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The sodium-iodide symporter (NIS, SLC5A5) is expressed at the basolateral membrane of the thyroid follicular cell, and facilitates the thyroidal iodide uptake required for thyroid hormone biosynthesis. Biallelic loss-of-function mutations in NIS are a rare cause of dyshormonogenic congenital hypothyroidism. Affected individuals typically exhibit a normally sited, often goitrous thyroid gland, with absent uptake of radioiodine in the thyroid and other NIS-expressing tissues. We report a novel homozygous NIS mutation (c.1067 C>T, p.S356F) in four siblings from a consanguineous Indian kindred, presenting with significant hypothyroidism. Functional characterization of the mutant protein demonstrated impaired plasma membrane localization and cellular iodide transport.

Objective: Placental iodide transport is necessary for maintaining an adequate iodide supply to the developing fetus. We hypothesized that compounds from the placental barrier can compensate for de...

We report herein a series of pore-containing polymeric nanotubes based on an H-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of ~ 6.5 A in diameter, are interestingly found to mediate highly efficient transport of diverse types of anions, rather than cations, across lipid membrane. Polymer channel 1a, having an averaged molecular weight of 18.2 KDa and 3.6 nm in helical height, exhibits the highest anion transport activities with iodide (EC50 = 0.042 μM or 0.028 mol% relative to lipid) being transported 10 times more efficiently than chlorides (EC50 = 0.47 μM). Notably, even in cholesterol-rich environment, iodide transport activity still remains high with EC50 of 0.37 μM. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.

International audience; The sodium/iodide symporter (NIS) expresses at the basolateral plasma membrane of the thyroid follicular cell and mediates iodide accumulation required for normal thyroid hormonogenesis. Loss-of-function NIS variants cause congenital hypothyroidism due to impaired iodide accumulation in thyroid follicular cells underscoring the significance of NIS for thyroid physiology. Here we report novel findings derived from the thorough characterization of the nonsense NIS mutant p.R636* NIS-leading to a truncated protein missing the last eight amino acids-identified in twins with congenital hypothyroidism. R636* NIS is severely mislocalized into intracellular vesicular compartments due to the lack of a conserved carboxy-terminal type 1 PDZ-binding motif. As a result, R636* NIS is barely targeted to the plasma membrane and therefore iodide transport is reduced. Deletion of the PDZ-binding motif causes NIS accumulation into late endosomes and lysosomes. Using PDZ domain arrays, we revealed that the PDZ-domain containing protein SCRIB binds to the carboxy-terminus of NIS by a PDZ-PDZ interaction. Furthermore, in CRISPR/Cas9-based SCRIB deficient cells, NIS expression at the basolateral plasma membrane is compromised, leading to NIS localization into intracellular vesicular compartments. We conclude that the PDZ-binding motif is a plasma membrane retention signal that participates in the polarized expression of NIS by selectively interacting with the PDZ-domain containing protein SCRIB, thus retaining the transporter at the basolateral plasma membrane. Our data provide insights into the molecular mechanisms that regulate NIS expression at the plasma membrane, a topic of great interest in the thyroid cancer field considering the relevance of NIS-mediated radioactive iodide therapy for differentiated thyroid carcinoma.

Summary Function of the thyroid follicular cell depends on nuclear expression of thyroid transcription factor 1 (TTF1). Regulation of this key protein regulating iodide transport is not well known, but its loss is linked to the most lethal of thyroid malignancies. We examined TTF1 nuclear expression in the context of adverse pathological features, disease recurrence, and BRAF status in papillary thyroid carcinomas with (n = 182) and without (n = 303) nodal metastases. Overall nuclear expression level of TTF1 was strong and diffuse in approximately 73%, whereas 27% exhibited lower levels or a paucity of nuclear staining. In the same cohort, approximately 59% exhibited the BRAF mutation. On univariate analysis, low levels of TTF1 nuclear expression was linked to vascular invasion, extrathyroidal extension, and nodal metastases. Multivariate analysis indicated that low levels of TTF1 were most strongly linked to nodal metastases and vascular invasion. Interestingly, TTF1 levels were not linked to the BRAF mutation. TTF1 staining alone predicted disease recurrence, but when combined with BRAF status, the 2 markers exhibited a more marked influence. Patients lacking the BRAF mutation and exhibiting normal levels of TTF1 exhibited very low levels of disease recurrence (11% at 10 years). Conversely, patient tumors with low levels of TTF1 and the BRAF mutation recurred in 31% of cases in the same time frame. The mixed expression of BRAF under varying levels of differentiation may explain, in part, the contradictory studies regarding the impact of BRAF mutations on patient prognosis and also indicates a complex genomic signature for dedifferentiated thyroid cancer.

Background: The effect of smoking on thyroid is believed to be due to the compound thiocyanate, a potent inhibitor of iodide transport, potentially capable of affecting the thyroid function. TSH is the major regulator of the morphologic and functional states of the thyroid. All steps in the formation and release of thyroid hormones are stimulated by TSH secreted by the pituitary thyrotrophs. These include both pro- (e.g. thyroid stimulating) and anti-thyroid actions and also actions that increase susceptibility to or exacerbation of the manifestations of Graves’ disease. Thus, this study may be instrumental in early detection and management of thyroid disease in smokers. The aim of this study is to evaluate and compare TSH thyroid stimulating hormones status in smokers and non smokers.Methods: A prospective study is done with 60 patients divided into 2 groups. Group 1 (healthy male non-smokers) as control and Group 2 (healthy male smokers). Fasting blood samples were collected and serum TSH levels were estimated. The data was analyzed using unpaired t test.Results: In the present study significant decrease in TSH observed in the cases compared to the controls. Mean±S.D of TSH in Group 1 is 2.80±0.83 and Group 2 is 1.00±1.02, there is a significant decrease in serum TSH levels in Group 2.Interpretations & Conclusion: The finding in this study indicates that smoking is associated with biochemical hyperthyroidism. Hence evaluating thyroid hormone status in smokers might help in identifying occurrence of thyroid disorders and appropriate measures could be taken to prevent severity of morbidity and mortality associated with smoking.

New findings What is the central question of this study? The tracer 36 Cl- , currently used to measure transepithelial Cl- fluxes, has become prohibitively expensive, threatening its future use. 125 Iodide, previously validated alongside 36 Cl- as a tracer of Cl- efflux by cells, has not been tested as a surrogate for 36 Cl- across epithelia. What is the main finding and its importance? We demonstrate that 125 I- can serve as an inexpensive replacement for measuring Cl- transport across mouse large intestine, tracking Cl- transport in response to cAMP stimulation (inducing Cl- secretion) in the presence and absence of the main gastrointestinal Cl- -HCO3 - exchanger, DRA. Abstract Chloride transport is important for driving fluid secretion and absorption by the large intestine, with dysregulation resulting in diarrhoea-associated pathologies. The radioisotope 36 Cl- has long been used as a tracer to measure epithelial Cl- transport but is prohibitively expensive. 125 Iodide has been used as an alternative to 36 Cl- in some transport assays but has never been validated as an alternative for tracing bidirectional transepithelial Cl- fluxes. The goal of this study was to validate 125 I- as an alternative to 36 Cl- for measurement of Cl- transport by the intestine. Simultaneous fluxes of 36 Cl- and 125 I- were measured across the mouse caecum and distal colon. Net Cl- secretion was induced by the stimulation of cAMP with a cocktail of forskolin (FSK) and 3-isobutyl-1-methylxanthine (IBMX). Unidirectional fluxes of 125 I- correlated well with 36 Cl- fluxes after cAMP-induced net Cl- secretion, occurring predominantly through a reduction in the absorptive mucosal-to-serosal Cl- flux rather than by stimulation of the secretory serosal-to-mucosal Cl- flux. Correlations between 125 I- fluxes and 36 Cl- fluxes were maintained in epithelia from mice lacking DRA (Slc26a3), the main Cl- -HCO3 - exchanger responsible for Cl- absorption by the large intestine. Lower rates of Cl- and I- absorption in the DRA knockout intestine suggest that DRA might have a previously unrecognized role in iodide uptake. This study validates that 125 I- traces transepithelial Cl- fluxes across the mouse large intestine, provides insights into the mechanism of net Cl- secretion and suggests that DRA might be involved in intestinal iodide absorption.

Background and ObjectivesDefects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation.MethodsTwo hundred and seventy-three patients with primary CH were screened for mutations in SLC5A5 using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in SLC5A5. The functional activity of the mutants was further examined in vitro.ResultsIn 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in SLC5A5 were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. In vitro experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired.ConclusionThe undescribed compound heterozygous mutation of SLC5A5 was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of SLC5A5 in CH pathogenesis.

Radioactive iodine is commonly used for the treatment of different thyroid conditions since the 1940s. The EANM has developed a standard pre-therapeutic procedure to estimate patient specific thyroid uptake at treatment of benign thyroid diseases. The procedure which models the time dependent fractional thyroid uptake is based on a two-compartment fitting system, one representing the thyroid and the other the blood. The absorbed dose is however only estimated for the thyroid and not for any other organ in the body. A more detailed biokinetic model for iodine is given by the ICRP and includes an iodide transport in the whole body. The ICRP model has 30 different compartments and 48 transfer coefficients to model the biokinetics of iodide and to model different transfer for inorganic iodide and organic iodine. The ICRP model is a recirculation iodine model, and the optimization is performed on the whole model and not exclusively on the thyroid as in the EANM procedure. Combining the EANM method and the ICRP model gives both patient specific estimations of thyroid uptake and retention and include most organs in the body. The new software gives both an improved patient specific dosimetry for the thyroid and an estimation of the absorbed dose to non-target organs and tissues like kidneys, urinary bladder, stomach wall, and uterus. Using the method described in this paper, the repercussions on the daily routines will be minimal.

The sodium/iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues. NIS-mediated iodide uptake plays a pivotal role in the biosynthesis of thyroid hormones, of which iodide is an essential constituent. For 80 years, radioiodide has been used for the diagnosis and treatment of thyroid cancer, a successful theranostic agent that is extending its use to extrathyroidal malignancies. The purpose of this review is to focus on the most recent findings regarding the mechanisms that regulate NIS both in thyroid and extra-thyroidal tissues. Among other issues, we discuss the different transcriptional regulatory elements that govern NIS transcription in different tissues, the epigenetic modifications that regulate its expression, and the role that miRNAs play in fine-tuning NIS after being transcribed. A review on how hormones, cytokines, and iodide itself regulate NIS is provided. We also review the present stage of understanding NIS dysregulation in cancer, occupied mainly by convergent signaling pathways and by new insights in the route that NIS follows through different subcellular compartments to the plasma membrane. Furthermore, we cover NIS distribution and function in the increasing number of extrathyroidal tissues that express the symporter, as well as the role that NIS plays in tumor progression independently of its transport activity., The authors want to thank the support of the following Grants: PID2019-105303RB-I00/AEI/10.13039/501100011033 from MICIN and B2017/BMD3724 Tironet2 from Comunidad de Madrid (to P S); MICIU/FEDER RTI2018-099343-B-100 (to A D l V). The Asociación Española Contra el Cancer (AECC); GCB141423113) jointly awarded to P S and G R-E. PS, G R-E, and A D l V, belong to CIBERONC ISCIII.

Amiodarone, the most commonly used antiarrhythmic drug, can cause either hypothyroidism by inhibiting iodide transport into the thyroid gland or hyperthyroidism. We present a rare case of type 2 amiodarone-induced thyrotoxicosis with hypercalcemia. A 64-year-old man with systolic heart failure, hypertension, and hyperthyroidism presented with complaints of dyspnea on exertion, orthopnea, and vomiting for several days. Laboratory tests showed low thyroid stimulating hormone0.01 mIU/L, high free triiodothyronine (FT3) of 24.8 ng/dL, free thyroxine (FT4) of5.0 ng/dL, and hypercalcemia of 12.9 mg/dL. Hypercalcemia, a rare presentation of AIT, was treated with calcitonin and intravenous fluids. The patient was taken off methimazole and started on propylthiouracil for the persistent elevation of thyroid hormones, especially FT3, and to reduce the conversion of T4 to T3. The patient was not completely responding to treatment with propylthiouracil alone, so prednisone was added to the regimen on day 12, effectively returning the patient to the euthyroid state.

Objective Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral sodium-iodide-symporter (NIS (SLC5A5)) and the apical anion exchanger pendrin (PDS (SLC26A4)). Both transmembrane proteins have been described as autoantigens in thyroid disease, yet the reports on autoantibody (aAb) prevalence and diagnostic usefulness are conflicting. Reasons for the inconclusive findings may be small study groups and principle differences in the technologies used. Design We decided to re-evaluate this important issue by establishing novel non-radioactive tests using full-length antigens and comparable protocols, and analyzing a large cohort of thyroid patients (n = 323) and control samples (n = 400). Methods NIS and PDS were recombinantly expressed as fusion protein with firefly luciferase (Luc). Stably transfected HEK293 cells were used as reproducible source of the autoantigens. Results Recombinant NIS-Luc showed iodide transport activity, indicating successful expression and correct processing. Commercial antibodies yielded dose-dependent responses in the newly established assays. Reproducibility of assay signals from patient sera was verified with respect to linearity, stability and absence of matrix effects. Prevalence of PDS-aAb was similar in thyroid patients and controls (7.7% vs 5.0%). NIS-aAb were more prevalent in patients than controls (7.7% vs 1.8%), especially in Graves’ Disease (12.3%). Neither NIS-aAb nor PDS-aAb concentrations were related to TPO-aAb or TSH-receptor-aAb concentrations, or to serum zinc or selenium status. Conclusions Our data highlight a potential relevance of autoimmunity against NIS for thyroid disease, whereas an assessment of PDS-aAb in thyroid patients seems not to be of diagnostic value (yet).

Poly- and perfluoroalkyl substances (PFAS) are a class of endocrine disrupting chemicals (EDCs) reported to alter thyroid function. Iodide uptake by thyroid follicular cells, an early step in the synthesis of thyroid hormones, is a potential target for thyroid disruption by EDCs. The aim of the present study was to evaluate the acute effects of perfluorooctane sulfonic acid (PFOS) and perfluorooctane carboxylic acid (PFOA), two of the most abundant PFAS in the environment, on iodide transport by thyroid follicular cells in vitro. Dynamic changes in intracellular iodide concentration were monitored by live cell imaging using YFP-H148Q/I152, a genetically encoded fluorescent iodide biosensor. PFOS, but not PFOA, acutely and reversibly inhibited iodide accumulation by FRTL-5 thyrocytes, as well as by HEK-293 cells transiently expressing the Sodium Iodide Symporter (NIS). PFOS prevented NIS-mediated iodide uptake and reduced intracellular iodide concentration in iodide-containing cells, mimicking the effect of the NIS inhibitor perchlorate. PFOS did not affect iodide efflux from thyroid cells. The results of this study suggest that disruption of iodide homeostasis in thyroid cells may be a potential mechanism for anti-thyroid health effects of PFOS. The study also confirms the utility of the YFP-H148Q/I152 cell-based assay to screen environmental PFAS, and other EDCs, for anti-thyroid activity.

Sodium/iodide symporter (NIS)-mediated iodide uptake in thyroid follicular cells is the basis of clinical utilization of radioiodines. The cloning of the NIS gene enabled applications of NIS as a reporter gene in both preclinical and translational research. Non-invasive NIS imaging with radioactive iodides and iodide analogs has gained much interest in recent years for evaluation of thyroid cancer and NIS reporter expression. Although radioiodines and [99mTc]pertechnetate ([99mTc]TcO4-) have been utilized in positron emission tomography (PET) and single photon emission computed tomography (SPECT), they may suffer from limitations of availability, undesirable decay properties or imaging sensitivity (SPECT versus PET). Recently, [18F]tetrafluoroborate ([18F]TFB or [18F]BF4-) and other fluorine-18 labeled iodide analogs have emerged as a promising iodide analog for PET imaging. These fluorine-18 labeled probes have practical radiosyntheses and biochemical properties that allow them to closely mimic iodide transport by NIS in thyroid, as well as in other NIS-expressing tissues. Unlike radioiodides, they do not undergo organification in thyroid cells, which results in an advantage of relatively lower uptake in normal thyroid tissue. Initial clinical trials of [18F]TFB have been completed in healthy human subjects and thyroid cancer patients. The excellent imaging properties of [18F]TFB for evaluation of NIS-expressing tissues indicate its bright future in PET NIS imaging. This review focuses on the recent evolution of [18F]TFB and other iodide analogs and their potential value in research and clinical practice.

The finished products obtained when the surfaces of powders of refractory materials (diamond, boron nitride, silicon carbide, tungsten carbide, tungsten) were coated with thin films by the method of iodide transport are presented. The developed method enables to obtain powder composite materials of core-shell type that have surface thickness varying in the range from 1 nm to several micrometers. From the powders modified by the films of metals and thier compounds composite materials were developed, their physical and mechanical characteristics were studied. The characteristics turned out to be substantially higher in comparison to materials sintered from the same powders but without coating. The probable fields of use of the composites in question were determined.

We report here a synthetic ion channel developed from a shape-persistent porphyrin-based covalent organic cage. The cage was synthesized by employing a synthetically economical dynamic covalent chemistry (DCC) approach. The organic cage selectively transports biologically relevant iodide ions over other inorganic anions by a dehydration-driven, channel mechanism as evidenced by vesicle-based fluorescence assays and planar lipid bilayer-based single channel recordings. Furthermore, the organic cage appears to facilitate iodide transport across the membrane of a living cell, suggesting that the cage could be useful as a biological tool that may replace defective iodide channels in living systems.

Iodide Handling Disorders lead to defects of the biosynthesis of thyroid hormones (thyroid dyshormonogenesis, TD) and thereafter congenital hypothyroidism (CH), the most common endocrine disease characterized by low levels of circulating thyroid hormones. The prevalence of CH is 1 in 2000–3000 live births. Prevention of CH is based on prenatal diagnosis, carrier identification, and genetic counseling. In neonates a complete diagnosis of TD should include clinical examination, biochemical thyroid tests, thyroid ultrasound, radioiodine or technetium scintigraphy and perchlorate discharge test (PDT). Biosynthesis of thyroid hormones requires the presence of iodide, thyroid peroxidase (TPO), a supply of hydrogen peroxide (DUOX system), an iodine acceptor protein, thyroglobulin (TG), and the rescue and recycling of iodide by the action of iodotyrosine deiodinase or iodotyrosine dehalogenase 1 (IYD or DEHAL1). The iodide transport is a two-step process involving transporters located either in the basolateral or apical membranes, sodium iodide symporter (NIS) and pendrin (PDS), respectively. TD has been linked to mutations in the solute carrier family 5, member 5 transporter (SLC5A5, encoding NIS), solute carrier family 26, member 4 transporter (SLC26A4, encoding PDS), TPO, DUOX2, DUOXA2, TG and IYD genes. These mutations produce a heterogeneous spectrum of CH, with an autosomal recessive inheritance. Thereafter, the patients are usually homozygous or compound heterozygous for the gene mutations and the parents, carriers of one mutation. In the last two decades, considerable progress has been made in identifying the genetic and molecular causes of TD. Recent advances in DNA sequencing technology allow the massive screening and facilitate the studies of phenotype variability. In this article we included the most recent data related to disorders caused by mutations in NIS, TPO, TG and IYD. Fil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Citterio, Cintia Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Rivolta, Carina Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina

Iodide (I-) is an essential constituent of the thyroid hormones triiodothyronine (T3) and thyroxine (T4), and the iodide concentrating mechanism of the thyroid gland is essential for the synthesis of these hormones. In addition, differential uptake of iodine isotopes (radioiodine) is a key modality for the diagnosis and therapy of thyroid cancer. The sodium dependent iodide transport activity of the thyroid gland is mainly attributed to the functional expression of the Na+/I- Symporter (NIS) localized at the basolateral membrane of thyrocytes. In this paper, we review and summarize current data on molecular characterization, on structure and function of NIS protein, as well as on the transcriptional regulation of NIS encoding gene in the thyroid gland. We also propose that a better and more precise understanding of NIS gene regulation at the molecular level in both healthy and malignant thyroid cells may lead to the identification of small molecule candidates. These could then be translated into clinical practice for better induction and more effective modulation of radioiodine uptake in dedifferentiated thyroid cancer cells and in their distant metastatic lesions.İyot (I-), tiroid bezi kaynaklı hormonlar olan triiodotironin (T3) ve tiroksinin (T4) temel bileşenlerindendir, ve tiroid bezinde iyodun derişimini artıran moleküler mekanizmalar aynı zamanda bu hormonların sentezlenmesinde de anahtar rol oynarlar. Bunun yanı sıra, radyoaktif özellikler gösteren iyot izotoplarının normal ve neoplastik dokulara taşınma kinetiklerindeki farklılıklar, bu radyoizotopların tiroid kanserinin teşhis ve tedavisinde etkili olarak kullanılmalarına yol açmıştır. Tiroid bezinde bulunan bu sodium gradyanına eşlenmiş iyot taşıma aktivitesi, temel olarak tiroid folikül hücrelerinin bazolateral hücre zarında bulunan Na+/I- simporter (NIS) proteininin işlevsel ifadesine bağlıdır. Bu derlemede, NIS proteininin yapısı, işlevi ve transkripsiyon ve translasyon sonrası çeşitli moleküler mekanizmalar ile düzenlenmesinin moleküler belirleyicileri özetlenmiştir. Sağlıklı ve kanserleşme özelliği taşıyan tiroid dokularında NIS düzenlenmesinin moleküler detayları daha iyi ve daha detaylı şekilde anlaşıldıkça, hem genetik ve hem de protein düzeyinde NIS’in radyoiyot taşıma etkinliğini düzenleyecek yeni küçük moleküllerin tanımlanabileceğini, bunların klinik uygulamalara aktarılmasının ise özellikle dedifferansiye olmuş tiroid kanseri ve metastazlarının teşhis ve tedavisinde yenilikçi ve etkili uygulamalara yol açacağını öne sürüyoruz.

The diffusional chrome plating of nonalloy steel by the gas transport of iodides is investigated. The formation of chromium-bearing coatings on steels with different carbon content is studied. Iodide transport may effectively be used in diffusional chrome plating.

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

International audience; Dendrogenin A (DDA) is a tumor suppressor mammalian cholesterol-derived metabolite and a new class of ligand of the Liver X receptor (LXR), which displays tumor cell differentiation. In human MCF7 breast adenocarcinoma cells, DDA-induced cell differentiation was associated with an increased accumulation of neutral lipids and proteins found in milk indicating that DDA re-activates some functions of lactating cells. Active iodide transport occurs in the normal lactating mammary cells through the sodium/iodide symporter (NIS) and iodide (I) is secreted into milk to be used by the nursing newborn for thyroid hormones biosynthesis. In the present study, we assessed whether DDA may induce other characteristic of lactating cells such as NIS expression and iodine uptake in MCF7 breast cancer cells and extended this study to the papillary B-CPAP and undifferentiated anaplastic 8505c thyroid cancer cells. Moreover, we evaluated DDA impact on the expression of thyroid specific proteins involved in thyroid hormone biogenesis. We report here that DDA induces NIS expression in MCF7 cells and significantly increases the uptake of 131-I by acting through the LXR. In addition, DDA induces phenotypic, molecular and functional characteristics of redifferentiation in the two human thyroid carcinoma cell lines and the uptake of 131-I in the undifferentiated 8505c cells was associated with a strong expression of all the specific proteins involved in thyroid hormone biosynthesis, TSH receptor, thyroperoxidase and thyroglobulin. 131-I incorporation in the 8505c cells was stimulated by DDA as well as by the synthetic LXR ligand, GW3965. Together these data show that the re-differentiation of breast and thyroid cancer cells by DDA, is associated with the recovery of functional NIS expression and involves an LXR-dependent mechanism. These results open new avenues of research for the diagnosis of thyroid cancers as well as the development of new therapeutic approaches for radioiodine refractory thyroid cancers.

Iodide transport and storage in the thyroid follicles is crucial for thyroid hormone synthesis. Pendrin, the iodide exporter that transports iodide to thyroid follicles, is responsible for Pendred syndrome, a disorder characterized by congenital hypothyroidism and hearing loss. However, thyroid hormone levels are basically normal in patients with Pendred syndrome, indicating the presence of another unknown iodide transporter. Here, we show that SLC26A7 is a novel iodide transporter in the thyroid. We observe that SLC26A7 is specifically expressed in normal thyroid tissues and demonstrate its function in iodide transport. Using whole-exome sequencing, we also find a homozygous nonsense mutation in SLC26A7 (c.1498 C > T; p.Gln500Ter) in two siblings with congenital goitrous hypothyroidism. The mutated SLC26A7 protein shows an abnormal cytoplasmic localisation and lacks the iodide transport function. These results reveal that SLC26A7 functions as a novel iodide transporter in the thyroid and its dysfunction affects thyroid hormonogenesis in humans and causes congenital goitrous hypothyroidism., Jun Ishii and Atsushi Suzuki et al. report the identification of SLC26A7 as a novel iodide transporter expressed in the thyroid. They identify a nonsense mutation in SLC26A7 in siblings with congenital hypothyroidism and goitre using whole-exome sequencing, implicating this transporter in disease.

The sodium iodide symporter (NIS) is the plasma membrane glycoprotein that mediates active iodide transport in the thyroid and other tissues, such as the salivary, gastric mucosa, rectal mucosa, bronchial mucosa, placenta and mammary glands. In the thyroid, NIS mediates the uptake and accumulation of iodine and its activity is crucial for the development of the central nervous system and disease prevention. Since the discovery of NIS in 1996, research has further shown that NIS functionality and iodine transport is dependent on the activity of the sodium potassium activated adenosine 5′-triphosphatase pump (Na+, K+-ATPase). In this article, I review the molecular mechanisms by which F inhibits NIS expression and functionality which in turn contributes to impaired iodide absorption, diminished iodide-concentrating ability and iodine deficiency disorders. I discuss how NIS expression and activity is inhibited by thyroglobulin (Tg), tumour necrosis factor alpha (TNF-α), transforming growth factor beta 1 (TGF-β1), interleukin 6 (IL-6) and Interleukin 1 beta (IL-1β), interferon-γ (IFN-γ), insulin like growth factor 1 (IGF-1) and phosphoinositide 3-kinase (PI3K) and how fluoride upregulates expression and activity of these biomarkers. I further describe the crucial role of prolactin and megalin in regulation of NIS expression and iodine homeostasis and the effect of fluoride in down regulating prolactin and megalin expression. Among many other issues, I discuss the potential conflict between public health policies such as water fluoridation and its contribution to iodine deficiency, neurodevelopmental and pathological disorders. Further studies are warranted to examine these associations.

The sodium/iodide symporter (NIS), which is essential for iodide concentration in the thyroid, is reported to be transcriptionally regulated by sterol regulatory element-binding proteins (SREBP) in rat FRTL-5 thyrocytes. The SREBP are strongly activated after parturition and throughout lactation in the mammary gland of cattle and are important for mammary epithelial cell synthesis of milk lipids. In this study, we tested the hypothesis that the NIS gene is regulated also by SREBP in mammary epithelial cells, in which NIS is functionally expressed during lactation. Regulation of NIS expression and iodide uptake was investigated by means of inhibition, silencing, and overexpression of SREBP and by reporter gene and DNA-binding assays. As a mammary epithelial cell model, the human MCF-7 cell line, a breast adenocarcinoma cell line, which shows inducible expression of NIS by all- trans retinoic acid (ATRA), and unlike bovine mammary epithelial cells, is widely used to investigate the regulation of mammary gland NIS and NIS-specific iodide uptake, was used. Inhibition of SREBP maturation by treatment with 25-hydroxycholesterol (5 µ M ) for 48h reduced ATRA (1 µ M )-induced mRNA concentration of NIS and iodide uptake in MCF-7 cells by approximately 20%. Knockdown of SREBP-1c and SREBP-2 by RNA interference decreased the mRNA and protein concentration of NIS by 30 to 50% 48h after initiating knockdown, whereas overexpression of nuclear SREBP (nSREBP)-1c and nSREBP-2 increased the expression of NIS in MCF-7 cells by 45 to 60%, respectively, 48h after initiating overexpression. Reporter gene experiments with varying length of NIS promoter reporter constructs revealed that the NIS 5′-flanking region is activated by nSREBP-1c and nSREBP-2 approximately 1.5- and 4.5-fold, respectively, and activation involves a SREBP-binding motif (SRE) at −38 relative to the transcription start site of the NIS gene. Gel shift assays using oligonucleotides spanning either the wild-type or the mutated SRE at −38 of the NIS 5′-flanking region showed that in vitro-translated nSREBP-1c and nSREBP-2 bind only the wild-type but not the mutated SRE at −38 of NIS . Collectively, the present results from cell culture experiments with human mammary epithelial MCF-7 cells and from genetic studies show for the first time that the NIS gene and iodide uptake are regulated by SREBP in cultured human mammary epithelial cells. Future studies are necessary to clarify if the regulation of NIS expression and iodide uptake by SREBP also applies to the lactating bovine mammary epithelium.

Dedifferentiation of follicular cells is a central event in resistance to radioactive iodine and patient mortality in papillary thyroid carcinoma (PTC). We reveal that platelet derived growth factor receptor alpha (PDGFRα) specifically drives dedifferentiation in PTC by disrupting the transcriptional activity of thyroid transcription factor-1 (TTF1). PDGFRα activation dephosphorylates TTF1 consequently shifting the localization of this transcription factor from the nucleus to the cytoplasm. TTF1 is required for follicular cell development and disrupting its function abrogates thyroglobulin production and sodium iodide transport. PDGFRα also promotes a more invasive and migratory cell phenotype with a dramatic increase in xenograft tumor formation. In patient tumors we confirm that nuclear TTF1 expression is inversely proportional to PDGFRα levels. Patients exhibiting PDGFRα at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5 years than those patients lacking PDGFRα expression. Moreover, high levels of PDGFRα and low levels of nuclear TTF1 predict resistance to radioactive iodine therapy. We demonstrate in SCID xenografts that focused PDGFRα blockade restores iodide transport and decreases tumor burden by > 50%. Focused PDGFRα inhibitors, combined with radioactive iodine, represent an additional avenue for treating patients with aggressive variants of PTC., Graphical Abstract Image 1, Highlights • PDGFRα induces dedifferentiation of papillary thyroid cancer cells. • This depends on decreased phosphorylation and decreased nuclear targeting of TTF1. • Loss of nuclear TTF1 decreases thyroglobulin production and NaI transport. • PDGFRα expression is prognostic of PTC recurrence and treatment resistance. • Blocking PDGFRα activation is a potential therapeutic target. Treatment of papillary thyroid cancer historically relied upon a combination of surgery and radioactive iodine ablation with few alternatives if the disease progresses. We found that platelet derived growth factor receptor alpha (PDGFRα) is a key driver of metastatic disease and resistance to radioactive iodine therapy. PDGFRα expression can be tested in tumor specimens to predict aggressive disease. In addition, we show that targeting PDGFRα could restore sensitivity to radioactive iodine treatment that might slow disease growth and spread.

A series of previously published physiologically based pharmacokinetic (PBPK) models describe the effect of perchlorate on iodide uptake by the thyroid, with the mechanism being competitive inhibition of iodide transport by the sodium-iodide symporter (NIS). Hence a key parameter of these models is the affinity of perchlorate for the NIS, characterized as the Michaelis-Menten kinetic constant, Km . However, when model predictions were compared to published results of a human study measuring radio-iodide uptake (RAIU) inhibition after controlled perchlorate exposures, it was found to only fit the lowest exposure level and underpredicted RAIU inhibition at higher levels. Published in vitro data, in which perchlorate-induced inhibition of iodide uptake via the NIS was measured, were re-analyzed. Km for binding of perchlorate to the NIS originally derived from these data, 1.5 μm, had been obtained using Lineweaver-Burk plots, which allow for linear regression but invert the signal-noise of the data. Re-fitting these data by non-linear regression of the non-inverted data yielded a 60% lower value for the Km , 0.59 μm. Substituting this value into the PBPK model for an average adult human significantly improved model agreement with the human RAIU data for exposures

Background: Increased oxidative stress has been suggested as one of the underlying mechanisms in iodide excess-induced thyroid disease. Metallothioneins (MTs) are regarded as scavengers of reactive oxygen species (ROS) in oxidative stress. Our aim is to investigate the effects of propylthiouracil (PTU), a thyroid peroxidase inhibitor, perchlorate (KClO4), a competitive inhibitor of iodide transport, and thyroid stimulating hormone (TSH) on mitochondrial superoxide production instigated by high concentrations of iodide in the thyroids of MT-I/II knockout (MT-I/II KO) mice. Methods: Eight-week-old 129S7/SvEvBrd-Mt1 tm1Bri Mt2 tm1Bri /J (MT-I/II KO) mice and background-matched wild type (WT) mice were used. Results: By using a mitochondrial superoxide indicator (MitoSOX Red), lactate dehydrogenase (LDH) release, and methyl thiazolyl tetrazolium (MTT) assay, we demonstrated that the decreased relative viability and increased LDH release and mitochondrial superoxide production induced by potassium iodide (100 μM) can be relieved by 300 μM PTU, 30 μM KClO4, or 10 U/L TSH in the thyroid cell suspensions of both MT-I/II KO and WT mice (P

The article presents the results on the development of core-shell powders for additive manufacturing of articles for underground construction. Core-shell powders were obtained via advanced technologies involving gas (iodide) transport plating of ceramic and carbon materials with metal nanocoatings to improve the target performances (wear- and corrosion resistance, etc.) as well as the 3D simulation and preparation of triply periodic minimal surface (TPMS) structures with specific shapes, including Schoen Gyroid and Schwarz Diamond.