Thyroid Tumorigenesis is typically a well understood process, with well delineated oncogenic factors. Follicular and papillary thyroid cancers are typically survivable, with 5-year survival rates being >95% for Stage I-III of both cancer types. Anaplastic thyroid cancer, in contrast, lacks this prognosis, and is the most lethal of all endocrine-related cancers. The median survival time after a diagnosis is generally between 6-8 months, with a 5-year survival rate of <10%. Current treatment for anaplastic thyroid cancers routinely meet roadblocks, as resistance is quickly developed. Even non-discriminatory kinase inactivators, such as sorafenib, which are generally considered a drug of last resort, are unable to effect survival rates. As such, there is a clear need for further investigation of the causes of anaplastic thyroid cancer mechanisms. Previous work in the Carr lab revealed a novel regulatory pathway of an oncogene that is associated with several other endocrine-related cancers, as well as other non-endocrine-related cancers. Specifically, the Runt-related transcription factor 2 (Runx2) was found to be suppressed via direct binding of the thyroid hormone receptor beta 1 isoform (TRß1) to its proximal promotor. Runx2 was previously shown to be associated with increasing malignancy, with Runx2 occurring at low-levels in indolent cell lines, whilst occurring at high-levels in more malignant cell lines. TRß1, conversely, exhibited the opposite relationship. Endogenous levels of TRß1 were found to be high in indolent cell lines and were depleted in malignant cell lines. These findings were further confirmed via tissue microarrays. Restoration of TRß1 in malignant cell lines diminished Runx2 mRNA and protein levels, which was corroborated by evidence from electrophoretic mobility-shift assays, and chromatin immunoprecipitations that TRß1 was able to directly bind Runx2 promotor 1. Current studies have investigated the nuclear protein profile that associates with TRß1 to alter Runx2 transcription. Through EMSA-to-Mass Spectrometry methodologies, as well as novel DNA pulldown techniques, binding partners have been elucidated. Findings have also been confirmed via classical immunoprecipitations. Specifically, our findings show that TRß1 complexes with the brahma-related gene 1 (BRG1) protein, the nuclear co-repressor (NCOR), and BRG1-associated protein 60 (BAF60). BRG1 functions by preferentially recruiting histone deacetylases (HDAC), with BRG1 and the HDAC’s acting to alter chromatin, and thus transcription. Future studies aim at examining whether other proteins complex with TRß1 to alter Runx2 transcription, and whether these complexes are altered in aggressive cell lines.

Background: Anaplastic thyroid carcinoma (ATC) is a highly aggressive, undifferentiated carcinoma that may arise on top of normal or abnormal thyroid. Making the diagnosis by fine needle aspiration (FNA) of the thyroid with a long-standing history of multinodular goiter (MNG) is not uncommon. We report a case discussing the cytopathologic findings and the relationship with long-standing goiter and thyroid exposure to radioactive iodine treatment. Case: A 90-year-old male patient presented with a > 45-year history of MNG that was associated with thyrotoxicosis and multiple courses of radioiodine (I-131) treatment. He developed recent symptoms of dyspnea, dysphagia, neck swelling and unintentional weight loss. Computed tomography of the neck was done revealing a large MNG with retrosternal extension and calcifications. FNA was performed revealing highly anaplastic cells with a colloid background and presence of neutrophils. The diagnosis of ATC was made. The patient refused any kind of management and was discharged upon his request. He died 2 days after the procedure, and no autopsy was performed. Conclusion: ATC is an aggressive, undifferentiated thyroid carcinoma that can be diagnosed by FNA and save the patient a surgical intervention. A background of MNG and history of radioactive iodine therapy is not uncommon.

Perchlorate ion interferes with thyroid function by competitively inhibiting the sodium-iodide symporter, thus blocking iodide uptake into the thyroid gland. In this study, the effect of perchlorate exposure on thyroid function and thyroid-responsive gene expression were examined in (1) embryos from eggs laid by perchlorate-treated Japanese quail hens and (2) perchlorate-treated young Japanese quail. I hypothesized that perchlorate exposure would decrease thyroid function and that the consequent hypothyroidism would alter the expression of thyroid sensitive genes. Laying Japanese quail hens were treated with 2000 mg/l and 4000 mg/l ammonium perchlorate in drinking water. Eggs from these hens were incubated. Embryos, exposed to perchlorate in the egg, were sacrificed at day 14 of the 16.5 day incubation period. Japanese quail chicks, 4-5 days old, were treated with 2000 mg/l ammonium perchlorate in drinking water for 2 and 7.5 weeks. Thyroid status was evaluated by measuring plasma thyroid hormone concentrations, thyroid gland weight and thyroidal thyroid hormone storage. Expression of thyroid-responsive genes was evaluated by measuring the mRNA levels of Type 2 deiodinase (D2) in the brain and liver, RC3/neurogranin mRNA level in the brain and Spot 14 mRNA level in the liver. Maternal perchlorate exposure led to embryonic hypothyroidism, demonstrated by thyroid hypertrophy and very low embryonic thyroidal TH storage. Embryonic hypothyroidism decreased body growth and increased D2 mRNA level in the liver (a presumed compensatory response to hypothyroidism) but did not affect the mRNA levels of D2 and RC3 in the brain. Spot 14 mRNA was not detected in embryonic liver. In the second part of the study, quail chicks showed early signs of hypothyroidism after two weeks of 2000 mg/l ammonium perchlorate exposure; plasma concentration and thyroid gland stores of both T4 and T3 were significantly decreased. After 7.5 weeks of perchlorate exposure, all thyroid variables measured indicated that the chicks had become overtly hypothyroid. D2 mRNA level was increased, a compensatory response to hypothyroidism, and spot 14 mRNA level was decreased, a substrate-driven response in the liver of quail chicks after two weeks of perchlorate exposure. However, no difference was observed in the mRNA levels of D2 and spot 14 in the liver after 7.5 weeks of perchlorate exposure, suggesting there was some adaptation to the hypothyroid condition. The mRNA level of D2 and RC3 in the brain was not affected by perchlorate-induced hypothyroidism in quail chicks after either 2 or 7.5 weeks of perchlorate exposure. As in the embryos, this suggests the brain of chicks was "protected" from the hypothyroid body conditions. / Ph. D.

Yes / Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1-expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus.

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

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

Os nódulos de tireoide são frequentemente encontrados na prática clínica e, com o auxílio de ultrassonografia de alta resolução, podem ser identificados em 17 a 67% da população. A alta prevalência desses nódulos causa preocupação frequente aos pacientes e aos clínicos devido ao risco de malignidade, o que, por sua vez, leva a investigações laboratoriais de alto custo, invasivas e, eventualmente, a cirurgias desnecessárias. A punção aspirativa com agulha fina (PAAF) é o método diagnóstico pré-operatório mais preciso para identificação de um nódulo maligno de tireoide, mas não consegue excluir malignidade nos casos de citologia inadequada, nódulos com diagnóstico citológico de lesão folicular ou atipia de significado indeterminado e nas citologias sugestivas de neoplasia folicular. O objetivo deste estudo foi analisar as características clínicas, laboratoriais, ultrassonográficas e citológicas de uma população de pacientes com nódulos de tireoide submetidos a tireoidectomia e a relação entre estes achados e o risco de malignidade. Além disto, em relação aos nódulos malignos, verificar se o valor de TSH esteve associado a um estadiamento mais avançado da doença. Foram avaliados prontuários de 353 pacientes submetidos a tireoidectomia, acompanhados no Hospital das Clínicas da FMUSP de São Paulo, no período de fevereiro de 2002 a abril de 2010. O número total de nódulos nestes pacientes foi 392. As características clínicas e laboratoriais analisadas em cada paciente foram idade, sexo, valores séricos de TSH e T4 livre, presença de anticorpo anti-tireoperoxidase (anti- TPO) e anti-tireoglobulina (anti-TG). Foram avaliadas a presença de características ultrassonográficas sugestivas de benignidade (presença de halo periférico hipoecoico, aparência espongiforme, aspecto isoecóico ou hiperecoico) e de malignidade (nódulo sólido hipoecoico, contornos irregulares, presença de microcalcificações). Baseados nestas características, os nódulos foram classificados em benignos, indeterminados e suspeitos para malignidade. O diagnóstico citológico foi classificado em benigno, indeterminado, suspeito e maligno, e a análise combinada das características ultrassonográficas e citológicas também foi avaliada. Ao exame histopatológico, 200 nódulos eram malignos e 192 nódulos eram benignos. Os nossos resultados mostraram que sexo, idade, valores séricos de TSH e T4 livre e presença de anticorpo anti-TPO e anti-TG não estiveram associados a uma maior chance de malignidade. O valor de TSH sérico também não esteve associado a maior risco de recorrência ou estadiamento mais avançado nos pacientes com câncer Os nódulos maiores estiveram mais associados a benignidade quando avaliamos toda amostra. Na análise multivariada de toda amostra, após regressão logística, apenas a citologia maligna, hipoecogenicidade e presença de microcalcificações foram associados a malignidade. Já, a classificação ultrassonográfica que não se baseia em apenas uma característica mas em um conjunto de características, apresentou um alto valor preditivo de benignidade e foi útil na identificação de nódulos com citologia indeterminada. A classificação ultrassonográfica tem o potencial de reduzir o número de cirurgias para nódulos com citologia indeterminada / Thyroid nodules are often encountered in clinical practice, and with the use of high-resolution ultrasound may be identified in 17 to 67% of the population. The high prevalence of these nodules cause frequent concern to patients and clinicians due to the risk of malignancy, wich in turn leads on costly investigations, use of invasive diagnostic methods and sometimes unnecessary surgeries. Fine needle aspiration biopsy (FNAB) is the most accurate preoperative diagnostic method to identify a malignant thyroid nodule. However, FNAB cannot rule out malignancy in cases of inadequate cytology, follicular lesions, atypia of undetermined significance, and in cytology suggestive of follicular neoplasm. The aim of this study was to analyze clinical, laboratory, ultrasound and cytopathologic characteristics of a group of patients with thyroid nodules undergoing thyroidectomy and the relationship between serum levels of TSH and the risk of malignancy. In nodules found to be malignant in this cohort, we analyzed the association of TSH levels with advanced disease stage and risk of recurrence. We analyzed the records of 353 patients who were followed at Hospital das Clínicas - São Paulo Medical School, between February 2002 and April 2010, and who subsequently underwent thyroidectomy. The total number of nodules in these patients was 392. The clinical and laboratory characteristics included in the analysis were age, gender, serum levels of TSH and free T4, and presence of serum thyroid anti-peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies. We evaluated the presence of ultrasonographic features suggestive of benignity (isoechoic or hyperechoic appearance, presence of hypoechoic peripheral halo, spongiform appearance) and malignancy (hypoechoic appearance, irregular border, presence of microcalcifications). Based on these ultrasonographic characteristics, we classified the nodules as benign, indeterminate or suspicious for malignancy. According to the FNAB cytology, we also subdivided the nodules into benign, indeterminate, suspicious and malignant. The combined analysis of ultrasonographic features and cytopathology was also evaluated. On histopathology, 200 nodules were malignant and 192 were benign. Our results showed that gender, age, serum levels of TSH and free T4, as well as the presence of anti-TPO and anti-TG were not associated with increased risk of malignancy. Similarly, serum TSH value was not associated with increased risk of recurrence or more advanced stage in patients with thyroid cancer. A large nodule size was associated with benignity. In multivariate analysis, after logistic regression, only malignant cytology, hypoechoic appearance and presence of microcalcifications were associated with malignancy. Furthermore, the ultrasonographic classification, wich was not based in only one feature but in a set of characteristics, showed a high predictive value for benignity and seems to be useful in identifying nodules with indeterminate cytology at risk for malignancy. The use of ultrassonographic classification has the potential to reduce the number of surgeries for nodules with indeterminate cytology

Os nódulos de tireoide são frequentemente encontrados na prática clínica e, com o auxílio de ultrassonografia de alta resolução, podem ser identificados em 17 a 67% da população. A alta prevalência desses nódulos causa preocupação frequente aos pacientes e aos clínicos devido ao risco de malignidade, o que, por sua vez, leva a investigações laboratoriais de alto custo, invasivas e, eventualmente, a cirurgias desnecessárias. A punção aspirativa com agulha fina (PAAF) é o método diagnóstico pré-operatório mais preciso para identificação de um nódulo maligno de tireoide, mas não consegue excluir malignidade nos casos de citologia inadequada, nódulos com diagnóstico citológico de lesão folicular ou atipia de significado indeterminado e nas citologias sugestivas de neoplasia folicular. O objetivo deste estudo foi analisar as características clínicas, laboratoriais, ultrassonográficas e citológicas de uma população de pacientes com nódulos de tireoide submetidos a tireoidectomia e a relação entre estes achados e o risco de malignidade. Além disto, em relação aos nódulos malignos, verificar se o valor de TSH esteve associado a um estadiamento mais avançado da doença. Foram avaliados prontuários de 353 pacientes submetidos a tireoidectomia, acompanhados no Hospital das Clínicas da FMUSP de São Paulo, no período de fevereiro de 2002 a abril de 2010. O número total de nódulos nestes pacientes foi 392. As características clínicas e laboratoriais analisadas em cada paciente foram idade, sexo, valores séricos de TSH e T4 livre, presença de anticorpo anti-tireoperoxidase (anti- TPO) e anti-tireoglobulina (anti-TG). Foram avaliadas a presença de características ultrassonográficas sugestivas de benignidade (presença de halo periférico hipoecoico, aparência espongiforme, aspecto isoecóico ou hiperecoico) e de malignidade (nódulo sólido hipoecoico, contornos irregulares, presença de microcalcificações). Baseados nestas características, os nódulos foram classificados em benignos, indeterminados e suspeitos para malignidade. O diagnóstico citológico foi classificado em benigno, indeterminado, suspeito e maligno, e a análise combinada das características ultrassonográficas e citológicas também foi avaliada. Ao exame histopatológico, 200 nódulos eram malignos e 192 nódulos eram benignos. Os nossos resultados mostraram que sexo, idade, valores séricos de TSH e T4 livre e presença de anticorpo anti-TPO e anti-TG não estiveram associados a uma maior chance de malignidade. O valor de TSH sérico também não esteve associado a maior risco de recorrência ou estadiamento mais avançado nos pacientes com câncer Os nódulos maiores estiveram mais associados a benignidade quando avaliamos toda amostra. Na análise multivariada de toda amostra, após regressão logística, apenas a citologia maligna, hipoecogenicidade e presença de microcalcificações foram associados a malignidade. Já, a classificação ultrassonográfica que não se baseia em apenas uma característica mas em um conjunto de características, apresentou um alto valor preditivo de benignidade e foi útil na identificação de nódulos com citologia indeterminada. A classificação ultrassonográfica tem o potencial de reduzir o número de cirurgias para nódulos com citologia indeterminada / Thyroid nodules are often encountered in clinical practice, and with the use of high-resolution ultrasound may be identified in 17 to 67% of the population. The high prevalence of these nodules cause frequent concern to patients and clinicians due to the risk of malignancy, wich in turn leads on costly investigations, use of invasive diagnostic methods and sometimes unnecessary surgeries. Fine needle aspiration biopsy (FNAB) is the most accurate preoperative diagnostic method to identify a malignant thyroid nodule. However, FNAB cannot rule out malignancy in cases of inadequate cytology, follicular lesions, atypia of undetermined significance, and in cytology suggestive of follicular neoplasm. The aim of this study was to analyze clinical, laboratory, ultrasound and cytopathologic characteristics of a group of patients with thyroid nodules undergoing thyroidectomy and the relationship between serum levels of TSH and the risk of malignancy. In nodules found to be malignant in this cohort, we analyzed the association of TSH levels with advanced disease stage and risk of recurrence. We analyzed the records of 353 patients who were followed at Hospital das Clínicas - São Paulo Medical School, between February 2002 and April 2010, and who subsequently underwent thyroidectomy. The total number of nodules in these patients was 392. The clinical and laboratory characteristics included in the analysis were age, gender, serum levels of TSH and free T4, and presence of serum thyroid anti-peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies. We evaluated the presence of ultrasonographic features suggestive of benignity (isoechoic or hyperechoic appearance, presence of hypoechoic peripheral halo, spongiform appearance) and malignancy (hypoechoic appearance, irregular border, presence of microcalcifications). Based on these ultrasonographic characteristics, we classified the nodules as benign, indeterminate or suspicious for malignancy. According to the FNAB cytology, we also subdivided the nodules into benign, indeterminate, suspicious and malignant. The combined analysis of ultrasonographic features and cytopathology was also evaluated. On histopathology, 200 nodules were malignant and 192 were benign. Our results showed that gender, age, serum levels of TSH and free T4, as well as the presence of anti-TPO and anti-TG were not associated with increased risk of malignancy. Similarly, serum TSH value was not associated with increased risk of recurrence or more advanced stage in patients with thyroid cancer. A large nodule size was associated with benignity. In multivariate analysis, after logistic regression, only malignant cytology, hypoechoic appearance and presence of microcalcifications were associated with malignancy. Furthermore, the ultrasonographic classification, wich was not based in only one feature but in a set of characteristics, showed a high predictive value for benignity and seems to be useful in identifying nodules with indeterminate cytology at risk for malignancy. The use of ultrassonographic classification has the potential to reduce the number of surgeries for nodules with indeterminate cytology

L’hypothyroïdie congénitale (HC) est une maladie relativement fréquente, touchant un nouveau-né sur 3000-4000, et dont la majorité des cas sont causés par un défaut dans le développement embryonnaire de la glande. Il existe plusieurs arguments en faveur d’une cause génétique dans une minorité de ces dysgénésies thyroïdiennes mais, à ce jour, seuls quelques cas ont put être reliés à une mutation dans l’un ou l’autre de trois gènes codant pour des facteurs de transcription impliqués dans le développement de la thyroïde (TITF1, PAX8 et FOXE1).<p>Au cours de notre travail de thèse, nous avons caractérisé la 6ème mutation du gène PAX8 à l’état hétérozygote, dans un cas familial d’HC. Nous avons étudié l’impact fonctionnel de cette altération qui entraîne une perte de liaison de la protéine mutée à une séquence cible spécifique, ainsi qu’une diminution drastique de la synergie de transactivation en association avec Titf1. Le phénotype des patients est également intéressant à plus d’un titre. En effet, nous avons pu observer que les mutations de PAX8 sont compatibles avec le développement d’une thyroïde en place et de taille normale à la naissance, pouvant conduire à un diagnostic erroné de dyshormonogenèse. De plus, un des trois patients présente un phénotype rénal qu’il est tentant de relier à la mutation de PAX8 étant donné que ce gène est exprimé durant le développement de cet organe, tout comme dans la thyroïde.<p>Notre travail a également consisté en l’élaboration d’une librairie SAGE du bourgeon thyroïdien en développement, afin de rechercher de nouveaux gènes candidats impliqués dans le développement de la glande thyroïde. Grâce à une technique d’amplification d’ARN, nous avons obtenu une librairie d’environ 94.000 étiquettes à partir de bourgeons thyroïdiens provenant d’embryons de souris au 11ème jour de développement. Cette librairie nous a permis d’identifier une nouvelle isoforme du transcrit de Titf1 modifiant l’extrémité 3’-non codante du messager, ainsi qu’un gène de fonction inconnue mais dont le profil d’expression ainsi que sa grande conservation au cours de l’évolution laissent suggérer un rôle important, tant dans les tissus embryonnaires que dans les tissus adultes.<p>Ces deux découvertes valident le caractère prédictif de notre librairie qui constitue un outil de choix pour l’identification de nouveaux gènes de développement thyroïdien et donc de nouveaux candidats pour l’étude des mécanismes étiopathogéniques à la base des dysgénésies thyroïdiennes.<p>/<p>Congenital hypothyroidism (CH) is a relatively frequent disease affecting 1 every 3000-4000 newborns. The majority of CH cases are caused by a defect in the embryonic development of the gland. There exists several arguments in favor of a genetic cause for a minority of these thyroid dysgeneses but, to this day, only a few cases have been related to a mutation in one of three genes coding for transcription factors implicated in thyroid development (TITF1, PAX8 and FOXE1).<p>In the course of this work, we have caracterized the 6th mutation of the PAX8 gene, in the heterozygous state, in a familial case of CH. We have studied the functional impact of this modification which leads to a loss of the protein’s DNA-binding properties and to a severe reduction in the transactivation synergy in association with Titf1. The phenotype of the patients presents also interesting features. Indeed we have observed that the PAX8 mutations are compatible with the development of an in-place, normal-sized thyroid at birth, which could lead to an erroneous diagnostic of dyshormonogenesis. Moreover, one of the three patients presents with a renal phenotype (unilateral kidney agenesis) which is tempting to relate to the PAX8 mutation, given this gene is expressed during kidney development.<p>Our work also consisted in the generation of an embryonic thyroid bud SAGE library, which we used to search for new candidate genes implicated in thyroid development. With the help of a RNA amplification technique, we obtained a library of roughly 94.000 tags starting from mous thyroid buds at E11. This library allowed us to identify a new Titf1 splicing variant modifying the 3’-UTR of the transcript, and a gene of unknown function. The latter’s expression profile and high conservation throughout evolution suggest a crucial role in embryonic as well as adult tissues.<p>These two findings validate the predictive character of our library which constitutes a powerful tool to identify new thyroid developmental genes and new candidate genes for the study of the etiopathogenic mecanisms responsible for CH.<p><p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Abstract Maternal thyroid dysfunction and/or antibodies are present in 5–10% of pregnancies and may be associated with increased risks of adverse pregnancy and perinatal outcomes. In the present study maternal thyroid function and antibody status in the Northern Finland Birth Cohort 1986 was analyzed using early pregnancy serum samples. The impact of long-term storage on the stability of thyroid hormones and antibodies was studied and while TSH and thyroid hormone levels were not affected by storage time the concentrations of thyroid antibodies appeared to be significantly increased after 10 years of storage. Normal maternal thyroid function was evaluated by calculating thyroid hormone reference intervals in the thyroid antibody-negative population using a biobank of stored serum samples. Thyrotropin, free thyroxine and triiodothyronine reference intervals in the first and second trimester were 0.07–3.1 mU/L and 0.10–3.5 mU/L, 11.4–22.4 pmol/L and 11–18.9 pmol/L; and 3.4–7.0 pmol/L and 3.5–7.3 pmol/L, respectively, in this population (Abbott Architect method). Compared with thyroid antibody-negative mothers, antibody-positive mothers had significantly higher TSH and lower fT4 concentrations and an increased risk of experiencing death of an infant in the perinatal period with odds ratios (ORs) of 3.1 (95% confidence interval 1.4–7.1) for thyroid-peroxidase and OR 2.6 (1.1–6.2) for thyroglobulin antibody positivity. These infants were more often born very preterm, which could possibly explain these increased risks. Positive thyroid antibody status was not associated with preterm birth in this study. No other major pregnancy or perinatal complications were observed among mothers or newborns of mothers with thyroid dysfunction/antibodies. Mothers, who had hypothyroidism or thyroid antibodies during pregnancy, had a very high risk of subsequent thyroid disease: hazard ratio (HR) 17.7 (7.8–40.6) for overt hypothyroidism, 4.2 (2.3–7.4) for thyroid-peroxidase and 3.3 (1.9–6.0) for thyroglobulin antibody positivity. Mothers with hypothyroidism during pregnancy had increased risk of subsequent diabetes, (HR 6.0 [2.2–16.4]). Women at risk of thyroid dysfunction should be recognized and their prepregnancy counseling, blood sampling and treatment is probably beneficial. Whether universal screening of all pregnant women is justified is still under debate. / Tiivistelmä Kilpirauhasen toimintahäiriö tai ainoastaan kilpirauhasvasta-aineita (tyreoideaperoksidaasi- tai tyreoglobuliinivasta-aineita) esiintyy 5–10 % raskaana olevista naisista ja ne mahdollisesti lisäävät riskiä raskausajan ja vastasyntyneisyyskauden ongelmiin. Tässä väitöskirjatyössä tutkittiin Pohjois-Suomen syntymäkohorttia vuodelta 1985–1986. Äitien kilpirauhasen toimintaa tutkittiin alkuraskauden verinäytteiden avulla. Selvitimme pitkäaikaisen (20 vuotta) pakkassäilytyksen vaikutusta kilpirauhaslaboratoriokokeisiin. Tutkimuksessamme pakkassäilytyksellä ei ollut vaikutusta kilpirauhashormonien pitoisuuksiin, mutta kilpirauhasvasta-aineiden pitoisuudet olivat merkittävästi lähtötasoa korkeampia 10 säilytysvuoden jälkeen. Äitien normaali kilpirauhasen toiminta arvioitiin laskemalla aineistosta kilpirauhashormonien viitevälit kilpirauhasvasta-ainenegatiivisille naisille raskauden ensimmäiselle ja toiselle kolmannekselle käyttäen Abbott Architect metodia. Viitearvot olivat: tyreotropiinille 0.07–3.1 mU/l ja 0.10–3.5 mU/l, vapaalle tyroksiinille 11.4–22.4 ja 11–18.9 pmol/l sekä vapaalle trijodotyroniinille 3.4–7.0 ja 3.5–7.3 pmol/l. Äidin kilpirauhasen toimintahäiriöt eivät liittyneet vaikeisiin raskausajan tai vastasyntyneisyyskauden ongelmien, kuten ennenaikaisuuden ja kohtukuolemien esiintymiseen. Äidin kilpirauhasvasta-aineiden esiintyminen, mikä osoittaa kroonista autoimmuunityreoidiittia, lisäsi riskiä lapsen kohtukuolemaan ja ensimmäisen elinviikon kuolemaan; riski oli jopa kolminkertainen tyreoideaperoksidaasivasta-ainepositiivisten äitien vastasyntyneillä. Nämä vastasyntyneet olivat usein syntyneet hyvin ennenaikaisina (ennen 28. raskausviikkoa), mikä voi selittää tätä riskiä. Äidin kilpirauhasvasta-aineet eivät kuitenkaan lisänneet ennenaikaisten synnytysten riskiä tässä tutkimuksessa. Äideillä, joilla oli todettu kilpirauhasen vajaatoiminta tai kilpirauhasvasta-aineita, itsellään oli korkea, jopa 17-kertainen, riski sairastua myöhempiin kilpirauhasen sairauksiin, ja kilpirauhasen vajaatoiminta kuusinkertaisti sokeritautiin sairastumisriskin. Olisi tärkeää tunnistaa jo ennen raskautta ne naiset, joilla on riski sairastua kilpirauhasen vajaatoimintaan. Raskauden aikaisesta yleisestä seulonnasta ei vielä ole yksimielisyyttä.