RESUMO
Immune checkpoint inhibitors are reshaping the prognosis of many cancer and are progressively becoming the standard of care in the treatment of many tumour types. Immunotherapy is bringing new hope to patients, but also a whole new spectrum of toxicities for healthcare practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of patients with cancer are increasingly confronted with the therapeutic challenge of treating patients with severe and refractory immune-related adverse events. In this Personal View, we summarise the therapeutic strategies that have been used to manage such toxicities resulting from immune checkpoint inhibitor treatment. On the basis of current knowledge about their pathogenesis, we discuss the use of new biological and non-biological immunosuppressive drugs to treat severe and steroid refractory immune-related adverse events. Depending on the immune infiltrate type that is predominant, we propose a treatment algorithm for personalised management that goes beyond typical corticosteroid use. We propose a so-called shut-off strategy that aims at inhibiting key inflammatory components involved in the pathophysiological processes of immune-related adverse events, and limits potential adverse effects of drug immunosuppression on tumour response. This approach develops on current guidelines and challenges the step-by-step increase approach to drug immunosuppression.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Imunoterapia/efeitos adversos , Algoritmos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Humanos , Neoplasias/terapia , Medicina de PrecisãoRESUMO
OBJECTIVE: In 2016, there were an estimated 56 870 new cases of thyroid cancer (TC) in the USA. Fine needle aspiration cytology (FNAC) is the most safe, accurate and cost-effective method for the initial investigation of thyroid nodules. FNAC is limited by the inability to diagnose malignancy in follicular-patterned lesions accurately and, as a result, 20%-30% of cases under investigation for TC are classified as cytologically indeterminate, illustrating a problem with current FNAC procedure. Raman spectroscopy has shown promising results for the detection of many cancers; however, to date there has been no report on the performance of Raman spectroscopy on thyroid cytological samples. The aim of this study was to examine whether Raman spectroscopy could be used to correctly classify cell lines representing benign thyroid cells and various subtypes of TC. METHODS: A benign thyroid cell line and seven TC cell lines were prepared as ThinPrep® cytology slides and analysed with Raman spectroscopy. Principal components analysis and linear discriminant analysis were implemented to develop effective diagnostic algorithms for classification of Raman spectra of different TC subtypes. RESULTS: The spectral differences separating benign and TC cell lines were assigned to differences in the composition of nucleic acids, lipids, carbohydrates and protein in the benign and cancer cells. Good sensitivities (74%-85%), specificities (65%-93%) and diagnostic accuracies (71%-88%) were achieved for the identification of TC. CONCLUSION: These findings suggest that Raman spectroscopy has potential for preoperative TC diagnosis on FNAC samples.
Assuntos
Citodiagnóstico/métodos , Análise Espectral Raman/métodos , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/diagnóstico , Biópsia por Agulha Fina , Feminino , Humanos , Masculino , Período Pré-Operatório , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/patologiaRESUMO
The incidence of differentiated thyroid cancers has increased in the past 30 years, mainly due to overdiagnosis. It is therefore crucial to adapt diagnostic and therapeutic approaches to avoid overtreatment that exposes patients to unnecessary risks. Accordingly, international guidelines on the subject are regularly updated. Ultrasound and cytology guide the management for thyroid nodules. Some microcarcinomas can now be actively followed without immediate surgery, and some low-risk cancers can be adequately treated with lobo-isthmectomy. The indications for central neck dissection remain controversial. Technological advances allow minimizing specific complications of thyroid surgery and facilitate scarless surgery.
Face à l'augmentation d'incidence des cancers différenciés de la thyroïde principalement due au surdiagnostic, il est crucial d'adapter les attitudes diagnostiques et thérapeutiques afin d'éviter le « surtraitement ¼ qui expose les patients à des risques non nécessaires. Dans ce but, les recommandations internationales à ce sujet sont régulièrement mises à jour. L'ultrason et la cytologie permettent d'orienter la conduite à tenir devant un nodule thyroïdien. Certains microcarcinomes sont maintenant éligibles pour un suivi actif et une lobo-isthmectomie peut être proposée pour certains cancers avérés. Les indications aux curages ganglionnaires centraux sont toujours débattues. Des évolutions technologiques permettent de réduire les complications propres à la chirurgie thyroïdienne et facilitent la réalisation d'interventions sans cicatrice visible.
Assuntos
Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/cirurgia , Humanos , Tireoidectomia , UltrassonografiaRESUMO
Thyroid nodules are a very common problem whose prevalence increases with age. When treatment is considered, surgical excision is traditionally the first choice, except in the case of hyperfunctioning nodules, where treatment with radioactive iodine plays a major role. In recent years, there has been increasing experience in the thermal ablation of thyroid nodules by radiofrequency, with very encouraging results. This article aims to discuss the role of radiofrequency thermal ablation in the management of benign thyroid nodules by reviewing the indications, adverse effects and limitations of this method.
Les nodules thyroïdiens sont un problème très fréquent dont la prévalence augmente avec l'âge. Lorsqu'un traitement est envisagé, l'excision chirurgicale occupe jusqu'à présent la première place, sauf dans le cas des nodules hyperfonctionnels où la radiothérapie métabolique par iode 131 joue un rôle principal. Depuis quelques années, il existe une expérience croissante dans la thermoablation des nodules thyroïdiens par radiofréquence, avec des résultats très encourageants. Cet article a pour but de discuter la place de la thermoablation par radiofréquence dans la prise en charge des nodules thyroïdiens bénins en passant en revue les indications, les effets indésirables et les limitations de cette méthode.
Assuntos
Ablação por Cateter , Nódulo da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/terapia , Humanos , Radioisótopos do Iodo , Resultado do TratamentoRESUMO
Subclinical hypothyroidism, defined as an elevated level of thyrotropin hormone (TSH) and normal thyroxin, is more frequent in women and above 65 years old. This condition is associated with an increased cardiovascular risk, in particular with TSH > 10,0 mIU/L. Although overt hypothyroidism is rare (prevalence of 0,3 %), levothyroxine has become the most prescribed medication in the US, while its indications are still debated. The European-funded TRUST trial showed no improvement in Hypothyroid Symptoms and Tiredness scores among patients ≥ 65 years with subclinical hypothyroidism treated with levothyroxine, and no improvement in blood pressure, weight, muscle strength and cognition. The results of this study call for a revision of the current international recommendations on the treatment of subclinical hypothyroidism.
L'hypothyroïdie infraclinique, soit un taux élevé d'hormone thyréotrope (TSH) et une thyroxine normale, est plus fréquente chez les femmes et après 65 ans. Cette condition est associée à une élévation du risque cardiovasculaire, en particulier lors de TSH > 10,0 mUl/l. Bien que l'hypothyroïdie franche soit peu fréquente (prévalence de 0,3 %), la lévothyroxine est devenue le médicament le plus prescrit aux Etats-Unis, alors que ses indications restent controversées. L'étude européenne TRUST a montré l'absence d'amélioration des scores de fatigue et d'hypothyroïdie chez des personnes âgées ≥ 65 ans avec hypothyroïdie infraclinique sous lévothyroxine, ainsi qu'une absence de bénéfice pour la tension artérielle, le poids, la force et la cognition. Nous proposons ici d'adapter les recommandations internationales sur l'hypothyroïdie infraclinique.
Assuntos
Hipotireoidismo , Atenção Primária à Saúde , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Hipotireoidismo/tratamento farmacológico , Prevalência , Tireotropina/uso terapêutico , Tiroxina/uso terapêuticoRESUMO
Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
Assuntos
Fosfatase 6 de Especificidade Dupla/genética , Fatores de Crescimento de Fibroblastos/genética , Predisposição Genética para Doença/genética , Hipogonadismo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores de Interleucina/genética , Algoritmos , Animais , Sequência de Bases , Biologia Computacional , Feminino , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Padrões de Herança/genética , Masculino , Glicoproteínas de Membrana , Camundongos , Dados de Sequência Molecular , Mutação/genética , Análise de Sequência de DNA , Homologia de Sequência , Ressonância de Plasmônio de SuperfícieAssuntos
Mutação/genética , Miofibroblastos/patologia , Células Estromais/patologia , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , beta Catenina/genética , Sequência de Aminoácidos , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.
Assuntos
Hipogonadismo/congênito , Hipogonadismo/genética , Deformidades Congênitas dos Membros/genética , Mutação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Sequência Conservada , Feminino , Estudos de Associação Genética , Humanos , Hipogonadismo/metabolismo , Deformidades Congênitas dos Membros/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Linhagem , Fosforilação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.
Assuntos
Efeito Fundador , Mutação de Sentido Incorreto , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Reprodução , Evolução Molecular , Feminino , Hormônio Liberador de Gonadotropina/deficiência , Haplótipos , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Grupos Raciais/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/metabolismoRESUMO
BACKGROUND: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. METHODS: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. RESULTS: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. CONCLUSIONS: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.).
Assuntos
Amenorreia/genética , Hormônio Liberador de Gonadotropina/deficiência , Doenças Hipotalâmicas/genética , Mutação , Amenorreia/etiologia , Proteínas da Matriz Extracelular/genética , Feminino , Expressão Gênica , Predisposição Genética para Doença , Hormônio Liberador de Gonadotropina/genética , Humanos , Hipogonadismo/genética , Doenças Hipotalâmicas/complicações , Hormônio Luteinizante/metabolismo , Proteínas do Tecido Nervoso/genética , Precursores de Proteínas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores Acoplados a Proteínas G/genética , Receptores LHRH/genética , Receptores de Peptídeos/genética , Análise de Sequência de DNARESUMO
Proteasome is central to proteostasis maintenance, as it degrades both normal and damaged proteins. Herein, we undertook a detailed analysis of proteasome regulation in the in vivo setting of Drosophila melanogaster. We report that a major hallmark of somatic tissues of aging flies is the gradual accumulation of ubiquitinated and carbonylated proteins; these effects correlated with a ~50% reduction of proteasome expression and catalytic activities. In contrast, gonads of aging flies were relatively free of proteome oxidative damage and maintained substantial proteasome expression levels and highly active proteasomes. Moreover, gonads of young flies were found to possess more abundant and more active proteasomes than somatic tissues. Exposure of flies to oxidants induced higher proteasome activities specifically in the gonads, which were, independently of age, more resistant than soma to oxidative challenge and, as analyses in reporter transgenic flies showed, retained functional antioxidant responses. Finally, inducible Nrf2 activation in transgenic flies promoted youthful proteasome expression levels in the aged soma, suggesting that age-dependent Nrf2 dysfunction is causative of decreasing somatic proteasome expression during aging. The higher investment in proteostasis maintenance in the gonads plausibly facilitates proteome stability across generations; it also provides evidence in support of the trade-off theories of aging.
Assuntos
Envelhecimento/metabolismo , Drosophila melanogaster/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Envelhecimento/genética , Animais , Animais Geneticamente Modificados , Elementos de Resposta Antioxidante/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Feminino , Genes de Insetos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ovário/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Testículo/metabolismo , Distribuição Tecidual/genéticaRESUMO
Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.
Assuntos
Hipogonadismo/enzimologia , Hipogonadismo/genética , Mutação , Sulfotransferases/genética , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Criança , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Genes de Helmintos , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Síndrome de Kallmann/enzimologia , Síndrome de Kallmann/genética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Sulfotransferases/química , Sulfotransferases/deficiência , Sulfotransferases/metabolismoRESUMO
BACKGROUND: 18F-FDG PET/CT is performed for the assessment of radioactive iodine non-avid disease in patients with DTC. In patients prepared by THW, increased pituitary uptake of 18F-FDG in the absence of pituitary disease may reflect the physiological activation of pituitary thyrotroph cells by hypothyroidism. This study aimed to compare pituitary 18F-FDG uptake in patients with DTC under THW vs. rhTSH stimulation. METHODS: A total of 57 patients with DTC undergoing 18F-FDG PET/CT (40 under THW and 17 under rhTSH stimulation) were retrospectively analyzed. Pituitary metabolism was expressed as maximum standardized uptake value (SUVmax) and as SUVratio using the right cerebellum as reference. RESULTS: Pituitary hypermetabolism (SUVmax ≥ 4.1) was present in more patients in the THW group compared to the rhTSH group (62.5% vs. 23.5%; p = 0.01). Pituitary metabolism was significantly higher in the THW group compared to the rhTSH group, as assessed by either SUVmax (mean ± SD: 4.61 ± 1.22, 95%CI: 4.22-5.00 vs. 3.34 ± 0.86, 95%CI: 2.9-3.8; p < 0.001) or SUVratio (0.52 ± 0.11, 95%CI: 0.49-0.56 vs. 0.42 ± 0.07, 95%CI: 0.38-0.46; p < 0.001). Serum TSH levels correlated positively with SUVmax (r = 0.41, p < 0.01) and SUVratio (r = 0.44, p < 0.01) in the THW group only. CONCLUSIONS: The present findings support the hypothesis that pituitary hypermetabolism on 18F-FDG PET/CT in patients with DTC undergoing THW is a common physiological response to hypothyroidism. Awareness of this physiological hypermetabolism is important to avoid potential pitfalls in image interpretation.
RESUMO
Iodide plays a pivotal role in thyroid homeostasis due to its crucial involvement in thyroid hormone biosynthesis. Exposure to pharmacological doses of iodide elicits in the thyroid an autoregulatory response to preserve thyroid function, as well as an antioxidant response that is mediated by the Keap1/Nrf2 signaling pathway. The objective of the present study was to investigate the transcriptional response of the thyroid to excess iodide in a background of enhanced Nrf2 signaling. Keap1 knockdown (Keap1KD) mice that have activated Nrf2 signaling were exposed or not to excess iodide in their drinking water for seven days and compared to respective wild-type mice. RNA-sequencing of individual mouse thyroids identified distinct transcriptomic patterns in response to iodide, with Keap1KD mice showing an attenuated inflammatory response, altered thyroidal autoregulation, and enhanced cell growth/proliferative signaling, as confirmed also by Western blotting for key proteins involved in antioxidant, autoregulatory and proliferative responses. These findings underscore novel gene-environment interactions between the activation status of the Keap1/Nrf2 antioxidant response system and the dietary iodide intake, which may have implications not only for the goiter phenotype of Keap1KD mice but also for humans harboring genetic variations in KEAP1 or NFE2L2 or treated with Nrf2-modulating drugs.
Assuntos
Antioxidantes , Glândula Tireoide , Humanos , Camundongos , Animais , Antioxidantes/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Glândula Tireoide/metabolismo , Estresse Oxidativo , Iodetos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Interação Gene-Ambiente , Perfilação da Expressão Gênica , HomeostaseRESUMO
Technetium-99m sestamibi single-photon emission computed tomography/computed tomography (99mTc-sestamibi SPECT/CT) is a mainstay of the pre-operative localization of parathyroid lesions. We report here the case of a 30 year-old woman with a fortuitously discovered 2 cm cervical mass for which a parathyroid origin was originally suspected due to its retro-thyroidal localization and a personal history of nephrolithiasis. Normal serum calcium and parathyroid hormone (PTH) levels excluded primary hyperparathyroidism, raising suspicion of a non-functional parathyroid adenoma, and SPECT/CT imaging showed that the mass was 99mTc-sestamibi-avid. Fine-needle aspiration (FNA) was performed; cytology was non-diagnostic but the needle washout was negative for thyroglobulin, calcitonin and PTH, arguing against a thyroidal or parathyroidal origin of the mass. Core needle biopsy revealed a schwannoma, ostensibly originating from the recurrent laryngeal nerve; upon surgical resection, it was finally found to arise from the esophageal submucosa. This case illustrates the fact that endocrinologists, radiologists, nuclear medicine, head and neck, and other specialists investigating patients with cervical masses should be aware that schwannomas need to be considered in the differential diagnosis of focal 99mTc-sestamibi uptake in the neck region.
Assuntos
Adenoma , Neurilemoma , Neoplasias das Paratireoides , Tecnécio Tc 99m Sestamibi , Humanos , Feminino , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/patologia , Neoplasias das Paratireoides/cirurgia , Neoplasias das Paratireoides/diagnóstico , Adulto , Neurilemoma/diagnóstico por imagem , Neurilemoma/patologia , Neurilemoma/diagnóstico , Diagnóstico Diferencial , Adenoma/diagnóstico por imagem , Adenoma/diagnóstico , Adenoma/patologia , Adenoma/metabolismo , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Compostos RadiofarmacêuticosRESUMO
Background: The incidence of thyroid cancer is on the rise worldwide, with childhood exposure to radiation being the sole acknowledged catalyst for its emergence. Nonetheless, numerous other factors that may pose risks are awaiting thorough examination and validation. This retrospective study aims to explore the malignancies linked to thyroid cancer and contrast the survival rates of those afflicted with a solitary tumor versus those with multiple primary neoplasms (MPN). Methods: This retrospective study examined data from King Hussein Cancer Center (KHCC), Jordan. Among 563 patients diagnosed with thyroid cancer, 30 patients had thyroid malignancy as part of MPN. For a 1:3 propensity score-matched analysis, 90 patients with only a primary thyroid malignancy were also enrolled. Results: Hematologic and breast malignancies were among the most frequent observed cancers alongside thyroid neoplasm. Patients who had MPN were diagnosed at older age, had higher body mass index and presented with higher thyroglobulin antibody levels (p < 0.05 for each). Additionally, MPN patient displayed a stronger family history for cancers (p= 0.002). A median follow-up duration of 135 months unveiled that MPN patients faced a worse 5-year survival compared to their counterparts with a singular neoplasm (87% vs 100% respectively; p < 0.01). However, no distinction emerged in the 5-year event-free survival between these two groups. Conclusion: MPN correlates with a significantly altered survival outcome of thyroid cancer patients. The diagnosis of thyroid carcinoma at an older age, accompanied by elevated initial thyroglobulin antibody levels and a notable familial predisposition, may raise concerns about the potential occurrence of synchronous or metachronous tumors.
Assuntos
Neoplasias Primárias Múltiplas , Pontuação de Propensão , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/mortalidade , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Neoplasias Primárias Múltiplas/epidemiologia , Jordânia/epidemiologia , Taxa de Sobrevida , Idoso , Seguimentos , PrognósticoRESUMO
Keap1/Nrf2 signaling defends organisms against the detrimental effects of oxidative stress and has been suggested to abate its consequences, including aging-associated diseases like neurodegeneration, chronic inflammation, and cancer. Nrf2 is a prominent target for drug discovery, and Nrf2-activating agents are in clinical trials for cancer chemoprevention. However, aberrant activation of Nrf2 by keap1 somatic mutations may contribute to carcinogenesis and promote resistance to chemotherapy. To evaluate potential functions of Keap1 and Nrf2 for organismal homeostasis, we characterized the pathway in Drosophila. We demonstrate that Keap1/Nrf2 signaling in the fruit fly is activated by oxidants, induces antioxidant and detoxification responses, and confers increased tolerance to oxidative stress. Importantly, keap1 loss-of-function mutations extend the lifespan of Drosophila males, supporting a role for Nrf2 signaling in the regulation of longevity. Interestingly, cancer chemopreventive drugs potently stimulate Drosophila Nrf2 activity, suggesting the fruit fly as an experimental system to identify and characterize such agents.
Assuntos
Envelhecimento/fisiologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sequência Conservada , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Feminino , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 1 Associada a ECH Semelhante a Kelch , Expectativa de Vida , Masculino , Mutação , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Paraquat/toxicidade , Transdução de Sinais , Ativação TranscricionalRESUMO
Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.
Assuntos
Hormônio Liberador de Gonadotropina/deficiência , Hipogonadismo/genética , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Proteínas da Matriz Extracelular/genética , Feminino , Fator 8 de Crescimento de Fibroblasto/genética , Hormônios Gastrointestinais/genética , Redes Reguladoras de Genes , Variação Genética , Heterozigoto , Homozigoto , Humanos , Síndrome de Kallmann/genética , Masculino , Modelos Genéticos , Mutação , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Linhagem , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Kisspeptina-1 , Receptores LHRH/genética , Receptores de Peptídeos/genética , Fatores de Transcrição/genéticaRESUMO
The body temperature of mice is higher at night than during the day. We show here that global deletion of acid-sensing ion channel 1a (ASIC1a) results in lower body temperature during a part of the night. ASICs are pH sensors that modulate neuronal activity. The deletion of ASIC1a decreased the voluntary activity at night of mice that had access to a running wheel but did not affect their spontaneous activity. Daily rhythms of thyrotropin-releasing hormone mRNA in the hypothalamus and of thyroid-stimulating hormone ß mRNA in the pituitary, and of prolactin mRNA in the hypothalamus and pituitary were suppressed in ASIC1a-/- mice. The serum thyroid hormone levels were however not significantly changed by ASIC1a deletion. Our findings indicate that ASIC1a regulates activity and signaling in the hypothalamus and pituitary. This likely leads to the observed changes in body temperature by affecting the metabolism or energy expenditure.
Assuntos
Canais Iônicos Sensíveis a Ácido , Temperatura Corporal , Animais , Camundongos , Canais Iônicos Sensíveis a Ácido/genética , Metabolismo Energético/genética , Hipotálamo , RNA MensageiroRESUMO
The aim of this prospective pilot study was to evaluate the feasibility of a new hybrid imaging modality, free-hand single-photon computed tomography/ultrasonography (fhSPECT/US), for preoperative localization of parathyroid adenomas and to compare its performance with conventional ultrasonography and SPECT/CT. Twelve patients diagnosed with primary hyperparathyroidism underwent sequentially US and parathyroid scintigraphy, including SPECT/CT, followed by fhSPECT/US, allowing for real-time fusion between US and freehand-generated gamma-camera images. The fhSPECT/US detection rates were correlated with histopathology, when available, or with the imaging modality showing the most lesions. Based on a per patient analysis, the detection rate was significantly different when comparing SPECT/CT to fhSPECT/US (p = 0.03), and not significantly different when comparing SPECT/CT to US (p = 0.16) and US to fhSPECT/US (p = 0.08). Based on a per-lesion analysis, the detection rate of SPECT/CT was significantly higher than that of US (p = 0.01) and fhSEPCT/US (p = 0.003), and there was no significant difference in detection rate when comparing US to fhSPECT/US (p = 0.08). The main perceived limitations of fhSPECT/US in lesion detection were: (i) lesions localized at a depth ≥4.5 cm; (ii) imperfect image fusion due to tissue compression; (iii) limited spatial manipulation ability of the SPECT mobile camera handheld probe; and (iv) a wide spread of detected activity. In conclusion, clinical use of fhSPECT/US for localization of parathyroid adenomas is feasible, but shows lower sensitivity than conventional modalities and requires technical improvements.