients who must stay overnight for the 24-hr 131I RAIU procedure.

La thèse s’inscrit dans un projet de recherche global visant à caractériser les tumeurs thyroïdiennes sur le plan moléculaire, afin de mieux comprendre leur physiopathologie et afin d’identifier des biomarqueurs (signatures moléculaires) qui pourront être utilisés pour le diagnostic, le pronostic et leur traitement. Parmi celles-ci, nous distinguons les adénomes autonomes (AA) et folliculaires (FTA) tumeurs bénignes encapsulées, et les carcinomes, tumeurs malignes. Ceux-ci sont eux-mêmes subdivisés en carcinomes différenciés, folliculaires (FTC) ou papillaires (PTC), et peuvent évoluer en carcinomes anaplasiques (ATC), totalement dédifférenciés. Un autre type de tumeurs bénignes différenciées, très rares, existe: l’hyperthyroïdie non auto-immune familiale (FNAH). Ces tumeurs sont causées pour la plupart par des mutations qui activent de manière constitutive des cascades de signalisation, essentiellement la cascade de l’AMPc et la cascade des MAPK. Le but de notre thèse était de valider un système expérimental in vitro des PTC, d’étudier les profils d’expression génique des FNAH et de les comparer avec ceux des AA, et de définir les profils ARNm et miRNA des ATC pour les comparer à ceux des PTC pour identifier de nouvelles cibles thérapeutiques potentielles. Pour réaliser ces objectifs, nous avons utilisé la technologie des microarrays qui permet d’analyser simultanément l’expression de milliers de gènes dans différentes conditions. Nous avons donc utilisé une approche multidisciplinaire alliant une partie expérimentale et une partie bioinformatique.<p><p>La première partie du travail a consisté à réaliser un modèle d’étude in vitro pour caractériser les PTC au niveau moléculaire. A cet effet, des cultures primaires de thyrocytes ont été traitées avec de l’EGF et du sérum pendant différents temps (1,5h, 3h, 16h, 24h et 48h) ce qui stimule la cascade des MAPK, activée constitutivement dans les PTC. Nous avons hybridé sur des lames microarrays maison les différents échantillons et nous avons montré que les cultures primaires stimulées pendant des temps longs (24h et 48h) ont des profils d’expression génique qui ressemblent à ceux des PTC et constituent donc un bon modèle d’étude de cette tumeur. <p><p>La seconde partie a pour objectif de définir les phénotypes moléculaires et fonctionnels des FNAH et de les comparer aux AA. Ces deux pathologies résultent d’une mutation dans le récepteur de la TSH (TSHR) activant de manière constitutive la cascade de l’AMPc. Dans le cas des FNAH, la mutation est héréditaire et toute la glande est affectée contrairement aux AA où la mutation survient plus tard, généralement à l’âge adulte, et où seule une partie de la glande est affectée. Nous avons comparé le profil d’expression génique des FNAH avec celui des AA, par hybridation sur des lames microarrays HEEBO. L’intégration de ces différentes données montre que les AA et les FNAH sont deux sous-types différents de la même maladie: l’hyperthyroïdie génétique. Les caractéristiques de chacun de ces sous-types dépendent de l’intensité de la mutation, du nombre de cellules initialement affectées et du stade de développement au moment duquel la mutation survient.<p><p>Dans la dernière partie de ce travail, nous avons caractérisé les ATC au niveau du profil d’expression des ARNm et des miRNA par hybridation respectivement sur lames Affymetrix ou sur lames miRNA maison et au niveau de leur état mutationnel du gène p53. Le profil d’expression génique des ATC a été comparé avec celui des PTC afin de mettre en évidence des gènes différentiellement exprimés entre les 2 types de cancers, que nous avons ensuite tenté d’invalider par siRNA, dans un modèle in vitro de lignée cellulaire thyroïdienne dérivée d’un ATC (8505C). Les résultats obtenus jusqu’ici ne sont malheureusement pas prometteurs. Le profil d’expression des miRNA nous a permis d’identifier une signature de 34 miRNA caractéristique des ATC.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

New technologies to probe the global output of the normal and cancer genomes have recently reached widespread use. The resulting genomewide gene expression profiles, e.g, a gene expression measurement per gene and per tissue sample, remain challenging to analyze and interpret, but have already provided new insights into the pathophysiology of cancer and towards personalized care.<p><p><p>In vitro cell culture-based experimental models are used to elucidate cancer onset and progression because experimentation in humans is difficult practically and ethically unacceptable, and because they provide simplified, reproducible and controlled systems to test hypotheses. The thyroid tumors and their in vitro experimental models are particularly suited to compare the molecular phenotypes of experimental models and tumors. From one type of cell, the thyrocyte, at least five distinct benign and malignant tumors can arise. In addition, many immortalized tumor-derived cell lines and primary cultures models of these cells exist.<p><p><p>This thesis has focused on the bioinformatic comparison of these in vitro models to the in vivo tumors, from the point of view of their gene expression profiles, to gain insight into the pathogenesis of thyroid tumors, and of tumors in general.<p><p><p>In a first study, we showed that primary cultures of freshly isolated normal thyroid cells where proliferation and differentiation through the TSHR/cAMP pathway was chronically activated experimentally resemble specifically the autonomous thyroid adenomas, a type of benign thyroid tumor, and provide insight into a general mechanism of tumor progression: the suppression of negative feedbacks that normally restrain excessive cell division.<p><p><p>Subsequently, we found that immortalized thyroid tumor-derived cell lines have converged to a common phenotype regardless of their tumor subtype of origin. A TSHR/cAMP thyroid cell differentiation signature, derived from data obtained for the first study, was used to show that the cell lines were dedifferentiated. Accordingly, we showed that the cell lines resemble most the phenotype of the more dedifferentiated, clinically aggressive anaplastic thyroid cancers.<p><p><p>Finally, using large databases of gene expression profiles publicly available, we extended the comparison of cell lines and tumors to cancers of five other organs: breast, colon, kidney, ovary and lung. We discuss the correct use of these models and advance an hypothesis regarding the nature of the state to which these cells have converged: they could represent a surviving subpopulation of tumors cells, cancer stem cells, capable of initiating and maintaining tumor growth.<p><p><p>As other technologies designed to perturb the genome in experimental models are emerging, careful characterization and validation of the experimental models are needed to extrapolate the results in vivo.<p> / Doctorat en sciences biomédicales / info:eu-repo/semantics/nonPublished